REVIEW | doi:10.20944/preprints202306.1535.v1
Subject: Medicine And Pharmacology, Dentistry And Oral Surgery Keywords: type 1 diabetes; polymorphisms; interleukins; periodontitis; systemic inflammation; peripheral inflammation; childhood
Online: 21 June 2023 (11:01:48 CEST)
Diabetes may cause an increase blood levels of cytokines inducing a rising of C reactive protein (PCR) and fibrinogen stimulating a subclinical inflammation which lead to adhesive molecules expression and to endothelial disfunction. A comprehensive panel of type 1 diabetes mellitus (T1DM) interleukins polymorphisms is not provided yet. As chronic periodontitis (CP) is considered the sixth complication of DM, a clarification is needed about the inflammatory role managed by single nucleotides polymorphisms (SNPs). The goal of this review is to focus on the significant diversity of SNPs in T1DM patients with and without CP. After a digital search on PubMed and Scopus with reference to the last 5 years, 21 items were enrolled. Several ILs were analyzed. T1DM still needs to be thoroughly explored regarding the ILs polymorphisms panel, however the last 5 years have led to the increased independence of this condition, causing autonomous inflammatory effects which requires further investigations. CP and T1DM association in children and adolescents represents a severe gap in literature that should be filled, the scarce presence of studies also about adults serves as a motivation for ulterior clinical researches
REVIEW | doi:10.20944/preprints202307.0888.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: porous structure; peripheral nerve guidance conduit; peripheral nerve regeneration; permeability
Online: 13 July 2023 (10:05:55 CEST)
The porous structure is an important three-dimensional morphological feature of the peripheral nerve guidance conduit (NGC), which permits infiltration of cells, nutrients, and molecular signals, and the discharge of metabolic waste. Porous structures with precisely customised pore sizes, porosities, and connectivities were used to construct fully permeable, semi-permeable, and asymmetric peripheral NGCs to replace traditional nerve autografts in treatment of long-segment peripheral nerve injury. In this review, the features of porous structures and classification of NGCs based on these characteristics are discussed. Common methods for constructing 3D porous NGCs in current research are described, as well as the pore characteristics and the parameters used to tune the pores. The effects of the porous structure on the physical properties of NGCs including biodegradation, mechanical performance, and permeability were analysed. Pore structure affects the biological behaviour of Schwann cells, macrophages, fibroblasts, and vascular endothelial cells during peripheral nerve regeneration. Construction of ideal porous structures is a significant advancement in the regeneration of peripheral nerve tissue engineering materials. The purpose of this review is to generalise, summarise, and analyse the preparation methods for porous NGCs and their biological functions in promoting peripheral nerve regeneration to guide development of medical nerve repair materials.
ARTICLE | doi:10.20944/preprints202305.0532.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: endothelium; leukotrienes; vascular inflammation; peripheral arterial disease
Online: 8 May 2023 (11:05:28 CEST)
Leukotrienes are proinflammatory mediators that participate in the process of atherogenesis and contribute to the development of symptomatic peripheral arterial disease. The aim was to evaluate the relationship between leukotriene E4 (LTE4) and B4 (LTB4) with parameters reflecting endothelial vascular function in patients with chronic lower limb ischemia. This prospective observational study enrolled 50 consecutive patients undergoing endovascular treatment due to chronic lower limb ischemia (Rutherford 3). All participants were followed-up for one year (after 1, 3, 6 and 12 months), with a sequential assessment of urinary LTE4 and LTB4, as well as measures of endothelial and vascular function: Flow-Mediated Dilatation (FMD), Intima-Media Thickness (IMT), corrected Augmentation Index (AI75), Shear Rate (SR), Ankle-Brachial Index (ABI), Toe-Brachial Index (TBI). There was a significant relationship between LTE4 and measures of vascular function: FMD (R2 = 0.69, P<0.001), IMT (R2=0.12, P<0.01), AI75 (R2=0.43, P<0.001), SR (R2=0.48, P<0.001). Similar findings were noted for LTB4: FMD (R2=0.47, p<0.001), IMT (R2=0.23, P<0.001), AI75 (R2=0.61, P<0.001) and SR (R2=0.33, P<0.001). Alterations in parameters were significantly related: ΔLTE4 vs ΔFMD(R2=0.63, P<0.001), ΔSR (R2=0.42, P<0.001) and ΔLTB4 vs AI75(R2=0.40, P<0.001), SR(R2=0. 29, P<0.001). We conclude, that increasing concentrations of LTE4 and LTB4 are associated with impairment of vascular and endothelial function, which may lead to worse endovascular treatment clinical outcomes.
REVIEW | doi:10.20944/preprints202112.0478.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Mesenchymal stem cells; Nerve Guide Conduits; Nerve recovery; One Health; Peripheral nerve injury; Secretome
Online: 30 December 2021 (07:35:41 CET)
Peripheral nerve injuries (PNI) can have several etiologies, such as trauma and iatrogenic interventions that can lead to the loss of structure and/or function impairment. These changes can cause a partial or complete loss of motor and sensory functions, physical disability, and neuropathic pain, what in turn can affect the quality of life. For those reasons, PNI is a major public health concern. This review aims to revisit the concepts associated with the PNI. First, the anatomy of the peripheral nerve is detailed to explain the different types of injury. Then, some of the available therapeutic strategies are explained, including surgical methods, pharmacological therapies, and the use of cell-based therapies alone or in combination with biomaterials in the form of tube guides. Nevertheless, even with the various available treatments, it is difficult to achieve a perfect outcome with complete functional recovery. This review aims to explain the urge for new approaches and to understand the methods to evaluate nerve regeneration in a One Health perspective. In vitro models followed by in vivo models are very important to be able to translate the achievements to human medicine.
ARTICLE | doi:10.20944/preprints202308.0193.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Peripheral Nerve Injury; Peripheral Nerve Regeneration; Ultrasonography; Peroneal Common Nerve; Sheep Model.
Online: 2 August 2023 (10:21:36 CEST)
Peripheral nerve injury remains a medical challenge with no easy resolution. Over the last few decades, significant advances have been achieved in promoting peripheral nerve regeneration, and new assessment tools have been developed, both functional and imaging, to quantify the proportion and quality of nerve recovery. The exploration of new animal models, larger, more complex and with more similarities to humans, has made it possible to reduce the gap between the results obtained in classic animal models such as rodents and the application of new therapies in humans and animals of clinical interest. Ultrasonography is an imaging technique recurrently used in clinical practice to assess the peripheral nerves, allowing its anatomical and topographic characterization, and aiding in the administration of anesthesia and in the performance of nerve blocks. The use of this technique in animal models is scarce, but it could be a useful tool in monitoring the progression of nerve regeneration after the induction of controlled experimental lesions. In this work, sheep, a promising animal model in the area of peripheral nerve regeneration, were subjected to an ultrasonographic study of three peripheral nerves of the hind limb, the common peroneal, tibial and sciatic nerves, in order to establish values of dimensions and ultrasound appearance in healthy nerves and also landmarks for their identification. At the same time, an echographic evaluation of the cranial tibial muscle, an effector muscle of the common peroneal nerve, was also carried out, establishing normal values for the echographic aspect and dimensions. The results obtained will allow the use of these data as control values in future work exploring new therapeutic options for nerve regeneration after induction of common peroneal nerve injuries in sheep.
ARTICLE | doi:10.20944/preprints201810.0540.v1
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: maximal voluntary contraction; peripheral fatigue; neuromuscular activation; femoral nerve electrical stimulation; critical peripheral fatigue threshold; electromyography
Online: 23 October 2018 (15:12:43 CEST)
We asked whether the level of peripheral fatigue would differ when three consecutive exercise trials were completed to task failure, and whether there would be delayed recovery in maximal voluntary contraction (MVC) force, neuromuscular activation and peripheral fatigue following task failure. Ten trained sport students performed three consecutive knee extension isometric trials (T1, T2, T3) to task failure without breaks between trials. T1 and T2 consisted of repeated 5-s contractions followed by 5-s rest. In T1, contractions were performed at a target force at 60% pre-exercise MVC. In T2, all contractions were MVCs, and task failure occurred at 50% MVC. T3 was a sustained MVC performed until force fell below 15% MVC. Evoked force responses to supramaximal electrical femoral nerve stimulation were recorded to assess peripheral fatigue. Electromyography signals were normalized to M-wave amplitude to assess neuromuscular activation. Lower levels of evoked peak forces were observed at T3 compared to T2 and T1. Within 5 s of task failure in T3, MVC force and neuromuscular activation recovered substantially without any recovery in evoked peak force. Neuromuscular activation 5-10 s after T3 was unchanged from pre-exercise values, but evoked peak forces were substantially reduced. These results challenge the existence of a critical peripheral fatigue threshold that reduces neuromuscular activation. Since neuromuscular activation changed independently of any change in evoked peak force, immediate recovery in force production after exercise is due to increased central recruitment and not to peripheral mechanisms.
REVIEW | doi:10.20944/preprints202308.1540.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Anderson‐Fabry disease; Galactosidase‐alda; neurological; peripheral
Online: 23 August 2023 (03:09:54 CEST)
Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The impairment of the nervous system, in addition to the acroparesthesias, is characterized by hypohidrosis and cerebrovascular accidents. Gb3-accumulation supports the hypothesis that Gb3 is not solely responsible for disease manifestation. Overloading of lysosomes with Gb3 may simply lead to the rupture of cytoplasma and in consequence to cell death .Secondary effects of Gb3 accumulation which might be responsible for disease pathology include also inflammatory processes. Perturbed leukocyte function in Fabry disease compared to healthy controls and abnormal numbers of different immune cells, including lymphocytes, monocytes, CD8+ cells, B cells and dendritic cells . Noteworthy other studies reported no correlation between CRP-levels as a global inflammatory marker and the Mainz-Severity-Score-Index (MSSI) as a marker for disease severity . Other authors reported on auto-immunological reactions in α-galactosidase A deficiency. Others researchers found higher expressions of neuronal apoptosis inhibiting protein as a key anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Noteworthy, this upregulation did not change after institution of ERT, whereas apoptosis inducing factor appears to be upregulated under ERT. The authors were not able to explain their observations, but further research has to be directed on this topic. Gb3-accumulation has been reported to induce oxidative stress and/or the formation reactive oxygen species (ROS). Lipids and proteins may be oxidised and may be unable to function. Of note, ERT increased the generation of ROS in vitro, and up-regulated the intracellular adhesion molecule ICAM 1. The authors hypothesized that ERT may enhance endothelial damage, allowing to understand continuously occurring strokes in patients on treatment. Furthermore, Gb3-accumulation has been reported to induce oxidative stress and/or the formation reactive oxygen species (ROS). Lipids and proteins may be oxidised and may be unable to function. Of note, ERT increased the generation of ROS in vitro, and up-regulated the intracellular adhesion molecule ICAM 1. Another gateway into alteration of endothelial function may be given by the Nitric-Oxide-Synthase-3-genotypes. Endothelium-derived nitric oxide is a key regulator of vessel wall function and cardiovascular homeostasis. Thus, neurological complications seem to be linked to different pathogenetic molecular mechanisms.Progressive accumulation of GB3 represent a possible pathogenetic event of peripheral nerve involvement, whereas central nervous involvement in the clinical setting of cerebrovascular ischemic events seem to be due to the endotheliopathy of Anderson-Fabry Disease with lacunar lesions and white matter hyperintensities ( WMHs) . In this review manuscript we revised molecular mechanisms of peripheral and central neurological complications of Anderson-Fabry Disease.
REVIEW | doi:10.20944/preprints202307.1056.v1
Subject: Medicine And Pharmacology, Internal Medicine Keywords: atherosclerosis; inflammation; peripheral artery disease; glycocalyx; endothelial dysfunction
Online: 17 July 2023 (05:31:19 CEST)
Inflammation has a critical role in the development and progression of atherosclerosis. On the molecular level, inflammatory pathways negatively impact endothelial barrier properties and thus tissue homeostasis. Conformational changes and destruction of the glycocalyx further promote proinflammatory pathways also contributing to procoagulability and a prothrombotic state. In addition, changes in the extracellular matrix composition lead to (peri-)vascular remodelling and alterations of the vessel wall, e.g., aneurysm formation. Moreover, progressive fibrosis leads to reduced tissue perfusion due to loss of functional capillaries. The present review aims at discussing molecular and clinical effects of inflammatory processes on the micro- and microvas-culature with a focus on peripheral artery disease.
ARTICLE | doi:10.20944/preprints202308.2139.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: interventional radiology; embolization; peripheral vascular lesions; coils; safety
Online: 31 August 2023 (12:33:19 CEST)
: Background: A wide variety of coils are available for vascular embolization. This study aims to evaluate the safety and efficacy of a new Prestige coil. Method: Retrospective analysis of a multicentre registry data collected between February 2022 and November 2022. The choice of the embolization agent used was left at the investigator’s discretion to treat peripheral vascular anomalies. Patients for whom at least one Prestige coil was used were included in Series 1. All other patients were included in Series 2. Efficacy and safety were evaluated. Patients were followed up for one month. Results: 220 patients were included, 110 in each series. Patients were 149 men (67.7%) and 71 women (32.3%), of median age 62.5 years [IQR: 35.8-73], similar in the two series. The complete occlusion of the targeted vessel was reported in 96.4% (N=106/110) in Series 1 and in 99.7% (N=109/110) in Series 2. 4 patients experienced non-serious adverse events (1.8%, N=4/220): 1 back pain, 1 vomiting in Series 1, 1 off-target embolization and 1 puncture site hematoma in Series 2. 16 patients (7.2%, N=16/220) were lost to follow up. Improvement of the patient’s general state at one month was reported in 79.0% (N=83/105) in Series 1 and in 74.7% (N=74/99) in Series 2. 10 deaths occurred, 5 in Series 1 (4.8 %, N=5/105) and 5 in Series 2 (5.1%, N=5/99). They all concerned critically ill patients embolized for emergent arterial bleeding. Conclusion: the 1-month follow-up showed that the Prestige coils, alone or in combination, are efficient and safe.
ARTICLE | doi:10.20944/preprints201810.0758.v1
Subject: Biology And Life Sciences, Plant Sciences Keywords: latent PPO; optimisation; peripheral membrane POD; total phenol content
Online: 1 November 2018 (18:00:20 CET)
The present protocol described extraction of active polyphenol oxidase and peroxidase from a plant rich in phenolics and chlorophylls in the post-harvest browning syndrome of B. myrtifolia. Initially, general optimisation using conventional enzyme extractions was performed. However, along with membrane-bound proteins, chlorophylls and phenols were also released with Triton X (TTX). With a view to obtaining high enzymatic activity, removal of the released chlorophylls and phenols by formation of TTX-114 micelles in the detergent rich phase after high-temperature induced phase separation was tested.
ARTICLE | doi:10.20944/preprints202007.0567.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: peripheral arterial disease; exercise; platelet; mitochodria
Online: 23 July 2020 (13:12:36 CEST)
Exercise training influences the risk of vascular thrombosis in patients with peripheral arterial disease (PAD). Mitochondrial functionalities in platelets involve the cellular bioenergetics and thrombogenesis. This study aimed to elucidate the effect of cycling exercise training (CET) on platelet mitochondrial bioenergetics in PAD patients. Forty randomly selected patients with PAD engaged in general rehabilitation (GR) with CET (i.e., cycling exercise at ventilation threshold for 30 min/day, 3 days/week) (GR+CET, n=20) or to a control group that only received GR course (n=20) for 12 weeks. Systemic aerobic capacity and platelet mitochondrial bioenergetics that included oxidative phosphorylation (OXPHOS) and electron transport system (ETS) were measured using automatic gas analysis and high-resolution respirometry, respectively. The experimental results demonstrated that GR+CET for 12 weeks significantly (i) elevated VO2peak and lowered VE-VCO2 slope, (ii) raised resting ankle-brachial index and enhanced cardiac output response to exercise, (iii) increased the distance in 6-minute walk test and raised the Short Form-36 physical/mental component scores, and (iv) enhanced capacities of mitochondrial OXPHOS and ETS in platelets by activating FADH2 (Complex II)-dependent pathway. Moreover, changes in VO2peak levels were positively associated with changes in platelet OXPHOS and ETS capacities. However, no significant changes in systemic aerobic capacity, platelet mitochondrial bioenergetics, and health-related quality of life (HRQoL) occurred following GR alone. Hence, we conclude that CET effectively increases the capacities of platelet mitochondrial bioenergetics by enhancing Complex II activity in patients with PAD. Moreover, the exercise regimen also enhanced functional exercise capacity, consequently improving HRQoL in PAD patients.
ARTICLE | doi:10.20944/preprints201808.0033.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: sonic hedgehog; microparticles; peripheral artery disease
Online: 2 August 2018 (05:20:58 CEST)
Sonic Hedgehog (Shh) is a prototypical angiogenic agent with a crucial role in the regulation of angiogenesis. Experimental studies have shown that Shh is upregulated in response to ischemia. Also, Shh may be found on the surface of circulating microparticles (MPs) and MPs bearing Shh (Shh+ MPs) have shown the ability to contribute to reparative neovascularization after ischemic injury in mice. In this study, the plasma number of Shh+ MPs in patients with peripheral artery disease (PAD) and control subjects without PAD. We found significantly higher number of Shh+ MPs in plasma of subjects with PAD, compared to controls, while the global number of MPs – produced either by endothelial cells, platelets, leukocytes, and erythrocytes – was not different between PAD patients and controls. Interestingly, the concentration of Shh protein unbound to MPs – which was measured in MP-depleted plasma – was not different between subjects with PAD and controls, indicating that, in the setting of PAD, the call for Shh recapitulation does not lead to secretion of protein into the blood but to binding of the protein to the membrane of MPs. These findings provide novel insights on the mechanisms through which the Shh signaling is reactivated during ischemia in humans, with potentially important fundamental and clinical implications.
REVIEW | doi:10.20944/preprints202208.0417.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: axon guidance; peripheral nerves regeneration; bioengineering approach; optogenetic stimulation
Online: 24 August 2022 (08:39:01 CEST)
Despite a significant advance in the pathophysiological understanding of peripheral nerve damage, the successful treatment of large nerve defects remains an unmet medical need. In this article, axon growth guidance for peripheral nerve regeneration is systematically reviewed and discussed mainly from the engineering perspective. In addition, the common approach to surgery, bioengineering approaches to emerging technologies (i.e. optogenetic stimulation and magnetic stimulation) for functional recovery are discussed, with pros and cons. Alternatively, clear future perspectives of axon guidance and nerve regeneration are addressed.
ARTICLE | doi:10.20944/preprints202305.1240.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: DNP; PNS; Diabetic neuropathic pain; Peripheral pain; Distal symmetric polyneuropathy; diabetic neuropathy; diabetes mellitus; DM; T1D; T2D; DPN; DPNP; Diabetic peripheral neuropathic pain; Diabetic peripheral neuropathy
Online: 17 May 2023 (10:55:11 CEST)
Diabetes mellitus is the global epidemic of the 21st century affecting millions worldwide. Usually, patients with long-standing type one diabetes (T1D) or type two diabetes (T2D) tend to develop complications. A common complication is the degenerative of the nerves in the peripheral nervous system (PNS). This complication is known as distal symmetric polyneuropathy or just diabetic neuropathy. A variety of symptoms can be experienced with this complication, including pain and numbness. One characterization of this complication is the sensory loss that begins in the lower extremities and spreads substantially to the fingers and hand. There is no clear mechanism for how this happens in diabetic patients. Studies have shown that nerve damage from this complication can be due to oxidative stress, sorbitol accumulation, and advanced glycation end products (AGEs). Some of the most common medications being provided for diabetic neuropathic pain (DNP) include amitriptyline and desipramine. Other medications also include gabapentin and duloxetine. There are noninvasive options, such as acupuncture, that could provide beneficial data if rigorous studies are conducted. A number of new studies are being completed to identify more effective treatments for this condition.
ARTICLE | doi:10.20944/preprints202010.0002.v1
Subject: Business, Economics And Management, Accounting And Taxation Keywords: Peripheral areas; local development; heritagisation; sustainable rural tourism; stakeholders
Online: 1 October 2020 (08:42:54 CEST)
In the context of multiple repurposing of rural spaces, tourism represents a path for development, with the potential to revitalize these areas. The conservation and restoration of heritage, and its promotion through tourism, can become an opportunity for local development, in which a range of stakeholders fulfil different roles in the carrying out of the processes involved. The aim of the study was to analyse the process and results of channelling heritagisation through tourism in Mértola (Baixo Alentejo, Portugal). A series of interviews with the chief stakeholders in the process was conducted, from which the contexts and conceptualisations of development were determined. On the basis of secondary data (statistics), an analysis of the impacts of the process of heritagisation and the development of tourism was undertaken. The objectives of this study consisted in determining: a) the importance of the process of heritagisation in Mértola; b) the viability of the project, given the cost and lack of comprehensive conservation, in creating a unified whole; d) the performance of, and power relationships between, the various stakeholders; e) the limited participation of locals due to disaffection with the project; f) the correlation between heritage, rural tourism and local development.
ARTICLE | doi:10.20944/preprints202306.0275.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: day-case angioplasty; critical limb ischaemia; peripheral artery disease
Online: 5 June 2023 (08:37:51 CEST)
We evaluated the impact of COVID-19 restriction on the angioplasty service and outcome of critical limb ischaemia (CLI) patients undergoing lower limb angioplasty in a UK secondary care setting. Consecutive patients were analysed retrospectively. Pre-COVID-19 (08/2018-02/2020), 106 CLI-patients (91% Fontaine 4; 60% diabetes mellitus) and during COVID-19 (03/2020-07/2021) 94 patients were treated (86% Fontaine 4; 66% diabetes mellitus). While the average monthly number of patients treated did not change, the proportion of day cases significantly increased (53% to 80%) and hospitalised patients decreased. Patients treated in <=14/5 days after referral significantly increased to 64/63%. Kaplan-Meier survival analysis (30-day/1-year) showed that neither wound healing nor mortality were significantly changed during COVID-19. In day cases, 1-year but not 30-day major amputations significantly increased, and clinically driven target lesion revascularisation decreased during COVID-19. 1-year mortality was significantly worse in hospitalised as compared to day cases (14% vs 43%) at similar wound healing rates (83% vs 84%). The most frequent known-causes-of-death were infectious disease (64%) and cardiovascular (21%) was less frequent. Despite COVID-19 restriction a safe and effective angioplasty service was maintained while shortening waiting times. Very high mortality rates in hospitalised patients may indicate that CLI should be treated more aggressively and earlier.
REVIEW | doi:10.20944/preprints202205.0068.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Chemotherapy-induced peripheral neuropathy; pain management; target therapy; immuno-therapy
Online: 6 May 2022 (09:14:17 CEST)
Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. The disorder may require a dose reduction of chemo-therapy and its most common sensory symptoms are severe pain, tingling, and numbness in the hands and feet. CIPN affects dramatically the patient's quality of life (QoL). Pain and sensory abnormalities may occur for months, or even years after the termination of chemotherapy. This disease has complicated pathophysiology featured by underlying mechanisms not completely known. Although many pharmaco-logical and non-pharmacological therapeutic approaches have been tested to overcome these symptoms, there is currently no standardized cure to prevent or treat CIPN. According to current guidelines, Duloxe-tine is the only recommended agent for painful neuropathic symptoms. Therefore, finding effective thera-pies for CIPN is mandatory. The purpose of this review is to dissect CIPN, the target and immunothera-py-based approaches to this disorder, as well as to offer new insights for novel therapeutic perspectives.
ARTICLE | doi:10.20944/preprints201808.0206.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: cardiovascular variability; heart-rate variability; peripheral arterial disease; photoplethysmography; pulse
Online: 10 August 2018 (13:43:45 CEST)
Photoplethysmography (PPG) is a simple-to-perform vascular optics measurement technique that can detect changes in blood volume in the microvascular tissue bed. Beat-to-beat analysis of the PPG waveform enables the study of the variability of pulse features such as amplitude and pulse arrival time (PAT), and when quantified in the time and frequency domains, has considerable potential to shed light on perfusion changes associated with peripheral arterial disease (PAD). In this pilot study innovative multi-site bilateral finger and toe PPG recordings from 43 healthy control subjects and 31 PAD subjects were compared (recordings each at least 5 minutes, collected in a warm temperature-controlled room). Beat-to-beat normalized amplitude and PAT variability was then quantified in the time-domain using SD and IQR measures and in the frequency-domain bilaterally using Magnitude Squared Coherence (MSC). Significantly reduced normalized amplitude variability (healthy control 0.0384 (IQR 0.0217-0.0744) vs PAD 0.0160 (0.0080-0.0338) (p<0.001) and significantly increased PAT variability (healthy control 0.0063 (0.0052-0.0086) vs PAD 0.0093 (0.0078-0.0144) (p<0.001) was demonstrated in PAD using the time-domain analysis. Frequency-domain analysis demonstrated significantly lower MSC values across a range of frequency bands for PAD patients. These changes suggest a loss of right-to-left body side coherence and cardiovascular control in PAD. This study has also demonstrated the feasibility of using these measurement and analysis methods in studies investigating multi-site PPG variability for a wide range of cardiac and vascular patient groups.
ARTICLE | doi:10.20944/preprints202012.0567.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Peripheral Nerve Injury; Peripheral Nerve Regeneration; Peroneal Common Nerve; Animal Model; Sheep Model; Nerve Anatomy; Neurological Exam; Nerve Stereology
Online: 22 December 2020 (16:07:28 CET)
Thousands of people worldwide suffer from injuries in the peripheral nerve and deal daily with the resulting physiological and functional deficits. Recent advances in this field are still insufficient to guarantee effective outcomes, and the development of new and effective therapeutic options requires the use of valid preclinical models that effectively replicate the characteristics and challenges associated with these injuries in humans. In this study, we established a sheep model for common peroneal nerve injuries that can be applied in preclinical research with the advantages associated with the use of large animal models. In an integrative way, this article includes a detailed description of the anatomy and functionality of the peripheral nerves of sheep’s hind limb, the surgical protocol for accessing the common peroneal nerve, the induction of different types of nerve damage and the application of possible therapeutic options. A neurological exam protocol directed to the common peroneal nerve was also established, allowing to identify the changes and deficits related with the nerve injury and to evaluate the functional progression over time. Finally, a preliminary stereological study was carried out to establish control values for the healthy peroneal common nerves of this model and to identify preliminary differences between therapeutic methods. The ultimate goal is to demonstrate that sheep is a valid model of peripheral nerve injury to be used in pre-clinical and translational works and to evaluate the efficacy and safety of nerve injury therapeutic options before its clinical application in human and veterinary patients.
ARTICLE | doi:10.20944/preprints202111.0320.v1
Subject: Medicine And Pharmacology, Hematology Keywords: Arteriogenesis; Arterial structure; extracellular matrix; peripheral arterial disease; collateral circulation
Online: 18 November 2021 (10:59:12 CET)
When a large artery becomes occluded, hemodynamic changes stimulate remodeling of arterial networks to form collateral arteries in a process termed arteriogenesis. However, the structural changes necessary for collateral remodeling have not been defined. We hypothesize that decon-struction of the extracellular matrix is essential to the remodeling of smaller arteries into effective collaterals. Using multiphoton microscopy, we analyzed collagen and elastin structure in maturing collateral arteries isolated from ischemic rat hindlimbs. Collateral arteries harvested at different timepoints showed progressive diameter expansion associated with striking rearrangement of in-ternal elastic lamina (IEL) into a loose fibrous mesh, a pattern persisting at 8 weeks. Despite a 2.5-fold increase in luminal diameter, total elastin content remained unchanged in collaterals compared with control arteries. Among the collateral midzones, baseline elastic fiber content is low. Outward remodeling of these vessels with a 10-20 fold diameter increase was associated with fractures of the elastic fibers and evidence of increased wall tension as demonstrated by straight-ening of the adventitial collagen. Inhibition of lysyl oxidase (LOX) function with β-aminopropionitrile resulted in severe fragmentation or complete loss of continuity of the IEL in developing collaterals. Collateral artery development is associated with permanent redistribution of existing elastic fibers to accommodate diameter growth. We found no evidence of new elastic fiber formation. Stabilization of the arterial wall during outward remodeling is necessary and dependent on LOX activity.
REVIEW | doi:10.20944/preprints202306.1900.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: COVID-19; first-visit; peripheral facial palsy; Korean Medicine hospital
Online: 27 June 2023 (12:20:33 CEST)
(1) Background: The COVID-19 pandemic has affected healthcare utilization rates on a global scale. This study aimed to analyze whether the COVID-19 pandemic affected the characteristics of first-visit patients with peripheral facial palsy visiting a Korean Medicine hospital and to observe characteristics changes in them. (2) Methods: This study analyzed the electronic medical records of 2,310 first-visit patients with peripheral facial palsy who visited the Facial Palsy Center, Korean Medicine Hospital, Kyung Hee University Medical Center from January 1, 2019 to December 31, 2021 in terms of demographic characteristics, disease phase, residence locations, hospital visit route, and patient care type. (3) Results: There were significant relationships between the presence of the COVID-19 pandemic (i.e., before and during) and the number of patients by disease phase (p=0.043), residence locations (p=0.003), residence locations in Seoul (p=0.003), and patient care types (p=0.003). (4) Conclusions: There were several differences in characteristics of first-visit patients with peripheral facial palsy visiting a Korean Medicine hospital during COVID-19 pandemic in terms of demographic characteristics, disease phase, residence locations, residence locations in Seoul, and patient care types.
REVIEW | doi:10.20944/preprints202304.0492.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: migraine; headache; peripheral sensory neurons; transient receptor potential channels; TRPC4; CGRP
Online: 18 April 2023 (05:23:02 CEST)
Migraine is a neurovascular disorder that affects approximately 12% of the global population. While its exact causes are still being studied, researchers believe that nociceptors in the trigeminal ganglia play a key role in the pain signals of migraine. These nociceptors innervate the intracranial meninges and convey pain signals from the meninges to the thalamus. Targeting these nociceptors is considered promising due to their accessibility and distinct molecular profile, which includes the expression of several transient receptor potential (TRP) channels. These channels have been linked to various pain conditions, including migraine. This review discusses the role and mechanisms of nociceptors in migraine, the challenges of current antimigraine drugs, and the evidence for well-studied and emerging TRP channels, particularly TRPC4, as novel targets for migraine prevention and treatment.
REVIEW | doi:10.20944/preprints201811.0051.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: peripheral and meningeal lymphatics 1; blood-brain barrier 2; neurorehabilitation 3.
Online: 2 November 2018 (10:53:09 CET)
The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the meningeal lymphatics functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in the brain drainage, clearance and recovery are still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on how to recruit the meningeal lymphatics by the opening of blood-brain barrier as a trigger mechanism of activation of the meningeal lymphatic drainage. This leads to innovative strategies in neurorehabilitation therapy.
ARTICLE | doi:10.20944/preprints202204.0274.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Peripheral Nerve Injury; peripheral nerve regeneration; sciatic nerve; Olfactory Mucosa Mesenchymal Stem/Stromal Cells; Olfactory Ensheating Cells; secretome; conditioned medium; nerve guidance conduit; tibial cranial muscle; rat
Online: 28 April 2022 (05:49:40 CEST)
Cell secretome has been explored as a cell-free technique with high scientific and medical interest for Regenerative Medicine. In this work, the secretome produced and collected from Olfactory Mucosa Mesenchymal Stem Cells and Olfactory Ensheating Cells was analyzed and therapeutically applied to promote peripheral nerve regeneration. The analysis of the conditioned medium revealed the production and secretion of several factors with immunomodulatory functions, capable of intervening beneficially in the phases of nerve regeneration. Subsequently, the conditioned medium was applied to sciatic nerves of rats after neurotmesis, using Reaxon® as tube-guides. Over 20 weeks, the animals were subjected to periodic functional assessments, and after this period, the sciatic nerves and cranial tibial muscles were evaluated stereologically and histomorphometrically, respectively. The results obtained allowed to confirm the beneficial effects resulting from the application of this therapeutic combination. The administration of conditioned medium from Olfactory Mucosal Mesenchymal Stem Cells led to the best results in motor performance, sensory recovery, and gait patterns. Stereological and histomorphometric evaluation also revealed the ability of this therapeutic combination to promote nervous and muscular histologic reorganization during the regenerative process. The therapeutic combination discussed in this work shows promising results and should be further explored to clarify irregularities found in the outcomes and to allow establishing the use of cell secretome as a new therapeutic field applied in the treatment of peripheral nerves after injury.
REVIEW | doi:10.20944/preprints202305.0598.v1
Subject: Biology And Life Sciences, Aging Keywords: circadian rhythms; aging; suprachiasmatic nucleus; peripheral clock; inflammatory response
Online: 9 May 2023 (08:19:43 CEST)
The circadian clock regulates daily changes in behavioral, endocrine and metabolic activities in mammals. Circadian rhythms in cellular physiology are significantly affected by aging. In particular, we previously found that aging has profound impact on daily rhythms in mitochondrial functions, leading to increased oxidative stress. However, this is unlikely due to malfunction of molecular clocks in the suprachiasmatic nucleus or peripheral tissues, as robust clock oscillations are observed therein in old animals. Nonetheless, aging induces changes in gene expression levels and rhythms in various peripheral and probably central tissues. In this article, we review findings on the roles of the circadian clock and aging in regulating mitochondrial rhythms and redox homeostasis. Chronic sterile inflammation is implicated in mitochondrial dysfunction and increased oxidative stress during aging. In particular, upregulation of CD38 by inflammatory response can disturb mitochondrial functions in multiple ways.
CASE REPORT | doi:10.20944/preprints202008.0435.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: balance; sensory substitution; neuroprosthesis; peripheral neuropathy; fall risk; diabetes
Online: 20 August 2020 (06:06:06 CEST)
Background:Peripheral neuropathy (PN) can result in either partial or complete loss of distal sensation resulting in an increased fall risk. Walkasins® uses a shoe insert to detect the magnitude and direction of sway and sends signals to a leg unit that provides sensory balance cues. The objective of this case report is to describe the long-term influence of the Walkasins® lower limb sensory neuroprosthesis on balance and gait for an individual with diabetic PN.Case Description:A fifty-one-year-old male with a 3-year history of PN and a 10-year history of type II diabetes mellitus was fitted with Walkasins® and utilized the shoe inserts 8-10 hours/day for more than 1 year. Although, vibration and tactile thresholds were severely impaired at his 1st metatarsophalangeal joint and the lateral malleolus bilaterally he could perceive tactile stimuli from the Walkasins® above the ankles.Outcomes:Following Walkasins® use, his Activities-specific Balance Confidence Scale (ABC) scores improved from 33% to 80%. His mean Vestibular Activities of Daily Living (VADL) scores decreased from 3.54 to 1. His Functional Gait Assessment (FGA) scores increased from 13/30 to 28/30 and his miniBESTest scores improved from 15/28 to 26/28. Gait speed increased from 0.23 m/sec to 1.5 m/sec. The patient described a decrease in pain and cramping throughout his lower extremities and an increase in function.Discussion:Gait and balance improved with the use of the Walkasins® and participation in the Neuro Wellness Program. This improvement suggests that the use of sensory substitution devices, such as the Walkasins®, may replace sensory deficits related to gait and balance dysfunction experienced by patients with PN. Further research is needed to determine if other patients will have a similar response and what the necessary threshold of sensory function is to benefit from use of the Walkasins®.
ARTICLE | doi:10.20944/preprints202205.0305.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: peripheral nerve regeneration; lymphangiogenesis; Schwann cells; lymphatic endothelial cells
Online: 23 May 2022 (11:02:07 CEST)
Peripheral nerve injuries pose a major clinical concern world-wide, and functional recovery after segmental peripheral nerve injury is often unsatisfactory, even in case of autografting. Although it is well established that angiogenesis plays a pivotal role during nerve regeneration, the influence of lymphangiogenesis is strongly underinvestigated. In this study, we analyzed the presence of lymphatic vasculature in healthy and regenerated murine peripheral nerves, revealing that nerve autografts contained increased numbers of lymphatic vessels after segmental damage. This led us to elucidate the interaction between lymphatic endothelial cells (LECs) and Schwann cells (SCs) in vitro. We show that SC and LEC secretomes do not influence the respective other cell types’ migration and proliferation in 2D scratch assay experiments. Furthermore, we successfully created lymphatic microvascular structures in SC-embedded 3D fibrin hydrogels in the presence of supporting cells, whereas SCs seemed to exert anti-lymphangiogenic effects when cultured with LECs alone. Here, we describe for the first time increased lymphangiogenesis after peripheral nerve injury and repair. Furthermore, our findings indicate a potential lymph-repellent property of SCs, thereby providing a possible explanation for the lack of lymphatic vessels in the healthy endoneurium. Our results highlight the importance to elucidate the molecular mechanisms of SC-LEC interaction.
REVIEW | doi:10.20944/preprints202306.1281.v1
Subject: Biology And Life Sciences, Life Sciences Keywords: microcirculation; peripheral circulation; remodelling; small resistance arteries; vascular biology
Online: 19 June 2023 (04:11:00 CEST)
Arterial hypertension is a common condition worldwide and an important risk factor for cardio- and cerebrovascular events, renal diseases as well as microvascular eye diseases. Established hypertension leads to chronic vasoconstriction of small arteries as well as to decreased lumen diameter and thickening of the arterial media or wall with a consequent increased media-to-lumen ratio (MLR) or wall-to-lumen ratio (WLR). This process, defined as vascular remodeling, was first demonstrated in small resistance arteries isolated from subcutaneous biopsies and measured by micromyography, and this is still considered the gold-standard method for the assessment of structural alteration in small resistance arteries; however microvascular remodeling seems to represent a generalized phenomenon. An increased MLR may impair organ flow reserve, being relevant in the maintenance and, probably, also in the progressive worsening of hypertensive disease, as well as in the development of hypertension-mediated organ damage/cardiovascular events, possessing, therefore, a prognostic relevance. New, non-invasive techniques, such as Scanning Laser Doppler Flowmetry or Adaptive Optics, are presently under development, focusing mainly on the evaluation of WLR in retinal arterioles; recently, also retinal microvascular WLR was demonstrated to have a prognostic impact in term of cardio- and cerebrovascular events. A rarefaction of capillary network has also been reported in hypertension which may contribute to flow reduction and impairment in oxygen delivery to different tissues. These microvascular alterations seem to represent an early step in hypertension-mediated organ damage since they might concur to microvascular angina, stroke, and renal dysfunction. In addition, they could be a marker useful in monitoring the beneficial effect of antihypertensive treatment. Also conductance arteries may be affected by a remodeling process in hypertension, and a cross-talk may exist between structural changes in the small and large arteries. The review will address the possible relations between structural microvascular alterations and hypertension-mediated organ damage and their potential improvement with antihypertensive treatment.
ARTICLE | doi:10.20944/preprints202104.0205.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: chronic limb-threatening ischemia; peripheral arterial disease; calcification pattern
Online: 7 April 2021 (14:45:17 CEST)
Objectives The most severe type of peripheral arterial disease (PAD) is critical limb ischaemia (CLI). In CLI, calcification of the vessel wall plays an important role in symptoms, amputation rate and mortality. However, calcified arteries are also found in asymptomatic persons (non-PAD patients). We investigated whether the calcification pattern in CLI patients and non- PAD patients are different and could possibly explain the symptoms in CLI patients. Materials and Methods 130 CLI and 204 non-PAD patients underwent a CT of the lower extremities. This resulted in 118 CLI patients (mean age 72±12, 70.3% male) that were age-matched with 118 non-PAD patients (mean age 71±11, 51.7% male). The characteristics severity, annularity, thickness and continuity were assessed in the femoral and crural arteries and analysed by binary multiple logistic regression. Results Nearly all CLI patients have calcifications and these are equally frequent in the femoropopliteal (98.3%) and crural arteries (97.5%), while the non-PAD patients had in just 67% any calcifications with more calcifications in the femoropopliteal (70.3%) than in the crural arteries (55.9%, p<0.005). The crural arteries of the CLI patients had significantly more complete annular calcifications (OR 2.92, p=0.001.) while in the non-PAD patients dot-like calcifications dominated. In CLI patients, the femoropopliteal arteries had more severe, irregular / patchy and thick calcifications (OR 2.40, 3.27, 1.81, p≤0.05, respectively) while in non-PAD patients, thin continuous calcifications prevailed. Conclusions Compared with non-PAD patients CLI patients are more frequently and extensively calcified. Annular calcifications were found in the crural arteries of CLI patients while dot-like calcifications were mostly present in the non-PAD patients. These different patterns of calcifications in CLI point at different etiology and can have prognostic and eventually therapeutic consequences.
ARTICLE | doi:10.20944/preprints202310.1438.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: peripheral nerve tissue engineering; electrical stimulation; hydrogels; PC12 cells
Online: 23 October 2023 (11:14:08 CEST)
Extensive damage to peripheral nerves is a health problem with few therapeutic alternatives. In this context, the development of tissue engineering seeks to obtain materials that can help recreate environments conducive to cellular development and functional repair of peripheral nerves. Different hydrogels have been studied and presented as alternatives for future treatments to emulate the morphological characteristics of nerves. Along with this, other research proposes the need to incorporate electrical stimuli into treatments as agents that promote cell growth and differentiation; however, no precedent correlates the simultaneous effects of the types of hydrogel and electrical stimuli. In this research, the neural differentiation of PC12 cells we are evaluated, relating the effect of collagen, alginate, GelMA, and PEGDA hydrogels with electrical stimulation modulated in four different ways. Our results show significant correlations for different culture conditions, allowing us to develop new experimental schemes for new materials in peripheral nerve engineering.
ARTICLE | doi:10.20944/preprints202111.0022.v1
Subject: Environmental And Earth Sciences, Environmental Science Keywords: Particulate Matter; Genotoxicity; Peripheral Blood Lymphocytes; Atomic Absorption Spectroscopy; In-vitro Micronucleus Test
Online: 1 November 2021 (15:22:09 CET)
Urban air quality is increasingly being studied as a fraction of the world's population is now living in megacities. In this study, particulate matter (PM) along Taft Avenue, Manila, Philippines, is investigated in terms of its ability to induce genetic damage on human peripheral blood lymphocytes (PBL). Size-segregated roadside air samples were obtained from 2015-2016 near the university gate and analyzed using in vitro micronucleus and cytokinesis-block proliferation tests. While cellular proliferation was unaffected by 0 – 0.1 kg·m-3 of PM1.0 and PM2.5, PBL cells treated with PM2.5 displayed significantly higher micronucleus count (p = 0.03) compared to the cells treated with PM1.0. Atomic Absorption Spectroscopy revealed greater amounts of Cd, Ca, Pb, K, Na, and Zn in PM2.5 compared to PM1.0. The results indicate the differences in composition of the two size fractions of air particulates are associated with their genotoxicities.
REVIEW | doi:10.20944/preprints202307.1210.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: Peripheral arterial diseases; Somatic mutation; Thrombosis; Atherosclerosis; Inflammation; Genetic disorders
Online: 18 July 2023 (10:13:12 CEST)
Peripheral arterial diseases (PAD) are complex cardiovascular conditions influenced by environmental factors and somatic mutations in multiple genes involved in hematopoiesis and inflammation. While traditional risk factors such as smoking, hypercholesterolemia, and hypertension have been extensively studied, the role of somatic mutations in PAD progression remains underexplored. This article aims to provide a comprehensive review of the molecular mechanisms, genetic landscape, prognostic significance, and clinical implications of somatic mutations in PAD. The expansion of clonal hematopoiesis of indeterminate potential (CHIP) clones in the circulating blood, named clonal hematopoiesis (CH), leads to the infiltration of these clones into atherosclerotic plaques and the production of inflammatory cytokines, increasing the risk of cardiovascular diseases including PAD. Furthermore, recent experimental evidence has demonstrated the involvement of somatically mutated TP53 genes with a high variant allele frequency (VAF) in PAD development and prognosis. The review delves into the relationship between CH and PAD, elucidating the prevalence, impact, and underlying mechanisms of this association. This understanding paves the way for novel therapeutic approaches targeting CHIP to promote tissue regeneration and improve outcomes in PAD patients. It emphasizes the need for further re-search to fully unravel the genetic footprint of the disease and highlights potential clinical implications. The findings presented in this article lay the foundation for personalized medicine approaches and open avenues for the development of targeted therapies based on somatic mutation profiling.
ARTICLE | doi:10.20944/preprints202308.0554.v2
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: endovascular procedure; peripheral arterial disease; femoral popliteal bypass; prosthetic graft
Online: 10 August 2023 (08:37:05 CEST)
Aim. Atherosclerotic complex femoropopliteal lesions have traditionally been treated with bypass surgery. A prosthetic graft is used to save the vein graft for more distal revascularization or when unavailable. However, the endovascular approach has gained popularity and is offered as first-line strategy for complex lesions. This study aimed to evaluate whether endovascular procedures for complex femoropopliteal native lesions can be a first-line treatment strategy over open surgery with prosthetic bypass in patients with peripheral arterial disease (PAD). Methods. A retrospective study was conducted between 2013 and 2021 to identify patients with symptomatic PAD who required limb revascularization at the femoropopliteal segment and complex lesions (TASC II C and D). Primary endpoints were technical success, primary patency, freedom from clinically driven target lesion revascularization (cdTLR), freedom from major adverse limb and cardiovascular events (MALE and MACE), freedom from limb loss, and survival. Secondary endpoints were length of in-hospital stay, duration of the procedure, and costs. Results. We identified 185 limbs among 174 suitable candidates for comparison, wherein 105 were treated with endovascular procedure and 80 with femoral popliteal prosthetic bypass. Most patients in both groups presented with chronic limb-threatening limb ischemia, and all were ASA >3. There were more octogenarians (p = 0.02) and patients with coronary disease (p = 0.004) in the endovascular group. Median follow-up was 30 months. Technical failure rate for endovascular procedures was 4.8% vs 0% in the open group (p 0.003). Freedom from MACE was similar in both groups. The endovascular group showed superior primary patency (p<0.0001), cdTLR (p<0.0001), MALE (p<0.0001), and freedom from limb loss (p = 0.0018) at 24 months. Further analysis performed for the open above-the-knee subgroup showed that the aforementioned endpoints were similar at 12 months, and favoured the endovascular group at 24 months. Procedural time and in-hospital stay were longer in the open group (p<0.0001 and p<0.001). Finally, procedural cost was 10-fold lower in the endovascular bypass group than in the prosthetic bypass group. Conclusion. Endovascular procedures for complex femoropopliteal lesions are safe in patients at high risk for surgery and show better outcomes at 24 months than prosthetic bypasses. The latter may be considered as an alternative in cases of endovascular failure.
CASE REPORT | doi:10.20944/preprints202309.2139.v1
Subject: Medicine And Pharmacology, Dentistry And Oral Surgery Keywords: Peripheral giant-cell granuloma; giant-cell epulis; giant- cell hyperplasia
Online: 30 September 2023 (07:21:15 CEST)
The Peripheral giant cell granuloma (PGCG) is an asymptomatic, non-neoplastic and proliferative lesion of unknown etiology. Some possible pre-disposing factors such as hormonal changes dur-ing pregnancy, have been suggested. However, the association between PGCG and pregnancy is controversial. There are few reported clinical cases of pregnancy-associated PGCG in the litera-ture, and they occurred only in the lower jaw. The present report is on a 35-year-old female pa-tient at 36 weeks of gestation who presented with a PGCG in the central and lateral incisors of the upper jaw. The management consisted of surgical excision, along with curettage of the affected bony walls. The diagnosis was based on clinical results and imaging examinations, and it was histopathologically confirmed. The patient underwent postoperative follow-up evaluations at 3, 6 and 12 months, and there were no signs of recurrence.
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: peripheral blood mononuclear cells; spinal cord injury; pigs; fibrin matrix
Online: 18 November 2020 (13:00:26 CET)
Peripheral blood is an available source of adult stem cells for both fundamental research and clinical use. Peripheral blood mononuclear cells (PBMCs) contain a number of different multipotent populations of progenitor cells and possess a potential to differentiate into various types of cells under appropriate conditions. We have evaluated a regenerative potential of PBMCs embedded into fibrin matrix (FM) in a model of pig spinal cord injury. The distribution of transplanted PBMCs in the injured spinal cord was previously evaluated, which demonstrated the ability of these cells to penetrate into deep layers of the spinal cord and to concentrate mainly in the grey matter. The pilot study conducted demonstrated that the tissue structure could be improved and the conduction along posterior columns of the spinal cord could be partially recovered in animals in the setting of FM+РВМCs application. The multiplex analysis of blood serum and cerebrospinal fluid (CSF) showed the cytokine imbalance to occur without significantly shifting towards pro-inflammatory or anti-inflammatory cytokine cascades in the setting therapy provided.
REVIEW | doi:10.20944/preprints202306.1260.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: Coronary artery disease; Peripheral Artery Disease; Polyvascular Diseae; Anti-thrombotic therapy; Personalized treatment
Online: 16 June 2023 (16:17:19 CEST)
Despite evidence-based therapies, patients presenting with atherosclerosis involving more than one vascular bed, such as those with peripheral artery disease (PAD) and concomitant coronary artery disease (CAD), constitute a particular vulnerable group characterized by enhanced residual long-term risk for major adverse cardiac events (MACE), as well as major adverse limb events (MALE). The latter are progressively emerging as a hard outcome to be targeted, being correlated with increased mortality. Antithrombotic therapy is the mainstay of secondary prevention in both patients with PAD or CAD however, the optimal intensity of such therapy is still topic of debate, particularly in the post-acute and long-term setting. Recent well powered randomized clinical trials (RCTs) have provided data in favor of a more intense antithrombotic therapy, such as prolonged dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor or a therapy with aspirin combined with an anticoagulant drug. Both approaches increase bleeding and patients selection is a key issue. The aim of this review is therefore to discuss and summarize the most updated available evidences for different strategies of anti-thrombotic therapies in patients with chronic PAD and CAD, particularly focusing on studies enrolling patients with both type of atherosclerotic disease and comparing a higher versus a lower intensity antithrombotic strategy. The final objective is to identify the optimal tailored approach in this setting, to achieve the greatest cardiovascular benefit and improving precision medicine.
ARTICLE | doi:10.20944/preprints202311.1145.v1
Subject: Public Health And Healthcare, Public Health And Health Services Keywords: lower extremity revascularization; peripheral artery disease; hemodialysis; geriatric nutritional risk index; C-reactive protein
Online: 17 November 2023 (07:43:26 CET)
Background: Although lower extremity revascularization is commonly performed in hemodialysis patients, poor prognosis remains a major problem. Protein-energy wasting is reportedly associated with chronic inflammation and advanced atherosclerosis in hemodialysis patients. We investigated the association between the geriatric nutritional risk index (GNRI) as a surrogate marker of protein-energy wasting, C-reactive protein (CRP), and their joint roles in the prediction of amputation and/or mortality. Methods: We enrolled 800 patients successfully underwent lower extremity revascularization. Patients were divided into low, middle and high tertile (T1, T2 and T3) according to GNRI and CRP levels, respectively. Results: Amputation-free survival rates for 8 years were 47.0%, 56.9%, and 69.5% in T1, T2, and T3 of the GNRI, and 65.8%, 58.7%, and 33.2% for T1, T2, and T3 of CRP, respectively (p<0.0001 for both). Declined GNRI [adjusted hazard ratio (aHR) 1.78, 95% confidence interval (CI) 1.24-2.59, p=0.0016 for T1 vs. T3] and elevated CRP (aHR 1.86, 95%CI 1.30-2.70, p=0.0007 for T3 vs. T1) were independent predictors of amputation and/or mortality. In the combined setting of both variables, the risk was 3.77-fold higher (95% CI 1.97-7.69, p<0.0001) in the T1 of GNRI with T3 of CRP than in the T3 of GNRI with T1 of CRP. Conclusions: Patients with pre-procedural decreased GNRI and elevated CRP levels frequently experienced amputation and/or mortality, and a combination of both variables could more accurately stratify the risk.
COMMUNICATION | doi:10.20944/preprints202012.0823.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: neuroscience; rheumatology; osteoarthritis; pain; peripheral nerve; biological drug; growth factor; peptide; monoclonal antibody; ion channel
Online: 31 December 2020 (15:41:05 CET)
Neuroscience is a vast discipline that deals with the anatomy, biochemistry, molecular biology, physiology and pathophysiology of central and peripheral nerves. Advances made through basic, translational, and clinical research in the field of neuroscience have great potential for long-lasting and beneficial impacts on human health. The emerging field of biological therapy is intersecting with the disciplines of neuroscience and rheumatology, creating new horizons for interdisciplinary and applied research. Biological drugs, growth factors, neuropeptides and monoclonal antibodies are being developed and tested for the treatment of painful arthritic and rheumatic diseases. This concise communication focuses on the solutions provided by the fields of neuroscience and neuroimmunology for real-world clinical problems in the field of rheumatology, focusing on synovial joint pain and the emerging biological treatments that specifically target pathways implicated in osteoarthritis pain in peripheral nerves.
ARTICLE | doi:10.20944/preprints202107.0013.v1
Subject: Engineering, Electrical And Electronic Engineering Keywords: Authentication and Key Agreement; Internet of Things; Physical Layer Authentication, Universal Software Radio Peripheral
Online: 1 July 2021 (11:11:46 CEST)
In this paper, we propose a lightweight physical layer aided authentication and key agreement (PL-AKA) protocol in the internet of things (IoT). Conventional evolved packet system AKA (EPS-AKA) used in long-term evolution (LTE) systems may suffer from congestions in core networks by the large signaling overhead as the number of IoT devices increases. Thus, in order to alleviate the overhead, we consider a cross-layer authentication by integrating physical layer approaches to cryptography-based schemes. To demonstrate the feasibility of the PL-AKA, universal software radio peripheral (USRP) based tests are conducted as well as numerical simulations. The proposed scheme shows a significant reduction in signaling overhead compared to the conventional EPS-AKA in both simulation and experiment. Therefore, the proposed lightweight PL-AKA has the potential for practical and efficient implementation of large-scale IoT networks.
REVIEW | doi:10.20944/preprints202308.1664.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: peripheral arterial disease; critical limb ischemia; chronic limb-threatening ischemia; survival; mortality; limb salvage
Online: 25 August 2023 (02:41:49 CEST)
Chronic Limb Threatening Ischemia (CLTI) represents the end stage form of peripheral arterial disease (PAD) and is associated to very poor prognosis with high risk of limb loss and mortality. It can be considered very similar to a terminal cancer disease reflecting a large impact on quality of life and healthcare costs. The aim of this study is to offer an overview of the relationship between CLTI, limb salvage and mortality with a focus on the need of a fast-track team-based management, that’s a driver to achieve better survival results. This review can be useful to improve management of this growing impact disease, and promote standardisation of care and communication between specialist and non-specialist health care professionals.
ARTICLE | doi:10.20944/preprints202306.1100.v1
Subject: Biology And Life Sciences, Forestry Keywords: released longitudinal maturation stresses; wood properties; Populus×euramericana ‘Zhonglin46’; tension wood; peripheral positions; heights
Online: 15 June 2023 (09:45:51 CEST)
Understanding maturation stress and wood properties of poplar tension wood are critical for improving lumber yields and utilization ratio. In this study, Released Longitudinal Maturation Strains (RLMS), anatomical features, physical and mechanical properties, and nano-mechanical properties of the cell wall were analyzed at different peripheral positions and heights in nine inclined, 12-year-old poplar (Populus×euramericana ‘Zhonglin46’) trees. The correlations between RLMS and wood properties were determined. The results showed that there were mixed effects of artificial inclination on wood quality and properties. The upper sides of inclined stems had higher RLMS, proportion of G-layer, bending modulus of elasticity, and elastic modulus of cell wall but lower microfibril angle than the lower sides. At heights between 0.7 m and 2.2 m, only the double wall thickness increased with height, RLMS and other wood properties such as fiber length and basic density fluctuated or changed little with height. RLMS was a good indicator of wood properties in the tension wood area and at heights between 0.7 m and 1.5 m. The results of this study present opportunities to identify and select better quality wood in poplar trees.
REVIEW | doi:10.20944/preprints202308.1892.v1
Subject: Public Health And Healthcare, Physical Therapy, Sports Therapy And Rehabilitation Keywords: Electrical muscle stimulation; Peripheral neuromodulation; Walking; Kinematics; Kinetics; Spatiotemporal; Able-bodied.
Online: 29 August 2023 (03:50:59 CEST)
Background: This systematic review aimed to provide a comprehensive overview of the effects of Functional Electrical Stimulation (FES) on gait characteristics in healthy individuals. Methods: Six electronic databases (PubMed, Embase, Epistemonikos, PEDro, COCHRANE Library, Scopus) were searched for studies evaluating the effects of FES on spatiotemporal, kinematic and kinetic gait parameters in healthy individuals. Two examiners evaluated the eligibility and quality of included studies using the PEDro scale. Results: A total of 15 studies met the inclusion criteria. Findings from the literature reveal that FES can be used to modify lower-limb joint kinematics, i.e., to increase or reduce the range of motion of hip, knee and ankle joints. In addition, FES can be used to alter kinetics parameters, including ground reaction forces, center of pressure trajectory, or knee joint reaction force. As a consequence of these kinetics and kinematics changes, FES can lead to changes in spatiotemporal gait parameters, such as gait speed, step cadence, and stance duration. Conclusion: The findings of this review improve our understanding of the effects of FES on gait biomechanics in healthy individuals, and highlight the potential of this technology as a training or assistive solution for improving gait performance in this population.
REVIEW | doi:10.20944/preprints202104.0761.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Peripheral Artery Disease; Exercise Intolerance; Exercise Limitations; Intermittent Claudication; Exercise Training
Online: 28 April 2021 (17:16:32 CEST)
Intermittent claudication (IC) is the most common symptom of peripheral artery disease (PAD). IC affects the quality of life and results in marked exercise intolerance and limitation to daily activities with increased risk of cardiovascular complications. Exercise training is the first line of conservative management in PAD. However, patients with IC Patient cannot tolerate exercise because of leg discomfort induced by physical effort. This review will address alternative rehabilitation strategies to reduce exercise limitations and improve exercise tolerance in patients with IC.
ARTICLE | doi:10.20944/preprints202307.1966.v1
Subject: Medicine And Pharmacology, Internal Medicine Keywords: peripheral artery disease; biomarker; ceramides; CERT; mortality; MACE; risk factors; statin
Online: 28 July 2023 (11:43:11 CEST)
Background: Ceramides are a new kind of lipid biomarkers and have already been demonstrated to be valuable risk predictors in coronary patients. Patients with peripheral artery disease (PAD) are a population with worse prognosis and higher mortality risk compared to coronary artery disease (CAD) patients. However, the value of ceramides for risk prediction in PAD patients is still vague and has been addressed in the present study. Methods: This observational study included 379 PAD patients. The primary endpoint was all-cause mortality at 10 years of follow-up. A set of ceramides was measured by LC-MS/MS and combined according to the coronary event risk test (CERT) score which categorizes patients into one of four risk groups (low risk, moderate risk, high risk, very high risk). Results: Kaplan Meier survival curves revealed that the overall survival of patients has decreased with the increasing risk predicted by the four CERT categories, advancing from low risk to very high risk. Cox regression analysis demonstrated that every 1-step increase in category resulted in a 35% rise in overall mortality risk (HR=1.35 [1.16-1.58]). Multivariable adjustment, including amongst others age, T2DM, and statin treatment before baseline, did not abrogate this significant association (HR=1.22 [1.04-1.43]). Moreover, we found that the beneficial effect of statin is significantly stronger in patients with a higher risk according to CERT. Conclusion: We conclude that the ceramide-based risk score CERT is a strong predictor of the 10-year mortality risk in patients with PAD.
ARTICLE | doi:10.20944/preprints202310.1420.v1
Subject: Public Health And Healthcare, Other Keywords: acute coronary syndrome; peripheral perfusion index; arterial blood gas; lactate; diagnostic metrics; noninvasive techniques
Online: 23 October 2023 (10:30:37 CEST)
This study aimed to investigate the potential correlations and differences between patients with Acute Coronary Syndrome (ACS) and controls. Emphasis was placed on examining the relationship between arterial blood gas PH value and arterial blood gas lactate value as well as assessing the utility of the Peripheral Perfusion Index (PI) in ACS management. Materials and Methods: A prospective observational study was conducted between January 1, 2023, and July 1, 2023, involving 60 ACS patients and 30 control subjects in an emergency department. The diagnosis of ACS was confirmed by experienced emergency physicians, and various parameters, such as peripheral perfusion index, blood gas values, and cardiac biomarker values, were collected. The statistical analyses included Pearson’s chi-square test, Mann-Whitney U test, Student’s t-test, and others, using SPSS version 18.0. There were significant differences in the mean age, perfusion index, and lactate levels between the patient and control groups. A robust negative correlation was found between age and PI, and a moderate negative correlation was observed between pH and lactate levels (r = -0.301, p=0.004). The perfusion index in the patient group was significantly lower, indicating its potential diagnostic utility. The findings demonstrate the importance of arterial blood gas pH and lactate values in understanding ACS patient profiles, emphasizing the potential of PI as a noninvasive diagnostic method. The negative correlation between pH and lactate levels may offer valuable insights into risk stratification and treatment strategies for patients with ACS.
ARTICLE | doi:10.20944/preprints201809.0529.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: hemodialysis; end stage renal disease; diabetes; motor performance; gait; balance; wearable; aging; frailty; diabetic peripheral neuropathy
Online: 27 September 2018 (04:19:43 CEST)
Motor functions are deteriorated by aging. Some conditions may magnify this deterioration. To examine whether hemodialysis (HD) process would negatively impact gait and balance beyond diabetes condition among mid-age adults (48-64 years) and older adults (65+ years). One hundred and ninety-six subjects (age=66.2±9.1 years, body-mass-index=30.1±6.4 kg/m2, female=56%) in 5 groups were recruited: mid-age adults with diabetes undergoing HD (Mid-age HD+, n=38) and without HD (Mid-age HD-, n=40); older adults with diabetes undergoing HD (Older HD+, n=36) and without HD (Older HD-, n=37); and non-diabetic older adults (Older DM-, n=45). Gait parameters (stride velocity, stride length, gait cycle time, and double support) and balance parameters (ankle, hip, and center of mass sways) were quantified using validated wearable platforms. Groups with diabetes had overall poorer gait and balance compared to the non-diabetic group (p<0.050). Among people with diabetes, the HD+ had significantly worsened gait and balance when comparing to the HD- (Cohen’s effect size d=0.63-2.32, p<0.050). Between-group difference was more pronounced among older adults with the largest effect size observed for stride length (d=2.32, p<0.001). Results suggested that deterioration in gait speed among the HD+ was correlated with age (r=-0.440, p<0.001), while this correlation was diminished among the HD-. Interestingly, results also suggested that poor gait in the Older HD- related to poor balance, while no correlation was observed between poor balance and poor gait among the Older HD+. Using objective assessments, results confirmed that the presence of diabetes can deteriorate gait and balance, and this deterioration can be magnified by HD process. Among non-HD people with diabetes, poor static balance described poor gait. However, among people with diabetes undergoing HD, age was a dominate factor describing poor gait irrespective of static balance. Results also suggested feasibility of using wearable platforms to quantify motor performance during routine dialysis clinic visits. These objective assessments may assist in identifying early deterioration in motor function, which in turn may promote timely intervention.
REVIEW | doi:10.20944/preprints202310.1080.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: peripheral nerve regeneration; delayed surgical nerve repair; regeneration associated genes; electrical stimulation
Online: 17 October 2023 (11:02:56 CEST)
Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. However, functional recovery after surgical repair is often disappointing. The basis for the poor recovery is the progressive deterioration with time and distance, of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. This is despite the retained capacity of chronically denervated and atrophic muscle to accept reinnervation. Progressive decline in regeneration associated genes in both axotomized neurons and denervated SCs accounts for the decline in regenerative success in association with silencing of neural activity in sensory neurons due to their disconnection from their sense organs and, in motoneurons due to loss of their synaptic contacts in the spinal cord. Whilst exogenous neurotrophic factors promote nerve regeneration, the profuse axonal outgrowth and difficulties in delivery are avoided by promoting their endogenous expression with brief (1 hour) low frequency (20Hz) electrical stimulation (ES) proximal to the injury site. ES accelerates axon outgrowth and in turn, target reinnervation in both animals and human subjects. Applying ES to intact nerve days prior to nerve injury, conditional ES (CES) increases axonal outgrowth and regeneration rate with the potential for application in nerve transfer surgeries and end-to-side neurorrhaphies. However, the additional surgery for applying CES electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes.
ARTICLE | doi:10.20944/preprints202305.0837.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Alzheimer's Disease; Noninvasive Diagnosis; Metabolic Abnormalities; Biomarker; Peripheral blood; Multi-Machine Learning
Online: 11 May 2023 (09:47:20 CEST)
Alzheimer's disease (AD) is an incurable neurodegenerative disorder. Early screening, particularly in blood has been regarded as an effective approach for AD diagnosis and prevention. In addition, metabolic dysfunction has been demonstrated to be closely related to AD, which might be reflected in whole blood transcriptome. Hence, we hypothesized that establishment of diagnostic model based on metabolic signatures of blood is a workable strategy. To the end, we initially constructed metabolic pathway pairwise (MPP) signatures to characterize the interplay among metabolic pathways. Then, a series of bioinformatic methodologies, e.g., differential expression analysis, functional enrichment analysis, and network analysis, etc. were used to investigate the molecular mechanism behind AD. Moreover, an unsupervised clustering analysis based on the MPP signature profile via Non-Negative Matrix Factorization (NMF) algorithm was utilized to stratify AD patients. Finally, aimed at distinguishing AD patients from non-AD group, a metabolic pathway-pairwise scoring system (MPPSS) was established using multi-machine learning methods. As a result, many metabolic pathways correlated to AD were disclosed, including oxidative phosphorylation and fatty acid biosynthesis, etc. NMF clustering analysis divided AD patients into two subgroups (S1 and S2), which exhibit distinct activities of metabolism and immunity. Typically, oxidative phosphorylation in S2 exhibits a lower activity than that in S1 and non-AD group, suggesting the patients in S2 might possess a more compromised brain metabolism. Additionally, Immune infiltration analysis showed that the patients in S2 might have phenomena of immune suppression, compared with S1 and non-AD group. These findings indicated that S2 probably have a more severe progression of AD. Finally, MPPSS could achieve an AUC of 0.73 in training dataset, 0.71 in testing dataset and an AUC of 0.82 on weighted average in five external validation datasets. Overall, our study successfully established a novel metabolism-based scoring system for AD diagnosis using blood transcriptome, and provided new insight into the molecular mechanism of metabolic dysfunction implicated in AD.
ARTICLE | doi:10.20944/preprints202004.0509.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: nodal peripheral T-cell lymphomas; peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS); ALK-negative anaplastic large-cell lymphoma (ALCL/ALK-); Angioimmunoblastic T-cell lymphoma (AITL); diagnosis; prognosis; GATA3 gene expression
Online: 29 April 2020 (12:48:00 CEST)
Background: Nodal peripheral T-cell lymphomas (nPTCLs) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in the clinical practice. Accurate biomarkers to refine the different subtypes of nPTCLs and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA3 gene expression, and its capability to discriminate the different subtypes of nPTCLs. Patients and Methods: From 2000 to 2017, 80 patients with nPTCLs were eligible for GATA3 gene expression analysis that was assessed retrospectively by quantitative real time PCR (qRT-PCR) of neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE). Results: Median age was 49 years old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years. Of them, 36.3% were classified as PTCL/NOS, 31.2% ALK-negative ALCL, 21.2% ALK-positive ALCL and 11.3% AITL. The majority of cases had advanced stage (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA3 gene expression level was 0.49% (range 0 – 7.07) in all cohort, it was 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL/NOS and 0.67% for AITL. The difference of GATA3 gene expression among distinct variants of nPTCLs was statistically significant (p < 0.001). GATA3 gene expression levels ≥ 0.71% discriminate PTCL/NOS from ALK-negative ALCL and AITL with sensitivity of 62% and specificity of 80.3%. GATA3 gene expression levels ≥ median was associated with poor 2-year OS for PTCL/NOS (46.7% x 21.4%, p=0.04) and for ALK-negative ALCL (85.7% x 54.5%, p=0.04). Conclusion: Despite the relative small and heterogeneous group of patients with nPTCLs, GATA3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL/NOS and ALK-negative ALCL. Moreover it may also discriminate different subtypes of nPTCLs. Further studies with larger series of patients should confirm our findings.
ARTICLE | doi:10.20944/preprints202111.0303.v1
Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Microvascular complications; Cardiac autonomic neuropathy; Diabetic peripheral neuropathy; Diabetic nephropathy; Diabetic retinopathy; patient profiles; machine learning
Online: 17 November 2021 (11:54:23 CET)
Microvascular complications are one of the key causes of mortality among type-2 diabetic patients. This study was sought to investigate the use of a novel machine learning approach for predicting these complications from patient demographic, clinical, and laboratory profiles only. A total of 96 Bangladeshi participants having type-2 diabetes were recruited during their routine hospital visits. All patient profiles were assessed by using a Chi-squared (2) test to statistically determine the most important markers in predicting four microvascular complications; namely cardiac autonomic neuropathy (CAN), diabetic peripheral neuropathy (DPN), diabetic nephropathy (NEP), and diabetic retinopathy (RET). A machine learning approach based on random forest (RF) and support vector machine (SVM) was then developed to ensure automated clinical testing for microvascular complication in diabetic patients. The highest prediction accuracies were obtained by RF using diastolic blood pressure, Albumin-Creatinine ratio, and gender for CAN testing (98.67%), Microalbuminuria, smoking history, and hemoglobin A1C for DPN testing (67.78%), Albumin-Creatinine ratio for NEP testing (100%), and hemoglobin A1C, Microalbuminuria, and smoking history for RET testing (84.38%). This study suggests machine learning as a promising automated tool for predicting microvascular complications in diabetic patients using their profiles, which could help prvent those patients from further microvascular complications leading to early death.
ARTICLE | doi:10.20944/preprints202304.0539.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: adeno-associated virus; metachromatic leukodystrophy; arylsulfatase A; gene therapy; central nervous system; peripheral nervous system; neurodegeneration
Online: 19 April 2023 (04:17:50 CEST)
Metachromatic leukodystrophy (MLD) is a hereditary neurodegenerative disease characterized by demye-lination and motor and cognitive impairment due to the deficiency of the lysosomal enzyme arylsulfatase A (ARSA) or the saposin B activator protein (SapB). Current treatments are limited; however, gene therapy using adeno-associated virus (AAV) vectors for ARSA delivery has shown promising results. The main challenges for MLD gene therapy include optimizing AAV dosage, selecting the most effective serotype, and determining the best route of administration for ARSA delivery into the central nervous system. This study aims to evaluate the safety and efficacy of AAV serotype 9 encoding ARSA (AAV9-ARSA) gene therapy when administered intrave-nously or intrathecally in minipigs, a large animal model with anatomical and physiological similarities to humans. By comparing these two administration methods, this study contributes to the understanding of how to improve the effectiveness of MLD gene therapy and offers valuable insights for future clinical applications.
REVIEW | doi:10.20944/preprints202001.0376.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: myelin; intrinsically disordered protein; multiple sclerosis; peripheral neuropathies; myelination; protein folding; protein-membrane interaction; protein-protein interaction
Online: 31 January 2020 (04:55:04 CET)
Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbour pathophysiological roles in myelin disease. Many myelin proteins share common attributes, including small size, high hydrophobicity, multifunctionality, longevity, and intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin and correlate these with their various functions, including susceptibility to post-translational modifications, function in protein-protein and protein-membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved.
ARTICLE | doi:10.20944/preprints202306.1018.v1
Subject: Medicine And Pharmacology, Veterinary Medicine Keywords: Rabbit; animal model; peripheral nerve block; regional anaesthesia; sciatic nerve block; femoral nerve block; orthopaedic surgery; cadaver
Online: 14 June 2023 (08:41:02 CEST)
The rabbit is a popular animal model for human biomechanical research involving surgery at the hind limb. General anesthesia in rabbits is associated with significantly higher mortality rates than in dogs and cats. In addition, as prey animals, rabbits tend to mask signs of pain, making early detection particularly difficult. Regional anaesthesia, as an adjunct to general anaesthesia, may markedly reduce the need for systemic anaesthetic and analgesic drugs, limiting their associated side effects. In other species, a block of the sciatic (ScN) and the femoral nerves (FN) is usually applied in patients undergoing hind limb surgery. In phase 1 of this study, the ScN and the FN have been localized and an appropriate approach under sonographic guidance has been evaluated. In phase 2, a mixture of methylene blue and lidocaine have been administered to the ScN and the FN in 10 cadavers (20 hind limbs). Staining of the nerves was evaluated by dissection. Ultrasonographically, the ScN appeared as a binocular structure surrounded by a hyperechoic rim. The FN appeared as a hypoechoic structure in the dorsal part of the IPM, becoming hyperechoic/honey-comb-like in the ventral part. Both nerves could be successfully stained in all animals over a median length of 2.3 cm which was considered effective. This technique allows a feasible and accurate access to block of the ScN and the FN and may lead to successful analgesia in rabbits undergoing hind limb surgery.
ARTICLE | doi:10.20944/preprints202308.1792.v1
Subject: Social Sciences, Urban Studies And Planning Keywords: peripheral neighborhoods; public space assessment tools; co-location network; open access data; geospatial data science; network analysis; cartography.
Online: 25 August 2023 (09:18:00 CEST)
Adequate public spaces and urban green areas are key criteria for urban development and infrastructure implementation of healthy cities. Latterly, there has been an increasing number of research methods using artificial intelligence (AI) to monitor, quantify, and control the state of these spaces with an aim towards pioneering research in Urban Studies. However, in informal areas, open-data access tends to lack adequate and updated information, making it difficult to use AI methods. Hence, we propose a methodology for restricted open data collection and preparation for future use in machine learning or spatial data science models for similar areas. To that extent, we examine two peripheral and low-income neighborhoods in Quito, Ecuador, La Bota and Toctiuco, to analyze their public spaces, urban green areas, points of interest, and road networks, and how they address healthy cities criteria. We develop an original methodological approach that combines an index of proximity, accessibility, quantity, and quality of these spaces with geospatial and network analysis techniques. Results indicate that the connectivity and structure of these spaces are centralized and nodal, representing exclusion and segregation. This work provides insights on potential healthy spaces, and information to urban planners and policymakers in decision-making for healthy urban infrastructure.
ARTICLE | doi:10.20944/preprints202305.1315.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: peripheral nerve ultrasound; tibial nerve; amyotrophic lateral sclerosis; inflammatory neuropathy; hereditary neuropathy; cross-sectional area; nerve microvascular blood flow
Online: 18 May 2023 (09:42:40 CEST)
Background and Objectives: Ultrasound (US) is a non-invasive tool for the in-vivo detection of peripheral nerve alterations. Materials and Methods: In this study we applied nerve US to assist the discrimination between the spectrum of Amyotrophic Lateral Sclerosis (ALS, n=11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n=5) and genetically confirmed Charcot-Marie-Tooth disease (CMT, n=5). All participants and n=15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. Nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms and nerve conduction studies. Analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (T) magnetic resonance neurography (MRN). Results: Patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. Blood flow was greatest in CIDP, and higher than in CMT, ALS and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP and CMT, even in small sample sized groups. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants along the disease groups.
REVIEW | doi:10.20944/preprints202005.0222.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: myelin; myelination; development; peripheral neuropathies; protein folding; transmembrane protein; protein-membrane interaction; protein-protein interaction
Online: 13 May 2020 (04:51:20 CEST)
Myelin protein zero (P0), a type I transmembrane protein, is the most abundant protein in peripheral nervous system (PNS) myelin – the lipid-rich, periodic structure that concentrically encloses long axonal segments. Schwann cells, the myelinating glia of the PNS, express P0 throughout their development until the formation of mature myelin. In the intramyelinic compartment, the immunoglobulin-like domain of P0 bridges apposing membranes together via homophilic adhesion, forming a dense, macroscopic ultrastructure known as the intraperiod line. The C-terminal tail of P0 adheres apposing membranes together in the narrow cytoplasmic compartment of compact myelin, much like myelin basic protein (MBP). In mouse models, the absence of P0, unlike that of MBP or P2, severely disturbs the formation of myelin. Therefore, P0 is the executive molecule of PNS myelin maturation. How and when is P0 trafficked and modified to enable myelin compaction, and how disease mutations that give rise to incurable peripheral neuropathies alter the function of P0, are currently open questions. The potential mechanisms of P0 function in myelination are discussed, providing a foundation for the understanding of mature myelin development and how it derails in peripheral neuropathies.
REVIEW | doi:10.20944/preprints202309.1715.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: chronic limb-threatening ischemia; peripheral arterial disease; endovascular treatment; tibial vessels; percutaneous deep venous arterialization
Online: 26 September 2023 (04:44:37 CEST)
Endovascular techniques are currently considered as a first line treatment options for lower limb chronic limb-threatening ischemia (CLTI), defined by the presence of ischemic rest pain and severe tissue loss such as ulcers or gangrene. Although the technical success rate of endovascular revascularization is high, in specific patients with advanced infrapopliteal disease and absence of run-off tibial vessels ("desert foot"), the chance of successful revascularization is minimal. In order to avoid primary amputation several treatment option are currently being investigated, including different strategies such as gene therapy or venous arterialization techniques. This review focuses on the percutaneous deep venous arterialization technique, recently introduced in everyday clinical practice, as a promising, minimally invasive treatment option for limb salvage in CLTI patients presenting with “desert foot”.
REVIEW | doi:10.20944/preprints202209.0165.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: Diabetic foot; Diabetic neuropathies; Peripheral arterial disease; Foot ulcer; Gait; Walking; Postural balance; Wearable electronic devices; Gait analysis; Digital technology
Online: 13 September 2022 (09:28:22 CEST)
People with diabetic foot frequently exhibit poor gait and balance. However, there is no review to inform digital biomarkers of poor gait and balance related to diabetic foot, measurable by wearables outside traditional gait laboratories. Such information could assist in designing remote patient monitoring platform to track changes in gait and balance dysfunction among people with diabetic foot for timely referral and intervention. Accordingly, we conducted a web-based review using PubMed. Our search was limited to human subjects and English-written papers published in peer-reviewed journals. We identified 20 papers in this review. We found preliminary evidence of digital biomarkers of gait and balance dysfunction in people with diabetic foot, measured by wearables, such as slow gait speed, large gait variability, unstable gait initiation, and large body sway. However, due to heterogeneities in included papers in terms of study design, movement tasks, and small sample size, more studies are recommended to confirm this preliminary evidence. Additionally, based on our review, we recommend establishing appropriate strategies to successfully implement wearable-based assessment into clinical practice for diabetic foot care.
REVIEW | doi:10.20944/preprints202011.0193.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: Cell therapy, Peripheral arterial disease, Bone marrow, Adipose tissue, Mesenchymal stem cells, Exosome, Critical limb ischemia.
Online: 4 November 2020 (12:37:47 CET)
Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. Aims: This review offers an up-to-date critical overview of the knowledge and data of evidence-based medicine on the position of cell therapy in the treatment of PAD. It provides an overview of current evidence and appraises the future perspectives of cell-based therapy, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. Results: Meta-analyses focused on cell therapy problems in PAD treatment confirm a significantly greater chance of limb salvage in the first year after the cell therapy administration. The opportunity of defect healing is at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective.
ARTICLE | doi:10.20944/preprints202012.0784.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Bacillus subtilis; flow cytometry; gastrointestinal health; peripheral blood mononuclear cells (PBMC); probiotic; short chain fatty acid
Online: 31 December 2020 (09:46:43 CET)
Probiotics make up a large and growing segment of the commercial market of dietary supplements and are touted as offering a variety of human health benefits. Some of the purported positive impacts of probiotics include, but are not limited to, stabilization of the gut microbiota, prevention of gastrointestinal disorders and modulation of the host immune system. Current research suggests that the immunomodulatory effects of probiotics are strain specific and vary in mode of action. Here, we examined the immunomodulatory properties of Bacillus subtilis strain DE111 in a healthy human population. In a randomized, double blind, placebo-controlled four-week intervention, we examined peripheral blood mononuclear cells (PBMCs) at basal levels pre- and post-treatment as well as in response to stimulation with bacterial lipopolysaccharide (LPS). We observed an anti-inflammatory effect of B. subtilis, manifested as a decrease in immune cell populations within the basal state along with an increase in anti-inflammatory immune cells in response to LPS stimulation. Overall gastrointestinal health, microbiota, and circulating and fecal markers of inflammation and gut barrier function were largely unaffected by DE111 treatment. These data suggest that the novel probiotic B. subtilis DE111 may have clinical applications in modulating immune homeostasis via anti-inflammatory mechanisms.
ARTICLE | doi:10.20944/preprints202208.0292.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Chronic Hepatitis B Virus Infection; Liver; Pregnant Women; Cord blood; PBMCs (Peripheral Blood Mononuclear Cells); subclinical index
Online: 16 August 2022 (14:17:53 CEST)
BACKGROUND&AIMS: Hepatitis B virus (HBV) infection remains a major public health problem. The interaction between HBV and the host inflammatory response is an important factor contributing to liver damage and disease development. We compared the correlation between the subclinical index and PBMCs concentration in two groups of pregnant women (HBsAg positive), which are different in HBV DNA concentration in Vietnam. METHODS: The Hierarchical cluster analysis (HCA) was run with 20 different clustering methods on data collected from 80 Vietnamese pregnant women and their babies (60/80 cord blood). RESULTS: In the high viral load group (HBV DNA ≥ 5x10^7 copies/ml), a strong correlation between CBMCs with serum maternal Haemoglobin concentration and maternal platelet and maternal ALT. Their R values are: -0.88, 0.82, and 0.84 with p=8.97E-03, 2.41E-02 and 1.75E-01, respectively. CONCLUSIONS: We found a significant correlation shift of subclinical index between the two groups, which may be important in diagnosing pregnant women with chronic hepatitis B virus infection.
ARTICLE | doi:10.20944/preprints202205.0145.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: abdominal aorta; arterial embolism; B-Flow sonography; contrast enhanced ultrasound; endovascular aortic repair; flashlight sign; peripheral arteries; wall adherent floating structures
Online: 11 May 2022 (03:44:41 CEST)
This study aimed on evaluating the potential diagnostic value of a novel, sonographic, B-Flow Imaging (BFI)-based sign (“flashlight sign”, FLS) for the detection of wall-adherent, floating arterial structures (WAFAS). The FLS, characterized by a fast moving, very bright, intraluminal signal was detected in 28 patients with WAFAS. We divided this cohort into three subgroups, depending on the affected vascular segments: (1) peripheral arteries (n = 10), (2) native abdominal aorta (n = 8), and (3) abdominal aorta after endovascular aortic repair (EVAR; n = 10). Clinical characteristics were analyzed and BFI-findings were compared with contrast enhanced ultrasound (CEUS) and computed tomography angiography (CTA). Seven patients (25%) suffered from arterial embolism downstream to the FLS (EVAR, n = 4; native abdominal aorta, n = 1; peripheral arteries, n = 2). WAFAS of the abdominal aorta (native or after EVAR), as indicated by the FLS, were visible by CEUS and CTA in 60% and 93.3%, respectively. Based on the so far largest cohort of patients with WAFAS, we propose a clinically useful, BFI-based sonographic sign for detection of these so far underrated arterial pathologies in the abdominal aorta and the peripheral arteries.
ARTICLE | doi:10.20944/preprints202212.0069.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: human adipose mesenchymal stem cell; human peripheral blood mononuclear cells; cytokine; immune cell frequency; C57BL/6 mouse; ICR mouse
Online: 5 December 2022 (09:01:51 CET)
Human adipose stem cell-derived extracellular vesicles (hASC-EVs) are key mediators of paracrine signaling with promising therapeutic applications. Although hASC-EVs are derived from human cells and are less immunogenic, their immunogenicity cannot be completely excluded. Here, we evaluate the immune responses of ICR and C57BL/6 mice to high doses of hASC-EVs for 10 days after injection. Lymphocyte subpopulations are analyzed using flow cytometry at 0.5, 1, 3 and 24 h post injection. In the spleen and blood of C57BL/6 mice, neutrophils sharply increased at 0.5 h and decreased at 3 h following hASC-EV treatment. We observe increased proportions of monocytes, macrophages, and natural killer cells at 3 h but returned to similar level of vehicle control at 24 h post injection in the spleen and blood of ICR mice. Although the in vivo experiments reveal different immune responses to hASC-EV treatment in C57BL/6 and ICR strains, no major changes occur in human peripheral blood mononuclear cell composition after applying hASC-EVs in vitro. In conclusion, unlike those in mice, immune responses to hASC-EVs in humans are not detectable, indicating a minimal risk of fatal side-effects from hASC-EV-based therapies.
CASE REPORT | doi:10.20944/preprints202301.0379.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: Combined Peripheral Nerve Stimulation; occipital nerve stimulation; secondary headache disor-ders; chronic post-intracranial disorder headache and case report
Online: 23 January 2023 (00:57:59 CET)
The introduction of ventricular shunts dramatically changed the outcome and quality of life of hydrocephalic patients. However, shunt surgery continues to be associated with numerous adverse events. Headache is one of the most common complications after shunt operation. It is often over a prolonged duration, the symptoms resemble migraine, and pain does not respond to medication. We propose invasive peripheral nerve stimulation as a possible solution in the treatment of patients suffering from chronic headache associated with shunted hydrocephalus. A young woman with daily holocephalic headache with diffuse pain exacerbated by lying down. Imaging revealed panventricular enlargement and possible stenosis of the aqueduct. When a ventriculoperitoneal shunt was placed, clinical symptoms resolved. Nevertheless, she gradually exacerbated after a second valve replacement due to wound infection. Imaging revealed decompressed ventricles and appropriate shunt placement. The diagnosis of chronic post-intracranial disorder headache was set. Therefore, occipital nerve stimulation was applied and considering that the patient had not a total response, bilateral parietal stimulation was added. Three months after the combined PNS she experienced total remission of headache. Combined PNS eases refractory headaches much more than occipital nerve stimulation alone and could be considered as a solution for shunted hydrocephalus associated headache.
ARTICLE | doi:10.20944/preprints202305.2005.v1
Subject: Public Health And Healthcare, Nursing Keywords: Catheters; Cost Benefit Analysis; Economic evaluation; Healthcare-associated infections; Nursing care; Peripherally Inserted Central Catheter; Peripheral Venous Catheters; Ultrasound.
Online: 29 May 2023 (09:58:33 CEST)
Background: The use of peripherally inserted central catheters and midline catheters is growing due to their potential benefits. These devices can increase patient safety and satisfaction while reducing the use of resources. As a result, many hospitals are establishing vascular access specialist teams staffed by nurses who are trained in the insertion and maintenance of these catheters. Objective: Evaluate ex-ante whether the benefits of replacing peripheral venous catheters, peripherally inserted central catheters and midline catheters with ultrasound-guided peripherally inserted central catheters and midline catheters by a vascular access specialist team outweigh their costs. Methods: Cost-benefit analysis from the perspective of the healthcare provider based on administrative data. The study estimates the reduction in resources used when replacing peripherally inserted central catheters, midline catheters and peripheral venous catheters with ultrasound-guided peripherally inserted central catheters and midlines, as well as the additional resources required for their use. Results: Each ultrasound-guided peripherally inserted central catheter replacing a peripherally inserted central catheter, results in a measurable resource reduction of approximately €31. When 3 peripheral venous catheters are replaced by an ultrasound-guided peripherally inserted central catheter, the saving is €63. Similarly, each ultrasound-guided midline catheter replacing a midline, results in a reduction of €16, while each ultrasound-guided midline catheter replacing 3 peripheral venous catheters results in a reduction of €96. Conclusion: The benefits of replacing peripheral venous catheters, peripherally inserted central catheters and midline catheters by introducing a vascular access specialist team trained in the implantation of ultrasound-guided peripherally inserted central catheters and midline catheters, outweigh its cost mainly because of the decrease in hospital stay due to the lowered risk of healthcare-associated infections. These results motivate the implementation of the service, adding to previous experience suggesting that it is also preferable from the point of view of patient safety and satisfaction.
ARTICLE | doi:10.20944/preprints202310.1753.v1
Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Convolutional Neural Net (CNN); Vision Transformer (ViT); ImageNet Models; Transfer Learning (TL); Machine Learning (ML); Deep Learning (DP); Blood Cell Classification; Peripheral Blood Cell (PBC); Blood Cell Count and Detection (BCCD)
Online: 27 October 2023 (05:16:12 CEST)
Deep Learning (DL) has made significant advances in computer vision with the advent of Vision Transformers (ViT). Unlike Convolutional Neural Networks (CNNs), ViTs use self-attention to extract both local and global features from image data, and then use residual connections to feed these features directly into a fully networked multilayer perceptron head. In hospitals, hematologists prepare peripheral blood smears (PBSs) and read them under a medical microscope to detect abnormalities in blood counts such as leukemia. However, this task is time-consuming and prone to human error. This study investigates the transfer learning process of Google ViT and ImageNet CNNs to automate the reading of PBSs. The study used two online PBS datasets, PBC and BCCD, and transferred them into balanced datasets to investigate the influence of data amount and noise immunity on both neural networks. The PBC results show that Google ViT is an excellent DL neural solution for data scarcity. The BCCD results show that Google ViT is superior to ImageNet CNNs in dealing with unclean, noisy image data because it is able to extract both global and local features and use residual connections, despite the additional time and computational overhead.
ARTICLE | doi:10.20944/preprints202112.0041.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: Vascular inflammation; Peripheral arterial disease (PAD); Chronic limb-threatening ischemia (CLTI); GHAS trial; TNF-α; hs-CRP; Neutrophil-to-lymphocyte ratio (NLR); NOX4; eNOS; VEGF-A.
Online: 3 December 2021 (09:44:42 CET)
Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analy-sis was performed by using univariate (Spearman, t-Student, X2) and multivariate (multiple lo-gistic regression) tests. Results: 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age:71.4±12.4 (79.4% male); TNF-α:10.7±4.9; hs-CRP:1.6±2.2; Neutrophil-to-lymphocyte ratio (NLR):3.5±2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hs-CRP (≥0.5) in 60.5%. Diabetic patients with high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p=0.0346). Plasma TNF-α had a negative correlation with eNOS expression (-0.5, p=0.015) and hs-CRP with VEGF-A (-0.63, p=0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p=0.037), especial-ly in DM. Cumulative mortality at 12-month was related to NLR ≥3 (p=0.019) and TNF-α ≥8.1 (p=0.048). The best cut-off point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hs-CRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suita-ble markers of mortality in CLTI. These results are novel because they connect muscle gene expres-sion and plasma information in patients with advanced PAD, deepening the search of new and ac-curate targets for this condition.
REVIEW | doi:10.20944/preprints202111.0253.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: Cell therapy; chronic limb-threating ischemia; peripheral artery disease; diabetes; atherosclerosis obliterans; thromboangiitis obliterans; personalized medicine; artificial intelligence; machine learning; genome-wide association studies; transcriptome-wide association studies; clonal hematopoiesis of indeterminate potential.
Online: 15 November 2021 (11:18:43 CET)
Stem/progenitor cell transplantation is a potential novel therapeutic strategy to induce angiogenesis in ischemic tissue, which can prevent major amputation in patients with advanced peripheral artery disease (PAD). Thus, clinicians can use cell therapies worldwide to treat PAD. However, some cell therapy studies did not report beneficial outcomes. Clinical researchers suggested that classical risk factors and comorbidities may adversely affect the efficacy of cell therapy. Some studies have indicated that the response to stem cell therapy varies among patients even in those harboring limited risk factors. This suggested the role of undetermined risk factors, including genetic alterations, somatic mutations, and clonal hematopoiesis. Personalized stem cell-based therapy can be developed by analyzing individual risk factors. These approaches must consider several clinical biomarkers and perform studies (such as genome-wide association studies (GWAS)) on disease-related genetic traits and integrate the findings with those of transcriptome-wide association studies (TWAS) and whole-genome sequencing in PAD. Additional unbiased analyses with state-of-the-art computational methods, such as machine learning-based patient stratification, are suited for predictions in clinical investigations. The integration of these complex approaches into a unified analysis procedure for the identification of responders and non-responders before stem cell therapy, which can decrease treatment expenditure, is a major challenge to increase the efficacy of therapies.
ARTICLE | doi:10.20944/preprints202311.0949.v1
Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Convolutional Neural Net (CNN); Vision Transformer (ViT); ImageNet Models; Transfer Learning (TL); Machine Learning (ML); Deep Learning (DP); Blood Cell Classification, Peripheral Blood Cell (PBC), CBAM, Naturalize
Online: 14 November 2023 (15:18:08 CET)
In this paper, we redefine the boundaries of blood cell classification, expanding from 5 to 11 distinct blood cell types using the challenging 11-class PBC dataset. This shift enables a deeper understanding of blood cell diversity, overcoming previous limitations in medical image analysis. Our approach combines state-of-the-art deep learning techniques, including pre-trained ConvNets, ViTb16 models, and custom CNN architectures. We employ transfer learning, fine-tuning, and ensemble strategies, such as CBAM and Averaging ensembles, to achieve unprecedented accuracy and interpretability. Our fully fine-tuned EfficientNetV2 B0 model sets a new standard, with a macro-average precision, recall, and F1-score of 91%, 90%, and 90%, respectively, and an average accuracy of 93%. This breakthrough underscores the transformative potential of 11-class blood cell classification for more precise medical diagnoses. Moreover, our groundbreaking "Naturalize" augmentation technique produces remarkable results. The 2K-PBC dataset generated with "Naturalize" boasts a macro-average precision, recall, and F1-score of 97%, along with an average accuracy of 96% when leveraging the fully fine-tuned EfficientNetV2 B0 model. This innovation not only elevates classification performance but also addresses data scarcity and bias in medical deep learning. Our research marks a paradigm shift in blood cell classification, enabling more nuanced and insightful medical analyses. The "Naturalize" technique’s impact extends beyond blood cell classification, emphasizing the vital role of diverse and comprehensive datasets in advancing healthcare applications through deep learning.
REVIEW | doi:10.20944/preprints201805.0303.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: glial bridge; ctgfa; Fgf signaling; MAPK signaling; shh; slit2/3; Wnt signaling; genetic compensation; glial bridge cycle; spinal cord regeneration; termination signal; central nervous system; peripheral nervous system; zebrafish
Online: 22 May 2018 (12:09:09 CEST)
Zebrafish have been found to be the premier model organism in biological and biomedical research, specifically offering many advantages in developmental biology and genetics. This unique aquatic species has been found to have the capacity to regenerate their spinal cord after injury. However, the complete molecular and cellular mechanisms behind glial bridge formation in the central and peripheral nervous systems upon glial cell injury remains unclear. This review paper focuses on the molecular mechanisms and cellular processes that underlie spinal cord regeneration in four initial phases: proliferation and initial migration; migration and differentiation; glial bridge formation; and remodeling. We propose that within these four phases the cellular mechanisms that underlie spinal cord regeneration each express a terminating signal that aborts one step of the process and initiates the next. Specifically, future studies would be devoted to investigate transmitting signals in the spinal cord injury micro-environment in hope to contribute to the understanding of underlying cellular mechanisms by connecting each process of spinal cord regeneration in zebrafish.
ARTICLE | doi:10.20944/preprints202109.0031.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: spinal cord stimulation (SCS); peripheral nerve field stimulation (PNfS); SubQ-stimulation; hybrid stimulation; multidimensional pain assessment; pain mapping; pain software; persistent spinal pain syndrome - T2 (PSPS-T2); failed back surgery syndrome; failed spinal cord stimulation syndrome (FSCSS); salvage therapy; salvage algorithm
Online: 1 September 2021 (18:16:10 CEST)
While Spinal Cord Stimulation (SCS) provides satisfaction to almost 2/3 of Persistent Spinal Pain Syndrome-Type 2 (PSPS-T2) patients implanted for refractory chronic back and/or leg pain when not adequately addressed the back pain component, leaves patients in a therapeutic cul-de-sac. Peripheral Nerve field Stimulation (PNfS) has shown interesting results addressing back pain in the same population. Far from placing these two techniques in opposition, we suggest that these approaches could be combined to better treat PSPS-T2 patients. We designed a RCT (CUMPNS), with a 12-month follow-up, to assess the potential added value of PNfS, as a salvage therapy, in PSPS-T2 patients experiencing a “Failed SCS Syndrome” in the back pain component. Fourteen patients were included in this study and randomized into 2 groups (“SCS + PNfS” group/n=6 vs “SCS only” group/n=8). The primary objective of the study was to compare the percentage of back pain surface decrease after 3 months, using a computerized interface to obtain quantitative pain mappings, combined with multi-dimensional SCS outcomes. Back pain surface decreased significantly greater for the ”SCS+PNfS” group (80.2% ± 21.3%) compared to the “SCS only” group (13.2% ± 94.8%) (p=0.012), highlighting the clinical interest of SCS+PNfS, in cases where SCS fails to address back pain.
REVIEW | doi:10.20944/preprints202008.0696.v1
Subject: Biology And Life Sciences, Virology Keywords: COVID-19; SARS-CoV-2; neurotropic virus; Blood-nervous system barrier; bloodcerebrospinal-fluid-barrier; blood-brain-barrier; blood-nerve barrier; olfactory route; Lymphatic brain drainage route; Peripheral nerve or neuronal retrograde route; Macrophage/monocytes cargo route; Double membrane vesicles cargo route; nicotinic acetylcholine receptor
Online: 31 August 2020 (04:43:34 CEST)
Without protective and/or therapeutic agents the SARS-CoV-2 infection known as coronavirus disease 2019 (COVID-19) is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body crosstalk between organs. The majority of SARS-CoV-2 infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial-barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.