Assessing Rat Diaphragm Motor Unit Connectivity Outcome Measures as Quantitative Biomarkers of Phrenic Motor Neuron Degeneration and Compensation.

Loss of ventilatory muscle function is a consequence of motor neuron injury and neurodegeneration (e.g., cervical spinal cord injury and amyotrophic lateral sclerosis, respectively). Phrenic motor neurons are the final link between the central nervous system and muscle, and their respective motor units (groups of muscle fibers innervated by a single motor neuron) represent the smallest functional unit of the neuromuscular ventilatory system. Compound muscle action potential (CMAP), single motor unit potential (SMUP), and motor unit number estimation (MUNE) are established electrophysiological approaches that enable the longitudinal assessment of motor unit integrity in animal models over time but have mostly been applied to limb muscles. Therefore, the objectives of this study are to describe an approach in preclinical rodent studies that can be used longitudinally to quantify the phrenic MUNE, motor unit size (represented as SMUP), and CMAP, and then to demonstrate the utility of these approaches in a motor neuron loss model. Sensitive, objective, and translationally relevant biomarkers for neuronal injury, degeneration, and regeneration in motor neuron injury and diseases can significantly aid and accelerate experimental research discoveries to clinical testing.

Unraveling Dysregulated Cell Signaling Pathways, Genetic and Epigenetic Mysteries of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent and burdensome neurodegenerative disorder that has been extensively researched to understand its complex etiology, diagnosis, and treatment. The interplay between genetic and environmental factors in PD makes its pathophysiology difficult to comprehend, emphasizing the need for further investigation into genetic and epigenetic markers involved in the disease. Early diagnosis is crucial for optimal management of the disease, and the development of novel diagnostic biomarkers is ongoing. Although many efforts have been made in the field of recognition and interpretation of the mechanisms involved in the pathophysiology of the disease, the current knowledge about PD is just the tip of the iceberg. By scrutinizing genetic and epigenetic patterns underlying PD, new avenues can be opened for dissecting the pathology of the disorder, leading to more precise and efficient diagnostic and therapeutic approaches. This review emphasizes the importance of studying dysregulated cell signaling pathways and molecular processes associated with genes and epigenetic alterations in understanding PD, paving the way for the development of novel therapeutic strategies to combat this devastating disease.

Stimulated Single Fiber Electromyography (SFEMG) for Assessing Neuromuscular Junction Transmission in Rodent Models.

As the final connection between the nervous system and muscle, transmission at the neuromuscular junction (NMJ) is crucial for normal motor function. Single fiber electromyography (SFEMG) is a clinically relevant and sensitive technique that measures single muscle fiber action potential responses during voluntary contractions or nerve stimulations to assess NMJ transmission. The assessment and quantification of NMJ transmission involves two parameters: jitter and blocking. Jitter refers to the variability in timing (latency) between consecutive single-fiber action potentials (SFAPs). Blocking signifies the failure of NMJ transmission to initiate an SFAP response. Although SFEMG is a well-established and sensitive test in clinical settings, its application in preclinical research has been relatively infrequent. This report outlines the steps and criteria employed in performing stimulated SFEMG to quantify jitter and blocking in rodent models. This technique can be used in preclinical and clinical studies to gain insights into NMJ function in the context of health, aging, and disease.

YTHDF2 governs muscle size through a targeted modulation of proteostasis.

The regulation of proteostasis is fundamental for maintenance of muscle mass and function. Activation of the TGF-ß pathway drives wasting and premature aging by favoring the proteasomal degradation of structural muscle proteins. Yet, how this critical post-translational mechanism is kept in check to preserve muscle health remains unclear. Here, we reveal the molecular link between the post-transcriptional regulation of m6A-modified mRNA and the modulation of SMAD-dependent TGF-ß signaling. We show that the m6A-binding protein YTHDF2 is essential to determining postnatal muscle size. Indeed, muscle-specific genetic deletion of YTHDF2 impairs skeletal muscle growth and abrogates the response to hypertrophic stimuli. We report that YTHDF2 controls the mRNA stability of the ubiquitin ligase ASB2 with consequences on anti-growth gene program activation through SMAD3. Our study identifies a post-transcriptional to post-translational mechanism for the coordination of gene expression in muscle.

Acute Ischemic Stroke in a Patient with Multiple Sclerosis after Initiating Teriflunomide Treatment: A Challenging Case.

Multiple sclerosis is an autoimmune disease of the central nervous system, during which vascular events, including atherosclerosis, are more common and progress faster. Teriflunomide (TFN) is an oral drug that studies have indicated has low side effects alongside high efficiency. In this article, a middle-aged woman with multiple sclerosis was introduced, whose medication was changed to TFN. Thirty-five days later, she presented with focal neurologic symptoms, and investigations reported a lacunar infarction. Having excluded potential causes of acute ischemic stroke, such as vascular and rheumatologic factors, the only identifiable factor was the introduction of a new medication. The process of conclusively attributing TFN as the causative agent requires further clarification in future studies.

Safety and efficacy of levetiracetam and carbamazepine monotherapy in the management of pediatric focal epilepsy: a randomized clinical trial.

Due to the limited number of studies in children with focal epilepsy and the importance of choosing the most suitable drug to control seizures in children, the administration of the most effective medication with the most negligible adverse events is vital. This study aimed to evaluate the effectiveness and adverse events of carbamazepine vs. levetiracetam monotherapy in children with focal seizures. A monocentric, randomized, controlled, double-blind, parallel-group clinical trial was designed. This study was approved by the Iranian Registry of Clinical Trials (registration number: IRCT20170216032603N2) on June 19, 2020, and conducted at the neurology department of Imam Ali Hospital, Karaj, Iran, from February 2020 to March 2021. This study assessed 120 patients with recently diagnosed focal seizures aged 2 to 14. Patients were randomly divided into two groups, who received carbamazepine (CBZ) 15 to 20 mg/kg and levetiracetam (LEV) 20 to 40 mg/kg daily, respectively. Patients were evaluated for improvement and complications at weeks 4, 12, and 24. Out of 120 patients included in the study, six patients were excluded due to various complications of CBZ. The mean number of seizures at the end of the fourth, twelfth, and twenty-fourth weeks were 1.09 ± 0.75, 0.62 ± 0.27, and 0.39 ± 0.12 in the carbamazepine group and 1.11 ± 0.63, 0.52 ± 0.21, and 0.37 ± 0.11 in the LEV group, respectively (P > 0.05). Similarly, the number of seizure-free patients was 34, 44, and 48 in the CBZ group compared to 41, 50, and 54 in the LEV group, respectively (P > 0.05). On the other hand, the frequency of somnolence, dermatologic complications, and agitation was considerably higher in the CBZ group (P < 0.05). Although both medicines were equally effective in seizure control, CBZ was associated with considerably more adverse events and less patient compliance. Physicians should be aware of this difference to prevent unwanted consequences.

DNA Methylation in Cancer: Epigenetic View of Dietary and Lifestyle Factors.

Background: Alterations in DNA methylation play an important role in cancer development and progression. Dietary nutrients and lifestyle behaviors can influence DNA methylation patterns and thereby modulate cancer risk. Introduction: To comprehensively review available evidence on how dietary and lifestyle factors impact DNA methylation and contribute to carcinogenesis through epigenetic mechanisms. Materials and methods: A literature search was conducted using PubMed to identify relevant studies published between 2005 and 2022 that examined relationships between dietary/lifestyle factors and DNA methylation in cancer. Studies investigating the effects of dietary components (eg, micronutrients, phytochemicals), physical activity, smoking, and obesity on global and gene-specific DNA methylation changes in animal and human cancer models were included. Data on specific dietary/lifestyle exposures, cancer types, DNA methylation targets and underlying mechanisms were extracted. Results: Multiple dietary and lifestyle factors were found to influence DNA methylation patterns through effects on DNA methyltransferase activity, methyl donor availability, and generation of oxidative stress. Altered methylation of specific genes regulating cell proliferation, apoptosis, and inflammation were linked to cancer development and progression. Conclusion: Dietary and lifestyle interventions aimed at modulating DNA methylation have potential for both cancer prevention and treatment through epigenetic mechanisms. Further research is needed to identify actionable targets for nutrition and lifestyle-based epigenetic therapies.

Neurological Involvements in COVID-19: A hospital-based study.

Objectives: The SARS-CoV-2 pandemic is the most challenging crisis in the contemporary world. Besides severe pulmonary involvement, the disease also has several extrapulmonary manifestations, and new signs and symptoms are associated with it every dayThe present study aimed to inquire about the frequency of neurological manifestations and risk factors of COVID-19. Materials & Methods: This retrospective, descriptive study included patients with neurological involvement admitted to the Alborz University of Medical Sciences academic hospitals from March 2020 to July 2020 with confirmed COVID-19 infection. The data included in the analysis were the patient's demographic information, underlying diseases, neurological manifestations, and laboratory findings. Results: The study included ninety-five patients with a mean age of fifty-nine. Neurological symptoms and signs were observed in 91.6% and 10.5% of the patients, respectively. The most frequently associated neurological symptoms of COVID-19 were fatigue (49.5%), headache (47.4%), and dizziness (45.3%). Furthermore, the most common neurological involvements included gait disorders (6.3%), cerebellar dysfunction (4.2%), and cerebrovascular accidents (3.15%). Positive troponin was shown to be the strongest predictor of neurological signs (OR=21, P=0.017), followed by WBC≥15,000 (OR = 20.75, P=0.018) and a history of respiratory disease (OR=7.42, P=0.007). Conclusion: Neurological symptoms were observed in more than 91% of the patients, while neurological signs were present in 10.5% of the COVID-19 patients. Additionally, positive troponin, WBC≥15,000, and a history of respiratory disease were the strongest predictors of neurological signs.

The role of neurotransmitters in glioblastoma multiforme-associated seizures.

GBM, or glioblastoma multiforme, is a brain tumor that poses a great threat to both children and adults, being the primary cause of death related to brain tumors. GBM is often associated with epilepsy, which can be debilitating. Seizures and the development of epilepsy are the primary symptoms that have a severe impact on the quality of life for GBM patients. It is increasingly apparent that the nervous system plays an essential role in the tumor microenvironment for all cancer types, including GBM. In recent years, there has been a growing understanding of how neurotransmitters control the progression of gliomas. Evidence suggests that neurotransmitters and neuromodulators found in the tumor microenvironment play crucial roles in the excitability, proliferation, quiescence, and differentiation of neurons, glial cells, and neural stem cells. The involvement of neurotransmitters appears to play a significant role in various stages of GBM. In this review, the focus is on presenting updated knowledge and emerging ideas regarding the interplay between neurotransmitters and neuromodulators, such as glutamate, GABA, norepinephrine, dopamine, serotonin, adenosine, and their relationship with GBM and the seizures induced by this condition. The review aims to explore the current understanding and provide new insights into the complex interactions between these neurotransmitters and neuromodulators in the context of GBM-related seizures.

Efficacy of fibroblast transplantation in the healing of cutaneous leishmaniasis scar: A case report.

Autologous fibroblast transplantation has been proven to be a promising method in wound healing with no side effects. This is the first study aimed to determine the efficacy and safety of autologous fibroblast cell injection to the atrophic scar caused by cutaneous leishmaniasis as an endemic disease in many middle-eastern countries. It causes chronic skin lesions and permanently disfiguring scars. Autologous fibroblasts were obtained from the patient's ear skin and were injected intradermally twice at 2-month intervals. Outcomes were measured using ultrasonography, VisioFace, and Cutometer. No adverse reaction was observed. The results showed improvements in epidermal thickness and density, melanin level, and skin lightening. Moreover, the skin elasticity in the scar area increased after the second transplantation. No improvement was observed in dermal thickness and density. A longer follow-up with more patients is recommended to investigate the effectiveness of fibroblast transplantation better.

Bone mineral density status in patients with recent-onset rheumatoid arthritis.

Background: Osteoporosis is a sizable comorbidity complication in Rheumatoid Arthritis (RA) sufferers. In the current study, the prevalence of osteopenia and osteoporosis in active RA sufferers and the association of disease-related factors of osteoporosis and reduced bone mineral density (BMD) have been examined. Methods: In this cross-sectional study, 300 new-onset symptoms (less than one year) RA patients without a history of glucocorticoids or DMARDs were selected. Biochemical blood measurements and BMD status were performed with dual-energy X-ray absorptiometry. According to the T-scores of the patients, they were divided into three groups: osteoporosis<-2.5, -2.5 < osteopenia <-1, and - 1 < normal. Also, the MDHAQ questionnaire, DAS-28, and FRAX criteria were calculated for all patients. Multivariate logistic regression was used to determine the associated factors of osteoporosis and osteopenia. Results: The Prevalence of osteoporosis and osteopenia was 27% (95%CI:22-32) and 45% (95%CI:39-51), respectively. The multivariate regression analysis showed that age could play a role as an associated factor for spine/hip Osteoporosis and Osteopenia. The female gender is also a predictor of Spine osteopenia Patients with Total hip Osteoporosis were more likely to have higher DAS-28 (OR 1.86, CI 1.16-3.14) and positive CRP (OR 11.42, CI 2.65-63.26). Conclusion: recent-onset RA patients are at risk for osteoporosis and its complications, regardless of using glucocorticoids or DMARDs. Demographic factors (e.g. age and female gender), patients' MDHAQ scores, and disease-related factors(e.g., DAS-28, positive CRP were associated with reduced BMD levels. Therefore, it is recommended that clinicians investigate early BMD measurements to have a reasonable judgment for further interventions. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01200-w.

Salivary levels of disease-related biomarkers in the early stages of Parkinson's and Alzheimer's disease: A cross-sectional study.

Introduction: Finding a non-invasive and repeatable tool has been recommended to make an accurate diagnosis of Alzheimer's disease (AD) and Parkinson's disease (PD). Methods: 70 volunteers participated in three groups: 24 with mild dementia of AD, 24 in the first and second stages of PD, and 22 healthy controls. After valuing the scores of cognitive tests, the salivary levels of phosphorylated tau (p-tau), total alpha-synuclein (α-syn), and beta-amyloid 1-42 (Aß) proteins have been evaluated. Finally, the cutoff points, receiver operating characteristic (ROC), sensitivity, and specificity have been calculated to find accurate and detectable biomarkers. Results: Findings showed that the salivary level of Aß was higher in both PD (p < 0.01) and AD (p < 0.001) patients than in controls. Moreover, the level of α-syn in both PD and AD patients was similarly lower than in controls (p < 0.05). However, the level of p-tau was only higher in the AD group than in the control (p < 0.01). Salivary Aß 1-42 level at a 60.3 pg/ml cutoff point revealed an excellent performance for diagnosing AD (AUC: 0.81). Conclusion: Evaluation of p-tau, α-syn, and Aß 1-42 levels in the saliva of AD and PD patients could help the early diagnosis. The p-tau level might be valuable for differentiation between AD and PD. Therefore, these hopeful investigations could be done to reduce the usage of invasive diagnostic methods, which alone is a success in alleviating the suffering of AD and PD patients. Moreover, introducing accurate salivary biomarkers according to the pathophysiology of AD and PD should be encouraged.

Masitinib: The promising actor in the next season of the Amyotrophic Lateral Sclerosis treatment series.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.

Fistulectomy and primary sphincteroplasty in complex anal fistula treatment: a hospital-based long-term follow-up study.

BACKGROUND: Currently, there is no agreement on the best treatment for complex anal fistulas with the least recurrence and lowest complication rate. The aim of this study was to evaluate the long-term recurrence and incontinence after fistulectomy and primary sphincteroplasty (FIPS) in a group of patients with complex perianal fistula. METHODS: This prospective observational study was done at the colorectal ward of Taleghani Hospital of Tehran from January 2010 to December 2020. Patients with anal fistula who underwent FIPS were studied. After surgery, patients were evaluated regularly by a colorectal surgeon for fistula recurrence and incontinence. Recurrence was described as a new fistula tract formation after the initial cure and failure of healing in the operation site or any purulent discharge from the fistula tract and openings. In addition, the patient's continence was assessed based on the Wexner score. RESULTS: There were 335 patients (66 men and 269 women, mean age 42.74 ± 12.44 years), 191 of them with low fistula and 144 with high fistula. Thirteen patients (3.90%) experienced recurrence (all had a low fistula). Thirty-nine patients (11.64%), 19 patients with high and 20 patients with low fistula, had a Wexner score ≥ 3 during the follow-up. Fifteen patients were lost to follow-up. Male patients (OR = 2.67, 95% CI 0.84, 8.45, p = 0.094, adjusted OR = 4.41, 95% CI 1.05, 18.48, p = 0.042), patients with low fistula (p = 0.001), and recurrent cases had a significantly higher rate of recurrence (OR = 10.38, 95% CI 3.24-33.20 p ≤ 0.001, adjusted OR = 23.36, 95% CI 4.35-125.39, p ≤ 0.001). A significant correlation between body mass index > 35 kg/m2 and incontinence was found (OR = 4.40, 95% CI 1.35, 14.33, p = 0.014). CONCLUSIONS: In the present study, an acceptable healing rate and a low percentage of complications following FIPS were seen in patients with complex anal fistula. Randomized clinical trials with appropriate follow-up duration and sample size comparing different surgical methods in these patients are needed to confirm these results.

Cerebral venous sinus thrombosis following intracerebral hemorrhage after COVID-19 AstraZeneca vaccination: A case report.

The patient was a 55-year-old female patient who presented with sudden onset of left hemiplegia, facial hemiparesis, and hypoesthesia. She has received her first dose of the AstraZeneca COVID-19 vaccine. This case indicates that vaccination may raise the hypercoagulable state even in a condition of post-ICH and anticoagulant prophylaxis.

IgG4-related disease associated with the primary manifestation of recurrent cerebral venous thrombosis: A rare case report.

Nervous system involvement in IgG4-related systemic disease (IgG4-RD) is rarely reported and manifests as hypertrophic pachymeningitis and hypophysitis. In this report, a 33-year-old woman with neurological manifestations was diagnosed with IgG4-RD by biopsy. The patient showed improvement in symptoms after treatment.

Heart Failure Status among Acute Ischemic Stroke Patients: A Hospital-Based Study.

Background: Since heart failure (HF) and ischemic stroke have common risk factors, their concurrent occurrence is likely. Strokes in HF patients could be life-threatening and lead to severe disabilities, longer hospitalization time, and mortality. The present study aims to investigate the prevalence of HF and its severity based on ejection fraction (EF) in patients with acute ischemic stroke. Methods: The present cross-sectional study included acute ischemic stroke patients admitted to Shahid Rajaei hospital in Karaj in 2020-2021. The diagnosis of HF was based on transthoracic echocardiography within 48 hours of symptom onset, and HF was classified into two groups: 41-49% as mildly reduced EF (HFmrEF) and ≤40% as reduced EF (HFrEF). Patients who did not complete cardiac studies were excluded. Results: 257 acute ischemic stroke patients (62.6% male) were included. Among stroke patients, the prevalence of HF, including HFrEF and HFmrEF, was 30.0% (95% CI: 21.4-38.6). HFmrEF and HFrEF was diagnosed in 32 (12.5%) and 45 (17.5%) patients, respectively. HF was significantly associated with older age, hypertension, past myocardial infarction (MI), and arrhythmia. A history of previous MI significantly increased the odds of heart failure (OR: 3.25, 95% CI: 1.82-5.81). Conclusion: There is a high prevalence of HF among acute ischemic stroke patients. Older patients with a history of hypertension and previous MI are at higher risk. Since patients with HF have a higher mortality and morbidity rate after experiencing an ischemic stroke, close cooperation between the neurology and cardiology specialists for providing advanced care for survivors is required.

Modulation of autophagy by melatonin via sirtuins in stroke: From mechanisms to therapies.

Sirtuins perform an important effect on the neural cell fate following stroke. Several mechanisms that have been correlated with stroke are oxidative stress, apoptosis, necrosis and autophagy. Autophagy is usually regarded as unitary of the neural cell survival mechanisms. Recently, the importance of the sirtuins effect on autophagy by antioxidant agents for stroke treatment mentioned in various studies. One of these agents is melatonin. Melatonin can modulate autophagy by changing on sirtuin pathways. Melatonin and its metabolites adjust various sirtuins pathways related to apoptosis, proliferation, metastases, autophagy and inflammation in case of stroke. In this review, we will discuss about the modulation of autophagy by melatonin via sirtuins in stroke.

Acute polyneuropathy as the main manifestation of primary Sjogren's syndrome: A case report.

Sjogren's syndrome is an inflammatory disease affecting many systems. We report a Sjogren case with the presenting feature of an acute motor-predominant polyneuropathy resembling Guillain-Barre syndrome. Upon further investigation, it was found that the patient had sicca symptoms for months. Scrupulous history should be taken to prevent a missed diagnosis.

Multiple Complex Complications After Redo Bariatric Surgery (Infrequent Complication: Fistula Between the Splenic Artery and the Remnant of the Stomach): A Case Report.

With the epidemic prevalence of obesity in today's society, bariatric surgery has become very popular in treating severe obesity. Although the complications of this surgery have decreased with the advancement of medicine and post-treatment care, there are still complications that can lead to death if neglected. In this case report, we present a 44-year-old patient who underwent redo bariatric surgery. She was discharged from the hospital in good general condition but returned a few days later with a major complaint of abdominal pain and sudden bleeding from the upper gastrointestinal tract. After performing CT and endoscopy and considering the results, the patient underwent laparotomy, which showed a fistula between the splenic artery and the remnant of the stomach. After surgery and after the recovery period, the patient was discharged from the hospital. In this case report, we describe for the first time an uncommon and unique complication following redo bariatric surgery. We suggest that a fistula between the splenic artery and the remnant of the stomach should be considered in patients with abdominal pain and upper gastrointestinal bleeding who underwent redo bariatric surgery.