Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis:a narrative review

Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.

Two-stage corrective operation for the treatment of pes cavovarus in patients with spina bifida

BACKGROUND Pes cavovarus has an estimated incidence of 8%-17%in patients with spina bifida(SB).The majority of the current literature on surgical treatment of cavovarus feet in children and adolescents includes a variety of diagnoses.There are currently no case series describing a treatment algorithm for deformity correction in this specific patient population.The authors of this study present the results of a retrospective case series performed to assess the radiographic outcomes of two-stage corrective surgery in patients with SB.METHODS Retrospective chart review was performed on patients with SB with a diagnosis of pes cavovarus at a freestanding children’s hospital who underwent surgical correction of the deformity.Patients were excluded for lack of two-stage corrective operation,nonambulatory status,lack of at least six months follow-up,and age>18 years at the time of surgery.This resulted in a cohort of 19 patients.Radiographic analysis was performed on 11 feet that had a complete series of preoperative and postoperative weightbearing X-rays.Preoperative and postoperative radiographic outcome measurements were compared using a two-sample t-test.RESULTS Significant changes between the preoperative and postoperative measurements were seen in Meary’s angle,the anteroposterior talo-first metatarsal(AP TMT1)angle,and the talonavicular coverage.Mean values of Meary’s angle were 17.9±13.1 preoperatively and 4.7±10.3 postoperatively(P=0.016).Mean AP TMT1 angle was 20.6±15.1 preoperatively and 9.3±5.5 postoperatively(P=0.011).Mean talonavicular coverage values were-10.3±9.6 preoperatively and-3.8±10.1 postoperatively(P=0.025).CONCLUSION The two-stage corrective procedure demonstrated efficacy in correcting cavovarus deformity in patients with SB.Providers should strongly consider employing the staged surgical algorithm presented in this manuscript for management of these patients.

Nature’s Pharmacy under Siege: Investigating Antibiotic Resistance Pattern in Endophytic Bacteria of Medicinal Plants

Antibiotic resistance poses a significant global health threat, necessitating a thorough understanding of its prevalence in various ecological contexts. Medicinal plants, renowned for their therapeutic properties, host endophytic bacteria that produce bioactive compounds. Understanding antibiotic resistance dynamics in these bacteria is vital for human health and antibiotic efficacy preservation. In this study, we investigated antibiotic resistance profiles in endophytic bacteria from five medicinal plants: Thankuni, Neem, Aparajita, Joba, and Snake plant. We isolated and characterized 113 endophytic bacteria, with varying resistance patterns observed against multiple antibiotics. Notably, 53 strains were multidrug-resistant (MDR), with 14 exhibiting extensive drug resistance (XDR). Thankuni-associated bacteria displayed 44% MDR and 11% XDR, while Neem-associated bacteria showed higher resistance (60% MDR, 13% XDR). Aparajita-associated bacteria had lower resistance (22% MDR, 6% XDR), whereas Joba-associated bacteria exhibited substantial resistance (54% MDR, 14% XDR). Snake plant-associated bacteria showed 7% MDR and 4% XDR. Genus-specific distribution revealed Bacillus (47%), Staphylococcus (21%), and Klebsiella (11%) as major contributors to MDR. Our findings highlight diverse drug resistance patterns among plant-associated bacteria and underscore the complexity of antibiotic resistance dynamics in diverse plant environments. Identification of XDR strains emphasizes the severity of the antibiotic resistance problem, warranting further investigation into contributing factors.

Quantifying Operational Impacts of Variations in Work Zone Setups, Traffic Demand, and Traffic Composition: A Case Study

The presence of work zones due to pavement repair and rehabilitation is very common in highway facilities. Lane closures associated with work zones result in capacity reduction, which, in turn, often leads to increased congestion at such locations. This paper documents findings from a study that investigated the performance of freeway facilities in the presence of work zones under various Temporary Traffic Control (TTC) and lane closure scenarios while taking under consideration traffic composition and driving behaviors. The study site was an approximately 10-mile freeway segment of Interstate 65 (I-65) located in Birmingham, AL. The testbed was coded in PTV VISSIM, a microscopic simulation analysis platform, for: 1) baseline conditions (i.e., no work zone presence) and 2) work zone conditions with single lane closure (i.e., 3-to-2 lane closure). Work zone scenarios were coded for two TTC strategies, namely, early merge and late merge control and for three different positions of the lane closure (i.e., left, right, and center lane closures). The length of the work zones varied from 1000 to 2000, and 3000 ft. Sensitivity analysis was performed to document the operational impacts of varying heavy vehicle percentages, changes in drivers’ aggressiveness, and projected traffic demand changes. The impacts were quantified using linked-based measures of effectiveness (MOEs) such as travel time, and travel time index. The study results show that there is no significant change in travel time index due to the variation of work zone length across the study corridor. Under similar traffic control and demand conditions, a center lane closure consistently results in significantly higher travel time index than a left or right lane closure and should be avoided. Consideration of operational impacts of changes in truck percentage indicates that the corridor can absorb an increase in truck percentage from 10% to 15%, while performance rapidly deteriorates when a higher percentage of trucks is present in the traffic stream. The study findings can be used to guide transportation agencies in their future efforts to develop strategic lane closure plans that minimize congestion.

Quantifying the Impact of Transportation Network Companies on Urban Congestion in a Medium Sized City

In the recent years,TNCs(transportation network companies)and on-demand ridesharing services have grown rapidly.Given conflicting reports on TNC impacts,a need exists to study mode choice shifts in the presence of TNC services and their effects on urban congestion.Using Birmingham,AL(Alabama)as a case study,this paper showcases the feasibility of modeling TNC services using the MATSim(Multi-Agent Transport Simulation)platform,and evaluating the impact of such services on traffic operations.Data used for the study were gathered from Uber drivers and riders through surveys,as well as the US Census.The results indicate that when 200,400,and 800 TNC vehicles are added to the network,the VKT(vehicle kilometers traveled)increase by 22%,23.6%,and 23.2%,respectively,compared to the baseline scenario(no TNC service).Analysis of hourly average speeds,hourly average travel times,and hourly volumes along study corridors further indicate that TNC services increase traffic congestion,in particular,during the AM/PM peak periods.Moreover,the study shows that the optimal TNC fleet size for the Birmingham region is 400 to 500 active TNC vehicles per day.Such fleet size minimizes idle time and the number of TNC vehicles hovering,which have adverse impacts on TNC drivers,and the environment while ensuring TNC service availability and reasonable waiting times for TNC customers.

Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis.To provide clinical practice recommendations on the immune function in sepsis,an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed.Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed,Web of Science,and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire.Then,the Delphi method was used to form consensus opinions,and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions.This consensus achieved satisfactory results through two rounds of questionnaire survey,with 2 statements rated as perfect consistency,13 as very good consistency,and 9 as good consistency.After summarizing the results,a total of 14 strong recommended opinions,8 weak recommended opinions and 2 non-recommended opinions were produced.Finally,a face-to-face discussion of the consensus opinions was performed through an online meeting,and all judges unanimously agreed on the content of this consensus.In summary,this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Rising tide: The global surge of type 2 diabetes in children and adolescents demands action now

Childhood-onset obesity has emerged as a major public healthcare challenge across the globe,fueled by an obesogenic environment and influenced by both genetic and epigenetic predispositions.This has led to an exponential rise in the incidence of type 2 diabetes mellitus in children and adolescents.The looming wave of diabetes-related complications in early adulthood is anticipated to strain the healthcare budgets in most countries.Unless there is a collective global effort to curb the devastation caused by the situation,the impact is poised to be pro-found.A multifaceted research effort,governmental legislation,and effective social action are crucial in attaining this goal.This article delves into the current epidemiological landscape,explores evidence concerning potential risks and consequences,delves into the pathobiology of childhood obesity,and discusses the latest evidence-based management strategies for diabesity.

Autophagy and mitophagy as potential therapeutic targets in diabetic heart condition:Harnessing the power of nanotheranostics

Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition(DHC),which encompasses a complex range of cardiovascular issues linked to diabetes and associated cardiomyopathies.Despite significant progress in reducing mortality rates from cardiovascular diseases(CVDs),heart failure remains a major cause of increased morbidity among diabetic patients.These cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components,and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and treatment.While a variety of conventional diagnostic and therapeutic strategies are available,DHC continues to present a significant challenge.Point-of-care diagnostics,supported by nanobiosensing techniques,offer a promising alternative for these complex scenarios.Although conventional medications have been widely used in DHC patients,they raise several concerns regarding various physiological aspects.Modern medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC,offering a promising approach to deliver drugs beyond the limitations of traditional therapies.This article aims to explore the potential connections between autophagy,mitophagy and DHC,while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.

Use of Dental Health Services within the Past Year among Adults at Risk of Diabetes in the Alabama Black Belt

Objective: We evaluated the use of dental health services within the past year among adults at risk of diabetes in the Alabama Black Belt. Methods: Data for this cross-sectional study was collected in 2005-2006 through the Flying Sparks project. In addition to descriptive statistics and univariate analysis (Chi-square), we used multiple logistic regression analysis to examine the association between dental care use and diabetic status. Results: 1355 individuals responded the survey (mean age 51 years). 67.9% were females and 89.5% African-Americans. 16.7% reported history of diabetes. Overall, 54.5% of individuals had visited a dentist within the past year. Adults with diabetes were less likely than those without diabetes to have seen a dentist (13.4% vs 86.6%, p < 0.01). Females were more likely to visit a dentist in the past year (adjusted OR = 1.4, 95% CI 1.11-1.90) than males. African-Americans were less likely than whites to have seen a dentist (adjusted OR = 0.6, 95% CI 0.43-0.97). Lower levels of education and household income were associated with a greater likelihood of not seeing a dentist in the previous year. After controlling for gender, health insurance, race, education, report of limited community health services, routine medical check-up within past year, and annual household income, individuals with diabetes were significantly less likely than those without diabetes to have seen a dentist within the preceding year (OR = 0.6, 95% CI 0.43-0.84). Conclusions: Individuals with history of diabetes in the Alabama Black Belt should be encouraged to have annual dental visits as part of a comprehensive diabetes care plan.

Conversion of One- to Two-Way Streets in Birmingham, Alabama

This paper summarizes the approach, findings and evaluation methodology for a study that investigated the feasibility and potential impacts of street conversion options on traffic operations in downtown Birmingham, Alabama. Of particular interest were issues related to conversion of grid systems from one-way to two-way operations. Recommendations on the most promising design and control configurations for implementation are also provided. A literature review was performed that threw light on the issues and challenges associated with implementation of street conversions, and the available best practices. A comprehensive traffic impact analysis that ensued employed the SYNCHRO computer simulation model to represent current and future operations so as to assess the implications of two-way conversions at and around the test sites. Detailed realistic two-way operations scenarios were developed that considered geometric and right-of-way restrictions, the location of land uses that generate and/or attract vehicular and pedestrian traffic, connectivity with the street grid, and accessibility to nearby freeway facilities, as well as practical concerns.

Study of tree shrew biology and models: A booming and prosperous field for biomedical research

The tree shrew(Tupaia belangeri)has long been proposed as a suitable alternative to non-human primates(NHPs)in biomedical and laboratory research due to its close evolutionary relationship with primates.In recent years,significant advances have facilitated tree shrew studies,including the determination of the tree shrew genome,genetic manipulation using spermatogonial stem cells,viral vector-mediated gene delivery,and mapping of the tree shrew brain atlas.However,the limited availability of tree shrews globally remains a substantial challenge in the field.Additionally,determining the key questions best answered using tree shrews constitutes another difficulty.Tree shrew models have historically been used to study hepatitis B virus(HBV)and hepatitis C virus(HCV)infection,myopia,and psychosocial stress-induced depression,with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases.Despite these efforts,the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research.This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model.We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies.The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models,meeting the increasing demands of life science and biomedical research.

Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease （NAFLD） is an increasingly recognized cause of liver-related morbidity and mortality. It can develop secondary to numerous causes but a great majority of NAFLD cases occur in patients who are obese or present with other components of metabolic syndrome （hypertension, dyslipidemia, diabetes）. This is called primary NAFLD and insulin resistance plays a key role in its pathogenesis. Obesity is characterized by expanded adipose tissue, which is under a state of chronic inflammation. This disturbs the normal storage and endocrine functions of adipose tissue. In obesity, the secretome （adipokines, oytokines, free fatty acids and other lipid moieties） of fatty tissue is amplified, which through its autocrine, paracrine actions in fat tissue and systemic effects especially in the liver leads to an altered metabolic state with insulin resistance （IR）. IR leads to hyperglycemia and reactive hyperinsulinemia, which stimulates lipid-accumulating processes and impairs hepatic lipid metabolism. IR enhances free fatty acid delivery to liver from the adipose tissue storage due to uninhibited lipolysis. These changes result in hepatic abnormal fat accumulation, which may initiate the hepatic IR and further aggravate the altered metabolic state of whole body. Hepatic steatosis can also be explained by the fact that there is enhanced dietary fat delivery and physical inactivity. IR and NAFLD are also seen in various lipodystrophic states in contrary to popular belief that these problems only occur due to excessive adiposity in obesity. Hence, altered physiology of adipose tissue is central to development of IR, metabolic syndrome and NAFLD.

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

Mitochondrial dysfunction is known to be a contributing factor to a number of diseases including chronic alcohol induced liver injury. While there is a detailed understanding of the metabolic pathways and proteins of the liver mitochondrion, little is known regarding how changes in the mitochondrial proteome may contribute to the development of hepatic pathologies. Emerging evidence indicates that reactive oxygen and nitrogen species disrupt mitochondrial function through post-translational modifications to the mitochondrial proteome. Indeed, various new affinity labeling reagents are available to test the hypothesis that post-translational modification of proteins by reactive species contributes to mitochondrial dysfunction and alcoholic fatty liver disease. Specialized proteomic techniques are also now available, which allow for identification of defects in the assembly of multi-protein complexes in mitochondria and the resolution of the highly hydrophobic proteins of the inner membrane. In this review knowledge gained from the study of changes to the mitochondrial proteome in alcoholic hepatotoxicity will be described and placed into a mechanistic framework to increase understanding of the role of mitochondrial dysfunction in liver disease.

Effect of transjugular intrahepatic portosystemic shunt on pulmonary gas exchange in patients with portal hypertension and hepatopulmonary syndrome

AIM: To assess the impact of transjugular intrahepatic portosystemic shunt (TIPS) on pulmonary gas exchange and to evaluate the use of TIPS for the treatment of hepatopulmonary syndrome (HPS).METHODS: Seven patients, three of them with advanced HPS, in whom detailed pulmonary function tests were performed before and after TIPS placementat the University of Alabama Hospital and at the Hospital Clinic, Barcelona, were considered.RESULTS: TIPS patency was confirmed by hemodynamic evaluation. No changes in arterial blood gases were observed in the overall subset of patients. Transient arterial oxygenation improvement was observed in only one HPS patient, early after TIPS, but this was not sustained 4 mo later.CONCLUSION: TIPS neither improved nor worsened pulmonary gas exchange in patients with portal hypertension. This data does not support the use of TIPS as a specific treatment for HPS. However, it does reinforce the view that TIPS can be safely performed for the treatment of other complications of portal hypertension in patients with HPS.

Imaging of the temporomandibular joint: An update

Imaging of the temporomandibular joint(TMJ) is continuously evolving with advancement of imaging technologies. Many different imaging modalities are currently used to evaluate the TMJ. Magnetic resonance imaging is commonly used for evaluation of the TMJ due to its superior contrast resolution and its ability to acquire dynamic imaging for demonstration of the functionality of the joint. Computed tomography and ultrasound imaging have specific indication in imaging of the TMJ. This article focuses on state of the art imaging of the temporomandibular joint. Relevant normal anatomy and biomechanics of movement of the TMJ are discussed for better understanding of many TMJ pathologies. Imaging of internal derangements is discussed in detail. Different arthropathies and commontumors are also discussed in this article.

Lymph node imaging in initial staging of prostate cancer:An overview and update

Accurate nodal staging at the time of diagnosis of prostate cancer is crucial in determining a treatment plan for the patient. Pelvic lymph node dissection is the most reliable method, but is less than perfect and has increased morbidity. Cross sectional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) are non-invasive tools that rely on morphologic characteristics such as shape and size of the lymph nodes. However, lymph nodes harboring metastatic disease may be normal sized and non-metastatic lymph nodes may be enlarged due to reactive hyperplasia. The optimal strategy for preoperative staging remains a topic of ongoing research. Advanced imaging techniques to assess lymph nodes in the setting of prostate cancer utilizing novel MRI contrast agents as well as positron emission tomography (PET) tracers have been developed and continue to be studied. Magnetic resonance lymphography utilizing ultra-small super paramagnetic iron oxide has shown promising results in detection of metastatic lymph nodes. Combining MRL with diffusion-weighted imaging may also improve accuracy. Considerable efforts are being made to develop effective PET radiotracers that are performed using hybrid-imaging systems that combine PET with CT or MRI. PET tracers that will be reviewed in this article include [18F]fluoro-D-glucose, sodium [18F]fluoride, [18F]choline, [11C]choline, prostate specific membrane antigen binding ligands, [11C]acetate, [18F]fluciclovine, gastrin releasing peptide receptor ligands, and androgen binding receptors. This article will review these advanced imaging modalities and ability to detect prostate cancer metastasis to lymph nodes. While more research is needed, these novel techniques to image lymph nodes in the setting of prostate cancer show a promising future in improving initial lymph node staging.

Etiology and evaluation of diarrhea in AIDS:a global perspective at the millennium

INTRODUCTIONIt has now been almost 20 years since the initialdescriptions of a heretofore unrecognized disorderafflicting homosexual men and manifesting asPneumocystis carinii pneumonia and Kaposi’ssarcoma.With the identification of the humanimmunodeficiency virus(HIV) as the etiology ofthis syndrome,there has been exponential growth inour understanding of this devastating

Targeted treatment of cancer with radiofrequency electromagnetic fields amplitude-modulated at tumor-specific frequencies

In the past century, there have been many attempts to treat cancer with low levels of electric and magnetic fields. We have developed noninvasive biofeedback examination devices and techniques and discovered that patients with the same tumor type exhibit biofeedback responses to the same, precise frequencies. Intrabuccal administration of 27.12 MHz radiofrequency(RF) electromagnetic fields(EMF), which are amplitude-modulated at tumor-specific frequencies, results in long-term objective responses in patients with cancer and is not associated with any significant adverse effects. Intrabuccal administration allows for therapeutic delivery of very low and safe levels of EMF throughout the body as exemplified by responses observed in the femur, liver, adrenal glands, and lungs. In vitro studies have demonstrated that tumor-specific frequencies identified in patients with various forms of cancer are capable of blocking the growth of tumor cells in a tissue- and tumor-specific fashion. Current experimental evidence suggests that tumor-specific modulation frequencies regulate the expression of genes involved in migration and invasion and disrupt the mitotic spindle. This novel targeted treatment approach is emerging as an appealing therapeutic option for patients with advanced cancer given its excellent tolerability. Dissection of the molecular mechanisms accounting for the anti-cancer effects of tumor-specific modulation frequencies is likely to lead to the discovery of novel pathways in cancer.

Fever as the only manifestation of hypersensitivity reactions associated with oxaliplatin in a patient with colorectal cancer Oxaliplatin-induced hypersensitivity reaction

Hypersensitivity reactions （HSR） to oxaliplatin in patients with colorectal cancer include facial flushing, erythema, pruritis, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. We report a patient with fever as the sole manifestation of initial HSR, review the literature and discuss the management of HSR. A 57-year-old female with T3N2M0 rectal adenocarcinoma received modified FOLFOX-6. She tolerated the first 8 cycles without any toxicities except grade 1 peripheral neuropathy and nausea. During 9th and 10th infusions, she developed fever to a maximum of 38.3℃ with stable hemodynamic status despite medications. During 11th infusion, she developed grade 3 HSR consisting of symptomatic bronchospasm, hypotension, nausea, vomiting, cough, and fever. On examination, she was pale, cyanotic, with a temperature of 38.8℃, BP dropped to 95/43 mm Hg, pulse of 116/min and O2 saturation of 88%-91%. She was hospitalized for management and recovered in 24 h. Fever alone is not a usual symptom of oxaliplatin HSR. It may be indicative that the patient may develop serious reactions subsequently, as did our patient who developed hypotension with the third challenge. Treatment and prevention consists of slowing the infusion rate, use of steroids and antagonists of Type 1 and 2 histamine receptor antagonists, whereas desensitization could help to provide the small number of patients who experience severe HSR with the ability to further receive an effective therapy for their colorectal cancer.

Small regulators making big impacts:regulation of neural stem cells by small non-coding RNAs

Neurodegeneration and traumatic brain injuries are leading causes of disability and present an enormous disease burden both in terms of patient suffering and healthcare cost.Treatment of brain lesions remains as a major challenge in medicine largely because of the limited regenerative capacity of the adult brain.