Myostatin's marvels: From muscle regulator to diverse implications in health and disease.

Myostatin, a member of the transforming growth factor-ß superfamily, is a pivotal regulator of skeletal muscle growth in mammals. Its discovery has sparked significant interest due to its multifaceted roles in various physiological processes and its potential therapeutic implications. This review explores the diverse functions of myostatin in skeletal muscle development, maintenance and pathology. We delve into its regulatory mechanisms, including its interaction with other signalling pathways and its modulation by various factors such as microRNAs and mechanical loading. Furthermore, we discuss the therapeutic strategies aimed at targeting myostatin for the treatment of muscle-related disorders, including cachexia, muscular dystrophy and heart failure. Additionally, we examine the impact of myostatin deficiency on craniofacial morphology and bone development, shedding light on its broader implications beyond muscle biology. Through a comprehensive analysis of the literature, this review underscores the importance of further research into myostatin's intricate roles and therapeutic potential in human health and disease.

Long-term clinical outcomes in critically ill patients with sepsis and pre-existing low muscle mass: a retrospective cohort study.

PURPOSE: Critically ill patients with sepsis account for significant disease morbidity and healthcare costs. Low muscle mass has been proposed as an independent risk factor for poor short-term outcomes, although its effect on long-term outcomes remains unclear. METHODS: Retrospective cohort analysis of patients treated at a quaternary care medical center over 6 years (09/2014 - 12/2020). Critically ill patients meeting Sepsis-3 criteria were included, with low muscle mass defined by [Formula: see text] 5th percentile skeletal muscle index, measured at the L3 lumbar level (L3SMI) on Computed-Tomography (CT) scan ([Formula: see text] 41.6 cm2/m2 for males and [Formula: see text] 32.0 cm2/m2 for females). L3SMI was calculated by normalizing the CT-measured skeletal muscle area to the square of the patient's height (in meters). Measurements were taken from abdominal/pelvic CT scan obtained within 7 days of sepsis onset. The prevalence of low muscle mass and its association with clinical outcomes, including in-hospital and one-year mortality, and post-hospitalization discharge disposition in survivors, was analyzed. Unfavorable post-hospitalization disposition was defined as discharge to a location other than the patient's home. RESULTS: Low muscle mass was present in 34 (23%) of 150 patients, with mean skeletal muscle indices of 28.0 ± 2.9 cm2/m2 and 36.8 ± 3.3 cm2/m2 in females and males, respectively. While low muscle mass was not a significant risk factor for in-hospital mortality (hazard ratio 1.33; 95% CI 0.64 - 2.76; p = 0.437), it significantly increased one-year mortality after adjusting for age and illness severity using Cox multivariate regression (hazard ratio 1.9; 95% CI 1.1 - 3.2; p = 0.014). Unfavorable post-hospitalization discharge disposition was not associated with low muscle mass, after adjusting for age and illness severity in a single, multivariate model. CONCLUSION: Low muscle mass independently predicts one-year mortality but is not associated with in-hospital mortality or unfavorable hospital discharge disposition in critically ill patients with sepsis.

Treatment of Paget's Disease of Bone with Denosumab: Case Report and Literature Review.

Paget's disease is a condition involving focal overactivity of bone cells (osteoblasts and osteoclasts), which can result in significant skeletal morbidity. It is unclear in which bone cells the causative lesion resides. It is managed effectively with potent bisphosphonates, but treatment is difficult if these drugs are contraindicated. We describe a 75-year-old woman with Paget's disease involving the skull who was intolerant of bisphosphonates, so was treated with denosumab. This intervention normalized serum alkaline phosphatase for 4-8 months after each injection and led to some symptomatic improvement. Scintigraphic activity in the lesion was improved but not normalized. We conclude that reduction in RANKL activity by denosumab only partially corrects pagetic activity, indicating that the osteoclast overactivity of Paget's disease is not wholly mediated by RANKL. Denosumab has some clinical utility in Paget's disease and may become a second-line agent in those with contraindications to intravenous bisphosphonates.

Remineralizing potential of Calcium Sucrose Phosphate in white spot lesions: A Systematic Review.

BACKGROUND: This systematic review aimedto evaluate the remineralizing efficacy of calcium sucrose phosphate (CaSP) for the treatment of white spot lesions (WSLs) that commonly occur after orthodontic treatment with fixed appliances using various randomized controlled trials (RCTs) available in the literature todate. HIGHLIGHTS: Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, RCTs that assessed the efficacious remineralizing potential of CaSP on WSLs and demineralized enamel and compared it with either no intervention or other remineralizing agents wereselected. The methodological rigor of the included studies was subjected to the Risk of Bias tool-2 (ROB-2) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tools. Furthermore, a Begg's Funnel Plot was used to assess publication bias. The qualitative analysis encompassed a corpus of 36 studies. The remineralization potential of CaSP was investigated using an array of parameters, including surface microhardness, surface morphology, surface roughness, mineral content, and lesion size and depth. Based on the ROB-2 tool, most of the included studies were judged to be high risk, largely attributable to the presence of attrition bias. Using the GRADE framework, the certainty of evidence was determined to be moderate. CONCLUSION: This systematic review reveals that CaSP yields favorableoutcomes in terms of increased surface microhardness and calcium-phosphate content, reduced demineralized area and surface roughness, and enhanced surface topography.

Presence of single nucleotide polymorphisms in transforming growth factor ß and insulin-like growth factor 1 in class II malocclusions due to retrognathic mandible.

AIM: The aim of this study was to evaluate specific single nucleotide polymorphisms (SNP) of transforming growth factor-beta (TGF-ß) (rs1800469) and insulin-like growth factor-1 (IGF-1) (rs17032362) genes in Class II individuals with a normal maxilla and retrognathic (short) mandible.

Exploring the genetic expression of Sdf1, Foxc1 and histologic changes following mandibular advancement and recovery phase in Wistar rats.

PURPOSE: This study evaluated the impact of mandibular advancement on Sdf1 and Foxc1 gene expression in the mandibular condylar cartilage of young Wistar rats. By examining the changes that occur during a unique one-month recovery period, it highlights the critical role of gene expression and condylar adaptation during the recovery phase. The analysis focused on whether, during the recovery period, reversal changes occur when functional appliances are removed and whether genetic expression important for condyle growth and adaptation downregulates. MATERIAL AND METHODS: The study involved 30 male Wistar rats divided into 2 control groups Appliance Control and Recovery Control groups, and 2 experimental groups, the Appliance group with mandibular advancement bite-jumping appliance for 30 days, and the Recovery group with appliance for 30 days followed by a 30-day recovery. Molecular analysis of condylar cartilage using real-time RT-PCR and histological assessments was conducted. RESULTS: Significant genetic expression alterations were noted in both the experimental groups for Sdf1 (p < 0.05) and Foxc1 (p < 0.05). According to histological investigations, significant alterations with an increase in the proliferative and hypertrophic layer in condylar cartilage were seen. CONCLUSION: Mandibular advancement bite-jumping appliances induce proliferative and hypertrophic layer changes in mandibular condylar cartilage, shown by elevated Foxc1 levels and decreased Sdf1 levels. Post-appliance removal, persistent gene expression reveals a true joint stimulation.

Outpatient Ketamine Infusions for the Treatment of Fibromyalgia and Chronic Pain Syndrome: A Case Report.

Intravenous (IV) ketamine has demonstrable efficacy for chronic pain management. Its use in an outpatient setting has provided relief from myriad pain syndromes and additionally may reduce dependence on opioids. Nevertheless, its long-term ability to provide these benefits is understudied. Here, we present the case of a 68-year-old female who presented to our clinic with persistent fibromyalgia, accompanied by other pain symptoms that had been recalcitrant to traditional pain management therapy including nerve blocks, ablations, spinal cord stimulation, and morphine medication. We administered seven increasing IV ketamine doses over two weeks. The patient reported significant, widespread pain relief. The patient continued to receive IV ketamine twice weekly for over a year and remains on this schedule. Pain relief has persisted under this regimen, along with a demonstrable improvement in quality of life, a reduced use of morphine, and the cessation of anti-depressant medication. This case indicates that long-term ketamine infusions show promise for chronic pain management and that more longitudinal studies on this treatment are warranted.

Long-Term Clinical Outcomes in Critically Ill Patients with Sepsis and Pre-existing Sarcopenia: A Retrospective Cohort Study.

Purpose: Critically ill patients with sepsis account for significant disease morbidity and healthcare costs. Sarcopenia has been proposed as an independent risk factor for poor short-term outcomes, although its effect on long-term outcomes remains unclear. Methods: Retrospective cohort analysis of patients treated at a tertiary care medical center over 6 years (09/2014 - 12/2020). Critically ill patients meeting Sepsis-3 criteria were included, with sarcopenia defined by skeletal muscle index at the L3 lumbar area on abdominal Computed-Tomography scan. The prevalence of sarcopenia and its association with clinical outcomes was analyzed. Results: Sarcopenia was present in 34 (23%) of 150 patients, with median skeletal muscle indices of 28.1 cm 2 /m 2 and 37.3 cm 2 /m 2 in sarcopenic females and males, respectively. In-hospital mortality was not associated with sarcopenia when adjusted for age and illness severity. One year mortality was increased in sarcopenic patients, after adjustment for illness severity (HR 1.9, p = 0.02) and age (HR 2.4, p = 0.001). However, it was not associated with increased likelihood for discharge to long-term rehabilitation or hospice care in adjusted analyses. Conclusion: Sarcopenia independently predicts one year mortality but is not associated with unfavorable hospital discharge disposition in critically ill patients with sepsis.

Gene Expression and Survival of Acute Lymphoblastic Leukemia Cells After Allogeneic Transplant.

BACKGROUND/AIM: This study explored the mechanisms of the allogeneic graft versus leukemia effect in acute lymphoblastic leukemia (ALL) cells by examining whether they change gene expression in the post-transplant environment containing cytokines and the immunosuppressant cyclosporine, and if such changes affect ALL cell survival. MATERIALS AND METHODS: RNASeq was used to assess leukemia global gene expression and flow cytometry to measure ALL survival in the presence of T cells, NK cells, cytokines, and cyclosporine. RESULTS: A total of 4,805 genes were differentially expressed. Gene set enrichment analysis demonstrated up-regulation of biological processes related to cytokine responses, control of viral infection, and regulation of leukocyte function including proliferation. Down-regulated genes were related to mesenchymal tissue morphogenesis. ALL cells exposed to cytokines and cyclosporine retained susceptibility to T and NK cell killing, and also exhibited increased cell death without exposure to killer cells. CONCLUSION: A significant portion of the graft versus leukemia effect may be mediated by cytokines and cyclosporine.

Acute and chronic bupropion treatment does not prevent morphine-induced conditioned place preference in mice.

A substantial barrier to the treatment of Opioid Use Disorder (OUD) is the elevated relapse rates in affected patients, and a significant contributor to these events of relapse is exposure to cues and contexts that are intensely associated with prior drug abuse. The neurotransmitter dopamine plays a key role in reward-related behaviors, and previous studies have illustrated that dopamine hypofunction in periods of abstinence serves to prompt drug craving and seeking. We hypothesized that restoration of dopaminergic signaling could attenuate drug-seeking behaviors. Therefore, we investigated whether use of an FDA-approved drug, bupropion, an inhibitor of the dopamine transporter (DAT), or a dopamine uptake inhibitor with high affinity for DAT, JHW 007, was able to decrease preference for a drug-paired context. In these experiments, mice underwent 5 days of non-contingent morphine (10 mg/kg) exposure in a conditioned place preference (CPP) paradigm. We found that systemic injection of bupropion (20 mg/kg, i. p.) or intracranial injection of JHW 007 into the nucleus accumbens shell did not prevent the expression of morphine CPP. We then investigated whether chronic bupropion treatment (via implanted osmotic pumps) would influence morphine CPP. We observed that chronic bupropion treatment for 21 days following morphine conditioning did not attenuate the prolonged preference for morphine-paired contexts. Overall, with our dose and paradigm, neither acute nor chronic bupropion diminishes morphine CPP. Continued studies should address FDA-approved medications and their potential for recovery in OUD patients.

Ketamine Blocks Morphine-Induced Conditioned Place Preference and Anxiety-Like Behaviors in Mice.

Patients suffering from opioid use disorder often relapse during periods of abstinence, which is posited to be caused by negative affective states that drive motivated behaviors. Here, we explored whether conditioning mice with morphine in a conditioned place preference (CPP) training paradigm evoked anxiety-like behavior during morphine abstinence. To do this, mice were conditioned with morphine (10 mg/kg, i.p.) for 5 days. Twenty-four hours following conditioning, anxiety levels were tested by measuring time in the open arms of the elevated plus-maze. The next day, mice were placed in the three-compartment chamber to measure morphine-induced CPP. Our results show that following morphine conditioning, mice spent significantly less time in the open arm of the elevated plus-maze and expressed robust morphine CPP on CPP test day. Furthermore, we found that an acute treatment with (R,S)-ketamine (10 mg/kg, i.p.), a medication demonstrating promise for preventing anxiety-related phenotypes, 30 min before testing on post-conditioning day 1, increased time spent in the open arm of the elevated plus-maze in saline- and morphine-conditioned mice. Additionally, we found that the second injection of ketamine 30 min before CPP tests on post-conditioning day 2 prevented morphine-induced CPP, which lasted for up to 28 days post-conditioning. Furthermore, we found that conditioning mice with 10% (w/v) sucrose using an oral self-administration procedure did not evoke anxiety-like behavior, but elicited robust CPP, which was attenuated by ketamine treatment 30 min before CPP tests. Overall, our results suggest that the ketamine-induced block of morphine CPP may not be attributed solely to alleviating negative affective states, but potentially through impaired memory of morphine-context associations.

Accrual of Bone Mass in Children and Adolescents With Cystic Fibrosis.

Context: Low bone density is a complication of cystic fibrosis (CF). Hypothesis: Accrual of bone mass is most impaired in the sickest children, as judged by nutritional status and pulmonary function. Design: Retrospective analysis of correlation between lumbar spine bone mineral density (BMD), body mass index (BMI), and forced expiratory volume in 1 second (FEV1) z scores in children and adolescents with CF. Setting: Pediatric hospital specialist CF service. Patients: Sixty participants aged 5.9 to 18.8 years (24 female) with confirmed CF. Interventions: Lumbar spine BMD, BMI, and FEV1 z scores measured at first BMD scan; 40 participants had sequential scans. Change in L1-L4 z scores over time was used as a measure of bone accrual, and BMI as a measure of nutritional status. Outcome Measures: Correlations between lumbar spine BMD, BMI, and FEV1 z scores. Results: Mean BMI and BMD z scores were strongly correlated at the initial scan (P < 0.0001), suggesting that nutritional status is a major determinant of BMD. In the sequential scan at a mean age of 16.1 years, height centile was maintained, indicating normal linear growth. Changes in BMI and BMD z scores were positively correlated (P = 0.001), indicating that patients failing to gain weight appropriately with growth were also failing to acquire bone normally. Change in FEV1 z score was correlated with change in both BMD (P < 0.0001) and BMI z scores (P = 0.02). Conclusion: Although young people with CF may be maintaining normal growth in height, bone accrual is impaired in those with the poorest nutritional status and lung function.

BK Virus in Kidney Transplant: Current Concepts, Recent Advances, and Future Directions.

BK virus nephropathy is a challenging clinical problem in kidney transplant recipients with wide range of surveillance and management practices, based on individual experience. BK virus reactivation in kidney transplant recipients can result in BK virus nephropathy and graft loss. The most effective strategy for early diagnosis and treatment of BK virus nephropathy is regular monitoring for BK virus, currently achieved by quantification of viral DNA in blood by quantitative polymerase chain reaction. Immunosuppression reduction remains the mainstay of treatment; however, viral clearance is often followed by acute rejection, likely secondary to a delay between immune reconstitution and viral clearance. Impaired cell-mediated immune response to BK virus has been shown to correlate with progression to BK virus nephropathy, while reconstitution of this response correlates with resolution of nephropathy. There is recent research to support monitoring BK virus-specific cell-mediated immune response as a predictor of disease progression and resolution. In this article, we review the current concepts and recent developments in understanding BK virus-associated disease in the context of kidney transplant and outline areas for future research.