The effects of exercise and mitochondrial transplantation alone or in combination against Doxorubicin-induced skeletal muscle atrophy.

Doxorubicin (DOX) is a chemotherapy drug used to treat various types of cancer, but it is associated with significant side effects such as skeletal muscle atrophy. Exercise has been found to prevent skeletal muscle atrophy through the modulation of mitochondrial pathways. Mitochondrial transplantation (MT) may mitigate toxicity, neurological disorders, kidney and liver injury, and skeletal muscle atrophy. The objective of this study was to evaluate the effects of MT, exercise, and MT with exercise on DOX-induced skeletal muscle atrophy. Male Sprague Dawley rats were randomly assigned to the following groups: control, DOX, MT with DOX, exercise with DOX, and exercise with MT and DOX. A 10-day treadmill running exercise and MT (6.5 µg/100 µL) to tibialis anterior (TA) muscle were administered prior to a single injection of DOX (20 mg/kg). Our data showed that exercise and MT with exercise led to an increase in cross-sectional area of the TA muscle. Exercise, MT and MT with exercise reduced inflammation and maintained mitochondrial enzyme activity. Additionally, exercise and MT have been shown to regulate mitochondrial fusion/fission. Our findings revealed that exercise and MT with exercise prevented oxidative damage. Furthermore, MT and MT with exercise decreased apoptosis and MT with exercise triggered mitochondrial biogenesis. These findings demonstrate the importance of exercise in the prevention of skeletal muscle atrophy and emphasize the significant benefits of MT with exercise. To the best of our knowledge, this is the first study to demonstrate the therapeutic effects of MT with exercise in DOX-induced skeletal muscle atrophy.

An adolescent male with persistent urinary symptoms.

An 11-year-old male child who presented with increased frequency of urination, thirst and feeling of incomplete void was initially diagnosed with diabetes mellitus (DM) based on elevated blood sugar. Polyuria and polydipsia were confirmed even after normalisation of blood sugar. A standardised water deprivation test showed presence of central diabetes insipidus (DI) and patient was started on desmopressin. Presence of DM and DI led to suspicion of DIDMOAD/Wolfram syndrome and ophthalmic examination confirmed bilateral optic atrophy. Despite treatment for DM and DI the urinary complaints persisted, and ultrasound showed persistent bilateral hydronephroureterosis. Bladder workup including voiding cystourethrography (VCUG) and urodynamic study reported thickened trabeculated bladder wall along with overactivity, poor compliance and high bladder pressure. Bladder dysfunction has been documented to be associated with Wolfram syndrome and often may lead to chronic kidney disease which can be prevented by early diagnosis and appropriate management. The case highlights the need for comprehensive evaluation of children with urinary symptoms.

Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus.

Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA by the U.S. Food and Drug Administration, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein or intracranial injection on embryonic day 75 (E75) . Umbilical vein injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term = E150). There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), without DRG toxicity and excellent transduction of diaphragm and quadriceps muscles. However, we found evidence of systemic toxicity (fetal growth restriction) and maternal exposure to the viral vector (transient elevation of total bilirubin and a trend toward elevation in anti-AAV9 antibodies). There were no antibodies against GFP in ewes or lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with low levels of integration-specific reads, without integration in select proto-oncogenes. These results suggest potential therapeutic benefit of AAV9 PSCGT for neuromuscular disorders, but warrant caution for exposure of female germ cells.

Analysis of the impact of obesity on the prognosis of IgA nephropathy according to renal function and sex.

BACKGROUND: Few studies have observed the direct effect of obesity on renal prognoses in immunoglobulin A nephropathy (IgAN) or separately evaluated its effects according to sex. We aimed to evaluate the direct and indirect effects of obesity on the renal outcomes of IgAN and observe these effects separately according to renal function and sex. METHODS: We extracted patients with body mass index (BMI) descriptions from a multicenter retrospective cohort analysis in Japan, and excluded those with < 30 days of follow-up, diabetes mellitus, and steroid treatment. Patients were divided into normal (n = 720; 18.5 ≤ BMI < 25) and obese (n = 212; BMI ≥ 25) groups, which were then compared. The endpoints were a 1.5-fold increase in serum creatinine levels and the initiation of renal replacement therapy. RESULTS: The obese group was older, included more males, and was more likely have hypertension, dyslipidemia, proteinuria, tubular atrophy, and lower renal function than the normal group. Patients with an eGFR < 60 mL/min/1.73 m2 had well-matched characteristics between the groups; however, hypertension, low high-density lipoprotein cholesterol, and hypertriglyceridemia were more common in the obese group. Obesity contributed to tubular atrophy, even when adjusted for renal function. In addition, it contributed to proteinuria only in females. However, obesity itself was not a significant prognostic factor. CONCLUSIONS: Although no independent effect on renal prognosis was observed during the study period, the obese group had more risk factors for IgAN progression and obesity contributed to tubular atrophy and female proteinuria. Our results suggest that separately analyzing the prognostic effect of obesity according to sex is important.

A cohort study of 19 patients with gyrate atrophy of the choroid and retina (GACR).

PURPOSE: Gyrate atrophy of the choroid and retina (GACR) is an autosomal recessive inherited metabolic disorder (IMD) characterised by progressive retinal degeneration, leading to severe visual impairment. The rapid developments in ophthalmic genetic therapies warrant knowledge on clinical phenotype of eligible diseases such as GACR to define future therapeutic parameters in clinical trials. METHODS: Retrospective chart analysis was performed in nineteen patients. Data were analysed using IBM SPSS Statistics version 28.0.1.1. RESULTS: Nineteen patients were included with a mean age of 32.6 years (range 8-58). Mean age at onset of ophthalmic symptoms was 7.9 years (range 3-16). Median logMAR of visual acuity at inclusion was 0.26 (range -0.18-3.00). Mean age at cataract surgery was 28.8 years (n = 11 patients). Mean spherical equivalent of the refractive error was -8.96 (range -20.87 to -2.25). Cystoid maculopathy was present in 68% of patients, with a loss of integrity of the foveal ellipsoid zone (EZ) in 24/38 eyes. Of the 14 patients treated with dietary protein restriction, the four patients who started the diet before age 10 showed most benefit. CONCLUSION: This study demonstrates the severe ophthalmic disease course associated with GACR, as well as possible benefit of early dietary treatment. In addition to visual loss, patients experience severe myopia, early-onset cataract, and CME. There is a loss of foveal EZ integrity at a young age, emphasising the need for early diagnosis enabling current and future therapeutic interventions.

Giant 20/20 Meningioma: The Diagnostic Value of Confrontation Visual Fields.

Meningiomas are benign tumors of the central nervous system (CNS) that usually result in compression to adjacent structures and rarely cause pathology on their own. Meningiomas can affect the visual pathways originating from perineural or optic nerve sheath meningioma (ONSM), sellar, or clinoid, to the frontal-temporal-parietal-occipital lobes. Frontal meningiomas have an indolent presentation with frequent behavioral changes (i.e., personality or emotional changes, visual hallucinations), but they rarely present with visual disturbances. We present a case of a giant frontal meningioma causing progressive visual field loss despite preserved visual acuity and no behavioral changes. We aim to highlight the diagnostic value of performing a detailed ophthalmologic evaluation with confrontation visual field (CVF) testing and interpretation in aiding the discovery and diagnosis of intracranial tumors.

The endoscopic model for gastric carcinogenesis and Helicobacter pylori infection: a potential visual mind-map during gastroscopy examination.

Helicobacter pylori (Hp) is the main trigger of gastric chronic atrophy and the main leading cause of gastric cancer. Hp infects the gastric normal mucosa and can lead to chronic inflammation, glandular atrophy, intestinal metaplasia, dysplasia and finally adenocarcinoma. Chronic inflammation and gastric atrophy associated with Hp infection appear initially in the distal part of the stomach (the antrum) before progressing to the proximal part (the corpus-fundus). In recent years, endoscopic developments have allowed for the characterization of various gastric conditions including the normal mucosa (pyloric/fundic gland pattern and regular arrangement of collecting venules), Hp-related gastritis (Kyoto classification), glandular atrophy (Kimura-Takemoto classification), intestinal metaplasia (Endoscopic Grading of Gastric Intestinal Metaplasia), and dysplasia/adenocarcinoma (Vessel plus Surface classification). Despite being independent classifications, all these scales can be integrated into a single model: the endoscopic model for gastric carcinogenesis. This model would assist endoscopists in comprehending the process of gastric carcinogenesis and conducting a systematic examination during gastroscopy. Having this model in mind would enable endoscopists to promptly recognize the implications of Hp infection and the potential patient's risk of developing gastric cancer.

Blood flow restriction Exercise in the perioperative setting to Prevent loss of muscle mass in patients with pancreatic, biliary tract, and liver cancer: study protocol for the PREV-Ex randomized controlled trial.

BACKGROUND: Patients diagnosed with pancreatic, biliary tract, and liver cancer often suffer from a progressive loss of muscle mass. Given the considerable functional impairments in these patients, high musculoskeletal weight loads may not be well tolerated by all individuals. The use of blood-flow restricted resistance training (BFR-T) which only requires low training loads may allow for a faster recovery of muscle due to avoidance of high levels of mechanical muscle stress associated with high-load resistance exercise. This study aims to investigate whether BFR-T can prevent or slow down the loss of skeletal muscle mass and enhance the functional capacity and mental health of patients with pancreatic, biliary tract, and liver cancer. METHODS: The PREV-Ex exercise trial is a multicenter two-armed randomized controlled trial. Patients will be randomized to an exercise program consisting of home-based low-load BFR-T during a combined pre- and postoperative period for a total of 6-10 weeks (prehabilitation and rehabilitation), or to a control group. Protein supplementation will be given to both groups to ensure adequate protein intake. The primary outcomes, skeletal muscle thickness and muscle cross-sectional area, will be assessed by ultrasound. Secondary outcomes include the following: (i) muscle catabolism-related and inflammatory bio-markers (molecular characteristics will be assessed from a vastus lateralis biopsy and blood samples will be obtained from a sub-sample of patients); (ii) patient-reported outcome measures (self-reported fatigue, health-related quality of life, and nutritional status will be assessed through validated questionnaires); (iii) physical fitness/performance/activity (validated tests will be used to evaluate physical function, cardiorespiratory fitness and maximal isometric muscle strength. Physical activity and sedentary behavior (assessed using an activity monitor); (iv) clinical outcomes: hospitalization rates and blood status will be recorded from the patients' medical records; (v) explorative outcomes of patients' experience of the exercise program which will be evaluated using focus group/individual interviews. DISCUSSION: It is worthwhile to investigate new strategies that have the potential to counteract the deterioration of skeletal muscle mass, muscle function, strength, and physical function, all of which have debilitating consequences for patients with pancreatic, biliary tract, and liver cancer. The expected findings could improve prognosis, help patients stay independent for longer, and possibly reduce treatment-related costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05044065. Registered on September 14, 2021.

Ospemifene for Genitourinary Syndrome of Menopause: Patient Selection.

Vulvar vaginal atrophy is a common condition affecting postmenopausal women, significantly impacting their quality of life. Fortunately, various treatment options are available, ranging from hormonal to non-hormonal therapies. Ospemifene has emerged as a promising non-hormonal alternative for managing vulvar vaginal atrophy. Its targeted approach, unique mechanism of action, favorable safety profile particularly for breast tissue, and efficacy make it a valuable option for women seeking relief from symptoms such as vaginal pain, dryness and dyspareunia and cannot receive estrogen supplementations. This is particularly the case for breast cancer survivors or women with a significant family history of estrogen-dependent cancers. Hence, tailored treatment plans, considering individual preferences and health circumstances, are essential in optimizing outcomes and improving the overall well-being of affected individuals.

A novel function of claudin-5 in maintaining the structural integrity of the heart and its implications in cardiac pathology.

This study aims to investigate the role of claudin-5 (Cldn5) in cardiac structural integrity. Proteomic analysis was performed to screen the protein profiles in enlarged left atrium from atrial fibrillation (AF) patients. Cldn5 shRNA adeno-associated virus (AAV) or siRNA was injected into the mouse left ventricle or added into HL1 cells respectively to knockdown Cldn5 in cardiomyocytes to observe whether the change of Cldn5 influences cardiac morphology and function, and affects those protein expressions stem from the proteomic analysis. Mitochondrial density and membrane potential were also measured by Mitotracker staining and JC-1 staining under the confocal microscope in HL1 cells. Cldn5 was reduced in cardiomyocytes from the left atrial appendage of AF patients compared to non-AF donors. Proteomic analysis showed 83 proteins were less abundant and 102 proteins were more abundant in AF patients. KEGG pathway analysis showed less abundant CACNA2D2, CACNB2, MYL2 and MAP6 were highly associated with dilated cardiomyopathy. Cldn5 shRNA AAV injection caused severe cardiac atrophy, dilation and myocardial dysfunction in mice. The decreases in mitochondrial numbers and mitochondrial membrane potentials in HL1 cells were observed after Cldn5 knockdown. We demonstrated for the first time the mechanism of Cldn5 downregulation-induced myocyte atrophy and myocardial dysfunction might be associated with the downregulation of CACNA2D2, CACNB2, MYL2 and MAP6, and mitochondrial dysfunction in cardiomyocytes.

Long-term endoscopic gastric mucosal changes up to 20 years after Helicobacter pylori eradication therapy.

Helicobacter pylori eradication therapy reduces the risk of gastric cancer. However, it is unclear whether the severity of risk factors for gastric cancer such as atrophy and intestinal metaplasia are reduced after eradication in the long term. We aimed to study long-term changes in endoscopic risk factors for gastric cancer up to 20 years post-eradication. The endoscopic severity of gastritis according to the Kyoto Classification of Gastritis in 167 patients was retrospectively evaluated over an average follow-up 15.7 years. A significant improvement in mean total gastric cancer risk score (4.36 ± 1.66 to 2.69 ± 1.07, p < 0.001), atrophy (1.73 ± 0.44 to 1.61 ± 0.49, p = 0.004), and diffuse redness (1.22 ± 0.79 to 0.02 ± 0.13, p < 0.001) was observed compared to baseline in the Eradication group. However, there was no change in the never infection and current infection groups. The frequency of map-like redness increased over time until 15 years (3.6% to 18.7%, p = 0.03). The Cancer group had significantly higher risk scores at all time points. Endoscopic atrophy significantly improved in eradicated patients over long-term, suggested that eradication is one of the key elements in gastric cancer prevention. Individualized surveillance strategies based on endoscopic gastritis severity before eradication may be important for those at risk of gastric cancer.

Deubiquitinases in muscle physiology and disorders.

In vivo, muscle and neuronal cells are post-mitotic, and their function is predominantly regulated by proteostasis, a multilayer molecular process that maintains a delicate balance of protein homeostasis. The ubiquitin-proteasome system (UPS) is a key regulator of proteostasis. A dysfunctional UPS is a hallmark of muscle ageing and is often impacted in neuromuscular disorders (NMDs). Malfunction of the UPS often results in aberrant protein accumulation which can lead to protein aggregation and/or mis-localization affecting its function. Deubiquitinating enzymes (DUBs) are key players in the UPS, controlling protein turnover and maintaining the free ubiquitin pool. Several mutations in DUB encoding genes are linked to human NMDs, such as ATXN3, OTUD7A, UCHL1 and USP14, whilst other NMDs are associated with dysregulation of DUB expression. USP5, USP9X and USP14 are implicated in synaptic transmission and remodeling at the neuromuscular junction. Mice lacking USP19 show increased maintenance of lean muscle mass. In this review, we highlight the involvement of DUBs in muscle physiology and NMDs, particularly in processes affecting muscle regeneration, degeneration and inflammation following muscle injury. DUBs have recently garnered much respect as promising drug targets, and their roles in muscle maturation, regeneration and degeneration may provide the framework for novel therapeutics to treat muscular disorders including NMDs, sarcopenia and cachexia.

Outcomes of Blood Flow Restriction Training After ACL Reconstruction in NCAA Division I Athletes.

Background: Blood flow restriction training (BFRT) is a safe and potentially effective adjunctive therapeutic modality for postoperative rehabilitation related to various knee pathologies. However, there is a paucity of literature surrounding BFRT in high-performance athletes after anterior cruciate ligament reconstruction (ACLR). Purpose: To (1) compare the overall time to return to sports (RTS) in a cohort of National Collegiate Athletic Association (NCAA) Division I athletes who underwent a standardized rehabilitation program either with or without BFRT after ACLR and (2) identify a postoperative time interval for which BFRT has the maximum therapeutic benefit. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 55 student-athletes who underwent ACLR between 2000 and 2023 while participating in NCAA Division I sports at a single institution were included in this study. Athletes were allocated to 1 of 2 groups based on whether they participated in a standardized postoperative rehabilitation program augmented with BFRT (BFRT group; n = 22) or completed the standardized protocol alone (non-BFRT group [control]; n = 33). Our primary outcome measure was time to RTS. The secondary outcome measure was handheld dynamometry quadriceps strength testing at various postoperative time points, converted to a limb symmetry index (LSI). Quadriceps strength was not tested between the BFRT and non-BFRT groups because of the limited amount of data on the control group. Results: The mean age at the date of surgery was 18.59 ± 1.10 years for the BFRT group and 19.45 ± 1.30 years for the non-BFRT group (P = .011), and the mean RTS time was 409 ± 134 days from surgery for the BFRT group and 332 ± 100 days for the non-BFRT cohort (P = .047). For the BFRT group, the mean quadriceps strength LSI increased by 0.67% (95% CI, 0.53%-0.81%) for every week of rehabilitation, and there was a significantly positive rate of change in quadriceps strength in weeks 13-16 compared with weeks 9-12 (ΔLSI, 8.22%; P < .001). Conclusion: In elite NCAA Division I athletes, a statistically significant delay was observed in RTS with BFRT compared with standardized physical therapy alone after undergoing ACLR. There also appeared to be an early window during the rehabilitation period where BFRT had a beneficial impact on quadriceps strength.

Xanthogranulomatous Orchitis With Testicular Atrophy in a Case of Chronic Pyocele: A Rare Case.

Xanthogranulomatous orchitis (XGO) is a benign non-inflammatory condition predominantly affecting the testicular tissue and characterized by the infiltration of lipid-laden macrophages leading to substantial tissue damage. We present the case of an 80-year-old gentleman with chronic pyocele and concurrent testicular atrophy secondary to XGO, a seldom-reported manifestation in the testicular milieu. The patient presented with a protracted history of left-sided scrotal swelling and underwent left orchidectomy subsequent to preoperative diagnosis via ultrasonography. Intraoperative exploration revealed the presence of purulent fluid, and histopathological analysis confirmed characteristic features of XGO, including seminiferous tubule destruction and infiltration of fibroconnective tissue by histiocytes and dilated blood vessels. Differential diagnosis with testicular neoplasms posed a challenge, accentuating the pivotal role of histopathological scrutiny in achieving precise diagnosis. Orchidectomy remains the cornerstone of treatment for XGO. This case underscores the imperative of considering XGO in the diagnostic spectrum of testicular masses and the indispensable role of histopathology in confirming the diagnosis and guiding optimal therapeutic interventions.

Radiopharmaceuticals for Skeletal Muscle PET Imaging.

The skeletal muscles account for approximately 40% of the body weight and are crucial in movement, nutrient absorption, and energy metabolism. Muscle loss and decline in function cause a decrease in the quality of life of patients and the elderly, leading to complications that require early diagnosis. Positron emission tomography/computed tomography (PET/CT) offers non-invasive, high-resolution visualization of tissues. It has emerged as a promising alternative to invasive diagnostic methods and is attracting attention as a tool for assessing muscle function and imaging muscle diseases. Effective imaging of muscle function and pathology relies on appropriate radiopharmaceuticals that target key aspects of muscle metabolism, such as glucose uptake, adenosine triphosphate (ATP) production, and the oxidation of fat and carbohydrates. In this review, we describe how [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), [18F]fluorocholine ([18F]FCH), [11C]acetate, and [15O]water ([15O]H2O) are suitable radiopharmaceuticals for diagnostic imaging of skeletal muscles.

Drug- and Toxin-Induced Opsoclonus - a Systematized Review, including a Case Report on Amantadine-Induced Opsoclonus in Multiple System Atrophy.

Background: Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval, resulting from dysfunction within complex neuronal pathways in the brainstem and cerebellum. While most cases of opsoclonus are associated with autoimmune or paraneoplastic disorders, infectious agents, trauma, or remain idiopathic, opsoclonus can also be caused by medications affecting neurotransmission. This review was prompted by a case of opsoclonus occurring in a patient with Multiple System Atrophy, where amantadine, an NMDA-receptor antagonist, appeared to induce opsoclonus. Methods: Case report of a single patient and systematized review of toxic/drug-induced opsoclonus, selecting articles based on predefined criteria and assessing the quality of included studies. Results: The review included 30 articles encompassing 158 cases of toxic/drug-induced opsoclonus. 74% of cases were attributed to bark scorpion poisoning, followed by 9% of cases associated with chlordecone intoxication. The remaining cases were due to various toxics/drugs, highlighting the involvement of various neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, glycine, and sodium channels, in the development of opsoclonus. Conclusion: Toxic/drug-induced opsoclonus is very rare. The diversity of toxics/drugs impacting different neurotransmitter systems makes it challenging to define a unifying mechanism, given the intricate neuronal pathways underlying eye movement physiology and opsoclonus pathophysiology.

Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats.

BACKGROUND: The rate and magnitude of skeletal muscle wasting after severe spinal cord injury (SCI) exceeds most other disuse conditions. Assessing the time course of molecular changes can provide insight into the progression of muscle wasting post-SCI. The goals of this study were (1) to identify potential targets that may prevent the pathologic features of SCI in soleus muscles and (2) to establish therapeutic windows for treating these pathologic changes. METHODS: Four-month-old Sprague-Dawley male rats received T9 laminectomy (SHAM surgery) or severe contusion SCI. Hindlimb locomotor function was assessed weekly, with soleus muscles obtained 1 week, 2 weeks, 1 month and 3 months post-surgery (n = 6-7 per group per timepoint). RNA was extracted from muscles for bulk RNA-sequencing analysis (n = 3-5 per group per timepoint). Differentially expressed genes (DEGs) were evaluated between age-matched SHAM and SCI animals. Myofiber size, muscle fibre type and fibrosis were assessed on contralateral muscles. RESULTS: SCI produced immediate and persistent hindlimb paralysis, with Basso-Beattie-Bresnahan locomotor scores remaining below 7 throughout the study, contributing to a progressive 25-50% lower soleus mass and myofiber atrophy versus SHAM (P < 0.05 at all timepoints). Transcriptional comparisons of SCI versus SHAM resulted in 184 DEGs (1 week), 436 DEGs (2 weeks), 133 DEGs (1 month) and 1200 DEGs (3 months). Upregulated atrophy-related genes included those associated with cell senescence, nuclear factor kappa B, ubiquitin proteasome and unfolded protein response pathways, along with upregulated genes that negatively influence muscle growth through the transforming growth factor beta pathway and inhibition of insulin-like growth factor-I/Akt/mechanistic target of rapamycin and p38/mitogen-activated protein kinase signalling. Genes associated with extracellular matrix (ECM), including collagens, collagen crosslinkers, proteoglycans and those regulating ECM integrity, were enriched within upregulated DEGs at 1 week but subsequently downregulated at 2 weeks and 3 months and were accompanied by >50% higher ECM areas and hydroxyproline levels in SCI muscles (P < 0.05). Myofiber remodelling genes were enriched in upregulated DEGs at 2 weeks and 1 month and were downregulated at 3 months. Genes that regulate neuromuscular junction remodelling were evident in muscles post-SCI, along with slow-to-fast fibre-type shifts: 1 week and 2 weeks SCI muscles were composed of 90% myosin heavy chain (MHC) type I fibres, which decreased to only 16% at 3 months and were accompanied by 50% fibres containing MHC IIX (P < 0.05). Metabolism genes were enriched in upregulated DEGs at 1 month and were further enriched at 3 months. CONCLUSIONS: Our results substantiate many known pathologic features of SCI-induced wasting in rat skeletal muscle and identify a progressive and dynamic transcriptional landscape within the post-SCI soleus. Future studies are warranted to consider these therapeutic treatment windows when countering SCI muscle pathology.

The Shehata technique for undescended testes that cannot be brought into the scrotum in one operation-a case series and meta-analysis.

Background: Fowler-Stephens orchiopexy is commonly used for testes that cannot be brought into the scrotum in one operation. However, this surgical technique may result in a higher rate of testicular atrophy postoperatively. Methods: During the period between 2019 and 2023, we analyzed the cases of 20 patients in whom the Shehata technique was applied for testes that could not be brought into the scrotum in one operation, and we conducted a meta-analysis to explore the incidence of testicular atrophy vis-à-vis the Shehata technique and Fowler-Stephens orchiopexy. Results: The average age of the 20 patients was 3.78 (0.76-11.42) years. The blood supply to the testes was satisfactory, with the absence of atrophy, and the testes could be brought into the scrotum in stage II surgery. A postoperative reexamination with ultrasound revealed that the testes were securely positioned within the scrotum, with good blood supply and no atrophy, which was in contrast to their condition before the operation. The volume of the testes postoperatively was significantly greater than that of the preoperative testes (p = 0.009). There were no statistically significant differences in the growth rate of volume of the testes between the surgically treated side and the contralateral side (p = 0.25). The meta-analysis showed that the Shehata technique resulted in a lower incidence of testicular atrophy compared with Fowler-Stephens orchiopexy (p = 0.01). Conclusions: The Shehata technique preserves the main vessels of the testes with a lower incidence of testicular atrophy, which may be a valid and safe alternative to the Fowler-Stephens technique.

Gene therapy: principles, challenges and use in clinical practice.

INTRODUCTION: Gene therapy is an emerging topic in medicine. The first products have already been licensed in the European Union for the treatment of immune deficiency, spinal muscular atrophy, hemophilia, retinal dystrophy, a rare neurotransmitter disorder and some hematological cancers, while many more are being assessed in preclinical and clinical trials. OBJECTIVE: The purpose of this review is to provide an overview of the core principles of gene therapy along with information on challenges and risks. Benefits, adverse effects and potential risks are illustrated based on the examples of hemophilia and spinal muscular atrophy. RESULTS: At present, in-vitro and in-vivo gene addition or gene augmentation is the most commonly established type of gene therapy. More recently, more sophisticated and precise approaches such as in situ gene editing have moved into focus. However, all types of gene therapy require long-term observation of treated patients to ensure safety, efficacy, predictability and durability. Important safety concerns include immune reactions to the vector, the foreign DNA or the new protein resulting from gene therapy, and a remaining low cancer risk based on insertional mutagenesis. Ethical and regulatory issues need to be addressed, and new reimbursement models are called for to ease the financial burden that this new treatment poses for the health care system. CONCLUSION: Gene therapy holds great promise for considerable improvement or even cure of genetic diseases with serious clinical consequences. However, a number of questions and issues need to be clarified to ensure broad accessibility of safe and efficacious products.

Inflammation-associated intramyocellular lipid alterations in human pancreatic cancer cachexia.

BACKGROUND: Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia. METHODS: Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n = 10 without cachexia, n = 20 cachectic without inflammation (CRP < 10 mg/L), n = 10 cachectic with inflammation (CRP ≥ 10 mg/L). L3-CT scans were analysed to assess body composition based on validated thresholds in Hounsfield units (HU). Muscle sections were stained with Oil-Red O and H&E to assess general lipid accumulation and atrophy. Untargeted lipidomic analyses were performed on laser-microdissected myotubes using LC-MS/MS. The spatial distribution of intramyocellular lipids with differential abundance between groups was visualized by mass-spectrometry imaging. Genes coding for inflammation markers and enzymes involved in de novo ceramide synthesis were studied by qPCR. RESULTS: Muscle radiation attenuation was lower in cachectic patients with inflammation (median 24.3 [18.6-30.8] HU) as compared with those without inflammation (34.2 [29.3-38.7] HU, P = 0.033) or no cachexia (37.4 [33.9-42.9] HU, P = 0.012). Accordingly, intramyocellular lipid content was lower in non-cachectic patients (1.9 [1.6-2.1]%) as compared with those with cachexia with inflammation (5.5 [4.5-7.3]%, P = 0.002) or without inflammation (4.8 [2.6-6.0]%, P = 0.017). Intramyocellular lipid accumulation was associated with both local IL-6 mRNA levels (rs = 0.57, P = 0.015) and systemic CRP levels (rs = 0.49, P = 0.024). Compared with non-cachectic subjects, cachectic patients had a higher relative abundance of intramyocellular glycerophospholipids and a lower relative abundance of glycerolipids. Furthermore, increases in several intramyocellular lipids such as SM(d36:1), PC(34:1), and TG(48:1) were found in cachectic patients with inflammation and correlated with specific cachexia features. Altered intramyocellular lipid species such as PC(34:1), LPC(18:2), and TG(48:1) showed an uneven distribution in muscle sections of cachectic and non-cachectic patients, with areas featuring abundance of these lipids next to areas almost devoid of them. CONCLUSIONS: Intramyocellular lipid accumulation in patients with cachexia is associated with both local and systemic inflammation, and characterized by changes in defined lipid species such as glycerolipids and glycerophospholipids.