Stabilization Of Function Research Articles

Type-1 spinal muscular atrophy cohort before and after disease-modifying therapies.

Spinal muscular atrophy (SMA-5q) is a neurodegenerative disease characterized by progressive muscle atrophy, hypotonia, and weakness, with SMA 1 presenting symptoms within the first 6 months of life. Disease-modifying therapies have been approved, with better outcomes with earlier treatment. To describe the safety and clinical efficacy of disease-modifying therapies based on SMN1 and SMN2 gene strategies concerning motor, respiratory, and bulbar function. Patients with SMA 1 were divided into 2 groups: those exclusively on nusinersen (group 1) and those transitioning to onasemnogene abeparvovec (OA) (group 2). Over 18 months, patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale, developmental milestones, ventilation needs and duration, nutritional support needs, consistency of food, and signs of dysphagia. There were ten patients, divided between the groups; in group 1, the average age for starting nusinersen was 53.6 (12-115) months, and, in group 2, the age was 7 (1-12) months for nusinersen and 15.2 (10-19) months for OA. Our results indicate that 70% of patients reached some motor milestones, with group 1 increasing by 10.2 points on the CHOP-INTEND scale, while group 2 increased by 33 points. Additionally, 90% of the patients experienced no respiratory decline, and 30% maintained oral feeding. No serious adverse effects or deaths were recorded. Both groups showed improvement in motor function and stabilization of respiratory and bulbar function, with the difference between the groups possibly being related to the earlier treatment initiation. Thus, the present study provides valuable insights into the real-world safety and clinical efficacy of disease-modifying therapies for SMA 1 patients.

Efficacy of Nusinersen Treatment in Type 1, 2, and 3 Spinal Muscular Atrophy: Real-World Data from a Single-Center Study

Background: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease characterized by progressive muscle weakness and atrophy due to the absence of the survival motor neuron 1 (SMN1) gene. SMA is classified into types 0 through 4 based on the age of symptom onset and the severity of motor function decline. Recent advances in SMA treatment, including nusinersen, onasemnogene abeparvovec, and risdiplam, have significantly improved the prognosis of SMA patients. This study evaluated the safety and efficacy of nusinersen in pediatric patients with SMA types 1, 2, and 3 in a real-world clinical setting. Methods: This prospective observational single-center study assessed the treatment effects of nusinersen in 23 pediatric patients with genetically confirmed SMA over a 22-month observation period. All the participants received intrathecal loading doses of 12 mg of nusinersen on days 1, 14, 28, and 63, followed by maintenance doses every four months. Functional assessments were conducted using the CHOP-INTEND scale. Data were collected during routine patient visits, including clinical laboratory tests and vital sign parameters, and adverse events were recorded. The inclusion criteria were defined by the national reimbursement program for nusinersen treatment in Poland. Results: Initially, 37 patients ranging from 1 month old to 18 years old were included, but 23 were ultimately observed due to changes in treatment regimens or assessment scales. The patients showed significantly improved CHOP-INTEND scores over the 22-month period. At 6 months, the average increase was 4.2 points, continuing to 17.8 points at 22 months. By the end of the study, 100% of patients showed either stabilization or improvement, with significant clinical improvements observed in several patients. Nusinersen was generally well-tolerated, with post-lumbar puncture headache and lower back pain being the most common adverse events. Conclusions: Nusinersen treatment significantly enhances motor function in pediatric patients with SMA types 1, 2, and 3. This study demonstrates the importance of early and sustained treatment, with most patients showing the continuous improvement or stabilization of motor function. These findings support the use of nusinersen as an effective therapy for SMA; however, further research is needed to understand the long-term outcomes and optimize treatment strategies.

Evaluation of early treatment with intravenous idursulfase and intrathecal idursulfase-IT on cognitive function in siblings with neuronopathic mucopolysaccharidosis II.

Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked, heterogeneous lysosomal storage disease. Approximately two-thirds of patients develop cognitive impairment, which is difficult to assess in clinical trials, partly owing to the variable nature of cognitive impairment. Analyzing data from siblings can help to minimize this heterogeneity. We report analyses of cognitive function from siblings with MPS II enrolled in clinical trials: a natural history study (NCT01822184), a randomized, open-label, phase 2/3 study of intravenous (IV) idursulfase with or without intrathecal idursulfase (idursulfase-IT; NCT02055118), and its extension (NCT2412787). Cognitive function was assessed using Differential Abilities Scales, Second Edition General Conceptual Ability (DAS-II GCA) scores; Bayley Scales of Infant and Toddler Development, Third Edition; and Vineland Adaptive Behavior Scales, Second Edition Adaptive Behavior Composite (VABS-II ABC). Seven sets of siblings (six pairs and one set of three) were included. All patients received IV idursulfase and 10 received subsequent idursulfase-IT. Younger siblings initiated IV idursulfase at an earlier age than their older sibling(s) in six of the sets; the younger sibling started treatment before 1 year of age in three sets. Monthly idursulfase-IT was generally associated with a stabilization of cognitive function: DAS-II GCA and VABS-II ABC scores were higher at age-matched assessments in the majority of those who either received idursulfase-IT earlier than their sibling or who received idursulfase-IT versus no idursulfase-IT. These data suggest that early initiation of intrathecal enzyme replacement therapy may stabilize or slow cognitive decline in some patients with neuronopathic MPS II.

ADVANTAGES OF USING DEXMEDETOMIDINE AS AN ADJUVANT IN LAPAROSCOPIC BARIATRIC SURGERIES

The global rise in obesity rates has necessitated an increased frequency of bariatric surgeries, posing intricate challenges in anesthesia management. Dexmedetomidine, an α2-adrenergic receptor agonist, has emerged as a potential adjunct to general anesthesia in this context. This study aimed to evaluate the efficacy and safety of dexmedetomidine in 1306 adult patients undergoing elective bariatric surgery between January 2017 and September 2023, comparing outcomes with a placebo group.Dexmedetomidine was administered during both the maintenance phase of anesthesia. Key parameters including intraoperative and postoperative complications, analgesic requirements, hemodynamics, and recovery profiles were meticulously monitored and analyzed. Dexmedetomidine demonstrated sedative and analgesic-sparing effects, coupled with cardiovascular stabilization and preservation of respiratory function. Notably, it significantly reduced the utilization of anesthetic drugs, postoperative opioids, and propofol during the surgical procedure. Furthermore, dexmedetomidine exhibited efficacy in attenuating propofol injection pain, mitigating stress responses during the critical phase of extubation, and diminishing postoperative pain along with associated analgesic requirements. However, a nuanced approach to dosage was imperative, as higher doses correlated with delayed respiratory recovery and an increased incidence of bradycardia.To summarize, dexmedetomidine as an adjuvant to general anesthesia in bariatric surgery presents notable advantages in enhancing recovery profiles, mitigating complications, and improving patient comfort. Optimal dosing strategies are paramount to harnessing its benefits while mitigating potential adverse effects, thereby optimizing perioperative care in this patient population.

The Impact of Physical Activity on Depression Treatment: A Literature Review

Introduction Engaging in physical exercise can have a significant impact on the treatment of mild-to-moderate mental health conditions, including depression. Existing antidepressant medications have limited clinical effectiveness as they fail to achieve a complete response in around 30% of depressed patients and do not induce remission in these individuals. Physical exercise can enhance the effects of antidepressant therapy in individuals with depression by boosting the health of neurons and improving the responsiveness to medication. Aim of the study The aim of the study is to investigate the role of physical activity in in the management of mental health diseases, especially depression. Materials and methods This study represents the current state of knowledge about the antidepressant effects of physical activity, particularly in the context of depressive disorders. It presents a comprehensive overview of how regular exercise can serve as an effective therapeutic strategy for managing depressive symptoms. PubMed and Google Scholar database was searched for articles written in English. The search included the keywords. Results Regular exercise significantly alleviates depressive symptoms through various mechanisms. Exercise enhances the production of endorphins, which improve mood and reduce anxiety. It also influences neurotransmitter systems, including serotonin, dopamine, and norepinephrine, which are crucial in regulating mood and emotion. Additionally, physical activity stimulates the production of brain-derived neurotrophic factor (BDNF) and transforming growth factor-beta 1 (TGF-β1), both of which support neurogenesis and synaptic plasticity, contributing to improved cognitive function and mood stabilization.

Semi-time-dependent stabilization results for asynchronously switched systems: An extended persistent dwell time switching strategy involving admissible transition information

This study investigates the stabilization problem for a kind of continuous-time asynchronously switched systems via a set of edge- or mode-dependent state-feedback controllers. To this end, an innovative switching strategy of admissible chain-dependent (or admissible edge-dependent) persistent dwell time property is presented by injecting the admissible transition chain (or admissible transition edge) notion into the existing persistent dwell time concept. Based on the admissible transition edges in a directed graph reported in the literature, the corresponding admissible transition chains can be determined. The individual allocation of transition weights for each admissible transition chain makes the presented admissible chain-dependent persistent dwell time switching less conservative than the other presented admissible edge-dependent persistent dwell time and the already existing mode-dependent persistent dwell time switching. Further, different from the Lyapunov functions commonly used in previous asynchronous stabilization works, a new semi-time-dependent Lyapunov function in a unique form that fits the nature of the discussed systems is suggested to provide a broader family of allowable switching signals. By the introduced switching and Lyapunov function approaches, new stability and stabilization criteria are formulated, through which the expected edge- or mode-dependent state-feedback controllers are devised. At last, the validity and applicability of the obtained stabilization solutions are demonstrated by a numerical example and a practical thermal system.

An observational cohort study examined the change point of kidney function stabilization in the initial period after transplantation

Baseline kidney function following kidney transplantation is often used in research and clinical decision-making yet is not well defined. Here, a method to determine baseline function was proposed and validated on three single-center retrospective cohorts consisting of 922 patients from Belgium (main cohort) and two validation cohorts of 987 patients from the Netherlands and 519 patients from Germany. For each transplant, a segmented regression model was fitted on the estimated glomerular filtration rate (eGFR) evolution during the first-year post-transplantation. This yielded estimates for change point timing, rate of eGFR change before and after change point and eGFR value at change point, now considered the “baseline function”. Associations of eGFR evolution with recipient/donor characteristics and the graft failure rate were assessed with linear regression and Cox regression respectively. The change point occurred on average at an eGFR value of 43.7±14.6 mL/min/1.73m2, at a median time of 6.5 days post-transplantation. Despite significant associations with several baseline donor-recipient characteristics (particularly, donor type; living vs deceased), the predictive value of these characteristics for eGFR value and timing of the change point was limited. This followed from a large heterogeneity within eGFR trajectories, which in turn indicated that favorable levels of kidney function could be reached despite a suboptimal initial evolution. Segmented regression consistently provided a good fit to early eGFR evolution, and its estimate of the change point can be a useful reference value in future analyses. Thus, our study shows that baseline kidney function after transplantation is heterogeneous and partly related to pretransplant donor characteristics.

Association between chronic intestinal failure etiology and eGFR trajectory in adults receiving home parenteral nutrition: A retrospective longitudinal cohort study.

Patients with chronic intestinal failure (CIF) are at increased risk of developing renal impairment. The aim of this study was to evaluate the occurrence of chronic kidney disease (CKD) in patients dependent on home parenteral nutrition (HPN) and assess risk factors for renal impairment, including patients with all mechanisms of CIF. This was a cohort study of patients initiated on HPN between March 1, 2015, and March 1, 2020, at a national UK IF Reference Centre. Patients were followed from their first discharge with HPN until HPN cessation or the end of follow-up on December 31, 2021. There were 357 patients included in the analysis. Median follow-up time was 4.7 years. At baseline, >40% of patients had renal impairment, with 15.4% fulfilling the criteria for CKD. Mean estimated glomerular filtration rate (eGFR) decreased significantly during the first year after initiation of HPN from 93.32 ml/min/1.73 m2 to 86.30 ml/min/1.73 m2 at the first year of follow-up (P = 0.002), with sequential stabilization of renal function. Increased age at HPN initiation and renal impairment at baseline were associated with decreased eGFR. By the end of follow-up, 6.7% patients developed renal calculi and 26.1% fulfilled the criteria for CKD. This is the largest study of renal function in patients receiving long-term HPN. After the first year following HPN initiation, the rate of decline in eGFR was similar to that expected in the general population. These findings should reassure patients and clinicians that close monitoring of renal function can lead to good outcomes.

#636 A phase 4, open label, multicenter prospective study of the safety and efficacy of agalsidase beta in Chinese patients with Fabry disease

Abstract Background and Aims Fabry disease (FD) is a rare inherited lysosomal storage disease caused by pathogenic GLA gene variants which result in a deficiency of the enzymatic activity of α-galactosidase A. Enzyme replacement therapy (ERT) is the mainstay of FD-specific treatment, but there are currently no reported clinical trials of ERT for FD in the Chinese population. This is the first phase 4 study to evaluate the safety and efficacy of ERT for FD in China since the approval of agalsidase beta in China in 2019. Method A 54-week, phase 4, open label, single arm, prospective, post-marketing surveillance (PMS) study of agalsidase beta (NCT05054387) was performed at 6 sites in China. Twenty-two Chinese ERT-naïve FD participants (≥8 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled and received infusions of agalsidase beta (Fabrazyme®, Sanofi) at a dose of 1.0 mg/kg every 2 weeks for up to 48 weeks. The primary endpoint was safety and tolerability of agalsidase beta. The endpoints of clinical efficacy included the changes of plasma globotriaosylceramide (GL-3), globotriaosylsphingosine (Lyso-GL-3), FD symptoms (including angiokeratoma, hypohidrosis, anhidrosis, abdominal pain, headache, tinnitus, heat tolerance, and activity tolerance), and eGFR from baseline to week 48. A post-hoc subgroup analysis was conducted to explore the differences in ERT efficacy between two subgroups of different ages (<30 years and ≥30 years). Results All 22 patients completed the study intervention. There were 18 males (81.8%) and the mean age of ERT initiation was 29.0 ± 13.5 years. Treatment-related adverse events (AEs) and infusion-associated reactions (IARs) were reported in 8 participants (36.4%), which was less than ∼60% as previously reported for IARs. Most AEs were mild or moderate and no AE caused permanent treatment discontinuation or death. The mean plasma GL-3 and Lyso-GL-3 levels decreased remarkably at week 6 and remained stable throughout the trial, with the mean percentage reduction from baseline to week 6 through week 48 ranged from −34.6% ± 27.4% to ­41.9% ± 14.9% and −58.8% ± 20.2% to ­64.9% ± 12.7%, respectively (Fig. 1a and b). The reduction was more remarkable for the classic male patients (n = 18; GL-3: 7.99 ± 2.19 ug/mL at baseline and 4.31 ± 1.71 ug/mL at week 48, −46.0% ± 18.4%; Lyso-GL-3: 83.11 ± 25.69 ng/mL at baseline and 25.89 ± 13.43 ng/mL at week 48, −67.8% ± 17.6%). Thirteen (59.1%) participants experienced improved FD symptoms at week 48, with no cases of worsening symptoms. The mean eGFR was 115.6 ± 37.3 mL/min/1.73 m2 at baseline and 118.4 ± 42.9 mL/min/1.73 m2 at week 48, with a change of 0.0 ± 12.4 mL/min/1.73 m2 from baseline to week 48 (Fig. 1c). In the subgroup analysis, participants were divided into the younger group with age <30 years (n = 11) and the older group with age ≥30 years (n = 11) according to their age of ERT initiation. At week 48, the reduction of mean plasma GL-3 (−47.1% ± 23.6% vs −22.0% ± 26.0%) and Lyso-GL-3 levels (−72.4 ± 17.3% vs −48.2% ± 19.8%), the stabilization of renal function (the mean change of eGFR from baseline to week 48: 5.2 ± 7.9 mL/min/1.73 m2 vs −5.2 ± 14.1 mL/min/1.73 m2) and the percentage of symptom improvement (81.8% vs. 36.4%) were generally more remarkable in the younger group than in the older group (Table 1). Conclusion This first phase 4 study of ERT for Fabry disease in China demonstrates that agalsidase beta is safe and well tolerated with a relatively low IAR rate, and effective in reducing plasma GL-3 and Lyso-GL-3, improving symptoms, and stabilizing renal function in Chinese patients with FD. Furthermore, the present study implies that patients who initiate ERT at a younger age benefit more from the therapy. Funding: Commercial support - Sanofi Pharmaceuticals.

#2811 Factor B inhibition with iptacopan in C3 glomerulopathy recurrence after transplantation: a case presentation

Abstract Background and Aims C3 glomerulopathy (C3G) is a clinical-pathological entity resulting from dysregulation of the alternative pathway of the complement system (APC) in the fluid phase. The recurrence risk of C3G after kidney transplantation is about 70% with high risk of graft loss. Standard treatment relies on nephroprotection and unspecific immunosuppression but there are currently new molecules that target specifically APC under development. A novel factor B inhibitor, iptacopan, has shown promising results both in native kidney and transplant recurrence cases in a phase II trial. Method We present a real-world clinical case of early C3G recurrence after kidney transplantation treated with iptacopan (Novartis MAPs program). Patient was vaccinated for encapsulated bacteria. Iptacopan was initiated 200 mg BID. We also present histological response. Results 38-year-old male with chronic kidney disease secondary to C3G initially presented with nephrotic syndrome and hematuria at the age of 31y following a respiratory infection. Blood test showed low serum C3 levels and the presence of C3 nephritic factor without pathological genetic alterations. Kidney biopsy confirmed membranoproliferative glomerulonephritis (MPGN) with predominant C3 deposition. He progressed to CKD stage G5 requiring hemodialysis instead of nephroprotection and immunosuppression with corticosteroids and mycophenolate; and addition with cyclophosphamide and rituximab after 19 months from onset. Five years later, the patient was admitted as first kidney transplant recipient from deceases donor Maastricht-III. Induction therapy included thymoglobulin, and tacrolimus, mycophenolate, and corticosteroids. He experienced delayed graft function requiring hemodialysis. An early biopsy proved C3G recurrence with endocapillary proliferation without C4d deposit and absence of donor specific antibodies. Despite conventional immunosuppression and addition of rituximab and plasma exchange; hemodialysis requirement still be present. So, because C3G pathophysiological base, iptacopan was begun with successful clinical response as he reached hemodialysis discontinuation; and kidney function stabilized after one year of treatment with an estimated glomerular filtration rate about 30 mL/min/1.73 m2. In the follow-up biopsy 5 months later, deposit of C3 in the glomerulus disappeared compared to the post-transplant recurrence but with persistence of endocapillary and mesangial proliferation (see Fig. 1). However, interestingly, he experienced a clinical recurrence with acute kidney injury and hematuria after unintentional iptacopan discontinuation, which was resolver after reinitiating and recovering its previous graft function. No infectious complications were observed after one year of treatment with factor B inhibitor. Conclusion New molecules under development that specifically target APC (fluid phase) may change the treatment scenario of C3G and its recurrence in kidney transplantation. We expose a real-practice early C3G recurrence after kidney transplantation successfully treated with iptacopan. The patient reached kidney function stabilization and disappearance of C3 deposits on immunofluorescence of the follow-up biopsy, identical results as the phase II clinical trial of iptacopan in C3G. So, we might conclude that iptacopan is an effective and safe option for C3G recurrence after kidney transplantation. But, data from randomized studies are needed in order to confirm the efficacy and safety of new inhibitors of the APC as iptacopan.

Giant Congenital Lobar Emphysema: A Rare Cause of Persistent Respiratory Distress in Neonatal Intensive Care

Congenital lobar emphysema (CLE) is a rare congenital anomaly of the lung causing excessive aeration of one or more lobes of a histologically normal lung. It manifests in the first weeks of life and rarely in the neonatal period, with respiratory distress due to compression atelectasis and often associated with mediastinal displacement. CLE poses a challenge in terms of diagnosis and positive pressure ventilation due to air trapping. We report the case of a newborn presenting with persistent respiratory distress. A thoracic CT scan was performed, confirming the diagnosis of CLE. The definitive diagnosis is provided by histology of the operative specimen, revealing emphysematous lesions. Treatment involves lobectomy after stabilization of respiratory function. Surgical abstention is possible for asymptomatic or paucisymptomatic lesions.

Long term outcomes and impact on renal function following radical cystectomy.

To assess clinical, oncological outcomes and impact on renal function in patients who underwent the radical cystectomy with pelvic lymphadenectomy for muscle invasive and high risk non-muscle invasive transitional cell carcinoma of urinary bladder without evidence of non-regional lymph nodes and distant metastasis. With curative intent total 156 patients underwent radical cystectomy with pelvic lymphadenectomy from January 2015 to December 2022. Total 132/156 patients had primary transitional cell carcinoma of bladder. Thirty patients, presented with obstructive nephropathy, operated after stabilization of renal function. Pre-operatively and post-operatively eGFR calculated using modified diet in renal disease formula. In present study 114 (86.36%) patients had high grade TCC, 70 (53.02%) patients had organ confined disease. Nodal extension seen in 74 (56.06%) patients. Perioperative mortality noted in 36 (27.2%) patients. The overall survival and recurrence free survival (RFS) over 5 years was 66.67 and 45.45%. RFS was significantly related to pathological stage, nodal status, histological-grade, positivity of surgical margin and time of surgery from diagnosis. Total 92/132 (69.7%) patients had recurrence. Pelvic recurrence in 10/92 (10.87%) whereas 82/92 (89.13%) patients had distant recurrence. Pre-operatively mean creatinine was 2.6 mg/dl and mean eGFR was 38.9 ml/h in patients who presented with obstructive nephropathy after stabilization of renal function. Post-operatively in 46/132 (34.8%) patients had improvement in eGFR while 86/132 (65.2%) patients had deterioration of eGFR over 62 months of median follow up. Radical cystectomy provides good overall survival outcomes. Pre-operative eGFR has significant impact on post-operative renal function in long term.

Our Experience in Using Extracorporeal Membrane Oxygenation in Patients with Refractory Cardiogenic Shock

Background Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is a critical care treatment option for patients with refractory cardiogenic shock. This method of temporary support of the cardiorespiratory system gives us and the patient time to restore organ function or is a «bridge» to other methods of treatment. Nevertheless, the issue of identifying the optimal time for VA ECMO implantation in patients with acute myocardial infarction complicated by refractory cardiogenic shock remains relevant.Aim To evaluate the efficiency of extracorporeal membrane oxygenation in various clinical situations in patients with acute myocardial infarction complicated by refractory cardiogenic shock and post-infarction damage to the valves of the heart.Material and method We present 3 patients with acute coronary syndrome complicated by refractory cardiogenic shock, of different age groups and comorbidities, who underwent veno-arterial extracorporeal oxygenation in various SCAI shock stages, and mechanical complications associated with acute myocardial infarction.Results In all the cases, stabilization of hemodynamics and heart function was achieved, and there were no hypoxic disorders of organs. In one case, a hemorrhagic complication associated with the VA ECMO procedure was noted. In one case, VA ECMO was performed as an intermediate stage for the correction of post-infarction mitral valve injury.Conclusion These clinical cases demonstrate the efficiency of the timely start of VA ECMO before the development of organ dysfunction, which allows restoring myocardial function, and helps maintain hemodynamic normalization before the cardiac surgical stage of treatment.

Nasal septum-derived chondroprogenitor cells control mandibular condylar resorption consequent to orthognathic surgery: a clinical trial.

Condylar resorption is an aggressive and disability form of temporomandibular joint (TMJ) degenerative disease, usually non-respondent to conservative or minimally invasive therapies and often leading to surgical intervention and prostheses implantation. This condition is also one of the most dreaded postoperative complications of orthognathic surgery, with severe cartilage erosion and loss of subchondral bone volume and mineral density, associated with a painful or not inflammatory processes. Because regenerative medicine has emerged as an alternative for orthopedic cases with advanced degenerative joint disease, we conducted a phase I/IIa clinical trial (U1111-1194-6997) to evaluate the safety and efficacy of autologous nasal septal chondroprogenitor cells. Ten participants underwent biopsy of the nasal septum cartilage during their orthognathic surgery. The harvested cells were cultured in vitro and analyzed for viability, presence of phenotype markers for mesenchymal stem and/or chondroprogenitor cells, and the potential to differentiate into chondrocytes, adipocytes, and osteoblasts. After the intra-articular injection of the cell therapy, clinical follow-up was performed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and computed tomography (CT) images. No serious adverse events related to the cell therapy injection were observed during the 12-month follow-up period. It was found that autologous chondroprogenitors reduced arthralgia, promoted stabilization of mandibular function and condylar volume, and regeneration of condylar tissues. This study demonstrates that chondroprogenitor cells from the nasal septum may be a promise strategy for the treatment of temporomandibular degenerative joint disease that do not respond to other conservative therapies.

Respiratory function in adult patients with spinal muscular atrophy treated with nusinersen - a monocenter observational study.

Insufficiency of respiratory muscles is the most important reason for mortality in the natural history of SMA. Thus, improvement or stabilization of respiratory function by disease-modifying therapies (DMT) is a very important issue. We examined respiratory function using forced vital capacity (FVC) in 42 adult SMA patients (2 SMA type 1, 15 SMA type 2, 24 SMA type 3, 1 SMA type 4, median age 37 years, range 17-61 years) treated with nusinersen for a median of 22.1 months (range 2.1 to 46.7 months). Change in FVC was assessed using mixed effects linear regression models. Baseline FVC differed significantly between SMA type 1 (4.0, 8.0%), 2 (median 22.0%, IQR 18.0-44.0), 3 (median 81.0%, IQR 67.0-90.8) and, respectively, type 4 (84.0%) patients reflecting the heterogeneity of respiratory impairment based on the SMA type in adulthood (p < 0.0001). FVC remained stable during follow-up (mean -0.047, 95% CI -0.115 to 0.020, p = 0.17); however, subgroup analysis showed an increase in FVC of type 2 patients (mean 0.144, 95% CI 0.086 to 0.202, p < 0.0001) and a decrease in FVC of type 3/4 patients (-0.142, 95% CI -0.239 to -0.044, p = 0.005). The observed improvement in FVC in patients with SMA type 2 can be seen as a therapeutic response differing from the progressive decline typically seen in the spontaneous course. For SMA type 3/4 patients approaching normal spirometry at baseline, FVC may only be of limited use as an outcome parameter due to ceiling effects.

An assessment of crucial structural contributors of HDAC6 inhibitors through fragment-based non-linear pattern recognition and molecular dynamics simulation approaches

Amidst the Zn2+-dependant isoforms of the HDAC family, HDAC6 has emerged as a potential target associated with an array of diseases, especially cancer and neuronal disorders like Rett’s Syndrome, Alzheimer’s disease, Huntington’s disease, etc. Also, despite the availability of a handful of HDAC inhibitors in the market, their non-selective nature has restricted their use in different disease conditions. In this situation, the development of selective and potent HDAC6 inhibitors will provide efficacious therapeutic agents to treat different diseases. In this context, this study has been carried out to evaluate the potential structural contributors of quinazoline-cap-containing HDAC6 inhibitors via machine learning (ML), conventional classification-dependant QSAR, and MD simulation-based binding mode of interaction analysis toward HDAC6 binding. This combined conventional and modern molecular modeling study has revealed the significance of the quinazoline moiety, substitutions present at the quinazoline cap group, as well as the importance of molecular property, number of hydrogen bond donor-acceptor functions, carbon-chlorine distance that significantly affects the HDAC6 binding of these inhibitors, subsequently affecting their potency . Interestingly, the study also revealed that the substitutions such as the chloroethyl group, and bulky quinazolinyl cap group can affect the binding of the cap function with the amino acid residues present in the loops proximal to the catalytic site of HDAC6. Such contributions of cap groups can lead to both stabilization and destabilization of the cap function after occupying the hydrophobic catalytic site by the aryl hydroxamate linker-ZBG functions.

Optimal intestinal graft selection for reconstruction of extended ureteral stricture: an animal model study

Introduction. The prevalence of patients with extended ureteral strictures has been steadily increasing over the past decades. When it is not possible to perform reconstruction with the tissues of the urinary system, the best solution is intestinal replacement plasty. However, despite the great world experience, the search for the optimal method of intestinal reconstruction does not stop, which determines the relevance of conducting an experimental prospective study.Objective. To evaluate morphological changes in renal parenchyma after ureteral replacement reconstruction by segments of small and large intestine.Materials &amp; methods. Fifteen white giant rabbits (6-months-old, weighing 5 kg) were divided into three groups. Group A (n = 5) underwent small intestine [ilealplasty] replacement plasty. Group B (n = 5) double-flap ileoplasty using the Yang-Monti technique. Group C (n = 5) – large intestine [coloplasy] ureteral reconstruction. Before the operation and before withdrawal from the experiment, the level of creatinine and electrolytes was assessed, kidney ultrasound was performed on days 2, 5, 10. Excretory urography was performed to assess the patency of the anastomoses. Animals were withdrawn from the experiment from day 10 to 30. The material used for morphological study included kidneys from the operated and intact sides, proximal and distal anastomoses.Results. No increase in creatinine level, metabolic disorders were detected in animals. According to ultrasound data, hydronephrosis developed in all animals on day 2 and remained unchanged during the entire follow-up. Group A: no complications were detected. Histologically, the renal parenchyma showed moderate signs of chronic inflammation, single foci of lymphoid infiltration, but there were no irreversible processes in the form of necrosis and sclerosis. Group B: complications — stricture in the anastomosis area of the detubularised fragments and necrosis of the small intestine due to compression of the mesentery by the graft vascular stem. Histologically there were marked dilatation of the tubules at all levels, enlargement of the Bowman-Shumlansky capsule, as well as signs of moderate inflammatory process, there were hydropic and hyaline-droplet dystrophy, tubular necrosis foci. Group C: complications — accumulation of a significant amount of grit, mucus, and fibrin in the colocystoanastomosis area. Histologically, the renal parenchyma showed a marked inflammatory process, in particular, purulent inflammation with demarcation zones, infiltration with polymorphonuclear leukocytes and bacterial cells, foci of necrosis and sclerosis of both stroma and tubules, dilatation of tubules and Bowman-Schumlansky capsules.Conclusion. The use of an unchanged ileal-graft reconstruction of an extended ureteral defect showed acceptable histological results in an animal model, which confirms the feasibility of its use in clinical practice. The absence of foci of necrosis and fibrosis in the renal parenchyma indicates the preserved functional potential, which suggests the stabilization of renal function in the long term.

Evolving Role of Viltolarsen for Treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is one of the most prevalent X-linked inherited neuromuscular disorders, with an estimated incidence between 1 in 3500 and 5000 live male births. The median life expectancy at birth is around 30years due to a rapid and severe disease progression. Currently, there is no cure for DMD, and the standard of care is mainly palliative therapy and glucocorticoids to mitigate symptoms and improve quality of life. Recent advances in phosphorodiamidate morpholino antisense oligonucleotide (PMO) technology has proven optimistic in providing a disease-modifying therapy rather than a palliative treatment option through correcting the primary genetic defect of DMD by exon skipping. However, as a result of the high variance in mutations of the dystrophin gene causing DMD, it has been challenging to tailor an effective therapy in most patients. Viltolarsen is effective in 8% of patients and accurately skips exon53, reestablishing the reading frame and producing a functional form of dystrophin and milder disease phenotype. Results of recently concluded preclinical and clinical trials show significantly increased dystrophin protein expression, no severe adverse effects, and stabilization of motor function. In summary, viltolarsen has provided hope for those working toward giving patients a safe and viable treatment option for managing DMD. This review summarizes an overview of the presentation, pathophysiology, genetics, and current treatment guidelines of DMD, pharmacological profile of viltolarsen, and a summary of the safety and efficacy with additional insights using recent clinical trial data.

Stereotactic high-dose irradiation for intramedullary metastases

To study the results of stereotactic high-dose irradiation for IMM considering local control of metastases, neurological status and life expectancy. Nineteen patients with 29 IMMs underwent high-dose irradiation (Cyber Knife G4 and TrueBeam STx devices) between 2016 and 2022. There were 1-10 fractions, radiation dose 14.0-35.0 Gy with isodose 70-100%. Local control and new spinal cord metastases were assessed using contrast-enhanced MRI. Clinical status and neurological functions were assessed using the Karnofsky and McCormick scales. Local control rates were 91% and 78% after 6 and 12 months, respectively. Overall survival after treatment was 7.3 months, 6- and 12-month overall survival - 58% and 37%, respectively. In addition, 8 patients were available for follow-up. Of these, 6 ones demonstrated improvement or stabilization of neurological function after treatment. The main cause of death was progression of the underlying disease. No significant treatment-related toxic effects were observed. High-dose irradiation is a safe, effective and time-saving treatment for IMM. Considering unadvisable surgical methods and chemotherapy for this pathology, we can recommend high-dose irradiation for patients with spinal cord metastases.

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort.

Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history of patients with OAs remains unresolved, specifically with regard to the impact of cardiac complications. We therefore performed a retrospective study to address this issue at our Referral Center for Pediatric Inherited Errors of Metabolism. Sixty patients with OAs (propionic (PA), methylmalonic (MMA) and isovaleric acidemias and maple syrup urine disease) diagnosed from 2000 to 2022 were systematically assessed at baseline and at follow-up. Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). The presence of DCM was associated with the worst prognosis. The rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA with cardiomyopathy; 35% in MMA with cardiomyopathy; and 23% in MMA without cardiomyopathy. Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. Cardiac involvement was documented in about one third of children diagnosed with classical OAs, confined to PA and MMA, and was often associated with poor outcome in over 50%. Etiological diagnosis of OAs is essential in guiding management and risk stratification.