Introduction: Diabetic sensorimotor polyneuropathy (DSPN) is a common complication of long-standing diabetes mellitus marked by neuropathic pain and sensory deficits. Evidence supporting combination antioxidant and vitamin-based therapy remains limited, particularly in patients with chronic disease. This study aims to determine symptom improvement after 12 weeks of oral alpha-lipoic acid, vitamin B complex, and vitamin E (Bionerv E+) in chronic diabetic patients with symptomatic DSPN. Methodology: This single-centre, randomized, double-blind, placebocontrolled trial at HCTM enrolled 31 patients with symptomatic DSPN, assigned to Bionerv E+ (n = 16) or placebo (n = 15) for 12 weeks. Symptoms were assessed at baseline and post intervention using the Neuropathy Impairment Score–Lower Limb (NIS LL), Short Form McGill Pain Questionnaire (SF MPQ), Toronto Clinical Scoring System (TCSS), and nerve conduction studies (NCS). Results: A total of 31 participants were recruited; 18 completed the study (11 intervention, 7 placebo). The cohort was predominantly elderly (median age 68 ± 12 years), male (51.6%), with long-standing diabetes (mean duration of 18.6 ± 8.2 years), and a mean hemoglobin A1c of 7.3 ± 0.6%. A statistically significant reduction in TCSS score was observed in the intervention arm (5.5 ± 3.8 vs 3.3 ± 3.4; p = 0.002), indicating improvement in neuropathic symptom severity in this chronic population. The SF MPQ scores showed a downward trend in both arms, but were not statistically significant. Among intervention participants who completed sural NCS, three patients demonstrated normalization, and five showed partial amplitude gains, indicating directional improvement in nerve function. Four patients with normal baseline studies exhibited further amplitude gains. Otherwise, limited improvements were observed in those with abnormal conduction velocity parameters. Bionerv E+ was well tolerated, with only mild and self-limiting adverse events reported. Conclusion Short-term supplementation with Bionerv E+ showed improvement in neuropathic symptoms among longstanding diabetic patients. However, longer-term studies with larger cohorts are necessary to determine its effects on patients with DSPN.
Thioctic Acid ; Vitamin B Complex ; Polyneuropathies ; Vitamin E

BACKGROUND

Carney complex (CNC) is a rare multiple endocrine neoplasia syndrome caused by PRKAR1A gene mutation and  characterized by lentigines, myxomatous tumors and various endocrine neoplasms.

CASE PRESENTATION

This is a case of a 52-year-old male patient who underwent echocardiogram for intermittent palpitations and near-syncopal attack, which revealed a left atrial myxoma. The patient also exhibited multiple lentigines and had a history of histologicallyconfirmed papillary thyroid carcinoma. Surgical excision and subsequent histopathologic examination confirmed cardiac myxoma, fulfilling three major Stratakis criteria for CNC.

DISCUSSION

This case highlights the importance of a thorough history and physical examination with a strong understanding of the syndrome’s features being key to recognizing the disease. Increasing awareness and reinforcing knowledge of CNC are crucial for preventing misdiagnosis and ensuring effective management of this rare condition. To our knowledge, this is the first published case report of CNC in the Philippines, emphasizing the need for heightened regional awareness.

CONCLUSION

CNC may present with subtle or nonspecific symptoms and atypical tumor locations. Early recognition through a high index of suspicion, targeted imaging and a multidisciplinary approach is critical to optimize outcomes and guide family screening in this rare syndrome.

Human ; Male ; Middle Aged: 45-64 Yrs Old ; Multiple Endocrine Neoplasia ; Carney Complex ; Myxoma ; Syndrome ; Neoplasms ; Mutation ; Lentigo ; Genes

OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a child with hereditary Spastic paraplegia type 52 (SPG52) due to variant of AP4S1 gene. METHODS: A child diagnosed with SPG52 at the Department of Pediatrics of the First Affiliated Hospital of Anhui Medical University in May 2010 was selected as the study subject. Whole-exome sequencing (WES) was carried out for the child and his parents. Candidate variants were confirmed by Sanger sequencing. Pathogenicity of the candidate variant was interpreted according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). The study protocol was approved by the Ethics Committee of the Hospital (Ethics No.: PJ2024-04-56). RESULTS: The child had presented with global developmental delay from infancy, and featured progressive lower limb spasticity, contractures, talipes equinovarus, and muscle weakness, but with no significant facial dysmorphism. His first febrile seizure occurred before one year of age, followed by several afebrile seizures. The seizures had remitted after 3 to 4 years of antiepileptic therapy, and electroencephalography was normal. However, he had severe intellectual disability, and MRI revealed reduced white matter. WES identified a homozygous AP4S1 c.289C>T (p.Arg97*) variant in the child, for which both of his parents were heterozygous carriers. The variant was rated as pathogenic based on the ACMG guidelines. Literature review has identified 8 publications on SPG52, involving 18 patients from 12 pedigrees. Combined with our case, 14 had carried homozygous variants of the AP4S1 gene, 3 had compound heterozygous variants, and 2 had heterozygous variants, involving 12 distinct variant sites. The cohort included 7 males and 12 females. All patients exhibited progressive lower limb spasticity and weakness as the primary feature, with certain loss of independent ambulation. Most patients had intellectual disability, some had distinctive facial features, though febrile seizures or epilepsy were common. Electroencephalography often showed increased slow-wave activity. Brain MRI frequently demonstrated ventriculomegaly, a thin corpus callosum, and reduced white matter. CONCLUSION The homozygous c.289C>T (p.Arg97*) variant of the AP4S1 gene probably underlay the pathogenesis of SPG52 in this child. Above discovery has expanded the mutational spectrum of AP4S1 and provided valuable insights for the genetic diagnosis, counseling, and clinical management of SPG52.
Humans ; Male ; Spastic Paraplegia, Hereditary/genetics* ; Child, Preschool ; Female ; Exome Sequencing ; Child ; Infant ; Adaptor Protein Complex 4/genetics* ; Phenotype ; Mutation

OBJECTIVE: To explore the clinical characteristics and genetic etiology of STISS syndrome (an autosomal dominant disorder characterized by ubiquitin-proteasome system dysfunction) in a child. METHODS: A child with STISS syndrome diagnosed at the Affiliated Women and Children's Hospital of Ningbo University in September 2024 due to "abnormal development of external genitalia" was selected as the study subject. Clinical data were retrospectively collected. Peripheral blood samples were obtained from the child and his family members. Following genomic DNA extraction, whole-exome sequencing (WES) and Sanger sequencing validation were carried out. Pathogenicity of the candidate variants was assessed based on the guidelines from American College of Medical Genetics and Genomics (ACMG). The study was approved by the Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The proband, a 16-year-old boy, presented with micropenis, testicular hypoplasia, delayed sexual development, insulin resistance, diabetes mellitus, and obesity. WES revealed that he has harbored a c.934del; p.Met312TrpfsTer3 frameshifting variant of the PSMD12 gene, which was unreported previously. Sanger sequencing confirmed that the variant to be de novo in origin. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2_supporting+PM6_supporting). The variant was predicted to result in a premature termination codon. Bioinformatics analysis suggested that the amino acid at position 312 is highly conserved, and the variant may therefore affect the protein structure. CONCLUSION Patients with STISS syndrome exhibit clinical features including psychomotor retardation, intellectual disability, distinctive facial features, and urogenital abnormalities. The c.934del (p.Met312TrpfsTer3) frameshift variant of the PSMD12 gene probably underlay the pathogenesis in the proband. Above finding has enriched the mutational spectrum of the PSMD12 gene.
Adolescent ; Humans ; Male ; Exome Sequencing ; Mutation ; Proteasome Endopeptidase Complex/genetics* ; Syndrome

OBJECTIVES

o demonstrate the utility of the supraclavicular artery island flap (SCAIF) as a viable alternative to free tissue transfer for reconstruction of large cervicofacial defects.

METHODS

Design:Case Report

Setting:Tertiary National University Hospital

Patient: One

RESULTS

A 43-year-old woman with a giant cavernous hemangioma measuring 21.43 x 9.91 x 20.75cm underwent tumor resection and immediate reconstruction using SCAIF. Following preoperative embolization and complete tumor excision, an 11 x 15cm cervicofacial defect was successfully reconstructed using SCAIF. The patient experienced post-operative complications including multiple wound dehiscences and hypertrophic scar formation but achieved significant functional and aesthetic improvement. At three months follow up, the patient reported cessation of bleeding episodes, improved feeding capacity, and enhanced quality of life despite persistent tracheostomy dependence. Plans for secondary surgery include scar revision, commissuroplasty, and intralesional steroid injections.

CONCLUSION

The supraclavicular artery island flap presents a practical, cost-effective alternative to free tissue transfer for extensive cervicofacial reconstruction, particularly in resource-limited environments or in patients where free tissue transfer is contraindicated. Advantages include good color match, wide arc of rotation, and ease of harvest. Despite potential complications, it offers excellent functional and aesthetic outcomes with acceptable donor site morbidity.

Human ; Female ; Young Adult: 19-24 Yrs Old ; Aids-related Complex ; Neoplasms ; Costs And Cost Analysis ; General Surgery ; Environment ; Research Report ; Steroids ; Tracheostomy ; Hospitals

Posterior fossa malformations are rare cyst-like pathologies of the central nervous system. Outcomes of patients with these conditions are largely documented in fetal or early childhood studies as most cases are non-compatible with life. Also, different schemes to categorize these occurrences have been proposed. One classification puts forth that the entities are a continuum of pathologies, called the Dandy Walker Complex, wherein Mega Cisterna Magna is the most benign to Dandy Walker Malformation as the most severe form. We report the first case of a patient with a mixed presentation of Mega Cisterna Magna having extracranial manifestations of Dandy Walker Malformation reaching her adult years. The patient is a 26-year-old female who was apparently well until she presented with recurrent headache and seizure episodes of 2-year duration. She had an unremarkable birth and childhood history, apart from learning difficulties in school. In her adult years, she gave birth to an infant with multiple physical anomalies. She has a maternal uncle with abnormal facie and intellectual disability. Physical examination of the patient exhibited a bulging occiput, hypertelorism, down-slanting palpebral fissures, large globular nose, large ear lobules, high arched palate, and clinodactyly. Neurologic examination was unremarkable. Magnetic resonance imaging confirmed Mega Cisterna Magna and was deemed non-surgical. She remained seizure-free during admission as well as on followup, maintained on Phenytoin. The existence of a Dandy-Walker continuum is still debated, as the link among the disease entities are yet to be established using developmental or genetic studies. This case, however, supports the Dandy-Walker Complex classification by demonstrating a rare combination of Mega Cisterna Magna with features of Dandy-Walker Malformation in an adult. This can contribute to disease definition and eventually to the discovery of the pathobiological mechanisms of posterior fossa cysts, and to appropriate diagnosis and management.

Human ; Female ; Adult: 25-44 Yrs Old ; Dandy-walker Malformation ; Dandy-walker Complex ; Dandy-walker Syndrome ; Rare Diseases

OBJECTIVES: To investigate the mechanism of DDX17 for regulating proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) during the development of pulmonary hypertension (PH). METHODS: In murine PASMCs cultured under normoxic or hypoxic conditions, the effects of transfection with si-Ddx17 and insulin treatment, alone or in combination, on cell proliferation and migration were evaluated using Ki-67 immunofluorescence staining, scratch assay and Transwell assay. Western Blotting was performed to detect the changes in protein expression levels of DDX17, 4EBP1, S6, p-4EBP1, and p-S6. In a mouse model of PH induced by intraperitoneal injection of monocrotaline (MCT), the changes in pulmonary vasculature were examined using HE staining following tail vein injection of AD-Ddx17i. RESULTS: The PASMCs in hypoxic culture exhibited significantly enhanced cell proliferation and migration and protein expressions of p-4EBP1 and p-S6, and these changes were obviously reversed by transfection with si-Ddx17. Treatment with insulin significantly attenuated the effect of si-Ddx17 against hypoxic exposure-induced changes in PASMCs. In the mouse model of MCT-induced PH, transfection with AD-Ddx17i obviously alleviated pulmonary vascular stenosis and intimal hyperplasia. CONCLUSIONS The expression of DDX17 is elevated in hypoxia-induced PASMCs and PH mice, and silencing DDX17 significantly inhibits PASMC proliferation and migration in vitro and pulmonary vascular remodeling in PH mice by reducing mTORC1 activity.
Animals ; Cell Proliferation ; Cell Movement ; DEAD-box RNA Helicases/metabolism* ; Myocytes, Smooth Muscle/metabolism* ; Mice ; Pulmonary Artery/cytology* ; Hypertension, Pulmonary/metabolism* ; Mechanistic Target of Rapamycin Complex 1 ; Cells, Cultured ; Muscle, Smooth, Vascular/cytology*

Anxiety disorder is a major symptom of autism spectrum disorder (ASD) with a comorbidity rate of ~40%. However, the neural mechanisms of the emergence of anxiety in ASD remain unclear. In our study, we found that hyperactivity of basolateral amygdala (BLA) pyramidal neurons (PNs) in Shank3 InsG3680 knock-in (InsG3680^+/+) mice is involved in the development of anxiety. Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs. Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680^+/+ mice. Further study found that the diminished control of the BLA by medial prefrontal cortex (mPFC) and optogenetic activation of the mPFC-BLA pathway also had a rescue effect, which increased the feedforward inhibition of the BLA. Taken together, our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680^+/+ mice.
Animals ; Prefrontal Cortex/metabolism* ; Basolateral Nuclear Complex/metabolism* ; Mice ; Anxiety/metabolism* ; Nerve Tissue Proteins/genetics* ; Male ; Gene Knock-In Techniques ; Pyramidal Cells/physiology* ; Mice, Transgenic ; Neural Pathways/physiopathology* ; Mice, Inbred C57BL ; Microfilament Proteins

Ferroptosis is a form of cell death elicited by an imbalance in intracellular iron concentrations, leading to enhanced lipid peroxidation. In neurological disorders, both oxidative stress and mitochondrial damage can contribute to ferroptosis, resulting in nerve cell dysfunction and death. The ubiquitin-proteasome system (UPS) refers to a cellular pathway in which specific proteins are tagged with ubiquitin for recognition and degradation by the proteasome. In neurological conditions, the UPS plays a significant role in regulating ferroptosis. In this review, we outline how the UPS regulates iron metabolism, ferroptosis, and their interplay in neurological diseases. In addition, we discuss the future application of small-molecule inhibitors and identify potential drug targets. Further investigation into the mechanisms of UPS-mediated ferroptosis will provide novel insights and strategies for therapeutic interventions and clinical applications in neurological diseases.
Ferroptosis/physiology* ; Humans ; Proteasome Endopeptidase Complex/metabolism* ; Nervous System Diseases/metabolism* ; Animals ; Ubiquitin/metabolism* ; Iron/metabolism*

Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis. However, mechanisms associated with stem cell senescence require further investigation. In this study, we conducted a proteomic analysis of human dental pulp stem cells (HDPSCs) obtained from individuals of various ages. Our findings showed that the expression of NUP62 was decreased in aged HDPSCs. We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo. Conversely, the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs. Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression, we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1. This, in turn, stimulates the transcription of the epigenetic enzyme NSD2. Finally, the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes (HMGA1, HMGA2, and SIRT6). Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.
Humans ; Dental Pulp/cytology* ; Nuclear Pore Complex Proteins/genetics* ; Cellular Senescence/genetics* ; Stem Cells/metabolism* ; Epigenesis, Genetic ; Cell Proliferation ; Cell Differentiation ; Histone-Lysine N-Methyltransferase/metabolism* ; Cells, Cultured ; Cellular Reprogramming ; Cell Movement ; Proteomics