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

Introduction: Vitamin D-dependent rickets type 2 (VDDR2) is traditionally defined by biallelic vitamin D receptor (VDR) mutations causing resistance to 1,25(OH)₂D. We describe a case of the classical VDDR2 phenotype with a single VDR mutation and an interesting physiological adaptation. Case: A female diagnosed with rickets at age three presented with a femoral fracture, severe short stature, hypocalcemia (2.1 mmol/L; NR 2.35–2.70), hypophosphatemia (0.8 mmol/L; NR 1.5–2.10), and evidence of renal phosphate wasting (TMP/GFR 0.5 mmol/L; NR 1.5–2.4). Biochemistry showed markedly elevated alkaline phosphatase (1,227 IU/L; NR 50–136) and secondary hyperparathyroidism (20.7 pmol/L; NR 0.8–7.8). Despite hypocalcemia, 1,25(OH)₂D was significantly elevated (>450 pmol/L; NR 60–150), consistent with VDDR2. There was no initial family history; however, subsequent evaluation of her mother—prompted by the patient’s diagnosis—revealed a similar biochemical profile, along with short stature (142 cm) and a history of multiple fractures. Genetic analysis in both individuals identified a heterozygous missense mutation in exon 10 of the VDR gene, affecting the ligand-binding domain, supporting a pattern of dominant inheritance. The patient was treated with cholecalciferol (1,200 IU daily), calcitriol (5–6 µg daily), and calcium carbonate (2,000 mg daily). Although biochemical responsiveness to therapy was evident, poor adherence resulted in suboptimal metabolic control throughout childhood and adolescence, including a second fracture at age 15 and a final adult height of 124 cm. Notably, calcium and phosphate levels progressively normalized after puberty, with sustained biochemical stability despite the patient omitting the treatment. Conclusion This case provides two important insights. First, it represents the fourth reported case worldwide demonstrating a dominant-negative effect of a VDR gene mutation, whereby a single mutant receptor interferes with wildtype VDR function. Second, it highlights postpubertal calcium adaptation, in which vitamin D–independent intestinal absorption may restore mineral homeostasis, and disease severity can attenuate over time through adaptive physiological mechanisms.
Calcium ; Mutation ; Vitamin D ; Rickets

Abstract Vitamin D deficiency is a significant health issue, particularly among office workers. This literature review emphasizes the availability of evidence on vitamin D deficiency and its impacts on musculoskeletal health and immune functions, especially amongst office workers. A literature search of PubMed, Scopus, and Web of Science identified relevant studies on the relationship between vitamin D status and musculoskeletal health and infection risks, highlighting the prevalence of vitamin D deficiency in office workers due to limited sunlight exposure and sedentary lifestyles. The risks of osteoporosis, muscle weakness, and musculoskeletal pain, as well as impaired immune system function, are carefully examined. Potential intervention strategies include implementing work schedules allowing for outdoor breaks, providing access to vitamin D-fortified foods or supplements, and routine screening for vitamin D levels. Addressing the low level of vitamin D in office workers is essential for promoting musculoskeletal health, supporting immune functions, and enhancing workforce productivity. This review underscores the need for further research and the implementation of evidence-based interventions to mitigate the impact of vitamin D deficiency in this population.
Vitamin D deficiency ; office workers ; musculoskeletal ; Immunity

INTRODUCTION

Despite advancements in surgical techniques aimed at preserving parathyroid function, postoperative hypocalcemia (PoH) remains a challenge following elective total thyroidectomy. Management typically involves postoperative calcium supplementation; however, some studies suggest preoperative calcium and/or vitamin D supplementation may prevent PoH. This paper analyzed existing studies to determine efficacy of preoperative calcium, with or without vitamin D, in preventing hypocalcemia in total thyroidectomy patients. Level of Evidence: Meta-analysis, Level IV.

A systematic review and meta-analysis was conducted with PROSPERO Registration No. CRD42024426410. Searches were performed on PubMED, PubMED Central, Embase, Cochrane Library, and HERDIN without date or language restrictions. Relevant studies underwent multiple screenings, with accepted individual studies assessed for bias or quality. Meta-analysis was performed using SPSS version 24.

A total of 345 studies were initially identified. Following deduplication, exclusion, and quality appraisal, 8 studies were included for analysis. Random effects model was utilized for all analysis due to heterogeneity in data. Results indicate that preoperative calcium, with or without vitamin D supplementation, correlated with higher postoperative calcium levels (z = 3.09, p < 0.001), reduced incidence of laboratory (z= 2.05, p = 0.03) and clinical hypocalcemia (z= 2.94, p < 0.001), and shorter hospital stay (z= 2.32, p = 0.01).

Results from the conducted meta-analysis support the proposed practice of providing calcium with or without vitamin D supplementation among patients who are to undergo total thyroidectomy procedures to prevent postoperative hypocalcemia.

Lichen planus (LP) is a chronic inflammatory dermatosis with a prevalence of 0.1%-4%, typically affecting individuals aged 30-60 years. Isolated lip involvement is uncommon, seen in 0.51%-8.9% of cases, predominantly in middle-aged men. We report a 58-year-old male with well-controlled diabetes who developed isolated lower lip LP, initially misdiagnosed as herpes simplex virus infection and unresponsive to oral acyclovir. Dermoscopy and histopathology confirmed the diagnosis. The patient was managed with a novel regimen: Tacrolimus 0.1% ointment (morning) and tretinoin 0.025% cream (night), alongside sunscreen and petroleum jelly. After 4 weeks, marked improvement was observed with flattened lesions and reduced pruritus. This case underscores the potential efficacy of combining a calcineurin inhibitor and a retinoid as a corticosteroid-sparing alternative for localized LP. Clinically, this approach offers a valuable treatment option for patients with lip LP showing suboptimal response to initial corticosteroid therapy, minimizing steroid-related adverse effects and improving therapeutic outcomes.

OBJECTIVES: To investigate the changes in blood levels of calcium and bone metabolism biochemical markers in patients with primary osteoporosis receiving treatment with denosumab. METHODS: Seventy-three patients with primary osteoporosis treated in our Department between December, 2021 and December 2023 were enrolled. All the patients were treated with calcium supplements, vitamin D and calcitriol in addition to regular denosumab treatment every 6 months. Blood calcium, parathyroid hormone (PTH), osteocalcin (OC), type I procollagen amino-terminal propeptide (PINP), and type I collagen carboxy-terminal telopeptide β special sequence (β‑CTX) data before and at 3, 6, 9, and 12 months after the first treatment were collected from each patient. RESULTS: Three months after the first denosumab treatment, the bone turnover markers (BTMs) OC, PINP, and β-CTX were significantly decreased compared to their baseline levels by 39.5% (P<0.001), 56.2% (P<0.001), and 81.8% (P<0.001), respectively. At 6, 9, and 12 months of treatment, OC, PINP, and β-CTX remained significantly lower than their baseline levels (P<0.001). Blood calcium level was decreased (P<0.05) and PTH level increased (P<0.05) significantly in these patients at months of denosumab treatment, but their levels were comparable to the baseline levels at 6, 9, and 12 months of the treatment (P>0.05). CONCLUSIONS Denosumab can suppress BTMs and has a good therapeutic effect in patients with primary osteoporosis, but reduction of blood calcium and elevation of PTH levels can occur during the first 3 months in spite of calcium supplementation. Blood calcium and PTH levels can recover the baseline levels as the treatment extended, suggesting the importance of monitoring blood calcium and PTH levels during denosumab treatment.
Humans ; Denosumab/therapeutic use* ; Calcium/blood* ; Parathyroid Hormone/blood* ; Biomarkers/blood* ; Osteoporosis/blood* ; Osteocalcin/blood* ; Procollagen/blood* ; Female ; Collagen Type I/blood* ; Peptide Fragments/blood* ; Bone Density Conservation Agents/therapeutic use* ; Bone and Bones/metabolism* ; Male ; Middle Aged ; Vitamin D ; Peptides/blood* ; Aged

OBJECTIVES: To prepare a stable mouse model of chronic liver fibrosis induced by dietary vitamin A (VA) deficiency combined with CCl₄ injections. METHODS: A total of 126 Balb/c mice were randomized into 3 groups for feeding with a normal VA diet or a VA-deficient diet containing 500 or 200 IU/kg VA. After 4 weeks of feeding, half of the mice in each group were given intraperitoneal injections of 5% CCl₄ (10 mL/kg, twice a week) for 8 weeks. Serum retinol, ALT/AST and liver index of the mice were examined, liver tissue pathologies were observed with HE and Masson staining, and liver fibrosis score and oxidative stress level were evaluated. RESULTS: Four weeks of VA-deficient feeding, especially at 200 IU/kg, significantly lowered serum retinol level of the mice. CCl₄ injections for 8 weeks obviously increased liver index and ALT/AST and caused obvious liver fibrosis in all the mice, but liver pathologies were more severe in the 2 VA-deficient groups; severe liver necrosis with inflammatory cell infiltration was observed in 200 IU/kg VA group, where 2 mice died. After discontinuation of CCl₄, the mice with normal dietary VA showed gradual recovery of the liver index, ALT/AST, liver cord structure and liver fibrosis; the mice with VA deficiency, however, showed no significant improvements in these parameters, and the mice with 200 IU/kg VA still had serious abdominal adhesion, false lobules and massive inflammatory cell infiltration with a fibrosis stage score of 3. The oxidative damage index 8-OHdG was significantly higher in 500 IU/kg VA group than in normal VA group after CCl₄ modeling. CONCLUSIONS Feeding with diet containing 500 IU/kg VA for 4 weeks and 10 mL/kg CCl₄ injections for 8 weeks can result in stable moderate to severe liver fibrosis in mice without spontaneous reversal at 8 weeks of drug withdrawal.
Animals ; Mice ; Mice, Inbred BALB C ; Disease Models, Animal ; Carbon Tetrachloride ; Vitamin A Deficiency/complications* ; Male ; Liver Cirrhosis/etiology* ; Oxidative Stress ; Vitamin A/blood*

General anesthesia, pivotal for surgical procedures, requires precise depth monitoring to mitigate risks ranging from intraoperative awareness to postoperative cognitive impairments. Traditional assessment methods, relying on physiological indicators or behavioral responses, fall short of accurately capturing the nuanced states of unconsciousness. This study introduces a machine learning-based approach to decode anesthesia depth, leveraging EEG data across different anesthesia states induced by propofol and esketamine in rats. Our findings demonstrate the model's robust predictive accuracy, underscored by a novel intra-subject dataset partitioning and a 5-fold cross-validation method. The research diverges from conventional monitoring by utilizing anesthetic infusion rates as objective indicators of anesthesia states, highlighting distinct EEG patterns and enhancing prediction accuracy. Moreover, the model's ability to generalize across individuals suggests its potential for broad clinical application, distinguishing between anesthetic agents and their depths. Despite relying on rat EEG data, which poses questions about real-world applicability, our approach marks a significant advance in anesthesia monitoring.
Animals ; Machine Learning ; Electroencephalography/methods* ; Ketamine/administration & dosage* ; Rats ; Male ; Propofol/administration & dosage* ; Rats, Sprague-Dawley ; Anesthesia, General/methods* ; Brain/physiology* ; Intraoperative Neurophysiological Monitoring/methods*

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans ; Antiviral Agents/therapeutic use* ; Animals ; Male ; Adult ; Mice ; Female ; Endonucleases/antagonists & inhibitors* ; Influenza, Human/drug therapy* ; Young Adult ; Dibenzothiepins/pharmacology* ; Oseltamivir/pharmacology* ; Middle Aged ; Triazines/pharmacology* ; Thiepins/pharmacology* ; Influenza B virus/drug effects* ; Influenza A Virus, H1N1 Subtype/drug effects* ; Pyridines/pharmacology* ; Morpholines ; Pyridones