Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin‐2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant‐negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS‐disease gene and expands its clinical and genetic spectrum to include recessive loss‐of‐function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.     

Nutrient-related issues affecting successful experimental orthotopic small bowel transplantation

BACKGROUND: This study tested the effectiveness of a nutrient-rich preservation solution in a small animal model of orthotopic whole small bowel transplantation. METHODS: Lewis rats received syngeneic total orthotopic small bowel graft after cold storage for 6 h. Donor small bowel was flushed vascularly with University of Wisconsin (UW) solution and flushed luminally with UW solution or an amino acid-rich (AA) solution as follows: Group 1, no luminal flush; Group 2, UW solution; Group 3, AA solution. Biopsies were taken over 14 days posttransplant; energetics, oxidative stress, neutrophil recruitment and histologic injury were assessed. RESULTS: All animals in Groups 1 and 2 failed to survive 12 h posttransplant due to hemorrhagic shock and fluid loss. In contrast, all animals in Group 3 survived the operation; survival after 14 days was 80% (4/5). In Group 3, full recovery of tissue adenylates (ATP and energy charge) to freshly isolated tissue values occurred within 3 days. Oxidative stress as assessed by malondialdehyde (MDA) levels was low in Group 3 throughout 14 d; Groups 1 and 2 exhibited high oxidative stress over the initial 35 min reperfusion (P<0.05). Neutrophil recruitment (myeloperoxidase activity) was significantly reduced in Group 3 tissues, as was histologic injury (P<0.05 compared to Groups 1 and 2). By day 14, Group 3 exhibited complete mucosal restoration. CONCLUSIONS: The data presented in this communication supports the use of an intraluminal preservation solution that is tailored to the metabolic requirements of the small bowel.     

Inherited disorders of the IL-12-IFN-γ axis in patients with disseminated BCG infection

Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN- axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN- circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN- receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12R1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN- circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN- circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.     

Accuracy of somatosensory evoked potentials in diagnosis of mild idiopathic carpal tunnel syndrome

OBJECTIVE: Concerning prevalence of carpal tunnel syndrome (CTS) and the difficulties with electromyography (EMG) and nerve conduction studies (NCS), this study was designed to evaluate the power of somatosensory evoked potential (SSEP) in CTS diagnosis among Iranian patients. PATIENTS AND METHODS: SSEP was performed on 100 asymptomatic hands of 50 healthy participants (40 female, age range 38-59 years) and on 61 hands of 46 patients (39 female, age range 34-58 years). Mean difference between N(20) latency of the middle finger and the wrist (median nerve innervation) as well as N(20) latency of the third finger and the fifth finger (ulnar nerve innervation) were measured. Using receiver operating characteristic (ROC) curve analysis, the upper limits of these variables were defined as 6.0 and 1.5 ms, respectively. Higher amounts in either of these variables were considered as positive SSEP for diagnosis of CTS. Measures of accuracy for SSEP were measured getting clinical diagnosis by two separate neurologists as the reference standard. In the patients' group who underwent both techniques of SSEP and EMG-NCS, kappa statistic as the agreement coefficient between two procedures was calculated. RESULTS: Sensitivity, specificity, and likelihood ratios for positive and negative results of SSEP in diagnosis of CTS were 70.4%, 91.0%, 7.83 and 0.32, respectively. Sensitivity of EMG-NCS in diagnosis of CTS was measured as 81.9%. Measure of agreement between two procedures (kappa) was calculated as 0.42. CONCLUSION: This study showed that positive results of SSEP might have a role in diagnosis of CTS. However, larger studies to demonstrate diagnostic power of SSEP in comparison with EMG-NCS seem necessary.     

Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term daily oral administration to healthy young men

OBJECTIVE: To determine the effects of dehydroepiandrosterone (DHEA) supplementation on the pharmacokinetics of DHEA and its metabolites and the reproductive axis of healthy young men. DESIGN: A prospective, randomized, double-blind, placebo-controlled pharmacokinetic study. SETTING: General Clinical Research Center and laboratories at the Keck School of Medicine of the University of Southern California, Los Angeles, California. PATIENT(S): Fourteen healthy men, ages 18-42 years. INTERVENTION(S): Daily oral administration of placebo (n = 5), 50 mg DHEA (n = 4), or 200 mg DHEA (n = 5) for 6 months. Blood samples were collected at frequent intervals on day 1 and at months 3 and 6 of treatment. MAIN OUTCOME MEASURE(S): Quantification of DHEA, DHEA sulfate (DHEAS), androstenedione, T, E(2), dihydrotestosterone (DHT), and 5alpha-androstane-3alpha-17beta-diol glucuronide (ADG). Physical examination, semen analysis, serum LH, FSH, prostate-specific antigen, and general chemistries were carried out. RESULT(S): Baseline DHEA, DHEAS, and ADG levels increased significantly from day 1 to months 3 and 6 in the DHEA treatment groups but not in the placebo group. No significant changes were observed in pharmacokinetic values. Clinical parameters were not affected. CONCLUSION(S): DHEA, DHEAS, and ADG increased significantly during 6 months of daily DHEA supplementation. Although the pharmacokinetics of DHEA and its metabolites are not altered, sustained baseline elevation of ADG, a distal DHT metabolite, raises concerns about the potential negative impact of DHEA supplementation on the prostate gland.     

Metastatic burst fracture risk prediction using biomechanically based equations

Clinical guidelines are a useful adjunct to select patients with spinal metastases for prophylactic intervention. The objective of this study is to determine the ability of biomechanically based models to accurately predict metastatic burst fracture risk. Ninety-two vertebrae with osteolytic spinal metastases were examined retrospectively. Vertebrae were categorized as burst fractured, wedge fractured, or intact and analyzed using three predictive models: vertebral bulge (maximum radial displacement under load), vertebral axial displacement (maximum axial displacement under load), and a volumetric estimate of tumor size. The load-bearing capacity parameter (tumor volume, bone mineral density, disc quality, pedicle involvement) was determined from computed tomography while the load-bearing requirement parameter (pressure load, loading rate) was determined using computed tomography and patient records (retrieved for 37 patients [52%]). Fracture prediction was optimized using the vertebral bulge model considering only load-bearing capacity with a specificity, sensitivity, and confidence interval of 1 to yield a clear threshold for burst fracture risk. Fracture prediction in the other two models, vertebral axial displacement considering only load-bearing capacity and tumor size, also was strong with receiver-operator curve values of 0.992 and 0.988, respectively. The predictive power of these models can provide useful clinical information for prophylactic decision-making.     

Intranasal bioavailability of insulin from carbopol-based gel spray in rabbits

The purpose of this study was to investigate the nasal absorption of insulin from a carbopol-based nasal gel spray in rabbits. An insulin nasal gel was prepared by dispersing carbopol in distilled water, followed by the addition of insulin solution, then neutralization and viscosity adjustment. The nasal absorption of insulin from the gel, in conscious rabbits, was evaluated in comparison with absorption from an insulin solution. The absolute bioavailability of insulin from the nasal gel was studied using blood glucose level in comparison to intravenous injection. The insulin gel formulation produced a significant hypoglycemic response in rabbits, whereas no response was seen following administration of the insulin solution formulation. The bioavailability of insulin from the nasal gel formulation was 20.6% compared with the intravenous injection. The results of the present study suggest that the carbopol gel promotes the nasal absorption of insulin in rabbit model and due to its sprayability with commercially available spray pumps, could be considered as a preferred platform in nasal drug administration.     

Dental implant treatment in diabetic patients

The purpose of the present study was twofold: (1) to investigate how many diabetic patients and types of cases that are treated with dental implants in our clinic; and (2) assess the outcome of such treatment. Medical records from 782 patients were examined in patients treated by the Br?nemark method for partial or total edentulism with implant supported bridges. From these records, 25 patients (3.2%) with diabetes before implant treatment (136 implants) were identified and further studied with respect to age, gender, type of diabetes, treated jaw, degree of edentulism, bone graft, implant survival, periimplant inflammation, bleeding on probing, and radiographic bone loss. Furthermore, the patients' opinion about the outcome of the treatment was registered. The implant success rate was 96.3% during the healing period and 94.1% 1 year after surgery. Of all 38 bridges, one was lost. Few complications occurred and all patients, except for one, were satisfied with the treatment. Today, diabetic patients are being treated successfully for all types of edentulism, including bone-grafting treatment. Diabetics that undergo dental implant treatment do not encounter a higher failure rate than the normal population, if the diabetics' plasma glucose level is normal or close to normal as assessed by personal interviews.