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.     

Combustion Synthesis of High Density ZrN/ZrSi2 Composite: Influence of ZrO2 Addition on the Microstructure and Mechanical Properties

In this study, a high-density ZrN/ZrSi₂ composite reinforced with ZrO₂ as an inert phase was synthesized under vacuum starting with a Zr-Si₄N₃-ZrO₂ blend using combustion-synthesis methodology accompanied by compaction. The effects of ZrO₂ additions (10–30 wt%) and compression loads (117–327 MPa) on the microstructure, porosity and hardness of the samples were studied. The process was monitored using XRD, SEM, EDS, porosity, density and hardness measurements. Thermodynamic calculations of the effect of ZrO₂ addition on the combustion reaction were performed including the calculation of the adiabatic temperatures and the estimation of the fractions of the liquid phase. The addition of up to 20 wt% ZrO₂ improved the hardness and reduced the porosity of the samples. Using 20 wt% ZrO₂, the sample porosity was reduced to 1.66 vol%, and the sample hardness was improved to 1165 ± 40.5 HV at 234 MPa.     

An Experimental Investigation of Static Properties of Bio-Oils and SAE40 Oil in Journal Bearing Applications

Considerable research has been conducted in the past decade and a half regarding the bio-lubricants potential to replace mineral-based lubricants as mainstream lubricants such as engine oil, hydraulic oil, compressor oil, and metalworking oil. This study studied several bio-lubricants (rapeseed oil, palm olein, and soybean oil) and a mineral-based lubricant, SAE40. The bio-lubricants have better physiochemical, tribological characteristics and environmental friendly nature, and are promising to replace mineral-based lubricants. In this study, a journal bearing test rig (JBTR) was developed in order to investigate the effect of journal speed on the temperature of oil film with time. Additionally, the load-carrying capacity of bio-oils was tested against the mineral-based lubricant SAE40 by adding a load on the journal. For all three speeds, i.e., 1000, 1500, and 2000 rpm, the bio-lubricants recorded minimum temperature. At 1000 rpm, rapeseed oil recorded a 9.2% lower temperature than SAE40. Similarly, at 2000 rpm, rapeseed oil recorded a minimum temperature that was 2.5% lower than SAE40; in comparison, at 1500 rpm, palm olein recorded a minimum temperature that was 1.8% less than SAE40. Overall, the results of this study revealed that bio-oils recorded a lower temperature rise than mineral oil. These results are very encouraging for further research in this area.     

Half Metallic Ferromagnetism and Transport Properties of Zinc Chalcogenides ZnX2Se4 (X = Ti,V, Cr) for Spintronic Applications

In ferromagnetic semiconductors, the coupling of magnetic ordering with semiconductor character accelerates the quantum computing. The structural stability, Curie temperature (T_c), spin polarization, half magnetic ferromagnetism and transport properties of ZnX₂Se₄ (X = Ti, V, Cr) chalcogenides for spintronic and thermoelectric applications are studied here by density functional theory (DFT). The highest value of T_c is perceived for ZnCr₂Se₄. The band structures in both spin channels confirmed half metallic ferromagnetic behavior, which is approved by integer magnetic moments (2, 3, 4) μ_B of Ti, V and Cr based spinels. The HM behavior is further measured by computing crystal field energy ΔE _crystal, exchange energies Δ _x(d), Δ _x (pd) and exchange constants (N_o α and N_o β ). The thermoelectric properties are addressed in terms of electrical conductivity, thermal conductivity, Seebeck coefficient and power factor in within a temperature range 0–400 K. The positive Seebeck coefficient shows p-type character and the PF is highest for ZnTi2Se4 (1.2 × 10¹¹ W/mK²) among studied compounds.     

Early and late survival in Hodgkin disease among whites and blacks living in the United States

Background. The independent effect of race on response to treatment and prognosis in Hodgkin disease is unclear. Methods. The study included 9482 patients with histologically confirmed Hodgkin disease reported by 1084 different hospitals and institutions in the United States. The independent effect of race on response to treatment and recurrence was estimated using the logistic model. Cox proportional hazard model was applied to determine the independent effect of race and other covariables on risk of death. Results. Complete remission occurred in more white patients (67.3%) than black patients (58.2%). Recurrences were reported more often in black patients than in white patients (40.3% and 30.9% respectively). Controlling for confounding variables, race has a significant independent effect on remission and recurrence (P < 0.05). In the first 5 years after diagnosis of Hodgkin disease, the patient age at diagnosis, clinical stage, and histologic type were significant predictors for the risk of death. At 5–10 years after a diagnosis of Hodgkin disease, age, clinical stage, and race of the patient were found to be significant risk factors (whites versus blacks: RR = 0.56; P < 0.05). Conclusions. Race is a significant predictor for remission, recurrence and survival in Hodgkin disease. Black patients have a more unfavorable prognosis than do white patients.     

Flow cytometric DNA analysis of fresh prostatic resections: Correlation with conventional prognostic parameters in patients with prostate cancer

Background. DNA ploidy analysis has been investigated as a prognostic indicator in prostate cancer. Most of the data is derived from retrospective studies using paraffin-embedded tissue. This method has drawbacks related to the quality of DNA histograms and uncontrolled data collection. Methods. DNA ploidy analysis of freshly resected prostatic tissue was prospectively compared with conventional prognostic variables in 97 men treated with radical prostatectomy for localized prostate cancer. Results. Regarding the patients, 31.9% were African American and 66% had pathologic Stages C or D1 disease. Only 9.6% of patients with Stages A2 and B had a prostate-specific antigen (PSA) value greater than 10 ng/ml, whereas 97% of patients with PSA values greater than 20 ng/ml had pathologic Stages C and D1. PSA levels correlated with Gleason score (P = < 0.05); 51% and 100% of patients with Gleason score 5–7 and 8–10, respectively, had PSA values greater than 10 ng/ml. Twenty-two patients (23%) had DNA aneuploid tumors. Comparisons of mechanical to enzymatic cell suspensions indicated that DNA aneuploidy was better preserved in mechanical cell preparations. DNA ploidy correlated with pathologic stage (P = < 0.05) and Gleason score (P = < 0.05). Fifteen of 79 patients (18.9%) with Gleason score 5–7 had DNA aneuploid tumors versus 71.4% of patients with Gleason score 8–10. PSA groups correlated with ploidy status (P = 0.01). Although the majority of patients (19 of 22) with DNA aneuploid tumors had elevated preoperative PSA levels, none had a PSA value greater than 50 ng/ml. Conclusions. DNA ploidy analysis correlated with established prognostic indicators in prostate cancer; however, its independent correlation with natural history and treatment outcome must be established for it to have an effect on therapeutic decisions.     

Autoinflammatory diseases in childhood,part 1: monogenic syndromes

Autoinflammatory diseases constitute a family of disorders defined by aberrant stimulation of inflammatory pathways without involving antigen-directed autoimmunity. They may be divided into monogenic and polygenic types. Monogenic autoinflammatory syndromes are those with identified genetic mutations, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency or hyperimmunoglobulin D syndrome, cryopyrin-associated periodic fever syndromes (CAPS), pyogenic arthritis pyoderma gangrenosum and acne (PAPA) syndrome, interleukin-10 and interleukin-10 receptor deficiencies, adenosine deaminase 2 deficiency and pediatric sarcoidosis. Those without an identified genetic mutation are known as polygenic and include systemic-onset juvenile idiopathic arthritis, idiopathic recurrent acute pericarditis, Behçet syndrome, chronic recurrent multifocal osteomyelitis and inflammatory bowel disease among others. Autoinflammatory disorders are defined by repeating episodes or persistent fever, rash, serositis, lymphadenopathy, arthritis and increased acute phase reactants, and thus may mimic infections clinically. Most monogenic autoinflammatory syndromes present in childhood. However, because of their infrequency, diverse and nonspecific presentation, and the relatively new genetic recognition, diagnosis is usually delayed. In this article, which is Part 1 of a two-part series, the authors update monogenic autoinflammatory diseases in children with special emphasis on imaging features that may help establish the correct diagnosis.