A Small Conductance Calcium-Activated K⁺ Channel in C. elegans, KCNL-2, Plays a Role in the Regulation of the Rate of Egg-Laying

In the nervous system of mice, small conductance calcium-activated potassium (SK) channels function to regulate neuronal excitability through the generation of a component of the medium afterhyperpolarization that follows action potentials. In humans, irregular action potential firing frequency underlies diseases such as ataxia, epilepsy, schizophrenia and Parkinson's disease. Due to the complexity of studying protein function in the mammalian nervous system, we sought to characterize an SK channel homologue, KCNL-2, in C. elegans, a genetically tractable system in which the lineage of individual neurons was mapped from their early developmental stages. Sequence analysis of the KCNL-2 protein reveals that the six transmembrane domains, the potassium-selective pore and the calmodulin binding domain are highly conserved with the mammalian homologues. We used widefield and confocal fluorescent imaging to show that a fusion construct of KCNL-2 with GFP in transgenic lines is expressed in the nervous system of C. elegans. We also show that a KCNL-2 null strain, kcnl-2(tm1885), demonstrates a mild egg-laying defective phenotype, a phenotype that is rescued in a KCNL-2-dependent manner. Conversely, we show that transgenic lines that overexpress KCNL-2 demonstrate a hyperactive egg-laying phenotype. In this study, we show that the vulva of transgenic hermaphrodites is highly innervated by neuronal processes and by the VC4 and VC5 neurons that express GFP-tagged KCNL-2. We propose that KCNL-2 functions in the nervous system of C. elegans to regulate the rate of egg-laying. © 2013 Chotoo et al

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring

Multiple dimensions of health locus of control in a representative population sample: ordinal factor analysis and cross-validation of an existing three and a new four factor model

<p>Abstract</p> <p>Background</p> <p>Based on the general approach of locus of control, health locus of control (HLOC) concerns control-beliefs due to illness, sickness and health. HLOC research results provide an improved understanding of health related behaviour and patients' compliance in medical care. HLOC research distinguishes between beliefs due to Internality, Externality powerful Others (POs) and Externality Chance. However, evidences for differentiating the POs dimension were found. Previous factor analyses used selected and predominantly clinical samples, while non-clinical studies are rare. The present study is the first analysis of the HLOC structure based on a large representative general population sample providing important information for non-clinical research and public health care.</p> <p>Methods</p> <p>The standardised German questionnaire which assesses HLOC was used in a representative adult general population sample for a region in Northern Germany (N = 4,075). Data analyses used ordinal factor analyses in LISREL and Mplus. Alternative theory-driven models with one to four latent variables were compared using confirmatory factor analysis. Fit indices, chi-square difference tests, residuals and factor loadings were considered for model comparison. Exploratory factor analysis was used for further model development. Results were cross-validated splitting the total sample randomly and using the cross-validation index.</p> <p>Results</p> <p>A model with four latent variables (Internality, Formal Help, Informal Help and Chance) best represented the HLOC construct (three-dimensional model: normed chi-square = 9.55; RMSEA = 0.066; CFI = 0.931; SRMR = 0.075; four-dimensional model: normed chi-square = 8.65; RMSEA = 0.062; CFI = 0.940; SRMR = 0.071; chi-square difference test: p < 0.001). After excluding one item, the superiority of the four- over the three-dimensional HLOC construct became very obvious (three-dimensional model: normed chi-square = 7.74; RMSEA = 0.059; CFI = 0.950; SRMR = 0.079; four-dimensional model: normed chi-square = 5.75; RMSEA = 0.049; CFI = 0.965; SRMR = 0.065; chi-square difference test: p < 0.001). Results were confirmed by cross-validation. Results based on our large community sample indicated that western general populations separate health-related control-beliefs concerning formal and informal assistance.</p> <p>Conclusions</p> <p>Future non-clinical HLOC studies in western cultures should consider four dimensions of HLOC: Internality, Formal Help, Informal Help and Chance. However, the standardised German instrument needs modification. Therefore, confirmation of our results may be useful. Future research should compare HLOC structure between clinical and non-clinical samples as well as cross-culturally.</p