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ObjectiveTo describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology.MethodsWe used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav 1.4.ResultsClinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav 1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics.InterpretationWe conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function.

Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one third of cases. Synaptic GABAA receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring benzodiazepine resistance, which is believed to be a major cause of treatment failure. GABAA receptor positive allosteric modulator neuroactive steroids, such as allopregnanolone, also potentiate synaptic GABAA receptors, but in addition they enhance extrasynaptic GABAA receptors that mediate tonic inhibition. Extrasynaptic GABAA receptors are not internalized, and desensitization of these receptors does not occur during continuous seizures in status epilepticus models. Here we review the broad-spectrum antiseizure activity of allopregnanolone in animal seizure models and the evidence for its activity in models of status epilepticus. We also demonstrate that allopregnanolone inhibits ongoing behavioral and electrographic seizures in a model of status epilepticus, even when there is benzodiazepine resistance. Parenteral allopregnanolone may provide an improved treatment for refractory status epilepticus.

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel subunit (NaV1.1) are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and accelerated recovery from slow inactivation. Unlike three other GEFS+ alleles that we recently characterized, neither R1657C nor I1656M gave rise to a persistent, noninactivating current. In contrast, two other GEFS+ mutations (A1685V and V1353L) and L986F, an SMEI-associated allele, exhibited complete loss of function. In conclusion, our data provide evidence for a wide spectrum of sodium channel dysfunction in familial epilepsy and demonstrate that both GEFS+ and SMEI can be associated with nonfunctional SCN1A alleles.

Purpose: We evaluate a compact portable system for immediate automated postoperative ex vivo analysis of urinary stone composition using Raman spectroscopy. Analysis of urinary stone composition provides essential information for the treatment and metaphylaxis of urolithiasis. Currently infrared spectroscopy and x-ray diffraction are used for urinary stone analysis. However, these methods may require complex sample preparation and costly laboratory equipment. In contrast, Raman spectrometers could be a simple and quick strategy for immediate stone analysis. Materials and Methods: Pure samples of 9 stone components and 159 human urinary calculi were analyzed by Raman spectroscopy using a microscope coupled system at 2 excitation wavelengths. Signal-to-noise ratio, peak positions and the distinctness of the acquired Raman spectra were analyzed and compared. Background fluorescence was removed mathematically. Corrected Raman spectra were used as a reference library for automated classification of native human urinary stones (50). The results were then compared to standard infrared spectroscopy. Results: Signal-to-noise ratio was superior at an excitation wavelength of 532 nm. An automated, computer based classifier was capable of matching spectra from patient samples with those of pure stone components. Consecutive analysis of 50 human stones demonstrated 100% sensitivity and specificity compared to infrared spectroscopy (for components with more than 25% of total composition). Conclusions: Our pilot study indicates that Raman spectroscopy is a valid and reliable technique for determining urinary stone composition. Thus, we propose that the development of a compact and portable system based on Raman spectroscopy for immediate, postoperative stone analysis could represent an invaluable tool for the metaphylaxis of urolithiasis. [Copyright &y& Elsevier]

Myotonia is a symptom of many different acquired and genetic muscular conditions that impair the relaxation phase of muscular contraction. Myotonia congenita is a specific inherited disorder of muscle membrane hyperexcitability caused by reduced sarcolemmal chloride conductance due to mutations in CLCN1, the gene coding for the main skeletal muscle chloride channel ClC-1. The disorder may be transmitted as either an autosomal-dominant or recessive trait with close to 130 currently known mutations. Although this is a rare disorder, elucidation of the pathophysiology underlying myotonia congenita established the importance of sarcolemmal chloride conductance in the control of muscle excitability and demonstrated the first example of human disease associated with the ClC family of chloride transporting proteins. [ABSTRACT FROM AUTHOR]

In many cases sabotage was arguably in the service of the consumer, who was not so much exploited as extorted by the capitalist class. "Open mouth" sabotage was particularly effective in this regard; druggists and workers in the food industry should be sabotaging their bosses by announcing the myriad ways that food and pharmaceuticals are adulterated. Sabotage is a thing that's banned, By labor fakirs throughout the land, By rebel workers used for ages To make the bosses increase wages Sabotage can always be used To gain justice when workers are abused: Bad bosses, too, are tamed in a day When a little sab kitten strays their way. " 8 Although organized labor does not - and indeed its more "legitimate" organs never did - officially endorse sabotage as a negotiating tactic or a form of worker control at the point of production, sabotage has always been an important weapon in the workers' arsenal. Worker sabotage and capitalist sabotage often intersected, as in cases of open mouth sabotage where the worker's interference was composed of announcing employer sabotage. Thorstein Veblen borrowed the I.W .W. framework of capitalist and worker sabotage for his 1921 work Engineers and the Price System, where he elaborated on the necessity of sabotage to normal economic activity under financialized capitalism. [Extracted from the article]

Objectives: Attaining castration resistance in metastatic prostate cancer (mCRPC) represents a pivotal juncture in the progression of the patient's illness and treatment regimen. Within this therapeutic context, novel hormonal agents (NHA) constitute a fundamental component of pharmacological intervention. However, the efficacy of NHA therapy remains uncertain for patients with a compromised general condition, as indicated by an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≥2. Notably, most clinical trials excluded individuals with an ECOG PS ≥2, leaving a gap in our understanding of the potential benefits of NHA therapy for this specific patient cohort., Methods: We conducted an analysis of fifty-three NHA-naïve men characterized by attaining mCRPC at an ECOG PS of ≥2 subsequent to androgen deprivation monotherapy between 2008 and 2023. Patients were then treated with either NHA or Best Supportive Care (BSC) based on individual decisions. Survival and adverse event (AE) analysis was performed to assess the outcomes of NHA therapy compared to BSC., Results: Among the patients, 30 (56.6%) received NHA, whereas the remaining 23 (43.4%) choose BSC. No significant differences in baseline characteristics were observed between the NHA and BSC group. Median overall survival (OS) was 9.1 months in the BSC group and 7.0 months in the NHA group, with no significant OS benefits associated with NHA treatment. AEs and severe AEs commonly occurred, but remained indifferent between treatment groups., Conclusions: Our findings suggest that NHA therapy may confer reduced survival benefits in mCRPC patients with ECOG PS ≥2. While hope for NHA treatment persists, particularly given its oral administration and tolerability, careful consideration and discussion with patients regarding treatment expectations and palliative care goals are warranted in this challenging patient population., Competing Interests: TB received speaker honorary from Astellas and travel fees from Ipsen and MSD. PL received speaker honorary from Astellas, Apogepha, Novartis, Bayer, Ipsen, MSD, Jansen‐Cilag, BMS, travel fees from Janssen‐Cilag and Ferring and paid advisory role for Medac. PK received speaker honorary from Novartis. SH received speaker honorary from Astellas, Novartis, Bayer, Ipsen, MSD, Janssen‐Cilag, BMS, travel fees from Ipsen and paid advisory role for Ipsen, Merck and BMS. All other authors declare no conflict of interest., (© 2024 The Author(s). Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.)

Background: The prognosis of metastatic castration-resistant prostate cancer (mCRPC) is influenced by numerous individual factors. Despite various proposed prognostic models, the clinical application of these remains limited, probably due to complexity. Our study aimed to evaluate the predictive value of the Bellmunt risk score, which is well-known for urothelial carcinoma and easily assessed, in mCRPC patients., Methods: The Bellmunt risk score was calculated from three risk factors (Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥1, serum hemoglobin <10 g/dL, presence of liver metastases) in 125 patients who received first-line mCRPC treatment between 2005 and 2023. In addition, a modified score was established (one point each for hemoglobin <10 g/dL and the presence of liver metastases added to the ECOG PS). Associations with overall survival (OS) under first- and second-line therapy were tested using Cox regression analyzes, log-rank tests, concordance index (C-index) and time-dependent receiver operating characteristic., Results: There is a significant correlation between the level of the Bellmunt risk score and shorter OS (hazard ratio: 3.23, 95% confidence interval: 2.06-5.05; log-rank p < 0.001; C-index: 0.724). The semi-quantitative modified risk score showed even better prognostic discrimination (log-rank p < 0.001, C-index: 0.764). The score and its dynamics were also predictive in the second-line setting (log-rank p < 0.001 and = 0.01; C-index: 0.742 and 0.595)., Conclusions: The Bellmunt risk score is easy to assess and provides useful prognostic information in mCRPC, and can support physicians in their treatment decisions., (© 2024 The Authors. The Prostate published by Wiley Periodicals LLC.)