Evaluating the use of baclofen as adjunct treatment for muscle tension dysphonia.

OBJECTIVE: To explore whether use of baclofen as adjunct treatment to voice therapy (VT) led to improvement in subjective throat symptoms in patients with primary muscle tension dysphonia (MTD). MTD is associated with excessive paralaryngeal muscle contraction, and baclofen is a muscle relaxant. STUDY DESIGN: Cross-sectional, questionnaire-based study. METHODS: An initial pool of patients, who were diagnosed with primary MTD and received 1+ VT session(s) at a single tertiary-care center from 2015 to 2019, were placed into either a baclofen group (prescribed 10 mg baclofen t.i.d. PRN along with VT) based on symptomatology or non-baclofen group (VT alone). They were administered questionnaires via postage mail or phone that included the Voice Handicap Index-10 (VHI-10), Reflux Symptom Index (RSI), and other survey elements. A retrospective chart review collected demographic and other clinical data from recruited participants. RESULTS: A total of 314 non-baclofen and 63 baclofen patients met the inclusion criteria of this study, with 37 non-baclofen patients (mean age = 47.5 years, 62.2% female) and 15 baclofen patients (mean age = 45.5 years, 73.3% female) recruited. There was no significant difference in mean [SD] VHI-10 scores (11.30 [8.20] vs. 12.60 [10.75]; p = 0.638) and RSI scores (13.46 [10.44] vs. 16.20 [10.65]; p = 0.398) between non-baclofen and baclofen groups, respectively. CONCLUSION: There was no significant difference in voice psychometric outcomes between non-baclofen and baclofen groups, measured primarily by the VHI-10 and RSI questionnaire components. Further studies are warranted to assess the efficacy and safety of baclofen as a therapeutic option for MTD.

Functional determinants of a small protein controlling a broadly conserved bacterial sensor kinase.

The PhoQ/PhoP two-component system plays a vital role in the regulation of Mg2+ homeostasis, resistance to acid and hyperosmotic stress, cationic antimicrobial peptides, and virulence in Escherichia coli, Salmonella and related bacteria. Previous studies have shown that MgrB, a 47 amino acid membrane protein that is part of the PhoQ/PhoP regulon, inhibits the histidine kinase PhoQ. MgrB is part of a negative feedback loop modulating this two-component system that prevents hyperactivation of PhoQ and may also provide an entry point for additional input signals for the PhoQ/PhoP pathway. To explore the mechanism of action of MgrB, we have analyzed the effects of point mutations, C-terminal truncations and transmembrane region swaps on MgrB activity. In contrast with two other known membrane protein regulators of histidine kinases in E. coli, we find that the MgrB TM region is necessary for PhoQ inhibition. Our results indicate that the TM region mediates interactions with PhoQ and that W20 is a key residue for PhoQ/MgrB complex formation. Additionally, mutations of the MgrB cytosolic region suggest that the two N-terminal lysines play an important role in regulating PhoQ activity. Alanine scanning mutagenesis of the periplasmic region of MgrB further indicates that, with the exception of a few highly conserved residues, most residues are not essential for MgrB's function as a PhoQ inhibitor. Our results indicate that the regulatory function of the small protein MgrB depends on distinct contributions from multiple residues spread across the protein. Interestingly, the TM region also appears to interact with other non-cognate histidine kinases in a bacterial two-hybrid assay, suggesting a potential route for evolving new small protein modulators of histidine kinases.

Systemic diseases affecting the breast: Imaging, diagnosis, and management.

Various systemic diseases of benign or malignant etiologies can clinically manifest in the breast. Some imaging findings of breast lesions can be pathognomonic for a given condition, while others are non-specific, mimicking primary breast carcinoma and requiring tissue biopsy for definitive diagnosis. In addition to obtaining a detailed clinical history, radiologists should be familiar with the diverse clinical and imaging characteristics of these conditions to help exclude primary breast cancer and avoid unnecessary interventions. This review aims to discuss the clinical presentations, imaging features, pathologic findings, and management of systemic conditions that may affect the breast.

Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity.

Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control.