AKAP150-anchored PKA regulation of synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the lateral habenula.

Numerous studies of hippocampal synaptic function in learning and memory have established the functional significance of the scaffolding A-kinase anchoring protein 150 (AKAP150) in kinase and phosphatase regulation of synaptic receptor and ion channel trafficking/function and hence synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a critical role in brain's processing of rewarding/aversive experiences. Here we focused on an unexplored role of AKAP150 in the lateral habenula (LHb), a diencephalic brain region that integrates and relays negative reward signals from forebrain striatal and limbic structures to midbrain monoaminergic centers. LHb aberrant activity (specifically hyperactivity) is also linked to depression. Using whole cell patch clamp recordings in LHb of male wildtype (WT) and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), we found that the genetic disruption of PKA anchoring to AKAP150 significantly reduced AMPA receptor (AMPAR)-mediated glutamatergic transmission and prevented the induction of presynaptic endocannabinoid (eCB)-mediated long-term depression (LTD) in LHb neurons. Moreover, ΔPKA mutation potentiated GABAA receptor (GABAAR)-mediated inhibitory transmission postsynaptically while increasing LHb intrinsic neuronal excitability through suppression of medium afterhyperpolarizations (mAHPs). Given that LHb is a highly stress-responsive brain region, we further tested the effects of corticotropin releasing factor (CRF) stress neuromodulator on synaptic transmission and intrinsic excitability of LHb neurons in WT and ΔPKA mice. As in our earlier study in rat LHb, CRF significantly suppressed GABAergic transmission onto LHb neurons and increased intrinsic excitability by diminishing small-conductance potassium (SK) channel-mediated mAHPs. ΔPKA mutation-induced suppression of mAHPs also blunted the synaptic and neuroexcitatory actions of CRF in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPAR and GABAAR synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPAR and potassium channel trafficking and eCB signaling within the LHb.

Subjective cognitive changes following premenopausal risk-reducing bilateral salpingo-oophorectomy.

OBJECTIVE: Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Cognitive symptoms during natural menopause transition are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, we explored the cognitive experiences of women within 24 months post BSO. METHODS: This observational cross-sectional sub-study is part of a larger project, the Early Menopause and Cognition Study (EM-COG). We investigated perceived cognitive experiences in Australian women (n = 16) who underwent risk-reducing BSO using qualitative interviews. Thematic analysis was undertaken to identify key themes. RESULTS: Fifteen out of 16 participants (93.75%) reported changes to cognition within 24 months post BSO. The key cognitive symptoms reported were brain fog, memory and retrieval difficulties, slower processing speed as well as attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. CONCLUSION: Findings from this study suggest that women experience subjective cognitive changes within 24 months post BSO. This period could be a vulnerable time for women's cognitive health. While these findings need to be confirmed by a large prospective study, our research indicates that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.

Sertraline treatment influences [18F]FE-PE2I PET imaging for Parkinsonism.

BACKGROUND: The dopamine transporter (DaT) PET ligand [18F]FE-PE2I is used to aid the diagnosis of Parkinson's disease. After encountering four patients with a history of daily sertraline use, who all showed atypical findings on [18F]FE-PE2I PET, we suspected that the selective serotonin reuptake inhibitor (SSRI), sertraline, might interfere with the results and lead to globally reduced striatal [18F]FE-PE2I binding due to sertraline's high affinity for DaT. METHODS: We rescanned the four patients with [18F]FE-PE2I PET after a 5-day sertraline pause. Sertraline plasma concentration was estimated based on body weight and dose, and specific binding ratios (SBR) in caudate nucleus, known to be more preserved in Parkinson's, were used to estimate the effect on tracer binding. Comparison was made to a patient with [18F]FE-PE2I PET before and after a 7-day Modafinil pause. RESULTS: We found a significant effect of sertraline on caudate nucleus SBR (p = 0.029). The effect showed a linear dose-dependent relationship that corresponds to a reduction in SBR by 0.32 or 0.44 for a 75 kg male or a 65 kg female, respectively, taking a daily dose of 50 mg sertraline. CONCLUSION: Sertraline is one of the most commonly used antidepressants and in contrast to other SSRI's, sertraline show high affinity for DaT. We recommend that sertraline treatment is taken into account when patients are undergoing [18F]FE-PE2I PET especially in patients showing apparent globally reduced PE2I binding. If tolerable, pausing of the sertraline treatment should be considered, especially for doses above 50 mg/day.

Identifying the cognitive underpinnings of voice-hearing by comparing never, past and current voice-hearers.

OBJECTIVE: The current study aimed to compare specific cognitive profiles corresponding to auditory verbal hallucinations (AVH) status and elucidate which pattern of cognitive deficits may predict voice-hearing status. METHOD: Clinical participants with schizophrenia spectrum disorders were partitioned into: (i) current voice-hearers (n = 46), (ii) past voice-hearers (n = 37) and (iii) never voice-hearers (n = 40), and compared with 319 non-clinical controls. Cognitive assessment employed the MATRICS Consensus Cognitive Battery (MCCB), supplemented by the Delis-Kaplan Executive Function System (D-KEFS) Colour-Word Interference Test (Stroop) as a robust measure of executive function. RESULTS: On the Visual Learning domain, current and past voice-hearers had significantly poorer performance relative to never voice-hearers, who in turn had significantly poorer performance than non-clinical controls. Current and never voice-hearers had significantly poorer performance on the Social Cognition domain relative to non-clinical controls. Current voice-hearers also had significantly poorer performance on the Inhibition domain relative to non-clinical controls. Binary logistic regression revealed that Visual Learning was the only significant cognitive predictor of AVH presence. CONCLUSION: Visual learning, and potentially inhibition, may be viable therapeutic targets when addressing cognitive mechanisms associated with AVHs. Future research should focus on investigating additional cognitive mechanisms, employing diverse voice-hearing populations and embarking on related longitudinal studies.

Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors.

High-throughput differential scanning fluorimetry of GFP-tagged proteins (HT-DSF-GTP) was applied for the identification of novel enzyme inhibitors acting by a mechanism termed: selective protein unfolding (SPU). Four different protein targets were interrogated with the same library to identify target-selective hits. Several hits selectively destabilized bacterial biotin protein ligase. Structure-activity relationship data confirmed a structure-dependent mechanism of protein unfolding. Simvastatin and altenusin were confirmed to irreversibly inactivate biotin protein ligase. The principle of SPU combined with HT-DSF-GTP affords an invaluable and innovative workflow for the identification of new inhibitors with potential applications as antimicrobials and other biocides.

A green fluorescent protein-based assay for high-throughput ligand-binding studies of a mycobacterial biotin protein ligase.

Biotin protein ligase (BirA) has been identified as an emerging drug target in Mycobacterium tuberculosis due to its essential metabolic role. Indeed, it is the only enzyme capable of covalently attaching biotin onto the biotin carboxyl carrier protein subunit of the acetyl-CoA carboxylase. Despite recent interest in this protein, there is still a gap in cost-effective high-throughput screening assays for rapid identification of mycobacterial BirA-targeting inhibitors. We present for the first time the cloning, expression, purification of mycobacterial GFP-tagged BirA and its application for the development of a high-throughput assay building on the principle of differential scanning fluorimetry of GFP-tagged proteins. The data obtained in this study reveal how biotin and ATP significantly increase the thermal stability (ΔTm=+16.5°C) of M. tuberculosis BirA and lead to formation of a high affinity holoenzyme complex (Kobs=7.7nM). The new findings and mycobacterial BirA high-throughput assay presented in this work could provide an efficient platform for future anti-tubercular drug discovery campaigns.

Functional characterisation of Burkholderia pseudomallei biotin protein ligase: A toolkit for anti-melioidosis drug development.

Burkholderia pseudomallei (Bp) is the causative agent of melioidosis. The bacterium is responsible for 20% of community-acquired sepsis cases and 40% of sepsis-related mortalities in northeast Thailand, and is intrinsically resistant to aminoglycosides, macrolides, rifamycins, cephalosporins, and nonureidopenicillins. There is no vaccine and its diagnosis is problematic. Biotin protein ligase (BirA) which is essential for fatty acid synthesis has been proposed as a drug target in bacteria. Very few bacterial BirA have been characterized, and a better understanding of these enzymes is necessary to further assess their value as drug targets. BirA within the Burkholderia genus have not yet been investigated. We present for the first time the cloning, expression, purification and functional characterisation of the putative Bp BirA and orthologous B. thailandensis (Bt) biotin carboxyl carrier protein (BCCP) substrate. A GFP-tagged Bp BirA was produced and applied for the development of a high-throughput (HT) assay based on our differential scanning fluorimetry of GFP-tagged proteins (DSF-GTP) principle as well as an electrophoretic mobility shift assay. Our biochemical data in combination with the new HT DSF-GTP and biotinylation activity assay could facilitate future drug screening efforts against this drug-resistant organism.

[Rhinoplasty and computerized cephalometry. Subcutaneous tissue and bony landmarks]. / Rhinoplastie et céphalométrie informatisée. Tissu sous-cutané et références osseuses.

We describe a computerised cephalometric method which allows ideal positioning of the tip of the nose and chin (bone and skin) for use when rhinoplasty is planned.

The cost of treating persons with AIDS in four hospitals in metropolitan New York in 1985.

From hospital accounting data on 402 patients, this study calculated annual, lifetime and perdiem cost, assessed the relationship to cost risk group, diagnosis, payer, and DRG, and estimated how the cost burden was shared between hospitals and third-party payers. Conclusions were as follows: Annual impatient hospital cost for adults with AIDS averaged +22,300, incurred during an average of 38 hospital days. Lifetime inpatient hospital costs averaged +38,200, incurred during an average of 62 hospital days. Patients with AIDS did not make more intensive use of hospital ancillary services than the average medical/surgical patient. They incurred exceptional per diem costs for laboratory and pharmacy services, but this was offset by lower operating room costs. Cost did not bear a statistically significant relationship to risk group in adult patients, but hospital utilization, and thus annual cost, ws very different for pediatric patients. There was limited evidence of a relationship between cost and diagnosis and between cost and payer. Eighty-two percent of the total cost was reimbursed by third-party payers: Medicaid (28 percent), Blue Cross (26 percent), Medicare (3 percent) and commercial insurance and other payers (25 percent). We estimate that self-pay patients paid 13 percent of the cost, and that 5 percent was unreimbursed.

Treating handicapped newborns: suggestions for institutional policy.

KIE: In October 1984 a conference of physicians and other health professionals, attorneys, members of the press, ethicists, and social scientists met at the State University of New York at Stony Brook to consider the medical, ethical, and social issues raised by the treatment of handicapped newborns. Presented here is a summary of guidelines for the implementation of their most important recommendation--the establishment of institutional policies concerning the internal decision making process regarding treatment and the procedures for sharing information about controversial cases with the public. The guidelines address the medical problems of diagnosis, prognosis, and clinical decision making; institutional responses to controversy within the institution and to the media and the public; and the composition and role of institutional review committees.^ieng