Hypercapnic ventilatory response in mice lacking the 65 kDa isoform of Glutamic Acid Decarboxylase (GAD65)

BACKGROUND: Recent reports have shown that there are developmental changes in the ventilatory response to hypercapnia in the rat. These are characterized by an initial large response to carbon dioxide immediately after birth followed by a decline with a trough at one week of age, followed by a return in sensitivity. A second abnormality is seen at postnatal day 5 (P5) rats in that they cannot maintain the increase in frequency for 5 min of hypercapnia. In mice lacking GAD65 the release of GABA during sustained synaptic activation is reduced. We hypothesized that this developmental pattern would be present in the mouse which is also less mature at birth and that GABA mediates this relative respiratory depression. METHODS: In awake C57BL/6J and GAD65-/- mice the ventilatory response to 5% carbon dioxide (CO2) was examined at P2, P4, P6, P7, P12.5, P14.5 and P21.5, using body plethysmography. RESULTS: Minute ventilation (VE) relative to baseline during hypercapnia from P2 through P7 was generally less than from P12.5 onwards, but there was no trough as in the rat. Breaking VE down into its two components showed that tidal volume remained elevated for the 5 min of exposure to 5% CO2. At P6, but not at other ages, respiratory frequency declined with time and at 5 min was less that at 2 and 3 min. GAD65-/- animals at P6 showed a sustained increase in respiratory rate for the five mins exposure to CO2. CONCLUSION: These results show, that in contrast to the rat, mice do not show a decline in minute ventilatory response to CO2 at one week of age. Similiar to the rat at P5, mice at P6 are unable to sustain an increase in CO2 induced respiratory frequency and GAD65 contributes to this fall off

B743: Primary Health Care and the Developmentally Disabled: An Analysis of the Normalization Principle in the State of Maine

At the time of publication, there existed an estimated group of 10 million American people defined as developmentally disabled. Stimulated in part by the often observed dehumanizing environment of institutional arrangement for the mentally disabled, the search for more humane treatment and management alternative has pointed in the direction of what has been termed \u27 normalization. In 1969, the Danish Mental Retardation Service defined normalization as \u27\u27 letting the mentally retarded obtain an existence as close to normal as possible. The focus of this study is on barriers to the normalization principle in the provision of primary health care to the developmentally disabled in the State of Maine. Possible barriers include attitudes toward the developmentally disabled, accessibility and quality of community based services, and lack of viable coordination mechanisms. Since 1971, the Maine Department of Mental Health and Corrections has made a concerted effort to encourage services based upon the principle of normalization. As pressures for normalization intensify, it seems warranted that those community-based structures which carry out the concept be examined as to their receptivity and the feasibility of further efforts in this direction. Although the principle of normalization has demonstrated its usefulness and potential, it is not without its limitations (Mesibov 1976). This study made no attempt to examine these limitations of the principle itself.https://digitalcommons.library.umaine.edu/aes_bulletin/1127/thumbnail.jp

Deficiency of GABAergic synaptic inhibition in the Kölliker-Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome

Life threatening breathing irregularity and central apnoeas are highly prevalent in children suffering from Rett syndrome. Abnormalities in inhibitory synaptic transmission have been associated with the physiopathology of this syndrome, and may underlie the respiratory disorder. In a mouse model of Rett syndrome, GABAergic terminal projections are markedly reduced in the Kölliker–Fuse nucleus (KF) in the dorsolateral pons, an important centre for control of respiratory rhythm regularity. Administration of a drug that augments endogenous GABA localized to this region of the pons reduced the incidence of apnoea and the respiratory irregularity of Rett female mice. Conversely, the respiratory disorder was recapitulated by blocking GABAergic transmission in the KF area of healthy rats. This study helps us understand the mechanism for generation of respiratory abnormality in Rett syndrome, pinpoints a brain site responsible and provides a clear anatomical target for the development of a translatable drug treatment

Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic AhR modulating agent (TAMA)

Tapinarof, a novel, first-in-class small-molecule topical therapeutic aryl hydrocarbon receptor (AhR) modulating agent (TAMA), is in clinical development for the treatment of psoriasis and atopic dermatitis. The efficacy of tapinarof in psoriasis is attributed to its specific binding and activation of AhR, a ligand-dependent transcription factor, leading to the downregulation of pro-inflammatory cytokines, including interleukin-17, and regulation of skin barrier protein expression to promote skin barrier normalization. AhR signaling regulates gene expression in immune cells and skin cells, and has critical roles in the regulation of skin homeostasis. Tapinarof-mediated AhR signaling underlies the mechanistic basis for the significant efficacy and acceptable tolerability observed in early phase clinical trials of tapinarof cream in the treatment of psoriasis

Transcriptome adaptation of the bovine mammary gland to diets rich in unsaturated fatty acids shows greater impact of linseed oil over safflower oil on gene expression and metabolic pathways

Differentially expressed genes implicated in apoptosis of cows in LSO treatment as compared to the same cows on the control diet. Expression direction of several genes predicted to decrease apoptosis. (DOCX 35 kb

Selective preservation of protein kinase C-ζ in the chemoprevention of azoxymethane-induced colonic tumors by piroxicam

AbstractWhile nonsteroidal anti-inflammatory drugs have been shown to exert preventive effects against the development of colonic tumors in humans and in chemically-induced tumors in animal models, the mechanism(s) involved in this phenomenon is unclear. We have recently demonstrated that one such agent, piroxicam, when supplemented (75 ppm) in the diets of rats administered azoxymethane, reduced the incidence of rats bearing tumors. To date, the effects of piroxicam on protein kinase C, a family of serine/threonine kinases which may be intimately involved in the colonic malignant transformation process, have not been examined. It was, therefore, of interest to determine whether piroxicam altered the expression of one or more isoforms of this kinase in these tumors. The present studies demonstrate that dietary piroxicam selectively preserved the expression of protein kinase C-ζ in azoxymethane-induced tumors; suggesting that this is at least one mechanism involved in this agent's chemopreventive actions in this organ

Substantial Dose-response Relationship with Clinical Outcome for Lung Stereotactic Body Radiotherapy (SBRT) Delivered via Online Image Guidance

Purpose: To examine potential tumor dose-response relationships with various non-small cell lung cancer (NSCLC) SBRT fractionation regimens delivered with online CT-based image guidance. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

Cumulative childhood trauma and complex psychiatric symptoms in pregnant women and expecting men

Background: Women and men having been exposed to childhood trauma would be at high risk of various mental health symptoms while awaiting a child. This study aimed to evaluate the association between cumulative childhood trauma and the accumulation of symptoms belonging to different psychiatric problems in pregnant women and expecting men. Methods: We first examined prevalence rates of childhood trauma across our samples of 2853 pregnant women and 561 expecting men from the community. Second, we evaluated the association between cumulative childhood trauma and symptom complexity (i.e., the simultaneous presentation of symptoms belonging to multiple psychiatric problems) using subsamples of 1779 pregnant women and 118 expecting men. Participants completed self-reported measures of trauma (Childhood Trauma Questionnaire) and psychiatric symptoms (PTSD Checklist for DSM-5; Kessler Psychological Distress Scale; State-Trait Anger Expression Inventory-2; Self and Interpersonal Functioning Scale). Results: Trauma was more frequent in pregnant women than in expecting men and in participants reporting sociodemographic risk factors than in those not reporting any. A dose-response relationship was observed between the number of different traumas reported by pregnant women and expecting men and the complexity of their psychiatric symptoms, even when controlling for the variance explained by other risk factors. Women having been exposed to cumulative childhood trauma were 4.95 times more at risk of presenting comorbid psychiatric problems during pregnancy than non-exposed women. Conclusions: Childhood trauma is frequent in the general population of pregnant women and expecting men and is associated with symptom complexity during the antenatal period. These findings call for delivering and evaluating innovative trauma-informed antenatal programs to support mental health and adaptation to parenthood in adults having been exposed to childhood trauma. © 2021, The Author(s)