Protein kinase signalling requirements for metabotropic action of kainate receptors in rat CA1 pyramidal neurones

Hippocampal pyramidal neurones display a Ca²⁺-dependent K⁺ current responsible for the slow afterhyperpolarization ( I _sAHP), a prominent regulator of excitability. There is considerable transmitter convergence onto I _sAHP but little information about the interplay between the kinase-based transduction mechanisms underlying transmitter action. We have added to existing information about the role of protein kinase C (PKC) in kainate receptor actions by demonstrating that direct postsynaptic activation of PKC with either 1-oleoyl-2-acethylsn-glycerol (OAG) or indolactam is sufficient to inhibit I _sAHP. The physiological correlate of this action – activation of PKC by kainate receptors – requires Gα_i/o proteins. The cAMP/PKA system is well documented to subserve the actions of monoamine transmitters. We have found an additional role for the cAMP/PKA system as a requirement for kainate receptor-mediated inhibition of I _sAHP. Inhibition of adenylyl cyclase with dideoxyadenosine or PKA with either H89 or RpcAMPs blocked kainate receptor-mediated actions but did not prevent the actions of direct PKC activation with either OAG or indolactam. We therefore propose that the PKA requirement is upstream from the actions of PKC. We additionally report a downstream link in the form of increased mitogen-activated protein (MAP) kinase activity, which may explain the long duration of metabotropic actions of kainate receptors on I _sAHP.     

The somatostatin analogue, octreotide, modifies both steroidogenesis and IGFBP-1 secretion in human luteinizing granulosa cells

The effect of the somatostatin analogue octreotide on the secretion of progesterone and insulin-like growth factor binding protein-1 (IGFBP-1) from human granulosa-luteal cells was investigated. Octreotide (10(- 11), 10(-10) and 10(-9) M) alone induced a significant decrease in progesterone secretion (maximum suppression 69 +/- 5% of control: P < 0.0001). In contrast, treatment with octreotide in combination with human chorionic gonadotrophin (HCG), at 1 IU/ ml potentiated the stimulatory effect of HCG on progesterone secretion (HCG alone 201 +/- 3% of control: HCG + octreotide 10(-9) M 318 +/- 16%: P < 0.001). Treatment with octreotide increased the secretion of IGFBP-1 (maximum stimulation 254 +/- 25% of control: P < 0.01). No effect of HCG was seen on secretion of IGFBP-1. These findings raise the possibility that somatostatin may have a modulatory role in regulating steroidogenesis by the human corpus luteum. Further studies are required to establish the physiological significance of any such function.      

T cells discriminate between differentially phosphorylated forms of alphaB-crystallin, a major central nervous system myelin antigen

Factors such as developmental stage or physiological and infectious stress may change patterns of post-translational protein modification. In order to determine whether such regulated types of modification may influence T cell responsiveness to self proteins we examined the T cell response of SJL (H-2s) mice to alphaB-crystallin, a small heat shock protein that can exist in differentially phosphorylated forms. Epitope mapping revealed the presence of two T cell epitopes that are presented by I-As. One major epitope including residues 41-56 contains an amino acid residue (Ser45) that can be phosphorylated as the result of aging or stress. Accordingly, T cells from SJL mice discriminate between preparations of alphaB-crystallin that differ in their extent of phosphorylation at the level of whole protein as well as at the level of determinant-specific responses. Phosphorylation at Ser45 does not prevent binding of the peptide 41-56 to I-As and computer-assisted modelling of the peptide-MHC complex suggests that the phosphate group of the bound peptide extends outwards from the peptide-binding cleft and may thus be available for direct contact with TCR. Together, our data provide evidence that stress-inducible phosphorylation of alphaB- crystallin creates neo-determinants for T cells and, therefore, may contribute to the breakdown of peripheral tolerance to this self protein.      

In ovo non‐invasive quantification of the myocardial function and mass of chick embryos using magnetic resonance imaging

Magnetic resonance imaging (MRI) has evolved as one of the major non‐invasive tools to study healthy and diseased hearts in animal models, especially rodent models. Even though, the chick embryo has long been used as a model for cardiovascular research, MRI has not yet been used for in vivo cardiac studies. Part of the reason for this is the difficulty in monitoring the ECG and respiration of the chick embryo in the magnet for gating purposes. To overcome this complication, this paper presents the use of retrospective Cine MRI to measure the cardiac function of chick embryos in ovo for the first time, without the need for respiratory or cardiac gating. The resulting left ventricular functional parameters, from six chick embryos at 20 days of incubation, were (mean ± SD) EDV 69 ± 15 µL, ESV 31 ± 7 µL, SV 38 ± 9 µL and EF 54.5 ± 2%. The use of retrospective Cine MRI at earlier stages of development is also discussed and difficulties have been highlighted. Copyright © 2009 John Wiley & Sons, Ltd.     

Variable effect of growth hormone on growth and final adult height in Scottish patients with Turner's syndrome

The aim of this work was to assess the outcome of recombinant growth hormone (rGH) therapy in a large unselected group (72) of patients with Turner's syndrome (TS), 26 of whom have reached final height. Growth data were collected from Scottish patients with TS and outcome was assessed in three ways: response to therapy in the first year, response in subsequent years and final height. Phenotypic, auxological, genetic and biochemical factors, all of which may have affected the first-year response, were investigated. Fifty-one percent of the cohort had a clinically "good" first-year response to therapy and 49% had a "poor" response; a "good" response was defined as a change in the TS standard deviation score (SDS) of +0.5 or more and a "poor" response as a change in the TS SDS of less than +0.5. The percentage of children showing a positive change in TS SDS after 2, 3 and 4 years of therapy declined (88%, 78%, 41%). Mean (range) final height was 142.6 (133.4–153.6) cm, mean (range) pretreatment TS SDS was -0.27 (-2.1 to +1.09) and mean (range) final TS SDS was -0.05 (-1.4 to +1.59). Thirteen (50%) patients attained a final height that was greater than projected, eleven did not attain their projected final height and two achieved their exact projected final height. Short girls with TS appear to benefit more from rGH supplementation than tall girls, but otherwise there was no significant correlation between any of the parameters studied and the response to treatment. It is concluded that large-scale prospective studies are still required to assess the impact of rGH on final height in TS and to identify factors responsible for the variability in response.     

A cross‐sectional study of psychological morbidity in patients with acne,psoriasis and atopic dermatitis in specialist dermatology and general practices

Background There is considerable evidence for an association of skin diseases with psychological morbidity. This relationship is best established for acne, psoriasis and atopic eczema. Previous studies have mostly been performed in specialist dermatological practice, and there is a lack of studies that include patients from general practice and a lack of controlled studies employing multivariate analysis. Aims/objectives This study aims to examine the relationship of acne, psoriasis and atopic eczema with psychological morbidities in patients recruited from general practice as well as specialist dermatology practice. Methods and subjects In this cross‐sectional study, 108 patients from general and specialist dermatology practices with the three diseases had disease severity assessed and completed measures of minor psychological disturbance (General Health Questionnaire‐12), anxiety and depression (Hospital Anxiety and Depression Scale), public self‐consciousness and social anxiety (Fenigstein Self‐Consciousness Scale), and neuroticism and extraversion/introversion (Eysenck Personality Inventory). Demographic data were also collected, along with self‐ratings of disease severity. Control subjects were 96 patients without skin disease recruited from the same general practices as the subjects. Results On univariate analyses, patients with skin disease had higher levels of minor psychological disturbance, public self‐consciousness and neuroticism than did controls. There were no differences in psychological measures between specialist and general practice patients or between patients with different skin diseases. On multivariate analyses, the significant differences did not persist. Conclusions This study demonstrates confounding in the relationship of skin diseases with psychological morbidity. The complex relationship of skin disease and psychological morbidity should be re‐examined.     

Development of the Verbal Autopsy Instrument for COVID-19 (VAIC)

BackgroundImproving accuracy of identification of COVID-19-related deaths is essential to public health surveillance and research. The verbal autopsy, an established strategy involving an interview with a decedent’s caregiver or witness using a semi-structured questionnaire, may improve accurate counting of COVID-19-related deaths.ObjectiveTo develop and pilot-test the Verbal Autopsy Instrument for COVID-19 (VAIC) and a death adjudication protocol using it.Methods/Key ResultsWe used a multi-step process to design the VAIC and a protocol for its use. We developed a preliminary version of a verbal autopsy instrument specifically for COVID. We then pilot-tested this instrument by interviewing respondents about the deaths of 15 adults aged ≥65 during the initial COVID-19 surge in New York City. We modified it after the first 5 interviews. We then reviewed the VAIC and clinical information for the 15 deaths and developed a death adjudication process/algorithm to determine whether the underlying cause of death was definitely (40% of these pilot cases), probably (33%), possibly (13%), or unlikely/definitely not (13%) COVID-19-related. We noted differences between the adjudicated cause of death and a death certificate.ConclusionsThe VAIC and a death adjudication protocol using it may improve accuracy in identifying COVID-19-related deaths.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-06842-1.KEY WORDS: COVID-19, mortality, verbal autopsy