Spatial and temporal dynamics of corticosterone and corticosterone binding globulin are driven by environmental heterogeneity

The question of whether changes in glucocorticoid concentrations reflect consistent changes in physiology associated with transitions between different stages of reproduction, or whether they reflect responses to environmental conditions, is one the central issues in field endocrinology studies. We examined the temporal and spatial dynamics of corticosterone (CORT, baseline, and acute stress-induced) and corticosterone binding globulin (CBG) concentrations in blood of Black-legged Kittiwakes (Rissa tridactyla) breeding at four major colonies in the Bering Sea, Alaska, during 1999-2005. We found that total CORT, free CORT, and CBG capacity varied inconsistently among reproductive stages, colonies, and years. Total CORT levels were positively correlated with CBG capacity. Variation in free CORT was largely driven by variation in total CORT. Results suggest that the adrenocortical function and CBG in breeding kittiwakes do not vary as a consequence of stage-specific modulation associated with a particular reproductive stage as in some short-lived passerine birds. Rather, in accord with predictions for a long-lived species, the lack of consistent colony, year, and reproductive stage patterns in baseline and maximum CORT, and CBG indicates that environmental factors, probably local dynamics of food availability, drive variation in these factors.     

Electrogastrography in patients with Roux-en-Y reconstruction after previous Billroth gastrectomy

BACKGROUND/AIMS: The aim of this prospective study was to characterize gastric myoelectrical activity in patients with Roux-en-Y reconstruction after previous Billroth gastrectomy. METHODOLOGY: Thirteen patients entered the study (6 men and 7 women, aged 35-57). The mean time from Roux-en-Y reconstruction to electrogastrography (EGG) recording was 5 years. Surface cutaneous EGG was recorded using a Digitrapper EGG in the morning both fasting and after a standard solid test meal. All patients assessed their dyspeptic symptoms at the time of EGG in a semi-quantitative subjective scale. RESULTS: EGG was abnormal in all studied patients (but one postprandial recording). Dyspepsia was not meal-related and was not more severe in Helicobacter pylori positive patients. There was a significant negative correlation between time from Roux-en-Y reconstruction to EGG recording and bradygastria percent activity, both fasted and postprandial (r = -0.576; p = 0.0022). There was an inverse trend between severity of dyspepsia and normal slow-wave rhythm percent activity. Older patients tended to have more severe dyspepsia. CONCLUSIONS: The results of this study suggest that abnormal EGG recording is associated with dyspepsia in patients after Roux-en-Y reconstruction.     

Validity of transhepatic pulp pressure measurements

Cineangiographic studies were undertaken in conjunction with pressure measurements to determine the reliability of transhepatic pulp pressure manometry in assessing portal pressure. Pressure measurements obtained by wedged hepatic vein and/or umbilical-portal vein catheterization were used as a reference. An accurate index to intrasinusoidal pressure was provided when the needle was introduced into the sinusoidal bed and created a vascular “puddle.” Pressures were inaccurate when the needle entered a hepatic venule, the subcapsular space, or a bile duct. Reversible increases in transhepatic pressure were noted with proliferation of sinusoidal-mesenchymal cells attendant to acute liver injury or hyperplasia of the endoplasmic reticulum following administration of drugs that are metabolized in microsomes.     

Socioeconomic status and diagnosed diabetes incidence

AIMS: To investigate the association between socioeconomic status (SES) and incidence of diabetes. METHODS: We investigated three measures of SES and incidence of diagnosed diabetes among women and men in the NHANES I Epidemiologic Followup Study, 1971-1992, who were free of diagnosed diabetes in 1980. RESULTS: Among women, diabetes incidence was inversely associated with income (measured as percent of the poverty level), education, and occupational status, adjusting for age and race/ethnicity. The hazard ratio (HR) for women with > 16 years education was 0.26 (95% confidence interval (CI) 0.13-0.54) relative to those with < 9 years of education. Adjustment for potential mediators, including body size variables, diet, physical activity, and alcohol and tobacco use, substantially attenuated the associations with income and education. Among men a trend toward lower diabetes incidence with higher income and higher education was evident (the HR for men with household income > 5 times the poverty level was 0.44 (95% CI 0.19-0.98) relative to those under the poverty line), but there was no inverse association of diabetes incidence with occupational status. CONCLUSIONS: SES, assessed with any of three common measures, is a risk factor for diagnosed diabetes in women. Among men these associations are less consistent.     

Long-Term Antibody Response and Vaccination Efficacy in Patients with COVID-19: A Single Center One-Year Prospective Study from the Czech Republic

Background: The diagnosis of SARS-CoV-2 is almost exclusively performed by PCR or antigen detection. The detection of specific antibodies has not yet been considered in official diagnostic guidelines as major laboratory evidence for a case definition. The aim the present study is to analyze antibody responses in outpatient and inpatient cohorts of COVID-19 patients in the Czech Republic over a 12-month period, and assess the potential of antibodies as a diagnostic tool. Methods: A total of 644 patients was enrolled in the prospective study. IgA, IgM and IgG antibody levels, as well as virus neutralization titers, were analyzed over a 12-month period. Results: Our study showed low antibody positivity levels at the admission. However, at 2 weeks after infection, 98.75% and 95.00% of hospitalized patients were IgA and IgG positive, respectively. Even in the outpatient cohort characterized by milder disease courses, the IgG antibody response was still sustained at 9 and 12 months. The data show a high correlation between the IgG levels and virus neutralization titers (VNTs). Samples from later time-points showed positive antibody responses after vaccination in both cohorts characterized by high IgG levels and VNT over 1:640. The samples from unvaccinated persons indicated a relatively high level of reinfection at 6.87%. Conclusions: Our results show that the detection of antibodies against the SARS-CoV-2 shows an increasing sensitivity from week 2 after infection and remains highly positive over the 12-month period. The levels of IgG antibodies correlate significantly with the VNTs. This suggests that the serological data may be a valuable tool in the diagnosis of SARS-CoV-2 infection.     

Genetic evidence for a protein-kinase-A-mediated presynaptic component in NMDA-receptor-dependent forms of long-term synaptic potentiation

The synaptic vesicle protein Rab3A is a small GTP-binding protein that interacts with rabphilin and RIM1alpha, two presynaptic substrates of protein kinase A (PKA). Mice lacking RIM1alpha and Rab3A have a defect in PKA-dependent and NMDA receptor (NMDAR)-independent presynaptic long-term potentiation (LTP) at hippocampal mossy-fiber and cerebellar parallel-fiber synapses. In contrast, the NMDAR-dependent and PKA-independent early phase of LTP at hippocampal CA3-CA1 synapses does not require these presynaptic proteins. Here, we ask whether Rab3A and RIM1alpha participate in forms of LTP that require both PKA and NMDAR activation. We find that Rab3A is necessary for corticoamygdala LTP and late-phase LTP at CA3-CA1 synapses, two forms of LTP that require NMDAR and PKA activation. The latter form of LTP also requires RIM1alpha. These results provide genetic evidence that presynaptic proteins are required in LTP induced through the postsynaptic activation of NMDARs. Thus Rab3A and its effectors are general modules for four distinct types of PKA-dependent LTP in the brain.     

Sites of Replication of Chromosomal DNA in a Eukaryotic Cell

In mouse cells (line P815), newly synthesized DNA labeled for 20-30 sec during exponential growth is found by electron microscope autoradiography at sites throughout the cell nucleus. These sites are relatively more concentrated in the peripheral region of the nucleus (averaged over a random population of S-phase cells), probably reflecting a higher local concentration of DNA in this region. Newly synthesized DNA is not preferentially associated with purified nuclear envelopes, but is found in a fraction of the chromosomal deoxynucleoprotein whose buoyant density in CsCl after formaldehyde treatment is about 1% lower than that of the deoxynucleoprotein peak. Kinetics experiments suggest that this material is a precursor of mature deoxynucleoprotein; it may represent regions of deoxynucleoprotein containing replicating DNA and the additional proteins involved in DNA replication. Other complexes of newly replicated DNA that are found in the interphase after phenol extraction of nuclei are formed during the extraction procedure, probably due to the partially single-stranded nature of replicating DNA, and do not appear to exist in vivo.     

3,4-Diarylmaleimides-a novel class of kinase inhibitors-effectively induce apoptosis in FLT3-ITD-dependent cells

FLT3 kinase has become an attractive drug target in AML with up to 30% of cases harboring internal-tandem-duplication (ITD) mutations. For these, conferring a worse prognosis and decreased overall survival, several FLT3 tyrosine kinase inhibitors (TKIs) are currently being tested in clinical trials. However, when using these drugs as monotherapy, the problem of short duration of remissions and high incidence of TKI resistance has emerged. Here, we investigated two members of a novel class of tyrosine kinase inhibitors, 3,4-diarylmaleimides, for their efficacy on mutated FLT3 kinase. These compounds inhibit FLT3 kinase in an ATP-competitive manner and effectively inhibit phosphorylation of downstream targets. 3,4-Diarylmaleimides (DHF125 and 150) induce apoptosis in FLT3-ITD-dependent cells lines and patient blasts at low micromolar concentrations. They are retained in the cytoplasm of exposed cells for more than 24?h and synergize with chemotherapy and midostaurin. Both 3,4-diarylmaleimides show inhbition of FLT3-ITD-related kinase autophosphorylation at distinct tyrosine residues when compared to midostaurin. In conclusion, this novel group of compounds shows differential inhibition patterns with regard to FLT3 kinase and displays a promising profile for further clinical development. Currently, experiments evaluating toxicity in murine models and unraveling the exact binding mechanism are under way to facilitate a potential clinical application.     

Comparative analysis of learning curve in complex robot-assisted and laparoscopic liver resection

Background

There is no comparative analysis of the learning curves for robot-assisted and laparoscopic liver resection. We aimed to compare learning curves in complex robotic and conventional laparoscopic liver resections with regards to estimation of the difficulty index score.