C-reactive protein concentration is not related to islet autoimmunity status in offspring of parents with type 1 diabetes

Autoimmunity may be associated with acute or chronic inflammation. In order to determine whether the inflammatory marker C-reactive protein (CRP) was an indicator of inflammatory events that precede, predict, or associate with islet autoimmunity or type 1 diabetes, CRP was measured in sequential antibody-negative, seroconversion, and follow-up-positive samples from 65 prospectively studied islet autoantibody-positive children. Although changes in CRP concentrations were observed in some children, overall CRP concentrations were similar in antibody-negative samples (median, 0.21 mg/L), antibody-positive samples (median, 0.26 mg/L), and samples at seroconversion (median, 0.26 mg/L). CRP concentrations at diabetes onset (median, 0.59 mg/L) were not significantly increased over antibody-negative samples (P = 0.07). CRP concentrations did not predict diabetes development. CRP concentrations were related to age (r = 0.26; P < 0.001) and were increased in samples obtained from October to January (P < 0.001). These findings suggest that CRP concentrations are not a valuable marker of progression to type 1 diabetes and highlight the importance of correcting analyses for seasonal variations.     

Adrenocorticotropic cell distribution in adult and embryonic pituitaries of the little (lit) mutant mouse

Summary Immunofluorescence and colloidal gold immunocytochemistry were used to analyze the regional distribution of adrenocorticotropic (ACTH) cells and their ultrastructural relationship with growth hormone (GH) cells in adult and 17-day embryonic little (lit/lit) mice that exhibit GH cell defects. Adult lit/lit pituitaries lack the distinctive regionalization of ACTH cells that characterizes normal pituitaries, although typical ultrastructural relationships occur between some ACTH and GH cells. In 17-day embryos, normal and lit/lit pituitaries show similar distributions of ACTH cells. However, in lit/lit pituitaries the pars distalis cells are more loosely arranged, with poorly defined clusters and cords, than in normal glands. The results indicate that whereas the lack of ACTH cell regionalization in adult glands may be a secondary effect of the GH cell defect, the differences in overall integrity of the 17-day embryonic glands suggest the possibility of a developmental disturbance during early stages of gestation in this mutant.Supported by research grant No. HD12308 from the National Institute of Child Health and Human Development, National Institutes of Health (USA)     

COVID-19- und influenzaassoziierte Sterbefälle in München ab März 2020 – eine standardisierte Auswertung von Todesbescheinigungen

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Vor dem Hintergrund der derzeitigen COVID-19-Pandemie entstand die Idee zur Durchführung einer Studie, in der die...     

Übelkeit und Erbrechen als Symptome in der Notfallmedizin

Notfall + Rettungsmedizin - Übelkeit und Erbrechen (Nausea und Vomitus, NV) sind geläufige Symptome in der Notfallmedizin, mit etwa 3–4 % der Behandlungsanlässe auf...     

Protroca: A Noninterventional Study on Prophylactic Lipegfilgrastim against Chemotherapy-Induced Neutropenia in Nonselected Breast Cancer Patients

BackgroundProtroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT).Patients and MethodsOf the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed.ResultsNine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis (n = 222) had febrile neutropenia of grade 3–4 (5 patients) or infection of grade 3–4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim.ConclusionsApplication of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer.     

HA1 (Hemagglutinin) quantitation for influenza A H1N1 and H3N2 high yield reassortant vaccine candidate seed viruses by RP-UPLC

The only effective measure to decrease morbidity and mortality caused by the influenza virus in the human population is worldwide vaccination. Vaccination produces neutralizing antibodies that target the HA1 subunit of the HA (hemagglutinin) protein and are strain specific. The effectiveness of new influenza vaccines are linked to two factors, the correct prediction of the circulating strains in the population in a particular season and the concentration of the HA1 protein in the vaccine formulation. With the advent of the licensing of quadrivalent vaccines, pharmaceutical manufacturers are under considerable pressure due to time constraints and dedicated resources to deliver 194–198 million doses (2020–2021 U.S. market) of vaccine. Considering the valuable resources needed to produce the influenza vaccine in a timely manner, the efficient quantitation of the HA1 protein (the main component in the influenza vaccine) is required. Currently the only method approved by regulatory agencies for quantitation of the HA antigen in vaccines is the single radial immunodiffusion assay (SRID), an antibody dependent assay that is not time efficient. Time efficient methods that are antibody independent e.g. reverse phase-high performance liquid chromatography (RP-HPLC) or size exclusion-HPLC (SE-HPLC) are available. An improved method implementing reverse phase-ultra performance liquid chromatography (RP-UPLC) has been developed to quantitate the HA1 protein antigen present in the high yield reassortant vaccine seed viruses from influenza A H1N1 and H3N2 subtypes harvested from inoculated embryonated chicken eggs. This method differentiates between high yield and lower yielding reassortants in order to select the best vaccine candidate seed virus with the highest growth ‘in ovo’. This direct capability to monitor the HA1 concentration of potential reassortant seed viruses and to choose the best yielding HA influenza reassortant when faced with multiple viral seed candidates provides a major advantage on the industrial scale to the influenza vaccine process.     

Demonstration of pro-opiomelanocortin mRNA in pituitary adenomas and para-adenomatous gland in cushing's disease and Nelson's syndrome

Pro-opiomelanocortin (POMC) mRNA was demonstrated in pituitary adenomas from 16 patients with Cushing's disease and 10 with Nelson's syndrome. The intensity of signal was significantly greater in Nelson's syndrome than in Cushing's disease and there was a trend towards a greater proportion of positive cells. This probably reflects inhibition of POMC gene expression by the high circulating levels of cortisol in Cushing's disease. In the para-adenomatous gland, the intensity of signal was variable in cells showing Crooke's hyaline change, ranging from negative to strongly positive, in keeping with the functional heterogeneity of corticotrophs. In one case, junctional corticotrophs were present and these were more intensely stained than anterior lobe corticotrophs in the same gland. This supports the concept that these cells are subject to different regulatory influences from corticotrophs in the anterior lobe. Whether this is related to differences in embryological origins or to local factors is at present unclear.     

Biochemical interactions between methotrexate and 1-β-d-arabinofuranosylcytosine in hematopoietic cells of children: a Pediatric Oncology Group study

Summary Children with acute lymphocytic leukemia (ALL) in remission were treated with overlapping sequential infusions of methotrexate (MTX) and 1--d-arabinofuranosylcytosine (araC) as part of continuation therapy. The doses and the sequence were chosen to mimic conditions that produced greater than additive antineoplastic activity with these two drugs in preclinical studies. To assess the potential for the drug combination to exhibit greater than additive effect in vivo, we investigated several biochemical parameters that had been associated with synergism in vitro. Because the patients were in remission, the intracellular parameters could only be measured in cytologically normal hematopoietic cells. We observed that (1) the mean plasma concentrations of MTX and araC were above those required to obtain a greater than additive cytotoxicity with the two drugs in tissue culture; (2) MTX did not have a significant antipurine effect in bone marrow mononuclear cells; (3) the mean intracellular concentration of deoxycytidine triphosphate (dCTP) was significantly lower after treatment with the drug combination than after therapy with araC alone; and (4) the ratio of araC triphosphate (araCTP) to dCTP was 2.6 times higher after treatment with the combination than after araC alone. These results indicate that it is possible to achieve in patients the biochemical conditions associated with the greater than additive antineoplastic activity of MTX and araC in vitro.Abbreviations ALL acute lymphocytic leukemia - araC 1--d-arabinofuranosyluracil - araCTP araC triphosphate - araU 1--d-arabinofuranosyluracil - dNTPs deoxyribonucleoside triphosphates - MTX methotrexate - TCA trichloroacetic acid Supported in part by grants from the National Cancer Institute, National Institutes of Health (CA-38 053; CA-33572, CA-32278, CA-38 859, CA-29 691, and CA-30 969). Preliminary reports on the biochemical data were published by E. M. N., A. M. T., and D. P. inProc Am Assoc Cancer Res 24: 133 (1983) and those on the clinical data, by R. A K., E. M. N., D. P. R. B. R., M. B. H., Y. R., and A. I. F. inProc Am Soc Clin Oncol 3: 201 (1984)     

Characterization of the muscarinic receptor subtype(s) mediating contraction of the guinea-pig lung strip and inhibition of acetylcholine release in the guinea-pig trachea with the selective muscarinic receptor antagonist tripitramine

1. The muscarinic receptor subtypes mediating contraction of the guinea-pig lung strip and inhibition of the release of acetylcholine from cholinergic vagus nerve endings in the guinea-pig trachea in vitro have previously been characterized as M₂-like, i.e. having antagonist affinity profiles that are qualitatively similar but quantitatively dissimilar compared to cardiac M₂ receptors. The present study sought to establish definitely the identity of these receptor subtypes by using the selective muscarinic receptor antagonist, tripitramine. Guinea-pig atria and guinea-pig trachea (postjunctional contractile response) were included for reference.
2. It was found that tripitramine antagonized methacholine-induced contractions of the guinea-pig lung strip with a pK_B value of 8.76±0.05. Both the parallel shifts of the concentration-response curves and the slope of the Schild plot being not significantly different from unity (when antagonist preincubation was for 2 h) indicated the involvement of a single population of receptors in the contractile response. From the pK_B values obtained with tripitramine and a range of other selective muscarinic receptor antagonists (cf. Roffel et al., 1993), this single population of receptors can only be classified as M₂-like.
3. Tripitramine antagonized methacholine-induced negative chronotropic and inotropic responses in guinea-pig right and left atria with apparent pK_B values of 9.4–9.6. However, such values were only obtained when antagonist preincubation was relatively long and/or antagonist concentration relatively high (e.g. with 1 h at 100 or 300 nM but 3 h at 30 nM). It thus appears that low concentrations of tripitramine do not readily equilibrate with M₂ receptors in guinea-pig atria nor with M₂-like receptors in the guinea-pig lung strip.
4. Tripitramine increased electrical field stimulation-induced cholinergic twitch contractions in guinea-pig trachea in concentrations of 0.3–100 nM, by blocking prejunctional muscarinic inhibitory autoreceptors; with higher concentrations, twitch contractions were progressively diminished, as a result of blocking postjunctional M₃ receptors (apparent pK_B value 6.07±0.15). The pEC₂₀ value (−log concentration that increases twitch by 20% of maximum) was 8.29±0.08, which would suggest that M₄ receptors are involved in this response.
5. Oxotremorine-induced inhibition of the release of prelabelled [³H]-acetylcholine from guinea-pig trachea, under conditions where there is no auto-feedback, was blocked by tripitramine (2 h preincubation) with a pK_B value of 8.56±0.06. The slope of the corresponding Schild plot was not significantly different from unity, which together with the parallel shifts of the concentration-response curves indicated the involvement of a single muscarinic receptor subtype.
6. Since the pK_B value for tripitramine at prejunctional receptors in guinea-pig trachea is in between the affinities towards M₂ and M₄ receptors, correlation plots were constructed to compare the pK_B values obtained with tripitramine and a range of other selective muscarinic receptor antagonists (cf. Kilbinger et al., 1995) to reported affinities at M₁–M₄ receptors. This showed rather similar distribution patterns of the data points around the line of equality in the case of M₂ and M₄ receptor subtypes. However, the correlation coefficient was markedly better for M₂ (0.9667) than for M₄ (0.5976). Since recent evidence suggests that M₄ receptors are not expressed in cholinergic nerves from guinea-pig trachea, it is concluded that prejunctional muscarinic autoinhibitory receptors in this tissue exhibit an atypical M₂ type character, with a pharmacological profile distinct from cardiac M₂ receptors.