Second messenger systems underlying amine and peptide actions on cardiac muscle in the horseshoe crab, Limulus polyphemus

The biochemical mechanisms by which octopamine, catecholamines and the peptide proctolin exert their actions on Limulus cardiac muscle were investigated. Amines produced long-lasting increases in the amplitude of contractions evoked by electrical stimulation. At 10(−5) mol l-1, the apparent order of potency for amine-induced increases in evoked contraction amplitude was dopamine approximately equal to octopamine greater than norepinephrine approximately equal to epinephrine. At this dose, amines produced long-lasting increases in the levels of cyclic AMP (octopamine greater than dopamine approximately equal to norepinephrine approximately equal to epinephrine), but not of cyclic GMP, in Limulus cardiac muscle. Like the amines, the adenylate cyclase activator forskolin enhanced cardiac muscle contractility and increased levels of cyclic AMP, but not of cyclic GMP. The phosphodiesterase inhibitor IBMX produced a transient increase in cardiac muscle contractility, but typically produced long-lasting negative inotropy. This agent increased levels of both cyclic AMP and cyclic GMP in Limulus cardiac muscle. Proctolin and the protein kinase C activator phorbol dB increased the contraction amplitude of the intact heart and the electrically stimulated myocardium. These compounds, as well as dopamine, elicited sustained contractures and rhythmic contractions when applied to deganglionated Limulus cardiac muscle rings. Unlike the amines, proctolin and phorbol dB did not increase cardiac muscle cyclic AMP levels. These results suggest that several second-messenger systems may be utilized by amines and peptides to produce excitatory actions on cardiac muscle fibers of the Limulus heart. Cyclic AMP appears to be an important second messenger underlying the effects of amines to enhance cardiac muscle contractility. Pharmacological data suggest that proctolin may alter cardiac muscle contractility and excitability by a mechanism which involves the phosphatidylinositol pathway. Dopamine, unlike the other amines, produces a number of proctolin-like effects and may activate both the cyclic AMP and the phosphatidylinositol systems in Limulus cardiac muscle

Involvement of cyclic AMP in multiple, excitatory actions of biogenic amines on the cardiac ganglion of the horseshoe crab Limulus polyphemus

Cyclic AMP appears to be involved in several excitatory actions of amines on neurones of the Limulus cardiac ganglion. Amines selectively increase levels of cardiac ganglion cyclic AMP with a magnitude and time course similar to that observed for amine-induced excitation of cardiac ganglion burst rate. With respect to either the physiological or biochemical effect, the apparent order of potency is octoparnine\u3eepinephrine==dopamine\u3enorepinephrine. Elevation of cardiac ganglion cyclic AMP levels by octopamine or dopamine is dose-dependent and is potentiated by the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (IBMX). Several pharmacological agents which influence cyclic nucleotide metabolism, including forskolin, IBMX and 8-substituted cyclic AMP analogues, have amine-like effects on the Limulus cardiac ganglion. These effects include increased burst rate of the isolated cardiac ganglion and decreased burst duration, interburst interval and number of spikes per burst in follower neurones. Forskolin and IBMX increase levels of cardiac ganglion cyclic AMP, and IBMX also increases cyclic GMP levels in this tissue. Amines, forskolin and IBMX have direct effects on follower neurones pharmacologically isolated from pacemaker cell input. Octopamine, forskolin and IBMX depolarize follower neurones, while dopamine hyperpolarizes these cells. Amines, forskolin and IBMX elicit burst-like potentials in follower neurones, and increase the size of evoked, unitary junction potentials recorded in cardiac muscle fibres. These pharmacological and biochemical data suggest that multiple, excitatory effects of biogenic amines on the Limulus cardiac ganglion are mediated by simultaneous increases in cyclic AMP at several loci within this neural network

The onset of classical QCD dynamics in relativistic heavy ion collisions

The experimental results on hadron production obtained recently at RHIC offer a new prospective on the energy dependence of the nuclear collision dynamics. In particular, it is possible that parton saturation -- the phenomenon likely providing initial conditions for the multi--particle production at RHIC energies -- may have started to set in central heavy ion collisions already around the highest SPS energy. We examine this scenario, and make predictions based on high density QCD for the forthcoming 22 GeV run at RHIC.Comment: 4 pages, 2 figures, revte

How random is your heart beat?

We measure the content of random uncorrelated noise in heart rate variability using a general method of noise level estimation using a coarse grained entropy. We show that usually - except for atrial fibrillation - the level of such noise is within 5 - 15% of the variance of the data and that the variability due to the linearly correlated processes is dominant in all cases analysed but atrial fibrillation. The nonlinear deterministic content of heart rate variability remains significant and may not be ignored.Comment: see http://urbanowicz.org.p

Presence of exon 5-deleted oestrogen receptor in human breast cancer: functional analysis and clinical significance.

A variant form of the human oestrogen receptor (ER) mRNA lacking sequences encoded within exon 5 has been described (Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malloy BW, McGuire WL 1991, Cancer Res 51: 105-109). We have examined the expression of the exon 5-deleted ER (HE delta5) mRNA variant in breast biopsies using reverse transcriptase polymerase chain reaction (RT - PCR). HE delta5 mRNA was present in only 13% of non-malignant breast tissues compared with 32% of carcinomas (95% CI, P=0.05). Presence of the HE delta5 mRNA was associated with the presence of immunohistochemically detected ER (P=0.015) and progesterone receptor (PR) (P=0.02). There was a positive correlation between the presence of HE delta5 and disease-free survival (P=0.05), suggesting that the presence of HE delta5 may be an indicator of better prognosis. We have raised a monoclonal antibody specific to the C-terminal amino acids of HE delta5. This antibody recognized the variant but not the wild-type ER protein. We show that HE delta5 protein is present in breast cancer using immunohistochemical techniques. We also analysed trans-activation by HE delta5 in mammalian cells and showed that, in MCF-7 cells, HE delta5 competes with wild-type ER to inhibit ERE-dependent trans-activation. Our results indicate that this variant is unlikely to be responsible for endocrine resistance of breast cancer, but its presence at both the mRNA and protein level suggest that it may, nevertheless, be involved in regulating the expression of oestrogen-responsive genes in breast cancer

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series

Background: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. Methods: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms “RSV”, “respiratory syncytial virus”, or “respiratory syncytial viral” combined with “mortality”, “fatality”, “death”, “died”, “deaths”, or “CFR” for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. Findings: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3–11·0) in low-income or lower middle-income countries, 4·0 months (2·0–10·0) in upper middle-income countries, and 7·0 months (3·6–16·8) in high-income countries. Interpretation: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries

Diagnostic testing practices for diarrhoeal cases in South African public hospitals

BACKGROUND : Stool samples submitted for diagnostic testing represent a proportion of diarrhoeal cases seeking healthcare, and an even smaller proportion of diarrhoeal cases in the community. Despite this, surveillance relies heavily on these laboratory results. This study described diarrhoeal diagnostic practices and aetiological agents of diarrhoea in patients admitted to three South African public hospitals in order to understand biases in surveillance data, and inform guidelines, diagnostic and laboratory practices to improve clinical management. METHODS : A doctors’ survey was conducted to determine sample submission, diarrhoeal treatment and barriers to submitting samples for testing. Results for all samples submitted for routine diagnostics were obtained from the NHLS Central Data Warehouse. An enhanced surveillance study enrolled patients with acute diarrhoea at the same hospitals over the same period. Differences between routine culture results and molecular testing from the surveillance study were described. RESULTS : Stool samples were seldom submitted for diagnostic testing (median of 10% of admitted cases). Current diagnostic guidelines were not useful, hence most doctors (75.1%) relied on their own clinical judgement or judgement of a senior clinician. Although most doctors (90.3%) agreed that diagnostics were helpful for clinical management, they reported patients being unwilling to provide samples and long laboratory turnaround times. Routine diagnostic data represent cases with chronic diarrhoea and dysentery since doctors are most likely to submit specimens for these cases. Pathogen yield (number of pathogens detected for samples tested for specific pathogens) was significantly higher in the surveillance study, which used molecular methods, than through routine diagnostic services (73.3% versus 8.2%, p < 0.001), including for viruses (48.9% versus 2.6%, p < 0.001), bacteria (40.1% versus 2.2%, p < 0.001) and parasites (16.2% versus 3.6%, p < 0.001). Despite viruses being commonly detected in the surveillance study, viral testing was seldom requested in routine diagnostic investigations. CONCLUSIONS : Comprehensive diagnostic and treatment guidelines are required for diarrhoeal diseases. These guidelines should be informed by local epidemiological data, where diagnostic testing is reserved for cases most likely to benefit from specific treatment. Optimisation of current diagnostic processes and methods are required for these cases, specifically in terms of minimising turnaround times while maximising diagnostic acumen.The ANDEMIA study was supported by the German Federal Ministry of Education and Research.http://www.biomedcentral.com/bmcinfectdisam2023Medical VirologyPaediatrics and Child Healt

Case-control vaccine effectiveness studies: Data collection, analysis and reporting results

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a \u27real world\u27 context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies