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Aims. We explored multiple cardiometabolic patterns, including inflammatory and congestive pathways, in patients with heart failure (HF). Methods and Results. We enrolled 270 HF patients with reduced (

International agencies reported that cases of pericarditis occur very rarely following the administration of coronavirus disease 2019 (COVID-19) vaccines. Herewith, we described a series of patients from the community diagnosed with acute pericarditis after vaccination.We retrospectively included 28 patients (median age 51 years, 79% female) with or without a positive history of acute respiratory syndrome coronavirus 2 recovered infection who were diagnosed with acute pericarditis following the administration of COVID-19 vaccine. We excluded specific identifiable causes of pericarditis, including infectious, autoimmune, neoplastic and metabolic disease. Patients were referred for a complete cardiovascular evaluation. Transthoracic echocardiography (TTE) was performed and diagnosis of acute pericarditis was achieved according to current guidelines.There were 16 patients administered with Pfizer-BioNTech/Comirnaty vaccine, 8 with Moderna/Spikevax vaccine and 4 with Astra Zeneca/Vaxzevria vaccine. Nine patients had been previously diagnosed with COVID-19, while the others had no prior history of COVID-19. Eleven patients had no comorbidity while the others had between one and four comorbidities. Ten patients had a history of rheumatic or autoimmune diseases. Chest pain was present in 24 patients. Minor ECG abnormalities were detected in 10 patients, T-wave inversion in 6, and 7 patients had concave ST elevation. The majority of patients showed mild pericardial effusions at TTE. Only two patients exhibited large pericardial effusions.This case series shows a higher incidence of acute pericarditis in patients administered with COVID-19 vaccines than previously estimated, probably because of a more comprehensive assessment of clinical as well as echocardiographic parameters.

Background and AimType 2 diabetes mellitus (T2DM) is a known risk factor in patients with heart failure (HF), but its impact on phenotypic presentations remains unclear. This study aimed to prospectively examine the relationship between T2DM and functional exercise capacity, assessed by the 6-min walk test (6-MWT) in chronic HF.MethodsWe studied 344 chronic patients with HF (mean age 61 ± 10 years, 54% female) in whom clinical, biochemical, and anthropometric data were available and all patients underwent an echo-Doppler study and a 6-MWT on the same day. The 6-MWT distance divided the cohort into; Group I: those who managed ≤ 300 m and Group II: those who managed >300 m. Additionally, left ventricular (LV) ejection fraction (EF), estimated using the modified Simpson's method, classified patients into HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF).ResultsThe results showed that 111/344 (32%) patients had T2DM, who had a higher prevalence of arterial hypertension (p = 0.004), higher waist/hips ratio (p = 0.041), higher creatinine (p = 0.008) and urea (p = 0.003), lower hemoglobin (p = 0.001), and they achieved shorter 6-MWT distance (p < 0.001) compared with those with no T2DM. Patients with limited exercise (p < 0.001), arterial hypertension (p = 0.004), and atrial fibrillation (p = 0.001), higher waist/hips ratio (p = 0.041), higher glucose level (p < 0.001), lower hemoglobin (p < 0.001), larger left atrium (LA) (p = 0.002), lower lateral mitral annular plane systolic excursion (MAPSE) (p = 0.032), septal MAPSE (p < 0.001), and tricuspid annular plane systolic excursion (TAPSE) (p < 0.001), compared with those performing >300 m. In the cohort as a whole, multivariate analysis, T2DM (p < 0.001), low hemoglobin (p = 0.008), atrial fibrillation (p = 0.014), and reduced septal MAPSE (p = 0.021) independently predicted the limited 6-MWT distance.In patients with HFpEF, diabetes [6.083 (2.613–14.160), p < 0.001], atrial fibrillation [6.092 (1.769–20.979), p = 0.002], and septal MAPSE [0.063 (0.027–0.184), p = 0.002], independently predicted the reduced 6-MWT, whereas hemoglobin [0.786 (0.624–0.998), p = 0.049] and TAPSE [0.462 (0.214–0.988), p = 0.041] predicted it in patients with HFrEF.ConclusionPredictors of exercise intolerance in patients with chronic HF differ according to LV systolic function, demonstrated as EF. T2DM seems the most powerful predictor of limited exercise capacity in patients with HFpEF.

Background The shortage of doctors in postwar Okinawa has led to the creation of co-medicals. They were called medical service personnel and authorized to handle certain medical treatments. This included tasks such as providing injections and vaccinations under the supervision of the doctor in the health center. Issue/problem The system of co-medicals only applied in Okinawa and not in Japan. As such, when Okinawa was reverted back to Japan in 1972, it was proposed to abolish the system. In the current emergency of the new coronavirus pandemic, we are facing a similar situation in terms of the shortage of medical personnel. Description of the problem In Japan, like many countries, there is a shortage of health resources due to the COVID-19 pandemic. The focus will be on healthcare personnel, those who have taken on the role of COVID-19 vaccinators in Japan, and a comparison of the situation in other countries. Results In Japan, vaccinations are legally limited to being administered by doctors and nurses. However, pharmacists have taken on the role of administering vaccinations in the UK, US, Ireland, Canada, and Italy, thus COVID-19 vaccinations could be easily integrated into these routine procedures.Even vaccinations by medical students have been carried out. In addition, non-healthcare volunteers have been trained as vaccinators in UK and Italy. The coverage has reached 50% in the UK, 42% in the US, and 30% in Canada, whereas 1.8% in Japan in April (Our World in Data, 2021). Lessons Although the COVID-19 situation is substantially different from the case of postwar Okinawa, it will be necessary to take resilient measures to solve the medical personnel shortage. Additionally, the strict measures of limiting vaccinations by medical doctors may need to be reconsidered in Japan. Establishing a system of allowing co-medicals to have a shared role could offer innumerable benefits for all. Key messages Expanding the task of vaccinations to co-medicals has had beneficial results in several countries. Dividing roles of medical doctor need to be considered.

Pathophysiological mechanisms behind cardio-pulmonary impairment in heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fraction are likely different. We analysed them using combined cardiopulmonary-exercise stress echocardiography (CPET-ESE).We matched 1:1 subjects with HFrEF (n = 90) and HFpEF (n = 90) for age, sex, body mass index (BMI), peak oxygen consumption, and minute ventilation/carbon dioxide production slope. All patients underwent a symptom-limited graded ramp bicycle CPET-ESE compared with 40 age-, sex- and BMI-matched healthy controls.During a median follow-up of 25 months, we observed 22 deaths and 80 HF hospitalisations, with similar distribution between HFpEF and HFrEF. Compared with HFrEF, HFpEF had a higher prevalence of metabolic syndrome (p = 0.02) with higher levels of high-sensitivity C-reactive protein and uric acid (p 0.01). The multipoint mean pulmonary artery pressure/cardiac output (mPAP/CO) slope showed equally increased values in HFrEF and HFpEF (3.5 ± 1.8 and 3.7 ± 1.5 mmHg/L/min) compared with controls (1.8 ± 1.1 mmHg/L/min; p 0.0001). During exercise, HFpEF displayed more adverse interaction of right ventricle-pulmonary artery (RV-PA; tricuspid annular plane systolic excursion/systolic pulmonary artery pressure: 0.40 ± 0.2 vs 0.47 ± 0.2 mm/mmHg in HFrEF; p 0.01) and left atrium-left ventricle (LA-LV; LA reservoir strain/LV global longitudinal strain: 1.5 ± 0.8 vs 2.2 ± 1.1 in HFrEF; p 0.01). The latter were independent predictors of mPAP/CO slope, along with hs-CRP (adjusted R2: 0.21; p 0.0001).Despite similar disease severity, HFpEF and HFrEF show different pathophysiological mechanisms. HFpEF is characterised by a worse LA-LV and RV-PA interaction than HFrEF, with more prevalent low-grade systemic inflammation. In HFpEF, these features may have a role in exercise-induced pulmonary hypertension.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Background In Germany, a higher life expectancy of women coincides with shortages of health professionals. Besides gynecologists (Gyns), the main providers of ambulatory healthcare for women 50+ are general practitioners (GPs), which do not provide gynecological care. However, GPs and Gyns willingness share tasks has not yet been analysed systematically. The aim of this research project is to explore approval among and consent between GPs and Gyns for task sharing in women 50+. Methods In a quantitative postal survey (March-May 2018), a random sample of 66% of all GPs (n = 3,514) and all Gyns (n = 1,031) in the three German states was interviewed. The response rate was 25.5% for GPs and 51.2% for Gyns. The approval for task sharing (yes/no) was collected for 21 medical consultation themes (83 sub items) regarding women's health and general health of women 50+. For each sub item, the approval rates among and consent between the professional groups was calculated and sub items were group into medically coherent modules for interprofessional care. Multivariable regressions were calculated in order to explore the association of professional group with the medically coherent modules adjusted for covariates. Results In both professional groups, highest approval was reached for shared care of urinary incontinence, vaginal complaints and recurrent urinary tract infections. High approval and consent was present only for the sub items counselling for sexual health (GP = 52.30%, Gyn=48.91%) and colorectal cancer screening (GP = 48.66%, Gyn=44.70%). Approval was higher for counselling as compared to diagnostics and therapy. Cancer related task went along with low approval rates in both professional groups. Approval towards task sharing was higher among Gyns for all modules except for cancer screening. Conclusions The analysis identified single tasks for sharing in both groups and allows setting priorities through the classification according to approval and consent. Key messages Task sharing among GPs and Gyn could be an opportune answer to improve access to care of women 50+. Knowledge on GPs and Gyns attitudes towards task sharing can serve as common empiric ground for meaningful dialogues between research, policy and practice.

Background In many countries demographic changes and regional differences lead to inequalities in healthcare provision. In Germany, this applies especially to rural regions and could affect the healthcare situation of middle-aged and older women in particular. Our study, which is part of the project “Frauen 5.0”, explores the health and healthcare situation of women 50 years and older in Northeastern Germany, with focus on outpatient gynaecological and general medical care and reasons for healthcare utilisation. Methods Our analyses comprise the health situation of women aged 50 years and older, their utilisation of outpatient gynaecologists and general practitioners (GPs), reasons for utilisation, access barriers to outpatient care, the demographic situation and the spatial distribution of gynaecological and GP practices in Northeastern Germany. We use a variety of data sources; main data source is the German Health Interview and Examination Survey for Adults (DEGS1, 2008-2011), which was carried out by the Robert Koch Institute and is representative of the German adult population. Results There is an unequal distribution of gynaecologic and GP practices in Northeastern Germany, with the highest density in and around Berlin. About 30% of gynaecologists and GPs in the study region are aged 60 years and older. Whereas in all age groups at least 80% of women used GP services in the last 12 months, the use of gynaecologic services declines from 80% in 18- to 29 year-old to 45% in 70- to 79 year-old women. Most important reasons for seeking gynaecological treatment are menopause and early detection of cancer. Conclusions The analyses show that there is need to ensure adequate health care for women aged 50 and over in rural regions in Germany. Based on the results, within the project “Frauen 5.0” innovative solutions for this task, e.g. interprofessional cooperation, will be identified. Key messages Analyses of outpatient healthcare services show an unequal distribution of gynaecologic and GP practices in Northeastern Germany; about 30% of the gynaecologists and GPs are aged 60 years and older. Whereas in all age groups at least 80% of women used GP services in the last 12 months, the use of gynaecologic services declines from 80% in 18- to 29 year-old to 45% in 70- to 79 year-old women.

Background A higher life expectancy for women in Germany coincides with shortages in health professionals. Besides gynecologists (Gyn), the main providers of ambulatory healthcare services for women 50+ are general practitioners (GPs), which are not providing any gynecological services. The project “Frauen 5.0” aims to identify strategies for improving health care provision for women 50+ in three north-east states of Germany by analyzing health system indicators and exploring the perspective of service providers, users, practitioners and policy makers. Methods Mixed-methods combined with participatory research including 1) secondary data analysis (Robert Koch-Institute and Zentralinstitut); 2) postal quantitative survey of all Gyn (n = 1.031) and of a randomized sample of 66% of GPs (n = 3.514); 3) qualitative interviews of women 50 + (n = 25); and 4) round tables with practitioners and policy makers. Results In Germany 25% of the population are women 50+, from which 41% do not use Gyn services. Users expressed the need that GPs/Gyn actively address women’s health issues during consultation. The survey (response rate 51% Gyn; 25% GPs) revealed a high willingness to collaborate among GPs and Gyn. Barriers and synergies in organizational, professional and user aspects were identified. Task-sharing between GP and Gyn, delegation to non-medical personnel and the introduction of financial incentives showed to be a key element to improve health care services for women 50+. Dissusion In the SDG era of “leaving no one behind” acknowledging and addressing the unmet needs of women 50+ is from a public health perspective an issue of utmost urgency as is closing the gap between research, policy and practice. Conclusions New strategies to improve health care services for women 50+ were developed by integrating the evidence from actual data in meaningfull dialogues between research, policy and practice. Key messages New models of health care provision are required to adress and improve the health of women 50+. Closer collaboration between research policy and practice can be achieved by participatory methods.

Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis.

A prominent role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels has been suggested based on their expression and (dys)function in dorsal root ganglion (DRG) neurons, being likely involved in peripheral nociception. Using HCN blockers as antinociceptive drugs is prevented by the widespread distribution of these channels. However, tissue-specific expression of HCN isoforms varies significantly, HCN1 and HCN2 being considered as major players in DRG excitability. We characterized the pharmacological effect of a novel compound, MEL55A, able to block selectively HCN1/HCN2 isoforms, on DRG neuron excitability in-vitro and for its antiallodynic properties in-vivo. HEK293 cells expressing HCN1, HCN2, or HCN4 isoforms were used to verify drug selectivity. The pharmacological profile of MEL55A was tested on mouse DRG neurons by patch-clamp recordings, and in-vivo in oxaliplatin-induced neuropathy by means of thermal hypersensitivity. Results were compared to the non-isoform-selective drug, ivabradine. MEL55A showed a marked preference toward HCN1 and HCN2 isoforms expressed in HEK293, with respect to HCN4. In cultured DRG, MEL55A reduced Ih amplitude, both in basic conditions and after stimulation by forskolin, and cell excitability, its effect being quantitatively similar to that observed with ivabradine. MEL55A was able to relieve chemotherapy-induced neuropathic pain. In conclusion, selective blockade of HCN1/HCN2 channels, over HCN4 isoform, was able to modulate electrophysiological properties of DRG neurons similarly to that reported for classical Ih blockers, ivabradine, resulting in a pain-relieving activity. The availability of small molecules with selectivity toward HCN channel isoforms involved in nociception might represent a safe and effective strategy against chronic pain.

Purpose Cardiomyocytes progenitor cells (CMPCs) are a candidate cell source for cardiac regenerative therapy. To assess their full potential for cardiac regeneration, it is essential to know if and how CMPCs sense and respond to the three-dimensional (3D) environment and the mechanical stimuli provided by the beating heart. Therefore, we study the response to cyclic strain of undifferentiated and predifferentiated human CMPCs in a 2D environment, as well as CMPC responses to unidirectionally constrained versus stress-free (unconstrained) 3D environments. The latter responses were studied using a hydrogel system that allows for interaction of the cells with a simulated ‘host’ tissue. Methods To test mechanosensitivity of CMPCs in 2D and 3D environments, the response of L9TB CMPCs to uniaxial (cyclic) strain (10% with 0.5 Hz) was investigated. To represent the 3D environment, CMPCs were cultured in unidirectionally constrained and stress-free collagen/Matrigel hydrogels, where the constrainment provides a static strain to the cells. The cellular mechanoresponse to the applied (cyclic) strain was quantified by cellular re-orientation away from the strain direction (strain avoidance). Next to cellular re-orientation, the effect of strain on cell differentiation was analyzed. Results Our results indicate that while undifferentiated cells maintain their original orientation, upon early cardiomyogenic differentiation (predifferentiated) CMPCs exhibit a distinct strain avoidance response during 48hrs of cyclic straining in a 2D environment. In 3D unidirectionally constrained hydrogels, undifferentiated CMPCs retain their cardiomyogenic profile. CMPCs cultured in 3D collagen/Matrigel hydrogels respond to static mechanical strains as expected by cell alignment. Conclusions Our results suggest that CMPCs respond to the presence of mechanical stimuli, in this research mimicked by the application of uniaxial (cyclic) strain in 2D and 3D environments, suggesting that CMPCs are indeed mechanosensitive. Although in 2D environments, mechanosensitivity of the CMPCs is dependent on their differentiation status. Our findings provide the first understanding of the ability of human CMPCs to sense mechanical stimuli, which is the first initial step in mechanotransduction. Mechanotransduction is essential for optimal recruitment, migration, and mechanical integration of progenitor cells into the injured myocardium. Therefore, the presented results can contribute to enhance efficacy of current treatments of cardiac disease, as well as to develop novel endogenous regeneration strategies.

According to the German social insurance code §20 Sec. 1, statutory health insurance companies can reimburse up to 80% of costs incurred by primary prevention programs in physical activity, nutrition, stress management and drug consumption. Whether and how many general practitioners (GPs) provide their patients with information on such programs as part of their own practice is unknown. In this study, we investigate to which primary prevention programs primary care physicians refer their patients and whether they take into account reimbursability of programs.Between November 2010 and February 2011, all GPs with a practice in Berlin (n=1 168) received a questionnaire that assessed if patients were referred to prevention programs and the type of programs they were referred to, if they ensured they are reimbursable and if they themselves offered prevention programs. Descriptive statistics and multivariate logistic regression was used for analysis.Of 474 respondents (response rate: 41%), 67% were female. Of the respondents, 22% offered reimbursable prevention programs and 42% at out-of-pocket expense. Patients were referred to reimbursable programs by 63%. GPs younger than 50 were twice as likely to offer reimbursable programs in their practice compared to those older than 50 (OR=1.7; 95% KI 1.1-2,8; p-value 0.025).A successful implementation of the new German prevention law needs awareness among GPs about reimbursable prevention programs, which may be lacking in some groups.Nach dem fünften Sozialgesetzbuch §20 Abs. 1 können die Gesetzlichen Krankenversicherungen (GKV) Kosten für primärpräventive Programme im Bereich Bewegung, Ernährung, Stressmanagement und Suchtmittelkonsum bis zu 80% rückerstatten. Inwieweit Allgemeinärzte in ihrer Praxis auf solche Angebote verweisen oder selbst im Primärpräventionsbereich Programme nach §20 oder als individuelle Gesundheitsleistungen (IGeL) anbieten, ist unbekannt. Ziel der hier dargestellten Befragung war es, zu erfassen, an welche Anbieter sie für Primärpräventionsangebote verweisen und inwieweit sie dabei berücksichtigen, ob diese erstattungsfähig sind. Zusätzlich wurde untersucht, inwieweit Allgemeinärzte/innen individuelle Gesundheitsleistungen (IGeL) in diesen Bereichen anbieten.Zwischen November 2010 und Februar 2011 erhielten alle Allgemeinärzte mit Praxissitz in Berlin (n=1 168) einen Fragebogen, der erfasste ob und auf welche Präventionsprogramme sie ihre Patienten hinweisen, inwieweit sie dabei berücksichtigen, dass diese erstattungsfähig sind und ob sie Präventionsprogramme nach §20 oder als IGeL anbieten. Deskriptive Statistik und multivariate logistische Regression wurden durchgeführt.Von 474 Teilnehmenden (Rücklaufquote: 41%) waren 67% weiblich. In der eigenen Praxis boten 22% der Allgemeinärzte Präventionsprogramme nach §20 und 42% IGeL an. Von den Befragten gaben 63% an, darauf zu achten, dass Präventionsprogramme teilerstattungsfähig sind. Allgemeinärzte, die jünger als 50 Jahre alt waren, boten fast doppelt so häufig Präventionsprogramme nach §20 als Ärzte über 50 Jahren an (OR=1,7; 95% KI 1,1–2,8; p-Wert 0,025).Eine erfolgreiche Umsetzung des neuen Präventionsgesetztes erfordert ein Wissen zu teilerstattungsfähigen Präventionsprogrammen bei Ärzten. Hier ist zum Teil ein Informationsdefizit vorhanden.

Introduction The electronic health record (EHR) is a very important potential source of data for various areas, such as medical decision support tools, evidence-based medicine or epidemiological surveillance. Much of this data is available in text format. Methods of natural language processing can be used to perform data mining and facilitate interpretation. The purpose of this project was to develop a generic semantic solution for extracting and structuring medical data for epidemiological analyses or for medical decision-support. The solution was developed with the objective of making it as independent as possible from the field of medical application in order to allow any new user to write his or her own expert rules regardless of their area of medical expertise. Material and methods SYNODOS offers a modular architecture that makes a clear distinction between the linguistic rules and the medical expert rules. Different modules have been developed or adapted for this purpose: an interface between the multi-terminology server and semantic analyzer during the extraction phase, linguistic rules to extract temporal expressions, expert rules adapted to two areas of application (nosocomial infections, cancer), an interface between the engine and the linguistic knowledge base. Results Modular integrations were performed consecutively. The multi-terminology extractor and semantic analyzer were first interfaced during the extraction phase. Output of this data processing was then integrated into a knowledge base. A user interface to access documents and write business rules was developed. Expert rules for the detection of nosocomial infections and for the evaluation of colon cancer management have been developed. It was necessary to develop an additional module the need for which had not been identified during the drafting of the protocol. This module aims to structure the output of the data processing described above, according to the patient's care pathway. This module is based on the writing of medical expert rules. Evaluation indicators were obtained at different stages of the process (terminology extraction, semantic relations, data structuring, detection of events of interest). Discussion This project helped to highlight the value of combining different technologies (natural language processing, terminology, expert systems integration) to allow for the use of unstructured data in epidemiology. However, the need to develop an additional module of expert rules did not allow a complete and operational solution. Furthermore the multi-terminology extractor (ECMT V2) response time is too long (6 min per report). A change in technology was envisaged at the end of the project to reduce this time. Conclusions The originality of the SYNODOS project is the development of a single solution that integrates different technologies needed for the production of epidemiological indicators in the context of hospital activity. The project results confirm the interest but certain technological obstacles concerning the processing time need to be resolved in order to render the solution operational in a hospital environment.

Congest Heart Fail. ****;**:**–**. ©2012 Wiley Periodicals, Inc. The aim of this study was to evaluate whether small left ventricular (LV) volumes increase the negative prognostic impact of a restrictive filling pattern (RFP) and that of mitral regurgitation (MR) in patients with nonischemic heart failure (HF). The Meta-analysis Research Group in Echocardiography (MeRGE) is a meta-analysis that collated individual patient data from several prospective echocardiography outcome studies. This analysis was restricted to 10 studies and 601 patients with nonischemic HF. The role of MR was tested in a subgroup of 252 patients. A total of 106 deaths occurred during a median follow-up of 32 months. At multivariate analysis, RFP (hazard ratio [HR], 4.16; 95% confidence interval [CI], 1.54–11.23; P=.005) and New York Heart Association class III or IV (HR, 2.15; 95% CI, 1.33–3.47; P=.001) were the independent predictors of poor prognosis, and there was no statistically significant interaction between LV dilation and RFP. Moderate/severe MR was associated with poorer outcome in the group of patients with normal volumes, whereas it was not a significant predictor of mortality in patients with any degree of LV dilation. In patients with nonischemic HF, RFP is the most important indicator of poor prognosis, irrespective of the degree of LV dilation. Normal LV volumes increase the negative prognostic impact of moderate to severe MR.

The present study was designed to investigate the effect of a proteinaceous dietary supplement, fishmeal, on gossypolinduced spermatotoxicity. Twenty-five adult male Wistar rats, averaging 205 g b.w., were randomly sorted into four experimental groups (I-IV) of 5 animals each, and a control group. Crude cottonseed oil was administered orally to each animal in groups I-IV at a rate that provided 14 mg/kg/d free gossypol; in addition, 3 g/d, 7 g/d, and 10 g/d of fishmeal was provided as meal supplement to each animal in groups I, II and III respectively. The control group received rat pellets and water freely. At the end of the 53-day treatment period, all animals were placed under chloroform anaesthesia; the caudal epididymides were removed, minced and placed in Ham’s F10 solution for the evaluation of sperm count and motility. The testes were also processed for histological studies using the eosin and haematoxylin (H & E) method. Our findings revealed a dose-dependent inhibition of gossypol-induced spermatotoxicity by the supplemented fishmeal; this suggests that proteinaceous diets are protective against gossypol-induced male infertility.

Numerous prognostic markers have shown to be predictive of patient outcome in heart failure (HF). The recent guidelines of the European Society of Cardiology for the diagnosis and treatment of acute and chronic HF have identified as many as 57 individual markers in patients with HF, including demographic data, etiology, comorbidities, clinical, radiological, hemodynamic, echocardiographic and biochemical parameters. If more accurate risk stratification is required, several scoring systems have been proposed. This article reviews scoring systems for HF prognostication. Although most of the models include readily available clinical information, usually NYHA functional class, left ventricular ejection fraction (LVEF) and comorbidities, quite a few of them comprise Doppler echocardiographic variables, other than LVEF, and circulating levels of natriuretic peptides. In order to achieve a better prediction of the outcome, an ideal score should be based on a comprehensive Doppler echocardiographic examination, the assessment of circulating biomarkers, and a more objective evaluation of exercise tolerance.

To determine the prognostic implications of diastolic filling grades and identify whether age-stratified E/A ratio alone can identify patients at high risk of death post-AMI and HF. We hypothesized that in response to ageing and pathology, a normal E/A (1) could be considered abnormal in patients post-AMI older than 65years, and that in patients with symptomatic HF, a normal E/A always represents advanced diastolic dysfunction.This is a sub-analysis of the Meta-analysis Research Group in Echocardiography (MeRGE) which combined individual patient data from 30 prospective studies and demonstrated that restrictive filling was an important and independent predictor of all-cause mortality. This sub-analysis is restricted to those studies in which continuous E/A data were available (20 studies) and includes a total of 3082 AMI and 2321 HF patients. Patients were classified at the time of echocardiography into four filling patterns: normal, abnormal relaxation, pseudonormal, and restrictive filling. Post-AMI patients were divided into four groups on the basis of age and E/A, while patients with HF were classified into three groups, based on only E/A. Mortality across groups was compared using Kaplan-Meier survival analysis and Cox proportional hazards. In multivariable analyses in the AMI patients, age-stratified E/A was an independent predictor of outcome (HR 1.43 (95% CI: 1.31-1.56)), and in the HF cohort, E/A was confirmed as an independent predictor of mortality (HR 1.12 (95% CI 1.09-1.16)) alongside age and ejection fraction.Age-stratified E/A is an independent predictor of mortality after AMI and in HF patients, regardless of left ventricular ejection fraction, age and gender. E/A ratio could be a first step echocardiographic risk stratification, which could precede and indicate the need for more advanced diagnostic and prognostic considerations in high-risk AMI and HF patients.

Summary Objectives To investigate the association between oral health, in terms of dental caries and gingivitis, and sociodemographic factors, dental plaque, oral hygiene behaviours, infant feeding and dietary practices in 4–5-year-old Jordanian children. Methods Two-stage random sampling procedure was used to select children enrolled in kindergartens in Amman, Jordan. Clinical examinations were carried out by one examiner. Mothers completed questionnaires relating to sociodemographic factors, oral hygiene behaviours, infant feeding and dietary practices of the children. Results About 67% of the children had caries, 31% had dmft greater than 4 and 66% had gingivitis. Of the children who had been wholly breast-fed, 86% had been fed on demand. Mothers of children attending kindergartens with the lowest tuition fees were more likely to have breast-fed their children on demand and for more than 18 months (prolonged breast feeding) compared to those attending kindergartens with higher fees. Savory snacks were consumed by 82%, confectionery by 76% and teas with sugar by 42% of the children. Multivariate analysis showed age, dental plaque, sleeping beside the mother, use of comforters and selected dietary habits to have an independent effect on caries prevalence. Dental plaque and prolonged breast feeding exerted an independent effect on caries severity and gingivitis. The strongest association with gingivitis was dental plaque. Conclusions In Jordan as elsewhere health promotion strategies need to be targeted to mothers from less advantaged backgrounds. Messages about infant breast feeding should emphasise that the method is beneficial to the oral health of the children if appropriately used.

The influence of nitric oxide synthetase (NOS)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase I (cGKI) pathway in adult cardiac performances is well defined. Indeed, physiological amounts of NO generated by NOS1 and NOS3 or pharmacological administration of NO-donor drugs can influence cardiac contractility and increase coronary blood flow throughout the Ser/Thr phosphorylation (sGC/cGKI pathway) and directly by S-nitrosylation of several proteins. Although the role of NOS/sGC/cGKI is already extensively studied in adult cardiac cells, the influence of this pathway as trigger/modulator of cardiac differentiation of embryonic stem cells (ESCs) is less defined. Therefore, we decided to investigate the influence of NOS/sGC/cGKI in the early stage of cardiac differentiation of mouse embryonic cells, studying i) enzyme expressions and activities during the cardiac maturation and ii) the acute and chronic effect of pathway alteration. The mouse embryonic cell line CGR8 was used for these experiments: cells were cultured in undifferentiated form using LIF. Hanging drop methodology was used to promote CGR8 cardiac differentiation. This method allowed cells to aggregate and eventually form embryoid bodies (EBs). The cardiac maturation process was followed for 21 days. Beating EBs were monitored starting from 7-10 day. At different stages of cardiac maturation, mNos3, mGuCy1b and mPrkgI expressions were detected by real-time PCR (Q-PCR); western blot analysis and enzymatic activity were used for protein evaluation. Cytosolic calcium dynamics was evaluated using epifluorescence microscopy in spontaneous beating EBs from 13-16 day of differentiation. Real-time PCR showed that during differentiation the expression of the enzymes increased in a time-dependent mode and different time-courses. The peak of mNos3 expression was measured at day 8 of differentiation and then rapidly decreased. mGuCy1b and mPrkgI were detected starting from day 5 and increased until day 14, maintaining similar values until the end of observation period. Protein expressions were in line with RNA messenger measures, with detectable level of NOS3 only at the beginning of differentiation (days 5 and 8). Enzymatic activities were tested at day 15: sGC activity was increased of 3 times with the NO-donor SNAP and inhibited by 50% with ODQ. Moreover, cyclic GMP was reduced when EBs were incubated for 30 min with L-NMA, suggesting an endogenous activity of NOS. The phosphorylation of Ser/Thr residues on target proteins, were increased by membrane permeable cyclic GMP, isosorbide-5-mononitrate and SNAP and reduced by KT5823, a selective cGKI inhibitor. Functionally, cell incubation with isosorbide-5-mononitrate from the beginning of differentiation slightly increased the percentage of beating EBs at early stages of cardiac maturation (days 5 and 8). In spontaneous beating EBs, acute block of NOS endogenous activity with L-NMA (100 μmol/L) caused a 50% increase of calcium transient frequency. The effect developed progressively during 10 minute exposure and remained constant thereafter. Additionally, a 30-40% reduction of calcium transient amplitude was observed upon NOS blockade, associated with a slight speed of calcium transient decay velocity. The time-dependent expression of NOS/sGC/cGKI during cardiac differentiation suggests a potential role of these pathways to trigger cardiomyogenesis and modulate calcium handling properties in the developing cardiomyocytes. Further functional data will clarify its role in cardiac maturation.

Objective To investigate the association between type of food and drink consumption, sociodemographic factors and prevalence and severity of caries in 4–5-year-old Jordanian children. Method Two-stage random sampling procedure was used to select children enrolled in kindergartens in Amman. Clinical examinations were carried out by one examiner. Mothers completed a questionnaire relating to sociodemographic factors and food and drink consumption. Results Snack foods were consumed by a high percentage of children. Amongst the most popular 'high in NME sugar snacks', confectionery was reported to be regularly consumed by 76% and biscuits and cakes by 71% of them. More than 50% had carbonated drinks. Children from a lower social class, attending a kindergarten with lower tuition fees had more dessert, squashes and more teas with sugar. When all variables were considered, consumption of confectionery was independently associated with caries prevalence and consumption of teas with sugar was independently associated with caries severity. Conclusion The types of foods and drinks consumed as snacks by young Jordanian children were similar to those of Western countries. In the absence of more widespread oral health promotion measures and in the presence of high prevalence and severity of caries, the oral health of Jordanian children is a matter of concern.

–Objectives: To investigate the relationships between socio-demographic factors, infant feeding habits, oral hygiene and the prevalence and patterns of caries in Brazilian 3–4-year-olds. Methods: Systematic random sampling was used to select children enrolled in municipal nurseries in Araraquara, Brazil, in 1998. Clinical examinations were carried out by one examiner using dmft and dmfs indices and WHO criteria. Questionnaires for information related to the socio-demographic background, oral hygiene and dietary history of the children were completed by their mothers. Results: Caries was seen in 46% of the children; 17% of them had the more extensive pattern involving molars and incisors. Social class, mother’s education, and age at which breast-feeding terminated showed statistically significant associations with caries. Feeding bottles with added sugars were still being given to 80% of the children. When the significant variables were taken into account only age at which breast-feeding terminated showed a significant relationship to the pattern of disease. Children who were never breast-fed or were breast-fed beyond the age of 24 months had a higher prevalence of the more extensive pattern of caries. Conclusions: The association between the length of time a mother breast-feeds and extensive caries should be a consideration in any local infant feeding policies or health promotion strategies. The duration for appropriate breast- or bottle-feeding should be emphasised.

The salinity tolerance of various early life stages (prelarvae, larvae and fry) of the Adriatic sturgeon (Acipenser naccarii) was investigated using acute exposures in a 96h-LC50 test. The results were compared with a series of parallel observations on the morphological development of the osmoregulatory organs. The highest salinities tolerated by prelarave and larvae were approximately iso-osmotic with sturgeon plasma. Once, however. the organs involved in homeostatic osmoregulatory mechanisms in the adult had developed (renal-branchial-gut system), the sturgeon was able to switch from hyperosmoregulation to hypo-osmoregulation. Nevertheless, at the most advanced age tested (150 days old), water at a salinity of approximately 20 parts per thousand appeared to be the upper threshold for tolerance of acute exposure by this species.

Summary The purpose of this study was to define the pattern of caries in 3–6 year old children from two districts in Araraquara, SP, Brazil, fluoridated for more than 10 years and from a much more recently fluoridated one in the same city, using two different indices. The study included 1,066 children (903 from the two first districts and 163 from the third). Patterns of disease were described in terms of prevalence and dmft in molars, incisors (and/or canines) individually and together. Pattern was also described according to the ‘caries analysis system’. In both areas the majority of 3–4 year olds had disease confined to primary molars. In the areas fluoridated for more than 10 years, the highest proportion of 5–6 year olds with caries also had the disease confined to primary molars (36 per cent) but in the more recently fluoridated area, similar proportions of children had caries in primary molars alone as had caries in both primary molars and incisors (40 per cent and 44 per cent, respectively). Results according to the ‘caries analysis system’ showed that in both areas the prevalence of fissure caries and posterior bucco-lingual surface pattern in 5–6 year olds were twice as great as those observed in 3–4 year olds. Differences between the areas were obvious whichever method was used to define pattern, confirming the benefits of water fluoridation. The simpler method of grouping tooth type affected showed the differences as effectively as the more complex ‘caries analysis system’. Resume La raison de cette etude etait de definir, en utilisant deux indices, le schema carieux d'enfants de 3 a 6 ans venant de deux quartiers d'Araraquara, SP, au Bresil, qui etaient fluores depuis plus de dix ans et d'un autre quartier de la meme ville dont la fluoration etait bien plus recente. L'etude portait sur 1.066 enfants (903 des deux premiers quartiers et 163 du troisieme), Les schemas de maladie etaient exprimes en terme de prevalence et de dents cao pour les molaires, les incisives (et/ou les canines) individuellement et globalement. Les schemas etaient egalement decrits selon le “systeme d'analyse des caries”. Dans les deux zones, pour la majorite des enfants de 3 a 4 ans, la maladie se limitait principalement aux molaires primaires. Dans les regions fluorees depuis plus de 10 ans, pour la majorite des enfants de 5 a 6 ans avec des caries, la maladie se confinait egalement aux molaires primaires (36 pour cent), mais dans la zone la plus recemment fluoree, des pourcentages semblables d'enfants presentaient des caries dans les molaires primaires uniquement, ainsi que des caries tant dans les molaires primaires que les incisives (40 pour cent et 44 pour cent, respectivement). Les resultats, selon le “systeme d'analyse des caries” ont montre que, dans les deux regions, la prevalence de fissures carieuses et d'un schema de la surface bucco-lingale posterieure chez les enfants de 5 a 6 ans etait deux fois plus importante que celle observee chez les enfants de 3 a 4 ans. Des differences entre les regions etaient evidentes, quelle qu'ait ete la methode utilisee pour definir le schema, confirmant ainsi les benefices de la fluoration de l'eau. La methode plus simple, visant a regrouper le type de dents touchees, montrait les differences de maniere aussi effective qu'avec le systeme plus complexe “d'analyse des caries”. Zusammenfassung Das Ziel dieser Studie bestand in der Ermittlung der Kariesstruktur bei 3–6jahrigen Kindern in zwei Bezirken von Araraquara, einem Gebiet der brasilianischen Hauptstadt Sao Paulo, das bereits seit mehr als 10 Jahren uber fluoridierte Trinkwasserversorgung verfugt. Parallel wurde in einem Stadtteil mit kurzerer Fluoridierungsgeschichte unter Kindern der gleichen Altersgruppe die gleiche Studie durchgefuhrt. An der gesamten Untersuchung nahmen 1.066 Kinder (903 aus den beiden erstgenannten Distrikten sowie 163 aus dem dritten) teil. Zur Beschreibung des Krankheitsbildes wurden zwei Kriterien herangezogen: Zahntyp/dmf, d.h. Anzahl karioser, fehlender und gefullter Molaren, Schneidezahne (und/oder Eckzahne) bei jedem einzelnen Kind/bei allen Kindern und das ‘Kariesanalysesystem’. Bei der Mehrzahl der 3-4jahrigen Kinder in beiden Stadtteilen trat Karies nur an den Molaren auf. Bei der Mehrheit der 5-6jahrigen Kinder in den Gebieten mit uber 10jahriger fluoridierter Trinkwasserversorgung wiesen ebenfalls nur die ersten Molaren Karies (36%) auf. In dem Gebiet mit jungerer Fluoridierungsgeschichte wies etwa der gleiche Anteil von Kindern (40%) Karies ausschlieslich an den ersten Molaren auf und zusatzlich trat bei 44% Karies sowohl an den Molaren als auch Schneidezahnen auf. Die Ergebnisse laut ‘Kariesanalysesystem’ besagen, das in beiden Gebieten Fissurenkaries und Karies der hinteren bukkolingualen Flachen bei den 5-6jahrigen doppelt so haufig vorkam wie bei den 3-4jahrigen Kindern. In bezug auf beide Faktoren bestanden ganz eklatante Unterschiede zwischen den untersuchten Gebieten, wobei die Ergebnisse zugunsten der fluoridierten Trinkwasserversorgung ausfielen. Die einfachere, den berroffenen Zahntyp zugrundelegende Vorgehensweise weist die bestehenden Unterschiede ebenso zuverlassig auf wie die auf dem ‘Kariesanalysesystem’ basierende Methode. Resumen El objetivo de este estudio fue el de definir, mediante dos indices diferentes, los patrones de caries en ninos de 3 a 6 anos de edad de dos distritos de Araraquara, San Pablo, Brasil, en los que se habia introducido la fluoracion hace mas de 10 anos, y de otro distrito de la misma ciudad, recientemente fluoridado. En el estudio participaron 1.066 ninos (903 de los dos primeros distritos y 163 del tercero). Los patrones de la enfermedad fueron descritos en funcion de prevalencia y de cpo en molares, incisivos (y/o caninos) individualmente y juntos. Fueron tambien descritos de acuerdo al “sistema de analisis de caries”. En ambas zonas, y en la mayoria de los ninos de 3 a 4 asos de edad, la enfermedad estaba limitada a los molares primarios. En las zonas fluoradas desde hace mas de diez anos, se observo igualmente que la enfermedad estaba confinada, en la mayoria de los ninos de 5 a 6 anos con caries, a los molares primarios (36 por ciento), pero en la zona recientemente fluorada, una proporcion similar de ninos tenia caries unicamente en los molares primarios, pero tambien en los molares primarios e incisivos (40 y 44 por ciento respectivamente). Los resultados conforme al “sistema de analisis de caries”, indicaron que en ambas zonas la prevalencia de caries de fisura y el patron de la superficie/cara buco-lingual posterior en los ninos de 5 a 6 anos de edad, eran el doble de los observados en los ninos de 3 a 4 anos de edad. Las diferencias entre las zonas eran obvias, independientemente del metodo utilizado para definir los patrones, lo que confirma los beneficios de la fluoracion del agua. El metodo mas simple de agrupar el tipo de diente afectado demostro las diferencias tan efectivamente como el sistema de analisis de caries mas complejo.