Atemwegserkrankungen und Allergien

Aufgrund ihrer großen Oberfläche und des dort stattfindenden Gasaustauschs ist die Lunge den zahlreichen Luftschadstoffen unmittelbar ausgesetzt. Besonders empfindlich hierfür ist die noch wachsende Lunge. Atemwegserkrankungen und Allergien können dann die Folge sein. Sowohl in Mitteleuropa wie auch in den sog. Entwicklungsländern sind Atemwegserkrankungen eine bedeutende Ursache der Krankheitslast (Burden of Disease). Betroffen sind vorwiegend Kinder und ältere Menschen. In Entwicklungsländern tragen Lungenentzündung und Tuberkulose signifikant zur Gesamtmortalität bei, in den westlichen Industrienationen sind chronische Atemwegserkrankungen wie COPD und Asthma für einen erheblichen Teil der Gesamtmorbidität verantwortlich. In diesem Abschnitt betrachten wir die Entwicklung der Lungenfunktion im Laufe des Lebens, die unterschiedliche Vulnerabilität der Lunge gegenüber Umwelteinflüssen in den verschiedenen Entwicklungsstadien sowie die globale Krankheitslast als Folge von respiratorischen Erkrankungen. Anschließend beschreiben wir das Asthma und die COPD hinsichtlich ihrer Risikofaktoren und erörtern, mit welchen präventiven Maßnahmen diese Erkrankungen zu verhindern wären. Schweizerische Lernziele: CPH 40

Infektionskrankheiten

Trotz bedeutender Fortschritte im Bereich der Prävention und der Therapie gehören Infektionen noch immer weltweit zu den wichtigsten Ursachen menschlicher Morbidität und Mortalität. Ein markantes Merkmal von Infektionskrankheiten ist ihre Übertragbarkeit, die je nach Übertragungsweg und Mitbeteiligung von lebenden Überträgern (Vektoren) auch stark durch Umweltfaktoren beeinflusst werden kann. In diesem Kapitel geben wir eine Übersicht über die wesentlichen epidemiologischen Aspekte der Infektionskrankheiten, berücksichtigen dabei geografische Unterschiede und gehen in diesem Rahmen auch auf die Konzepte der Übertragungsdynamik ein. Wir konzentrieren uns dabei auf Infektionen und Konzepte, die aktuell von großer Bedeutung sind oder deren Bedeutung in Zukunft zunehmen wird. Schweizerische Lernziele: CPH 49–58

Globale Gesundheit

Durch die Globalisierung werden wir zunehmend mit Problemen konfrontiert, welche Landesgrenzen überschreiten. Auch viele gesundheitspolitische Entscheidungen werden heute auf europäischer Ebene oder unter der Mitarbeit internationaler Organisationen getroffen. In diesem Kapitel betrachten wir Gesundheitsindikatoren sowie Krankheits- und Todesursachen im Hinblick auf das Bevölkerungseinkommen und die Entwicklung in verschiedenen Ländern. Wir analysieren die wichtigsten Faktoren, die die Gesundheit der Menschen in Industrie- und Entwicklungsländern beeinflussen und beschäftigen uns schließlich mit den Strategien und Akteuren, welche die Globale Gesundheit heute prägen. Schweizerische Lernziele: CPH 46 – 48

Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations

To assess drug-related problems in patients with liver cirrhosis by investigating the prevalence of inadequately dosed drugs and their association with adverse drug reactions (ADRs) and hospitalizations.

Agonist specific L-type Ca(2+)-current stimulation in ventricular myocytes by a novel steroid-like compound

In cardiac muscle the amplitude of Ca(2+) transients can be increased by enhancing Ca(2+) influx. Among the processes leading to increased Ca(2+) influx, agonists of the L-type Ca(2+)-channel can play an important role. Known pharmacological Ca(2+)-channel agonists act on different binding sites on the channel protein, which may lead not only to enhanced peak currents, but also to distinct changes in other biophysical characteristics of the current. In this study, membrane currents were recorded with the patch-clamp technique in the whole-cell configuration in guinea pig isolated ventricular myocytes in combination with confocal fluorescence Ca(2+) imaging techniques and a variety of pharmacological tools. Testing a new positive inotropic steroid-like compound, we found that it increased the L-type Ca(2+)-current by 2.5-fold by shifting the voltage-dependence of activation by 20.2 mV towards negative potentials. The dose-response relationship revealed two vastly different affinities (EC(50(high-affinity))=4.5+/-1.7 nM, EC(50(low-affinity))=8.0+/-1.1 microM) exhibiting differential pharmacological interactions with three classes of Ca(2+)-current antagonists, suggesting more than one binding site on the channel protein. Therefore, we identified and characterized a novel positive inotropic compound (F90927) as a member of a new class of Ca(2+)-channel agonists exhibiting unique features, which set it apart from other presently known L-type Ca(2+)-channel agonists.

Synthesis and two-photon photolysis of 6-(ortho-nitroveratryl)-caged IP3 in living cells

The synthesis of a photolabile derivative of inositol-1,4,5-trisphosphate (IP3) is described. This new caged second messenger (6-ortho-nitroveratryl)-IP3 (6-NV-IP3) has an extinction coefficient of 5000 M(-1) cm(-1) at 350 nm, and a quantum yield of photolysis of 0.12. Therefore, 6-NV-IP3 is photolyzed with UV light about three times more efficiently than the widely used P(4(5))-1-(2-nitrophenyl)ethyl-caged IP3 (NPE-IP3). 6-NV-IP3 has a two-photon cross-section of about 0.035 GM at 730 nm. This absorbance is sufficiently large for effective two-photon excitation in living cells at modest power levels. Using near-IR light (5 mW, 710 nm, 80 MHz, pulse-width 70 fs), we produced focal bursts of IP3 in HeLa cells, as revealed by laser-scanning confocal imaging of intracellular Ca2+ concentrations. Therefore, 6-NV-IP3 can be used for efficient, subcellular photorelease of IP3, not only in cultured cells but also, potentially, in vivo. It is in the latter situation that two-photon photolysis should reveal its true forte.

A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle

Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction. The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca2+ current I(Ca(L)) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. alpha- and beta-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 microM, 0.36 mg kg(-1), respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

Efficacy of drug eluting stents in patients with and without diabetes mellitus: indirect comparison of controlled trials

To examine whether polymer based coronary stents eluting sirolimus or paclitaxel are equally effective in patients with and without diabetes.

Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta-analysis of randomised controlled trials

To assess the impact of lipid lowering treatment with fibrates on cardiovascular endpoints in patients with type 2 diabetes mellitus.

Accuracy of B-type natriuretic peptide tests to exclude congestive heart failure: systematic review of test accuracy studies

BACKGROUND: Congestive heart failure (CHF) is a major public health problem. The use of B-type natriuretic peptide (BNP) tests shows promising diagnostic accuracy. Herein, we summarize the evidence on the accuracy of BNP tests in the diagnosis of CHF and compare the performance of rapid enzyme-linked immunosorbent assay (ELISA) and standard radioimmunosorbent assay (RIA) tests. METHODS: We searched electronic databases and the reference lists of included studies, and we contacted experts. Data were extracted on the study population, the type of test used, and methods. Receiver operating characteristic (ROC) plots and summary ROC curves were produced and negative likelihood ratios pooled. Random-effect meta-analysis and metaregression were used to combine data and explore sources of between-study heterogeneity. RESULTS: Nineteen studies describing 22 patient populations (9 ELISA and 13 RIA) and 9093 patients were included. The diagnosis of CHF was verified by echocardiography, radionuclide scan, or echocardiography combined with clinical criteria. The pooled negative likelihood ratio overall from random-effect meta-analysis was 0.18 (95% confidence interval [CI], 0.13-0.23). It was lower for the ELISA test (0.12; 95% CI, 0.09-0.16) than for the RIA test (0.23; 95% CI, 0.16-0.32). For a pretest probability of 20%, which is typical for patients with suspected CHF in primary care, a negative result of the ELISA test would produce a posttest probability of 2.9%; a negative RIA test, a posttest probability of 5.4%. CONCLUSIONS: The use of BNP tests to rule out CHF in primary care settings could reduce demand for echocardiography. The advantages of rapid ELISA tests need to be balanced against their higher cost.

Predicting the risk of hospital admission in older persons--validation of a brief self-administered questionnaire in three European countries

OBJECTIVES: To validate the Probability of Repeated Admission (Pra) questionnaire, a widely used self-administered tool for predicting future healthcare use in older persons, in three European healthcare systems. DESIGN: Prospective study with 1-year follow-up. SETTING: Hamburg, Germany; London, United Kingdom; Canton of Solothurn, Switzerland. PARTICIPANTS: Nine thousand seven hundred thirteen independently living community-dwelling people aged 65 and older. MEASUREMENTS: Self-administered eight-item Pra questionnaire at baseline. Self-reported number of hospital admissions and physician visits during 1 year of follow-up. RESULTS: In the combined sample, areas under the receiver operating characteristic curves (AUCs) were 0.64 (95% confidence interval (CI)=0.62-0.66) for the prediction of one or more hospital admissions and 0.68 (95% CI=0.66-0.69) for the prediction of more than six physician visits during the following year. AUCs were similar between sites. In comparison, prediction models based on a person's age and sex alone exhibited poor predictive validity (AUC or= 0.5) were 2.3 times as likely (95% CI=2.1-2.6) as low-risk individuals to have a hospital admission, and 2.1 times as likely (95% CI=2.0-2.2) to have more than six physician visits. CONCLUSION: The Pra instrument exhibits good validity for predicting future health service use on a population level in different healthcare settings. Administrative data have shown similar predictive validity, but in practice, such data are often not available. The Pra is likely of high interest to governments and health insurance companies worldwide as a basis for programs aimed at health risk management in older persons.

Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries

BACKGROUND: Highly active antiretroviral therapy (HAART) is being scaled up in developing countries. We compared baseline characteristics and outcomes during the first year of HAART between HIV-1-infected patients in low-income and high-income settings. METHODS: 18 HAART programmes in Africa, Asia, and South America (low-income settings) and 12 HIV cohort studies from Europe and North America (high-income settings) provided data for 4810 and 22,217, respectively, treatment-naive adult patients starting HAART. All patients from high-income settings and 2725 (57%) patients from low-income settings were actively followed-up and included in survival analyses. FINDINGS: Compared with high-income countries, patients starting HAART in low-income settings had lower CD4 cell counts (median 108 cells per muL vs 234 cells per muL), were more likely to be female (51%vs 25%), and more likely to start treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI) (70%vs 23%). At 6 months, the median number of CD4 cells gained (106 cells per muL vs 103 cells per muL) and the percentage of patients reaching HIV-1 RNA levels lower than 500 copies/mL (76%vs 77%) were similar. Mortality was higher in low-income settings (124 deaths during 2236 person-years of follow-up) than in high-income settings (414 deaths during 20,532 person-years). The adjusted hazard ratio (HR) of mortality comparing low-income with high-income settings fell from 4.3 (95% CI 1.6-11.8) during the first month to 1.5 (0.7-3.0) during months 7-12. The provision of treatment free of charge in low-income settings was associated with lower mortality (adjusted HR 0.23; 95% CI 0.08-0.61). INTERPRETATION: Patients starting HAART in resource-poor settings have increased mortality rates in the first months on therapy, compared with those in developed countries. Timely diagnosis and assessment of treatment eligibility, coupled with free provision of HAART, might reduce this excess mortality.