[Multimorbidity and successful aging: the population-based KORA-Age study]. / Multimorbidität und erfolgreiches Altern: Ein Blick auf die Bevölkerung im Rahmen der KORA-Age-Studie.

BACKGROUND: The objective of the KORA-Age research consortium is to assess the determinants and consequences of multimorbidity in the elderly and to look into reasons for successful aging in the general public. PATIENTS AND METHODS: In the KORA-Age cohort study 9,197 persons were included who where born in the year 1943 or before and participants of previous KORA cohort studies conducted between 1984 and 2001 (KORA: Cooperative Health Research in the Region of Augsburg). The randomized intervention study KORINNA (Coronary infarct follow-up treatment in the elderly) tested a nurse-based case management program with 338 patients with myocardial infarct and included an evaluation in health economics. RESULTS: A total of 2,734 deaths were registered, 4,565 participants submitted a postal health status questionnaire and 4,127 participants were interviewed by telephone (response 76.2% and 68.9% respectively). A gender and age-stratified random sample of the cohort consisting of 1,079 persons took part in a physical examination (response 53.8%). CONCLUSION: The KORA-Age consortium was able to collect data in a large population-based sample and is contributing to the understanding of multimorbidity and successful aging.

[Networking and integrated disease management. Advantages and disadvantages from the medical point of view]. / Vernetzung und integrierte Versorgung. Vor- und Nachteile aus medizinischer Sicht.

At the moment the terms "networking", "cost reduction" and "integrated disease management" are frequently discussed in all branches of the German health care system. Unfortunately there are different interpretations of these terms. "Integrated disease management" in the meaning of communication between clinical and outpatient health care has al ready existed for years now. Traditional ways of communication lead to information loss. Losing information is a reason for low cost effectiveness and a prolonged healing process directly harming the patient. A computer network may prevent information loss and may in crease the performance of data transfer. Different sides have al ready started networking, and it is now necessary to bundle the interests. This necessity has been recognized by the German legislative. To lead this project to success it is important to know and to fulfil some medical criteria. Defining and describing these conditions is the topic of this paper. Our special intent is to show that digital technique is necessary to improve cooperation among physicians.

T-cell-independent granuloma formation in response to Mycobacterium avium: role of tumour necrosis factor-alpha and interferon-gamma.

We used Mycobacterium avium infection in severe combined immunodeficiency (SCID) mice to examine T-cell-independent mechanisms of inflammatory cell recruitment. SCID mice infected with a virulent strain of M. avium (TMC724) were able to recruit macrophages to sites of mycobacterial replication and formed organized and coherent granulomas in the absence of functional T cells. Phagocyte recruitment was almost totally ablated by neutralization of either tumour necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma) in vivo demonstrating that granuloma formation was dependent on the presence of these cytokines. This was concomitant with a reduction in the in situ cytokine mRNA levels otherwise induced in infected mice, for chemokines, pro-inflammatory and regulatory cytokines, including TNF-alpha, IFN-gamma, macrophage inflammatory protein-1 alpha, interleukin-1 beta (IL-1 beta) and IL-10. Furthermore, in vivo treatment of infected mice with anti-asialo GM-1 antisera, which depletes natural killer (NK) cells, prevented recruitment of inflammatory cells. In vitro studies confirmed that M. avium was able to elicit IFN-gamma from SCID spleen in a dose-dependent manner. These data show for the first time that secretion of IFN-gamma from NK cells can mediate a T-cell-independent pathway of granuloma formation and cellular infiltration in response to mycobacteria.

Mechanisms of granuloma formation in murine Mycobacterium avium infection: the contribution of CD4+ T cells.

Infection with the virulent Mycobacterium avium strain TMC 724 caused progressive infection in C57BL/6 and BALB/c mice, while infection with a less virulent strain (M. avium SE 01) resulted in chronically persistent bacterial loads. Livers of mice infected with TMC 724 were characterized by progressively expanding tumor-like infiltrations of epithelioid macrophages, while SE 01 induced well-developed, compact epithelioid granulomas that remained constant in size and number for at least 4 months. When C57BL/6 mice were depleted of CD4+ T cells by i.p. administration of specific mAb at the time of infection, their capacity to initiate granuloma formation was completely abrogated during the first 4 weeks of infection. Semi-quantitative competitive RT-PCR of liver homogenates obtained 3 weeks after infection revealed that depletion of CD4+ T cells was accompanied by a 25-fold reduced expression of IFN-gamma mRNA and a 5-fold reduced expression of tumor necrosis factor (TNF)-alpha mRNA when compared to control infected mice. Granuloma morphology in response to either TMC 724 or SE 01 was similar in immunodeficient SCID mice to that observed in syngeneic BALB/c mice. However, SCID mice developed granulomas in a delayed fashion and were less efficient in surrounding infected Kupffer cells with an inflammatory infiltration. The delayed kinetics of granuloma initiation in infected SCID mice was paralleled by a lower mRNA expression for IFN-gamma and TNF-alpha compared to that observed in infected BALB/c mice. mAb-mediated neutralization of IFN-gamma in BALB/c mice significantly reduced inflammatory infiltrations and granuloma formation. These data support the conclusion that CD4+ T cells accelerate granuloma formation by enhancing the production of TNF-alpha and IFN-gamma at the site of infection.

Liposomal amikacin for treatment of M. avium infections in clinically relevant experimental settings.

In an effort to optimize rational chemotherapy against M. avium infections in a clinically meaningful context, we tested whether liposome-encapsulated amikacin would effectively reduce the bacterial load in (i) intravenously infected immunodeficient SCID mice, (ii) immunocompetent mice in both early and late stages of intravenous infection, and (iii) immunocompetent mice with pulmonary M. avium infection. Although complete eradication of M. avium was never achieved following intravenous infection, mycobacterial CFUs decreased by 3 to 4 logs in the spleens and livers of mice treated for three weeks with twice-weekly intravenous injections of liposomal amikacin and continued to stay low in the liver, even in the absence of specific immunity. Mice treated in the chronic stage of infection equally benefited from therapy and showed signs of attenuated granulomatous inflammation in the liver. Even moribund mice responded to liposomal amikacin by significantly gaining weight and survived their infected untreated littermates by at least 4 months. In contrast, during pulmonary M. avium infection, treatment with liposome-encapsulated amikacin only resulted in a transient plateau of bacterial proliferation in the lungs, and the infection exacerbated immediately after cessation of therapy.