Therapie der frühen Stadien des Seminoms

Germinale Hodenmalignome werden ausnahmslos in fakultativ-kurativer Intention behandelt. Bei Frühstadien werden mit multimodalen Therapiekonzepten exzellente Ergebnisse erreicht, dabei weisen testikul?re Seminome Heilungsraten von nahe 100% auf. Diese sind beispielgebend für interdisziplin?re stadiengerechte onkologische Behandlungen solider Organtumoren. Solche Erfolge begründen Bemühungen, die Therapie ohne Kompromittierung erreichter Heilungsraten weiter zu reduzieren und dabei therapiebedingte Einschr?nkungen an Lebensqualit?t für die Patienten und hierfür aufzuwendende sozio?konomische Kosten so gering wie m?glich zu halten. Erforderlich sind solche Bemühungen vor dem Hintergrund steigender Inzidenzraten und alternativer Behandlungsmodalit?ten. Ihre klinische Relevanz ergibt sich aus dem hohen Anteil in Frühstadien diagnostizierter Erkrankungsf?lle. Bei identischer diagnostischer Strategie für alle testikul?ren Keimzellmalignome ist für die postoperativen Behandlungsoptionen bei frühen Stadien zwischen den radiosensiblen Seminomen und den Nicht-Seminomen zu unterscheiden. Für die Seminome werden in dieser Arbeit, orientiert am jeweiligen Tumorstadium, die perkutane Strahlentherapie nach Orchiektomie als Standardtherapie erl?utert und deren Alternativen im Stadium cS I, systemische Carboplatin-Monozytostase oder Surveillance-Strategie, bzw. im Stadium cS IIA/B, systemische Chemotherapie, vergleichend dargestellt.     

How the war on drugs impacts social determinants of health beyond the criminal legal system

There is a growing recognition in the fields of public health and medicine that social determinants of health (SDOH) play a key role in driving health inequities and disparities among various groups, such that a focus upon individual-level medical interventions will have limited effects without the consideration of the macro-level factors that dictate how effectively individuals can manage their health. While the health impacts of mass incarceration have been explored, less attention has been paid to how the “war on drugs” in the United States exacerbates many of the factors that negatively impact health and wellbeing, disproportionately impacting low-income communities and people of colour who already experience structural challenges including discrimination, disinvestment, and racism. The U.S. war on drugs has subjected millions to criminalisation, incarceration, and lifelong criminal records, disrupting or altogether eliminating their access to adequate resources and supports to live healthy lives. This paper examines the ways that “drug war logic” has become embedded in key SDOH and systems, such as employment, education, housing, public benefits, family regulation (commonly referred to as the child welfare system), the drug treatment system, and the healthcare system. Rather than supporting the health and wellbeing of individuals, families, and communities, the U.S. drug war has exacerbated harm in these systems through practices such as drug testing, mandatory reporting, zero-tolerance policies, and coerced treatment. We argue that, because the drug war has become embedded in these systems, medical practitioners can play a significant role in promoting individual and community health by reducing the impact of criminalisation upon healthcare service provision and by becoming engaged in policy reform efforts.

KEY MESSAGES

• A drug war logic that prioritises and justifies drug prohibition, criminalisation, and punishment has fuelled the expansion of drug surveillance and control mechanisms in numerous facets of everyday life in the United States negatively impacting key social determinants of health, including housing, education, income, and employment.
• The U.S. drug war’s frontline enforcers are no longer police alone but now include physicians, nurses, teachers, neighbours, social workers, employers, landlords, and others.
• Physicians and healthcare providers can play a significant role in promoting individual and community health by reducing the impact of criminalisation upon healthcare service provision and engaging in policy reform.

     

The TETAMI Trial: The Safety and Efficacy of Subcutaneous Enoxaparin versus Intravenous Unfractionated Heparin and of Tirofiban versus Placebo in the Treatment of Acute Myocardial Infarction for Patients Not Thrombolyzed: Methods and Design

Patients with acute myocardial infarction (AMI) who do not receive early reperfusion therapy are at high risk of reinfarction or death, and the efficacy and safety of antithrombotic therapy in this group of patients has not been evaluated. Enoxaparin is a low-molecular-weight heparin (LMWH) that has previously been shown to reduce the incidence of ischemic events in patients with unstable angina or non–Q-wave MI. The principal aims of the TETAMI study are to investigate the efficacy and safety of treatment with enoxaparin or tirofiban (a glycoprotein IIb/IIIa receptor antagonist) alone or in combination for 2 to 8 days in patients with AMI who are not eligible for early reperfusion therapy. In this 2 by 2 factorial design study approximately 900 patients will be randomly assigned, in a blinded manner, to one of four treatments: enoxaparin alone, enoxaparin plus tirofiban, unfractionated heparin (UFH), or UFH plus tirofiban, with appropriate matched placebos. The primary end point is the composite of death, recurrent AMI, and recurrent angina, analyzed at 30 days after AMI. The design and methods of the TETAMI study are described in this article.     

Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention: The pharmacokinetics of enoxaparin in PCI (PEPCI) study.

The objective of this study was to evaluate the pharmacokinetic response to intravenous (IV) enoxaparin given 8-12 hr after subcutaneous (SC) dosing in patients undergoing percutaneous coronary intervention (PCI). Fifty-five patients received SC enoxaparin (1 mg/kg every 12 hr) followed by an IV bolus (0.3 mg/kg) 8-12 hr after the last SC dose, at the start of PCI or during catheterization. Anti-Xa levels were within the target range in 98% of patients 2-8 hr after the last SC dose, in 96% of patients following the IV bolus, and in 91% of patients for a further 2 hr. Subcutaneous enoxaparin (1 mg/kg every 12 hr) provides sufficient anti-Xa levels for PCI 2-8 hr after the last dose. An additional 0.3 mg/kg enoxaparin dose given IV 8-12 hr after the last SC dose reliably maintains anti-Xa levels within the target for at least 2 additional hr.     

The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase

Notch signaling is involved in numerous cell fate decisions in invertebrates and vertebrates. The Notch receptor is a type I transmembrane (TM) protein that undergoes two proteolytic steps after ligand binding, first by an ADAM (a distintegrin and metalloprotease) in the extracellular region, followed by gamma-secretase-mediated cleavage inside the TM domain. We demonstrate here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner. Identification of the ADAM-mediated shedding site localized 10 aa N-terminal to the TM domain has enabled us to generate a noncleavable mutant. Kuzbanian/ADAM10 is involved in this processing event, but other proteases can probably substitute for it. We then show that Dll1 is part of a high-molecular-weight complex containing presenilin1 and undergoes further cleavage by a gamma-secretase-like activity, therefore releasing the intracellular domain that localizes in part to the nucleus. Using the shedding-resistant mutant, we demonstrate that this gamma-secretase cleavage depends on prior ectodomain shedding. Therefore Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.     

A thyroid nodule revealing a paraganglioma in a patient with a new germline mutation in the succinate dehydrogenase B gene

A 32-year-old asymptomatic female was diagnosed with an isolated thyroid nodule of 2.5 cm diameter. Fine needle aspiration suggested a medullary thyroid carcinoma. Consequently, a total thyroidectomy was performed. The nodule stained positive for chromogranin A, neurone-specific enolase and synaptophysin, but not for calcitonin. Finally, pathological analysis showed a thyroid paraganglioma. Although the tumour appeared to be sporadic in a patient with no personal or familial history of paraganglioma and/or pheochromocytoma, we have identified a new mutation (392delC) of the succinate dehydrogenase-B (SDHB) gene in the genomic DNA extracted from the leukocytes of the patient. That mutation induced a shift in the reading frame of the gene creating a premature stop codon (P131fsX135) which was predicted to result in a truncated SDHB protein of 135 amino acids.This report highlights the difficulties of this unexpected diagnosis of hereditary thyroid paraganglioma. It also discusses the clinical involvements in terms of familial screening and the necessary follow-up of the patient.     

Colonization of Extended-Spectrum-β-Lactamase- and NDM-1-Producing Enterobacteriaceae among Pregnant Women in the Community in a Low-Income Country: a Potential Reservoir for Transmission of Multiresistant Enterobacteriaceae to Neonates

The spread of extended-spectrum-β-lactamase-producing Enterobacteriaceae (ESBL-PE) in low-income countries, where the burden of neonatal sepsis is high, may have a serious impact on neonatal mortality rates. Given the potential for mother-to-child transmission of multiresistant bacteria, this study investigated the ESBL-PE rectal colonization among pregnant women at delivery in the community in Madagascar and estimated a prevalence of 18.5% (95% confidence interval, 14.5% to 22.6%). One strain of Klebsiella pneumoniae isolated was also a New Delhi metallo-β-lactamase-1 (NDM-1) producer.