Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

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Rho kinase inhibition in severe malaria: thwarting parasite-induced collateral damage to endothelia

Acute clinical manifestations of falciparum malaria, such as multiorgan failure and cerebral malaria, occur unpredictably and lead to coma and death within hours if left untreated. Despite the emergency administration of effective antimalarial drugs, 15%-20% of patients die. Other therapeutic approaches are therefore urgently needed. There is increasing evidence that endothelial changes play a key role in the pathogenesis of severe malaria. We therefore used coculture models to study interactions between infected erythrocytes and endothelium. We found that adhesion of Plasmodium falciparum to endothelial cells in vitro activated the Rho kinase signaling pathway, which is strongly involved in various vascular diseases. When added concomitantly with parasites, the Rho kinase inhibitor fasudil (HA-1077), a drug already in clinical use, decreased both NF-kappaB activation and endothelial cell apoptosis. Fasudil also helped to restore endothelial barrier integrity after P. falciparum adhesion. Rho kinase inhibition thus appears to be a promising adjunctive therapeutic approach to the management of severe human malaria.     

Early and late effects of captopril treatment after large myocardial infarction in rats

The early (after 21 days) and late (after 4 months) effects of continuous treatment with captopril on left ventricular performance, weight and volumes were studied in rats with myocardial infarction. Early effects were examined in rats subjected to coronary ligation and randomized to either immediate treatment with captopril (2 g/liter drinking water) starting 2 h after surgery or no treatment. After 21 days, the treated group showed reductions in mean arterial, left ventricular systolic and left ventricular end-diastolic pressures compared with untreated rats. Right and left ventricular weight and left ventricular volumes were decreased and the ejection fraction index was increased by captopril treatment. To study the late effects of captopril, a second group of rats was randomized to immediate captopril treatment (starting 2 h after surgery), delayed captopril treatment (starting 21 days after surgery) or no treatment. When studied after 4 months of treatment, rats started on captopril treatment 2 h after infarction showed no differences compared with rats started on treatment 21 days after infarction. Treatment with captopril for 4 months produced changes that were similar to those in rats treated for 21 days. Captopril treatment improved hemodynamic function after myocardial infarction in rats examined after either 21 days or 4 months of treatment. The extent of the benefit was similar in the two treatment periods. Initiation of captopril therapy immediately after infarction did not appear to produce a greater effect than treatment started at 21 days after infarction in rats studied after the drug had been administered for 4 months.     

Stimulation of collagenase 3 expression in synovial fibroblasts of patients with rheumatoid arthritis by contact with a three-dimensional collagen matrix or with normal cartilage when coimplanted in NOD/SCID mice

OBJECTIVE: To study the expression of collagenase 3 (matrix metalloproteinase 13 [MMP-13]) and collagenase 1 (MMP-1) in synovial fibroblasts from patients with rheumatoid arthritis (RA) when cultured within 3-dimensional collagen gels or coimplanted with normal cartilage in immunodeficient NOD/SCID mice. METHODS: Messenger RNA (mRNA) and protein expression of collagenase 3 and collagenase 1 were characterized in synovial and skin fibroblasts by Northern blot and Western blot analysis. The mRNA expression of both collagenases in cell-cartilage implants in NOD/SCID mice was investigated by in situ hybridization in combination with immunohistochemistry of human fibroblasts. RESULTS: Synovial fibroblasts coimplanted with normal cartilage in NOD/SCID mice deeply invaded adjacent cartilage tissue. In this in vivo system of cartilage destruction, collagenase 3 mRNA was induced in synovial fibroblasts at sites of cartilage erosion, while the expression of collagenase 1 mRNA could not be detected. Culture of synovial fibroblasts within 3-dimensional collagen gels was associated with a marked increase in collagenase 3 mRNA expression and proenzyme production. This stimulatory effect was 1 order of magnitude higher in comparison with a 2-4-fold increase upon treatment with interleukin-1beta or tumor necrosis factor a. In contrast, mRNA expression and proenzyme production of collagenase 1 were increased strongly, and to a similar extent, either by contact with 3-dimensional collagen or by proinflammatory cytokines. CONCLUSION: The expression of collagenase 3, in contrast to that of collagenase 1, is preferentially stimulated in synovial fibroblasts by 3-dimensional collagen rather than by proinflammatory cytokines. The induction of collagenase 3 by cell-matrix interactions represents a potential mechanism contributing to the invasive phenotype of synovial fibroblasts at sites of synovial invasion into cartilage in RA.     

Enhancement of chemotactic factor-stimulated neutrophil oxidative metabolism by leukotriene B4

Leukotriene B4 (LTB4) is a potent primary stimulator of neutrophil chemotaxis, aggregation, and degranulation and induces superoxide production at higher concentrations. In order to determine whether LTB4 modulates neutrophil responses to oxidative stimuli, human neutrophils (PMNs) were incubated with LTB4 prior to stimulation with f-Met-Leu-Phe (fMLP, 10(-7) mol/L), opsonized zymosan (OZ, 250 micrograms/mL), or phorbol myristate acetate (PMA, 32 nmol/L). Superoxide (O2-) production by stimulated PMNs was assessed by the superoxide dismutase-inhibitable reduction of cytochrome c. LTB4 alone did not stimulate O2- production in concentrations below 10(-7) mol/L and had no effect on the O2- assay. In the concentration range of 10(-12) to 10(-8) mol/L, LTB4 did not alter O2- release induced by OZ or PMA. In contrast, LTB4-treated cells demonstrated enhanced O2- production following exposure to fMLP, and in the presence of 10 nmol/LLTB4, generated 180% +/- 41% of O-2 quantities produced by control cells (n = 23). Enhancement was LTB4 dose-dependent, was maximal in the range of 1 to 10 nmol/L LTB4, was not reversed by removal of the lipid from the medium prior to fMLP stimulation, and was not dependent on the presence of Ca++ or Mg++ in the suspending medium. Chemiluminescence of fMLP-stimulated neutrophils was increased to 323% of controls in neutrophils preincubated with 10 nmol/L LTB4. Unlike augmentation of oxidative responses to fMLP seen with other degranulating stimuli, enhancement by LTB4 was not correlated with an increase in 3H-fMLP receptor binding. These results indicate that, in addition to its primary effects on neutrophil function, LTB4 modulates PMN oxidative responses to the chemotactic peptide and, thus, may amplify the release of oxygen metabolites at inflammatory foci.     

A prospective national study on colonoscopy and sigmoidoscopy in 2000 in France

AIM: The aim of this study was to evaluate the practice of colonoscopy and sigmoidoscopy in France in 2000. METHODS: A prospective study was conducted in November 2000 using questionnaires sent to all gastroenterologists practicing in France (N=2858) who were asked to reply to items concerning colonoscopies and sigmoidoscopies performed on two workdays chosen in advance. The response rate was 32.8%. Data were extrapolated to establish estimates for the entire year. RESULTS: An estimated 894000 colonoscopies and 115320 sigmoidoscopies were performed in 2000. Single-use material was used in 22.1% of the procedures. Indications for endoscopy were mainly hematochezia (21.6%), gastrointestinal symptoms (35%) and surveillance of patients with a history of previous polypectomy (15%). Colorectal cancer screening was the indication for 20% of colonoscopies. Abnormal findings were reported for 54.8% of the endoscopies (polyps for 287218 procedures and cancer for 32799). Failure was noted in 4.9% of colonoscopies. The complication rate was 0.48%. Most polyps were adenomas (64.4%) or hyperplasic polyps (28.1%). The overall estimated number of colonoscopies with polypectomy was 224133. CONCLUSION: In 2000 there was an increased rate of colonoscopy for colorectal cancer screening (20%) but an overall decrease (2.5%) in the total number of colonoscopies compared to 1999. Abnormal findings were disclosed by 54.8% of the procedures. Extrapolation from these data indicates that colonoscopic screening enabled the diagnosis of 32799 colorectal cancers.     

Establishing a Research Agenda on Mobile Health Technologies and Later-Life Pain Using an Evidence-Based Consensus Workshop Approach

The rapid growth of mobile health (mHealth) devices holds substantial potential for improving care and care outcomes in all patient populations, including older adults with pain. However, existing research reflects a substantial gap in knowledge about how to design, evaluate, and disseminate devices to optimally address the many challenges associated with managing pain in older persons. Given these knowledge gaps, we sought to develop a set of practice-based research priorities to facilitate innovation in this field. We employed the Cornell Research-Practice Consensus Workshop Model, an evidence-based approach to generating research priorities. Sixty participants attended the conference, where stakeholder groups included older adults with pain and their caregivers, behavioral and social scientists, healthcare providers, pain experts, and specialists in mHealth and health policy. Participants generated 13 recommendations classified into 2 categories: 1) implications for designing research on mHealth among older adults (eg, conduct research on ways to enhance accessibility of mHealth tools among diverse groups of older adults with pain, expand research on mHealth sensing applications), and 2) implementation of mHealth technology into practice and associated regulatory issues (eg, promote research on ways to initiate/sustain patient behavior change, expand research on mHealth cybersecurity and privacy issues).