Schistosoma mansoni in mice: modulation of granulomatous response after reinfection and chemotherapeutic treatment

Mice previously infected with Schistosoma mansoni, and cured by specific treatment (400mg/kg oxamniquine, p. o.) in the chronic phase of the disease, were reinfected 20 days after treatment to assess their capacityfor modulation ofthe granulomatous response. Histopathologic examination of the animals ' liver, at 60 days after reinfection, evidenced the presence of typical granulomas of the chronic phase in most animals. This infer that the capacity for modulation of the granulomatous response had been maintained, thus preventing a new acute phase of the disease. Conversely, a group of previously infected mice, untreated and submitted to reinfection, showed reactivation of the granulomatous response in 50% of the animals. The possible implications of these findings in human schistosomiasis mansoni are discussed.

Neurodegeneration and neurogenesis in organotypic hippocampal slice cultures after oxygen and glucose deprivation

Organotypic hippocampal slice cultures, neurogenesis, posterior periventricle, oxygen-glucose deprivation, microglia, inflammation

Clinical Coronary In-Stent Restenosis Follow-Up after Treatment and Analyses of Clinical Outcomes

Background: Clinical in-stent restenosis (CISR) is the main limitation of coronary angioplasty with stent implantation. Objective: Describe the clinical and angiographic characteristics of CISR and the outcomes over a minimum follow-up of 12 months after its diagnosis and treatment. Methods: We analyzed in 110 consecutive patients with CISR the clinical presentation, angiographic characteristics, treatment and combined primary outcomes (cardiovascular death, nonfatal acute myocardial infarction [AMI]) and combined secondary (unstable angina with hospitalization, target vessel revascularization and target lesion revascularization) during a minimal follow-up of one year. Results: Mean age was 61 ± 11 years (68.2% males). Clinical presentations included acute coronary syndrome (ACS) in 62.7% and proliferative ISR in 34.5%. CISR was treated with implantation of drug-eluting stents (DES) in 36.4%, Bare Metal Stent (BMS) in 23.6%, myocardial revascularization surgery in 18.2%, balloon angioplasty in 15.5% and clinical treatment in 6.4%. During a median follow-up of 19.7 months, the primary outcome occurred in 18 patients, including 6 (5.5%) deaths and 13 (11.8%) AMI events. Twenty-four patients presented a secondary outcome. Predictors of the primary outcome were CISR with DES (HR = 4.36 [1.44–12.85]; p = 0.009) and clinical treatment for CISR (HR = 10.66 [2.53–44.87]; p = 0.001). Treatment of CISR with BMS (HR = 4.08 [1.75–9.48]; p = 0.001) and clinical therapy (HR = 6.29 [1.35–29.38]; p = 0.019) emerged as predictors of a secondary outcome. Conclusion: Patients with CISR present in most cases with ACS and with a high frequency of adverse events during a medium-term follow-up.

Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy with continuous spike-waves during slow-wave sleep.

PURPOSE: To present the long-term follow-up of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to nonlesional focal, mainly frontal, epilepsy with continuous spike-waves during slow wave sleep (CSWS). METHODS: Past medical and electroencephalography (EEG) data were reviewed and neuropsychological tests exploring main cognitive functions were administered. KEY FINDINGS: After a mean duration of follow-up of 15.6 years (range, 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the active phase (AP) disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. Long-term outcome correlated best with duration of CSWS. SIGNIFICANCE: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence, as reported in adults with early destructive lesions of the frontal lobes. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.

Wound infection after excision and primary midline closure for pilonidal disease: risk factor analysis to improve patient selection.

BACKGROUND: Excision and primary midline closure for pilonidal disease (PD) is a simple procedure; however, it is frequently complicated by infection and prolonged healing. The aim of this study was to analyze risk factors for surgical site infection (SSI) in this context. METHODS: All consecutive patients undergoing excision and primary closure for PD from January 2002 through October 2008 were retrospectively assessed. The end points were SSI, as defined by the Center for Disease Control, and time to healing. Univariable and multivariable risk factor analyses were performed. RESULTS: One hundred thirty-one patients were included [97 men (74%), median age = 24 (range 15-66) years]. SSI occurred in 41 (31%) patients. Median time to healing was 20 days (range 12-76) in patients without SSI and 62 days (range 20-176) in patients with SSI (P < 0.0001). In univariable and multivariable analyses, smoking [OR = 2.6 (95% CI 1.02, 6.8), P = 0.046] and lack of antibiotic prophylaxis [OR = 5.6 (95% CI 2.5, 14.3), P = 0.001] were significant predictors for SSI. Adjusted for SSI, age over 25 was a significant predictor of prolonged healing. CONCLUSION: This study suggests that the rate of SSI after excision and primary closure of PD is higher in smokers and could be reduced by antibiotic prophylaxis. SSI significantly prolongs healing time, particularly in patients over 25 years.

Treatment of gastrointestinal stromal tumor after imatinib and sunitinib.

Purpose of review Tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, have changed the outcome of patients with gastrointestinal stromal tumor (GIST) and prolonged survival by many-fold. Unfortunately, treatment failure and tumor progression seem inevitable over time and constitute an unresolved clinical challenge. This article reviews current efforts to overcome drug resistance and progression. Recent findings The major mechanism of resistance toward imatinib and sunitinib is the development of secondary resistance mutations in the kinase domain of KIT. Recent efforts aim at inhibitors with increased activity against resistance mutations or a broader spectrum of activity. Other strategies include indirect KIT inhibition by modulating KIT chaperone proteins or inhibition of KIT-dependent and independent signaling pathways. Summary dThe rapid improvement of our understanding of GIST biology as well as resistance mechanisms towards imatinib and sunitinib will greatly facilitate the development of novel treatment strategies. This article summarizes the results of recently reported third and fourth-line clinical trials in patients with resistant GIST and reviews data of important proof-of-concept studies.

Appropriateness of colonoscopy in Europe (EPAGE II). Surveillance after polypectomy and after resection of colorectal cancer.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for surveillance after polypectomy and after curative-intent resection of colorectal cancer (CRC), and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of surveillance colonoscopy after polypectomy and after resection of CRC was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: Most CRCs arise from adenomatous polyps. The characteristics of removed polyps, especially the distinction between low-risk adenomas (1 or 2, small [< 1 cm], tubular, no high-grade dysplasia) vs. high-risk adenomas (large [> or = 1 cm], multiple [> 3], high-grade dysplasia or villous features), have an impact on advanced adenoma recurrence. Most guidelines recommend a 3-year follow-up colonoscopy for high-risk adenomas and a 5-year colonoscopy for low-risk adenomas. Despite the lack of evidence to support or refute any survival benefit for follow-up colonoscopy after curative-intent CRC resection, surveillance colonoscopy is recommended by most guidelines. The timing of the first surveillance colonoscopy differs. The expert panel considered that 56 % of the clinical indications for colonoscopy for surveillance after polypectomy were appropriate. For surveillance after CRC resection, it considered colonoscopy appropriate 1 year after resection. CONCLUSIONS: Colonoscopy is recommended as a first-choice procedure for surveillance after polypectomy by all published guidelines and by the EPAGE II criteria. Despite the limitations of the published studies, colonoscopy is also recommended by most of the guidelines and by EPAGE II criteria for surveillance after curative-intent CRC resection.

Survival and Molting Incidence after Heat and Cold Shocks in Panstrongylus megistus Burmeister

Survival and molting incidence were studied after heat (40°C) and cold (0°C) shocks in specimens of Panstrongylus megistus with the aim of establishing its response to temperature stress under laboratory rearing conditions and to understand occasional changes in the biological characteristics of specimens captured in nature. The response to the thermal shocks was found to vary as a function of the temperature and duration of the shock, developmental phase and sex of the specimens, and in certain cases, the insect habit and nourishment conditions. P. megistus specimens were found to be less resistant to the heat shock assay than Triatoma infestans, another reduviid species. The short cold shock affected survival of P. megistus more than did the heat shock, survival of fully-nourished specimens being preferential. The response of adults to the short cold shock was affected by sex, males being generally less resistant. The insect sylvatic habit was found to seldom affect the thermal shock response established for specimens with domestic habit. A decrease in molting frequency and sometimes a slowdown of the molting rate were found after the short heat and cold shocks, possibly promoted by change in hormonal balance, and differing from patterns reported for T. infestans. The results indicate that no generalization should be made for different reduviid species in terms of the effects of temperature shocks.

Expression of inducible nitric oxide synthase in bovine corneal endothelial cells and keratocytes in vitro after lipopolysaccharide and cytokines stimulation.

PURPOSE: To determine whether bovine corneal endothelial (BCE) cells and keratocytes express the inducible form of nitric oxide synthase (NOS) after exposure to cytokines and lipopolysaccharide (LPS), and to study the regulation of NOS by growth factors. METHODS: Cultures of bovine corneal endothelial cells and keratocytes were exposed to increasing concentrations of LPS, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). At selected intervals after exposure, nitrite levels in the supernatants were evaluated by the Griess reaction. Total RNA was extracted from the cell cultures, and messenger RNA levels for inducible NOS (NOS-2) were measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Exposure of BCE cells and keratocytes to LPS and IFN-gamma resulted in an increase of nitrite levels that was potentiate by the addition of TNF-alpha. Analysis by RT-PCR demonstrated that nitrite release was correlated to the expression of NOS-2 messenger RNA in BCE cells and keratocytes. Stereoselective inhibitors of NOS and cycloheximide inhibited LPS-IFN-gamma-induced nitrite release in both cells, whereas transforming growth factor-beta (TGF-beta) slightly potentiated it. Fibroblast growth factor-2 (FGF-2) inhibited LPS-IFN-gamma-induced nitrite release and NOS-2 messenger RNA accumulation in keratocytes but not in BCE cells. CONCLUSIONS: The results demonstrate that in vitro activation of keratocytes and BCE cells by LPS and cytokines induces NOS-2 expression and release of large amounts of NO. The high amounts of NO could be involved in inflammatory corneal diseases in vivo.

Where will conflicts between alien and rare species occur after climate and land-use change? A test with a novel combined modelling approach

Protecting native biodiversity against alien invasive species requires powerful methods to anticipate these invasions and to protect native species assumed to be at risk. Here, we describe how species distribution models (SDMs) can be used to identify areas predicted as suitable for rare native species and also predicted as highly susceptible to invasion by alien species, at present and under future climate and land-use scenarios. To assess the condition and dynamics of such conflicts, we developed a combined predictive modelling (CPM) approach, which predicts species distributions by combining two SDMs fitted using subsets of predictors classified as acting at either regional or local scales. We illustrate the CPM approach for an alien invader and a rare species associated to similar habitats in northwest Portugal. Combined models predict a wider variety of potential species responses, providing more informative projections of species distributions and future dynamics than traditional, non-combined models. They also provide more informative insight regarding current and future rare-invasive conflict areas. For our studied species, conflict areas of highest conservation relevance are predicted to decrease over the next decade, supporting previous reports that some invasive species may contract their geographic range and impact due to climate change. More generally, our results highlight the more informative character of the combined approach to address practical issues in conservation and management programs, especially those aimed at mitigating the impact of invasive plants, land-use and climate changes in sensitive regions

Look after yourself and others - Promoting mental health and suicide prevention within the Northern area

This leaflet lists the wide range of local support available in the Northern area to help improve mental health and emotional wellbeing and reduce the number of deaths by suicide. This leaflet is aimed at individuals and organisations to raise awareness of the support for individuals and communities.

Do you look after someone? And are you from a black or minority ethnic background? (English and translations)

This leaflet is for BME (Black and Minority Ethnic) Carers. Carers can be people of all ages including children, young people, parents, older people. There is a cut off slip for BME Carers to fill in with their details. This information can then be sent to the Carer Worker in their local Trust. Details are on the leaflet.

Antibody reactivity against potato apyrase, a protein that shares epitopes with Schistosoma mansoni ATP diphosphohydrolase isoforms, in acute and chronically infected mice, after chemotherapy and reinfection

Schistosoma mansoni ATP diphosphohydrolase isoforms and potato apyrase share conserved epitopes. By enzyme-linked immunosorbent assays, elevated levels of IgM, IgG2a and IgG1 antibody reactivity against potato apyrase were observed in S. mansoni-infected BALB/c mice during the acute phase of infection, while only IgM and IgG1 antibody reactivity levels maintained elevated during the chronic phase of infection. Antibody reactivity against potato apyrase was monitored over an 11-month period in chronically-infected mice treated with oxamniquine. Eleven months later, the level of seropositive IgM decreased significantly (~30%) compared to the level found in untreated, infected mice. The level of seropositive IgG1 decreased significantly four months after treatment (MAT) (61%) and remained at this level even after 11 months. The IgG2a reactivity against potato apyrase, although unchanged during chronic phase to 11 MAT, appeared elevated again in re-infected mice suggesting a response similar to that found during the acute phase. BALB/c mouse polyclonal anti-potato apyrase IgG reacted with soluble egg antigens probably due to the recognition of parasite ATP diphosphohydrolase. This study, for the first time, showed that the IgG2a antibody from S. mansoni-infected BALB mice cross-reacts with potato apyrase and the level of IgG2a in infected mice differentiates disease phases. The results also suggest that different conserved-epitopes contribute to the immune response in schistosomiasis.

Prolonged cholestasis after raloxifene and fenofibrate interaction: A case report.

Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistence of toxic cholestasis.

Modulation of MDR1 and MRP3 Gene Expression in Lung Cancer Cells after Paclitaxel and Carboplatin Exposure

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 μM) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 μM) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs.