Acute and Chronic Effects of Interval Training on the Immune System: A Systematic Review with Meta-Analysis.

PURPOSE: To summarize the evidence regarding the acute and chronic effects of interval training (IT) in the immune system through a systematic review with meta-analysis. DESIGN: Systematic review with meta-analysis. DATA SOURCE: English, Portuguese and Spanish languages search of the electronic databases Pubmed/Medline, Scopus, and SciELO. Eligibility criteria: Studies such as clinical trials, randomized cross-over trials and randomized clinical trials, investigating the acute and chronic effects of IT on the immune outcomes in humans. RESULTS: Of the 175 studies retrieved, 35 were included in the qualitative analysis and 18 in a meta-analysis. Within-group analysis detected significant acute decrease after IT on immunoglobulin A (IgA) secretory rate (n = 115; MD = -15.46 µg·min-1; 95%CI, -28.3 to 2.66; p = 0.02), total leucocyte count increase (n = 137; MD = 2.58 × 103 µL-1; 95%CI, 1.79 to 3.38; p < 0.001), increase in lymphocyte count immediately after exercise (n = 125; MD = 1.3 × 103 µL-1; 95%CI, 0.86 to 1.75; p < 0.001), and decrease during recovery (30 to 180 min post-exercise) (n = 125; MD = -0.36 × 103 µL-1;-0.57 to -0.15; p < 0.001). No effect was detected on absolute IgA (n = 127; MD = 47.5 µg·mL-1; 95%CI, -10.6 to 105.6; p = 0.11). Overall, IT might acutely reduce leucocyte function. Regarding chronic effects IT improved immune function without change leucocyte count. CONCLUSION: IT might provide a transient disturbance on the immune system, followed by reduced immune function. However, regular IT performance induces favorable adaptations on immune function.

High-resolution notch filters and diplexers based on SU-8 inverted rib waveguides.

We performed an end-to-end process, ranging from design, fabrication, and characterization of integrated polymeric optical devices under a mass production technology. Inverted rib waveguides formed by SU-8 photoresist deposited on top of full wafers, with trenches in silica, were used as a platform to implement such optical devices. Narrowband spectral filters based on microracetrack resonators and diplexers based on directional couplers, both with high extinction ratios, are demonstrated. Full wafers of those devices were processed in a complementary metal-oxide-semiconductor foundry's 150 mm-facility. We believe the results are promising for applications ranging from telecommunication components to sensing devices.

Chronic immunosuppressant use in colorectal cancer patients worsens postoperative morbidity and mortality through septic complications in a propensity-matched analysis.

AIM: Chronic immunosuppressant use increases the risk of septic complications after colectomy; however, adverse effects on other organ systems remain poorly understood. The aim of this study was to evaluate the multisystem organ effect(s) of chronic immunosuppressant(s) in colorectal cancer patients. METHODS: This was a retrospective study. The American College of Surgeons National Surgical Quality Improvement database (2005-2012) was queried. The primary end-points were 30-day mortality and 30-day morbidity after colectomy in patients on chronic immunosuppressant(s) compared to a non-immunosuppressant cohort. RESULTS: In total, 50 766 patients were identified, with 1203 (2.4%) taking chronic immunosuppressant(s). After propensity matching, 1197 patients in each cohort were evaluated with no differences seen in age, body mass index, male sex, wound classification, emergency case status, the presence of preoperative sepsis or operative time. On outcome analysis, 30-day mortality (5.7% vs 3.4%, P < 0.001) and 30-day overall morbidity (35.4% vs 29.0%, P = 0.001) were higher in patients on chronic immunosuppressant(s). Septic complications (10.6% vs 7.9%, P = 0.02) and surgical site infections (15.3% vs 12.3%, P = 0.03) were elevated with chronic immunosuppressant(s). There were no differences in cardiovascular, pulmonary, renal or neurological complications. Chronic immunosuppressant patients demonstrated longer total hospital stay (11.4 ± 11.7 vs 9.5 ± 9.4 days, P < 0.001) and postoperative length of stay (9.4 ± 9.2 vs 8.1 ± 7.6 days, P < 0.001). The limitation was that this was a retrospective study using a clinical dataset. CONCLUSION: In this study, immunosuppressant use is associated with worsened infective complications, without contributing to organ-specific complications following colectomy. Significant thought should be given to anastomosis vs stoma creation to possibly prevent worsened morbidity and mortality. Future study is required to determine specific pathways for risk reduction.

Data on tensile tests and NMR measurements of poly(vinilidene fluoride) before and after stress relaxation.

Poly(vinilidene fluoride) was characterized before and after stress relaxation by tensile tests and time-domain nuclear magnetic resonance (TD-NMR). Tensile tests were performed to provide mechanical properties, focused on the data of elastic modulus for this matter. The TD-NMR technique was used to calculate the fraction of crystalline, constrained amorphous and free amorphous phase, and the transversal relaxation time of each of these phases.

Differences in community, hospital and intensive care unit-acquired acute kidney injury: observational study in a nephrology service of a developing country.

BACKGROUND: Acute kidney injury (AKI) complicates more than 7% of all in-hospital patients. The aim of this study is to investigate the differences in community, hospital and intensive care unit-acquired AKI in patients undergoing nephrology consultation in a tertiary hospital in a developing country. METHODS: An observational cohort study of all patients with AKI admitted to the General Hospital of Fortaleza, Brazil was conducted. RIFLE criteria were used to classify the patients and to assess their association with death. Univariate and multivariate analyses were performed to investigate the factors associated with death. RESULTS: Of 491 AKI patients undergoing nephrology consultation, the mean age was 55.2 ± 22.9 years. Community-acquired AKI was observed in 55% of cases, general ward-acquired in 29% and ICU-acquired in 15.3%. Late Nephrology consultation was observed, and the great majority of patients had "Failure" classification (90%) according to RIFLE criteria. Intermittent hemodialysis was required in 68% of cases. The overall in-hospital mortality was 23%. The in-hospital mortality was higher in ICU-acquired AKI (33.6%). Community acquired AKI had a higher mortality than general ward-acquired AKI (23% vs. 11.6%, p = 0.001). Risk factors for death were infection (OR = 2.0, p = 0.003), neoplasms (OR = 1.89, p = 0.042), community acquired-AKI (OR = 1.27, p = 0.003), ICU acquired-AKI (OR = 2.76, p < 0.0001) and need for renal replacement therapy (OR = 2.64, p < 0.001). CONCLUSIONS: AKI is a frequent and frequently fatal condition. Mortality was higher in community and ICU-acquired than hospital ward-acquired AKI.

Acute kidney injury due to anabolic steroid and vitamin supplement abuse: report of two cases and a literature review.

BACKGROUND: The use of anabolic steroids and vitamin supplements has reached alarming proportions in the last decades. Adverse effects have been documented and include virilization, feminization, adverse lipid profile, psychiatric disorders, cardiac and liver disease. Acute kidney injury (AKI) is not frequently described. The purpose of this study is to report two cases of AKI associated with anabolic steroid and vitamin supplement abuse. CASE REPORT: Two men, aged 21 and 30 years, presented to the Emergency Department with abdominal pain, nausea and vomiting. They reported the use of anabolic steroids and veterinary supplements with vitamins A, D and E. Laboratory tests showed AKI (serum urea 79 and 52 mg/dl, serum creatinine 3.9 and 1.9 mg/dl) and hypercalcemia (calcium 13.2 and 11 mEq/l). Kidney biopsies showed inflammatory interstitial nephritis and acute tubular necrosis. Treatment consisted of vigorous hydration with simultaneous use of furosemide and discontinuation of the vitamins and anabolic substances, and resulted in recovery of renal function. CONCLUSIONS: AKI is an important complication of anabolic steroid and vitamin supplement abuse. The exact pathophysiology of this type of AKI remains unclear. The main cause of renal dysfunction in these cases seems to be the vitamin D intoxication and drug-induced interstitial nephritis. It is mandatory to start early treatment for serious hypercalcemia, with vigorous venous hydration, diuretics and corticosteroids.

An immune escape screen reveals Cdc42 as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression.

Adoptive cellular immunotherapy inducing a graft-versus-tumor (GVT) effect is the therapeutic mainstay of allogeneic hematopoietic stem cell transplantation (ASCT) for high-risk leukemias. Autologous immunotherapies using vaccines or adoptive transfer of ex vivo-manipulated lymphocytes are clinically explored in patients with various cancer entities. Main reason for failure of ASCT and cancer immunotherapy is progression of the underlying malignancy, which is more prevalent in patients with advanced disease. Elucidating the molecular mechanisms contributing to immune escape will help to develop strategies for the improvement of immunologic cancer treatment. To this end, we have undertaken functional screening and expression cloning of factors mediating resistance to antigen-specific cytotoxic T lymphocytes (CTLs). We have identified Cdc42, a GTPase regulating actin dynamics and growth factor signaling that is highly expressed in invasive cancers, as determinator of cancer cell susceptibility to antigen-specific CTLs in vitro and adoptively transferred immune effectors in vivo. Cdc42 prevents CTL-induced apoptosis via mitogen-activated protein kinase (MAPK) signaling and posttranscriptional stabilization of Bcl-2. Pharmacologic inhibition of MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) overcomes Cdc42-mediated immunoresistance and activation of Bcl-2 in vivo. In conclusion, Cdc42 signaling contributes to immune escape of cancer. Targeting Cdc42 may improve the efficacy of cancer immunotherapies.

Hiperlactatemia à admissão na UTI é um determinante de morbimortalidade em intervenções cirúrgicas não cardíacas de alto risco / Hyperlactatemia at ICU admission is a morbid-mortality determinant in high risk non-cardiac surgeries

JUSTIFICATIVA E OBJETIVOS: Um dos maiores desafios dos médicos intensivistas é o controle da hipoperfusão tecidual, sendo o lactato sérico classicamente aceito como indicador de hipóxia tecidual. Deste modo, estudos demonstraram boa correlação entre o lactato e o prognóstico no choque e durante a reanimação. O objetivo deste estudo foi avaliar a utilidade clínica do lactato arterial à admissão na UTI como indicador de morbimortalidade em pacientes críticos no pós-operatório de intervenções cirúrgicas não cardíacas de alto risco. MÉTODO: Estudo de coorte prospectivo observacional, realizado em UTI de hospital terciário no período de 4 meses. Foram coletados dados demográficos, lactato arterial e complicações no pós-operatório de pacientes submetidos à intervenções cirúrgicas de grande porte. Para análise estatística foi considerado significativo p < 0,05. A habilidade preditiva dos índices em diferenciar sobreviventes e não sobreviventes foi verificada utilizando curvas ROC. Estimativas de permanência na UTI foram calculadas utilizando o método de Kaplan Méier. RESULTADOS: Foram incluídos 202 pacientes, sendo 50,2 por cento do sexo feminino, com média da idade de 66,5 ± 13,6 anos, APACHE II 17,4 ± 3,0, mediana do MODS 4 (2-6). A duração mediana das intervenções foram 4h (3 a 6h), 70,7 por cento de cirurgias eletivas, a mortalidade na UTI e hospitalar foram 15,6 por cento e 33,7 por cento, respectivamente. O melhor valor de lactato que discriminou mortalidade foi 3,2 mmol/L, sensibilidade de 62,5 por cento e especificidade de 78,8 por cento, área sob a curva de 0,7. Não sobreviveram 62,5 por cento dos pacientes com lactato > 3,2 versus 21,2 por cento de sobreviventes (OR = 2,95 IC95 por cento 1,98 - 4,38, p < 0,0001). O tempo de permanência na UTI foi mais elevado quando lactato > 3,2 mmol/L (log rank 0,007). CONCLUSÕES: Os pacientes cirúrgicos não cardíacos de alto risco admitidos na UTI com hiperlactatemia, definida com...

BACKGROUND AND OBJECTIVES: One of the greatest challenges found by the intensivists in their daily activities is tissue hipoperfusion control. Blood lactate is generally accepted as a marker of tissular hypoxia and several studies have demonstrated good correlation between blood lactate and prognosis during shock and resuscitation. The aim of this study was to evaluate the clinical utility of arterial blood lactate as a marker of morbidity and mortality in critically ill patients in the post-operative period of high risk non-cardiac surgeries. METHODS: Prospective and observational cohort study realized in an ICU of a tertiary hospital during a four month period. Demographic data of the patients submitted to high risk surgeries were collected, besides arterial lactate measures and number and type of complications in the post-operative period. To the statistic analysis was considered as significant a p < 0.05. The predictive ability of the indexes to differentiate survivors from non-survivors was tested using ROC curves. Lenght of ICU stay estimation where calculated by Kaplan Meier method. RESULTS: Were included 202 patients. 50.2 percent were female and their mean age was 66.5 ± 13.6 years. APACHE II score was 17.4 ± 3.0 and the median of MODS score was 4 (2-6). Median lenght of surgeries was 4h (3-6h). 70.7 percent of the surgeries were elective ones. ICU and hospital mortality were 15.6 percent and 33.7 percent, respectively. The best lactate value to discriminate mortality was 3.2 mmol/L, with sensitivity of 62.5 percent, specificity of 78.8 percent and an area under the curve of 0.7. 62.5 percent of patients with lactate > 3.2 did not survive versus 21.2 percent of survivors (OR = 2.95 IC95 percent 1.98- 4.38, p < 0.0001). ICU lenght of stay was greater when > 3.2 mmol/L (log rank 0.007) lactate. CONCLUSIONS: High risk patients submitted to non cardiac surgeries and admitted to the ICU with hiperlactatemia, defined...

A doença oncológica não deve ser um fator limitante para admissão na UTI de pacientes submetidos a cirurgias de alto risco / Cancer disease should not be a limitative factor for admission of high risk surgical patients to an intensive care unit

JUSTIFICATIVA E OBJETIVOS: A doença oncológica per se é uma condição que muitas vezes influencia no tratamento dispensado ao paciente. O objetivo do presente estudo foi comparar o desfecho hospitalar de pacientes oncológicos e não oncológicos submetidos à procedimentos cirúrgicos eletivos com alto risco de óbito. MÉTODO: Estudo de coorte prospectivo observacional, realizado em UTI de hospital terciário no período de 01 de abril a 31 de julho de 2005. Foram coletados dados demográficos, escore APACHE II, MODS, variáveis hemodinâmicas, laboratoriais e avaliadas complicações definidas como re-operação, necessidade de ventilação mecânica, transfusão sangüínea e uso de cateter de artéria pulmonar no pós-operatório desses pacientes. Todos foram acompanhados até alta ou o óbito hospitalar. Para variáveis numéricas foi utilizado o teste t de Student e Mann-Whitney, para variáveis categóricas o teste do Qui-quadrado sendo considerado significativo o valor de p < 0,05. RESULTADOS: Foram incluídos no estudo 119 pacientes, 43 não oncológicos e 76 oncológicos, 52,9 por cento eram do sexo feminino. A média de idade foi 65,1 ± 14,1 anos, o escore médio de APACHE II 16,5 ± 5,8 e a mediana do MODS de 3 (2-6). A duração mediana da intervenção cirúrgica foi de 5 (3,3-7) horas e a mortalidade na UTI e hospitalar foram 10,9 por cento e 25,2 por cento, respectivamente. Os pacientes oncológicos apresentaram maiores tempos de internação hospitalar e de internação antes da cirurgia, sendo estes resultados estatisticamente significativos. A mortalidade hospitalar dos pacientes oncológicos não foi superior a dos pacientes sem neoplasia (22,4 por cento versus 30,2 por cento, p = 0,32). CONCLUSÕES: Nesta observação os pacientes oncológicos, submetidos à procedimentos cirúrgicos de alto risco, apresentaram mortalidade semelhante aos pacientes não oncológicos com gravidade de doença similar.

BACKGROUND AND OBJECTIVES: Oncologic diseases are conditions that have influence in the treatment offered to affected patients. The aim of this study was to compare hospitalar outcome of oncologic and non oncologic patients submitted to high risk elective surgery. METHODS: Prospective, observational cohort study realized in an ICU of a tertiary hospital during the period between 04/01/2005 and 07/31/2005. Demographic data, APACHE II and MODS scores and laboratorial and hemodynamic variables were collected and complications like re-intervention need for mechanical ventilation, red blood cell transfusions and pulmonary artery catheter use during the post-operative period were evaluated. All patients were followed until hospital discharge or death. T student and Mann Whitney tests were used to compare numerical variables. Chi-square test was used to compare categorical variables. A p < 0.05 was considered as significant. RESULTS: 119 patients were included in the study. 43 were oncologic and 76 were non-oncologic. 52.9 percent were female. Mean age was 65.1 ± 14.1 years. Mean APACHE II score was 16.5 ± 5.8 and MODS median was 3 (2-6). Median length of surgery was 5 (3.3-7) hours and ICU and hospital mortality were 10.9 percent and 25.2 percent, respectively. Oncologic patients had greater length of hospital stay and length of stay before surgery. These results were statistically significant. Hospital mortality of oncologic patients was not greater than non-oncologic patients (22.4 percent versus 30.2 percent, p = 0.32). CONCLUSIONS: In this series, oncologic patients submitted to high risk surgery had the same mortality rate as non-onconlogic patients with similar disease severity.

[Cancer disease should not be a limitative factor for admission of high risk surgical patients to an intensive care unit]. / A doença oncológica não deve ser um fator limitante para admissão na UTI de pacientes submetidos a cirurgias de alto risco.

BACKGROUND AND OBJECTIVES: Oncologic diseases are conditions that have influence in the treatment offered to affected patients. The aim of this study was to compare hospitalar outcome of oncologic and non oncologic patients submitted to high risk elective surgery. METHODS: Prospective, observational cohort study realized in an ICU of a tertiary hospital during the period between 04/01/2005 and 07/31/2005. Demographic data, APACHE II and MODS scores and laboratorial and hemodynamic variables were collected and complications like re-intervention need for mechanical ventilation, red blood cell transfusions and pulmonary artery catheter use during the post-operative period were evaluated. All patients were followed until hospital discharge or death. T student and Mann Whitney tests were used to compare numerical variables. Chi-square test was used to compare categorical variables. A p < 0.05 was considered as significant. RESULTS: 119 patients were included in the study. 43 were oncologic and 76 were non-oncologic. 52.9% were female. Mean age was 65.1 ± 14.1 years. Mean APACHE II score was 16.5 ± 5.8 and MODS median was 3 (2-6). Median length of surgery was 5 (3.3-7) hours and ICU and hospital mortality were 10.9% and 25.2%, respectively. Oncologic patients had greater length of hospital stay and length of stay before surgery. These results were statistically significant. Hospital mortality of oncologic patients was not greater than non-oncologic patients (22.4% versus 30.2%, p = 0.32). CONCLUSIONS: In this series, oncologic patients submitted to high risk surgery had the same mortality rate as non-onconlogic patients with similar disease severity.

[Hyperlactatemia at ICU admission is a morbid-mortality determinant in high risk non-cardiac surgeries]. / Hiperlactatemia à admissão na UTI é um determinante de morbimortalidade em intervenções cirúrgicas não cardíacas de alto risco.

BACKGROUND AND OBJECTIVES: One of the greatest challenges found by the intensivists in their daily activities is tissue hipoperfusion control. Blood lactate is generally accepted as a marker of tissular hypoxia and several studies have demonstrated good correlation between blood lactate and prognosis during shock and resuscitation. The aim of this study was to evaluate the clinical utility of arterial blood lactate as a marker of morbidity and mortality in critically ill patients in the post-operative period of high risk non-cardiac surgeries. METHODS: Prospective and observational cohort study realized in an ICU of a tertiary hospital during a four month period. Demographic data of the patients submitted to high risk surgeries were collected, besides arterial lactate measures and number and type of complications in the post-operative period. To the statistic analysis was considered as significant a p < 0.05. The predictive ability of the indexes to differentiate survivors from non-survivors was tested using ROC curves. Lenght of ICU stay estimation where calculated by Kaplan Meier method. RESULTS: Were included 202 patients. 50.2% were female and their mean age was 66.5 ± 13.6 years. APACHE II score was 17.4 ± 3.0 and the median of MODS score was 4 (2-6). Median lenght of surgeries was 4h (3-6h). 70.7% of the surgeries were elective ones. ICU and hospital mortality were 15.6% and 33.7%, respectively. The best lactate value to discriminate mortality was 3.2 mmol/L, with sensitivity of 62.5%, specificity of 78.8% and an area under the curve of 0.7. 62.5% of patients with lactate > 3.2 did not survive versus 21.2% of survivors (OR = 2.95 IC95% 1.98- 4.38, p < 0.0001). ICU lenght of stay was greater when > 3.2 mmol/L (log rank 0.007) lactate. CONCLUSIONS: High risk patients submitted to non cardiac surgeries and admitted to the ICU with hiperlactatemia, defined as an arterial lactate > 3.2 mmol/L, are prone to a longer ICU lenght of stay and to die.

Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis.

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease. Thus, we investigated the effects of acute and chronic exposure to increasing concentrations of amyloid beta (Abeta) on mitochondrial function and nitric oxide (NO) production in vitro and in vivo. Our data demonstrate that PC12 cells and human embryonic kidney cells bearing the Swedish double mutation in the amyloid precursor protein gene (APPsw), exhibiting substantial Abeta levels, have increased NO levels and reduced ATP levels. The inhibition of intracellular Abeta production by a functional gamma-secretase inhibitor normalizes NO and ATP levels, indicating a direct involvement of Abeta in these processes. Extracellular treatment of PC12 cells with comparable Abeta concentrations only leads to weak changes, demonstrating the important role of intracellular Abeta. In 3-month-old APP transgenic (tg) mice, which exhibit no plaques but already detectable Abeta levels in the brain, reduced ATP levels can also be observed showing the in vivo relevance of our findings. Moreover, we could demonstrate that APP is present in the mitochondria of APPsw PC12 cells. This presence might be directly involved in the impairment of cytochrome c oxidase activity and depletion of ATP levels in APPsw PC12 cells. In addition, APPsw human embryonic kidney cells, which produce 20-fold increased Abeta levels compared with APPsw PC12 cells, and APP tg mice already show a significantly decreased mitochondrial membrane potential under basal conditions. We suggest a hypothetical sequence of pathogenic steps linking mutant APP expression and amyloid production with enhanced NO production and mitochondrial dysfunction finally leading to cell death.

Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease.

Being major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and might therefore be particularly susceptible to oxidative injury. Mitochondrial damage may play a pivotal role in the cell death decision. Bolstered evidence indicates that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress occurring in Alzheimer's disease (AD) finally contributing to synaptic failure and neuronal degeneration. Accumulation and oligomerization of amyloid beta (Abeta) is also thought to play a central role in the pathogenesis of this disease by probably directly leading to mitochondrial dysfunction. Moreover, numerous lines of findings indicate increased susceptibility to apoptotic cell death and increased oxidative damage as common features in neurons from sporadic AD patients but also from familial AD (FAD) cases. Here we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote pathological events in AD. Finally, we emphasize a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, and Abeta production with mitochondrial dysfunction, caspase pathway, and neuronal loss.

Canine visceral leishmaniasis in Barra de Guaratiba, Rio de Janeiro, Brazil: assessment of risk factors.

Barra de Guaratiba is a coastal area of the city of Rio de Janeiro where American visceral leishmaniasis (AVL) is endemic. Although control measures including killing of dogs and use of insecticides have been applied at this locality, the canine seroprevalence remains at 25% and during 1995 and 1997 eight autochthonous human cases were notified. In order to evaluate factors related to the increase of the risk for Leishmania (Leishmania) chagasi infection in dogs we have screened 365 dogs by anti-Leishmania immunofluorescent antibody test (IFAT) and captured sandflies in the domestic and peridomestic environment. Some variables related to the infection were assessed by uni- and multivariate analysis. The distance of the residence from the forest border, its altitude and the presence of the opossum Didelphis marsupialis in the backyard, were found predictor factors for L. (L.) chagasi infection in dogs in Barra de Guaratiba. The presence of Lutzomyia longipalpis in the peridomestic environment indicates the possibility of appearence of new human cases. Our data also suggest the presence of a sylvatic enzootic cycle at this locality.

Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway.

Autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2. Simultaneously, evidence is provided that increased oxidative stress might play a crucial role in the rapid progression of the Swedish FAD. Here we investigated the effect of the Swedish double mutation (K670M/N671L) in the beta-amyloid precursor protein on oxidative stress-induced cell death mechanisms in PC12 cells. Western blot analysis and cleavage studies of caspase substrates revealed an elevated activity of the executor caspase 3 after treatment with hydrogen peroxide in cells containing the Swedish APP mutation. This elevated activity is the result of the enhanced activation of both intrinsic and extrinsic apoptosis pathways, including activation of caspase 2 and caspase 8. Furthermore, we observed an enhanced activation of JNK pathway and an attenuation of apoptosis by SP600125, a JNK inhibitor, through protection of mitochondrial dysfunction and reduction of caspase 9 activity. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a result of an increased vulnerability of neurons through activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress.

Canine visceral leishmaniasis in Barra de Guaratiba, Rio de Janeiro, Brazil: assessment of risk factors

Barra de Guaratiba is a coastal area of the city of Rio de Janeiro where American visceral leishmaniasis (AVL) is endemic. Although control measures including killing of dogs and use of insecticides have been applied at this locality, the canine seroprevalence remains at 25 percent and during 1995 and 1997 eight autochthonous human cases were notified. In order to evaluate factors related to the increase of the risk for Leishmania (Leishmania) chagasi infection in dogs we have screened 365 dogs by anti-Leishmania immunofluorescent antibody test (IFAT) and captured sandflies in the domestic and peridomestic environment. Some variables related to the infection were assessed by uni- and multivariate analysis. The distance of the residence from the forest border, its altitude and the presence of the opossum Didelphis marsupialis in the backyard, were found predictor factors for L. (L.) chagasi infection in dogs in Barra de Guaratiba. The presence of Lutzomyia longipalpis in the peridomestic environment indicates the possibility of appearence of new human cases. Our data also suggest the presence of a sylvatic enzootic cycle at this locality

Increased apoptotic cell death in sporadic and genetic Alzheimer's disease.

Mounting evidence indicates increased susceptibility to cell death and increased oxidative damage as common features in neurons from sporadic Alzheimer's disease (AD) patients but also from familial AD (FAD) cases. Autosomal dominant forms of FAD are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2 (PS1/2). We investigated the effect of the Swedish APP double mutation (APPsw) on oxidative stress-induced cell death mechanisms in PC12 cells. This mutation results in from three- to sixfold increased beta-amyloid (Abeta) production compared with wild-type APP (APPwt). Because APPsw cells secrete low Abeta levels similar to the situation in FAD brains, our cell model represents a very suitable approach to elucidate the AD-specific cell death pathways under more likely physiological conditions. We found that APPsw-bearing cells show decreased mitochondrial membrane potential after exposure to hydrogen peroxide. In addition, activity of the executor caspase 3 after treatment with hydrogen peroxide was elevated in APPsw cells, which seems to be the result of an enhanced activation of both intrinsic and extrinsic apoptosis pathways. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a consequence of an increased vulnerability of neurons by mitochondrial abnormalities resulting in activation of different apoptotic pathways as a consequence to elevated oxidative stress levels. Finally, we propose a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, Abeta production, mitochondrial dysfunction with caspase pathway, and neuronal loss.

Reduction of trophic support enhances apoptosis in PC12 cells expressing Alzheimer's APP mutation and sensitizes cells to staurosporine-induced cell death.

Mutations in the amyloid precursor protein (APP) gene are known as causative factors in the pathogenesis of early-onset familial Alzheimer's disease (FAD). In this study, the influence of the Swedish double-mutation form of APP (APPsw; KM670/671NL) on apoptosis regulation in PC12 cells was investigated. APPsw-transfected PC12 cells were compared with wild-type APP (APPwt)-expressing and vector-transfected PC12 cells with regard to their susceptibility to cell death induced by the reduction of trophic support or by additional treatment with staurosporine. Expression of APPsw markedly enhanced the level of apoptotic PC12 cells induced by serum reduction. A similar hypersensitivity of APPsw-expressing PC12 cells could be detected after differentiation with nerve growth factor under serum-reduced conditions. Likewise, the expression of APPsw rendered PC12 cells more vulnerable to staurosporine but only under serum-reduced conditions. This APPsw-effect disappeared in high serum-containing medium. Thus, expression of APPsw seems to enhance cellular sensitivity not in general but after the reduction of trophic factors probably by causing oxidative stress. This, in turn, may sensitize cells to secondary apoptotic stimuli. Moreover, the mutation-specific increase in vulnerability to cell death was only seen at the stage of apoptotic nuclei, but not using methods measuring cell death by determining metabolic activity or membrane integrity. Therefore, the expression of APPsw seems to affect specifically apoptotic cell death rather than overall cell death in vitro. Our study further emphasizes the pathogenic role of mutant APP and may provide new insights in the mechanisms underlying the massive neurodegeneration in brain from patients bearing the APPsw mutation.

Reducing risk factors for eating disorders: targeting at-risk women with a computerized psychoeducational program.

OBJECTIVE: This controlled study evaluated whether an 8-week program offered over the Internet would significantly decrease body image dissatisfaction, disordered eating patterns, and preoccupation with shape/weight among women at high risk for developing an eating disorder. METHOD: Fifty-six college women were recruited on the basis of elevated scores (> or =110) on the Body Shape Questionnaire (BSQ). Psychological functioning, as measured by the Eating Disorder Inventory Drive for Thinness (EDI-DT) subscale, Eating Disorder Examination-Questionnaire (EDE-Q), and the BSQ, was assessed at baseline, posttreatment, and at 10-week follow-up. RESULTS: All participants improved over time on most measures, although effect sizes suggest that the program did impact the intervention group. DISCUSSION: Findings suggest that technological interventions may be helpful for reducing disordered eating patterns and cognitions among high-risk women. Future research is needed to assess whether such programs are effective over time for prevention of and reduction in eating disorder symptomatology.

Reducing risk factors for eating disorders: comparison of an Internet- and a classroom-delivered psychoeducational program.

This controlled trial compared Internet- (Student Bodies [SB]) and classroom-delivered (Body Traps [BT]) psychoeducational interventions for the reduction of body dissatisfaction and disordered eating behaviors/attitudes with a control condition. Participants were 76 women at a private university who were randomly assigned to SB, BT, or a wait-list control (WLC) condition. Measures of body image and eating attitudes and behaviors were measured at baseline, posttreatment, and 4-month follow-up. At posttreatment, participants in SB had significant reductions in weight/shape concerns and disordered eating attitudes compared with those in the WLC condition. At follow-up, disordered behaviors were also reduced. No significant effects were found between the BT and WLC conditions. An Internet-delivered intervention had a significant impact on reducing risk factors for eating disorders.