The effect of overnight sleep deprivation after competitive rugby league matches on postmatch physiological and perceptual recovery

PURPOSE: This study examined the effects of overnight sleep deprivation on recovery following competitive rugby league matches. METHODS: Eleven male, amateur rugby league players performed two competitive matches, followed by either a normal night's sleep (~8h; CONT) or a sleep deprived night (~0h; SDEP) in a randomised fashion. Testing was conducted the morning of the match, and immediately post-match, 2h post and the next morning (16h post-match). Measures included counter-movement jump (CMJ) distance, knee extensor maximal voluntary contraction (MVC), voluntary activation (VA), venous blood creatine kinase (CK) and C-reactive protein (CRP), perceived muscle soreness and a word-colour recognition cognitive function test. Percent change between post- and 16h post-match was reported to determine the effect of the intervention the next morning. RESULTS: Large effects indicated a greater post- to 16h post-match percentage decline in CMJ distance following SDEP compared to CONT (P=0.10-0.16; d=0.95-1.05). Similarly, the percentage decline in incongruent word-colour reaction times were increased in SDEP trials (P=0.007; d=1.75). Measures of MVC did not differ between conditions (P=0.40-0.75; d=0.13-0.33), though trends for larger percentage decline in VA were detected in SDEP (P=0.19; d=0.84). Further, large effects indicated higher CK and CRP responses 16h post-match during SDEP compared to CONT (P=0.11-0.87; d=0.80-0.88). CONCLUSIONS: Sleep deprivation negatively affected recovery following a rugby league match, specifically impairing CMJ distance and cognitive function. Practitioners should promote adequate post-match sleep patterns or adjust training demands the next day to accommodate the altered physical and cognitive state following sleep deprivation.

Phase II trial of Oxaliplatin and 5-Fluorouracil/Leucovorin combination in epithelial ovarian carcinoma relapsing within 2 years of platinum-based therapy

Objective To evaluate the efficacy and toxicity of Oxaliplatin and 5-Fluorouracil (5-FU)/Leucovorin (LV) combination in ovarian cancer relapsing within 2 years of prior platinum-based chemotherapy in a phase II trial. Methods Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥ 60 IU/l, radiological evidence of disease progression and adequate hepatic, renal and bone marrow function. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Oxaliplatin (85 mg/m 2) was given on day 1, and 5-Fluorouracil (370 mg/m 2) and Leucovorin (30 mg) was given on days 1 and 8 of a 14-day cycle. Results Twenty-seven patients were enrolled. The median age was 57 years (range 42-74 years). The median platinum-free interval (PFI) was 5 months (range 0-17 months) with only 30% of patients being platinum sensitive (PFI > 6 months). Six patients (22%) had two prior regimens of chemotherapy. A total of 191 cycles were administered (median 7; range 2-12). All patients were evaluable for toxicity. The following grade 3/4 toxicities were noted: anemia 4%; neutropenia 15%; thrombocytopenia 11%; neurotoxicity 8%; lethargy 4%; diarrhea 4%; hypokalemia 11%; hypomagnesemia 11%. Among 27 enrolled patients, 20 patients were evaluable for response by WHO criteria and 25 patients were evaluable by Rustin's CA-125 criteria. The overall response rate (RR) by WHO criteria was 30% (95% CI: 15- 52) [three complete responses (CRs) and three partial responses (PRs)]. The CA-125 response rate was 56% (95% CI: 37-73). Significantly, a 25% (95% CI: 9-53) radiological and a 50% (95% CI: 28-72) CA-125 response rate were noted in platinum resistant patients (PFI < 6 months). The median response duration was 4 months (range 3-12) and the median overall survival was 10 months. Conclusion Oxaliplatin and 5-Fluorouracil/ Leucovorin combination has a good safety profile and is active in platinum-pretreated advanced epithelial ovarian cancer. © 2004 Elsevier Inc. All rights reserved.

Spirometric studies on the adult general population of Helsinki : bronchodilation responses, determinants, and intrasession repeatability of FEV1, FEV6, FVC, and forced expiratory time

Spirometry is the most widely used lung function test in the world. It is fundamental in diagnostic and functional evaluation of various pulmonary diseases. In the studies described in this thesis, the spirometric assessment of reversibility of bronchial obstruction, its determinants, and variation features are described in a general population sample from Helsinki, Finland. This study is a part of the FinEsS study, which is a collaborative study of clinical epidemiology of respiratory health between Finland (Fin), Estonia (Es), and Sweden (S). Asthma and chronic obstructive pulmonary disease (COPD) constitute the two major obstructive airways diseases. The prevalence of asthma has increased, with around 6% of the population in Helsinki reporting physician-diagnosed asthma. The main cause of COPD is smoking with changes in smoking habits in the population affecting its prevalence with a delay. Whereas airway obstruction in asthma is by definition reversible, COPD is characterized by fixed obstruction. Cough and sputum production, the first symptoms of COPD, are often misinterpreted for smokers cough and not recognized as first signs of a chronic illness. Therefore COPD is widely underdiagnosed. More extensive use of spirometry in primary care is advocated to focus smoking cessation interventions on populations at risk. The use of forced expiratory volume in six seconds (FEV6) instead of forced vital capacity (FVC) has been suggested to enable office spirometry to be used in earlier detection of airflow limitation. Despite being a widely accepted standard method of assessment of lung function, the methodology and interpretation of spirometry are constantly developing. In 2005, the ATS/ERS Task Force issued a joint statement which endorsed the 12% and 200 ml thresholds for significant change in forced expiratory volume in one second (FEV1) or FVC during bronchodilation testing, but included the notion that in cases where only FVC improves it should be verified that this is not caused by a longer exhalation time in post-bronchodilator spirometry. This elicited new interest in the assessment of forced expiratory time (FET), a spirometric variable not usually reported or used in assessment. In this population sample, we examined FET and found it to be on average 10.7 (SD 4.3) s and to increase with ageing and airflow limitation in spirometry. The intrasession repeatability of FET was the poorest of the spirometric variables assessed. Based on the intrasession repeatability, a limit for significant change of 3 s was suggested for FET during bronchodilation testing. FEV6 was found to perform equally well as FVC in the population and in a subgroup of subjects with airways obstruction. In the bronchodilation test, decreases were frequently observed in FEV1 and particularly in FVC. The limit of significant increase based on the 95th percentile of the population sample was 9% for FEV1 and 6% for FEV6 and FVC; these are slightly lower than the current limits for single bronchodilation tests (ATS/ERS guidelines). FEV6 was proven as a valid alternative to FVC also in the bronchodilation test and would remove the need to control duration of exhalation during the spirometric bronchodilation test.

Intrahepatic cholestasis of pregnancy : genetic background, epidemiology and hepatobiliary consequences

Intrahepatic cholestasis of pregnancy (ICP) is the most common cholestatic liver disease during pregnancy. The reported incidence varies from 0.4 to 15% of full-term pregnancies. The etiology is heterogeneous but familial clustering is known to occur. Here we have studied the genetic background, epidemiology, and long-term hepatobiliary consequences of ICP. In a register-based nation-wide study (n=1 080 310) the incidence of ICP was 0.94% during 1987-2004. A slightly higher incidence, 1.3%, was found in a hospital-based series (n=5304) among women attending the University Hospital of Helsinki in 1992-1993. Of these 16% (11/69) were familial and showed a higher (92%) recurrence rate than the sporadic (40%) cases. In the register-based epidemiological study, advanced maternal age and, to a lesser degree, parity were identified as new risk factors for ICP. The risk was 3-fold higher in women >39 years of age compared to women <30 years. Multiple pregnancy also associated with an elevated risk. In a genetic study we found no association of ICP with the genes regulating bile salt transport (ABCB4, ABCB11 and ATP8B1). The livers of postmenopausal women with a history of ICP tolerated well the short-term exposure to oral and transdermal estradiol, although the doses used were higher than those in routine clinical use. The response of serum levels of sex hormone-binding globulin (SHBG) to oral estradiol was slightly reduced in the ICP group. Transdermal estradiol had no effect on C-reactive protein (CRP) or SHBG. A number of liver and biliary diseases were found to be associated with ICP. Women with a history of ICP showed elevated risks for non-alcoholic liver cirrhosis (8.2 CI 1.9-36), cholelithiasis and cholecystitis (3.7 CI 3.2-4.2), hepatitis C (3.5 CI 1.6-7.6) and non-alcoholic pancreatitis (3.2 CI 1.7-5.7). In conclusion, ICP complicates around 1% of all full-term pregnancies in Finland and its incidence has remained unchanged since 1987. It is familial in 16% of cases with a higher recurrence rate. Although the cause remains unknown, several risk factors, namely advanced maternal age, parity and multiple pregnancies, can be identified. Both oral and transdermal regimens of postmenopausal hormone therapy (HT) are safe for women with a history of ICP when liver function is considered. Some ICP patients are at risk of other liver and biliary diseases and, contrary to what has been thought, a follow-up is warranted.

Antioxidant and antihepatotoxic effect of Spirulina laxissima against carbon tetrachloride induced hepatotoxicity in rats

The vast biodiversity of nature provides bioactive compounds that may be useful in the fight against chronic diseases. This study was designed to investigate the protective effects of the ethanol extract of Spirulina laxissima West (Pseudanabaenaceae) (EESL) against carbon tetrachloride (CCl4) induced hepatotoxicities in rats. Male albino rats of Sprague-Dawley strain were treated orally with the ethanol extract of S. laxissima (50, 100 mg kg(-1) body wt.) 1 h before each CCl4 administration. The ethanol extract of S. laxissima showed the maximum antioxidant property in vitro. There were statistically significant losses in the activities of antioxidant enzymes and an increase in TBARS and liver function marker enzymes in the serum of the CCl4-treated group compared with the control group. However, all the tested groups were able to counteract these effects. The antioxidant activity of the extracts might be attributable to its proton-donating ability, as evidenced by DPPH. In the present study, the decline in the level of antioxidant observed in CCl4-treated rats is a clear manifestation of excessive formation of radicals and activation of the lipid peroxidation system resulting in tissue damage. The significant increases in the concentration of antioxidant enzymes in tissues of animals treated with CCl4 + EESL indicate the antioxidant effect of EESL. This study suggests that EESL can protect the liver against CCl4-induced oxidative damage in rats, and the hepatoprotective effect might be correlated with its antioxidant and radical-scavenging effects.

Participação do estresse oxidativo na lesão pulmonar induzida por lipopolissacarídeo: repercussões inflamatórias estruturais e funcionais

O objetivo do presente estudo foi investigar o envolvimento do estresse oxidativo na lesão pulmonar aguda (LPA) induzida por lipopolissacarídeo (LPS) e as repercussões inflamatórias, estruturais e funcionais, através de análises bioquímicas de estresse oxidativo, prova de função pulmonar, análise histológica e RT-PCR para citocinas e fatores de transcrição pró-inflamatórios. Na primeira etapa foram utilizados camundongos machos C57BL6 foram divididos em sete grupos: Grupo controle (CTR) (50 μL de solução fisiológica) administrados via intratraqueal [it], LPS 6 horas (10 μL de LPS) [it], LPS 12 horas (10 μL de LPS) [it], LPS 24 horas (10 μL de LPS) [i], LPS 48 horas (10 μL de LPS). Para verificar que as alterações observadas eram estresse oxidativo dependentes camundongos machos C57BL6 foram pré-tratados com N-acetilcisteína (NAC) 1 hora antes do estímulo com LPS e sacrifícados 24 horas depois do estímulo com LPS. Os animais foram divididos da seguinte forma: Grupo LPS 24 horas (10 μL) [it], grupo NAC 40 mg/kg (gavagem) + LPS (10 μL) [it] e grupo NAC 100 mg/kg (gavagem) + LPS (10 μL) [it]. O sistema antioxidante enzimático protegeu o pulmão do estresse oxidativo nas primeiras 12 horas. O estresse oxidativo foi caracterizado em 24 horas e em 48 horas observou-se falência do sistema antioxidante enzimático. Parâmetros de função pulmonar se mostraram alterados nos grupo estimulados com LPS principalmente no grupo LPS. A elastância (p<0,001), resistência de via aérea periférica (ΔP2) (p<0,001), resistência de via aérea central (ΔP1) (p<0,001) e resistência de via aérea total (ΔPtot) (p<0,001) se mostraram principlamente alteradas no grupo LPS 24 horas. O pré-tratamento com NAC impediu o aumento dos parâmetros de elastância (p<0,001), resistência de via aérea periférica (ΔP2) (p<0,001) resistência de via aérea central (ΔP1) (p<0,05) e resistência de via aérea total (ΔPtot) (p<0,001) comparado com o grupo LPS 24 horas. As alterações histológicas como espessamento de septo alveolar, influxo de células inflamatórias e hemorragia mostraram-se tempo dependentes. O pré-tratamento NAC impediu as alterações observadas nos grupo estimulados com LPS. Alterações inflamatórias foram observadas no grupo estimulado com LPS como IL-6 (p<0,001), iNOS (p<0,001), COX2 (p<0,05), TNF-α (p<0,001) e NFκB (p<0,001) quando comparados ao grupo controle. O pré-tratamento com NAC impediu o aumento desses parâmetros como IL-6 (p<0,001), iNOS (p<0,001), COX2 (p<0,05), TNF-α (p<0,05) e NFκB (p<0,001) quando comparados ao grupo LPS 24 horas. Nossos resultados sugerem que o estresse oxidativo desempenha um papel importante nas respostas inflamatórios, estruturais e funcionais no modelo de LPA induzido por LPS e que essas alterações são estresse oxidativo dependentes.

Custo efetividade do uso do Peguinterferon alfa 2a combinado com Ribavirina no tratamento de respondedores virológicos lentos coinfectados com VHC/HIV

No mundo, as hepatites decorrentes de infecções virais têm sido uma das grandes preocupações em saúde pública devido a seu caráter crônico, curso assintomático e pela sua capacidade de determinar a perda da função hepática. Com o uso em larga escala de medicamentos antirretrovirais, a doença hepática relacionada à infecção pelo vírus da hepatite C (VHC) contribuiu para uma mudança radical na história natural da infecção pelo vírus da imunodeficiência humana (HIV). Não se sabe ao certo o peso da coinfecção VHC/HIV no Brasil, mas evidências apontam que independentemente da região geográfica, esses indivíduos apresentam maiores dificuldades em eliminar o VHC após o tratamento farmacológico, quando comparados a monoinfectados. No âmbito do SUS, o tratamento antiviral padrão para portadores do genótipo 1 do VHC e do HIV é a administração de peguinterferon associado à Ribavirina. Quanto ao período de tratamento e aos indivíduos que devem ser incluídos, os dois protocolos terapêuticos mais recentes possuem divergências. A diretriz mais atual preconiza o tratamento de indivíduos respondedores precoces somados a respondedores virológicos lentos, enquanto a diretriz imediatamente anterior exclui na 12 semana indivíduos que não respondem completamente. Com base nessa divergência, esse estudo objetivou avaliar o custo-efetividade do tratamento contra o VHC em indivíduos portadores do genótipo 1, coinfectados com o HIV, virgens de tratamento antiviral, não cirróticos e imunologicamente estabilizados, submetidos às regras de tratamento antiviral estabelecidos pelas duas mais recentes diretrizes terapêuticas direcionadas ao atendimento pelo SUS. Para tal, foi elaborado um modelo matemático de decisão, baseado em cadeias de Markov, que simulou a progressão da doença hepática mediante o tratamento e não tratamento. Foi acompanhada uma coorte hipotética de mil indivíduos homens, maiores de 40 anos. Adotou-se a perspectiva do Sistema Único de Saúde, horizonte temporal de 30 anos e taxa de desconto de 5% para os custos e consequências clínicas. A extensão do tratamento para respondedores lentos proporcionou incremento de 0,28 anos de vida ajustados por qualidade (QALY), de 7% de sobrevida e aumento de 60% no número de indivíduos que eliminaram o VHC. Além dos esperados benefícios em eficácia, a inclusão de respondedores virológicos lentos mostrou-se uma estratégia custo-efetiva ao alcançar um incremental de custo efetividade de R$ 44.171/QALY, valor abaixo do limiar de aceitabilidade proposto pela Organização Mundial da Saúde OMS - (R$ 63.756,00/QALY). A análise de sensibilidade demonstrou que as possíveis incertezas contidas no modelo são incapazes de alterar o resultado final, evidenciando, assim, a robustez da análise. A inclusão de indivíduos coinfectados VHC/HIV respondedores virológicos lentos no protocolo de tratamento apresenta-se, do ponto de vista fármaco-econômico, como uma estratégia com relação de custoefetividade favorável para o Sistema Único de Saúde. Sua adoção é perfeitamente compatível com a perspectiva do sistema, ao retornar melhores resultados em saúdeassociados a custos abaixo de um teto orçamentário aceitável, e com o da sociedade, ao evitar em maior grau, complicações e internações quando comparado à não inclusão.

Análise do processo sinérgico da deglutição em pacientes portadores de bronquiectasia atendidos no Hospital Universitário Pedro Ernesto

A respiração e a deglutição são vitais para o homem. Enquanto a primeira diz respeito a um ato primitivo da vida, a hematose, a segunda trata da manutenção da vida, oferecendo a energia necessária, nutrindo e hidratando, perpassando pelo prazer alimentar, ato tão importante na sociedade contemporânea. A relação funcional entre essas funções ainda não foi totalmente elucidada, porém é crescente o interesse e o número de estudos sobre esta temática. Considerando que a deglutição eficiente tem como pressuposto a capacidade de proteger via aérea inferior, a alteração de deglutição primária ou secundária a um dano pulmonar pode trazer repercussões severas para a integridade do sistema respiratório. O objetivo desse estudo é analisar o processo sinérgico da deglutição em portadores de bronquiectasia, a fim de verificar se há alteração na fisiologia da deglutição e caracterizá-la, assim como, identificar se há correspondência entre alteração da função pulmonar e alteração da deglutição.Para tal foram selecionados randomicamente 30 pacientes na faixa etária de 18 a 65 anos, atendidos no ambulatório de bronquiectasia do HUPE. Destes, 26 indivíduos responderam a um questionário dirigido sobre hábitos alimentares e possíveis dificuldades de alimentação; foram submetidos à avaliação clínica da deglutição; 22 fizeram espirometria no setor de prova de função pulmonar no HUPE e 17 avaliação videofluoroscópica da deglutição. Dos 26 indivíduos estudados 10 eram homens e 16 mulheres, com média de idade de 46,3 anos. Na avaliação clínica da deglutição observaram-se alterações estruturais e funcionais em todos os indivíduos estudados. As principais alterações estruturais detectadas referem-se e a dinâmica laríngea; enquanto na avaliação funcional detectou-se alterações referentes à ejeção oral, dinâmica hiolaríngea, trânsito faríngeo e presença de deglutições múltiplas. Com relação à espirometria 06 indivíduos apresentaram distúrbio obstrutivo leve; 04 distúrbio obstrutivo moderado e 09 distúrbio obstrutivo acentuado. A videofluoroscopia da deglutição corroborou os achados da avaliação clínica da deglutição e evidenciou episódios de penetração e aspiração laríngea Pode-se concluir que: (1) a avaliação clínica da deglutição associada à avaliação videofluoroscópica são métodos eficientes para a análise do processo sinérgico da deglutição; (2) identificou-se alteração do processo sinérgico da deglutição, nos indivíduos avaliados; (3) a ausculta cervical isoladamente, não demonstrou ser um método eficiente para predizer aspiração e/ou penetração laringotraqueal; (4) houve correspondência entre os resultados da avaliação clínica funcional da deglutição e videofluoroscópica, exceto quanto a presença de penetração e/ou aspiração e quanto a capacidade de avaliar a ejeção oral; (5) não foi possível identificar se há correspondência entre alteração da função pulmonar e processo sinérgico da deglutição.

Estudo do efeito do transplante de células mononucleares de medula óssea na bioenergética mitocondrial de ratos com fibrose hepática

A disfunção mitocondrial tem sido associada a várias doenças, incluindo a colestase hepática, caracterizada pela ativação de células de Kupffer e células fibrogênicas, as quais produzem matriz extracelular excessiva. O acúmulo de sais biliares tóxicos no parênquima hepático leva à lesão crônica com dano mitocondrial, redução da síntese de ATP, aumento de espécies reativas de oxigênio (ROS) e apoptose, resultando em comprometimento da função hepática. Trabalhos anteriores do nosso grupo mostraram o efeito positivo do transplante de células mononucleares da medula óssea (CMMO) na resolução da fibrose hepática e recuperação da função hepática em ratos com colestase, induzida pela ligadura de ducto biliar (LDB). Assim, o presente estudo teve como objetivo analisar a bioenergética mitocondrial após o transplante de CMMO no fígado de ratos com fibrose induzida por ligadura de ducto bilar (LDB). Ratos Wistar machos foram divididos em quatro grupos: animais normais, animais com fibrose hepática após 14 e 21 dias de LDB (F14d e F21d, respectivamente), e animais que após 14 dias de LDB receberam 1x107 CMMO, e foram eutanasiados sete dias após. Nossos dados demonstraram aumento do conteúdo de colágeno tipo I no grupo F21d em relação ao grupo normal, indicativo de fibrose, e sua diminuição após o transplante de CMMO. A análise da fisiologia mitocondrial do fígado mostrou diminuição significativa da taxa respiratória máxima estimulada por ADP (estado 3) nos grupos F14d e F21d, indicando redução da capacidade de oxidação de carboidratos e ácidos graxos. Além disso, a razão do controle respiratório (RCR), indicativa de acoplamento da fosforilação oxidativa com a produção de ATP, apresentou-se significativamente diminuída nos grupos F14d e F21d, sugerindo desacoplamento mitocondrial. No entanto, o transplante de CMMO aumentou significativamente nestes grupos tanto a capacidade oxidativa quanto o acoplamento mitocondrial a níveis semelhantes aos do grupo normal. Estes resultados foram confirmados por análise de western blotting, que mostrou aumento significativo no conteúdo de UCP2 e diminuição do conteúdo de PGC-1α no grupo F21d, com consequente restauração após o transplante de CMMO. Além disso, os resultados mostraram um aumento significativo do conteúdo de 4-HNE no grupo F14d com redução após o transplante CMMO. Assim, podemos concluir que o transplante de CMMO tem um efeito positivo sobre a bioenergética mitocondrial de fígados de ratos com colestase, com aumento da capacidade oxidativa e redução do estresse oxidativo, o que, por sua vez, contribui para a recuperação da função hepática.

基于安全策略模型的安全功能测试用例生成方法

实施第三方安全功能独立测试是信息安全产品测评中的一个重要环节,对于以安全数据库管理系统为代表的信息安全产品,其系统规约的测试并不能完全真实反映系统行为,还需要满足系统安全策略.提出了基于安全策略模型的安全功能测试用例自动生成方法,该方法包括基于语法的划分、基于规则的划分、基于类型的划分等步骤,依据形式化安全模型生成正确描述系统行为的操作测试用例集.该方法有助于提高测试质量,发现手工测试中难以发现的缺陷,并有助于减少测试过程中的重复劳动,实现测试自动化并提高测试效率.

Blood and urinary abnormalities induced during and after 24-hour continuous running: A case report

In this reported clinical case, a healthy and well-trained male subject [aged 37 years, maximal oxygen uptake (V[Combining Dot Above]O2max) 64 mL·kg·min] ran for 23 hours and 35 minutes covering 160 km (6.7 km/h average running speed). The analysis of hematological and biochemical parameters 3 days before the event, just after termination of exercise, and after 24 and 48 hours of recovery revealed important changes on muscle and liver function, and hemolysis. The analysis of urine sediments showed an increment of red and white blood cells filtrations, compatible with transient nephritis. After 48 hours, most of these alterations were recovered. Physicians and health professionals who monitor such athletic events should be aware that these athletes could exhibit transient symptoms compatible with severe pathologies and diseases, although the genesis of these blood and urinary abnormalities are attributable to transient physiological adaptations rather to pathological status.

A phase I study of the Heat Shock Protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced, solid tumours.

PURPOSE: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). PATIENTS AND METHODS: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which = 1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. RESULTS: Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P

A pilot study to evaluate aflatoxin exposure in a rural Ugandan population

Objectives: The fungal metabolite aflatoxin is a common contaminant of foodstuffs, especially when stored in damp conditions. In humans, high levels can result in acute hepatic necrosis and death, while chronic exposure is carcinogenic. We conducted a pilot study nested within an existing population cohort (the General Population Cohort), to assess exposure to aflatoxin, among people living in rural south-western Uganda. Methods: Sera from 100 adults and 96 children under 3 years of age (85 male, 111 female) were tested for aflatoxin-albumin adduct (AF-alb), using an ELISA assay. Socio-demographic and dietary data were obtained for all participants; HIV serostatus was available for 90 adults and liver function tests (LFTs) for 99. Results: Every adult and all but four children had detectable AF-alb adduct, including five babies reported to be exclusively breastfed. Levels ranged from 0 to 237.7 pg/mg albumin and did not differ significantly between men and women, by age or by HIV serostatus; 25% had levels above 15.1 pg/mg albumin. There was evidence of heterogeneity between villages (P = 0.003); those closest to trading centres had higher levels. Adults who consumed more Matooke (bananas) had lower levels of AF-alb adduct (P = 0.02) than adults who did not, possibly because their diet contained fewer aflatoxin-contaminated foods such as posho (made from maize). Children who consumed soya, which is not grown locally, had levels of AF-alb adduct that were almost twice as high as those who did not eat soya (P = 0.04). Conclusions: Exposure to aflatoxin is ubiquitous among the rural Ugandans studied, with a significant number of people having relatively high levels. Sources of exposure need to be better understood to instigate practical and sustainable interventions. © 2014 John Wiley & Sons Ltd.

Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis

Background This study evaluated the effect of statins in Primary biliary cirrhosis (PBC) on endothelial function, anti-oxidant status and vascular compliance. Methods Primary biliary cirrhosis patients with hypercholesterolaemia were randomized to receive 20mg simvastatin or placebo in a single blind, randomized controlled trial. Body mass index, blood pressure, glucose, liver function, lipid profile, immunoglobulin levels, serological markers of endothelial function and anti-oxidant status were measured as well as vascular compliance, calculated from pulse wave analysis and velocity, at recruitment and again at 3, 6, 9 and 12months. Results Twenty-one PBC patients (F=20, mean age = 55) were randomized to simvastatin 20mg (n=11) or matched placebo (n=10). At completion of the trial, serum cholesterol levels in the simvastatin group were significantly lower compared with the placebo group (4.91mmol/L vs. 6.15mmol/L, P=0.01). Low-density lipoprotein (LDL) levels after 12months were also significantly lower in the simvastatin group (2.33mmol/L vs. 3.53mmol/L, P=0.01). After 12months of treatment, lipid hydroperoxides were lower (0.49mol/L vs. 0.59mol/L, P=0.10) while vitamin C levels were higher (80.54mol/L vs. 77.40mol/L, P=0.95) in the simvastatin group. Pulse wave velocity remained similar between treatment groups at 12months (8.45m/s vs. 8.80m/s, P=0.66). Only one patient discontinued medication owing to side effects. No deterioration in liver transaminases was noted in the simvastatin group. Conclusions Statin therapy in patients with PBC appears safe and effective towards overall reductions in total cholesterol and LDL levels. Our initial study suggests that simvastatin may also confer advantageous effects on endothelial function and antioxidant status.