Phenotypic variability in a family with x-linked adrenoleukodystrophy caused by the p.Trp132Ter mutation

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease with clinical heterogeneity varying from presymptomatic individuals to rapidly progressive cerebral ALD forms. This disease is characterized by increased concentration of very long chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues. Affected individuals can be classified in different clinical settings, according to phenotypic expression and age at onset of initial symptoms. Molecular defects in X-ALD individuals usually result from ABCD1 gene mutations. In the present report we describe clinical data and the ABCD1 gene study in two boys affected with the childhood cerebral form that presented with different symptomatic manifestations at diagnosis. In addition, their maternal grandfather had been diagnosed with Addison's disease indicating phenotypic variation for X-ALD within this family. The mutation p.Trp132Ter was identified in both male patients; additionally, three females, out of eleven family members, were found to be heterozygous after screening for this mutation. In the present report, the molecular analysis was especially important since one of the heterozygous females was in first stages of pregnancy. Therefore, depending on the fetus outcome, if male and p.Trp132Ter carrier, storage of the umbilical cord blood should be recommended as hematopoietic stem cell transplantation could be considered as an option for treatment in the future.

Contribution Of Antepartum And Intrapartum Hemorrhage To The Burden Of Maternal Near Miss And Death In A National Surveillance Study

Objective To evaluate the occurrence of severe obstetric complications associated with antepartum and intrapartum hemorrhage among women from the Brazilian Network for Surveillance of Severe Maternal Morbidity.Design Multicenter cross-sectional study.Setting Twenty-seven obstetric referral units in Brazil between July 2009 and June 2010.Population A total of 9555 women categorized as having obstetric complications.Methods The occurrence of potentially life-threatening conditions, maternal near miss and maternal deaths associated with antepartum and intrapartum hemorrhage was evaluated. Sociodemographic and obstetric characteristics and the use of criteria for management of severe bleeding were also assessed in these women.Main outcome measures The prevalence ratios with their respective 95% confidence intervals adjusted for the cluster effect of the design, and multiple logistic regression analysis were performed to identify factors independently associated with the occurrence of severe maternal outcome.Results Antepartum and intrapartum hemorrhage occurred in only 8% (767) of women experiencing any type of obstetric complication. However, it was responsible for 18.2% (140) of maternal near miss and 10% (14) of maternal death cases. On multivariate analysis, maternal age and previous cesarean section were shown to be independently associated with an increased risk of severe maternal outcome (near miss or death).Conclusion Severe maternal outcome due to antepartum and intrapartum hemorrhage was highly prevalent among Brazilian women. Certain risk factors, maternal age and previous cesarean delivery in particular, were associated with the occurrence of bleeding.

Efeitos da administração diária da associação estavudina/nelfinavir sobre os fetos e placentas da rata albina

OBJETIVO: avaliar o efeito da administração da associação estavudina/nelfinavir durante toda a prenhez da rata, avaliando seu peso e dos conceptos, bem como o número de implantações, fetos, placentas, reabsorções e mortalidades materna e fetal. MÉTODOS: quarenta ratas albinas EPM-1 Wistar, prenhes, foram aleatoriamente divididas em quatro grupos: GCtrl (controle do veículo) e três experimentais, ExpI, ExpII e ExpIII, que receberam, respectivamente, 1/40, 3/120 e 9/360 mg/kg por dia de estavudina/nelfinavir por via oral. As drogas e o veículo (água destilada) foram administrados por gavagem em duas tomadas diárias (12/12 horas), desde o dia 0 até o 20º dia da prenhez. No último dia do experimento, todos os animais foram anestesiados e eutanasiados. Foram avaliados a evolução do peso materno no 7º, 14º e 20º dias, número de fetos, placentas, implantações, reabsorções, óbitos intrauterinos, malformações maiores e o peso dos fetos e das placentas. A análise estatística foi realizada por análise de variância (ANOVA), complementada pelo teste de Kruskal-Wallis (p<0,05). RESULTADOS: em relação ao peso corporal das ratas, houve ganho gradual e progressivo durante o decorrer da prenhez em todos os grupos, sendo este ganho mais evidente no período final; porém não foram constatadas diferenças estatisticamente significantes entre eles. O número de fetos, placentas, implantações, assim como os pesos fetais e placentários também não mostraram diferenças estatisticamente significantes entre os grupos analisados. Não foram observadas, também nos grupos experimentais, reabsorções e malformações fetais maiores externas, no entanto, observamos entre o 8º e o 14º dias de gestação um caso de morte materna em cada grupo experimental. CONCLUSÕES: a administração da associação estavudina/nelfinavir não mostrou efeitos deletérios sobre os conceptos.

Tratamento farmacológico da DPOC

Aproximadamente sete milhões de brasileiros acima de 40 anos são acometidos pela DPOC. Nos últimos anos, importantes avanços foram registrados no campo do tratamento medicamentoso dessa condição. Foi realizada uma revisão sistemática incluindo artigos originais sobre tratamento farmacológico da DPOC publicados entre 2005 e 2009, indexados em bases de dados nacionais e internacionais e escritos em inglês, espanhol ou português. Artigos com tamanho amostral menor de 100 indivíduos foram excluídos. Os desfechos sintomas, função pulmonar, qualidade de vida, exacerbações, mortalidade e efeitos adversos foram pesquisados. Os artigos foram classificados segundo o critério da Global Initiative for Chronic Obstructive Lung Disease para nível de evidência científica (grau de recomendação A, B e C). Dos 84 artigos selecionados, 40 (47,6%), 18 (21,4%) e 26 (31,0%) foram classificados com graus A, B e C, respectivamente. Das 420 análises oriundas desses artigos, 236 referiam-se à comparação de fármacos contra placebo nos diversos desfechos estudados. Dessas 236 análises, os fármacos mais frequentemente estudados foram anticolinérgicos de longa duração, a combinação β2-agonistas de longa duração + corticosteroides inalatórios e corticosteroides inalatórios isolados em 66, 48 e 42 análises, respectivamente. Nas mesmas análises, os desfechos função pulmonar, efeitos adversos e sintomas geraram 58, 54 e 35 análises, respectivamente. A maioria dos estudos mostrou que os medicamentos aliviaram os sintomas, melhoraram a qualidade de vida, a função pulmonar e preveniram as exacerbações. Poucos estudos contemplaram o desfecho mortalidade, e o papel do tratamento medicamentoso nesse desfecho ainda não está completamente definido. Os fármacos estudados são seguros no manejo da DPOC, com poucos efeitos adversos.

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC50 to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC50 of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.

Recommendations for folate intake in women: implications for public health strategies

Folate deficiency has been associated with anemia and other adverse outcomes in pregnancy such as neural tube defects. The current recommendations for prevention of such outcomes are difficult to achieve through diet only, and folic acid supplementation and food fortification are feasible public health strategies. However, it is necessary to determine the usual diet and supplement use among women of reproductive age, including an accurate assessment of other dietary micronutrients. In addition to the beneficial effects observed in randomized clinical trials, health risks to the population have also been widely evaluated and discussed in the scientific community: for a minority to benefit from fortification programs, many are exposed to high folic acid intake levels.

Influência do consumo alimentar na gestação sobre a retenção de peso pós-parto

OBJETIVO: Avaliar a influência da alimentação durante a gestação sobre a retenção de peso pós-parto. MÉTODOS: Foram acompanhadas 82 gestantes adultas e saudáveis que iniciaram o pré-natal em serviço público de saúde no Município de São Paulo, SP, entre abril e junho de 2005. As medidas de peso e estatura foram aferidas na primeira entrevista (até 16 semanas de gestação) e a medida de peso foi repetida em visita domiciliar 15 dias após o parto. O Recordatório de 24 horas foi usado para avaliar o consumo alimentar e foi aplicado nos três trimestres da gestação. Foi calculado o consumo médio de gordura saturada, fibras, açúcar adicionado, refrigerantes, alimentos processados, frutas, verduras e legumes, e a densidade energética da dieta. A retenção de peso foi obtida pela diferença entre a medida de peso pós-parto e a primeira medida realizada. A influência da alimentação sobre a retenção de peso pós-parto foi avaliada por meio de análise de regressão linear múltipla e foi realizado o teste para tendência linear. As variáveis utilizadas para ajuste do modelo foram: índice de massa corporal no início da gestação, estatura, renda familiar per capita, tabagismo, idade e escolaridade. RESULTADOS: O índice de massa corporal inicial médio foi de 24 kg/m² e a retenção média de peso foi de 1,9 kg. O aumento do consumo de gordura saturada (p = 0,005) e alimentos processados (p = 0,014) elevou de forma significativa a retenção de peso pós-parto, após ajuste pelas variáveis de controle. As demais variáveis de consumo alimentar não apresentaram relação significativa com a variável desfecho. CONCLUSÕES: O maior consumo de alimentos não saudáveis, como alimentos processados, e de gordura saturada influencia a elevação da retenção de peso pós-parto.

On the interference of clinical outcome on rabies transmission an perpetuation

Rabies is a viral zoonotic infectious disease that affects mammals and is caused by genotypes/species of the Lyssavirus genus (Rhabdoviridae, Mononegavirales), with the genotype 1 (classic rabies virus - RABV) being the most prevalent. Despite continuous efforts, rabies is still an incurable disease that causes thousands of deaths amongst humans worldwide. Due to a wide range of hosts and the different evolutionary paths of RABV in each host, several host-specific variants have arisen in an ongoing process. The result of RABV replication in nervous tissues may lead to two opposite clinical outcomes, i.e., paralytic/dumb form and encephalitic/furious one. The paralytic form creates dead-end hosts mainly amongst herbivores, while the furious form of the disease allows for augmented transmission when manifested in gregarious carnivores, as their natural aggressive behavior is accentuated by the disease itself. The aim of this article is to propose a theoretical model intended to explore how the rabies virus intrinsically modulates the immune system of different host classes, the pathological changes that the virus causes in these animals and how these elements favor its own perpetuation in nature, thus providing a basis for better prediction of the patterns this disease may present.

Neurobehavioral, reflexological and physical development of Wistar rat offspring exposed to ayahuasca during pregnancy and lactation

Ayahuasca is a hallucinogenic beverage prepared by the decoction of plants native to the Amazon Basin region. The beverage has been used throughout the world by members of some syncretic religious movements. Despite the recent legalization of ayahuasca in Brazil for religious purposes, there is little pre-clinical and clinical information attesting to its safety, particularly in relation to the use during pregnancy. The aim of the current work was to determine the effects of perinatal exposure to ayahuasca (from the 6th day of pregnancy to the 10th day of lactation) on physical, reflexology and neurobehavioral parameters of the Wistar rat offspring. The offspring showed no statistically significant changes in the physical and reflexology parameters evaluated. However, in adult rats, perinatally exposed to ayahuasca, an increase in frequency of entries in open arms in elevated plus-maze test, a decrease in total time of interaction in social interaction test, a decrease in time of latency for the animal to start swimming and a decrease of the minimum convulsant dose induced by pentylenetetrazol were observed. In conclusion, our results showed that the use of ayahuasca by mothers during pregnancy and lactation reduced the general anxiety and social motivation of the rat offspring. Besides, it promoted a higher sensitivity for initiation and spread of seizure activity.

Surveillance for adverse events after DTwP/Hib vaccination in Brazil: sensitivity and factors associated with reporting

We estimated the sensitivity, i.e., the proportion of all cases of adverse events following immunization (AEFIs) reported to the Brazilian passive surveillance for adverse events following immunization (PSAEFI) with the diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae type b (DTwP-Hib) vaccine, as well as investigating factors associated with AEFIs reporting. During 2003–2004, 8303 AEFIs associated with DTwP-Hib were reported; hypotonic-hyporesponsive episodes (HHEs), fever and convulsions being the most common. Cure without sequel was achieved in 98.4 per cent of the cases. The mean sensitivity of the PSAEFI was 22.3 per cent and 31.6 per cent, respectively, for HHE and convulsions, varying widely among states. Reporting rates correlated positively with the Human Development Index and coverage of adequate prenatal care, correlating negatively with infant mortality rates. Quality of life indicators and the degree of organization of health services are associated with greater PSAEFI sensitivity. In addition to consistently describing the principal AEFIs, PSAEFI showed the DTwP/Hib vaccine to be safe and allayed public fears related to its use

The relationship between cortisol concentrations in pregnancy and systemic vascular resistance in childhood

Objective. To assess the relationship between cortisol concentrations in the last trimester of pregnancy and systemic vascular resistance — SVR in childhood. Materials and methods. This study is part of a cohort involving 130 Brazilian pregnant women and their children, ages 5 to 7 years. Maternal cortisol was determined in saliva by an enzyme immunoassay utilizing the mean concentration of 9 samples of saliva (3 in each different day), collected at the same time, early in the morning. SVR was assessed by the HDI/PulseWave CR-2000 Cardiovascular Profiling System®. Socioeconomic and demographic characteristics and life style factors were determined by a questionnaire. The nutritional status of the women and children was assessed by the body mass index — BMI. The association between maternal cortisol and SVR in childhood was calculated by multivariate linear regression analysis. Results.There were statistically significant associations between maternal cortisol and SVR (p = 0.043) and BMI-z score of the children (p = 0.027), controlling for maternal BMI, birth weight, age, and gender of the children. Conclusion. As far as we know this is the first study in the literature assessing the association between cortisol concentrations in pregnancy and SVR in childhood. Overall, the data suggest that exposure to excess glucocorticoid in the prenatal period is associated to vascular complications in childhood, predisposing to cardiovascular diseases in later life

Motor Nerve-Conduction Studies in Obstetric Brachial Plexopathy for a Selection of Patients with a Poor Outcome

Background: The criteria and timing for nerve surgery in infants with obstetric brachial plexopathy remain controversial. Our aim was to develop a new method for early prognostic assessment to assist this decision process. Methods: Fifty-four patients with unilateral obstetric brachial plexopathy who were ten to sixty days old underwent bilateral motor-nerve-conduction studies of the axillary, musculocutaneous, proximal radial, distal radial, median, and ulnar nerves. The ratio between the amplitude of the compound muscle action potential of the affected limb and that of the healthy side was called the axonal viability index. The patients were followed and classified in three groups according to the clinical outcome. We analyzed the receiver operating characteristic curve of each index to define the best cutoff point to detect patients with a poor recovery. Results: The best cutoff points on the axonal viability index for each nerve (and its sensitivity and specificity) were <10% (88% and 89%, respectively) for the axillary nerve, 0% (88% and 73%) for the musculocutaneous nerve, <20% (82% and 97%) for the proximal radial nerve, <50% (82% and 97%) for the distal radial nerve, and <50% (59% and 97%) for the ulnar nerve. The indices from the proximal radial, distal radial, and ulnar nerves had better specificities compared with the most frequently used clinical criterion: absence of biceps function at three months of age. Conclusions: The axonal viability index yields an earlier and more specific prognostic estimation of obstetric brachial plexopathy than does the clinical criterion of biceps function, and we believe it may be useful in determining surgical indications in these patients.

Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study

The occurrence of chronic myeloid leukemia in pregnancy is rare and its management poses a clinical challenge for physicians treating these patients. We report a 30-year-old woman with chronic myeloid leukemia who became pregnant twice successfully. Philadelphia-positive CML in its chronic phase was diagnosed at 16 weeks of her first gestation. At that time, she received no treatment throughout her pregnancy. At 38 weeks of gestation, a normal infant was delivered by cesarean section. At six weeks postpartum, the patient underwent imatinib mesylate therapy but she could not tolerate the treatment. The treatment was then changed to nilotinib at 400 mg orally b.i.d. Two years later, she became pregnant again while she was on nilotinib 200 mg b.i.d. The unplanned pregnancy was identified during her 7.4 weeks of gestation. Because the patient elected to continue her pregnancy, nilotinib was stopped immediately, and no further treatment was given until delivery. Neither obstetrical complications nor structural malformations in neonates in both pregnancies were observed. Both babies' growth and development have been normal. Although this experience is limited to a single patient, the success of this patient demonstrates that the management of chronic myeloid leukemia in pregnant women may be individualized based on the relative risks and benefits of the patient and fetus.

The effect of laparoscopy access and antibiotics on the outcome of severe bacterial peritonitis in rats

Introduction: Treatment of severe bacterial peritonitis, especially by videolaparoscopy, is still a matter of investigation. The aim of the present study was to evaluate the effect of videolaparoscopy and laparotomy access with or without antibiotics on the outcome of severe bacterial peritonitis in rats. Materials and Methods: Sixty-four male Wistar rats were equally assigned to 8 groups: Sham surgery (SHAM), SHAM+antibiotics (SHAM+AB), cecal ligation and puncture (CLP), CLP+AB, CLP+videolaparoscopy (VLAP), CLP+laparotomy (LAP), VLAP+AB, and LAP+AB. All treated animals were submitted to an evaluation of bacteremia, white cell counts, and cytokine determinations: interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha). The groups treated with antibiotics received gentamicin and metronidazole. Survival was monitored over a period of 7 days. Results: Peritonitis induced by CLP was severe, with IL-1, IL-6, and TNF-alpha levels and lethality being significantly higher compared to the SHAM group. The IL-6 levels in the VLAP group were significantly higher compared to the CLP and VLAP+AB groups, and the TNF-alpha levels in the VLAP and LAP+AB groups were significantly higher compared to the LAP group. The survival time was significantly higher in the CLP+AB and VLAP+AB groups, when compared to the CLP group. There was no significant difference in bacteremia and lethality rates between the resources employed for treatment of peritonitis. Conclusions: Although the use of laparoscopic access itself exacerbates the inflammatory response, the combination with antibiotics minimizes this effect and increases the survival time. However, all of the resources used for treating severe peritonitis, when applied alone or in combination, have an equivalent influence on bacteremia and lethality rates.

Possibility for a full optical determination of photodynamic therapy outcome

The efficacy of photodynamic therapy (PDT) depends on a variety of parameters: concentration of the photosensitizer at the time of treatment, light wavelength, fluence, fluence rate, availability of oxygen within the illuminated volume, and light distribution in the tissue. Dosimetry in PDT requires the congregation of adequate amounts of light, drug, and tissue oxygen. The adequate dosimetry should be able to predict the extension of the tissue damage. Photosensitizer photobleaching rate depends on the availability of molecular oxygen in the tissue. Based on photosensitizers photobleaching models, high photobleaching has to be associated with high production of singlet oxygen and therefore with higher photodynamic action, resulting in a greater depth of necrosis. The purpose of this work is to show a possible correlation between depth of necrosis and the in vivo photosensitizer (in this case, Photogem (R)) photodegradation during PDT. Such correlation allows possibilities for the development of a real time evaluation of the photodynamic action during PDT application. Experiments were performed in a range of fluence (0-450 J/cm(2)) at a constant fluence rate of 250 mW/cm(2) and applying different illumination times (0-1800 s) to achieve the desired fluence. A quantity was defined (psi) as the product of fluorescence ratio (related to the photosensitizer degradation at the surface) and the observed depth of necrosis. The correlation between depth of necrosis and surface fluorescence signal is expressed in psi and could allow, in principle, a noninvasive monitoring of PDT effects during treatment. High degree of correlation is observed and a simple mathematical model to justify the results is presented.