Caesarean sections, prenatal and postnatal conditions and childhood acute lymphoblastic leukaemia: A case-control study in the State of São Paulo, Brazil.

INTRODUCTION: Brazil has high rates of caesarean sections, which has been suggested as a risk factor for acute lymphoblastic leukaemia (ALL). In addition, some pre- and postnatal conditions have been identified as relevant in the etiology of ALL. OBJECTIVES: Investigate the association of caesarean sections, pre- and postnatal conditions with childhood ALL in the State of São Paulo. METHODS: Population-based case-control study including children that are below10 years old. Information on study variables was obtained through face to face interviews, through a questionnaire, and the State of São Paulo Declarations of Live Births database. The conditional and unconditional logistic regression approaches were used to calculate the odds ratio (OR) of the associations between caesarean sections, pre- and postnatal conditions with ALL, and 95 % confidence intervals (95 % CI). RESULTS: We observed a weak and non-statistically significant risk for ALL among children exposed to caesarean sections (unconditional logistic regression OR 1.08; 95 % CI 0.70-1.66; conditional logistic regression OR 1.21; 95 % CI 0.72-2.02), but among children under 3 years old and born through a caesarean sections, the risk of ALL was greater (unconditional logistic regression OR 1.70; 95 % CI 0.69-4.21). A negative association for ALL was observed among children with mothers who reported 12 years of schooling or more (unconditional logistic regression OR 0.34; 95 % CI 0.16-0.69). CONCLUSIONS: We found a tenuous suggestive association between caesarean sections and childhood ALL. The mother's high level of education showed an inverse association with ALL.

Bringing dead proteins back to life.

A small molecule called EMD 57033 can repair motor proteins that have stopped working as a result of stress.

Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-ß peptide.

Alterations in the lipid composition of endosomal-lysosomal membranes may constitute an early event in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the possibility that GM2 ganglioside accumulation in a mouse model of Sandhoff disease might be associated with the accumulation of intraneuronal and extracellular proteins commonly observed in AD. Our results show intraneuronal accumulation of amyloid-ß peptide (Aß)-like, α-synuclein-like, and phospho-tau-like immunoreactivity in the brains of ß-hexosaminidase knock-out (HEXB KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal Aß-like immunoreactivity (iAß-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or Aß. In addition, we observed increased levels of Aß40 and Aß42 peptides in the lipid-associated fraction of HEXB KO mouse brains, and intraneuronal accumulation of ganglioside-bound Aß (GAß) immunoreactivity in a brain region-specific manner. Furthermore, α-synuclein and APP-CTFs and/or Aß were found to accumulate in different regions of the substantia nigra, indicating different mechanisms of accumulation or turnover pathways. Based on the localization of the accumulated iAß-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iAß-LIR may be associated with the lysosomal-autophagic turnover of Aß and fragments of APP-containing Aß epitopes. Importantly, intraneuronal GAß immunoreactivity, a proposed prefibrillar aggregate found in AD, was found to accumulate throughout the frontal cortices of postmortem human GM1 gangliosidosis, Sandhoff disease, and Tay-Sachs disease brains. Together, these results establish an association between the accumulation of gangliosides, autophagic vacuoles, and the intraneuronal accumulation of proteins associated with AD.

Caffeine stimulates cytochrome oxidase expression and activity in the striatum in a sexually dimorphic manner.

Epidemiological studies indicate that caffeine consumption reduces the risk of Parkinson's disease (PD) in men, and antagonists of the adenosine 2A receptor ameliorate the motor symptoms of PD. These findings motivated us to identify proteins whose expression is regulated by caffeine in a sexually dimorphic manner. Using mass spectroscopy, we found that Cox7c, a nuclear-encoded subunit of the mitochondrial enzyme cytochrome oxidase, is up-regulated in the striatum of male but not female mice after receiving a single dose of caffeine. The expression of two other Cox subunits, Cox1 and Cox4, was also stimulated by caffeine in a male-specific fashion. This up-regulation of Cox subunits by caffeine was accompanied by an increase in Cox enzyme activity in the male striatum. Caffeine-induced stimulation of Cox expression and activity were reproduced using the adenosine 2A receptor (A2AR)-specific antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261), and coadministration of the A2AR-specific agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) counteracted the elevation of Cox expression and activity by caffeine. Caffeine also increased Cox activity in PC-12 cells. In contrast, small interfering RNA (siRNA) knockdown of Cox7c expression in PC-12 cells blunted Cox activity, and this was counteracted by caffeine treatment. Caffeine was also found to increase Cox7c mRNA expression in the striatum and in PC-12 cells. This occurred at the level of transcription and was mediated by a segment of the Cox7c promoter. Overall, these findings indicate that cytochrome oxidase is a metabolic target of caffeine and that stimulation of Cox activity by caffeine via blockade of A2AR signaling may be an important mechanism underlying the therapeutic benefits of caffeine in PD.

Influenza immunisation: attitudes and beliefs of UK healthcare workers.

AIM: To explore attitudes to influenza immunisation and rates of uptake among staff working in acute hospitals in the UK. METHOD: A cross-sectional survey of 11,670 healthcare workers in six UK hospitals was carried out using a postal questionnaire. RESULTS: Among 6302 responders (54% of those mailed), 19% had taken up influenza immunisation during winter 2002/3. Vaccination was well tolerated, with a low prevalence of side effects (13%) and associated time off work (2%). The majority of subjects who accepted vaccination (66%) were most strongly influenced by the personal benefits of protection against influenza. Prevention of sickness absence and protection of patients were the prime motivation for only 10% and 7% of subjects, respectively. Among 3967 who declined vaccination, the most common primary demotivators were concern about safety (31%) and efficacy (29%). 22% were most strongly deterred by lack of time to attend for vaccination. Free text answers indicated that 37% declined because of a perceived low ratio of personal benefits to adverse effects. Subjects said they would be persuaded to take up vaccination in future by easier access (36%), more information about personal benefit and risk (34%) and more information about effects on staff absence (24%). CONCLUSIONS: These findings indicate that the uptake of influenza immunisation among UK healthcare workers remains low. There is some scope for increasing uptake by improving accessibility and encouragement from professional peers. However, the results suggest that perception of small personal benefit in relation to risk mitigates, importantly, against higher uptake of routine annual influenza vaccination. Thus, resource might better be allocated to ensuring efficient management in epidemic years. The effect of publicity about pandemic influenza on risk perception and vaccine uptake among healthcare workers during winter 2005/6 warrants further study.

High-resolution structure of a retroviral capsid hexameric amino-terminal domain.

Retroviruses are the aetiological agents of a range of human diseases including AIDS and T-cell leukaemias. They follow complex life cycles, which are still only partly understood at the molecular level. Maturation of newly formed retroviral particles is an essential step in production of infectious virions, and requires proteolytic cleavage of Gag polyproteins in the immature particle to form the matrix, capsid and nucleocapsid proteins present in the mature virion. Capsid proteins associate to form a dense viral core that may be spherical, cylindrical or conical depending on the genus of the virus. Nonetheless, these assemblies all appear to be composed of a lattice formed from hexagonal rings, each containing six capsid monomers. Here, we describe the X-ray structure of an individual hexagonal assembly from N-tropic murine leukaemia virus (N-MLV). The interface between capsid monomers is generally polar, consistent with weak interactions within the hexamer. Similar architectures are probably crucial for the regulation of capsid assembly and disassembly in all retroviruses. Together, these observations provide new insights into retroviral uncoating and how cellular restriction factors may interfere with viral replication.

Retroviral capsid determinants of Fv1 NB and NR tropism.

The specificity determinants for susceptibility to resistance by the Fv1 n and b alleles map to amino acid 110 of the murine leukemia virus CA protein. To study the interaction between Fv1 and CA, we examined changes in CA resulting in the loss of susceptibility to Fv1 resistance in naturally occurring NB- and NR-tropic viruses. A variety of amino acid changes affecting Fv1 tropism were identified, at CA positions 82, 92 to 95, 105, 114, and 117, and they all were mapped to the apparent exterior of virion-associated CA. These amino acids may form a binding surface for Fv1.

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.

OBJECTIVE: The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. SUMMARY BACKGROUND DATA: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. METHODS: A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. RESULTS: For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). CONCLUSIONS: This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.