Genetic heterogeneity of Alzheimer's disease: complexity and advances

Most of what we know about the pathological process of Alzheimer's disease (AD) results from research on the amyloid cascade hypothesis. This hypothesis in turn is derived largely from the characterization of rare disease-causing mutations in three genes, which code for the amyloid precursor protein (APP), presenilin 1 (PS-1) and presenilin 2 (PS-2) and account for most cases of early-onset autosomal dominant familial AD. These genetic findings also suggested that better understanding of the genetic components of AD, even in the late-onset sporadic forms of the disease, might help to identify central pathways of the AD process and lead to the rapid development of active molecules. Twin studies have reinforced the rationale of this approach, for they indicate that more than 50% of the late-onset AD risk may be attributable to genetic factors. The 1993 discovery that the apolipoprotein E4 (ApoE4) allele is genetically associated with increased risk in both sporadic and familial late-onset Alzheimer's disease strongly supports the validity of this genetic approach. Further progress based on this major finding has nonetheless been disappointing and raises questions about it. First, despite intensive researches, the exact role of APOE in the pathophysiological process still remains unknown. Second, the APOE gene is the only gene so far recognized as a consistent genetic determinant of sporadic forms of AD, even though numerous studies have looked for such genes; these disappointing results suggest persistent methodological limitations. However, recent methodologies allowing new strategies may allow important breakthrough.     

Inhibitors of the EGFR pathway in non small cell lung cancer: what's new in 2007?

Non small cell lung cancer (NSCLC) is a major health public issue because of its frequency and related mortality. Progress with chemotherapy in advanced NSCLC has reached a plateau and more effective and better tolerated therapeutic strategies are needed. Epidermal growth factor receptor (EGFR) is overexpressed in 80% of NSCLC and inhibitors of EGFR tyrosine kinase have now an important place in the management of NSCLC. Most significant results have been obtained with oral inhibitors like erlotinib or gefitinib. Erlotinib role in second and third line setting is firmly established. Recent data suggests that in the first line setting, interesting overall response rates improving survivals can be obtained, in specific subpopulations defined either by histology (adenocarcinomas, adenocarcinomas with bronchioloalveolar features), sex (women), non-smoking status (never-smokers) or biological markers (tumours with EGFR mutations in exons 18-21). Such improvements are especially valuable because inhibitors of EGFR tyrosine kinase are better tolerated than chemotherapy. The exact contribution of monoclonal antibodies like cetuximab is still unclear in NSCLC.     

Risk factors for early catheter-related infections in cancer patients

BACKGROUND: Early catheter-related infection is a serious complication in cancer treatment, although risk factors for its occurrence are not well established. The authors conducted a prospective study to identify the risk factors for developing early catheter-related infection. METHODS: All consecutive patients with cancer who underwent insertion of a central venous catheter were enrolled and were followed prospectively during 1 month. The study endpoint was occurrence of early catheter-related infection. RESULTS: Over 10,392 catheter-days of follow-up, 14 of 371 patients had early catheter-related infections (14 patients in 10,392 catheter-days or 1.34 per 1000 catheter-days). The causative pathogens were gram positive in 11 of 14 patients. In univariate analysis, the risk factors for early catheter-related infection were aged <10 years (P = .0001), difficulties during insertion (P < 10(-6)), blood product administration (P < 10(-3)), parenteral nutrition (P < 10(-4)), and use >2 days (P < 10(-6)). In multivariate analysis, 3 variables remained significantly associated with the risk of early catheter-related infection: age <10 years (odds ratio [OR], 18.4; 95% confidence interval [95% CI], 1.9-106.7), difficulties during insertion procedure (OR, 25.6; 95% CI, 4.2-106), and parenteral nutrition (OR, 28.5; 95% CI, 4.2-200). CONCLUSIONS: On the day of insertion, 2 variables were identified that were associated with a high risk of developing an early catheter-related infection: young age and difficulties during insertion. The results from this study may be used to identify patients who are at high risk of infection who may be candidates for preventive strategies.     

Prevention of surgical site infection after breast cancer surgery by targeted prophylaxis antibiotic in patients at high risk of surgical site infection

OBJECTIVE: We previously showed that previous chemotherapy and immediate breast reconstruction were associated with an increased risk of surgical site infection (SSI) in patients undergoing breast cancer surgery. The present before-after study evaluated a preventive strategy for high-risk patients. PATIENTS AND METHODS: We compared the incidence of SSI in two prospective observational cohorts of patients underwent clean procedure in curative intent for a-biopsy proven breast cancer: a historical cohort followed before implementation of a preventive strategy and a second cohort followed thereafter. The strategy consisted of identifying patients at risk of SSI and prophylaxis administration of cefuroxime to those patients. The impact of our strategy was analyzed using a logistic regression model adjusted for potential confounders. RESULTS: SSI incidence was estimated at 19/542 (3.5%) before preventive strategy versus 2/247 (0.8%) thereafter (crude odds ratio (OR) 0.22 confidence interval [95% CI 0.05-0.97], P = 0.03). After adjustment for confounders (breast reconstruction, previous breast surgery, and duration of surgery), our preventive strategy reduced the risk of SSI by 81% (adjusted OR 0.19 [95% CI 0.04-0.85], P = 0.03). CONCLUSION: These results showed that antibiotic prophylaxis is beneficial for patients at high-risk of WI after breast cancer surgery. Randomized controlled trials should now confirm these findings.     

A study of the association between the ADAM12 and SH3PXD2A (SH3MD1) genes and Alzheimer's disease

Several observations suggest that neurotoxicity in Alzheimer's disease (AD) can be partly attributed to β-amyloid (Aβ) and senile plaques. Recent work has suggested that the FISH (five SH3 domains) adapter protein and ADAM12 (a disintegrin and metalloprotease) may mediate the neurotoxic effect of Aβ. Both genes are located on chromosome 10, within a region linked to AD (for SH3PXD2A) or nearby (for ADAM12). A recent study reported a statistically significant interaction between 2 variants of these genes (rs3740473 for SH3PXD2A and rs11244787 for ADAM12) with respect to the risk of developing AD. With a view to replicating this observation, we genotyped the two SNPs in four European case-control cohorts of Caucasian origin (1913 cases and 1468 controls) but were unable to confirm the initial results.     

Norepinephrine differentially modulates different types of respiratory pacemaker and nonpacemaker neurons

Pacemakers are found throughout the mammalian CNS. Yet, it remains largely unknown how these neurons contribute to network activity. Here we show that for the respiratory network isolated in transverse slices of mice, different functions can be assigned to different types of pacemakers and nonpacemakers. This difference becomes evident in response to norepinephrine (NE). Although NE depolarized 88% of synaptically isolated inspiratory neurons, this neuromodulator had differential effects on different neuron types. NE increased in cadmium-insensitive pacemakers burst frequency, not burst area and duration, and it increased in cadmium-sensitive pacemakers burst duration and area, but not frequency. NE also differentially modulated nonpacemakers. Two types of nonpacemakers were identified: "silent nonpacemakers" stop spiking, whereas "active nonpacemakers" spontaneously spike when isolated from the network. NE selectively induced cadmium-sensitive pacemaker properties in active, but not silent, nonpacemakers. Flufenamic acid (FFA), a blocker of ICAN, blocked the induction as well as modulation of cadmium-sensitive pacemaker activity, and blocked at the network level the NE-induced increase in burst area and duration of inspiratory network activity; the frequency modulation (FM) was unaffected. We therefore propose that modulation of cadmium-sensitive pacemaker activity contributes at the network level to changes in burst shape, not frequency. Riluzole blocked the FM of isolated cadmium-insensitive pacemakers. In the presence of riluzole, NE caused disorganized network activity, suggesting that cadmium-insensitive pacemakers are critical for rhythm generation. We conclude that different types of nonpacemaker and pacemaker neurons differentially control different aspects of the respiratory rhythm.     

Open source challenges for hospital information system (HIS) in developing countries: a pilot project in Mali

Background  

We are currently witnessing a significant increase in use of Open Source tools in the field of health. Our study aims to research the potential of these software packages for developing countries. Our experiment was conducted at the Centre Hospitalier Mere Enfant in Mali.