ATM mutations in patients with hereditary pancreatic cancer

Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. SIGNIFICANCE: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.     

Colonization and Infection With Extensively Drug Resistant Gram-Negative Bacteria in Liver Transplant Recipients

Background

Infections due to extensively drug resistant Gram-negative bacteria (GNB) after solid organ transplantation are increasing in prevalence and are associated with high morbidity and mortality. Surveillance culture (SC) seems to be an important tool for extensively drug resistant GNB control. The aim of this study was to evaluate colonization rates and subsequent infections by XDR-GNB in liver transplant recipients.

Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guidelines—Recommendations on the use of biologicals in severe asthma

Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor α, is approved as add-on maintenance treatment for inadequately controlled type 2 severe asthma. This systematic review evaluated the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled severe asthma. PubMed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. Three RCTs including 2735 subjects >12 years old and 24-52 weeks of follow-up were included. Dupilumab reduced with high certainty severe asthma exacerbations (Incidence rate ratio 0.51; 95% CI 0.45-0.59) and the percentage use of oral corticosteroid use (mean difference (MD) −28.2 mg/d; 95% CI −40.7 to −15.7). Asthma control (ACQ-5), quality of life (AQLQ) and rescue medication use [puffs/d] improved, without reaching the minimal important clinical difference: ACQ-5 MD −0.28 (95% CI −0.39 to −0.17); AQLQ MD +0.28 (95% CI 0.20-0.37); and rescue medication MD −0.35 (95% CI −0.73 to +0.02). FEV₁ increased (MD +0.15; 95% CI +0.11 to +0.18) (moderate certainty). There was an increased rate of dupilumab-related adverse events (AEs) (moderate certainty) and of drug-related serious AEs (low certainty). The incremental cost-effectiveness ratio of dupilumab versus standard therapy was 464 000$/QALY (moderate certainty). More data on long-term safety are needed both for children and for adults, together with more efficacy data in the paediatric population.     

Website Designs for Communicating About Chemicals in Cigarette Smoke

ABSTRACT

The Family Smoking Prevention and Tobacco Control Act requires the US government to inform the public about the quantities of toxic chemicals in cigarette smoke. A website can accomplish this task efficiently, but the site’s user interface must be usable to benefit the general public. We conducted online experiments with national convenience samples of 1,451 US adult smokers and nonsmokers to examine the impact of four interface display elements: the chemicals, their associated health effects, quantity information, and a visual risk indicator. Outcomes were perceptions of user experience (perceived clarity and usability), motivation (willingness to use), and potential impact (elaboration about the harms of smoking). We found displaying health effects as text with icons, providing quantity information for chemicals (e.g., ranges), and showing a visual risk indicator all improved the user experience of a webpage about chemicals in cigarette smoke (all p < .05). Displaying a combination of familiar and unfamiliar chemicals, providing quantity information for chemicals, and showing a visual risk indicator all improved motivation to use the webpage (all p < .05). Displaying health effects or quantity information increased the potential impact of the webpage (all p < .05). Overall, interface designs displaying health effects of chemicals in cigarette smoke as text with icons and with a visual risk indicator had the greatest impact on the user experience, motivation, and potential impact of the website. Our findings provide guidance for accessible website designs that can inform consumers about the toxic chemicals in cigarette smoke.     

Characterization of glutathione S-transferase expression in lymphocytes from chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) is a disease state which frequently responds to alkylating agent chemotherapy but ultimately becomes refractory through acquired resistance mechanisms. In the present study, we have examined the expression of glutathione S-transferases (GST) in both CLL and normal control lymphocytes, as these enzymes have been implicated in mechanisms of natural and acquired resistance. Lymphocyte GST was purified from samples by high-pressure liquid affinity chromatography, and subunits were identified by two-dimensional gel electrophoresis and immunoblotting by using polyclonal antibodies specific for individual subunits. Analysis of CLL lymphocyte GST activity using the general substrate 1-chloro-2,4-dinitrobenzene showed a statistically significant 2-fold increase in cells from chlorambucil-resistant patients over those from untreated patients and normal individuals. Furthermore, chlorambucil therapy was seen to cause a 1.3- to 1.5-fold elevation of enzyme activity in three previously drug-naive patients. Analysis of GST isozyme subunits indicated that 95% of the CLL patients examined were positive for the pi isozyme, and this appeared quantitatively to be the major isozyme present. The alpha and mu isozymes were also expressed in 63 and 53% of the patients, respectively. Examination of control lymphocytes, as well as separated B- and T-cell subpopulations, yielded similar results. The present study indicates that a high degree of interindividual variation occurs and that the pattern of CLL lymphocyte GST expression differs from that of other tumor tissues. While there were no obvious correlations between the disease state or stage and isozymes expressed, the quantitative increase in GST activity in chlorambucil-resistant CLL patients may be of relevance to the overall resistant phenotype.     

An isolated perfused rat lung preparation for the study of aerosolized drug deposition and absorption

The isolated, perfused rat lung preparation was modified to allow characterized solid aerosol delivery. Deposition and airway-to-perfusate transfer of disodium fluorescein from 3-4 micron dae solid aerosols were studied under different ventilatory regimes. The lungs inhaled from an aerosol stream of constant concentration via a tracheal cannula. Air displacement from a sealed artificial thorax housing the lungs provided the driving force for inhalation. The lungs were suspended in a physiologically normal position and both left and right sides of the heart were cannulated for constant rate perfusate flow. Fractional deposition was inversely proportional to respiratory frequency implying that sedimentation was the primary deposition mechanism. Increasing tidal volumes similarly enhanced the ratio of amount deposited/amount administered. Fluorescein transfer to the perfusate occurred from the lung regions containing intact vasculature, was apparent first-order, and independent of perfusate flow. The average rate constant for transfer was 0.057 +/- 0.02 min-1 (t1/2 = 12.2 +/- 4.2 min-1). The ratio of transferable amount/amount deposited appeared to indicate the depth of aerosol penetration. This increased at high respiratory frequency and tidal volume, while decreasing with increasing aerosol particle size. Potential applications of the model are discussed in the light of these results.     

Zur Meßsicherheit der oszillometrischen Blutdruckmeßgeräte Dinamap 1846 und HP M-1008B

Using the PTB simulator, which emits real signals from patients, we examined the precision of the oscillometric blood pressure measurement with the Dinamap 1846 (Critikon) and the HP M-1008B (Hewlett Packard). For this purpose we simultaneously registered invasive arterial pulsewave, cuff pressure and cuff pressure oscillations of 20 patients from our intensive care unit and stored them in the database of the simulator. The invasive reference blood pressure values were determined following the recommendations given by the Association for the Advancement of Medical Instrumentation. The invasive system showed a cut-off frequency of 35?Hz; the damping constant was 0.21. With 49 record signals from patients we carried out 15 simulated measurements each. From a total of 49 bio-signals from patients the Dinamap 1846 was able to process 41 signals and the HP M-1008B 47 signals. The mean error of the oscillometric blood pressure measurement of the systolic, diastolic and mean arterial pressure amounted to ?2.50?mmHg, 3.35?mmHg (P<0.05) and 1.51?mmHg with the Dinamap 1846 and to ?8.5?mmHg (P<0.001), ?5.15?mmHg (P<0.001) and ?5.58?mmHg (P<0.001) for the HP M-1008B. The 95% confidence limit for the systolic, diastolic and the mean arterial pressure amounts to 56?mmHg, 30?mmHg and 35?mmHg for the Dinamap 1846 and 50?mmHg, 38?mmHg and 35?mmHg for the HP M-1008B. The differences between that two instruments could be caused by the different algorithms for the calculation of blood pressure values and different artefact detection and elimination techniques. The results of the performance tests we achieved with the PTB simulator correspond to the results of other clinical examinations. The American Association for the Advanecement of Medical Instrumentation recommends a maximum mean error of 5±8?mmHg. None of the examined instruments lay within these limits. Due to the systematic and stochastic errors, we think that the Dinamap 1846 (Critikon) and the HP M-1008B (Hewlett Packard) do not achieve performance levels that are adequate for measuring critically ill patients.