Lifestyle Advice Combined with Personalized Estimates of Genetic or Phenotypic Risk of Type 2 Diabetes, and Objectively Measured Physical Activity: A Randomized Controlled Trial

$\textbf{Background}$ Information about genetic and phenotypic risk of type 2 diabetes is now widely available and is being incorporated into disease prevention programs. Whether such information motivates behavior change or has adverse effects is uncertain. We examined the effect of communicating an estimate of genetic or phenotypic risk of type 2 diabetes in a parallel group, open, randomized controlled trial. $\textbf{Methods and Findings}$ We recruited 569 healthy middle-aged adults from the Fenland Study, an ongoing population-based, observational study in the east of England (Cambridgeshire, UK). We used a computer-generated random list to assign participants in blocks of six to receive either standard lifestyle advice alone (control group, $n$ = 190) or in combination with a genetic ($n$ = 189) or a phenotypic ($n$ = 190) risk estimate for type 2 diabetes (intervention groups). After 8 wk, we measured the primary outcome, objectively measured physical activity (kJ/kg/day), and also measured several secondary outcomes (including self-reported diet, self-reported weight, worry, anxiety, and perceived risk). The study was powered to detect a between-group difference of 4.1 kJ/kg/d at follow-up. 557 (98%) participants completed the trial. There were no significant intervention effects on physical activity (difference in adjusted mean change from baseline: genetic risk group versus control group 0.85 kJ/kg/d (95% CI −2.07 to 3.77, $p$ = 0.57); phenotypic risk group versus control group 1.32 (95% CI −1.61 to 4.25, $p$ = 0.38); and genetic risk group versus phenotypic risk group −0.47 (95% CI −3.40 to 2.46, $p$ = 0.75). No significant differences in self-reported diet, self-reported weight, worry, and anxiety were observed between trial groups. Estimates of perceived risk were significantly more accurate among those who received risk information than among those who did not. Key limitations include the recruitment of a sample that may not be representative of the UK population, use of self-reported secondary outcome measures, and a short follow-up period. $\textbf{Conclusions}$ In this study, we did not observe short-term changes in behavior associated with the communication of an estimate of genetic or phenotypic risk of type 2 diabetes. We also did not observe changes in worry or anxiety in the study population. Additional research is needed to investigate the conditions under which risk information might enhance preventive strategies. (Current Controlled Trials ISRCTN09650496; Date applied: April 4, 2011; Date assigned: June 10, 2011). $\textbf{Trial Registration}$ The trial is registered with Current Controlled Trials, ISRCTN09650496.This trial was conducted at the MRC Epidemiology Unit in Cambridge, UK. It was funded by the Medical Research Council (MC_U106179474), the Sixth Framework Programme (LSHM-CT-2006-037197), and the National Institute for Health Research (RP-PG- 0606-1259)

Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience

<p>Abstract</p> <p>Background</p> <p>Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of <it>APOE ε4 </it>allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to <it>APOE </it>genotype. With an eye toward defining ways in which <it>APOE ε3 </it>alleles may foster neuronal well-being in epilepsy and/or <it>APOE ε4 </it>alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either <it>APOE ε4,4 </it>or <it>APOE ε3,3 </it>genotype.</p> <p>Methods</p> <p>Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 <it>APOE ε3,3 </it>and 7 <it>APOE ε4,4 </it>(0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.</p> <p>Results</p> <p>Tissue levels of IL-1α were elevated in patients of both <it>APOE ε3,3 </it>and <it>APOE ε4,4 </it>genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (<it>APOE </it>ε<it>3,3 </it>vs <it>APOE ε4,4 </it>= 3.7 ± 1.2 vs 1.5 ± 0.4; <it>P </it>< 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that <it>APOE ε4,4 </it>genotype was associated with smaller neuron size (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 173 ± 27 vs 356 ± 45; <it>P </it>≤ 0.01) and greater DNA damage (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 67 ± 10 vs 39 ± 2; <it>P </it>= 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of <it>APOE </it>genotype (<it>APOE ε4,4 </it>age 10; <it>APOE ε3,3 </it>age 17).</p> <p>Conclusions</p> <p>Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of <it>APOE ε3,3 </it>genotype compared to <it>APOE ε4,4 </it>genotype carriers, are consistent with the idea that the <it>APOE </it>ε<it>3,3 </it>genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).</p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/10/36</url></p

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

Right pulmonary artery agenesis presenting with uncontrolled asthma in an adult: a case report

<p>Abstract</p> <p>Introduction</p> <p>Unilateral absence of the pulmonary artery (UAPA) or pulmonary artery agenesis is a rare congenital disorder presenting with a wide spectrum of symptoms. The clinical presentation is variable and many patients can be asymptomatic for many years and even throughout their lives.</p> <p>Case presentation</p> <p>We report the case of a 53-year-old African-American woman who was diagnosed with right pulmonary artery agenesis after presenting with uncontrolled asthma and recurrent bronchopulmonary infections.</p> <p>Conclusion</p> <p>In an unexplained case of recurrent respiratory infections and shortness of breath, the possibility of a rare congenital anomaly like UAPA should be considered and an appropriate evaluation should be done.</p

Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to ‘ALF’, defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats–13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability

Metabolomic Profiling of Drug Responses in Acute Myeloid Leukaemia Cell Lines

Combined bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) exert unexpected antileukaemic activities against acute myeloid leukaemia (AML) and these activities are associated with the generation of reactive oxygen species (ROS) within the tumor cells. Although the generation of ROS by these drugs is supported by preceding studies including our own, the interrelationship between the cellular effects of the drugs and ROS generation is not well understood. Here we report the use of NMR metabolomic profiling to further study the effect of BEZ and MPA on three AML cell lines and to shed light on the underlying mechanism of action. For this we focused on drug effects induced during the initial 24 hours of treatment prior to the onset of overt cellular responses and examined these in the context of basal differences in metabolic profiles between the cell lines. Despite their ultimately profound cellular effects, the early changes in metabolic profiles engendered by these drugs were less pronounced than the constitutive metabolic differences between cell types. Nonetheless, drug treatments engendered common metabolic changes, most markedly in the response to the combination of BEZ and MPA. These responses included changes to TCA cycle intermediates consistent with recently identified chemical actions of ROS. Notable amongst these was the conversion of α-ketoglutarate to succinate which was recapitulated by the treatment of cell extracts with exogenous hydrogen peroxide. These findings indicate that the actions of combined BEZ and MPA against AML cells are indeed mediated downstream of the generation of ROS rather than some hitherto unsuspected mechanism. Moreover, our findings demonstrate that metabolite profiles represent highly sensitive markers for genomic differences between cells and their responses to external stimuli. This opens new perspectives to use metabolic profiling as a tool to study the rational redeployment of drugs in new disease settings

Inverse planned stereotactic intensity modulated radiotherapy (IMRT) in the treatment of incompletely and completely resected adenoid cystic carcinomas of the head and neck: initial clinical results and toxicity of treatment

BACKGROUND: Presenting the initial clinical results in the treatment of complex shaped adenoid cystic carcinomas (ACC) of the head and neck region by inverse planned stereotactic IMRT. MATERIALS: 25 patients with huge ACC in different areas of the head and neck were treated. At the time of radiotherapy two patients already suffered from distant metastases. A complete resection of the tumor was possible in only 4 patients. The remaining patients were incompletely resected (R2: 20; R1: 1). 21 patients received an integrated boost IMRT (IBRT), which allow the use of different single doses for different target volumes in one fraction. All patients were treated after inverse treatment planning and stereotactic target point localization. RESULTS: The mean folllow-up was 22.8 months (91 – 1490 days). According to Kaplan Meier the three year overall survival rate was 72%. 4 patients died caused by a systemic progression of the disease. The three-year recurrence free survival was according to Kaplan Meier in this group of patients 38%. 3 patients developed an in-field recurrence and 3 patient showed a metastasis in an adjacent lymph node of the head and neck region. One patient with an in-field recurrence and a patient with the lymph node recurrence could be re-treated by radiotherapy. Both patients are now controlled. Acute side effects >Grade II did only appear so far in a small number of patients. CONCLUSION: The inverse planned stereotactic IMRT is feasible in the treatment of ACC. By using IMRT, high control rates and low side effects could by achieved. Further evaluation concerning the long term follow-up is needed. Due to the technical advantage of IMRT this treatment modality should be used if a particle therapy is not available

Ecological strategies in California chaparral: Interacting effects of soils, climate, and fire on specific leaf area

Background: High values of specific leaf area (SLA) are generally associated with high maximal growth rates in resource-rich conditions, such as mesic climates and fertile soils. However, fire may complicate this relationship since its frequency varies with both climate and soil fertility, and fire frequency selects for regeneration strategies (resprouting versus seeding) that are not independent of resource-acquisition strategies. Shared ancestry is also expected to affect the distribution of resource-use and regeneration traits. Aims: We examined climate, soil, and fire as drivers of community-level variation in a key functional trait, SLA, in chaparral in California. Methods: We quantified the phylogenetic, functional, and environmental non-independence of key traits for 87 species in 115 plots. Results: Among species, SLA was higher in resprouters than seeders, although not after phylogeny correction. Among communities, mean SLA was lower in harsh interior climates, but in these climates it was higher on more fertile soils and on more recently burned sites; in mesic coastal climates, mean SLA was uniformly high despite variation in soil fertility and fire history. Conclusions: We conclude that because important correlations exist among both species traits and environmental filters, interpreting the functional and phylogenetic structure of communities may require an understanding of complex interactive effects

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS