Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size

Markers for early detection of cancer: Statistical guidelines for nested case-control studies

BACKGROUND: Recently many long-term prospective studies have involved serial collection and storage of blood or tissue specimens. This has spurred nested case-control studies that involve testing some specimens for various markers that might predict cancer. Until now there has been little guidance in statistical design and analysis of these studies. METHODS: To develop statistical guidelines, we considered the purpose, the types of biases, and the opportunities for extracting additional information. RESULTS: The following guidelines: (1) For the clearest interpretation, statistics should be based on false and true positive rates – not odds ratios or relative risks (2) To avoid overdiagnosis bias, cases should be diagnosed as a result of symptoms rather than on screening. (3) To minimize selection bias, the spectrum of control conditions should be the same in study and target screening populations. (4) To extract additional information, criteria for a positive test should be based on combinations of individual markers and changes in marker levels over time. (5) To avoid overfitting, the criteria for a positive marker combination developed in a training sample should be evaluated in a random test sample from the same study and, if possible, a validation sample from another study. (6) To identify biomarkers with true and false positive rates similar to mammography, the training, test, and validation samples should each include at least 110 randomly selected subjects without cancer and 70 subjects with cancer. CONCLUSION: These guidelines ensure good practice in the design and analysis of nested case-control studies of early detection biomarkers

Healthcare costs and utilization for Medicare beneficiaries with Alzheimer's

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is a neurodegenerative disorder incurring significant social and economic costs. This study uses a US administrative claims database to evaluate the effect of AD on direct healthcare costs and utilization, and to identify the most common reasons for AD patients' emergency room (ER) visits and inpatient admissions.</p> <p>Methods</p> <p>Demographically matched cohorts age 65 and over with comprehensive medical and pharmacy claims from the 2003–2004 MEDSTAT MarketScan^®Medicare Supplemental and Coordination of Benefits (COB) Database were examined: 1) 25,109 individuals with an AD diagnosis or a filled prescription for an exclusively AD treatment; and 2) 75,327 matched controls. Illness burden for each person was measured using Diagnostic Cost Groups (DCGs), a comprehensive morbidity assessment system. Cost distributions and reasons for ER visits and inpatient admissions in 2004 were compared for both cohorts. Regression was used to quantify the marginal contribution of AD to health care costs and utilization, and the most common reasons for ER and inpatient admissions, using DCGs to control for overall illness burden.</p> <p>Results</p> <p>Compared with controls, the AD cohort had more co-morbid medical conditions, higher overall illness burden, and higher but less variable costs ($13,936 s.$10,369; Coefficient of variation = 181 vs. 324). Significant excess utilization was attributed to AD for inpatient services, pharmacy, ER visits, and home health care (all p < 0.05). In particular, AD patients were far more likely to be hospitalized for infections, pneumonia and falls (hip fracture, syncope, collapse).</p> <p>Conclusion</p> <p>Patients with AD have significantly more co-morbid medical conditions and higher healthcare costs and utilization than demographically-matched Medicare beneficiaries. Even after adjusting for differences in co-morbidity, AD patients incur excess ER visits and inpatient admissions.</p

Проблемы увеличения продуктивности АПК в Украине и пути повышения его потенциала

Целью статьи является изучение причин снижения показателей продуктивности в агропромышленном комплексе и путей повышения продуктивности сельскохозяйственных культур

CRISPR transcriptional repression devices and layered circuits in mammalian cells

A key obstacle to creating sophisticated genetic circuits has been the lack of scalable device libraries. Here we present a modular transcriptional repression architecture based on clustered regularly interspaced palindromic repeats (CRISPR) system and examine approaches for regulated expression of guide RNAs in human cells. Subsequently we demonstrate that CRISPR regulatory devices can be layered to create functional cascaded circuits, which provide a valuable toolbox for engineering purposes.National Institutes of Health (U.S.) (Grant 5R01CA155320-04)National Institutes of Health (U.S.) (Grant P50 GM098792)Korea (South). Ministry of Science, Information and Communication Technolgy. Intelligent Synthetic Biology Center of Global Frontier Project (2013M3A6A8073557

dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective.

Neurons rely on mitochondria as their preferred source of energy. Mutations in PINK1 and PARKIN cause neuronal death in early-onset Parkinson's disease (PD), thought to be due to mitochondrial dysfunction. In Drosophila pink1 and parkin mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes SHMT2 and NMDMC as a protective response to mitochondrial toxicity. Suppressing Shmt2 or Nmdmc caused motor impairment and mitochondrial defects in flies. Epistatic analyses showed that suppressing the upregulation of Shmt2 or Nmdmc deteriorates the phenotype of pink1 or parkin mutants. Conversely, the genetic enhancement of these one-carbon metabolism genes in pink1 or parkin mutants was neuroprotective. We conclude that mitochondrial dysfunction caused by mutations in the Pink1/Parkin pathway engages ATF4-dependent activation of one-carbon metabolism as a protective response. Our findings show a central contribution of ATF4 signalling to PD that may represent a new therapeutic strategy. A video abstract for this article is available at https://youtu.be/cFJJm2YZKKM

Arterial dP/dtmax accurately reflects left ventricular contractility during shock when adequate vascular filling is achieved

Background: Peak first derivative of femoral artery pressure (arterial dP/dt max) derived from fluid-filled catheter remains questionable to assess left ventricular (LV) contractility during shock. The aim of this study was to test if arterial dP/dt maxis reliable for assessing LV contractility during various hemodynamic conditions such as endotoxin-induced shock and catecholamine infusion.Methods: Ventricular pressure-volume data obtained with a conductance catheter and invasive arterial pressure obtained with a fluid-filled catheter were continuously recorded in 6 anaesthetized and mechanically ventilated pigs. After a stabilization period, endotoxin was infused to induce shock. Catecholamines were transiently administrated during shock. Arterial dP/dt maxwas compared to end-systolic elastance (Ees), the gold standard method for assessing LV contractility.Results: Endotoxin-induced shock and catecholamine infusion lead to significant variations in LV contractility. Overall, significant correlation (r = 0.51; p < 0.001) but low agreement between the two methods were observed. However, a far better correlation with a good agreement were observed when positive-pressure ventilation induced an arterial pulse pressure variation (PPV) ≤ 11% (r = 0.77; p < 0.001).Conclusion: While arterial dP/dt maxand Ees were significantly correlated during various hemodynamic conditions, arterial dP/dt maxwas more accurate for assessing LV contractility when adequate vascular filling, defined as PPV ≤ 11%, was achieved. © 2012 Morimont et al; licensee BioMed Central Ltd

Measurement of the Forward-Backward Asymmetry in the B -> K(*) mu+ mu- Decay and First Observation of the Bs -> phi mu+ mu- Decay

We reconstruct the rare decays $B^+ \to K^+\mu^+\mu^-$, $B^0 \to K^{*}(892)^0\mu^+\mu^-$, and $B^0_s \to \phi(1020)\mu^+\mu^-$ in a data sample corresponding to $4.4 {\rm fb^{-1}}$ collected in $p\bar{p}$ collisions at $\sqrt{s}=1.96 {\rm TeV}$ by the CDF II detector at the Fermilab Tevatron Collider. Using $121 \pm 16$ $B^+ \to K^+\mu^+\mu^-$ and $101 \pm 12$ $B^0 \to K^{*0}\mu^+\mu^-$ decays we report the branching ratios. In addition, we report the measurement of the differential branching ratio and the muon forward-backward asymmetry in the $B^+$ and $B^0$ decay modes, and the $K^{*0}$ longitudinal polarization in the $B^0$ decay mode with respect to the squared dimuon mass. These are consistent with the theoretical prediction from the standard model, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the $B^0_s \to \phi\mu^+\mu^- decay and measure its branching ratio${\mathcal{B}}(B^0_s \to \phi\mu^+\mu^-) = [1.44 \pm 0.33 \pm 0.46] \times 10^{-6}$using$27 \pm 6$signal events. This is currently the most rare$B^0_s$ decay observed.Comment: 7 pages, 2 figures, 3 tables. Submitted to Phys. Rev. Let

Goal-directed fluid management based on pulse pressure variation monitoring during high-risk surgery: a pilot randomized controlled trial

Abstract\ud \ud \ud \ud Introduction\ud \ud Several studies have shown that maximizing stroke volume (or increasing it until a plateau is reached) by volume loading during high-risk surgery may improve post-operative outcome. This goal could be achieved simply by minimizing the variation in arterial pulse pressure (ΔPP) induced by mechanical ventilation. We tested this hypothesis in a prospective, randomized, single-centre study. The primary endpoint was the length of postoperative stay in hospital.\ud \ud \ud \ud Methods\ud \ud Thirty-three patients undergoing high-risk surgery were randomized either to a control group (group C, n = 16) or to an intervention group (group I, n = 17). In group I, ΔPP was continuously monitored during surgery by a multiparameter bedside monitor and minimized to 10% or less by volume loading.\ud \ud \ud \ud Results\ud \ud Both groups were comparable in terms of demographic data, American Society of Anesthesiology score, type, and duration of surgery. During surgery, group I received more fluid than group C (4,618 ± 1,557 versus 1,694 ± 705 ml (mean ± SD), P < 0.0001), and ΔPP decreased from 22 ± 75 to 9 ± 1% (P < 0.05) in group I. The median duration of postoperative stay in hospital (7 versus 17 days, P < 0.01) was lower in group I than in group C. The number of postoperative complications per patient (1.4 ± 2.1 versus 3.9 ± 2.8, P < 0.05), as well as the median duration of mechanical ventilation (1 versus 5 days, P < 0.05) and stay in the intensive care unit (3 versus 9 days, P < 0.01) was also lower in group I.\ud \ud \ud \ud Conclusion\ud \ud Monitoring and minimizing ΔPP by volume loading during high-risk surgery improves postoperative outcome and decreases the length of stay in hospital.\ud \ud \ud \ud Trial registration\ud \ud NCT00479011The authors thank Maria De Amorim (Paris, France) and Julia Fukushima (São Paulo, SP, Brazil) for help in data analysis, Dr Julia Wendon (London, UK) for reviewing the manuscript, and Dixtal (Sao Paulo, SP, Brazil) for providing the software for the automatic calculation of ?PP.The authors thank Maria De Amorim (Paris, France) and Julia Fukushima (São Paulo, SP, Brazil) for help in data analysis, Dr Julia Wendon (London, UK) for reviewing the manuscript, and Dixtal (Sao Paulo, SP, Brazil) for providing the software for the automatic calculation of ?PP