Transcriptome and target DNA enrichment sequence data provide new insights into the phylogeny of vespid wasps (Hymenoptera: Aculeata: Vespidae).
The wasp family Vespidae comprises more than 5000 described species which represent life history strategies ranging from solitary and presocial to eusocial and socially parasitic. The phylogenetic relationships of the major vespid wasp lineages (i.e., subfamilies and tribes) have been investigated repeatedly by analyzing behavioral and morphological traits as well as nucleotide sequences of few selected genes with largely incongruent results. Here we reconstruct their phylogenetic relationships using a phylogenomic approach. We sequenced the transcriptomes of 24 vespid wasp and eight outgroup species and exploited the transcript sequences for design of probes for enriching 913 single-copy protein-coding genes to complement the transcriptome data with nucleotide sequence data from additional 25 ethanol-preserved vespid species. Results from phylogenetic analyses of the combined sequence data revealed the eusocial subfamily Stenogastrinae to be the sister group of all remaining Vespidae, while the subfamily Eumeninae turned out to be paraphyletic. Of the three currently recognized eumenine tribes, Odynerini is paraphyletic with respect to Eumenini, and Zethini is paraphyletic with respect to Polistinae and Vespinae. Our results are in conflict with the current tribal subdivision of Eumeninae and thus, we suggest granting subfamily rank to the two major clades of "Zethini": Raphiglossinae and Zethinae. Overall, our findings corroborate the hypothesis of two independent origins of eusociality in vespid wasps and suggest a single origin of using masticated and salivated plant material for building nests by Raphiglossinae, Zethinae, Polistinae, and Vespinae. The inferred phylogenetic relationships and the open access vespid wasp target DNA enrichment probes will provide a valuable tool for future comparative studies on species of the family Vespidae, including their genomes, life styles, evolution of sociality, and co-evolution with other organisms.


Mammalian mitochondrial translation - revealing consequences of divergent evolution.
Mitochondria are ubiquitous organelles present in the cytoplasm of all nucleated eukaryotic cells. These organelles are described as arising from a common ancestor but a comparison of numerous aspects of mitochondria between different organisms provides remarkable examples of divergent evolution. In humans, these organelles are of dual genetic origin, comprising ∼1500 nuclear-encoded proteins and thirteen that are encoded by the mitochondrial genome. Of the various functions that these organelles perform, it is only oxidative phosphorylation, which provides ATP as a source of chemical energy, that is dependent on synthesis of these thirteen mitochondrially encoded proteins. A prerequisite for this process of translation are the mitoribosomes. The recent revolution in cryo-electron microscopy has generated high-resolution mitoribosome structures and has undoubtedly revealed some of the most distinctive molecular aspects of the mitoribosomes from different organisms. However, we still lack a complete understanding of the mechanistic aspects of this process and many of the factors involved in post-transcriptional gene expression in mitochondria. This review reflects on the current knowledge and illustrates some of the striking differences that have been identified between mitochondria from a range of organisms.


Treating Metaphor Interpretation Deficits Subsequent to Right Hemisphere Brain Damage: Preliminary Results.
PURPOSE: This investigation sought to determine whether a structured intervention focused on improving use of semantic associations could improve patients' ability to provide oral interpretations of metaphors following Right Hemisphere Damage (RHD). METHODS: Principles of single subject experimental design provided the basis for the study. Five patients received either 10 or 20 baseline assessments of oral metaphor interpretation and, as a control, assessments of line orientation skill. They then received approximately 10 one-hour sessions of structured intervention to improve oral metaphor interpretation followed by post-training assessments and a 3 month follow up. RESULTS: Patients' performances revealed evidence of good response to training as shown by patients' ability to reach criterion on all intervention tasks and by their significant improvement on oral metaphor interpretation. There was relatively little improvement on the line orientation task. DISCUSSION: The results of this study support the clinical usefulness of this new approach to treating communication deficits associated with RHD due to stroke, even years post-onset. There are, however, questions that remain unanswered. For example, additional data will be needed to gauge how a patient's severity of impairment relates to the potential for improvement, to chart the durability and scope of improvement associated with the training, and to determine the type of visuospatial ability needed for using this type of pictorial material.


Associations between circulating IL-17 levels and rheumatoid arthritis and between IL-17 gene polymorphisms and disease susceptibility: a meta-analysis.
To systematically review evidence regarding the relationship between circulating interleukin-17 (IL-17) levels and rheumatoid arthritis (RA), and associations between polymorphisms in IL-17 genes and RA susceptibility. We performed a meta-analysis of serum/plasma IL-17 levels in patients with RA and controls, and evaluated evidence of associations between the rs2275913, rs3819024, rs4711998 and rs8193036 polymorphisms in IL-17A and the rs763780 and rs2397084 polymorphisms in IL-17F and risk for RA. Fourteen studies including 3118 patients with RA and 2725 controls were included. Our meta-analysis revealed that IL-17 levels were significantly higher in the RA group than in the control group (p=3.1×10-6). Subgroup analysis using sample size showed increased IL-17 levels in samples from both small (n≤100) and large (n>100) RA groups (p=1.1×10-4 and p=0.008, respectively). We found evidence of associations between RA and alleles from the IL-17A rs2275913 and IL-17F rs763780 polymorphisms in Caucasians (p=0.003 and p=0.037, respectively). In addition, we found an association between RA and alleles of the IL-17A rs3819024 polymorphism in the pooled RA cohort compared with matched controls (p=0.033). However, no evidence of association was found between the IL-17F rs2397084, IL-17A rs4711998 and IL-17A rs8193036 polymorphisms and RA susceptibility. Our meta-analysis revealed significantly higher circulating IL-17 levels in patients with RA, and found evidence of associations between the IL-17A rs2275913, IL-17F rs763780 and IL-17A rs3819024 polymorphisms and pathogenesis of RA.


Percolation in multiplex networks with overlap.
From transportation networks to complex infrastructures, and to social and communication networks, a large variety of systems can be described in terms of multiplexes formed by a set of nodes interacting through different networks (layers). Multiplexes may display an increased fragility with respect to the single layers that constitute them. However, so far the overlap of the links in different layers has been mostly neglected, despite the fact that it is an ubiquitous phenomenon in most multiplexes. Here, we show that the overlap among layers can improve the robustness of interdependent multiplex systems and change the critical behavior of the percolation phase transition in a complex way.


Histological assessment of chronic pancreatitis at necropsy.
To evaluate the histological criteria used to diagnose chronic pancreatitis; and to assess interobserver variation among general pathologists. Forty five cases of chronic pancreatitis diagnosed in necropsy were reviewed to determine whether the diagnosis was acceptable retrospectively. These cases were diagnosed initially as chronic pancreatitis in the final necropsy report complied by general pathologists. In reviewing these cases, special attention was paid to irregular fibrosis and destruction of the lobular architecture. The 45 cases were re-assigned to seven different diagnostic categories: chronic pancreatitis, 21 (47%) cases; interstitial fibrosis with or without chronic inflammation, 11 (24%) cases; repair stage of acute pancreatitis, four (9%) cases; severe fatty infiltration, three (7%) cases; chronic inflammation without interstitial fibrosis, two (4%) cases; haemochromatosis, one (2%) case; and undetermined, three (7%) cases. The histological spectrum of chronic pancreatitis was very wide and it was often misdiagnosed. Acinar atrophy, acinar dilation and intralobular fibrosis were diagnostic of chronic pancreatitis. Differential diagnoses include the repair stage of acute pancreatitis, severe fatty infiltration and haemochromatosis. Recognition of these findings may help to reduce overdiagnosis of chronic pancreatitis.


Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by anti-insulin serum and glucagon.
The enhanced capacity for long-chain fatty acid oxidation and ketogenesis that develops in the rat liver between 6 and 9 h after the onset of starvation was shown to be inducible much more rapidly by administration of anti-insulin serum or glucagon to fed rats. After only 1 h of treatment with either agent, the liver had clearly switched from a "nonketogenic" to a "ketogenic" profile, as determined by rates of acetoacetate and b-hydroxybutyrate production on perfusion with oleic acid. As was the case after starvation, the administration of insulin antibodies or glucagon resulted in depletion of hepatic glycogen stores and a proportional increase in the ability of the liver to oxidize long-chain fatty acids and (-)-octanoylcarnitine, suggesting that all three treatment schedules activated the carnitine acyltransferase system of enzymes. In contrast to anti-insulin serum, which produced marked elevations in plasma glucose, free fatty acid, and ketone body concentrations, glucagon treatment had little effect on any of these parameters, presumably due to enhanced insulin secretion after the initial stimulation of glycogenolysis. Thus, after treatment with glucagon alone, it was possible to obtain a "ketogenic" liver from a nonketotic animal. The results are consistent with the possibility that the activity of carnitine acyltransferase, and thus ketogenic capacity, is subject to bihormonal control through the relative blood concentrations of insulin and glucagon, as also appears to be the case with hepatic carbohydrate metabolism.


Satisfaction of patients fitted with implant-retained overdentures.
to evaluate patient satisfaction with implant-retained overdentures, and its relationship with age, sex, period of follow-up, the rehabilitated jaw (maxilla, mandible or both), number of implants, splinting, type of attachment and the antagonist. the study comprised patients with overdentures fitted between January 1996 and June 2007, and with a minimum follow-up of one year. Data regarding patients and prostheses were collected. The patients indicated their overall satisfaction on a visual analogue scale (VAS) from 0 to 10, as well as satisfaction for individual items such as aesthetics, speech, mastication, prosthetic stability and self-esteem. These data were collected one month after fitting the prostheses, at 12 months and at a final examination. Statistical analyses were made using the SPSS version 15, statistical significance was considered for p<0.05. the study included 95 patients, 43 men and 52 women, with a mean age of 55.9 years; 76 edentulous mandibles and 31 edentulous maxillae were rehabilitated with 107 overdentures. One hundred and thirty-seven implants were placed in the maxilla, and 224 in the mandible. The mean level of overall satisfaction was 9 at one month of fitting the prosthesis, 8.8 at 12 months and 8.7 at the final control (mean 71 months). the patients fitted with implant-retained overdentures expressed a high level of overall satisfaction, independently of age, sex, length of follow-up, rehabilitated jaw, number of implants per overdenture, whether splinted or non-splinted, and type of attachment. Men were more satisfied with mastication and stability.


Bortezomib for patients with advanced-stage bronchioloalveolar carcinoma: a California Cancer Consortium Phase II study (NCI 7003).
Bronchioloalveolar carcinoma (BAC), a subtype of non-small cell lung cancer, is a difficult disease to treat with low response rates with cytotoxic chemotherapy. Bortezomib, a proteasome inhibitor, has demonstrated objective responses in patients with BAC in early-phase clinical trials. We conducted a phase II study of bortezomib in patients with advanced-stage BAC. Patients with advanced BAC, adenocarcinoma with BAC features or BAC with adenocarcinoma features, and less than two prior regimens were eligible. Prior epidermal growth factor receptor (EGFR) inhibitor therapy was allowed. Bortezomib was administered intravenously at 1.6 mg/m on days 1 and 8 of every 21-day cycle until disease progression or unacceptable toxicity. The primary end point was response rate. The Simon two-stage design was used. Forty-two patients were enrolled, and the study was halted early for slow accrual. Patient characteristics were female 55%, median age 68 years, and Eastern Cooperative Oncology Group performance status of 0 and 1 in 31 and 11 patients, respectively. Twenty-six (62%) patients had received prior therapy with an EGFR inhibitor. A median of four cycles of therapy were administered. Objective responses were noted in 5%, whereas 57% had disease stabilization. The median progression-free survival and overall survival were 5.5 and 13.6 months, respectively. Grade 3 diarrhea and fatigue were noted in three and five patients, respectively. Bortezomib is tolerated well and is associated with modest anticancer activity in patients with advanced BAC, including patients who progressed on EGFR inhibitor therapy.


Wearing of caps and masks not necessary during cardiac catheterization.
Although cardiac catheterization-related infections are rare, caps and masks are often worn to minimize this complication. However, documentation of the value of caps and masks for this purpose is lacking. We, therefore, prospectively evaluated the experience of 504 patients undergoing percutaneous left heart catheterization, seeking evidence of a relationship between whether caps and/or masks were worn by the operators and the incidence of infection. No infections were found in any patient, regardless of whether a cap or mask was used. Thus, we found no evidence that caps or masks need to be worn during percutaneous cardiac catheterization.


Brain Computation Is Organized via Power-of-Two-Based Permutation Logic.
There is considerable scientific interest in understanding how cell assemblies-the long-presumed computational motif-are organized so that the brain can generate intelligent cognition and flexible behavior. The Theory of Connectivity proposes that the origin of intelligence is rooted in a power-of-two-based permutation logic (N = 2 i -1), producing specific-to-general cell-assembly architecture capable of generating specific perceptions and memories, as well as generalized knowledge and flexible actions. We show that this power-of-two-based permutation logic is widely used in cortical and subcortical circuits across animal species and is conserved for the processing of a variety of cognitive modalities including appetitive, emotional and social information. However, modulatory neurons, such as dopaminergic (DA) neurons, use a simpler logic despite their distinct subtypes. Interestingly, this specific-to-general permutation logic remained largely intact although NMDA receptors-the synaptic switch for learning and memory-were deleted throughout adulthood, suggesting that the logic is developmentally pre-configured. Moreover, this computational logic is implemented in the cortex via combining a random-connectivity strategy in superficial layers 2/3 with nonrandom organizations in deep layers 5/6. This randomness of layers 2/3 cliques-which preferentially encode specific and low-combinatorial features and project inter-cortically-is ideal for maximizing cross-modality novel pattern-extraction, pattern-discrimination and pattern-categorization using sparse code, consequently explaining why it requires hippocampal offline-consolidation. In contrast, the nonrandomness in layers 5/6-which consists of few specific cliques but a higher portion of more general cliques projecting mostly to subcortical systems-is ideal for feedback-control of motivation, emotion, consciousness and behaviors. These observations suggest that the brain's basic computational algorithm is indeed organized by the power-of-two-based permutation logic. This simple mathematical logic can account for brain computation across the entire evolutionary spectrum, ranging from the simplest neural networks to the most complex.


In vivo endomicroscopy improves detection of Barrett's esophagus-related neoplasia: a multicenter international randomized controlled trial (with video).
Confocal laser endomicroscopy (CLE) enables in vivo microscopic imaging of the GI tract mucosa. However, there are limited data on endoscope-based CLE (eCLE) for imaging Barrett's esophagus (BE). To compare high-definition white-light endoscopy (HDWLE) alone with random biopsy (RB) and HDWLE + eCLE and targeted biopsy (TB) for diagnosis of BE neoplasia. Multicenter, randomized, controlled trial. Academic medical centers. Adult patients with BE undergoing routine surveillance or referred for early neoplasia. Patients were randomized to HDWLE + RB (group 1) or HDWLE + eCLE + TB (group 2). Real-time diagnoses and management plans were recorded after HDWLE in both groups and after eCLE in group 2. Blinded expert pathology diagnosis was the reference standard. Diagnostic yield, performance characteristics, clinical impact. A total of 192 patients with BE were studied. HDWLE + eCLE + TB led to a lower number of mucosal biopsies and higher diagnostic yield for neoplasia (34% vs 7%; P < .0001), compared with HDWLE + RB but with comparable accuracy. HDWLE + eCLE + TB tripled the diagnostic yield for neoplasia (22% vs 6%; P = .002) and would have obviated the need for any biopsy in 65% of patients. The addition of eCLE to HDWLE increased the sensitivity for neoplasia detection to 96% from 40% (P < .0001) without significant reduction in specificity. In vivo CLE changed the treatment plan in 36% of patients. Tertiary-care referral centers and expert endoscopists limit generalizability. Real-time eCLE and TB after HDWLE can improve the diagnostic yield and accuracy for neoplasia and significantly impact in vivo decision making by altering the diagnosis and guiding therapy. ( NCT01124214.).


An interesting case of intramyometrial pregnancy.
A 27-year-old woman, gravida 3, para 1, at 9 weeks gestation, initially presented with clinical and ultrasonographic features suggestive of a missed spontaneous abortion for which surgical evacuation was performed. A diagnosis of ectopic pregnancy was made as on histological review no fetal or chorionic tissue was seen. Medical management for an ectopic pregnancy was initiated. Following methotrexate administration she was readmitted with severe abdominal pain. Findings on diagnostic laparoscopy revealed an asymmetrically enlarged swollen fundus. Hysteroscopy was performed concurrently demonstrating an empty uterine cavity. A diagnosis of intramyometrial pregnancy was made based on these findings. An MRI scan was performed postprocedure which supported the diagnosis. In view of her parity and future fertility medical management was adopted with methotrexate. She was followed up until hormone levels returned to baseline and serial scans showed a healed solid collection.


Scanning electron-microscopic evaluation of cuff shoulders in pediatric tracheal tubes.
Technical and conceptual shortcomings of cuffed pediatric tracheal tubes have been pointed out in the past, all representing a potential risk for mucosal damage of the pediatric airway. In this study, cuffed pediatric tracheal tubes from different manufacturers were investigated with regard to the cuff shoulder design using scanning electron microscopy (SEM). Cuffed pediatric tracheal tubes with the smallest internal diameter available were ordered from five manufacturers. SEM scans were performed from the tube shaft - cuff shoulder - tube cuff assembly and from the cuff shoulder alone. Each investigation was repeated in four samples of each tube brand. In addition, thickness of cuff membrane was measured. Major differences were found among the cuff shoulders investigated ranging from smooth transitions, softened borders to very sharp steps. There was also considerable difference in the thickness among the cuff membranes between the different tube brands ranging from 18 microm in polyurethane cuffs up to 90 microm in polyvinylchloride cuffs. Because the gap between the outer tracheal tube and the internal mucosal layer of the pediatric airway is often very narrow, some of the observed irregularities have the potential to injure the airway mucosa in pediatric patients, particularly during long-term use and firm fit of the tracheal tube in the airway. As cuffed tubes are increasingly used in small children, the observed irregularities in some tracheal tube brands may need to be improved and their safety should be proved by the manufacturers.


A role for the thromboxane receptor in L-NAME hypertension.
Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was administered to TP-deficient (Tp-/-) and wild-type (Tp+/+) control mice in drinking water for 21 wk along with a high-salt (HS; 6% NaCl) diet. Administration of L-NAME increased urinary excretion of TxB2 to a similar extent in both Tp+/+ and Tp-/- animals. L-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp-/- mice throughout the study period (P<0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6+/-2% increase in heart-to-body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1+/-2.6%; P<0.05). In contrast, kidney hypertrophy was exaggerated in the Tp-/- mice compared with controls (37.1+/-5.4 vs. 12.3+/-2.3%; P<0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization, and interstitial chronic inflammation was also enhanced in the Tp-/- group (P<0.01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury.


Trial-by-Trial Variations in Subjective Attentional State are Reflected in Ongoing Prestimulus EEG Alpha Oscillations.
Parieto-occipital electroencephalogram (EEG) alpha power and subjective reports of attentional state are both associated with visual attention and awareness, but little is currently known about the relationship between these two measures. Here, we bring together these two literatures to explore the relationship between alpha activity and participants' introspective judgments of attentional state as each varied from trial-to-trial during performance of a visual detection task. We collected participants' subjective ratings of perceptual decision confidence and attentional state on continuous scales on each trial of a rapid serial visual presentation detection task while recording EEG. We found that confidence and attentional state ratings were largely uncorrelated with each other, but both were strongly associated with task performance and post-stimulus decision-related EEG activity. Crucially, attentional state ratings were also negatively associated with prestimulus EEG alpha power. Attesting to the robustness of this association, we were able to classify attentional state ratings via prestimulus alpha power on a single-trial basis. Moreover, when we repeated these analyses after smoothing the time series of attentional state ratings and alpha power with increasingly large sliding windows, both the correlations and classification performance improved considerably, with the peaks occurring at a sliding window size of approximately 7 min worth of trials. Our results therefore suggest that slow fluctuations in attentional state in the order of minutes are reflected in spontaneous alpha power. Since these subjective attentional state ratings were associated with objective measures of both behavior and neural activity, we suggest that they provide a simple and effective estimate of task engagement that could prove useful in operational settings that require human operators to maintain a sustained focus of visual attention.


The creation of new rotation arc to the rat latissimus dorsi musculo-cutaneous flap with delay procedures.
Latissimus dorsi musculocutaneous flap is one of the most frequently performed reconstructive techniques in surgery. Latissimus dorsi muscle has two arcs of rotation. It is classified as type V muscle. This muscle can be elevated on the thoracodorsal artery to cover large defects in the anterior chest and also, the muscle can be elevated on the segmental vessels to cover midline defects posteriorly. The aim of this study was to create a new arc of rotation on a vertical axis for the muscle and investigate effectiveness of vascular and chemical delays on the latissimus dorsi muscle flap with an inferior pedicle in an experimental rat model. We hypothesized that the latissimus dorsi muscle would be based on inferior pedicle by delay procedures. We tested two different types of delay: vascular and combination of vascular and chemical. We also tried to determine how many days of "delay" can elicit beneficial effects of vascular and combination delays in an inferior pedicled latissimus dorsi musculocutaneous flap. To accomplish this, 48 male Sprague-Dawley rats were randomly subjected to vascular or combination delay (vascular and chemical). In addition, one ear of each rat was assigned into a delay procedure and the other ear was used as a control. Results were evaluated macroscopically, and micro-angiography and histological examinations were also performed. As a result, there was a significant difference in viable flap areas between vascular delay alone and control groups (p < 0.05). The higher rate of flap viability was obtained in seven-day vascular delay alone. However, there was no significant difference in the viability between seven-day vascular delay and five-day vascular delay (p < 0.05), so the earliest time when the flap viability could be obtained was at five days. The rate of flap viability was significantly higher in the vascular delay combined with chemical delay than the control group (p < 0.05). The combination of vascular and chemical delays increased the rate of viability. Nevertheless, there was no significant difference between vascular delay alone and combination of vascular and chemical delays. Chemical delay did not significantly decrease the delay period. Better histological and microangiographical results were achieved in delay groups compared to control groups. We concluded that the arch of the latissimus dorsi musculocutaneous flap can be changed and the flap can be used for various purposes with the delay procedures.


Fluvoxamine CR in the long-term treatment of social anxiety disorder: the 12- to 24-week extension phase of a multicentre, randomized, placebo-controlled trial.
Fluvoxamine CR has been reported effective in the short-term (12-wk) treatment of generalized social anxiety disorder (social phobia). Social anxiety disorder (SAD) is, however, a chronic disorder thought to require maintenance treatment. We report on data from the extension phase of a short-term study, in order to explore the efficacy and safety profile of fluvoxamine CR (100-300 mg/d) in the longer-term treatment of this disorder. Adult outpatients with generalized social anxiety disorder (GSAD) at 35 centres in Europe, South Africa, and USA were included in an acute phase study (12 wk). Subjects who demonstrated at least minimal improvement by endpoint (n=112), were offered participation in an extension phase, in which medication was continued for a further 12 wk under double-blind conditions. Efficacy was assessed using the Liebowitz Social Anxiety Disorder Scale (LSAS), the Clinical Global Impression Global Improvement score (CGI-I), the Clinical Global Impressions Severity of Illness score (CGI-S), and the Sheehan Disability Scale (SDS). Safety and tolerability assessments were also performed at regular intervals. Subjects treated with fluvoxamine CR had a numerically greater decrease in LSAS total scores than subjects treated with placebo at endpoint. Analysis of data from baseline (day 1) to endpoint (last observation carried forward) demonstrated that this difference tended towards significance, while severity of illness on the CGI-S and disability on the SDS were significantly lower in the fluvoxamine CR group than in the placebo group. The same trends were observed when only data from weeks 12-24 were included in the analysis; although the magnitude of changes was smaller in the extension phase than in the acute phase, fluvoxamine CR-treated subjects continued to show improvement compared to placebo-treated subjects. Most treatment-emergent signs and symptoms (TESS) were mild to moderate in severity. No unexpected abnormalities were reported on vital signs, electrocardiagrams, or laboratory investigations. These data support the long-term efficacy, safety, and tolerability of fluvoxamine CR in the treatment of GSAD. Given the prevalence, persistence, and disability associated with GSAD, and the relative paucity of long-term treatment studies of SAD, the current dataset provides empirical support for the current clinical consensus that pharmacotherapy of this disorder should be continued beyond the acute phase.


Plasma C4d+ Endothelial Microvesicles Increase in Acute Antibody-Mediated Rejection.
Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. Currently, AMR diagnosis relies on biopsy which is an invasive procedure. A noninvasive biomarker of acute AMR could lead to early diagnosis and treatment of this condition and improve allograft outcome. Microvesicles are membrane-bound vesicles released from the cell surface after injury. We hypothesized that because AMR is associated with allograft endothelial injury and C4d deposition, plasma microvesicles positive for endothelial (CD144) marker and C4d are increased in this condition. We studied microvesicle concentration in the plasma of 95 kidney transplant patients with allograft dysfunction and compared with 23 healthy volunteers. Biopsy diagnosis and scoring was performed using Banff classification. In the 28 subjects with AMR, the density of C4d+/CD144+ microvesicles was on average 11-fold (P = 0.002) higher than transplant recipients with no AMR and 24-fold (P = 0.008) than healthy volunteers. Densities of C4d+ and C4d+/annexin V+ (C4d+/AVB+) microvesicles were also increased in AMR patients compared with no AMR and healthy subjects. C4d+/AVB+ microvesicles correlated with AMR biopsy severity. Nine patients with acute AMR that received treatment showed a mean 72% decrease (P = 0.01) in C4d+/CD144+ microvesicle concentration compared with pretreatment values. Quantification of plasma C4d+ microvesicles provides information about presence of AMR, its severity and response to treatment in transplant patients.


Regulation of the properties of the heme-NO complexes in nitric-oxide synthase by hydrogen bonding to the proximal cysteine.
Nitric-oxide synthase (NOS) catalyzes the formation of NO and citrulline from l-arginine and oxygen. However, the NO so formed has been found to auto-inhibit the enzymatic activity significantly. We hypothesized that the NO reactivity is in part controlled by hydrogen bonding between the conserved tryptophan residue (position 409 in the neuronal isoform of NOS (nNOS)) and the cysteine residue that forms the proximal bond to the heme. By using resonance Raman spectroscopy and NO as a probe of the heme environment, we show that in the W409F and W409Y mutants of the oxygenase domain of the neuronal enzyme (nNOSox), the Fe-NO bond in the Fe3+NO complex is weaker than in the wild type enzyme, consistent with the loss of a hydrogen bond on the sulfur atom of the proximal cysteine residue. The weaker Fe-NO bond in the W409F and W409Y mutants might result in a faster rate of NO dissociation from the ferric heme in the Trp-409 mutants as compared with the wild type enzyme, which could contribute to the lower accumulation of the inhibitory NO-bound complexes observed during catalysis with the Trp-409 mutants (Adak, S., Crooks, C., Wang, Q., Crane, B. R., Tainer, J. A., Getzoff, E. D., and Stuehr, D. J. (1999) J. Biol. Chem. 274, 26907-26911). The optical and resonance Raman spectra of the Fe2+NO complexes of the Trp-409 mutants differ from those of the wild type enzyme and indicate that a significant population of a five-coordinate Fe2+NO complex is present. These data show that the hydrogen bond provided by the Trp-409 residue is necessary to maintain the thiolate coordination when NO binds to the ferrous heme. Taken together our results indicate that the heme environment on the proximal side of nNOS is critical for the formation of a stable iron-cysteine bond and for the control of the electronic properties of heme-NO complexes.


Target gene sequencing to characterize the penicillin G susceptibility of Neisseria meningitidis.
Clinical isolates of Neisseria meningitidis with reduced susceptibility to penicillin G (intermediate isolates, Pen(I)) harbor alterations in the penA gene encoding the penicillin binding protein 2 (PBP2). A 402-bp DNA fragment in the 3' half of penA was sequenced from a collection of 1,670 meningococcal clinical isolates from 22 countries that spanned 60 years. Phenotyping, genotyping, and the determination of MICs of penicillin G were also performed. A total of 139 different penA alleles were detected with 38 alleles that were highly related, clustered together in maximum-likelihood analysis and corresponded to the penicillin G-susceptible isolates. The remaining 101 penA alleles were highly diverse, corresponded to different genotypes or phenotypes, and accounted for 38% of isolates, but no clonal expansion was detected. Analysis of the altered alleles that were represented by at least five isolates showed high correlation with the Pen(I) phenotype. The deduced amino acid sequence of the corresponding PBP2 comprised five amino acid residues that were always altered. This correlation was not complete for rare alleles, suggesting that other mechanisms may also be involved in conferring reduced susceptibility to penicillin. Evidence of mosaic structures through events of interspecies recombination was also detected in altered alleles. A new website was created based on the data from this work (http://neisseria.org/nm/typing/penA). These data argue for the use of penA sequencing to identify isolates with reduced susceptibility to penicillin G and as a tool to improve typing of meningococcal isolates, as well as to analyze DNA exchange among Neisseria species.


3D differentiation of neural stem cells in macroporous photopolymerizable hydrogel scaffolds.
Neural stem/progenitor cells (NSPCs) are the stem cell of the adult central nervous system (CNS). These cells are able to differentiate into the major cell types found in the CNS (neurons, oligodendrocytes, astrocytes), thus NSPCs are the mechanism by which the adult CNS could potentially regenerate after injury or disorder. Microenviromental factors are critical for guiding NSPC differentiation and are thus important for neural tissue engineering. In this study, D-mannitol crystals were mixed with photocrosslinkable methacrylamide chitosan (MAC) as a porogen to enhance pore size during hydrogel formation. D-mannitol was admixed to MAC at 5, 10 and 20 wt% D-mannitol per total initial hydrogel weight. D-mannitol crystals were observed to dissolve and leave the scaffold within 1 hr. Quantification of resulting average pore sizes showed that D-mannitol addition resulted in larger average pore size (5 wt%, 4060±160 µm(2), 10 wt%, 6330±1160 µm(2), 20 wt%, 7600±1550 µm(2)) compared with controls (0 wt%, 3150±220 µm(2)). Oxygen diffusion studies demonstrated that larger average pore area resulted in enhanced oxygen diffusion through scaffolds. Finally, the differentiation responses of NSPCs to phenotypic differentiation conditions were studied for neurons, astrocytes and oligodendrocytes in hydrogels of varied porosity over 14 d. Quantification of total cell numbers at day 7 and 14, showed that cell numbers decreased with increased porosity and over the length of the culture. At day 14 immunohistochemistry quantification for primary cell types demonstrated significant differentiation to the desired cells types, and that total percentages of each cell type was greatest when scaffolds were more porous. These results suggest that larger pore sizes in MAC hydrogels effectively promote NSPC 3D differentiation.


A Taxonomy of Delivery and Documentation Deviations During Delivery of High-Fidelity Simulations.
We developed a taxonomy of simulation delivery and documentation deviations noted during a multicenter, high-fidelity simulation trial that was conducted to assess practicing physicians' performance. Eight simulation centers sought to implement standardized scenarios over 2 years. Rules, guidelines, and detailed scenario scripts were established to facilitate reproducible scenario delivery; however, pilot trials revealed deviations from those rubrics. A taxonomy with hierarchically arranged terms that define a lack of standardization of simulation scenario delivery was then created to aid educators and researchers in assessing and describing their ability to reproducibly conduct simulations. Thirty-six types of delivery or documentation deviations were identified from the scenario scripts and study rules. Using a Delphi technique and open card sorting, simulation experts formulated a taxonomy of high-fidelity simulation execution and documentation deviations. The taxonomy was iteratively refined and then tested by 2 investigators not involved with its development. The taxonomy has 2 main classes, simulation center deviation and participant deviation, which are further subdivided into as many as 6 subclasses. Inter-rater classification agreement using the taxonomy was 74% or greater for each of the 7 levels of its hierarchy. Cohen kappa calculations confirmed substantial agreement beyond that expected by chance. All deviations were classified within the taxonomy. This is a useful taxonomy that standardizes terms for simulation delivery and documentation deviations, facilitates quality assurance in scenario delivery, and enables quantification of the impact of deviations upon simulation-based performance assessment.


Rehospitalization among elderly patients with thyroid cancer after thyroidectomy are prevalent and costly.
Thyroid cancer increases in incidence and aggressiveness with age. The elderly are the fastest growing segment of the U.S. population. Reducing rates of rehospitalization would lower cost and improve quality of care. This is the first study to report population-level information characterizing rehospitalization after thyroidectomy among the elderly. The Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database was used to identify patients older than aged 65 years with thyroid cancer who underwent thyroidectomy from 1997-2002. Patient and hospital characteristics were studied to predict the risk of rehospitalization. Outcomes were 30-day unplanned rehospitalization rate, cost, and length of stay (LOS) of readmission. Of 2,127 patients identified, 69% were women, 84% had differentiated thyroid cancer, and 52% underwent total thyroidectomy. Mean age was 74 years. A total of 171 patients (8%) underwent 30-day unplanned rehospitalization. Rehospitalization was associated with increased comorbidity, advanced stage, number of lymph nodes examined, increased LOS of index admission, and small hospital size (all P < 0.05). Patients with a complication during index hospital stay were more likely to be readmitted (P < 0.001), whereas patients who saw an outpatient medical provider after index discharge returned less frequently (P < 0.001). Forty-seven percent of readmissions were for endocrine-related causes. Mean LOS and cost of rehospitalization were 3.5 days and $5,921, respectively. Unplanned rehospitalization was associated with death at 1 year compared with nonrehospitalized patients (18% vs. 6%; P < 0.001). Rehospitalization among Medicare beneficiaries with thyroid cancer after thyroidectomy is prevalent and costly. Further study of predictors could identify high-risk patients for whom enhanced preoperative triage, improved discharge planning, and increased outpatient support might prove cost-effective.


The longest (A+T) and (G+C) blocks in the human and other genomes.
We analysed complete or almost complete nucleotide sequences of the human, chimp, mouse, rat, chicken, dog, and other genomes to find that they contain extremely long (A+T) a (G+C) blocks that do not occur at all in the corresponding randomized sequences. The longest is an (A+T) block containing 1040 consecutive AT pairs that occurs in the 16th human chromosome. The longest human (G+C) block has 261 bp in length. About a half of the longest blocks occur in introns. The (A+T) blocks are discrete units whereas the (G+C) blocks are diffuse. They are imbedded in the genome through connectors longer than 1 kilobase where the (G+C) content gradually decreases to the value of 50%. Remarkably, the (A+T) as well as (G+C) blocks are substantially shorter in the chimp genome. Chicken is characteristic by very long (G+C) blocks that are even longer than in the human genome. Though much shorter, long (G+C) and especially (A+T) blocks occur in lower organisms as well, which means that AT and GC pair clustering is an ancient property that has evolved into large scales in higher eukaryote genomes and the human genome in particular. Very long (A+T) and (G+C) blocks confer specific biophysical properties on DNA that are likely to influence genome folding in cell nuclei and its functional properties.


Speech-driven environmental control systems--a qualitative analysis of users' perceptions.
To explore users' experiences and perceptions of speech-driven environmental control systems (SPECS) as part of a larger project aiming to develop a new SPECS. The motivation for this part of the project was to add to the evidence base for the use of SPECS and to determine the key design specifications for a new speech-driven system from a user's perspective. Semi-structured interviews were conducted with 12 users of SPECS from around the United Kingdom. These interviews were transcribed and analysed using a qualitative method based on framework analysis. Reliability is the main influence on the use of SPECS. All the participants gave examples of occasions when their speech-driven system was unreliable; in some instances, this unreliability was reported as not being a problem (e.g., for changing television channels); however, it was perceived as a problem for more safety critical functions (e.g., opening a door). Reliability was cited by participants as the reason for using a switch-operated system as back up. Benefits of speech-driven systems focused on speech operation enabling access when other methods were not possible; quicker operation and better aesthetic considerations. Overall, there was a perception of increased independence from the use of speech-driven environmental control. In general, speech was considered a useful method of operating environmental controls by the participants interviewed; however, their perceptions regarding reliability often influenced their decision to have backup or alternative systems for certain functions.


Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A.
The human polydeoxynucleotide cytidine deaminases APOBEC3A, APOBEC3C, and APOBEC3H are capable of mutating viral DNA in the nucleus, whereas APOBEC3A alone efficiently edits nuclear DNA. Deamination is rapidly followed by excision of uracil residues and can lead to double-stranded breaks. It is not known to which protein networks these DNA mutators belong. Using a yeast two-hybrid screen, we identified the human homolog of Drosophila Tribbles 3, TRIB3, as an interactor for APOBEC3A and APOBEC3C. The interaction was confirmed by co-affinity purification. Co-transfection of APOBEC3A with a TRIB3 expression vector reduced nuclear DNA editing whereas siRNA knockdown of TRIB3 increased the levels of nuclear DNA editing, indicating that TRIB3 functioned as a repressor of A3A. It also repressed A3A-associated γH2AX positive double-stranded breaks. The interaction results in degradation of A3A in a proteasome-independent manner. TRIB3 has been linked to cancer and via its own interactors and links the A3A DNA mutators to the Rb-BRCA1-ATM network. TRIB3 emerges as an important guardian of genome integrity.


Long-term clinical and visual outcomes after surgical resection of pediatric pilocytic/pilomyxoid optic pathway gliomas.
The choice of treatment modality for optic pathway gliomas (OPGs) is controversial. Chemotherapy is widely regarded as first-line therapy; however, subtotal resections have been reported for decompression or salvage therapy as first- and second-line treatment. The goal of this study was to further investigate the role and efficacy of resection for OPGs. A retrospective chart review was performed on 83 children who underwent surgical treatment for OPGs between 1986 and 2014. Pathology was reviewed by a neuropathologist. Clinical outcomes, including progression-free survival (PFS), overall survival (OS), and complications, were analyzed. The 5- and 10-year PFS rates were 55% and 46%, respectively. The 5- and 10-year OS rates were 87% and 78%, respectively. The median extent of resection was 80% (range 30%-98%). Age less than 2 years at surgery and pilomyxoid features of the tumor were found to be associated with significantly lower 5-year OS. No difference was seen in PFS or OS of children treated with surgery as a first-line treatment compared with children with surgery as a second- or third-line treatment. Severe complications included new disabling visual deficit in 5%, focal neurological deficit in 8%, and infection in 2%. New hormone deficiency occurred in 22% of the children. Approximately half of all children experience a long-term benefit from resection both as primary treatment and as a second-line therapy after failure of primary treatment. Primary surgery does not appear to have a significant benefit for children younger than 2 years or tumors with pilomyxoid features. Given the risks associated with surgery, an interdisciplinary approach is needed to tailor the treatment plan to the individual characteristics of each child.


Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis.
Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA-mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA-mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA-mutated HER2-negative metastatic breast cancer.


Kommerell Diverticulum: Right Aortic Arch with Anomalous Origin of Left Subclavian Artery and Duplicity of Right Vertebral Artery in a 16-Year-Old Girl.
BACKGROUND Kommerell diverticulum with a right-sided aortic arch is a rare congenital anatomical condition most often observed in adults. A possible etiology of the subclavian artery's anomalous origin would be an abnormality in regression of the fourth primitive aortic arch during embryonic development. CASE REPORT We report on the case of a 16-year-old female patient presenting with complaints of occasional tachycardia and mild non-specific dyspnea after anxiety crises. Physical examination revealed lower amplitude of the pulses in the left upper limb compared to the right upper limb, and difference in blood pressure (BP) values of 80×60 mmHg, and 100×60 mmHg, respectively. Different radiological imaging modalities were performed to elucidate a possible vascular abnormality. Multislice detector computed tomography angiography of the thoracic aorta and supra-aortic trunks showed a right-sided aortic arch and an aberrant origin of the left subclavian artery with a retroesophageal course and dilation of its emergence (Kommerell diverticulum), as well as duplicity of the right vertebral artery (RVA). Considering the actual small diameter of the diverticulum and the absence of dysphagia or severe external esophageal compression analyzed by the esophagogram, vascular surgery was not indicated. Since complications have been described in the literature, the patient must be kept under observation in the future. CONCLUSIONS Congenital vascular alterations, including Kommerell diverticulum with right-sided aortic arch and the aberrant origin of the left subclavian artery, should be suspected in otherwise asymptomatic young patients with few clinical manifestations. Investigation with different imaging methods helps to clarify the vascular abnormalities, to support a possible surgical procedure indication, and to monitor the patients in follow-up.


Mutations in Saccharomyces cerevisiae that block meiotic prophase chromosome metabolism and confer cell cycle arrest at pachytene identify two new meiosis-specific genes SAE1 and SAE3.
Two new meiosis-specific genes, SAE1 and SAE3, have been identified in a screen for mutations that confer an intermediate block in meiotic prophase. Such mutations confer a block to spore formation that is circumvented by addition of a mutation that eliminates meiotic recombination initiation and other aspects of chromosome metabolism, i.e., spo11. We show that sae1-1 and sae3-1 mutations each confer a distinct defect in meiotic recombination. sae1-1 produces recombinants but very slowly and ultimately to less than half the wild-type level; sae3-1 makes persistent hyper-resected meiotic double-strand breaks and has a severe defect in formation of recombinants. Both mutants arrest at the pachytene stage of meiotic prophase, sae1-1 temporarily and sae3-1 permanently. The phenotypes conferred by sae3-1 are similar to those conferred by mutation of the yeast RecA homologue DMC1, suggesting that SAE3 and DMC1 act at the same step(s) of chromosome metabolism. These results provide further evidence that intermediate blocks to prophase chromosome metabolism cause cell-cycle arrest. SAE1 encodes a 208-residue protein homologous to vertebrate mRNA cap-binding protein 20. SAE3 corresponds to a meiosis-specific RNA encoding an unusually short open reading frame of 50 codons.


Acute distal radioulnar joint instability.
The distal radioulnar joint (DRUJ) is critical for pronosupination of the forearm and for upper extremity function in general. Because of its critical role in tool handling, some authors place the human DRUJ on par with the opposable thumb in the evolution of man. This seemingly simple cylindrical joint is stabilized by a complex network of soft tissue constraints, primarily components of the triangular fibrocartilage complex. Chief among these are the dorsal and palmar radioulnar ligaments. Any injury that disrupts these stabilizers, their balanced tension, or the bony congruity of the joint will have a major deleterious effect on hand function. Although they can occur in isolation, injuries causing acute DRUJ instability generally are associated with other trauma to the forearm-wrist complex. When managing these associated injuries, it is paramount to have a high index of suspicion for associated acute DRUJ instability. If the DRUJ is evaluated and stabilized in the acute setting, the more difficult clinical problem of chronic DRUJ instability can be avoided.


Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element.
The human immunodeficiency virus type 1 (HIV) Rev protein is thought to be involved in the export of unspliced or singly spliced viral mRNAs from the nucleus to the cytoplasm. This function is mediated by a sequence-specific interaction with a cis-acting RNA element, the Rev response element (RRE), present in these intron-containing RNAs. To identify possible host proteins involved in Rev function, we fractionated nuclear cell extracts with a Rev affinity column. A single, tightly associated Rev-binding protein was identified; this protein is the mammalian nucleolar protein B23. The interaction between HIV Rev and B23 is very specific, as it was observed in complex cell extracts. The complex is also very stable toward dissociation by high salt concentrations. Despite the stability of the Rev-B23 protein complex, the addition of RRE, but not control RNA, led to the displacement of B23 and the formation of a specific Rev-RRE complex. The mammalian nucleolar protein B23 or its amphibian counterpart No38 is believed to function as a shuttle receptor for the nuclear import of ribosomal proteins. B23 may also serve as a shuttle for the import of HIV Rev from the cytoplasm into the nucleus or nucleolus to allow further rounds of export of RRE-containing viral RNAs.


30-day in-hospital mortality after acute myocardial infarction in Tuscany (Italy): an observational study using hospital discharge data.
Coronary heart disease is the leading cause of mortality in the world. One of the outcome indicators recently used to measure hospital performance is 30-day mortality after acute myocardial infarction (AMI). This indicator has proven to be a valid and reproducible indicator of the appropriateness and effectiveness of the diagnostic and therapeutic process for AMI patients after hospital admission. The aim of this study was to examine the determinants of inter-hospital variability on 30-day in-hospital mortality after AMI in Tuscany. This indicator is a proxy of 30-day mortality that includes only deaths occurred during the index or subsequent hospitalizations. The study population was identified from hospital discharge records (HDRs) and included all patients with primary or secondary ICD-9-CM codes of AMI (ICD-9 codes 410.xx) that were discharged between January 1, 2009 and November 30, 2009 from any hospital in Tuscany. The outcome of interest was 30-day all-cause in-hospital mortality, defined as a death occurring for any reason in the hospital within 30 days of the admission date. Because of the hierarchical structure of the data, with patients clustered into hospitals, random-effects (multilevel) logistic regression models were used. The models included patient risk factors and random intercepts for each hospital. The study included 5,832 patients, 61.90% male, with a mean age of 72.38 years. During the study period, 7.99% of patients died within 30 days of admission. The 30-day in-hospital mortality rate was significantly higher among patients with ST segment elevation myocardial infarction (STEMI) compared with those with non-ST segment elevation myocardial infarction (NSTEMI). The multilevel analysis which included only the hospital variance showed a significant inter-hospital variation in 30-day in-hospital mortality. When patient characteristics were added to the model, the hospital variance decreased. The multilevel analysis was then carried out separately in the two strata of patients with STEMI and NSTEMI. In the STEMI group, after adjusting for patient characteristics, some residual inter-hospital variation was found, and was related to the presence of a cardiac catheterisation laboratory. We have shown that it is possible to use routinely collected administrative data to predict mortality risk and to highlight inter-hospital differences. The distinction between STEMI and NSTEMI proved to be useful to detect organisational characteristics, which affected only the STEMI subgroup.


Enhancing Hybrid Prediction in Pearl Millet Using Genomic and/or Multi-Environment Phenotypic Information of Inbreds.
Genomic selection (GS) is an emerging methodology that helps select superior lines among experimental cultivars in plant breeding programs. It offers the opportunity to increase the productivity of cultivars by delivering increased genetic gains and reducing the breeding cycles. This methodology requires inexpensive and sufficiently dense marker information to be successful, and with whole genome sequencing, it has become an important tool in many crops. The recent assembly of the pearl millet genome has made it possible to employ GS models to improve the selection procedure in pearl millet breeding programs. Here, three GS models were implemented and compared using grain yield and dense molecular marker information of pearl millet obtained from two different genotyping platforms (C [conventional GBS RAD-seq] and T [tunable GBS tGBS]). The models were evaluated using three different cross-validation (CV) schemes mimicking real situations that breeders face in breeding programs: CV2 resembles an incomplete field trial, CV1 predicts the performance of untested hybrids, and CV0 predicts the performance of hybrids in unobserved environments. We found that (i) adding phenotypic information of parental inbreds to the calibration sets improved predictive ability, (ii) accounting for genotype-by-environment interaction also increased the performance of the models, and (iii) superior strategies should consider the use of the molecular markers derived from the T platform (tGBS).


The geochemical transformation of soils by agriculture and its dependence on soil erosion: An application of the geochemical mass balance approach.
Agricultural activities alter elemental budgets of soils and thus their long-term geochemical development and suitability for food production. This study examined the utility of a geochemical mass balance approach that has been frequently used for understanding geochemical aspect of soil formation, but has not previously been applied to agricultural settings. Protected forest served as a reference to quantify the cumulative fluxes of Ca, P, K, and Pb at a nearby tilled crop land. This comparison was made at two sites with contrasting erosional environments: relatively flat Coastal Plain in Delaware vs. hilly Piedmont in Pennsylvania. Mass balance calculations suggested that liming not only replenished the Ca lost prior to agricultural practice but also added substantial surplus at both sites. At the relatively slowly eroding Coastal Plain site, the agricultural soil exhibited enrichment of P and less depletion of K, while both elements were depleted in the forest soil. At the rapidly eroding Piedmont site, erosion inhibited P enrichment. In similar, agricultural Pb contamination appeared to have resulted in Pb enrichment in the relatively slowly eroding Coastal Plain agricultural soil, while not in the rapidly eroding Piedmont soils. We conclude that agricultural practices transform soils into a new geochemical state where current levels of Ca, P, and Pb exceed those provided by the local soil minerals, but such impacts are significantly offset by soil erosion.


Vitamin D Review: The Low Hanging Fruit for Human Health.
Vitamin D is an important hormone that is known for the regulation of calcium and phosphate metabolism. Vitamin D deficiency leads to rickets in children and osteoporosis in adults leading to poor bone mineralisation and can also lead to serious dental complications in the same population. Recent studies have shown vitamin D to work as a hormone needed not only in bone and teeth but also in other body organs from intrauterine life up to old age. It has been demonstrated that Vitamin D has various effects on biological processes that deal with cell growth, differentiation, cell death, immune regulation, DNA stability, and neuronal growth. Despite being readily formed in the body through the intervention of the sun, patients are still found to have low vitamin D levels. We review studies done to show how vitamin D works.


HEREDITARY DEFICIENCY OF SERUM ALPHA-L-ANTITRYPSIN.
Deficiency of the serum alpha(1),-antitrypsin appears to be under genetic control. The level of this protein is reduced to less than 10 percent of the norm in individuals homozygous for the trait, who may suffer from pulmonary emphysema. Heterozygous individuals have a concentration of serum alpha(1)-antitrypsin between 50 and 60 percent of normal, but appear to be in good health. The estimated heterozygous frequency of the trait in a small white population in Georgia is 2.1 percent.


What are the factors that contribute to the development of sexual dysfunction in breastfeeding women? A systematic scoping review protocol.
Female sexual dysfunction is a public health problem. Evidence suggests that the population of nursing women is more vulnerable to the phenomenon due to breast feeding. Thus, this protocol was developed to explore the factors that contribute to the development of sexual dysfunction in breastfeeding women. The systematic scoping review will be conducted in six stages, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. The databases used will be: PubMed, Excerpta Medica Database, Cumulative Index for Nursing and Allied Health Literature, PsycINFO, Science Direct, Web of Science and Google Scholar. The searches were made until 1 June 2018, and no retrospective time limit was used. For the organisation of the literature retrieved from the databases, the EndNote Basic manager will be used. The Cochrane model will be used for the data extraction. The analysis of the quantitative data will be carried out through descriptive statistics and the qualitative data will be submitted to thematic analysis. The methodological quality of the empirical studies will be evaluated using the Mixed Methods Appraisal Tool. As it will be a review study, without human involvement, there will be no need for ethical approval. The results will be disseminated in a scientific journal, as well as in various media, such as: conferences, seminars, congresses or symposia.


Expression of activated PIK3CA in ovarian surface epithelium results in hyperplasia but not tumor formation.
The Phosphatidylinositol 3'-kinase is a key regulator in various cancer-associated signal transduction pathways. Genetic alterations of its catalytic subunit alpha, PIK3CA, have been identified in ovarian cancer. Our in vivo data suggests that PIK3CA activation is one of the early genetic events in ovarian cancer. However, its role in malignant transformation of ovarian surface epithelium (OSE) is largely unclear. Using the Müllerian inhibiting substance type II receptor (MISIIR) promoter, we generated transgenic mice that expressed activated PIK3CA in the Müllerian epithelium. Overexpression of PIK3CA in OSE induced remarkable hyperplasia, but was not able to malignantly transform OSE in vivo. The consistent result was also observed in primary cultured OSEs. Although enforced expression of PIK3CA could not induce OSE anchorage-independent growth, it significantly increased anchorage-independent growth of OSE transformed by mutant K-ras. While PIK3CA activation may not be able to initiate OSE transformation, we conclude that activation of PIK3CA may be an important molecular event contributing to the maintenance of OSE transformation initiated by oncogenes such as K-ras.


Broadening the repertoire of melanoma-associated T-cell epitopes.
Immune therapy has provided a significant breakthrough in the treatment of metastatic melanoma. Despite the remarkable clinical efficacy and established involvement of effector CD8 T cells, the knowledge of the exact peptide-MHC complexes recognized by T cells on the tumor cell surface is limited. Many melanoma-associated T-cell epitopes have been described, but this knowledge remains largely restricted to HLA-A2, and we lack understanding of the T-cell recognition in the context of other HLA molecules. We selected six melanoma-associated antigens (MAGE-A3, NY-ESO-1, gp100, Mart1, tyrosinase and TRP-2) that are frequently recognized in patients with the aim of identifying novel T-cell epitopes restricted to HLA-A1, -A3, -A11 and -B7. Using in silico prediction and in vitro confirmation, we identified 127 MHC ligands and analyzed the T-cell responses against these ligands via the MHC multimer-based enrichment of peripheral blood from 39 melanoma patients and 10 healthy donors. To dissect the T-cell reactivity against this large peptide library, we used combinatorial-encoded MHC multimers and observed the T-cell responses against 17 different peptide-MHC complexes in the patient group and four in the healthy donor group. We confirmed the processing and presentation of HLA-A3-restricted T-cell epitopes from tyrosinase (TQYESGSMDK) and gp100 (LIYRRRLMK) and an HLA-A11-restricted T-cell epitope from gp100 (AVGATKVPR) via the cytolytic T-cell recognition of melanoma cell lines and/or K562 cells expressing the appropriate antigen and HLA molecule. We further found T-cell reactivity against two of the identified sequences among tumor-infiltrating lymphocytes from melanoma patients, suggesting a potential clinical relevance of these sequences.


Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle.
A therapeutic approach for Duchenne muscular dystrophy (DMD) is to up-regulate utrophin in skeletal muscle in an effort to compensate for the lack of dystrophin. We previously hypothesized that promotion of the slow, oxidative myogenic program, which triggers utrophin up-regulation, can attenuate the dystrophic pathology in mdx animals. Since treatment of healthy mice with the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) enhances oxidative capacity and elicits a fast-to-slow fiber-type transition, we evaluated the effects of chronic AMPK stimulation on skeletal muscle phenotype and utrophin expression in mdx mice. Daily AICAR administration (500 mg/kg/day, 30 days) of 5-7-week-old mdx animals induced an elevation in mitochondrial cytochrome c oxidase enzyme activity, an increase in myosin heavy-chain type IIa-positive fibers and slower twitch contraction kinetics in the fast, glycolytic extensor digitorum longus muscle. Utrophin expression was significantly enhanced in response to AICAR, which occurred coincident with an elevated β-dystroglycan expression along the sarcolemma. These adaptations were associated with an increase in sarcolemmal structural integrity under basal conditions, as well as during damaging eccentric contractions ex vivo. Notably, peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) and silent information regulator two ortholog 1 protein contents were significantly higher in muscle from mdx mice compared with wild-type littermates and AICAR further increased PGC-1α expression. Our data show that AICAR-evoked muscle plasticity results in beneficial phenotypic adaptations in mdx mice and suggest that the contextually novel application of this compound for muscular dystrophy warrants further study.


Effects of Crocetin Esters and Crocetin from Crocus sativus L. on Aortic Contractility in Rat Genetic Hypertension.
Endothelial dysfunction, characterized by an enhancement in vasoconstriction, is clearly associated with hypertension. Saffron (Crocus sativus L.) bioactive compounds have been recognized to have hypotensive properties. Recently, we have reported that crocetin exhibits potent vasodilator effects on isolated aortic rings from hypertensive rats. In this work, we have aimed to analyze the anticontractile ability of crocetin or crocetin esters pool (crocins) isolated from saffron. Thus, we have studied the effects of saffron carotenoids on endothelium-dependent and -independent regulation of smooth muscle contractility in genetic hypertension. We have measured the isometric responses of aortic segments with or without endothelium obtained from spontaneously hypertensive rats. The effects of carotenoids were studied by assessing the endothelial modulation of phenylephrine-induced contractions (10(-9)-10(-5) M) in the presence or absence of crocetin or crocins. The role of nitric oxide and prostanoids was analyzed by performing the experiments with L-NAME (NG-nitro-l-arginine methyl ester) or indomethacin (both 10(-5) M), respectively. Crocetin, and to a minor extent crocins, diminished the maximum contractility of phenylephrine in intact rings, while crocins, but not crocetin, increased this contractility in de-endothelizated vessels. In the intact vessels, the effect of crocetin on contractility was unaffected by indomethacin but was abolished by L-NAME. However, crocetin but not crocins, lowered the already increased contractility caused by L-NAME. Saffron compounds, but especially crocetin have endothelium-dependent prorelaxing actions. Crocins have procontractile actions that take place via smooth muscle cell mechanisms. These results suggest that crocetin and crocins activate different mechanisms involved in the vasoconstriction pathway in hypertension.


Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus.
To evaluate suggested associations between childhood vaccinations, particularly against hepatitis B and Haemophilus influenzae type b, and risk of developing type 1 diabetes; and to determine whether timing of vaccination influences risk. We conducted a case-control study within 4 health maintenance organizations (HMOs) that participate in the Vaccine Safety Datalink project of the Centers for Disease Control and Prevention. Study eligibility was restricted to children who met the following criteria: 1) born during 1988 through 1997; 2) HMO member since birth; 3) continuously enrolled for first 6 months of life; and 4) at least 12 months of HMO membership before diabetes incidence date (or index date for controls) unless incidence date was before 12 months of age. All 4 HMOs maintain registries of their members who have diabetes, and we used the registries to identify potential cases of diabetes. We conducted chart reviews to verify that potential cases met the World Health Organization epidemiologic case definition for type 1 diabetes mellitus (ie, a physician's diagnosis of diabetes plus treatment with daily insulin injections). We defined the incidence date of diabetes as the first date that the child received a diagnosis of diabetes. We attempted to match 3 controls to each case. Controls had the same eligibility criteria as cases and were matched to individual cases on HMO, sex, date of birth (within 7 days), and length of health plan enrollment (up to the incidence or index date). The index date for controls was defined as the incidence date of the case to which the control was matched. Chart abstraction was performed by trained chart abstractors using standardized forms. In addition to complete vaccination histories, the chart abstraction forms for both cases and controls included information on sociodemographic characteristics, selected medical conditions, history of breastfeeding, and family medical history. We used conditional logistic regression to estimate the odds ratio (OR) of diabetes associated with vaccination, with vaccine exposure defined as before the diabetes incidence date (or index date for controls). Two hundred fifty-two confirmed cases of diabetes and 768 matched controls met the study eligibility criteria. The OR (95% confidence interval) for the association with type 1 diabetes was 0.28 (0.07-1.06) for whole cell pertussis vaccine (predominantly in combination as diphtheria, tetanus toxoids and pertussis vaccine), 1.36 (0.70-2.63) for measles-mumps-rubella, 1.14 (0.51-2.57) for Haemophilus influenzae type b, 0.81 (0.52-1.27) for hepatitis B vaccine, 1.16 (0.72-1.89) for varicella vaccine, and 0.92 (0.53-1.57) for acellular pertussis-containing vaccines. Compared with children who had not received hepatitis B vaccine, the OR of diabetes was 0.51 (0.23-1.15) for children vaccinated at birth and 0.86 (0.54-1.35) for those first vaccinated against hepatitis B at 2 months of age or later. Race and ethnicity and family history of diabetes were independently associated with risk of type 1 diabetes, but adjustment for these factors did not materially alter the ORs for any of the vaccines. In this large, population-based, case-control study, we did not find an increased risk of type 1 diabetes associated with any of the routinely recommended childhood vaccines. Our study adds to previous research by providing data on newer vaccines, including hepatitis B, acellular pertussis, and varicella vaccines. For the older vaccines, our results are generally in agreement with previous studies in not finding any increased risks. Ours is the first epidemiologic study to evaluate the possibility that timing of vaccination is related to risk of clinical diabetes in children. Our results on hepatitis B vaccine do not support the hypothesis; risk of type 1 diabetes was not different between infants vaccinated at birth and those who received their first vaccination later in life. The results of our study and the preponderance of epidemiologic evidence do not support an association between any of the recommended childhood vaccines and an increased risk of type 1 diabetes. Suggestions that diabetes risk in humans may be altered by changes in the timing of vaccinations also are unfounded.


Optimized effective permittivity to improve imaging resolution of multilayered structures in the infrared.
Two periodic structures with different effective impedances, both comprising alternate layers of a positive and a negative permittivity material, are considered in the infrared. We find that the Fabry-Perot resonance effect periodically influences the sharpness of subwavelength focusing as the total thicknesses of the two structures increase, especially for the impedance-matched structure. On the basis of the improved multilayered structures, we design an optimized structure (i.e., the effective impedance is chosen between 0 and 1) for which a higher resolution less than lambda/12 (lambda is the wavelength in the air) can be obtained through weighing the advantages and disadvantages of the two different multilayered structures and choosing appropriate surface terminations.


Overprescribing of lipid lowering agents.
Undertreatment of hyperlipidemia has received considerable attention. However, little is known about trends in overprescribing of lipid lowering agents. We examined these trends and their associations with physician, practice, and organisational factors. 2034 physicians were surveyed twice: baseline (1996-7) and follow up (1998-9). On each occasion they were asked: "For what percentage of 50 year old men without other cardiac risk factors would you recommend an oral agent for total cholesterol of 240, LDL 150, and HDL 50 after 6 months on a low cholesterol diet?" During the survey period the National Cholesterol Education Program guidelines did not recommend prescribing for these patients. Binomial and multinomial logistic regressions assessed baseline overprescribing and longitudinal changes in overprescribing, accounting for complex sampling. 39% of physicians recommended prescribing at baseline (round 1), increasing at follow up (round 2) to 51% (p < 0.001). Physicians who were more likely to overprescribe at baseline were less likely to be board certified (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.38 to 0.63; p < 0.001), were in solo or two-physician practices (OR 1.88, 95% CI 1.46 to 2.41; p < 0.001), had more revenue from Medicare (OR 1.10, 95% CI 1.03 to 1.17; p = 0.004) or Medicaid (OR 1.09, 95% CI 1.01 to 1.18; p = 0.03), or were family physicians (OR 1.87, 95% CI 1.35 to 2.58; p < 0.001). Physicians with large increases in overprescibing were more likely than those with small increases in overprescribing to be international medical graduates (OR 2.09, 95% CI 1.20 to 3.64; p = 0.011) and to spend more hours in patient care (OR 1.14, 95% CI 1.03 to 1.26; p = 0.016). Overprescribing of lipid lowering agents is commonplace and increased. At baseline and longitudinally, overprescribing was primarily associated with physician and practice characteristics and not with organisational factors.


Prognosis in middle cerebral artery occlusion.
The natural history of MCA occlusion has become increasingly important since the surgical option of EC/IC bypass surgery has been available. The clinical course of 24 patients with angiographically-demonstrated occlusion of the MCA artery was reviewed. Eight patients presented with a major disabling stroke and five of these died during the acute phase of this ischemic event. The remaining 19 patients were followed for a mean of 54.2 months. There were five deaths in follow-up and two of these were due to subsequent strokes. Fourteen patients manifested a benign course: one of these had a further minor stroke and four had TIAs. Altogether, 3 strokes occurred during the follow-up period (2 fatal, 1 minor) and all were in the territory of the artery known to be occluded. Of those patients who survived their presenting ischemic event, 12 (63%) remained completely functional in terms of activities of daily living. MCA occlusion does not necessarily carry a poor prognosis with medial therapy alone and the role of bypass surgery hopefully will be clarified by the ongoing clinically randomized trial.


Sedentary and Physical Activity Patterns in Adults with Intellectual Disability.
Little is known about the patterns of sedentary time (ST) and physical activity (PA) levels throughout the week among adults and older adults with Intellectual Disability (ID). We analyzed ST and PA patterns of adults and older adults with ID. Forty-two adults and 42 older adults with mild to severe ID participated in this study. Height and weight were obtained to calculate Body Mass Index (BMI). Body fat and fat-free mass percentages were also obtained. Patterns of PA levels and ST were assessed with GT3X Actigraph accelerometers. Adults performed higher amounts of total PA and moderate to vigorous PA than older adults during the week, on weekdays and in center time (all p > 0.05). No differences between males and females were found for either PA levels or ST. Only 10.7% of the participants met the global recommendations on PA for health. The participants of the current study showed low PA levels and a high prevalence of ST. Interestingly, when comparing age and/or sex groups, no differences were observed for ST. Our findings provide novel and valuable information to be considered in future interventions aiming to increase PA levels and reduce ST.


Effects of aclidinium on determinants of COPD severity: symptoms and quality of life.
The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity.


Predictors and consequences of sexual "hookups" among college students: a short-term prospective study.
"Hookups," sexual interactions between partners who do not expect a romantic commitment, are believed to be common among adolescents and young adults. Most existing research is cross-sectional and has not investigated the antecedents or consequences of hookups. To our knowledge, this study provides the first prospective investigation of the hypothesized predictors of penetrative sex hookups (i.e., oral, vaginal, and anal sex) and the first exploration of the short-term mental health consequences of hookups. A total of 140 first-semester college students (109 females, 31 males) completed an anonymous survey early in their first semester; the survey assessed 18 potential predictors of hooking up that were identified from theory and past research. At the end of their first semester, students again responded to a survey and provided data on their oral and vaginal sex hookup behavior (occurrence and number of partners), distress, and self-esteem. Baseline and follow-up data were linked using unique codes that protected participants' anonymity. Pre-college hookup patterns, peak intoxication level, and situational triggers for hookups were consistent predictors of oral and vaginal sex hookup behavior (and number of hookup partners) in the first semester of college. Penetrative sex hookups increased psychological distress for females, but not for males. Implications for education and intervention as well as suggestions for future research are discussed.


Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer.
Screening ultrasound may depict small, node-negative breast cancers not seen on mammography. To compare the diagnostic yield, defined as the proportion of women with positive screen test results and positive reference standard, and performance of screening with ultrasound plus mammography vs mammography alone in women at elevated risk of breast cancer. From April 2004 to February 2006, 2809 women, with at least heterogeneously dense breast tissue in at least 1 quadrant, were recruited from 21 sites to undergo mammographic and physician-performed ultrasonographic examinations in randomized order by a radiologist masked to the other examination results. Reference standard was defined as a combination of pathology and 12-month follow-up and was available for 2637 (96.8%) of the 2725 eligible participants. Diagnostic yield, sensitivity, specificity, and diagnostic accuracy (assessed by the area under the receiver operating characteristic curve) of combined mammography plus ultrasound vs mammography alone and the positive predictive value of biopsy recommendations for mammography plus ultrasound vs mammography alone. Forty participants (41 breasts) were diagnosed with cancer: 8 suspicious on both ultrasound and mammography, 12 on ultrasound alone, 12 on mammography alone, and 8 participants (9 breasts) on neither. The diagnostic yield for mammography was 7.6 per 1000 women screened (20 of 2637) and increased to 11.8 per 1000 (31 of 2637) for combined mammography plus ultrasound; the supplemental yield was 4.2 per 1000 women screened (95% confidence interval [CI], 1.1-7.2 per 1000; P = .003 that supplemental yield is 0). The diagnostic accuracy for mammography was 0.78 (95% CI, 0.67-0.87) and increased to 0.91 (95% CI, 0.84-0.96) for mammography plus ultrasound (P = .003 that difference is 0). Of 12 supplemental cancers detected by ultrasound alone, 11 (92%) were invasive with a median size of 10 mm (range, 5-40 mm; mean [SE], 12.6 [3.0] mm) and 8 of the 9 lesions (89%) reported had negative nodes. The positive predictive value of biopsy recommendation after full diagnostic workup was 19 of 84 for mammography (22.6%; 95% CI, 14.2%-33%), 21 of 235 for ultrasound (8.9%, 95% CI, 5.6%-13.3%), and 31 of 276 for combined mammography plus ultrasound (11.2%; 95% CI. 7.8%-15.6%). Adding a single screening ultrasound to mammography will yield an additional 1.1 to 7.2 cancers per 1000 high-risk women, but it will also substantially increase the number of false positives. clinicaltrials.gov Identifier: NCT00072501.


Racial and age differences in colon examination surveillance following a diagnosis of colorectal cancer.
The purpose of this analysis is to describe factors associated with colorectal surveillance following diagnosis and treatment of nonmetastatic colorectal cancer. Subjects were identified as part of the HMO Cancer Research Network's study of colorectal cancer survivors. To be eligible for the main study, patients had to be part of the staff model components of health maintenance organizations in southeastern Michigan and Minnesota. Using computerized databases, individuals were identified who were 40 years or older with incident nonmetastatic colorectal cancer diagnosed between January 1, 1990, and December 31, 2000. Using data current through 2002, we analyzed the cohort using chi-square test statistics, life tables, and Cox proportional hazards models to understand variations in posttreatment surveillance practices. Subjects were followed up from date of diagnosis to date of recurrence, death, disenrollment from the health plan, or loss to follow-up, which ever came first. We assessed factors associated with colorectal surveillance at 1, 3, and 5 years after treatment. We also included an analysis comparing those who received an exam and those who didn't regardless of exam timing. A total of 908 patients were eligible for the main study. Of these, we excluded subjects who were not white or African American (n = 27), resulting in an analytic sample of 881 (97% of the eligible cohort). Twenty-five percent of subjects were African American, 43% were female, and 48% were aged 70 years or older. The proportion who received an exam at 1 year was 18%, at 3 years was 60%, and at 5 years was 67%. Chi-square tests showed that African Americans were statistically significantly less likely than whites to receive an exam at all three time points. The Cox proportional hazards model for examinations regardless of timing and adjusted for confounders showed that African Americans were still less likely than whites to receive an exam (hazard ratio = 0.62; 95% confidence interval [CI] = 0.51 to 0.75). The same trend in undersurveillance was also observed for those 80 years of age or older at diagnosis, with an adjusted hazard ratio of 0.39 (95% CI = 0.26 to 0.57). Our data indicate that colorectal cancer survivors who are African American or aged 80 years or more at diagnosis are less likely to receive posttreatment colorectal surveillance. Whether these differences are due to system or patient level barriers needs further study.


Rapid Consumption of Low Concentrations of Methyl Bromide by Soil Bacteria
A dynamic dilution system for producing low mixing ratios of methyl bromide (MeBr) and a sensitive analytical technique were used to study the uptake of MeBr by various soils. MeBr was removed within minutes from vials incubated with soils and ~10 parts per billion by volume of MeBr. Killed controls did not consume MeBr, and a mixture of the broad-spectrum antibiotics chloramphenicol and tetracycline inhibited MeBr uptake by 98%, indicating that all of the uptake of MeBr was biological and by bacteria. Temperature optima for MeBr uptake suggested a biological sink, yet soil moisture and temperature optima varied for different soils, implying that MeBr consumption activity by soil bacteria is diverse. The eucaryotic antibiotic cycloheximide had no effect on MeBr uptake, indicating that soil fungi were not involved in MeBr removal. MeBr consumption did not occur anaerobically. A dynamic flowthrough vial system was used to incubate soils at MeBr mixing ratios as low as those found in the remote atmosphere (5 to 15 parts per trillion by volume [pptv]). Soils consumed MeBr at all mixing ratios tested. Temperate forest and grassy lawn soils consumed MeBr most rapidly (rate constant [k] = 0.5 min-1), yet sandy temperate, boreal, and tropical forest soils also readily consumed MeBr. Amendments of CH4 up to 5% had no effect on MeBr uptake even at CH4:MeBr ratios of 10(7), and depth profiles of MeBr and CH4 consumption exhibited very different vertical rate optima, suggesting that methanotrophic bacteria, like those presently in culture, do not utilize MeBr when it is at atmospheric mixing ratios. Data acquired with gas flux chambers in the field demonstrated the very rapid in situ consumption of MeBr by soils. Uptake of MeBr at mixing ratios found in the remote atmosphere occurs via aerobic bacterial activity, displays first-order kinetics at mixing ratios from 5 pptv to ~1 part per million per volume, and is rapid enough to account for 25% of the global annual loss of atmospheric MeBr.


Evidence that asgB encodes a DNA-binding protein essential for growth and development of Myxococcus xanthus.
The asg mutants of Myxococcus xanthus are defective in production of extracellular A-signal, which serves as a cell density signal for fruiting-body development. The DNA sequence of asgB, one of the three asg genes, was determined. The deduced amino acid sequence of AsgB contains a DNA-binding helix-turn-helix motif near the C terminus. This putative helix-turn-helix is highly similar to the helix-turn-helix in region 4.2 of major sigma factors, which is the region that recognizes and interacts with -35 sequences of promoters. We propose that AsgB is a transcription factor that binds to DNA sequences similar to the -35 hexamer, TTGACA. Analyses of asgB RNA levels and expression of an asgB-lacZ translational fusion indicate that expression of asgB remains fairly constant during the transition from growth into early development. The mutation within the asgB480 allele was identified as an A-to-G transition that results in a threonine-to-alanine substitution in the predicted protein product. Attempts to replace the wild-type copy of asgB with a null allele failed, indicating that asgB may be essential for growth.


Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.
This was a 12-week randomized, placebo-controlled trial to assess the efficacy of quetiapine monotherapy in the treatment of posttraumatic stress disorder (PTSD). Eighty patients were randomly assigned to treatment with either quetiapine or placebo. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Secondary efficacy measures included the CAPS subscales, the Davidson Trauma Scale, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scales for severity of Illness and improvement, the Hamilton Depression Rating Scale (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). Safety measurements included adverse events, vital signs, the Abnormal Involuntary Movement Scale, the Barnes Akathisia Scale, the Simpson-Angus Scale, and the Arizona Sexual Experiences Scale. After a 1-week placebo run-in, quetiapine was started at a daily dosage of 25 mg and increased to a maximum of 800 mg; the average was 258 mg (range, 50-800 mg). Reductions in CAPS total, re-experiencing, and hyperarousal scores were significantly greater for the quetiapine group than for the placebo group. Greater improvements were also observed for quetiapine in scores on the Davidson Trauma Scale, CGI severity and improvement ratings, PANSS positive symptom and general psychopathology subscales, HAM-A, and HAM-D than for placebo. Adverse events were generally mild and expected based on prior studies of quetiapine in this and other patient population. There were no differences in safety measures between groups. Quetiapine monotherapy was efficacious in the treatment of PTSD. These findings suggest quetiapine as a single agent is effective in treating military PTSD.


Structure of an archaeal alanine:glyoxylate aminotransferase.
The crystal structure of a novel alanine:glyoxylate aminotransferase from the hyperthermophilic archaeon Thermococcus litoralis was determined at 2.3 A resolution. The asymmetric unit contains four homologous subunits and the functional tetramer is generated by noncrystallographic 222 symmetry. Although the main-chain coordinates of the monomer of the Thermococcus litoralis enzyme showed a high degree of similarity to those of aspartate aminotransferase from Thermus thermophilus HB8, the amino-acid residues involved in substrate binding in the aspartate aminotransferase are only partially conserved in the Thermococcus litoralis enzyme. This may account for the difference in the substrate specificities of the two enzymes.


Mapping and characterization of structural variation in 17,795 human genomes.
A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.


Multi institutional quantitative phantom study of yttrium-90 PET in PET/MRI: the MR-QUEST study.
Yttrium-90 (90Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level. Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with ≥ 0.60 MBq/ml, COVs were ≤ 25% in spheres ≥ 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%. Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for 90Y radioembolization.