Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice.
Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. We assessed the 5-year cumulative incidence, starting in 2003-05, of cervical cancer and CIN3 or worse for 331,818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. In 315,061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3.8 per 100,000 women per year, slightly higher than for the 306,969 who were both negative by HPV and Pap testing (3.2 per 100,000), and half the cancer risk of the 319,177 who were negative by Pap testing (7.5 per 100,000). 313,465 (99.5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16,757 positive by HPV testing (12.1%vs 5.9%; p<0.0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0.86%vs 0.16%; p=0.004). 12,208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, [corrected] 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.


Quantitative peptidomics of pituitary glands from mice deficient in copper transport.
We previously described a method of quantitating levels of peptides in Cpe(fat)/Cpe(fat) mice using affinity chromatography to isolate peptide-processing intermediates and differential isotopic labeling/mass spectrometry. In the present study, we compared two different isotopic labels, acetic anhydride and succinic anhydride for detection and quantitation of peptides in wild type mice. As previously found for acetic anhydride, succinic anhydride efficiently labels all primary amines in various peptides. Of these two reagents, succinic anhydride provides better resolution between the heavy and light peaks of the labelled peptides due to a greater mass difference between the deuterated (heavy) and non-deuterated (light) form of this label (4 Da for succinate, 3 Da for acetate). Using succinic anhydride labeling, the accuracy of measuring 1:1 and 1:2 ratios of peptides in pituitary extracts was within 5% of the theoretical value for most peptides. The accuracy with succinic anhydride is comparable to the accuracy of acetic anhydride and more peptides could be detected and quantitated with succinic anhydride. The two labels were then used to examine pituitary peptides in mice with a defect in copper transport (Atp7a mice) vs wild type mice. Using succinic anhydride, 13 peptides could be detected, 12 of which matched the theoretical mass of known pituitary peptides. Five of the six peptides which contain C-terminal amide groups were significantly decreased in the Atp7a mice relative to wild type mice, whereas only one non-amidated peptide was significantly decreased in Atp7a mice. With acetic anhydride, only five peptides could be quantitated. The three peptides which contain C-terminal amide groups were decreased approximately 30% in the Atp7a mice. The selective decrease in amidated peptides in Atp7a mice is consistent with the copper-requirement of the enzyme that forms C-terminal amides.


Felty's Syndrome, Insights and Updates.
Felty's syndrome (FS) is characterized by the triad of seropositive rheumatoid arthritis (RA) with destructive joint involvement, splenomegaly and neutropenia. Current data shows that 1-3 % of RA patients are complicated with FS with an estimated prevalence of 10 per 100,000 populations. The complete triad is not an absolute requirement, but persistent neutropenia with an absolute neutrophil count (ANC) generally less than 1500/mm3 is necessary for establishing the diagnosis. Felty's syndrome may be asymptomatic but serious local or systemic infections may be the first clue to the diagnosis. FS is easily overlooked by parallel diagnoses of Sjӧgren syndrome or systemic lupus erythematosus or lymphohematopoietic malignancies. The role of genetic (HLA DR4) is more prominent in FS in comparison to classic rheumatoid arthritis. There is large body of evidence that in FS patients, both cellular and humoral immune systems participate in neutrophil activation, and apoptosis and its adherence to endothelial cells in the spleen. It has been demonstrated that proinflammatory cytokines may have inhibitory effects on bone marrow granulopoiesis. Binding of IgGs to neutrophil extracellular chromatin traps (NET) leading to neutrophil death plays a crucial role in its pathophysiology. In turn, "Netting" neutrophils may activate auto-reactive B cells leading to further antibody and immune complex formation. In this review we discuss on basic pathophysiology, epidemiology, genetics, clinical, laboratory and treatment updates of Felty's syndrome.


Purification and characterization of the stage-specific embryonic enhancer-binding protein SSAP-1.
We have demonstrated that a highly conserved segment of DNA between positions -288 and -317 (upstream sequence element IV [USE IV]) is largely responsible for the transcriptional activation of the sea urchin H1-beta histone gene during the blastula stage of embryogenesis. This sequence is capable of acting as an embryonic enhancer element, activating target genes in a stage-specific manner. Nuclear extracts prepared from developmentally-staged organisms before and after the gene is activated all contain a factor which specifically binds to the enhancer. We have purified a 43-kDa polypeptide which binds to and footprints the USE IV enhancer element. We refer to this protein as stage-specific activator protein 1 (SSAP-1). Early in development before the enhancer is active, SSAP appears as a 43-kDa monomer, but it undergoes a change in its molecular weight beginning at about 12 h postfertilization (early blastula) which precisely parallels the increase in H1-beta gene expression. Modified SSAP has an apparent molecular mass of approximately 90 to 100 kDa and contains at least one 43-kDa SSAP polypeptide. Thus, it is the disappearance of the 43-kDa species and the appearance of the 90- to 100-kDa species which coincide with the H1-beta gene activation. The correlation between the change in molecular weight of SSAP and the stage-specific activation of H1-beta gene expression strongly suggests that this higher-molecular-weight form of SSAP is directly responsible for the blastula stage-specific transcriptional activation of the late H1 gene.


Shewanella putrefaciens in cultured tilapia detected by a new calcein-loop-mediated isothermal amplification (Ca-LAMP) method.
Shewanella putrefaciens is being increasingly isolated from a wide variety of sources and is pathogenic to many marine and freshwater fish. For better control of this pathogen, there is a need for the development of simple and inexpensive but highly specific, sensitive, and rapid detection methods suitable for application in field laboratories. Our colorogenic loop-mediated isothermal amplification (LAMP) assay combined with calcein (Ca-LAMP) for unaided visual confirmation of LAMP amplicons is a simple method for fish pathogen detection in cultured tilapia. Here, we describe the detection of S. putrefaciens using the same platform. As before, the method gave positive results (orange to green color change) in 45 min at 63°C with sensitivity 100 times higher than that of a conventional PCR assay, with no cross-amplification of other known fish bacterial pathogens tested. Using the assay with 389 samples of gonads, fertilized eggs, and fry of farmed Nile and red tilapia Oreochromis spp., 35% of samples were positive for S. putrefaciens. The highest prevalence was found in samples of gonads (55%) and fertilized eggs (55%) from adult breeding stocks, indicating that S. putrefaciens could be passed on easily to fry used for stocking production ponds. Tissue tropism assays revealed that the spleen showed the highest colonization by S. putrefaciens in naturally infected tilapia and that it would be the most suitable organ for screening and monitoring fish stocks for presence of the bacteria.


Prevalence and clinical course of depression: a review.
Depression is one of the leading causes of disease worldwide. Historically conceived as either a disease of the mind or of the brain, treatment options followed this aetiology. Current diagnostic assessment of depression is based on descriptions of symptoms, their presence and magnitude over time. Epidemiological studies demonstrate that depressive disorders are highly prevalent: displaying high rates of lifetime incidence, early age onset, high chronicity, and role impairment. These studies have deepened our understanding of the course of depression; remission, recovery, relapse and recurrence. An illustration of recovery rates has begun to demonstrate the complexity of the nature and course of depression. The majority recovers; however, recovery may not be permanent and future episodes carry the threat of chronicity. A key variable influencing rates of recovery, relapse, and recurrence is the presence of medical or psychiatric comorbid illnesses. The review considers the literature on Major Depression beginning with a brief historical overview, its classification, and a synthesis of the current knowledge regarding prevalence and course.


Mutational analysis of preamyloid intermediates: the role of his-tyr interactions in islet amyloid formation.
Islet amyloid polypeptide (IAPP or Amylin) is a 37-residue, C-terminally amidated pancreatic hormone, cosecreted with insulin that forms islet amyloid in type 2 diabetes. Islet amyloid formation is complex and characterizing preamyloid oligomers is an important topic because oligomeric intermediates are postulated to be the most toxic species produced during fibril formation. A range of competing models for early oligomers have been proposed. The role of the amidated C-terminus in amyloid formation by IAPP and in stabilizing oligomers is not known. Studies with unamidated IAPP have provided evidence for formation of an antiparallel dimer at pH 5.5, stabilized by stacking of His-18 and Tyr-37, but it is not known if this interaction is formed in the physiological form of the peptide. Analysis of a set of variants with a free and with an amidated C-terminus shows that disrupting the putative His-Tyr interaction accelerates amyloid formation, indicating that it is not essential. Amidation to generate the physiologically relevant form of IAPP accelerates amyloid formation, demonstrating that the advantages conferred by C-terminal amidation outweigh increased amyloidogenicity. The analysis of this variant argues that IAPP is not under strong evolutionary pressure to reduce amyloidogenicity. Analysis of an H18Q mutant of IAPP shows that the charge state of the N-terminus is an important factor controlling the rate of amyloid formation, even though the N-terminal region of IAPP is believed to be flexible in the amyloid fibers.


Werner Syndrome Associated with Poorly Differentiated Thyroid Carcinoma and Systemic Sclerosis-like Skin Manifestations: A Case Report.
Werner syndrome (WS) is an autosomal recessive disorder characterized by premature aging. WS patients often experience scleroderma-like manifestation including skin sclerosis and skin ulcer, making it difficult to differentiate WS from systemic sclerosis. Moreover, there is a high incidence of malignancy and arteriosclerosis-related disease in WS patients. We herein describe a 36-year-old woman with WS who had poorly differentiated thyroid carcinoma (PDTC), one of the rare phenotypes of thyroid tumor. This case suggested the importance to distinguish WS from systemic sclerosis and early diagnosis of malignancy.


Analyzing equity impacts of transit fare changes: Case study of Alameda-Contra Costa Transit, California.
Many public transit agencies consider increasing fares when faced with budget shortfalls. This paper analyzes the Alameda-Contra Costa (AC) Transit District's five alternative fare proposals introduced for public discussion in March 2005. The proposals combined fare hikes, base fare reductions, eliminations of free transfers, and discontinuation of periodic passes. Using the agency's 2002 on-board survey data, the study assessed the impacts of individual fare proposals on different subsets of riders and evaluated if they were equitable; and estimated potential fare revenues, using alternative price elasticities to estimate changes in ridership due to changes in price. The analysis revealed that proposals that increased the cost of transfers or eliminated unlimited-use passes produced dramatically unequal impacts on certain riders. Proposals for flat fares per ride were found to be least equitable, even when the base fare was lowered, because lower income riders, youth, and minorities made more trips and transferred more frequently than their more affluent counterparts. Proposals that maintained existing pass instruments and allowed transfers for small fees were the most favorable. The paper demonstrates the utility of on-board surveys and details an approach that could be widely used for evaluation of equity in public transit and other areas.


In vivo sensitivity of human melanoma to tumor necrosis factor (TNF)-alpha is determined by tumor production of the novel cytokine endothelial-monocyte activating polypeptide II (EMAPII).
Tumor necrosis factor (TNF)-alpha is a potent anticancer agent that seems to selectively target tumor-associated vasculature resulting in hemorrhagic necrosis of tumors without injury to surrounding tissues. The major limitation in the clinical use of TNF has been severe dose-limiting toxicity when administered systemically. However, when administered in isolated organ perfusion it results in regression of advanced bulky tumors. A better understanding of the mechanisms of TNF-induced antitumor effects may provide valuable information into how its clinical use in cancer treatment may be expanded. We describe here that the release of a novel tumor-derived cytokine endothelial-monocyte-activating polypeptide II (EMAPII) renders the tumor-associated vasculature sensitive to TNF. EMAPII has the unique ability to induce tissue factor production by tumor vascular endothelial cells that initiates thrombogenic cascades, which may play a role in determining tumor sensitivity to TNF. We demonstrate here that constitutive overexpression of EMAPII in a TNF-resistant human melanoma line by retroviral-mediated transfer of EMAPII cDNA renders the tumor sensitive to the effects of systemic TNF in vivo, but not in vitro. This interaction between tumors and their associated neovasculature provides an explanation for the focal effects of TNF on tumors and possibly for the variable sensitivity of tumors to bioactive agents.


Effect of Carica papaya Leaf Extract Capsule on Platelet Count in Patients of Dengue Fever with Thrombocytopenia.
Thrombocytopenia in dengue fever is a common and serious complication. However, no specific treatment is available for dengue fever induced thrombocytopenia. In few countries (Pakistan, Malaysia, Sri Lanka and other Asian countries) the leaf extract of Carica papaya has been effectively used for thrombocytopenia. So, the study is planned to access effect of Carica papaya leaf extract on platelet count in dengue fever patients. All participants were randomised into two groups, study group and control group; the study group was given papaya leaf extract capsule of 500 mg once daily and routine supportive treatment for consecutive five days. The controls were given only routine supportive treatment. Daily complete blood counts, platelet counts and haematocrit level, liver function test, renal function test of both groups were observed. On the first day platelet count of study group and control group was (59.82±18.63, 61.06±20.03 thousands, p value 0.36). On the 2nd day platelet count of both study and control groups was not significantly different (61.67±19.46 and 59.93±19.52 thousands, p value 0.20) but on 3rd day platelet count of study group was significantly higher than control group (82.96±16.72, 66.45±17.36 thousands, p value < 0.01). On 4th and 5th day platelet count of study group (122.43±19.36 and 112.47±17.49 thousands respectively) was also significantly higher than the control group (88.75±21.65 and 102.59±19.35 thousands) (p value < 0.01). On 7th day platelet count of study group and control group were not significantly different (124.47±12.35 and 122.46±19.76 thousands respectively, p value 0.08). Average hospitalization period of study group v/s control group was 3.65±0.97 v/s 5.42±0.98 days (p value < 0.01). Average platelet transfusion requirement in study group was significantly less than control group (0.685 units per patient v/s 1.19 units per patient) (p value <0.01). It is concluded that Carica papaya leaf extract increases the platelet count in dengue fever without any side effect and prevents the complication of thrombocytopenia. So, it can be used in dengue fever with thrombocytopenia patients.


Dry needling for the management of spasticity, pain, and range of movement in adults after stroke: A systematic review.
To summarise the available evidence about the effectiveness of deep dry needling (DN) on spasticity, pain-related outcomes, and range-of-movement (ROM) in adults after stroke. A computer search of Web of Science, Scopus, Medline, Cochrane Library, Cinahl, and Physiotherapy Evidence Database (PEDro) was conducted. A hand search of the reference lists of the selected studies and other relevant publications was also undertaken. Studies were assessed by two independent reviewers and included if they complied with the following criteria: (1) participants were adults after a stroke, (2) use of DN alone or within a multimodal approach, compared to no intervention or other treatments; (3) assessment of spasticity, pain, or joint ROM as a primary or secondary outcome. We included randomised controlled trials (RCTs), case series, and case reports. Data were extracted using a standardised protocol. The methodological quality of the studies was assessed with the Checklist for Measuring quality. A total of sixteen studies, 7 of which were RCTs, were selected. All studies generally reported an improvement of spasticity level, pain intensity, and ROM after the use of DN, alone or combined with other interventions, in stroke survivors. The management of adults after stroke with DN may impact positively on spasticity, pain, and ROM. However, there was significant heterogeneity across trials in terms of sample size, control groups, treated muscles, and outcome measures, and a meta-analysis was not feasible. Further research should include proper blinding, sham placebo DN as control intervention, and investigate long-term effects.


Food choices and practices during pregnancy of immigrant women with high-risk pregnancies in Canada: a pilot study.
Immigrant women may be regarded as a vulnerable population with respect to access and navigation of maternity care services. They may encounter difficulties when accessing culturally safe and appropriate maternity care, which may be further exacerbated by language difficulties and discriminatory practices or attitudes. The project aimed to understand ethnocultural food and health practices and how these intersect in a particular social context of cultural adaptation and adjustment in order to improve the care-giving capacities of health practitioners working in multicultural perinatal clinics. This four-phase study employed a case study design allowing for multiple means of data collection and different units of analysis. Phase one consists of a scoping review of the literature. Phases two and three incorporate pictorial representations of food choices with semi-structured photo-elicited interviews. This study was undertaken at a Prenatal and Obstetric Clinic, in an urban Canadian city. In phase four, the research team will inform the development of culturally appropriate visual tools for health promotion. Five themes were identified: (a) Perceptions of Health, (b) Social Support (c) Antenatal Foods (d) Postnatal Foods and (e) Role of Health Education. These themes provide practitioners with an understanding of the cultural differences that affect women's dietary choices during pregnancy. The project identified building collaborations between practitioners and families of pregnant immigrant women to be of utmost importance in supporting healthy pregnancies, along with facilitating social support for pregnant and breastfeeding mothers. In a multicultural society that contemporary Canada is, it is challenging for health practitioners to understand various ethnocultural dietary norms and practices. Practitioners need to be aware of customary practices of the ethnocultural groups that they work with, while simultaneously recognizing the variation within-not everyone follows customary practices, individuals may pick and choose which customary guidelines they follow. What women choose to eat is also influenced by their own experiences, access to particular foods, socioeconomic status, family context, and so on. The pilot study demonstrated the efficacy of the employed research strategies and we subsequently acquired funding for a national study.


The Lon-1 Protease Is Required by Borrelia burgdorferi To Infect the Mammalian Host.
Borrelia burgdorferi encodes a functional homolog of canonical Lon protease termed Lon-2. In addition, B. burgdorferi encodes a second Lon homolog called Lon-1. Recent studies suggest that Lon-1 may function differently from the prototypical Lon protease. However, the function of Lon-1 in B. burgdorferi biology remains virtually unknown. Particularly, the contribution of Lon-1 to B. burgdorferi fitness and infection remains hitherto unexplored. Herein, we show that Lon-1 plays a critical role for the infection of B. burgdorferi in a mammalian host. We found that lon-1 was highly expressed during animal infection, implying an important function of this protein in bacterial infection. We further generated a lon-1 deletion mutant and an isogenic complemented strain. Relative to that of the wild-type strain, the infectivity of the mutant was severely attenuated in a murine infection model. Our data also showed that the mutant displayed growth defects in regular BSK-II medium. Furthermore, bacterial resistance to osmotic stress was markedly reduced when lon-1 was inactivated. When exposed to tert-butyl hydroperoxide, survival of the lon-1 mutant was impaired. In addition, production of several virulence factors, such as BosR, RpoS, and OspC, was elevated in the mutant. These phenotypes were restored when the lon-1 mutation was complemented. Finally, we created a lon-1(S714A) mutant and found that this mutant failed to infect mice, suggesting that the proteolytic activity of Lon-1 is essential for bacterial infection. Taken together, these results demonstrate that Lon-1 is required by B. burgdorferi to infect animal hosts and to cope with environmental stresses.


Ultrasound-mediated DNA transfer for bacteria.
In environmental microbiology, the most commonly used methods of bacterial DNA transfer are conjugation and electroporation. However, conjugation requires physical contact and cell-pilus-cell interactions; electroporation requires low-ionic strength medium and high voltage. These limitations have hampered broad applications of bacterial DNA delivery. We have employed a standard low frequency 40 kHz ultrasound bath to successfully transfer plasmid pBBR1MCS2 into Pseudomonas putida UWC1, Escherichia coli DH5alpha and Pseudomonas fluorescens SBW25 with high efficiency. Under optimal conditions: ultrasound exposure time of 10 s, 50 mM CaCl(2), temperature of 22 degrees C, plasmid concentration of 0.8 ng/microl, P. putida UWC1 cell concentration of 2.5 x 10(9) CFU (colony forming unit)/ml and reaction volume of 500 microl, the efficiency of ultrasound DNA delivery (UDD) was 9.8 +/- 2.3 x 10(-6) transformants per cell, which was nine times more efficient than conjugation, and even four times greater than electroporation. We have also transferred pBBR1MCS2 into E. coli DH5alpha and P. fluorescens SBW25 with efficiencies of 1.16 +/- 0.13 x 10(-6) and 4.33 +/- 0.78 x 10(-6) transformants per cell, respectively. Low frequency UDD can be readily scaled up, allowing for the application of UDD not only in laboratory conditions but also on an industrial scale.


Morbidity and mortality in the surgical treatment of 10,242 adults with spondylolisthesis.
This is a retrospective review of 10,242 adults with degenerative spondylolisthesis (DS) and isthmic spondylolisthesis (IS) from the morbidity and mortality (M&M) index of the Scoliosis Research Society (SRS). This database was reviewed to assess complication incidence, and to identify factors that were associated with increased complication rates. The SRS M&M database was queried to identify cases of DS and IS treated between 2004 and 2007. Complications were identified and analyzed based on age, surgical approach, spondylolisthesis type/grade, and history of previous surgery. Age was stratified into 2 categories: > 65 years and ≤ 65 years. Surgical approach was stratified into the following categories: decompression without fusion, anterior, anterior/posterior, posterior without instrumentation, posterior with instrumentation, and interbody fusion. Spondylolisthesis grades were divided into low-grade (Meyerding I and II) versus high-grade (Meyerding III, IV, and V) groups. Both univariate and multivariate analyses were performed. In the 10,242 cases of DS and IS reported, there were 945 complications (9.2%) in 813 patients (7.9%). The most common complications were dural tears, wound infections, implant complications, and neurological complications (range 0.7%-2.1%). The mortality rate was 0.1%. Diagnosis of DS had a significantly higher complication rate (8.5%) when compared with IS (6.6%; p = 0.002). High-grade spondylolisthesis correlated strongly with a higher complication rate (22.9% vs 8.3%, p < 0.0001). Age > 65 years was associated with a significantly higher complication rate (p = 0.02). History of previous surgery and surgical approach were not significantly associated with higher complication rates. On multivariate analysis, only the grade of spondylolisthesis (low vs high) was in the final best-fit model of factors associated with the occurrence of complications (p < 0.0001). The rate of total complications for treatment of DS and IS in this series was 9.2%. The total percentage of patients with complications was 7.9%. On univariate analysis, the complication rate was significantly higher in patients with high-grade spondylolisthesis, a diagnosis of DS, and in older patients. Surgical approach and history of previous surgery were not significantly correlated with increased complication rates. On multivariate analysis, only the grade of spondylolisthesis was significantly associated with the occurrence of complications.


Myostatin: a Circulating Biomarker Correlating with Disease in Myotubular Myopathy Mice and Patients.
Myotubular myopathy, also called X-linked centronuclear myopathy (XL-CNM), is a severe congenital disease targeted for therapeutic trials. To date, biomarkers to monitor disease progression and therapy efficacy are lacking. The Mtm1 -/y mouse is a faithful model for XL-CNM, due to myotubularin 1 (MTM1) loss-of-function mutations. Using both an unbiased approach (RNA sequencing [RNA-seq]) and a directed approach (qRT-PCR and protein level), we identified decreased Mstn levels in Mtm1 -/y muscle, leading to low levels of myostatin in muscle and plasma. Myostatin (Mstn or growth differentiation factor 8 [Gdf8]) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing Dnm2 by genetic cross with Dnm2 +/- mice or by antisense oligonucleotides blocked or postponed disease progression and resulted in an increase in circulating myostatin. In addition, plasma myostatin levels inversely correlated with disease severity and with Dnm2 mRNA levels in muscles. Altered Mstn levels were associated with a generalized disruption of the myostatin pathway. Importantly, in two different forms of CNMs we identified reduced circulating myostatin levels in plasma from patients. This provides evidence of a blood-based biomarker that may be used to monitor disease state in XL-CNM mice and patients and supports monitoring circulating myostatin during clinical trials for myotubular myopathy.


Genome-wide insertion-deletion (InDel) marker discovery and genotyping for genomics-assisted breeding applications in chickpea.
We developed 21,499 genome-wide insertion-deletion (InDel) markers (2- to 54-bp in silico fragment length polymorphism) by comparing the genomic sequences of four (desi, kabuli and wild C. reticulatum) chickpea [Cicer arietinum (L.)] accessions. InDel markers showing 2- to 6-bp fragment length polymorphism among accessions were abundant (76.8%) in the chickpea genome. The physically mapped 7,643 and 13,856 markers on eight chromosomes and unanchored scaffolds, respectively, were structurally and functionally annotated. The 4,506 coding (23% large-effect frameshift mutations) and regulatory InDel markers were identified from 3,228 genes (representing 11.7% of total 27,571 desi genes), suggesting their functional relevance for trait association/genetic mapping. High amplification (97%) and intra-specific polymorphic (60-83%) potential and wider genetic diversity (15-89%) were detected by genome-wide 6,254 InDel markers among desi, kabuli and wild accessions using even a simpler cost-effective agarose gel-based assay. This signifies added advantages of this user-friendly genetic marker system for manifold large-scale genotyping applications in laboratories with limited infrastructure and resources. Utilizing 6,254 InDel markers-based high-density (inter-marker distance: 0.212 cM) inter-specific genetic linkage map (ICC 4958 × ICC 17160) of chickpea as a reference, three major genomic regions harboring six flowering and maturity time robust QTLs (16.4-27.5% phenotypic variation explained, 8.1-11.5 logarithm of odds) were identified. Integration of genetic and physical maps at these target QTL intervals mapped on three chromosomes delineated five InDel markers-containing candidate genes tightly linked to the QTLs governing flowering and maturity time in chickpea. Taken together, our study demonstrated the practical utility of developing and high-throughput genotyping of such beneficial InDel markers at a genome-wide scale to expedite genomics-assisted breeding applications in chickpea.


Differential effects of diazepam and pentobarbital on mood and behavior.
The effects of administering moderately high doses of diazepam and pentobarbital sodium for five consecutive days to subjects with histories of sedative drug abuse were examined. The two drugs produced similar dose-related effects on psychomotor performance, daytime sleeping, and ratings of magnitude of drug effects. Diazepam, but not pentobarbital, produced dose-related decreases in staff ratings of subjects' mood and social interactions and increases in staff ratings of subjects' hostility, complaining, and unusual behavior. During the placebo washout periods that followed drug administration. diazepam, but not pentobarbital, was associated with carry-over effects. The diazepam-produced deterioration in mood and social behavior was a subtle effect observed in a population for which usual therapeutic indications were lacking and at higher than usual therapeutic doses. The syndrome may, however, occur with long-term diazepam use or misuse in therapeutic settings and, hence, warrants clinical awareness in monitoring the course of treatment.


HIV seroprevalence and associated risk factors among male inmates at the Belize Central Prison.
To determine the seroprevalence of HIV and identify associated risk factors among inmates at the Belize Central Prison, managed by the Kolbe Foundation, Belize. A voluntary sample of 623 participants was obtained from the male inmate population incarcerated during the period from 15 January to 5 March 2005. HIV serostatus was determined on location using the Abbott Determine Assay for HIV-1/2 for screening, and the MedMira MiraWell Rapid HIV-1/2 Test for confirmatory testing. Remaining serum was tested by ELISA at the Central Medical Laboratory, Belize. Demographic and risk behavior data were collected using an interviewer administered pre-tested questionnaire. A multivariate logistic regression was used to adjust for potential confounders and to identify independent associations with HIV seropositivity. Of the 623 inmates in the sample, 25 tested positive for HIV-1/2 antibody for a seroprevalence of 4.0% (95% Confidence Interval 2.7, 6.0). After adjustment for confounding, HIV serostatus was positively associated with male-to-male sexual activity outside prison, age, and district of residence before current incarceration. The seroprevalence in the Central Prison was almost twice that estimated for the adult population of Belize in 2004 (2.4%). However, the social variables of importance to inmates appeared to reflect the epidemic in the general population, with the exception that male-to-male sex outside prison is likely more important to the male inmate population in Belize. The findings suggest that HIV is likely contracted by most inmates before their incarceration, largely due to same-sex activity.


Vibronic energy map and excited state vibrational characteristics of magnesium myoglobin determined by energy-selective fluorescence.
The vibrational frequencies of the singlet excited state of Mg-substituted myoglobin and relative absorption probabilities were determined by fluorescence line-narrowing spectroscopy. These spectra contain information on the structure of the excited state species, and the availability of vibrationally resolved spectra from excited state biomolecules should aid in elucidating their structure and reactivity.


Moderate alcohol consumption and increased bone mineral density: potential ethanol and non-ethanol mechanisms.
Mounting epidemiological evidence indicates an association between the moderate ingestion of alcoholic beverages and higher bone mineral density (v. abstainers). More limited findings provide some evidence for translation of this association into reduced fracture risk, but further studies are required. Here, these data are reviewed and caveats in their assimilation, comparison and interpretation as well as in the use and application of bone health indices are discussed. Whilst it is concluded that evidence is now strong for the moderate alcohol-bone health association, at least in relation to bone mineral density, mechanisms are less clear. Both ethanol and non-ethanol components have been implicated as factors that positively affect bone health in the light of moderate consumption of alcoholic beverages, and four particular areas are discussed. First, recent findings suggest that moderate ethanol consumption acutely inhibits bone resorption, in a non-parathyroid hormone- and non-calcitonin-dependent fashion, which can only partly be attributed to an energy effect. Second, critical review of the literature does not support a role for moderate ethanol consumption affecting oestrogen status and leading to a knock-on effect on bone. Third, Si is present at high levels in certain alcoholic beverages, especially beer, and may have a measurable role in promoting bone formation. Fourth, a large body of work indicates that phytochemicals (e.g. polyphenols) from alcoholic beverages could influence bone health, but human data are lacking. With further work it is hoped to be able to model epidemiological observations and provide a clear pathway between the magnitude of association and the relative contribution of these mechanisms for the major classes of alcoholic beverage.


English Stop-Smoking Services: One-Year Outcomes.
The UK is a global leader in stop-smoking support-providing free behavioral support and cessation medication via stop smoking services (SSS) without charge to smokers. This study aimed to explore the client and service characteristics associated with abstinence 52 weeks after quitting. A prospective cohort study of 3057 SSS clients in nine different areas of England who began their quit attempt between March 2012 and March 2013 was conducted. Important determinants of long-term quitting were assessed through quit rates and multivariable logistic regression. Our results showed that the overall weighted carbon monoxide validated quit rate for clients at 52 weeks was 7.7% (95% confidence interval (CI) 6.6-9.0). The clients of advisors, whose main role was providing stop-smoking support, were more likely to quit long-term than advisors who had a generalist role in pharmacies or general practices (odds ratio (OR) 2.3 (95% CI 1.2-4.6)). Clients were more likely to achieve abstinence through group support than one-to-one support (OR 3.4 (95% CI 1.7-6.7)). Overall, one in thirteen people who set a quit date with the National Health Service (NHS) Stop-Smoking Service maintain abstinence for a year. Improving abstinence is likely to require a greater emphasis on providing specialist smoking cessation support. Results from this study suggest that over 18,000 premature deaths were prevented through longer-term smoking cessation achieved by smokers who accessed SSS in England from March 2012 to April 2013, but outcomes varied by client characteristic and the type of support provided.


Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia.
Imaging tests can identify patients with pancreatic neoplastic cysts but not microscopic dysplasia. We investigated whether mutant TP53 can be detected in duodenal samples of secretin-stimulated pancreatic juice, and whether this assay can be used to screen for high-grade dysplasia and invasive pancreatic cancer. We determined the prevalence of mutant TP53 in microdissected pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and invasive adenocarcinomas. TP53 mutations were quantified by digital high-resolution melt-curve analysis and sequencing of secretin-stimulated pancreatic juice samples, collected from duodena of 180 subjects enrolled in Cancer of the Pancreas Screening trials; patients were enrolled because of familial and/or inherited predisposition to pancreatic cancer, or as controls. TP53 mutations were identified in 9.1% of intermediate-grade IPMNs (2 of 22), 17.8% of PanIN-2 (8 of 45), 38.1% of high-grade IPMNs (8 of 21), 47.6% of PanIN-3 (10 of 21), and 75% of invasive pancreatic adenocarcinomas (15 of 20); no TP53 mutations were found in PanIN-1 lesions or low-grade IPMNs. TP53 mutations were detected in duodenal samples of pancreatic juice from 29 of 43 patients with pancreatic ductal adenocarcinoma (67.4% sensitivity; 95% confidence interval, 0.52-0.80) and 4 of 8 patients with high-grade lesions (PanIN-3 and high-grade IPMN). No TP53 mutations were identified in samples from 58 controls or 55 screened individuals without evidence of advanced lesions. We detected mutant TP53 in secretin-stimulated pancreatic juice samples collected from duodena of patients with high-grade dysplasia or invasive pancreatic cancer. Tests for mutant TP53 might be developed to improve the diagnosis of and screening for pancreatic cancer and high-grade dysplasia. Clinical Trial numbers: NCT00438906 and NCT00714701.


Cord blood immune biomarkers in small for gestational age births.
Fetal growth restriction is a risk factor for development of adulthood diseases, but the biological mechanism of this association remains unknown. Limited biomarkers have been studied in settings of preterm birth and maternal inflammation, but the relationship between a wide range of immune biomarkers and fetal growth has not been studied. The hypothesis of this study was that fetal growth restriction is associated with altered immune biomarker levels. We examined the relationship between small for gestational age (SGA) status and 27 umbilical cord blood immune biomarkers. This study was part of a large-scale cohort study of preterm birth and low birth weight conducted at Boston Medical Center, an inner city, predominantly minority patient population. Growth status was determined based on birth weight standardized to an internal reference. There were 74 SGA births and 319 appropriate for age (AGA) births with complete clinical and biomarker data. Adjusting for covariates and using AGA as reference, SGA births had lower levels of log IL-1β (ng/l; β -0.38, 95% CI -0.57, -0.19, P < 0.01), log BDNF (β -0.29, 95% CI -0.55, -0.03, P < 0.05) and log NT-3 (β -0.46, 95% CI -0.77, -0.15, P < 0.01). No associations were found between other biomarkers and SGA. In conclusion, three biomarkers were selectively associated with SGA status. Our results provide information that could be used to guide additional studied aimed at determining mechanisms that contribute to fetal growth.


MOEA/D with adaptive weight adjustment.
Recently, MOEA/D (multi-objective evolutionary algorithm based on decomposition) has achieved great success in the field of evolutionary multi-objective optimization and has attracted a lot of attention. It decomposes a multi-objective optimization problem (MOP) into a set of scalar subproblems using uniformly distributed aggregation weight vectors and provides an excellent general algorithmic framework of evolutionary multi-objective optimization. Generally, the uniformity of weight vectors in MOEA/D can ensure the diversity of the Pareto optimal solutions, however, it cannot work as well when the target MOP has a complex Pareto front (PF; i.e., discontinuous PF or PF with sharp peak or low tail). To remedy this, we propose an improved MOEA/D with adaptive weight vector adjustment (MOEA/D-AWA). According to the analysis of the geometric relationship between the weight vectors and the optimal solutions under the Chebyshev decomposition scheme, a new weight vector initialization method and an adaptive weight vector adjustment strategy are introduced in MOEA/D-AWA. The weights are adjusted periodically so that the weights of subproblems can be redistributed adaptively to obtain better uniformity of solutions. Meanwhile, computing efforts devoted to subproblems with duplicate optimal solution can be saved. Moreover, an external elite population is introduced to help adding new subproblems into real sparse regions rather than pseudo sparse regions of the complex PF, that is, discontinuous regions of the PF. MOEA/D-AWA has been compared with four state of the art MOEAs, namely the original MOEA/D, Adaptive-MOEA/D, [Formula: see text]-MOEA/D, and NSGA-II on 10 widely used test problems, two newly constructed complex problems, and two many-objective problems. Experimental results indicate that MOEA/D-AWA outperforms the benchmark algorithms in terms of the IGD metric, particularly when the PF of the MOP is complex.


Classical analog of the quantum metric tensor.
We present a classical analog of the quantum metric tensor, which is defined for classical integrable systems that undergo an adiabatic evolution governed by slowly varying parameters. This classical metric measures the distance, on the parameter space, between two infinitesimally different points in phase space, whereas the quantum metric tensor measures the distance between two infinitesimally different quantum states. We discuss the properties of this metric and calculate its components, exactly in the cases of the generalized harmonic oscillator, the generalized harmonic oscillator with a linear term, and perturbatively for the quartic anharmonic oscillator. Finally, we propose alternative expressions for the quantum metric tensor and Berry's connection in terms of quantum operators.


Detuning in apodized point-by-point fiber Bragg gratings: insights into the grating morphology.
Point-by-point (PbP) inscription of fiber Bragg gratings using femtosecond laser pulses is a versatile technique that is currently experiencing significant research interest for fiber laser and sensing applications. The recent demonstration of apodized gratings using this technique provides a new avenue of investigation into the nature of the refractive index perturbation induced by the PbP modifications, as apodized gratings are sensitive to variation in the average background index along the grating. In this work we compare experimental results for Gaussian- and sinc-apodized PbP gratings to a coupled-mode theory model, demonstrating that the refractive index perturbation induced by the PbP modifications has a negative contribution to the average background index which is small, despite the presence of strong reflective coupling. By employing Fourier analysis to a simplified model of an individual modification, we show that the presence of a densified shell around a central void can produce strong reflective coupling with near-zero change in the average background index. This result has important implications for the experimental implementation of apodized PbP gratings, which are of interest for a range of fiber laser and fiber sensing technologies.


Bradykinin-induced functional competence and trafficking of the delta-opioid receptor in trigeminal nociceptors.
Peripheral opioid analgesia is increased substantially after inflammation. We evaluated the hypothesis that an inflammatory mediator, bradykinin (BK), evokes functional competence of the delta-opioid receptor (DOR) for inhibiting trigeminal ganglia (TG) sensory neurons. We also evaluated whether BK evokes trafficking of the DOR to the plasma membrane. Rat TG cultures were pretreated with BK (10 microm) or vehicle, and the effects of DOR agonists ([D-Pen2,5]-enkephalin or [D-Ala2, D-Leu5]-enkephalin) on BK (10 microm)/prostagladin E2 (PGE2; 1 microm)-stimulated immunoreactive calcitonin gene-related peptide (iCGRP) release or PGE2 (1 microm)-stimulated cAMP accumulation were measured. The effect of BK treatment on opioid receptor trafficking was evaluated by DOR immunohistochemistry, cell-surface DOR biotinylation, and live imaging of neurons transfected with mDOR-green fluorescent protein. BK pretreatment rapidly and significantly increased DOR agonist inhibition of evoked iCGRP release and cAMP accumulation. These effects of BK pretreatment were blocked by a B2 receptor antagonist (HOE-140; 10 microm) or a protein kinase C (PKC) inhibitor [bisindolymaleimide (BIS); 1 microm]. Moreover, BK treatment rapidly and significantly increased the accumulation of DOR in the plasma membrane. However, BK-induced trafficking of DOR was not reversed by pretreatment with BIS, nor was trafficking evoked by application of a PKC activator PMA (200 nm). These data suggest that BK, in a PKC-dependent manner, induces rapid functional competence of DOR for inhibiting TG nociceptors and in a PKC-independent manner rapidly induces trafficking of DOR to the plasma membrane. These findings indicate that exposure to certain inflammatory mediators rapidly alters the signaling properties and neuronal localization of DOR, possibly contributing to peripheral opioid analgesia.


Case-control study on radiology work, medical x-ray investigations, and use of cellular telephones as risk factors for brain tumors.
Ionizing radiation is a well-established risk factor for brain tumors. During recent years, microwave exposure from the use of cellular telephones has been discussed as a potential risk factor. To determine risk factors for brain tumors. A case-control study, with exposure assessed by questionnaires. A total of 233 currently living men and women, aged 20 to 80 years, were included. The case patients had histopathologically verified brain tumors and lived in the Uppsala-Orebro region (1994-1996) or the Stockholm region (1995-1996). Two matched controls to each case were selected from the Swedish Population Register. Ionizing radiation and use of cellular telephones as risk factors for brain tumors. A total of 209 cases (90%) and 425 controls (91%) answered the questionnaire. Work as a physician yielded an odds ratio (OR) of 6.00, with a 95% confidence interval (CI) of 0.62 to 57.7. All three case patients had worked with fluoroscopy. Radiotherapy of the head and neck region yielded an OR of 3.61 (95% CI, 0.65-19.9). Medical diagnostic x-ray examination of the same area yielded an OR of 2.10 (95% CI, 1.25-3.53), with a tumor induction period of 5 years or more. Chemical industry work yielded an OR of 4.10 (95% CI, 1.25-13.4), and laboratory work yielded an OR of 3.21 (95% CI, 1.16-8.85). Ipsilateral use of cellular telephones increased the risk for tumors in the temporal, temporoparietal, and occipital lobes (OR, 2.42; 95% CI, 0.97-6.05), ie, the anatomic areas with highest exposure to microwaves from a mobile telephone. The result was further strengthened (OR, 2.62; 95% CI, 1.02-6.71) in a multivariate analysis that included laboratory work and medical diagnostic x-ray investigations of the head and neck. Exposure to ionizing radiation, work in laboratories, and work in the chemical industry increased the risk of brain tumors. Use of a cellular telephone was associated with an increased risk in the anatomic area with highest exposure.


Systematic evaluation of alternating CID and ETD fragmentation for phosphorylated peptides.
CID has become a routine method for fragmentation of peptides in shotgun proteomics, whereas electron transfer dissociation (ETD) has been described as a preferred method for peptides carrying labile PTMs. Though both of these fragmentation techniques have their obvious advantages, they also have their own drawbacks. By combining data from CID and ETD fragmentation, some of these disadvantages can potentially be overcome because of the complementarity of fragment ions produced. To evaluate alternating CID and ETD fragmentation, we analyzed a complex mixture of phosphopeptides on an LTQ-Orbitrap mass spectrometer. When the CID and ETD-derived spectra were searched separately, we observed 2504, 491, 2584, and 3249 phosphopeptide-spectrum matches from CID alone, ETD alone, decision tree-based CID/ETD, and alternating CID and ETD, respectively. Combining CID and ETD spectra prior to database searching should, intuitively, be superior to either method alone. However, when spectra from the alternating CID and ETD method were merged prior to database searching, we observed a reduction in the number of phosphopeptide-spectrum matches. The poorer identification rates observed after merging CID and ETD spectra are a reflection of a lack of optimized search algorithms for carrying out such searches and perhaps inherent weaknesses of this approach. Thus, although alternating CID and ETD experiments for phosphopeptide identification are desirable for increasing the confidence of identifications, merging spectra prior to database search has to be carefully evaluated further in the context of the various algorithms before adopting it as a routine strategy.


Patient preferences for technical skills versus interpersonal skills in chiropractors and physiotherapists treating low back pain.
Little is known about which characteristics of chiropractors and physiotherapists matter to patients and influence their preferences when seeking care. To examine the impact of four factors (patient gender, practitioner gender, practitioner specialty-chiropractor or physiotherapist and practitioner reputation-technical ability or interpersonal skills) on patients' choice of therapist to treat low back pain. Questionnaire-based vignette study in which participants sampled from the general population rated the likelihood of consulting eight fictional therapists. Each fictional therapist represented a different combination of the three practitioner factors (e.g. male chiropractor with reputation for good technical ability). The study was administered as a postal survey to a simple random sample of residences in one postal town in England. Respondents (n = 657) consistently reported that they considered a practitioner's qualifications and technical skills important when choosing either a physiotherapist or a chiropractor; and just less than a third thought it was important that a practitioner was a good listener. As hypothesized, female respondents preferred female practitioners and respondents had a general preference for physiotherapists over chiropractors. Contrary to our hypothesis, the practitioner's reputation had the largest effect on respondents' preferences and all practitioners with a reputation for technical ability were preferred over those with a reputation for interpersonal skills. Similar factors are important to patients whether they are choosing an individual chiropractor or physiotherapist; patients particularly value information about technical competence. An awareness of these factors should help primary care providers to direct patients to relevant information and support their decision-making.


Three-dimensional computer model for simulating realistic solid-state lasers.
We developed an accurate and fast three-dimensional computer model for simulating realistic solid-state laser systems. An iteration of the beam propagation calculation was developed to account for the counterpropagation of the laser beams in the saturated gain medium and eventually obtain the converged solution for the output beam. An analytic method was devised to account for the curved cavity mirror and the surface deformation of the gain medium induced by the temperature gradient due to pump absorption. The temperature gradient induced thermal lensing and stress birefringence is also properly included in the model calculation. This model has been validated and shown to be very accurate and efficient for modeling three-dimensional laser systems in a personal computer.


Model microgravity enhances endothelium differentiation of mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are capable of differentiation into multilineage cell types under certain induction conditions. Previous studies have demonstrated that physical environments and mechanical force can influence MSC fate, indicating that these factors may be favorable inducers for clinical treatment. Our previous study found that MSCs are spread with a spindle shape when cultured in normal gravity (NG), and under modeled microgravity (MMG) for 72 h, they become unspread and round and their cytoskeleton fibers are reorganized. These morphological changes affected the function of MSCs through the activity of RhoA. We examined the responses of MSCs under MMG stimulation, followed with VEGF differentiation. We found that MSCs under MMG for 72 h were differentiated into endothelial-like cells by detecting the expression of endothelial-specific molecules (Flk-1 and vWF), which were also able to form a capillary network. Their endothelial differentiation potential was improved under MMG compared with that under NG. We believe that this method is a novel choice of MMG stimulation for neovascularization. This phenomenon may increase the potential of MSC differentiation, which might be a new strategy for the treatment of various vascular diseases and improve vascularization in tissue engineering.


Evaluation of DNA primase DnaG as a potential target for antibiotics.
Mycobacteria contain genes for several DNA-dependent RNA primases, including dnaG, which encodes an essential replication enzyme that has been proposed as a target for antituberculosis compounds. An in silico analysis revealed that mycobacteria also possess archaeo-eukaryotic superfamily primases (AEPs) of unknown function. Using a homologous recombination system, we obtained direct evidence that wild-type dnaG cannot be deleted from the chromosome of Mycobacterium smegmatis without disrupting viability, even in backgrounds in which mycobacterial AEPs are overexpressed. In contrast, single-deletion AEP mutants or mutants defective for all four identified M. smegmatis AEP genes did not exhibit growth defects under standard laboratory conditions. Deletion of native dnaG in M. smegmatis was tolerated only after the integration of an extra intact copy of the M. smegmatis or Mycobacterium tuberculosis dnaG gene, under the control of chemically inducible promoters, into the attB site of the chromosome. M. tuberculosis and M. smegmatis DnaG proteins were overproduced and purified, and their primase activities were confirmed using radioactive RNA synthesis assays. The enzymes appeared to be sensitive to known inhibitors (suramin and doxorubicin) of DnaG. Notably, M. smegmatis bacilli appeared to be sensitive to doxorubicin and resistant to suramin. The growth and survival of conditional mutant mycobacterial strains in which DnaG was significantly depleted were only slightly affected under standard laboratory conditions. Thus, although DnaG is essential for mycobacterial viability, only low levels of protein are required for growth. This suggests that very efficient inhibition of enzyme activity would be required for mycobacterial DnaG to be useful as an antibiotic target.


Single nucleotide polymorphism of the KIBRA gene in recurrent depressive disorders.
Depression is a disease of multifactor background. Episodic memory dysfunction is one of depression characterising disturbances, which may lead to its onset and development. Memory processes are controlled by a number of extra- and intracellular mechanisms. KIBRA, a newly discovered protein, belonging to signal transduction proteins, participates in the control of episodic memory. The presented study was designed to assess correlation between single nucleotide polymorphism (SNP) T/C (rs17070145) of the KIBRA gene and the risk of recurrent depressive disorder (DD). The study was carried out in a group of 181 patients with recurrent DD and 149 healthy control subjects. Genotyping was conducted by polymerase chain reaction (PCR)/restriction fragment length polymorphism (RLFP) method. TThe obtained results have revealed no significant correlation between the studied polymorphism and recurrent DD. Obtained value of the disease odds ratio (ORdis) suggests that presence of T/T homozygote decreases risk of development of recurrent DD, but the result was not statistically significant. Following the results, it may be concluded that the studied polymorphism does not influence either the onset mechanism or the course of recurrent DD. Even if T/C polymorphism of the KIBRA gene induces memory disturbances, they may be unspecific and unselective for recurrent DD. Further studies on the genes, which control characteristic processes of DD and influence their course, are demanded and mostly justified.


Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure.
The primary aims of the study were to examine the effect of resveratrol on skeletal muscle SIRT1 expression and energy expenditure in subjects with Type 2 diabetes mellitus (T2DM). Animal and in vivo studies indicate that resveratrol increases SIRT1 expression that stimulates PGC1α activity. Subsequent upregulation of AMPK and GLUT4 expression are associated with improved insulin sensitivity in peripheral tissues. Ten subjects with T2DM were randomized in a double-blind fashion to receive 3g resveratrol or placebo daily for 12 weeks. Secondary outcomes include measures of AMPK, p-AMPK and GLUT4 expression levels, energy expenditure, physical activity levels, distribution of abdominal adipose tissue and skeletal muscle fiber type composition, body weight, HbA1c, plasma lipid subfraction, adiponectin levels, and insulin sensitivity. There was a significant increase in both SIRT1 expression (2.01 vs. 0.86 arbitrary units [AU], p = .016) and p-AMPK to AMPK expression ratio (2.04 vs. 0.79 AU, p = .032) in the resveratrol group compared with the placebo group. Although the percentage of absolute change (8.6 vs. -13.9%, p = .033) and percentage of predicted resting metabolic rate (RMR; 7.8 vs. -13.9%, p = .013) were increased following resveratrol, there was a significant reduction in average daily activity (-38 vs. 43.2%, p = .028) and step counts (-39.5 vs. 11.8%, p = .047) when compared with placebo. In patients with T2DM, treatment with resveratrol regulates energy expenditure through increased skeletal muscle SIRT1 and AMPK expression. These findings indicate that resveratrol may have beneficial exercise-mimetic effects in patients with T2DM.


Comparative genomics and genotype-phenotype associations in Bifidobacterium breve.
Bifidobacteria are common members of the gastro-intestinal microbiota of a broad range of animal hosts. Their successful adaptation to this particular niche is linked to their saccharolytic metabolism, which is supported by a wide range of glycosyl hydrolases. In the current study a large-scale gene-trait matching (GTM) effort was performed to explore glycan degradation capabilities in B. breve. By correlating the presence/absence of genes and associated genomic clusters with growth/no-growth patterns across a dataset of 20 Bifidobacterium breve strains and nearly 80 different potential growth substrates, we not only validated the approach for a number of previously characterized carbohydrate utilization clusters, but we were also able to discover novel genetic clusters linked to the metabolism of salicin and sucrose. Using GTM, genetic associations were also established for antibiotic resistance and exopolysaccharide production, thereby identifying (novel) bifidobacterial antibiotic resistance markers and showing that the GTM approach is applicable to a variety of phenotypes. Overall, the GTM findings clearly expand our knowledge on members of the B. breve species, in particular how their variable genetic features can be linked to specific phenotypes.


Epineural ganglion causing cubital tunnel syndrome: A case report.
Although ganglions are the most common cause of ulnar tunnel syndrome, they are one of the rare causes of cubital tunnel syndrome (CuTS). In this article, we report a 49-year-old female patient admitted to the outpatient clinic complaining of numbness and tingling in the ring and little fingers of the right hand. There was no history of systemic disease or previous trauma. The patient was diagnosed with CuTS in the light of clinical examination and nerve conduction studies. Simple cubital tunnel decompression was performed under general anesthesia and microsurgical exploration revealed a 2x2 cm epineural ganglion cyst compressing the ulnar nerve. The cyst was excised without damaging the ulnar nerve and cutaneous nerves. Histopathology also confirmed the ganglion cyst. In the postoperative period, the patient's clinical improvement was more satisfactory than nerve conduction studies. The diagnosis of CuTS is established by physical examination, provocative test, and nerve conduction studies. In patients who cannot achieve a satisfactory outcome by conservative treatment, the cyst should be kept in mind among etiologic factors. Magnetic resonance imaging should be requested for accurate diagnosis and preoperative surgical planning.


Self-perception of disability and prospects for employment among U.S. veterans.
Barriers to employment in the civilian labor force are increasingly difficult problems for returning veterans with disabilities. Reduced self-perception of disability status because of predominant military norms can be particularly harmful to reintegration efforts. We analyze rates of self-identified and externally determined disability status among U.S. veterans. Evidence of a lower self-report rate would confirm the hypothesis that armed forces culture might hold back truly deserving veterans from seeking the benefits owed, including specialized employment training programs. We use data from the Current Population Survey Veterans Supplement over the sample period 1995-2010 on disability status and associated demographic characteristics to present descriptive measures and limited statistical inference. Over the entire sample period, federal agencies considered 29% of the survey respondents to have a service-connected disability versus a 9% self-identification rate. The rate of more severe service-connected disabilities has risen steadily, while less drastic disability rates have fallen. Non-white respondents and those with lower education levels were less likely to self-identify. Large disparities in internal and external disability status identification raise questions about targeting soldiers re-entering the labor force. Employment policy should focus on overcoming negative cultural stereotypes and encouraging self-identification.


A Two-Component DNA-Prime/Protein-Boost Vaccination Strategy for Eliciting Long-Term, Protective T Cell Immunity against Trypanosoma cruzi.
In this study, we evaluated the long-term efficacy of a two-component subunit vaccine against Trypanosoma cruzi infection. C57BL/6 mice were immunized with TcG2/TcG4 vaccine delivered by a DNA-prime/Protein-boost (D/P) approach and challenged with T. cruzi at 120 or 180 days post-vaccination (dpv). We examined whether vaccine-primed T cell immunity was capable of rapid expansion and intercepting the infecting T. cruzi. Our data showed that D/P vaccine elicited CD4+ (30-38%) and CD8+ (22-42%) T cells maintained an effector phenotype up to 180 dpv, and were capable of responding to antigenic stimulus or challenge infection by a rapid expansion (CD8>CD4) with type 1 cytokine (IFNγ+ and TFNα+) production and cytolytic T lymphocyte (CTL) activity. Subsequently, challenge infection at 120 or 180 dpv, resulted in 2-3-fold lower parasite burden in vaccinated mice than was noted in unvaccinated/infected mice. Co-delivery of IL-12- and GMCSF-encoding expression plasmids provided no significant benefits in enhancing the anti-parasite efficacy of the vaccine-induced T cell immunity. Booster immunization (bi) with recombinant TcG2/TcG4 proteins 3-months after primary vaccine enhanced the protective efficacy, evidenced by an enhanced expansion (1.2-2.8-fold increase) of parasite-specific, type 1 CD4+ and CD8+ T cells and a potent CTL response capable of providing significantly improved (3-4.5-fold) control of infecting T. cruzi. Further, CD8+T cells in vaccinated/bi mice were predominantly of central memory phenotype, and capable of responding to challenge infection 4-6-months post bi by a rapid expansion to a poly-functional effector phenotype, and providing a 1.5-2.3-fold reduction in tissue parasite replication. We conclude that the TcG2/TcG4 D/P vaccine provided long-term anti-T. cruzi T cell immunity, and bi would be an effective strategy to maintain or enhance the vaccine-induced protective immunity against T. cruzi infection and Chagas disease.


Antibiotic production and biocontrol activity by Bacillus subtilis CL27 and Bacillus pumilus CL45.
Bacillus subtilis CL27 and B. pumilus CL45 showed similar activity against Botrytis cinerea in in vitro plate assays. In a seedling bioassay, however, B. subtilis CL27 had activity similar to a commercial fungicide while B. pumilus CL45 failed completely to prevent seedling damping-off caused by Bot. cinerea. Antibiotic production by the two Bacillus strains was found to depend on the growth substrate and highest antibiotic production was found on media based on homogenized cabbage tissue. Antibiotic activity was found to depend on the pH and nutrient concentration in the assay medium. Antifungal antibiotics produced by B. subtilis CL27 and B. pumilus CL45 in different fermentation media were separated by thin layer chromatography. As suspected from the activity spectrum, three antibiotics (one with activity against Alternaria brassicicola, one with activity against Botrytis cinerea and one with activity against both fungi) could be detected in the fermentation broth of CL27, but only one in the fermentation broth of CL45. The two antibiotics produced by strain CL27 with activity against A. brassicicola were identified as peptides since their bands on the TLC plates developed a green to blue/green colour after treatment with 4,4'-tetramethyldiamino-diphenylmethane (TDM) reagent. The third antibiotics produced by strain CL27 and antibiotic produced by CL45 had a similar Rf-value and appeared not to be peptides based on the reaction with TDM. However, they showed a slightly different activity spectrum when tested against a range of different fungi. Antibiotic production was clearly indicated as the mode of action of in vivo biocontrol by strain CL27 against damping off caused by Bot. cinerea of Astilbe micro-plants, because a u.v.-induced antibiotic negative mutant strain CL27b showed no activity in seedling bioassays in vivo. Also the mutant strain CL27a which produced the two peptide antibiotics but had lost the ability to produce the non-peptide antibiotic, showed greatly reduced in vivo activity.


Photoacoustic probes for real-time tracking of endogenous H2S in living mice.
H2S is a key chemical mediator that exerts a vital role in diverse physiological and pathological processes. However, in vivo tracking of endogenous H2S generation still remains difficult due to the lack of reliable analytical methods. Herein, we present the first example of activatable photoacoustic probes for real-time imaging of H2S in living mice through the full utilization of the superiority of photoacoustic imaging modality at fine spatial resolution during deep tissue penetration. The designed probe can generate high NIR absorption at 780 nm in the presence of H2S, thus producing a strong photoacoustic signal output in the NIR region. Furthermore, this probe exhibits extremely fast and highly selective responsiveness, good water-solubility and excellent biocompatibility. In light of these outstanding features, this probe realizes the direct photoacoustic trapping of endogenous H2S generation in a HCT116 tumor-bearing mouse model. These preliminary imaging studies show that HCT116 colon tumors exhibit CBS upregulation activity, resulting in an increased rate of H2S generation.


Application of 3D-printed PEEK scapula prosthesis in the treatment of scapular benign fibrous histiocytoma: A case report.
Bone benign fibrous histiocytoma (BFH) is an invasive primary bone tumor. When the local excision is not complete, the risk of recurrence is high, and hence, one-piece resection is necessary. The major challenge for clinicians is to reconstruct the bone after resection of the tumor. The present study investigated the efficacy of 3-dimensional (3D) printing technique in the treatment of benign fibrous histiocytoma of the scapula. The patient with benign fibrous histiocytoma of scapular bone was treated with PEEK (polyetheretherketone) prosthesis replacement using the 3D printing technique. X-ray and computed tomography (CT) scans evaluated the relationship between the position of the prosthesis and that of the shoulder joint. Also, the constant score of the shoulder joint was calculated. The anteroposterior radiograph showed that the position of the left scapula prosthesis is satisfactory and that of the shoulder joint is normal. Three months after the operation, the X-ray examination indicated the lack of flexibility and shift, as well as, dislocation and disjunction of PEEK prosthesis. The constant score of the left shoulder function was 68 points. Active shoulder joint activity: 120° on the lift, 90° on abduction, 50° on the external rotation, and 70° on internal rotation. The application of 3D-printed PEEK scapula prosthesis with total shoulder replacement offers the possibility of accurate reconstruction, improves the operability of surgery, shortens the operation time, and allows early functional recovery of the patients.


Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.
Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-β-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.


An integrative analysis of DNA methylation and RNA-Seq data for human heart, kidney and liver.
Many groups, including our own, have proposed the use of DNA methylation profiles as biomarkers for various disease states. While much research has been done identifying DNA methylation signatures in cancer vs. normal etc., we still lack sufficient knowledge of the role that differential methylation plays during normal cellular differentiation and tissue specification. We also need thorough, genome level studies to determine the meaning of methylation of individual CpG dinucleotides in terms of gene expression. In this study, we have used (insert statistical method here) to compile unique DNA methylation signatures from normal human heart, lung, and kidney using the Illumina Infinium 27 K methylation arrays and compared those to gene expression by RNA sequencing. We have identified unique signatures of global DNA methylation for human heart, kidney and liver, and showed that DNA methylation data can be used to correctly classify various tissues. It indicates that DNA methylation reflects tissue specificity and may play an important role in tissue differentiation. The integrative analysis of methylation and RNA-Seq data showed that gene methylation and its transcriptional levels were comprehensively correlated. The location of methylation markers in terms of distance to transcription start site and CpG island showed no effects on the regulation of gene expression by DNA methylation in normal tissues. This study showed that an integrative analysis of methylation array and RNA-Seq data can be utilized to discover the global regulation of gene expression by DNA methylation and suggests that DNA methylation plays an important role in normal tissue differentiation via modulation of gene expression.


Soft Tensor Regression.
Statistical methods relating tensor predictors to scalar outcomes in a regression model generally vectorize the tensor predictor and estimate the coefficients of its entries employing some form of regularization, use summaries of the tensor covariate, or use a low dimensional approximation of the coefficient tensor. However, low rank approximations of the coefficient tensor can suffer if the true rank is not small. We propose a tensor regression framework which assumes a soft version of the parallel factors (PARAFAC) approximation. In contrast to classic PARAFAC where each entry of the coefficient tensor is the sum of products of row-specific contributions across the tensor modes, the soft tensor regression (Softer) framework allows the row-specific contributions to vary around an overall mean. We follow a Bayesian approach to inference, and show that softening the PARAFAC increases model flexibility, leads to improved estimation of coefficient tensors, more accurate identification of important predictor entries, and more precise predictions, even for a low approximation rank. From a theoretical perspective, we show that employing Softer leads to a weakly consistent posterior distribution of the coefficient tensor, irrespective of the true or approximation tensor rank, a result that is not true when employing the classic PARAFAC for tensor regression. In the context of our motivating application, we adapt Softer to symmetric and semi-symmetric tensor predictors and analyze the relationship between brain network characteristics and human traits.


The floral transcriptome of Eucalyptus grandis.
As a step toward functional annotation of genes required for floral initiation and development within the Eucalyptus genome, we used short read sequencing to analyze transcriptomes of floral buds from early and late developmental stages, and compared these with transcriptomes of diverse vegetative tissues, including leaves, roots, and stems. A subset of 4807 genes (13% of protein-coding genes) were differentially expressed between floral buds of either stage and vegetative tissues. A similar proportion of genes were differentially expressed among all tissues. A total of 479 genes were differentially expressed between early and late stages of floral development. Gene function enrichment identified 158 gene ontology classes that were overrepresented in floral tissues, including 'pollen development' and 'aromatic compound biosynthetic process'. At least 40 floral-dominant genes lacked functional annotations and thus may be novel floral transcripts. We analyzed several genes and gene families in depth, including 49 putative biomarkers of floral development, the MADS-box transcription factors, 'S-domain'-receptor-like kinases, and selected gene family members with phosphatidylethanolamine-binding protein domains. Expanded MADS-box gene subfamilies in Eucalyptus grandis included SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1), SEPALLATA (SEP) and SHORT VEGETATIVE PHASE (SVP) Arabidopsis thaliana homologs. These data provide a rich resource for functional and evolutionary analysis of genes controlling eucalypt floral development, and new tools for breeding and biotechnology.


Rapid genetic analysis of families with polycystic kidney disease 1 by means of a microsatellite marker.
Presymptomatic diagnosis of polycystic kidney disease 1 (PKD1) is possible by genetic linkage analysis with markers from both sides of the disease locus. The existing proximal markers are not informative in many families, so such analysis is difficult and time-consuming. We sought more useful length polymorphisms on the proximal side of the locus among simple sequence repeats (microsatellites). We identified two microsatellite polymorphisms that lie closer to the PKD1 locus than any previously described highly variable marker. One, SM7, is especially informative; we have found fourteen alleles and the observed heterozygosity in caucasians is 62.7%. Genetic linkage analysis in PKD1 families suggests that both of the markers lie proximal to the disease gene, closer than existing flanking markers. These polymorphisms can be simply assayed by polymerase chain reaction amplification of the variable regions, which generates DNA fragments that can be separated on non-denaturing acrylamide gels and directly examined after gel staining. This rapid, inexpensive, and non-radioactive method of linkage analysis allows the complete study of DNA samples within 8 h.


Effect of bcl-2 overexpression in mice on ovotoxicity caused by 4-vinylcyclohexene.
The occupational chemical 4-vinylcyclohexene (VCH) destroys small preantral ovarian follicles in mice following repeated daily dosing. The cell survival gene bcl-2 is thought to protect against follicular death during embryogenesis because primordial follicle numbers in newborn bcl-2 overexpressing (OE) mice are greater than in wild-type (WT) controls. Thus, this study was designed to determine if overexpression of bcl-2 protects against VCH-induced follicle loss during embryonic development. Pregnant bcl-2 OE or WT mice were dosed (p.o.) daily with VCH (500 mg/kg) or sesame oil (vehicle control) on days 8-18 of pregnancy. Ovaries were collected from moms and female pups on pup postnatal day (PND) 8. Nonpregnant OE and WT females were also treated with VCH (500 mg/kg p.o.) or vehicle and evaluated in the same manner. As previously reported, ovaries from PND8 OE female pups contained 50% more primordial follicles than WT pups (P < 0.05). Unlike WT pups, relative to vehicle controls, in utero exposure to VCH resulted in a reduction in primordial (25% of control), primary (38% of control), and secondary (33% of control) follicles in ovaries of OE pups (P < 0.05). VCH had no significant effect on follicle numbers in OE or WT moms. Conversely, in nonpregnant adults, VCH did not affect WT mice but caused loss of primordial (55% of control), primary (51% of control), and secondary (69% of control) follicles in OE mice (P < 0.05). These results demonstrate that bcl-2 overexpression does not protect against, but instead increases susceptibility to VCH-induced follicle loss in transplacentally exposed or in nonpregnant mice.


The impact of external donor support through the U.S. President's Emergency Plan for AIDS Relief on the cost of red cell concentrate in Namibia, 2004-2011.
External assistance can rapidly strengthen health programmes in developing countries, but such funding can also create sustainability challenges. From 2004-2011, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) provided more than $ 8 million to the Blood Transfusion Service of Namibia (NAMBTS) for supplies, equipment, and staff salaries. This analysis describes the impact that support had on actual production costs and the unit prices charged for red cell concentrate (RCC) units issued to public sector hospitals. A costing system developed by NAMBTS to set public sector RCC unit prices was used to describe production costs and unit prices during the period of PEPFAR scale-up (2004-2009) and the 2 years in which PEPFAR support began to decline (2010-2011). Hypothetical production costs were estimated to illustrate differences had PEPFAR support not been available. Between 2004-2006, NAMBTS sold 22,575 RCC units to public sector facilities. During this time, RCC unit prices exceeded per unit cost-recovery targets by between 40.3% (US$ 16.75 or N$ 109.86) and 168.3% (US$ 48.72 or N$ 333.28) per year. However, revenue surpluses dwindled between 2007 and 2011, the final year of the study period, when NAMBTS sold 20,382 RCC units to public facilities but lost US$23.31 (N$ 170.43) on each unit. PEPFAR support allowed NAMBTS to leverage domestic cost-recovery revenue to rapidly increase blood collections and the distribution of RCC. However, external support kept production costs lower than they would have been without PEPFAR. If PEPFAR funds had not been available, RCC prices would have needed to increase by 20% per year to have met annual cost-recovery targets and funded the same level of investments as were made with PEPFAR support. Tracking the subsidising influence of external support can help blood services make strategic investments and plan for unit price increases as external funds are withdrawn.


Kidney development in the absence of Gdnf and Spry1 requires Fgf10.
GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf-/-;Spry1-/- or Ret-/-;Spry1-/- double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf-/-;Spry1-/- mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals.


Anxiety and Depressive Symptom Trajectories in Adolescence and the Co-Occurring Development of Cognitive Biases: Evidence from the CogBIAS Longitudinal Study.
The development of negative cognitive biases, together with symptoms of anxiety and depression, has yet to be investigated longitudinally. Using a three-wave design, the present study examined developmental trajectories of anxiety and depressive symptoms and the co-occurrence of cognitive biases, in a large normative sample of adolescents (N = 504). Data was drawn from the CogBIAS Longitudinal Study (CogBIAS-L-S), which assessed a wide range of psychological variables, including cognitive biases and self-reported anxiety and depressive symptoms, when adolescents were approximately 13, 14.5, and 16 years of age. The results showed that overall levels of anxiety were low and stable, while levels of depression were low but increased slightly at each wave. Growth mixture modeling identified four distinct developmental classes with regard to anxiety and depressive symptoms. Multiple group analysis further showed that class membership was related to the development of cognitive biases. The majority of the sample (75%) was characterised by 'Low symptoms' of anxiety and depression and showed low interpretation and memory biases for negative stimuli at each wave. A second class (11%) displayed 'Decreasing anxiety symptoms' and showed decreasing interpretation bias, but increasing memory bias. A third class (8%) displayed 'Comorbid increasing symptoms' and showed increasing interpretation and memory biases. While the fourth class (6%) displayed 'Comorbid decreasing symptoms' and showed decreasing interpretation and memory biases. This longitudinal study sheds light on healthy and psychopathological emotional development in adolescence and highlights cognitive mechanisms that may be useful targets for prevention and early interventions.


Endoluminal aortic grafting: a preliminary animal study of graft-healing.
Our purpose was to evaluate the placement, long term performance, and healing of a transluminally delivered endoluminal graft and attachment system, in an animal model using large adult sheep. Nineteen sheep in the weight range of 105-125 kg were entered into this study. Under fluoroscopic guidance in anesthetized animals, an endoluminal delivery system was inserted through a common femoral arteriotomy into the infrarenal aorta, and the graft and attachment system were deployed. Fixation of the proximal and distal ends of the graft to the aortic wall was achieved by hooks on the self expanding attachment system, and seated by balloon expansion. Explantation of the prosthesis was performed prior to euthanasia at 1-, 3-, and 6-month intervals. Aortograms were obtained before and after implantation and before explantation for evaluation of placement, patency, anastomotic seal, migration, and graft infolding. In situ gross examination of the prosthesis under anesthesia prior to sacrifice was performed in all animals. Histologic sections were obtained from both attachment sites ("anastomoses"), from the midgraft and hook insertion sites, and from normal aorta inferior and superior to the endoluminal prosthesis. Scanning electron microscopy was performed randomly on specimens derived from the superior and inferior anastomotic sites at each time point. Selected intervals of healing were 1 month (N=5), 3 months (N=5), and 6 months (N=8). One sheep was euthanized at 1 week due to paraplegia. At all intervals, all prostheses were patent, were well incorporated at the aortic wall-anastomotic sites, and were without mural thrombus. The attachment hooks penetrated the aortic adventitia in all animals. There was no graft migration. At one month, initial pannus formation covered the anastomoses and the entire luminal graft, yet the endothelial-like surface coverage was incomplete. At 3 months and at 6 months, the anastomoses and luminal surfaces displayed more uniform pannus and endothelial-like surface coverage. We conclude that this endoluminal delivery system, passed through a femoral arteriotomy, can effectively deploy an endoluminal graft with self expanding attachment system having consistent patency, secure fixation, and incorporation of the anastomoses with the aortic wall in this animal model.


Mid-level visual features underlie the high-level categorical organization of the ventral stream.
Human object-selective cortex shows a large-scale organization characterized by the high-level properties of both animacy and object size. To what extent are these neural responses explained by primitive perceptual features that distinguish animals from objects and big objects from small objects? To address this question, we used a texture synthesis algorithm to create a class of stimuli-texforms-which preserve some mid-level texture and form information from objects while rendering them unrecognizable. We found that unrecognizable texforms were sufficient to elicit the large-scale organizations of object-selective cortex along the entire ventral pathway. Further, the structure in the neural patterns elicited by texforms was well predicted by curvature features and by intermediate layers of a deep convolutional neural network, supporting the mid-level nature of the representations. These results provide clear evidence that a substantial portion of ventral stream organization can be accounted for by coarse texture and form information without requiring explicit recognition of intact objects.


The burden and characteristics of enteric fever at a healthcare facility in a densely populated area of Kathmandu.
Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A (S. Typhi and S. Paratyphi A) remains a major public health problem in many settings. The disease is limited to locations with poor sanitation which facilitates the transmission of the infecting organisms. Efficacious and inexpensive vaccines are available for S. Typhi, yet are not commonly deployed to control the disease. Lack of vaccination is due partly to uncertainty of the disease burden arising from a paucity of epidemiological information in key locations. We have collected and analyzed data from 3,898 cases of blood culture-confirmed enteric fever from Patan Hospital in Lalitpur Sub-Metropolitan City (LSMC), between June 2005 and May 2009. Demographic data was available for a subset of these patients (n = 527) that were resident in LSMC and who were enrolled in trials. We show a considerable burden of enteric fever caused by S. Typhi (2,672; 68.5%) and S. Paratyphi A (1,226; 31.5%) at this Hospital over a four year period, which correlate with seasonal fluctuations in rainfall. We found that local population density was not related to incidence and we identified a focus of infections in the east of LSMC. With data from patients resident in LSMC we found that the median age of those with S. Typhi (16 years) was significantly less than S. Paratyphi A (20 years) and that males aged 15 to 25 were disproportionately infected. Our findings provide a snapshot into the epidemiological patterns of enteric fever in Kathmandu. The uneven distribution of enteric fever patients within the population suggests local variation in risk factors, such as contaminated drinking water. These findings are important for initiating a vaccination scheme and improvements in sanitation. We suggest any such intervention should be implemented throughout the LSMC area.


Sleep-induced changes in associative memory.
The notion that dreaming might alter the strength of associative links in memory was first proposed almost 200 years ago. But no strong evidence of such altered associative links has been obtained. Semantic priming can be used to quantify the strength of associative links between pairs of words; it is thought to measure the automatic spread of activation from a "node" representing one word to nodes representing semantically related words. Semantic priming could thus be used to test for global alterations in the strengths of associative links across the wake-sleep cycle. Awakenings from REM and nonREM (NREM) sleep produce a period of state carry-over during which performance is altered as a result of the brain's slow transition to full wakefulness, and cognitive testing in this period can provide information about the functioning of the brain during the prior sleep period. When subjects were tested across the night--before and after a night's sleep as well as immediately following forced awakenings from REM and NREM sleep--weak priming (e. g., thief-wrong) was found to be state dependent (p = 0.016), whereas strong priming (e.g., hot-cold) was not (p = 0.89). Weak primes were most effective in the presleep and REM sleep conditions and least effective in NREM and postsleep conditions. Most striking are analyses comparing weak and strong priming within each wake-sleep state. Contrary to the normal pattern of priming, subjects awakened from REM sleep showed greater priming by weak primes than by strong primes (p = 0.01). This result was seen in each of three protocols. In contrast, strong priming exceeded weak priming in NREM sleep. The shift in weak priming seen after REM sleep awakenings suggests that cognition during REM sleep is qualitatively different from that of waking and NREM sleep and may reflect a shift in associative memory systems, a shift that we hypothesize underlies the bizarre and hyperassociative character of REM-sleep dreaming. Known changes in brainstem activity that control the transition into and maintenance of REM sleep provide a possible explanation of this shift.


Enhanced optical emission during Crab giant radio pulses.
We detected a correlation between optical and giant radio pulse emission from the Crab pulsar. Optical pulses coincident with the giant radio pulses were on average 3% brighter than those coincident with normal radio pulses. Combined with the lack of any other pulse profile changes, this result indicates that both the giant radio pulses and the increased optical emission are linked to an increase in the electron-positron plasma density.