Rodent-avoidance, topography and forest structure shape territory selection of a forest bird.
Understanding the factors underlying habitat selection is important in ecological and evolutionary contexts, and crucial for developing targeted conservation action in threatened species. However, the key factors associated to habitat selection often remain poorly known. We evaluated hypotheses related to abiotic and biotic factors thought to affect territory selection of the wood warbler Phylloscopus sibilatrix, a passerine living in an unpredictable environment owing to irregular rodent outbreaks and showing long-term declines particularly in Western Europe. Comparing breeding territories to unoccupied areas located close-by revealed that territory occupancy in north-western Switzerland was positively related to slope steepness (topographic hypothesis supported) as well as to numbers of tussocks and trees, respectively, while it showed a unimodal relationship to cover of herb layer (forest structure hypothesis supported). Furthermore, a strong negative correlation between breeding territory occupancy and rodent numbers was found, suggesting that wood warblers avoid areas with high rodent densities (rodent-avoidance hypothesis supported). Comparing breeding territories to abandoned territories showed that breeding territories were located on steeper slopes (topography hypothesis supported), at larger distance from the forest edge (anthropogenic disturbance hypothesis supported) and harboured more trees (forest structure hypothesis supported) than abandoned territories. Aside from structural and topographic features of the habitat, wood warblers are affected by rodent numbers when settling, making habitat selection unpredictable from year to year. Forestry practices promoting relatively high tree densities, few bushes and an intermediate low-growing ground vegetation cover would enhance habitat quality for this declining passerine. In contrast, forestry practices aiming at increasing light in forests (selective thinning, group-felling) or keeping forest stands permanently covered with shrubs, bushes and trees of various sizes (continuous cover forestry) do not benefit the wood warbler.


Mouse prostate proteome changes induced by oral pentagalloylglucose treatment suggest targets for cancer chemoprevention.
Recent in vitro and in vivo preclinical studies have suggested that the Oriental herbal compound penta-1, 2, 3, 4, 6-O-galloyl-beta-D-glucose (PGG) is a promising chemopreventive agent for prostate cancer. Little is known of its safety for chronic chemoprevention use and virtually nothing is known of its in vivo responsive proteins in the target organ. Here we treated male C57BL/6 mice with daily oral administration of PGG at two dosages (1 and 2 mg per mouse) from 7 to 14 weeks of age and profiled proteomic patterns in the prostate with iTRAQ labeling and 2D LC-MS/MS analyses. While neither dose affected feed intake and body weight gain, the 2 mg dose (∼80-100 mg per kg) led to a minor but statistically significant decrease of the weight of prostate and thymus. For proteomic profiling, five prostates were pooled from each group for protein extraction. Proteins were denatured, reduced, alkylated and digested to peptides. The peptides were labeled with iTRAQ reagents, mixed and subjected to 2D LC-MS/MS analyses. PGG consumption suppressed the abundance of oncoproteins (e.g., fatty acid synthase, clusterin) and up-regulated that of tumor suppressor proteins (e.g., glutathione S-transferase M), signifying changes that may contribute to prostate cancer risk reduction.


Comparison of Local Anesthetic Effect of Bupivacaine versus Bupivacaine plus Dexamethasone in Nasal Surgery.
Adequate pain control is an important consideration in the post-surgical management of patients. Local nerve blockade added to general anesthesia can provide excellent pain control during and after most nasal surgical procedures. The aim of this study was to determine the combined effect of local anesthetic drugs with corticosteroids in nasal surgery. In this double-blind clinical study, 60 patients who underwent different nasal surgical procedures were matched and divided into two equal groups. Bilateral local nerve blockade was used in both groups. Bupivacaine or bupivacaine plus dexamethasone was administered by injection (groups B and B+D, respectively). Postoperative visual analog scale (VAS) pain values and the need for oral/intramuscular analgesic treatment in the first 24 h were recorded in all patients. Thirty-eight male (63.3%) and 22 female (36.7%) patients were included in this study, with a mean age of 28.3 ± 8.2 years. At 1, 2, 4, 6, and 12 h post surgery, VAS pain values were significantly lower in the B+D group than in the B group. The analgesic requirement was significantly lower in the B+D group compared with the B group. No relevant complications were seen during surgery or postoperative hospitalization.


Real-Time PCR Detection and Discrimination of the Southern and Common Corn Rust Pathogens Puccinia polysora and Puccinia sorghi.
Over the past several years, southern corn rust (SCR) outbreaks caused by the fungus Puccinia polysora have become increasingly problematic for corn growers in the United States. SCR is currently diagnosed through the visual examination of disease symptoms and pathogen morphology, including pigmentation, size, shape, and location of fruiting structures. However, these characteristics are similar to those produced by the common corn rust fungus P. sorghi, confounding accurate visual diagnosis of SCR. Here we report the development of a real-time polymerase chain reaction assay that discriminates between P. polysora and P. sorghi. Sequences of the rDNA internal transcribed spacer region were determined for P. polysora and P. sorghi. 5-Carboxyfluorescein fluorophore-labeled hydrolysis probes that differed at 14 nucleotide positions between the species were developed from these data and used to screen DNA extracted directly from rust-infected corn leaves. Species-specific, reproducible identifications of the pathogens were made from as little as 50 pg of DNA within 30 min, and were reliably performed from both recent collections and herbarium specimens. This assay will be useful for rapid and accurate diagnosis of SCR, and could serve as a tool to monitor the distribution and incidence of the disease in the United States.


Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa.
Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI. Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings. We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model. Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.


Breast irradiation postlumpectomy: development and evaluation of a decision instrument.
To develop an instrument to help clinicians inform patients about the benefits and risks of breast irradiation following lumpectomy and to help an informed patient decide whether she prefers this treatment. A Decision Board consisting of written material and visual aids was developed. It provides the patient with detailed information about her choices (breast irradiation or not), outcomes (breast recurrence and survival), probability of those outcomes, and quality of life associated with treatment and outcome. We studied the decision-making process in 82 consecutive node-negative lumpectomy patients who were seen in consultation by a radiation oncologist and oncology nurse. The Decision Board was used in the last 30 patients in the cohort. Patient comprehension following the consultation without the Decision Board was greater than 65% for all questions addressed, except for poor understanding of the lack of survival benefit associated with breast irradiation (12% of patients answered correctly) and that it could not be repeated (15% of patients answered correctly). Comprehension following the consultation with the Decision Board was similar, but understanding regarding the repetition of radiation (83%) was improved. Only 70% of patients in the no-Decision Board group felt they were offered a choice. This was increased to 97% in the Decision-Board group. Overall, 95% of patients chose breast irradiation, and this did not differ between groups. Patients reported several reasons for choosing breast irradiation, all of equal importance. The Decision Board facilitated shared decision making in node-negative lumpectomy patients who chose breast irradiation, but it did not affect a patient's choice to select breast irradiation.


Serum NGAL is Associated with Distinct Plasma Amyloid-β Peptides According to the Clinical Diagnosis of Dementia in Down Syndrome.
The majority of people with Down syndrome (DS) develop dementia due to Alzheimer's disease (AD). Neuropathological features are characterized by an accumulation of amyloid-β (Aβ) deposits and the presence of an activated immune response. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a newly identified (neuro)inflammatory constituent in AD. This study examines NGAL as an inflammatory marker in DS and its associations with plasma Aβ peptides according to the follow-up clinical diagnosis of dementia. Baseline serum NGAL and plasma Aβ40, Aβ42, Aβ(n40), and Aβ(n42) were quantified in 204 people with DS. The diagnosis of dementia in DS was established by follow-up clinical assessments. The following study groups were characterized: DS with AD at baseline (n = 67), DS without AD (n = 53), and non-demented DS individuals that converted to AD (n = 84). Serum NGAL was analyzed in 55 elderly non-DS, non-demented people. Serum NGAL levels were significantly increased in DS subjects compared to non-DS people. Serum NGAL levels were not associated with clinical dementia symptoms in DS. However, NGAL was positively associated with Aβ42 and Aβ(n42) in demented DS individuals and with Aβ40 and Aβ(n40) in the non-demented DS group. NGAL was negatively associated with Aβ42/Aβ40 and Aβ(n42)/Aβ(n40) ratios in converted DS subjects. These associations persisted for Aβ(n40), Aβ42/Aβ40, and Aβ(n42)/Aβ(n40) after adjusting for demographics measures, apolipoprotein E ε4 allele, platelets, and anti-inflammatory medication. Serum NGAL levels are increased in DS and associated with distinct species of Aβ depending on the progression of dementia as diagnosed by baseline and follow-up clinical assessments.


Guanidinoacetic acid loading affects plasma γ-aminobutyric acid in healthy men.
Guanidinoacetic acid (GAA), a precursor of creatine and an innovative dietary agent, activates γ-amino butyric acid (GABA) receptors yet clinical effects of dietary GAA on GABA metabolism are currently unknown. The main aim of this pilot research was to investigate whether GAA loading affected peripheral GABA homeostasis in healthy humans. Eight healthy male volunteers aged 22-25 years were randomized in a double-blind design to receive either GAA (three grams daily) or placebo by oral administration for 3 weeks. At baseline and after 3 weeks participants provided fasting blood samples for free plasma levels of GABA, GAA, creatine and glutamine. Following 3 weeks of intervention, plasma GABA level dropped significantly in participants receiving 3 g of GAA per day as compared to the placebo (P = 0.03). GAA loading significantly decreased plasma GABA by 88.8 nmol/L (95% confidence interval; 5.4-172.1) after 3 weeks of intervention as compared to the baseline (P = 0.03). GAA intervention positively affected both plasma GAA and creatine (P < 0.05), while no effects of intervention were reported for plasma glutamine. Results indicate that supplemental GAA affects peripheral GABA metabolism, and potentially down-regulates GABA synthesis in peripheral tissues. Possible GABAergic action of dietary GAA adds to the safety profile of this novel dietary supplement.


Factors affecting the quality of life of cancer patients undergoing chemotherapy: A questionnaire study.
This descriptive and cross-sectional study was undertaken to determine the factors affecting cancer patients' quality of life. We collected data from 352 chemotherapy patients of an Outpatient Chemotherapy Unit in a state hospital. We included volunteered chemotherapy patients with a signed informed consent and at least 50 Karnofsky Performance Scale points. We gathered data by Personal Information Form and Nightingale Symptom Assessment Scale (N-SAS) and analyzed via basic descriptive statistics and linear regression analysis. Patients were women (54.8%), married (83.5%), elementary school graduates (57.1%), housewives (44.6%) and undergoing fluorouracil-based therapy (47.2%), and almost all patients had religious and cultural rituals for the disease. Women experienced worse physical and social well-being than men (P = 0.001, P = 0.0001). Singles had worse psychological and general well-being (P = 0.0001, P = 0.0001). Housewives had the worst physical and social well-being (P < 0.05). No relationship existed between education level and life quality (P > 0.05). Breast cancer and sarcoma patients had the worst social well-being than other cancer patients. The N-SAS points of patients were not affected by blessings/prays, vow/sacrifice, consulting local herbalists and visiting "ocaks (folk physicians)" (P > 0.05). Patients with bad quality of life practiced lead pouring and amulets (P < 0.05). Gender was the first factor affecting the quality of life. Advanced studies on individual quality of life factors affecting cancer would empower nurses for better personal care techniques and patients for easily overcoming the disease.


Urodynamic effects of volume-adjustable balloons for treatment of postprostatectomy urinary incontinence.
To evaluate the urodynamic changes in patients treated with Adjustable Continence Therapy for men (ProACT) for postprostatectomy incontinence and to explore the clinical and urodynamic preimplantation parameters as predictors of clinical outcome. Patients underwent urodynamic studies before and after ProACT implantation. ProACT was considered successful if patients used none or 1 dry precautionary pad and nonsuccessful if the patient reported ≥1 wet pad/d. The pre- and postimplantation assessments were retrospectively compared within and between the success and nonsuccess groups. Multivariate logistic regression analysis was performed to investigate the association between the preimplantation variables and the clinical outcomes of ProACT implantation. A total of 49 patients were included, 37 with successful and 12 with nonsuccessful clinical outcome. Postimplantation urodynamic studies were performed a median of 9 months after ProACT implantation. In the successfully treated patients, maximum free flow rate, bladder contractility index, maximum of bladder contractility parameter W, and bladder voiding efficiency were significantly lower after implantation. The detrusor pressure at maximum flow rate, postvoid residual urine volume, and bladder outlet obstruction index were significantly higher. A longer duration of urinary incontinence, the use of >5 pads daily, and a smaller cystometric bladder capacity were all independently associated with nonsuccessful clinical outcome after ProACT implantation. ProACT implantation with successful clinical outcome resulted in greater urethral resistance during voiding and reduced bladder contraction strength. A longer duration of incontinence, the use of >5 pads daily, and a smaller cystometric bladder capacity were independent predictors of unsuccessful clinical outcomes, suggesting ProACT implantation should be considered sooner, rather than later, after conservative treatment of postprostatectomy incontinence has failed.


Rehabilitation professionals still do not communicate effectively about cognition.
To examine current use of descriptive labels for levels of cognitive impairment and types of memory to explore whether rehabilitation disciplines are now communicating more effectively. Survey of rehabilitation professionals. Hospital rehabilitation programs. Respondents (N=130) representing 8 facilities in 5 states completed surveys. Not applicable. Responses to survey questions about severity and types of memory impairment were examined with the Kruskal-Wallis test to determine the impact of profession on ratings. Post hoc Mann-Whitney U test comparisons of the 2 professions with the most cognitive assessment experience, psychologists/neuropsychologists and speech-language pathologists, were conducted. Ratings of various deficit levels differed significantly by profession (mild: H=39.780, P<.000; moderate: H=43.309, P<.000; severe: H=38.354, P<.000), but not by program location. In comparing psychologists/neuropsychologists and speech-language pathologists specifically, we found a significant discrepancy in ratings for percentile ranges associated with the terms mild (U=103.000, P<.001), moderate (U=78.000, P<.000), and severe (U=109.000, P<.001). Disagreement on the meaning of descriptive memory terms was noted among rehabilitation professionals in general, with large percentages of respondents not agreeing on the meanings of terms. A significant lack of consensus persists regarding the understanding of common cognitive terminology. This miscommunication affects cognitive impairment descriptors (eg, mild, moderate, severe) and categorization of types of memory. Only half of rehabilitation professionals appear aware of this discrepancy, suggesting that education is necessary to bring greater awareness of the potential for miscommunication.


Origin and neofunctionalization of a Drosophila paternal effect gene essential for zygote viability.
Although evolutionary novelty by gene duplication is well established, the origin and maintenance of essential genes that provide entirely new functions (neofunctionalization) is still largely unknown. Drosophila is a good model for the search of genes that are young enough to allow deciphering the molecular details of their evolutionary history. Recent years have seen increased interest in genes specifically required for male fertility because they often evolve rapidly. A special class of genes affecting male fertility, the paternal effect genes, have also become a focus of study to geneticists and reproductive biologists interested in fertilization and sperm-egg interactions. Using molecular genetics and the annotated Drosophila melanogaster genome, we identified CG14251 as the Drosophila paternal effect gene, ms(3)K81 (K81). This assignment was subsequently confirmed by P-element rescue of K81. A search for orthologous K81 sequences revealed that the distribution of K81 is surprisingly restricted to the 9 species comprising the melanogaster subgroup. Phylogenetic analyses indicate that K81 arose through duplication, most likely retroposition, of a ubiquitously expressed gene before the radiation of the melanogaster subgroup, followed by a period of rapid divergence and acquisition of a critical male germline-specific function. Interestingly, K81 has adopted the expression profile of a flanking gene suggesting that transcriptional coregulation may have been important in the neofunctionalization of K81. We present a detailed case history of the origin and evolution of a new essential gene and, in so doing, provide the first molecular identification of a Drosophila paternal effect gene, ms(3)K81 (K81).


Southern Ocean deep-water carbon export enhanced by natural iron fertilization.
The addition of iron to high-nutrient, low-chlorophyll regions induces phytoplankton blooms that take up carbon. Carbon export from the surface layer and, in particular, the ability of the ocean and sediments to sequester carbon for many years remains, however, poorly quantified. Here we report data from the CROZEX experiment in the Southern Ocean, which was conducted to test the hypothesis that the observed north-south gradient in phytoplankton concentrations in the vicinity of the Crozet Islands is induced by natural iron fertilization that results in enhanced organic carbon flux to the deep ocean. We report annual particulate carbon fluxes out of the surface layer, at three kilometres below the ocean surface and to the ocean floor. We find that carbon fluxes from a highly productive, naturally iron-fertilized region of the sub-Antarctic Southern Ocean are two to three times larger than the carbon fluxes from an adjacent high-nutrient, low-chlorophyll area not fertilized by iron. Our findings support the hypothesis that increased iron supply to the glacial sub-Antarctic may have directly enhanced carbon export to the deep ocean. The CROZEX sequestration efficiency (the amount of carbon sequestered below the depth of winter mixing for a given iron supply) of 8,600 mol mol(-1) was 18 times greater than that of a phytoplankton bloom induced artificially by adding iron, but 77 times smaller than that of another bloom initiated, like CROZEX, by a natural supply of iron. Large losses of purposefully added iron can explain the lower efficiency of the induced bloom(6). The discrepancy between the blooms naturally supplied with iron may result in part from an underestimate of horizontal iron supply.


The use of monoclonal antibodies to quantify the levels of sialoglycoproteins alpha and delta and variant sialoglycoproteins in human erythrocyte membranes.
By using radioiodinated monoclonal antibodies we have estimated that there are about 600 000 copies of sialoglycoprotein alpha (synonym glycophorin A) and 80 000 copies of sialoglycoprotein delta (synonym glycophorin B) per normal human erythrocyte. Erythrocytes expressing the product of only one alpha gene contain about 300 000 copies of alpha/cell. Two erythrocyte types containing alpha-delta hybrid molecules were studied. Those with heterozygous expression of the (alpha-delta)Mi.V gene contain about 100 000 alpha-delta copies per cell, whereas those with heterozygous expression of the En(UK) gene contain about 80 000 alpha-delta copies/cell. Erythrocyte types containing delta-alpha hybrid molecules were also studied. About 200 000 copies of (delta-alpha)Dantu were measured in cells with heterozygous expression of the (delta-alpha)Dantu gene (donor M.P.), whereas about 315 000 copies of the putative (delta-alpha)Dantu hybrid were found on the erythrocytes of donor J.O. [which also have heterozygous expression of the putative (delta-alpha)Dantu gene]. The erythrocytes of donor M.P. have normal levels of alpha, whereas those of donor J.O. have only about half-normal levels. It is proposed that the hybrid sialoglycoprotein of donor J.O. is of alpha-delta-alpha composition [(alpha-delta-alpha)Dantu] rather than delta-alpha and results from a double cross-over analogous to that which gives rise to haemoglobin Parchman.


Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2.
Heme oxygenase (HO) activity leads to accumulation of the antioxidant bilirubin, and degradation of the prooxidant heme. Moderate overexpression of the inducible form, HO-1, is associated with protection against oxidative injury. However, the role of HO-2 in oxidative stress has not been explored. We evaluated survival, indices of oxidative injury, and lung and HO expression in HO-2 null mutant mice exposed to > 95% O2 compared with wild-type controls. Similar basal levels of major lung antioxidants were observed, except that the knockouts had a twofold increase in total glutathione content. Despite increased HO-1 expression from HO-1 induction, knockout animals were sensitized to hyperoxia-induced oxidative injury and mortality, and also had significantly increased markers of oxidative injury before hyperoxic exposure. Furthermore, during hyperoxia, lung hemoproteins and iron content were significantly increased without increased ferritin, suggesting accumulation of available redox-active iron. These results demonstrate that the absence of HO-2 is associated with induction of HO-1 and increased oxygen toxicity in vivo, apparently due to accumulation of lung iron. These results suggest that HO-2 functions to augment the turnover of lung iron during oxidative stress, and that this function does not appear to be compensated for by induction of HO-1 in the knockouts.


Frequent hemodialysis schedules are associated with reduced levels of dialysis-induced cardiac injury (myocardial stunning).
Recurrent hemodialysis (HD)-induced ischemic cardiac injury (myocardial stunning) is common and associated with high ultrafiltration (UF) requirements, intradialytic hypotension, long-term loss of systolic function, increased likelihood of cardiovascular events, and death. More frequent HD regimens are associated with lower UF requirements and improved hemodynamic tolerability, improved cardiovascular outcomes, and reduced mortality compared with conventional thrice-weekly HD. This study investigated the hypothesis that modification of UF volume and rate with more frequent HD therapies would abrogate dialysis-induced myocardial stunning. A cross-sectional study of 46 patients established on hemodialysis >3 months compared four groups receiving the current range of quotidian therapies: conventional thrice-weekly HD (CHD3); more-frequent HD five to six times/week in a center (CSD) and at home (HSD); and home nocturnal HD (HN). Serial echocardiography quantitatively assessed regional systolic function to identify intradialytic left ventricular regional wall motion abnormalities (RWMAs). Cardiac troponin T (cTnT), N-terminal prohormone brain natriuretic peptide (NT-proBNP), and inflammatory markers were quantified. More frequent HD regimens were associated with lower UF volumes and rates compared with CHD3. Intradialytic fall in systolic BP was reduced in CSD and HSD groups and abolished in HN group. Mean RWMAs per patient reduced with increasing dialysis intensity (CHD3 > CSD > HSD > HN). Home-based groups demonstrated lower high-sensitivity C-reative protein levels, with trends to lower cTnT and NT-proBNP levels in the more frequent groups. Frequent HD regimes are associated with less dialysis-induced myocardial stunning compared with conventional HD. This may contribute to improved outcomes associated with frequent HD therapies.


Risk and predictors of suicide in colorectal cancer patients: a Surveillance, Epidemiology, and End Results analysis.
The risk of suicide is higher for patients with colorectal cancer (crc) than for the general population. Given known differences in morbidity and sites of recurrence, we sought to compare the predictors of suicide for patients with colon cancer and with rectal cancer. Using the U.S. Surveillance, Epidemiology, and End Results database, adult patients with confirmed adenocarcinoma of the colon or rectum during 1973-2009 were identified. Parametric and nonparametric tests were used to assess selected variables, and Cox proportional hazards regression models were used to determine predictors of suicide. The database identified 187,996 patients with rectal cancer and 443,368 with colon cancer. Compared with the rectal cancer group, the colon cancer group was older (median age: 70 years vs. 67 years; p < 0.001) and included more women (51% vs. 43%, p < 0.001). Suicide rates were similar in the colon and rectal cancer groups [611 (0.14%) vs. 337 (0.18%), p < 0.001]. On univariate analysis, rectal cancer was a predictor of suicide [hazard ratio (hr): 1.26; 95% confidence interval (ci): 1.10 to 1.43]. However, after adjusting for clinical and pathology factors, rectal cancer was not a predictor of suicide (hr: 1.05; 95% ci: 0.83 to 1.33). In the colon cancer cohort, independent predictors of suicide included older age, male sex, white race, and lack of primary resection. The aforementioned predictors, plus metastatic disease, similarly predicted suicide in the rectal cancer cohort. The suicide risk in crc patients is low (<0.2%), and no difference was found based on location of the primary tumour. Sex, age, race, distant spread of disease, and intact primary tumour were the main predictors of suicide among crc patients. Further studies and interventions are needed to target these high-risk groups.


Size-dependent commensurability and its possible role in determining the frictional behavior of adsorbed systems.
Recent nanofriction experiments of xenon on graphene revealed that the slip onset can be induced by increasing the adsorbate coverage above a critical value, which depends on temperature. Moreover, the xenon slippage on gold is much higher than on graphene in spite of the same physical nature of the interactions. To shed light on these intriguing results we have performed molecular dynamics simulations relying on ab initio derived potentials. By monitoring the interfacial structure factor as a function of coverage and temperature, we show that the key mechanism to interpret the observed frictional phenomena is the size-dependence of the island commensurability. The latter quantity is deeply affected also by the lattice misfit, which explains the different frictional behavior of Xe on graphene and gold.


Neural activity of the anterior insula in emotional processing depends on the individuals' emotional susceptibility.
Differences in personality factors between individuals may manifest themselves with different patterns of neural activity while individuals process stimuli with emotional content. We attempted to verify this hypothesis by investigating emotional susceptibility (ES), a specific emotional trait of the human personality defined as the tendency to "experience feelings of discomfort, helplessness, inadequacy and vulnerability" after exposure to stimuli with emotional valence. By administering a questionnaire evaluating the individuals' ES, we selected two groups of participants with high and low ES respectively. Then, we used functional magnetic resonance imaging to investigate differences between the groups in the neural activity involved while they were processing emotional stimuli in an explicit (focusing on the content of the stimuli) or an incidental (focusing on spatial features of the stimuli, irrespectively of their content) way. The results showed a selective difference in brain activity between groups only in the explicit processing of the emotional stimuli: bilateral activity of the anterior insula was present in subjects with high ES but not in subjects with low ES. This difference in neural activity within the anterior insula proved to be purely functional since no brain morphological differences were found between groups, as assessed by a voxel-based morphometry analysis. Although the role of the anterior insula in the processing of contexts perceived as emotionally salient is well established, the present study provides the first evidence of a modulation of the insular activity depending on the individuals' ES trait of personality.


Cardiac function in the treatment of arterial hypertension with propranolol.
1. Propranolol, when used for treating arterial hypertension, may influence determinants of both cardiac and vascular function; the consequent changes in cardiac performance may result from the interaction of different and possibly opposite effects. 2. Cardiac funtion was investigated in fifty-four primary hypertensive men in the pretreatment state and after 3 weeks of propranolol therapy at a daily dose of 320 mg. 3. beta-Receptor blockade caused depression of pre-injection left ventricular function, which was unrelated to the direction and the extent of changes in peripheral circulation. 4. The ejection left ventricular function could be either depressed or improved depending on the direction to which treatment shifted the vascular resistance, and consequently, the impedance to left ventricular ejection. 5. Withdrawal of the adrenergic support is probably the major factor responsible for the poor ventricular adaptation to an augmented impedance.


Requirement for TNF-alpha and IL-1 alpha in fetal thymocyte commitment and differentiation.
CD25 expression occurs early in thymocyte differentiation. The mechanism of induction of CD25 before T cell receptor rearrangement and the importance of this mechanism for T cell development are unknown. In a thymus reconstitution assay, tumor necrosis factor alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha), two cytokines produced within the thymic microenvironment, induced CD25 expression on early immature thymocytes. Either TNF-alpha or IL-1 alpha was necessary for further thymocyte maturation and CD4+CD8+ differentiation. In irradiated mice reconstituted with CD117+CD25+ thymocytes, commitment to the T cell lineage was marked by the loss of precursor multipotency.


Effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials.
To review the published literature on the effectiveness of interventions to promote physical activity in children and adolescents. Systematic review. Literature search using PubMed, SCOPUS, Psychlit, Ovid Medline, Sportdiscus, and Embase up to December 2006. Two independent reviewers assessed studies against the following inclusion criteria: controlled trial, comparison of intervention to promote physical activity with no intervention control condition, participants younger than 18 years, and reported statistical analyses of a physical activity outcome measure. Levels of evidence, accounting for methodological quality, were assessed for three types of intervention, five settings, and three target populations. The literature search identified 57 studies: 33 aimed at children and 24 at adolescents. Twenty four studies were of high methodological quality, including 13 studies in children. Interventions that were found to be effective achieved increases ranging from an additional 2.6 minutes of physical education related physical activity to 283 minutes per week of overall physical activity. Among children, limited evidence for an effect was found for interventions targeting children from low socioeconomic populations, and environmental interventions. Strong evidence was found that school based interventions with involvement of the family or community and multicomponent interventions can increase physical activity in adolescents. Some evidence was found for potentially effective strategies to increase children's levels of physical activity. For adolescents, multicomponent interventions and interventions that included both school and family or community involvement have the potential to make important differences to levels of physical activity and should be promoted. A lack of high quality evaluations hampers conclusions concerning effectiveness, especially among children.


Lisinopril attenuates renal oxidative injury in L-NAME-induced hypertensive rats.
Hypertension and related oxidative stress are involved in the pathogenesis of any renal diseases. Angiotensin-converting enzyme inhibitors have multi-directional renoprotective effects. In this study, we aimed to investigate whether lisinopril treatment has any biochemical alterations on renal tissue in L-NAME (Nε-nitro-L-arginine methyl ester) induced hypertension model. Twenty-eight Sprague-Dawley rats were included in this study and divided into four equal groups (n = 7): control group, L-NAME treated group (75 mg/kg/day), L-NAME plus lisinopril treated group and only lisinopril treated group (10 mg/kg/day). L-NAME and lisinopril were continued for 6 weeks. Systolic blood pressures were measured by using tail cuff method. In biochemical analysis, malondialdehyde (MDA, an index of lipid peroxidation) levels, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in renal tissues were used as markers of oxidative stress-induced renal impairment. Microalbumin and N-acetyl-β-D-glucosaminidase (NAG) in urine were determined as markers of renal tubular damage related to hypertension. Chronic L-NAME administration resulted in a significant depletion of serum nitric oxide (NO). When compared with control group, serum creatinine, microalbumin, urine NAG, renal tissue MDA level, and CAT activities were significantly high, while renal tissue SOD and GSH-Px activities low in L-NAME group. In the L-NAME plus lisinopril treated group, serum creatinine, microalbumin and urine NAG, renal MDA level and CAT activity decreased, whereas SOD, GSH-Px activities in renal tissue and serum NO levels were increased. Thus, lisinopril treatment reversed these effects. There were not any significant difference between L-NAME plus lisinopril treated group and control group concerning serum creatinine, renal tissue MDA level and SOD, GSH-Px, CAT activities. These results suggest that lisinopril could diminish biochemical alterations in L: -NAME induced hypertensive renal damage that occurs by oxidative stress.


Spatial and temporal heterogeneity in the population dynamics of Bulinus globosus and Biomphalaria pfeifferi and in the epidemiology of their infection with schistosomes.
Populations of Bulinus globosus and Biomphalaria pfeifferi were studied in a river habitat in Zimbabwe over a period of 12 months. Data were obtained on the prevalences of infections of Schistosoma haematobium (also S. mattheei) and S. mansoni respectively. Population parameters showed the following patterns for both snail species. (1) A patchy distribution correlated with the distributions of aquatic plants. (2) Life-expectancies of only a few weeks. (3) Recruitment rates correlated with water temperature and showing a distinct seasonal peak. (4) Spatial variation in recruitment. (5) A redistribution of snails during the rainy season. Epidemiological parameters showed the following patterns. (1) Large seasonal variations in the prevalence of patent infections. (2) Evidence from size-prevalence curves that suggests a variable force-of-infection from man to snail, correlated with water temperature. (3) Prevalences of infection that were higher in the vicinity of (+/- 60 m from) major water contact sites. Local prevalences of infection for B. globosus sometimes exceeded 50% and may have approached 100% if pre-patent infections are included. Snail numbers may limit transmission at these locations. Attention is drawn to the need to make field observations at an appropriate spatial scale and also to the implications for the effectiveness of focal snail control as a means of reducing transmission.


A Dictyostelium mutant lacking an F-actin cross-linking protein, the 120-kD gelation factor.
Actin-binding proteins are known to regulate in vitro the assembly of actin into supramolecular structures, but evidence for their activities in living nonmuscle cells is scarce. Amebae of Dictyostelium discoideum are nonmuscle cells in which mutants defective in several actin-binding proteins have been described. Here we characterize a mutant deficient in the 120-kD gelation factor, one of the most abundant F-actin cross-linking proteins of D. discoideum cells. No F-actin cross-linking activity attributable to the 120-kD protein was detected in mutant cell extracts, and antibodies recognizing different epitopes on the polypeptide showed the entire protein was lacking. Under the conditions used, elimination of the gelation factor did not substantially alter growth, shape, motility, or chemotactic orientation of the cells towards a cAMP source. Aggregates of the mutant developed into fruiting bodies consisting of normally differentiated spores and stalk cells. In cytoskeleton preparations a dense network of actin filaments as typical of the cell cortex, and bundles as they extend along the axis of filopods, were recognized. A significant alteration found was an enhanced accumulation of actin in cytoskeletons of the mutant when cells were stimulated with cyclic AMP. Our results indicate that control of cell shape and motility does not require the fine-tuned interactions of all proteins that have been identified as actin-binding proteins by in vitro assays.


Computer-aided detection of pulmonary pathology in pediatric chest radiographs.
A scheme for triaging pulmonary abnormalities in pediatric chest radiographs for specialist interpretation would be useful in resource-poor settings, especially those with a high tuberculosis burden. We assess computer-aided detection of pulmonary pathology in pediatric digital chest X-ray images. The method comprises four phases suggested in the literature: lung field segmentation, lung field subdivision, feature extraction and classification. The output of the system is a probability map for each image, giving an indication of the degree of abnormality of every region in the lung fields; the maps may be used as a visual tool for identifying those cases that need further attention. The system is evaluated on a set of anterior-posterior chest images obtained using a linear slot-scanning digital X-ray machine. The classification results produced an area under the ROC of 0.782, averaged over all regions.


Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA.
DNA methylation and hydroxylation are two ubiquitous reactions in DNA damage induction, yet insights are scarce concerning the free energy of activation within B-DNA. We resort to multiscale simulations to investigate the attack of a hydroxyl radical and of the primary diazonium onto a guanine embedded in a solvated dodecamer. Reaction free energy profiles characterize two strongly exergonic processes, yet allow unprecedented quantification of the barrier towards this damage reaction, not higher than 6 kcal mol-1 and sometimes inexistent, and of the exergonicities. In the case of the [G(C8)-OH]˙ intermediate, we challenge the functional dependence of such simulations: recently-proposed functionals, such as M06-2X and LC-BLYP, agree on a ∼4 kcal mol-1 barrier, whereas the hybrid GGA B3LYP functional predicts a barrier-less pathway. In the long term, multiscale approaches can help build up a unified panorama of DNA lesion induction. These results stress the importance of DFT/MM-MD simulations involving new functionals towards the sound modelling of biomolecule damage even in the ground state.


Cytokine production induced by non-encapsulated and encapsulated Porphyromonas gingivalis strains.
Although the exact reason is not known, encapsulated gram-negative Porphyromonas gingivalis strains are more virulent than non-encapsulated strains. Since difference in virulence properties may be due to difference in cytokine production following recognition of the bacteria or their products by the host inflammatory cells, we compared cytokine production following stimulation with bacteria or lipopolysaccharides (LPS) of a non-encapsulated and an encapsulated P. gingivalis strain (K(-) and K1). Tumour necrosis factor-alpha (TNF-α) production following stimulation of the cell-line Mono Mac 6 with bacteria or LPS of both P. gingivalis strains was determined using flow cytometry. Furthermore, we investigated the effects of the two P. gingivalis strains or their LPS on TNF-α and Interleukin (IL-1β, IL-6, IL-12 and IL-10) production in whole blood using Luminex. In both experiments, Escherichia coli bacteria and LPS were used as a reference. Both P. gingivalis strains induced lower cytokine production than E. coli with the exception of IL-6. P. gingivalis K1 bacteria elicited a higher overall cytokine production than P. gingivalis K(-). In contrast, P. gingivalis K1 LPS stimulation induced a lower cytokine production than P. gingivalis K(-) LPS. Our findings suggest that the encapsulated P. gingivalis K1 bacteria induce higher cytokine production than the non-encapsulated P. gingivalis K(-). This was not due to its LPS. The stronger induction of cytokines may contribute to the higher virulence of P. gingivalis K1.


Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.
The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species.


Numerical simulation of free evolution in solid-state nuclear magnetic resonance using low-order correlations in Liouville space.
The design of simulations of free evolution in dipolar-coupled nuclear-spin systems using low-order correlations in Liouville space (LCL) is discussed, and a computational scheme relying on the Suzuki-Trotter algorithm and involving minimal memory requirements is described. The unusual nature of the approximation introduced by Liouville-space reduction in a spinning solid is highlighted by considering the accuracy of LCL simulations at different spinning frequencies, the quasiequilibria achieved by spin systems in LCL simulations, and the growth of high-order coherences in the exact dynamics. In particular, it is shown that accurate LCL simulations of proton spin diffusion occur in a regime where the reduced space excludes the coherences that make the dominant contribution to ∥σ∥(2), the norm-squared of the density matrix.


Neural correlates of the pitch of complex tones. II. Pitch shift, pitch ambiguity, phase invariance, pitch circularity, rate pitch, and the dominance region for pitch.
1. The neural correlates of low pitches produced by complex tones were studied by analyzing temporal discharge patterns of auditory nerve fibers in Dial-anesthetized cats. In the previous paper it was observed that, for harmonic stimuli, the most frequent interspike interval present in the population of auditory nerve fibers always corresponded to the perceived pitch (predominant interval hypothesis). The fraction of these most frequent intervals relative to the total number of intervals qualitatively corresponded to strength (salience) of the low pitches that are heard. 2. This paper addresses the neural correlates of stimuli that produce more complex patterns of pitch judgments, such as shifts in pitch and multiple pitches. Correlates of pitch shift and pitch ambiguity were investigated with the use of harmonic and inharmonic amplitude-modulated (AM) tones varying either in carrier frequency or modulation frequency. Pitches estimated from the pooled interval distributions showed shifts corresponding to "the first effect of pitch shift" (de Boer's rule) that is observed psychophysically. Pooled interval distributions in response to inharmonic stimulus segments showed multiple maxima corresponding to the multiple pitches heard by human listeners (pitch ambiguity). 3. AM and quasi-frequency-modulated tones with low carrier frequencies produce very similar patterns of pitch judgments, despite great differences in their phase spectra and waveform envelopes. Pitches estimated from pooled interval distributions were remarkably similar for the two kinds of stimuli, consistent with the psychophysically observed phase invariance of pitches produced by sets of low-frequency components. 4. Trains of clicks having uniform and alternating polarities were used to investigate the relation between pitches associated with periodicity and those associated with click rate. For unipolar click trains, where periodicity and rate coincide, physiologically estimated pitches closely follow the fundamental period. This corresponds to the pitch at the fundamental frequency (F0) that is heard. For alternating click trains, where rate and periodicity do not coincide, physiologically estimated pitches always closely followed the fundamental period. Although these pitch estimates corresponded to periodicity pitches that are heard for F0s > 150 Hz, they did not correspond to the rate pitches that are heard for F0s < 150 Hz. The predominant interval hypothesis thus failed to predict rate pitch. 5. When alternating-polarity click trains are high-pass filtered, rate pitches are strengthened and can also be heard at F0s > 150 Hz. Pitches for high-pass-filtered alternating click trains were estimated from pooled responses of fibers with characteristic frequencies (CFs) > 2 kHz. Roughly equal numbers of intervals at 1/rate and 1/F0 were found for all F0s studied, from 80 to 160 Hz, producing pitch estimates consistent with the rate pitches that are heard after high-pass filtering. The existence region for rate pitch also coincided with the presence of clear periodicities related to the click rate in pooled peristimulus time histograms. These periodicities were strongest for ensembles of fibers with CFs > 2 kHz, where there is widespread synchrony of discharges across many fibers. 6. The "dominance region for pitch" was studied with the use of two harmonic complexes consisting of harmonics 3-5 of one F0 and harmonics 6-12 of another fundamental 20% higher in frequency. When the complexes were presented individually, pitch estimates were always close to the fundamental of the complex. When the complexes were presented concurrently, pitch estimates always followed the fundamental of harmonics 3-5 for F0s of 150-480 Hz. For F0s of 125-150 Hz, pitch estimates followed one or the other fundamental, and for F0s < 125 Hz, pitch estimates followed the fundamental of harmonics 6-12. (ABSTRACT TRUNCATED)


The role of tobacco promoting and restraining factors in smoking intentions among Ghanaian youth.
In Western countries, the relationship between smoking intentions and smoking behaviour is well established. However, youth smoking intentions and associated factors in developing countries are largely unexplored and the former may occur for a variety of reasons. We investigated youth smoking intentions in Ghana with regard to several tobacco promoting and restraining factors, including environmental, familial, attitudinal and knowledge measures. A school-based survey of a representative sample of 12-20-year-olds was conducted in 2008 in Ghana (N = 1338, response rate 89.7%). In a bivariate model, both among ever and never smokers, allowing smoking on school compound, exposure to tobacco advertisement and parental smoking were associated with future intention to smoke. Compared to those who agreed that smoking is harmful to health, smoking is difficult to quit and that tobacco should not be sold to minors, those who disagreed or were not sure were more likely to have an intention to smoke. In the multivariate analyses, these associations persisted, except that the attitude measures concerning the difficulty of quitting smoking once started and tobacco sales ban were no longer significantly associated with smoking intentions. These findings underscore the importance of school smoking policy, parental smoking behaviour and knowledge of the harmful effects of tobacco use in determining Ghanaian youths' future smoking intentions. Because current high percentages of smoking intentions may turn into high smoking rates in the future, the introduction of effective tobacco control measures at all levels of society to prevent youth smoking in Ghana may be essential.


[Oxygenation: the impact of face mask coupling.].
Different oxygenation techniques aim at promoting denitrogenation before apnea during induction. The main reason why CIO2 = 100% cannot be reached is the lack of adequate face mask coupling, allowing the entry of room air. Although anesthesiologists know this principle, not all of them apply it correctly, facilitating the entry of air in fresh gases flow and consequently diluting CIO2. This prospective study was performed to comparatively evaluate, through the variation of oxygen expired concentration (CEO2), the efficacy of the oxygenation technique via face mask in the conditions routinely used by anesthesiologists, simulating situations of progressive leaks. Oxygen end-tidal concentrations of 15 volunteers, physical status ASA I, were studied with 8 deep breaths (vital capacity) in 60 s with fresh gas flow of 10 L.min-1. The face mask was: tightly fitted with 100% CIO2 (Tf100) or varying from 50% to 90%, (Tf50, Tf60, Tf70, Tf80, Tf90); gravity-coupled to face and 100% CIO2 (Grav) and moved 1 cm away from face with 100% CIO2 (Aw). CEO2 was recorded at 10 s intervals. P < 0.05 was considered statistically significant. CEO2 has increased for all groups (p < 0.001), but only Tf100 reached values close to ideal (82.20 - 87). Comparing mean CEO2 of Grav and Tf100 at the end of 60s, (82.20 and 65.87) there was a difference of approximately 20% between both techniques, since gravity-coupled mask only did not provide adequate oxygenation. There were no significant differences between groups Tf70 and Grav (65.87 and 62.67) in all studied moments, suggesting that the latter simulates a 70% CIO2 at 60 s. Mean Aw group CEO2 increased to 47.20 at 60s showing that this technique may be associated to unacceptable risk of hypoxemia. All situations of face mask coupling gradually increased CEO2, although with decreased oxygenation efficacy due to situations of face mask malposition. This study has shown the need for attention during oxygenation, using well coupled face mask and eliminating normal practices of moved away or gravity-coupled masks.


Effectiveness of hand hygiene depends on the patient's health condition and care environment.
The present authors examined how patient hand contamination was associated with underlying disease and treatment environment in order to determine effective hand hygiene methods. Samples were collected from inpatients (45 with hematological malignancies, 48 postoperative), outpatients (48 undergoing hemodialysis, 55 on chemotherapy), and 44 individuals living in nursing homes. All participants provided informed consent for study participation. All subjects performed hand hygiene. Before and after hand hygiene, samples of bacteria were collected from the palm of the hand onto agar media. Bacteria were counted and bacterial strains were identified. The authors then collected smear samples from the contralateral palm and measured adenosine triphosphate (ATP) levels. Patient hand contamination was the highest in hemodialysis patients, followed by residents of nursing homes, postoperative patients, patients with cancer receiving chemotherapy, and patients of hematological malignancies. Regardless of the underlying disease and treatment environment, patients were able to reduce the number of bacterial colonies and ATP by proper hand hygiene. Compared with wet wipes, hand washing seemed to remove bacteria more effectively. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in 30 subjects, none of whom were patients of hematological malignancies. Of these, 19 tested negative for MRSA after performing proper hand hygiene. Patient hand contamination is affected by underlying disease and care environment, but can be reduced by encouraging proper hand washing. Proper patient hand hygiene can reduce MRSA on patients' hands, and thus may serve as an effective tool for prevention of healthcare-associated infections.


Right ventricular absolute myocardial blood flow in complex congenital heart disease.
A consequence in patients with d-transposition of the great arteries (d-TGA) and tetralogy of Fallot (TOF) is right ventricular hypertrophy (RVH) and right ventricular failure. Myocardial contrast echocardiography (MCE) permits the determination of the myocardial microvascular density reflected by the relative myocardial blood volume (rBV; ml/ml). This study was conducted to elucidate the relationship between RVH and myocardial microvascular changes by quantitative MCE in patients with d-TGA and TOF. Three groups of individuals were included in the study: 22 patients with d-TGA, 18 patients with TOF and 22 healthy individuals (controls). MCE was performed at rest and during adenosine-induced hyperaemia. rBV and myocardial blood flow (MBF; ml/min per gram) were derived from steady state and refill sequences of ultrasound contrast agent. Hyperaemic septal rBV differed significantly between the groups and was highest in controls: d-TGA 0.141+/-0.060 ml/ml, TOF 0.134+/-0.080 ml/ml, controls 0.189+/-0.074 ml/ml, p=0.005. Myocardial blood flow reserve (MBFR), that is the ratio of hyperaemic to baseline MBF, differed significantly between the groups and was lowest in d-TGA (2.68+/-1.13) versus TOF (3.37+/-1.57) and controls (4.22+/-1.17, p=0.001). Hyperaemic septal rBV, MBF and MBFR showed a significant correlation with right ventricular systolic function as determined by tricuspid annular plane systolic excursion. Right ventricular myocardial microvascular density of the septal wall in d-TGA and TOF patients with RVH due to pressure and/or volume overload is reduced. This appears to be related to a reduced myocardial perfusion reserve and impaired right ventricular systolic function.


Identification of methylated genes associated with aggressive bladder cancer.
Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment.


Bioprospecting around Arctic islands: Marine bacteria as rich source of biocatalysts.
We have investigated the biotechnological potential of Arctic marine bacteria for their ability to produce a broad spectrum of cold-active enzymes. Marine bacteria exhibiting these features are of great interest for both fundamental research and industrial applications. Macrobiota, water and sediment samples have been collected during 2010 and 2011 expeditions around the Lofoten and Svalbard islands. Bacteria were isolated from this material and identified through 16S rRNA gene sequence analysis for the purpose of establishing a culture collection of marine Arctic bacteria. Herein, we present the functional screening for different extracellular enzymatic activities from 100 diversely chosen microbial isolates incubated at 4 and 20 °C. The production of esterase/lipase, DNase, and protease activities were revealed in 67, 53, and 56% of the strains, respectively, while 41, 23, 9, and 7% of the strains possessed amylase, chitinase, cellulase, and xylanase activities, respectively. Our findings show that phylogenetically diverse bacteria, including many new species, could be cultured from the marine arctic environment. The Arctic polar environment is still an untapped reservoir of biodiversity for bioprospecting.


Semen parameters in a fertile versus subfertile population: a need for change in the interpretation of semen testing.
This prospectively designed study was conducted to compare a fertile and a subfertile population so as to define normal values for different semen parameters. Semen analyses were performed according to the World Health Organization (WHO) guidelines, except for sperm morphology (strict criteria). In the fertile population (n = 144), all patients had recently achieved pregnancy, within 12 months of unprotected coitus. As subfertile controls we examined semen samples from 143 consecutive men attending our infertility clinic during the same study period. Couples with tubal factor infertility and/or ovulatory disorders were excluded from our study. Using receiver operating characteristic (ROC) curve analysis we determined the diagnostic potential and cut-off values for single and combined sperm parameters. Sperm morphology scored best, with a value of 78% (area under the ROC curve). Summary statistics showed a shift towards abnormality for most semen parameters in the subfertile population. Using the 10th percentile of the fertile population as the cut-off value, the following results were obtained: 14.3 x 10(6)/ml for sperm concentration, 28% for progressive motility and 5% for sperm morphology. Using ROC analysis, cut-off values were 34 x 10(6)/ml, 45% and 10% respectively. Cut-off values for normality were different from those described in the WHO guidelines. Routine bacterial and non-bacterial cultures turned out to be of little prognostic value.


A Simple Predictive Enhancer Syntax for Hindbrain Patterning Is Conserved in Vertebrate Genomes.
Determining the function of regulatory elements is fundamental for our understanding of development, disease and evolution. However, the sequence features that mediate these functions are often unclear and the prediction of tissue-specific expression patterns from sequence alone is non-trivial. Previous functional studies have demonstrated a link between PBX-HOX and MEIS/PREP binding interactions and hindbrain enhancer activity, but the defining grammar of these sites, if any exists, has remained elusive. Here, we identify a shared sequence signature (syntax) within a heterogeneous set of conserved vertebrate hindbrain enhancers composed of spatially co-occurring PBX-HOX and MEIS/PREP transcription factor binding motifs. We use this syntax to accurately predict hindbrain enhancers in 89% of cases (67/75 predicted elements) from a set of conserved non-coding elements (CNEs). Furthermore, mutagenesis of the sites abolishes activity or generates ectopic expression, demonstrating their requirement for segmentally restricted enhancer activity in the hindbrain. We refine and use our syntax to predict over 3,000 hindbrain enhancers across the human genome. These sequences tend to be located near developmental transcription factors and are enriched in known hindbrain activating elements, demonstrating the predictive power of this simple model. Our findings support the theory that hundreds of CNEs, and perhaps thousands of regions across the human genome, function to coordinate gene expression in the developing hindbrain. We speculate that deeply conserved sequences of this kind contributed to the co-option of new genes into the hindbrain gene regulatory network during early vertebrate evolution by linking patterns of hox expression to downstream genes involved in segmentation and patterning, and evolutionarily newer instances may have continued to contribute to lineage-specific elaboration of the hindbrain.


Health surveillance of workers exposed to laboratory animal allergens.
Laboratory animal allergy (LAA) remains prevalent among workers exposed to laboratory animals. Pre-placement and health surveillance procedures vary between different employers. To determine evidence-based strategies for pre-placement and periodic health assessments for workers exposed to laboratory animals. Literature was searched systematically using Medline and EMBASE for articles published in all languages up to the end of May 2010. Evidence-based statements and recommendations were graded according to a modified Royal College of General Practitioner's star system. Hundred and nine studies were identified from the literature search; 59 of these were accessed for critical appraisal and 50 contributed to the evidence statements. We recommend that laboratory animal workers should have a baseline health assessment that includes a health questionnaire, face-to-face assessment and spirometry. Identification of specific immunoglobulin E to common aero-allergens and to domestic and laboratory animal allergens may be used to identify workers who would benefit from further advice about managing their exposure, where risk assessment indicates that this might be prudent. Thereafter health surveillance should be performed by administering an appropriate health questionnaire, covering upper and lower respiratory, eye and skin symptoms on exposure, and wheals with animal scratches. The questionnaire should be administered at increased frequency for the first few years, the frequency being determined by a risk assessment. Where a worker develops new symptoms suggestive of LAA or where an asthmatic employee experiences deterioration either in symptoms or in control, they should be assessed further and a multicause multidisciplinary investigation performed.


Concentration dependence of upconversion emission from Er:YAG fibers.
Fibers of Er:YAG have been grown using the laser-heated pedestal growth method. Fibers with Er concentrations ranging from 0.5 to 10 mol. % have been produced and excitation at 965 nm has been used to produce intense upconversion emission at green and red wavelengths. The dependence of ground state absorption and upconversion emission on dopant concentration has been studied and shown to exhibit lower levels of self-absorption than previously reported. At Er concentrations of 5 mol. % and above; however, the variation of upconversion emission intensity with pump power deviates from theoretical predictions, exhibiting saturation behavior consistent with concentration quenching.


The distribution of congenital anomalies within the VACTERL association among tumor necrosis factor antagonist-exposed pregnancies is similar to the general population.
To compare the distribution of congenital anomalies within the VACTERL association (vertebral defects, anal atresia, cardiac, tracheoesophageal, renal, and limb abnormalities) between patients exposed to tumor necrosis factor-α (TNF-α) antagonist and the general population. Analysis for comparison of proportional differences to a previous publication between anomaly subgroups, according to subgroup definitions of the European Surveillance of Congenital Anomalies (EUROCAT), a population-based database. Most EUROCAT subgroups belonging to the VACTERL association contained only one or 2 records of TNF-α antagonist exposure, so comparison of proportions was imprecise. Only the category "limb abnormalities" showed a significantly higher proportion in the general population. The high number of congenital anomalies belonging to the VACTERL association from a report of pregnancies exposed to TNF-α antagonists could not be confirmed using a population-based congenital anomaly database.


Hyperoxia-induced changes in estradiol metabolism in postnatal airway smooth muscle.
Supplemental oxygen, used to treat hypoxia in preterm and term neonates, increases the risk of neonatal lung diseases, such as bronchopulmonary dysplasia (BPD) and asthma. There is a known sex predilection for BPD, but the underlying mechanisms are not clear. We tested the hypothesis that altered, local estradiol following hyperoxia contributes to pathophysiological changes observed in immature lung. In human fetal airway smooth muscle (fASM) cells exposed to normoxia or hyperoxia, we measured the expression of proteins involved in estrogen metabolism and cell proliferation responses to estradiol. In fASM cells, CYP1a1 expression was increased by hyperoxia, whereas hyperoxia-induced enhancement of cell proliferation was blunted by estradiol. Pharmacological studies indicated that these effects were attributable to upregulation of CYP1a1 and subsequent increased metabolism of estradiol to a downstream intermediate 2-methoxyestradiol. Microarray analysis of mouse lung exposed to 14 days of hyperoxia showed the most significant alteration in CYP1a1 expression, with minimal changes in expression of five other genes related to estrogen receptors, synthesis, and metabolism. Our novel results on estradiol metabolism in fetal and early postnatal lung in the context of hyperoxia indicate CYP1a1 as a potential mechanism for the protective effect of estradiol in hyperoxia-exposed immature lung, which may help explain the sex difference in neonatal lung diseases.


Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.


Herpes Simplex Virus Organizes Cytoplasmic Membranes To Form a Viral Assembly Center in Neuronal Cells.
Herpes simplex virus (HSV) is a neuroinvasive virus that has been used as a model organism for studying common properties of all herpesviruses. HSV induces host organelle rearrangement and forms multiple, dispersed assembly compartments in epithelial cells, which complicates the study of HSV assembly. In this study, we show that HSV forms a visually distinct unitary cytoplasmic viral assembly center (cVAC) in both cancerous and primary neuronal cells that concentrates viral structural proteins and is a major site of capsid envelopment. The HSV cVAC also concentrates host membranes that are important for viral assembly, such as Golgi- and recycling endosome-derived membranes. Finally, we show that HSV cVAC formation and/or maintenance depends on an intact microtubule network and a viral tegument protein, pUL51. Our observations suggest that the neuronal cVAC is a uniquely useful model to study common herpesvirus assembly pathways and cell-specific pathways for membrane reorganization.IMPORTANCE Herpesvirus particles are complex and contain many different proteins that must come together in an organized and coordinated fashion. Many viruses solve this coordination problem by creating a specialized assembly factory in the host cell, and the formation of such factories provides a promising target for interfering with virus production. Herpes simplex virus 1 (HSV-1) infects several types of cells, including neurons, but has not previously been shown to form such an organized factory in the nonneuronal cells in which its assembly has been best studied. Here, we show that HSV-1 forms an organized assembly factory in neuronal cells, and we identify some of the viral and host cell factors that are important for its formation.


Parasitic co-infections: does Ascaris lumbricoides protect against Plasmodium falciparum infection?
A controlled randomized trial of antihelminthic treatment was undertaken in 1996-1997 in a rural area of Madagascar where populations were simultaneously infected with Ascaris lumbricoides and Plasmodium falciparum. Levamisole was administered bimonthly to 164 subjects, randomized on a family basis, whereas 186 were controls. While levamisole proved to be highly effective in reducing Ascaris egg loads in the treated group (P < 10(-3) at all bimonthly visits), subjects more than 5 years of age, treated with levamisole had a significant increase in their P. falciparum densities compared with controls (P = 0.02), whereas there was no effect of anti-helminthic treatment on children 6 months to 4 years of age. The demonstration of a clear negative interaction between Ascaris infection and malaria parasite density has important implications. Single community therapy programs to deliver treatments against several parasitic infections could avoid an increase of malaria attacks after mass treatment of ascariasis.


Desiccating Stress-Induced MMP Production and Activity Worsens Wound Healing in Alkali-Burned Corneas.
To evaluate the effects of dry eye on ocular surface protease activity and sight threatening corneal complications following ocular surface chemical injury. C57BL/6 mice were subjected to unilateral alkali burn (AB) with or without concomitant dry eye for 2 or 5 days. Mice were observed daily for appearance of corneal perforation. Whole corneas were harvested and lysed for RNA extraction. Quantitative real-time PCR was performed to measure expression of inflammation cytokines, matrix metalloproteinases (MMP). Matrix metalloproteinase-9 activity, gelatinase activity, and myeloperoxidase (MPO) activity were evaluated in corneal lysates. Presence of infiltrating neutrophils was evaluated by immunohistochemistry and flow cytometry. Eyes subjected to the combined model of AB and dry eye (CM) had 20% sterile corneal perforation rate as soon as 1 day after the initial injury, which increased to 35% by 5 days, delayed wound closure and increased corneal opacity. Increased levels of IL-1β, -6, and MMPs-1, -3, -8, -9, and -13, and chemokine (C-X-C motif) ligand 1 (CSCL1) transcripts were found after 2 days in CM compared with AB corneas. Increased MMP-1, -3, -9, and -13 immunoreactivity and gelatinolytic activity were seen in CM corneas compared with AB. Increased neutrophil infiltration and MPO activity was noted in the CM group compared with AB 2 days post injury. Desiccating stress worsens outcome of ocular AB, creating a cytokine and protease storm with greater neutrophil infiltration, increasing the risk of corneal perforation.


Plantar Pressure and Gait Symmetry in Individuals with Fractures versus Tendon Injuries to the Hindfoot.
The intent of this study was to determine whether differences in function, walking characteristics, and plantar pressures exist in individuals after operative fixation of an intra-articular calcaneal fracture (HFX) compared with individuals with operative repair of an Achilles tendon rupture (ATR). Twenty patients (ten with HFXs and ten with ATRs) were recruited approximately 3.5 months after operative intervention. All of the participants completed the Lower Extremity Functional Scale and had their foot posture assessed using the Foot Posture Index. Walking velocity was assessed using a pressure mat system, and plantar pressures were measured using an in-shoe sensor. In addition to between-group comparisons, the involved foot was compared with the uninvolved foot for each participant. There were no differences in age, height, weight, or number of days since surgery between the two groups. The HFX group had lower Lower Extremity Functional Scale scores, slower walking velocities, and different forefoot loading patterns compared with the ATR group. The involved limb of both groups was less pronated. The results indicate that individuals with an HFX spend more time on their involved limb and walk slower than those with an ATR. Plantar pressures in the HFX group were higher in the lateral forefoot and lower in the medial forefoot and in the ATR group were symmetrically lower in the forefoot.


Association of perioperative thromboprophylaxis on revision rate due to infection and aseptic loosening in primary total hip arthroplasty - new evidence from the Nordic Arthroplasty Registry Association (NARA).
Results regarding the impact of anticoagulants on revision rate are conflicting. We examined the association between the use of low molecular weight heparin (LMWH) or non-vitamin K oral anticoagulants (NOACs) as thromboprophylaxis after primary total hip arthroplasty (THA) and the revision rate due to infection, aseptic loosening, and all causes. We conducted a cohort study (n = 53,605) based on prospectively collected data from the national hip arthroplasty registries from Denmark and Norway. The outcome was time to revision due to infection, aseptic loosening, and all causes, studied separately. Kaplan-Meier (KM) survival analysis and a Cox proportional hazard model was used to estimate implant survival and cause-specific hazard ratios (HRs) with 95% confidence intervals (CI) adjusting for age, sex, Charlson Comorbidity Index, fixation type, start, and duration of thromboprophylaxis, and preoperative use of Vitamin K antagonists, NOAC, aspirin, and platelet inhibitors as confounders. We included 40,451 patients in the LMWH group and 13,154 patients in the NOAC group. Regarding revision due to infection, the 1-year and 5-year KM survival was 99% in both the LMWH group and in the NOAC group. During the entire follow-up period, the adjusted HR for revision due to infection was 0.9 (CI 0.7-1.1), 1.6 (CI 1.3-2.1) for aseptic loosening, and 1.2 (CI 1.1-1.4) for all-cause revision for the NOAC compared with the LMWH group. The absolute differences in revision rates between the groups varied from 0.2% to 1%. Compared with LMWH, NOACs were associated with a slightly lower revision rate due to infection, but higher revisions rates due to aseptic loosening and all-cause revision. The absolute differences between groups are small and most likely not clinically relevant. In addition, the observed associations might partly be explained by selection bias and unmeasured confounding, and should be a topic for further research.


What Can Long Terminal Repeats Tell Us About the Age of LTR Retrotransposons, Gene Conversion and Ectopic Recombination?
LTR retrotransposons constitute a significant part of plant genomes and their evolutionary dynamics play an important role in genome size changes. Current methods of LTR retrotransposon age estimation are based only on LTR (long terminal repeat) divergence. This has prompted us to analyze sequence similarity of LTRs in 25,144 LTR retrotransposons from fifteen plant species as well as formation of solo LTRs. We found that approximately one fourth of nested retrotransposons showed a higher LTR divergence than the pre-existing retrotransposons into which they had been inserted. Moreover, LTR similarity was correlated with LTR length. We propose that gene conversion can contribute to this phenomenon. Gene conversion prediction in LTRs showed potential converted regions in 25% of LTR pairs. Gene conversion was higher in species with smaller genomes while the proportion of solo LTRs did not change with genome size in analyzed species. The negative correlation between the extent of gene conversion and the abundance of solo LTRs suggests interference between gene conversion and ectopic recombination. Since such phenomena limit the traditional methods of LTR retrotransposon age estimation, we recommend an improved approach based on the exclusion of regions affected by gene conversion.


High prevalence of diabetes mellitus and metabolic syndrome in a South African coloured population: baseline data of a study in Bellville, Cape Town.
The coloured population has the second-highest prevalence of diabetes in South Africa. However, the data were based on a study conducted almost 20 years ago in a peri-urban coloured population of the Western Cape. We aimed to determine the prevalence of diabetes mellitus and metabolic syndrome in an urban coloured population in South Africa. In a cross-sectional survey, 642 participants aged ≥31 years were drawn from an urban community of Bellville South, Cape Town, from mid-January 2008 to March 2009. Type 2 diabetes was assessed according to the WHO criteria, and metabolic syndrome was based on the International Diabetes Federation (IDF), ATP III and 2009 Joint Interim Statement (JIS) definition. The crude prevalence of 28.2% (age-adjusted 26.3%, 95% confidence interval (CI) 22.0 - 30.3) for type 2 diabetes was: 4.4% (age-adjusted 3.2%, 95% CI 1.6 - 4.9) for impaired fasting glycaemia, and 15.3% (age-adjusted 15.0%, 95% CI 11.4 - 18.6) for impaired glucose tolerance. Undiagnosed type 2 diabetes was present in 18.1% (age-adjusted 16.8%, 95% CI 13.3 - 20.4). The crude prevalence of metabolic syndrome was higher with the JIS definition (62.0%) than the IDF (60.6%), and the National Cholesterol Education Program (NCEP) ATP III (55.4%). There was good overall agreement between the MetS criteria, k=0.89 (95% CI 0.85 - 0.92). The prevalence of diabetes has increased hugely in the coloured community, and the high prevalence of undiagnosed diabetes portends that cardiovascular diseases might grow to epidemic proportions in the near future in South Africa.


Vestibular signals in primate thalamus: properties and origins.
Vestibular activation is found in diverse cortical areas. To characterize the pathways and types of signals supplied to cortex, we recorded responses to rotational and/or translational stimuli in the macaque thalamus. Few cells responded to rotation alone, with most showing convergence between semicircular canal and otolith signals. During sinusoidal rotation, thalamic responses lead head velocity by approximately 30 degrees on average at frequencies between 0.01-4 Hz. During translation, neurons encoded combinations of linear acceleration and velocity. In general, thalamic responses were similar to those recorded in the vestibular and cerebellar nuclei using identical testing paradigms, but differed from those of vestibular afferents. Thalamic responses represented a biased continuum: most cells more strongly encoded translation and fewer cells modulated primarily in response to net gravitoinertial acceleration. Responsive neurons were scattered within a large area that included regions of the ventral posterior and ventral lateral nuclei, and so were not restricted to the known vestibular nuclei projection zones. To determine the origins of these responses, a retrograde tracer was injected into a dorsolateral thalamic site where rotation/translation-sensitive cells were encountered. This injection labeled neurons in the rostral contralateral anterior interposed and fastigial nuclei, but did not label cells within the vestibular nuclei. Examination of thalamic terminations after tracer injections into the cerebellar and vestibular nuclei indicated that most vestibular responsive units fall within the thalamic terminal zones of these nuclei. Thus, vestibular signals, which are supplied to the thalamus from both vestibular and cerebellar nuclei, are positioned for distribution to widespread cortical areas.


Deficiency of Atf3, an adaptive-response gene, protects islets and ameliorates inflammation in a syngeneic mouse transplantation model.
Islet transplantation is a potential therapeutic option for type 1 diabetes. However, the need for multiple donors per patient and heavy immunosuppression of the recipients limit its use. The goal of this study was to test whether the gene encoding activating transcription factor 3 (ATF3), a stress-inducible pro-apoptotic gene, plays a role in graft rejection in islet transplantation. We compared wild-type (WT) and Atf3 knockout (KO) islets in vitro using stress paradigms relevant to islet transplantation: isolation, inflammation and hypoxia. We also compared the WT and KO islets in vivo using a syngeneic mouse transplantation model. ATF3 was induced in all three stress paradigms and played a deleterious role in islet survival, as evidenced by the lower viability of WT islets compared with KO islets. ATF3 upregulated various downstream target genes in a stress-dependent manner. These target genes can be classified into two functional groups: (1) apoptosis (Noxa [also known as Pmaip1] and Bnip3), and (2) immunomodulation (Tnfalpha [also known as Tnf], Il-1beta [also known as Il1b], Il-6 [also known as Il6] and Ccl2 [also known as Mcp-1]). In vivo, Atf3 KO islets performed better than WT islets after transplantation, as evidenced by better glucose homeostasis in the recipients and the reduction of the following variables in the KO grafts: caspase 3 activation, macrophage infiltration and expression of the above apoptotic and immunomodulatory genes. ATF3 plays a role in islet graft rejection by contributing to islet cell death and inflammatory responses at the graft sites. Silencing the ATF3 gene may provide therapeutic benefits in islet transplantation.


Electron delocalization and electron density of small polycyclic aromatic hydrocarbons in singlet excited states.
The four lowest singlet electronic states of benzene, the acenes from naphthalene to pentacene, phenanthrene and pyrene were studied by means of theoretical methods. Their vertical excitation energies from the ground electronic states were computed at the CASPT2 approximation. As an attempt to explain the trends observed in the excitation energies, several descriptors based on the electron density were used and the similarity of these molecules with their ground state counterparts was analyzed. It was found that the changes of the topological properties at the C-C bond critical points do not explain the decreasing trends for the excitation energies with the increase of the number of rings, in part because the small changes that take place in the electron density occur above and below the molecular plane. A similarity index based on electron delocalization between quantum topological atoms was defined to compare a molecule in two different electronic states. It was found that, mainly for the acenes, this index goes in line with the excitation energies to the first excited state. Implications of the changes in electron delocalization on the aromatic character of these molecules are also discussed. In general, local aromaticity decreases upon excitation.


Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity.
Primary vesicoureteral reflux (VUR) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. It affects about 1% of the young children and is thus one of the most common hereditary diseases. Its associated nephropathy is an important cause of end-stage renal failure in children and adults. Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis. To begin to determine whether mutations in UP genes might play a role in human VUR, we genotyped all four UP genes in 76 patients with radiologically proven primary VUR by polymerase chain reaction (PCR) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences. Eighteen single nucleotide polymorphisms (SNPs) were identified, seven of which were missense, with no truncation or frame shift mutations. Since healthy relatives of the VUR probands are not reliable negative controls for VUR, we used a population of 90 race-matched, healthy individuals, unrelated to the VUR patients, as controls to perform an association study. Most of the SNPs were not found to be significantly associated with VUR. However, SNP1 of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP III affecting a C to G conversion and a Pro154Ala change, were marginally associated with VUR (both P= 0.08). Studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of UP III SNP7 in VUR (P= 0.036 adjusted for both subsets of cases vs. controls). Such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans.


Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group.
The outcome for patients with Ewing sarcoma family of tumors (ESFTs) of bone with metastases at diagnosis remains poor despite new approaches to treatment. We evaluated whether a dose-intensity chemotherapy regimen improved survival for patients with ESFTs of bone with metastases at diagnosis. We entered 60 patients with metastatic ESFTs of bone onto a single arm trial of a new intensive therapy. Treatment consisted of 51-weeks of chemotherapy and local control of the primary with radiation, surgery, or both. The chemotherapeutic protocol included two alternating blocks: one with vincristine (2 mg/m(2)), doxorubicin (90 mg/m(2)), and cyclophosphamide (2,200 mg/m(2)); and the second with ifosfamide (2,800 mg/m(2)/day x 5 days) and etoposide (100 mg/m(2)/day x 5 days). Of the 60 patients with metastatic ESFTs of bone enrolled onto this single arm trial, 12 had metastasis to lung only, 7 to bone marrow or bone only, 38 to multiple sites, 2 in other sites and 3 not specified. There were three toxic deaths. Six patients (6-year cumulative incidence: 9%) developed second malignant neoplasms and died. The 6-year overall event-free survival (EFS) was 28% (standard error (SE) 6%) and survival (S) was 29% (SE 6%). An intensified treatment regimen using higher doses of cyclophosphamide, ifosfamide, and doxorubicin increased toxicity and risk of second malignancy without improving EFS and S.


Shared origins of a key enzyme during the evolution of C4 and CAM metabolism.
CAM and C4 photosynthesis are two key plant adaptations that have evolved independently multiple times, and are especially prevalent in particular groups of plants, including the Caryophyllales. We investigate the origin of photosynthetic PEPC, a key enzyme of both the CAM and C4 pathways. We combine phylogenetic analyses of genes encoding PEPC with analyses of RNA sequence data of Portulaca, the only plants known to perform both CAM and C4 photosynthesis. Three distinct gene lineages encoding PEPC exist in eudicots (namely ppc-1E1, ppc-1E2 and ppc-2), one of which (ppc-1E1) was recurrently recruited for use in both CAM and C4 photosynthesis within the Caryophyllales. This gene is present in multiple copies in the cacti and relatives, including Portulaca. The PEPC involved in the CAM and C4 cycles of Portulaca are encoded by closely related yet distinct genes. The CAM-specific gene is similar to genes from related CAM taxa, suggesting that CAM has evolved before C4 in these species. The similar origin of PEPC and other genes involved in the CAM and C4 cycles highlights the shared early steps of evolutionary trajectories towards CAM and C4, which probably diverged irreversibly only during the optimization of CAM and C4 phenotypes.


Doubly resonant continuous-wave optical parametric oscillator pumped by a single-mode diode laser.
The performance characteristics of a doubly (signal and idler) resonant continuous-wave optical parametric oscillator based on periodically poled lithium niobate and pumped by a 100-mW single-mode laser diode at 810 nm are reported. Pump power thresholds as low as 16 mW and wavelength tuning over the range 1.15-1.25 microm at the signal and 2.31-2.66 microm at the idler were achieved through variation of crystal temperature, pump wavelength, and grating period. Up to 5 mW of signal output was obtained with the single-mode diode pump, and signal powers of up to 39 mW were obtained when pumping with a 400-mW injection-locked broad-area diode laser.


A low back-specific version of the SF-36 Physical Functioning scale.
A prospective repeated measures design was used to produce a back-specific version of the Short Form-36 Physical Functioning scale (SF-36 PF) by Rasch analysis of a pool of items from the SF-36 PF, Oswestry Disability Questionnaire, and the Quebec Back Pain Disability Scale. To identify items for a back-specific version of the SF-36 PF scale and to compare the psychometric properties of the new version with the original 10-item scale. Adequate assessment of patient function requires the administration of a generic and a condition-specific questionnaire. A back-specific version of the SF-36 PF would facilitate comprehensive patient assessment in the clinical setting. Consecutive patients with low back pain presenting for physiotherapy treatment were recruited at three public hospitals, three community health services, and four private practices. Patients completed questionnaires on two occasions 6 weeks apart. A scale of 18 items showed a better fit to the Rasch model than the original SF-36 PF scale. Items in the original scale that had a poor fit (INFIT/OUTFIT statistics outside the range 0.7-1.3) showed an acceptable fit in the new scale. The augmented scale had comparable reliability and improved responsiveness to the original 10-item SF-36 PF scale. The minimum detectable change (90% confidence) and the minimum clinically important difference were 12 points. Floor and ceiling effects were practically eliminated. The psychometric properties of the new scale were comparable to those of the Oswestry Disability Questionnaire. The Low-Back SF-36 PF18 comprises the 10-item SF-36 PF scale and four items each from the Oswestry and Quebec back pain questionnaires. The possible total score ranges from 0 to 100, with a higher score indicating better function. The new scale appears to offer advantages over the use of the original scale for the assessment of functioning in patients with low back pain.


Personality variation in a clonal insect: the pea aphid, Acyrthosiphon pisum.
Individuals are often consistent in their behavior but vary from each other in the level of behavior shown. Despite burgeoning interest in such animal personality variation, studies on invertebrates are scarce, and studies on clonal invertebrates nonexistent. This is surprising given the obvious advantages of using invertebrates/clones to tackle the crucial question why such consistent behavioral differences exist. Here we show that individuals of clonal pea aphids exhibit consistent behavioral differences in their escape responses to a predator attack (dropping vs. nondropping off a plant). However, behavior was not repeatable at the clonal level. Genetically identical clones expressed various phenotypes but different clones produced different proportions of each phenotype (dropper, nondropper, and inconsistent). Manipulations of early environmental conditions had little qualitative impact on such patterns. We discuss the importance of our findings for future studies of the evolutionary and ecological consequences of personality variation.