EL-4 metastases in spleen and bone marrow suppress the NK activity generated in these organs.
The relationship between metastatic cells in the spleen and bone marrow of tumor-bearing mice and the NK activity generated in vitro by cells obtained from these organs was investigated. EL-4 lymphoma and B16 melanoma cells injected intraperitoneally into syngeneic mice (10(6) cells/animal) killed the recipients in 16 days. These tumors had a different metastatic profile: EL-4 metastasized to the spleen and bone marrow while B16 did not. The number of metastatic cells was evaluated by plating spleen or bone-marrow cells of tumor-bearing mice in agarose cultures; in parallel, the ability of spleen and bone-marrow cells to generate NK activity in vitro was assessed. The presence of 10(5) EL-4 cells/10(6) spleen or bone-marrow cells correlated with a total lack of NK activity in these organs; in contrast, no decrease in NK activity was evident in the spleen or bone marrow of B16-bearing mice. The removal of metastatic EL-4 cells (by antibody and complement) from the spleen or bone marrow did not rescue the NK activity. The lack of NK activity in spleen and bone marrow colonized by metastatic cells was not due to induction of a suppressor cell in the host. Metastatic EL-4 cells appeared to have a direct and irreversible suppressive effect on the generation of NK activity by spleen or bone marrow. A possible cause-effect relationship between metastatic colonization of lymphoid organs and suppression of local NK activity is considered.


Ultracompact and broadband polarization beam splitter utilizing the evanescent coupling between a hybrid plasmonic waveguide and a silicon nanowire.
An ultracompact polarization beam splitter (PBS) is proposed based on an asymmetrical directional coupler consisting of a silicon hybrid plasmonic waveguide (HPW) and a silicon nanowire. The widths of the two coupling waveguides are chosen so that the phase-matching condition is satisfied for TE polarization only while the phase mismatch is significant for TM polarization. A sharply bent silicon HPW is connected at the thru port to play the role of polarizer by utilizing its polarization-dependent loss. With the present principle, the designed PBS has a footprint as small as only ~1.9 μm × 3.7 μm, which is the shortest PBS reported until now, even when large waveguide dimensions (e.g., the waveguide widths w(1,2) = ~300 nm and the gap width w(gap) = ~200 nm) are chosen to simplify the fabrication process. The numerical simulations show that the designed PBS has a very broad band (~120 nm) with an extinction ratio >12 dB and a large fabrication tolerance to allow a waveguide width variation of ± 30 nm.


Efficacy and Safety of Needle Acupuncture for Treating Gynecologic and Obstetric Disorders: An Overview.
Background: Acupuncture is being used increasingly to treat gynecologic and obstetric disorders. Objective: The aim of this review was to determine the efficacy and safety of acupuncture for treating pelvic and low-back pain during pregnancy, pain during labor, primary dysmenorrhea, and menopausal symptoms. Design: This is an overview of systematic reviews (SRs) and randomized controlled trials (RCTs). Search strategy: A literature search was conducted, in July 2010, in MEDLINE,® the Cochrane Database of Systematic Reviews, CENTRAL, the Database of Abstracts of Reviews of Effects, and Tripdatabase. Selection criteria: Published SRs and RCTs found during the literature search were included as well as RCTs that were published after completion of the literature search. Analysis: Data from SRs and RCTs that provided quantitative information were pooled. Results: Eight SRs and nine RCTs were included. One SR and 4 RCTs showed that acupuncture reduced pelvic and low-back pain, compared to physiotherapy or usual prenatal care. Results were contradictory when interventions were compared with sham acupuncture. With respect to reduction of pain during labor, two SRs showed no differences between acupuncture and sham acupuncture. None of the three SRs included on primary dysmenorrhea produced conclusive results. Two SRs of studies on menopausal symptoms showed no differences between acupuncture and sham acupuncture. A meta-analysis of three additional RCTs identified a favorable effect of acupuncture for reducing frequency and intensity of hot flashes. Adverse effects were mild and infrequent. Conclusions: Evidence for the efficacy of needle acupuncture for treating the disorders evaluated remains inconclusive. The intervention showed promising results for reducing pelvic and back pain during pregnancy and climacteric vasomotor symptoms, although well-designed studies are needed to make the results more precise and reliable.


A zwitterionic polymer as a novel inhibitor of protein aggregation.
We report the novel one-step synthesis of a zwitterionic polymer, polysulfobetaine, via living reversible addition fragmentation chain transfer (RAFT) polymerization. Lysozyme did not aggregate when heated in the presence of this polymer. Amyloid formation, the cause of many diseases, was also suppressed. The zwitterionic polymer was significantly more efficient than previously described inhibitors of protein aggregation. Lysozyme heated in the presence of polysulfobetaine retained its solubility and very high enzymatic efficiency, even after prolonged heating. The secondary structures of lysozyme change with increasing temperature, accompanied by an increase in the β-structure. This change was prevented by mixing the polymer with lysozyme. 1H-NMR before and after aggregation revealed the conformational changes taking place in the lysozyme: during aggregation, lysozyme is transformed into a random coil conformation, thus losing its secondary structure. Presence of the polymer facilitates retention of partial higher order structures and lysozyme solubility at higher temperatures. The high efficiency of the polyampholyte was ascribed to its ability to prevent collisions between aggregating species by acting as a molecular shield.


A triple threat: high population density, high foraging intensity and flexible habitat preferences explain high impact of feral cats on prey.
Alien mammalian carnivores have contributed disproportionately to global loss of biodiversity. In Australia, predation by the feral cat and red fox is one of the most significant causes of the decline of native vertebrates. To discover why cats have greater impacts on prey than native predators, we compared the ecology of the feral cat to a marsupial counterpart, the spotted-tailed quoll. Individual prey are 20-200 times more likely to encounter feral cats, because of the combined effects of cats' higher population densities, greater intensity of home-range use and broader habitat preferences. These characteristics also mean that the costs to the prey of adopting anti-predator behaviours against feral cats are likely to be much higher than adopting such behaviours in response to spotted-tailed quolls, due to the reliability and ubiquity of feral cat cues. These results help explain the devastating impacts of cats on wildlife in Australia and other parts of the world.


[Factors associated with adherence to school meals by adolescents in State public schools in Colombo, Paraná State, Brazil].
This study aimed to estimate the prevalence of adherence to school meals and associated factors among adolescent schoolchildren (N = 1,569). The adolescents completed an on-line questionnaire on adherence to school meals, and their parents answered another questionnaire on socioeconomic data. The chi-square test was used to assess the association between adherence to school meals and gender, nutritional status, per capita family income, maternal schooling, adolescents' opinions on the dining hall layout, whether they considered school meals healthy, and consumption of other foods. Variables with statistical significance for adherence to school meals were included in the multilevel proportional odds logistic regression model. The covariates for comprising the final model were defined by backward selection methods. The results of the adjusted model were presented as odds ratios with respective 95% confidence intervals (95%CI). Prevalence of adherence to school meals was low, especially effective adherence (19.8%). Adherence was associated with per capita family income less than one minimum wage, lower consumption of foods outside of school meals, the fact that adolescents considered the dining hall space adequate, and believing that school meals are healthy. Adherence to school meals in this study falls short of universal coverage for the program. Different factors contribute to incomplete program implementation, which may hinder achieving the food and nutritional security policy under the Brazilian National School Feeding Program (PNAE).


Identification and characterization of apocarotenoid modifiers and carotenogenic enzymes for biosynthesis of crocins in Buddleja davidii flowers.
Crocetin biosynthesis in Buddleja davidii flowers proceeds through a zeaxanthin cleavage pathway catalyzed by two carotenoid cleavage dioxygenases (BdCCD4.1 and BdCCD4.3), followed by oxidation and glucosylation reactions that lead to the production of crocins. We isolated and analyzed the expression of 12 genes from the carotenoid pathway in B. davidii flowers and identified four candidate genes involved in the biosynthesis of crocins (BdALDH, BdUGT74BC1, BdUGT74BC2, and BdUGT94AA3). In addition, we characterized the profile of crocins and their carotenoid precursors, following their accumulation during flower development. Overall, seven different crocins, crocetin, and picrocrocin were identified in this study. The accumulation of these apocarotenoids parallels tissue development, reaching the highest concentration when the flower is fully open. Notably, the pathway was regulated mainly at the transcript level, with expression patterns of a large group of carotenoid precursor and apocarotenoid genes (BdPSY2, BdPDS2, BdZDS, BdLCY2, BdBCH, BdALDH, and BdUGT Genes) mimicking the accumulation of crocins. Finally, we used comparative correlation network analysis to study how the synthesis of these valuable apocarotenoids diverges among B. davidii, Gardenia jasminoides, and Crocus sativus, highlighting distinctive differences which could be the basis of the differential accumulation of crocins in the three species.


Adherence of Candida albicans to a fibrin-platelet matrix formed in vitro.
The adherence of Candida albicans to a fibrin-platelet matrix formed in vitro was studied. Platelet-rich plasma obtained from rabbits was incubated with thrombin and CaCl2 to form a clot in tissue culture dishes. Such clots were then infected with 3 x 10(7) C. albicans cells per 0.3 ml prelabeled with [U14C]-glucose, and the percent adherence was measured after 30 min of incubation by counting the radioactivity in saline washes of the clot as well as a streptokinase-streptodornase digest of the corresponding clot. Heat- and formaldehyde-killed cells did not adhere as well as viable cells. Pretreatment of C. albicans with trypsin, chymotrypsin, and pronase reduced adherence to the clots. Normal rabbit serum and anti-Candida antiserum also inhibited adherence 40 and 100%, respectively, Diethylaminoethyl-purified anti-Candida gamma globulin (1:8) completely inhibited adherence, whereas purified normal serum gamma globulin did not. Several Candida spp. and Saccharomyces cerevisiae showed differences in their ability to adhere to clots. C. albicans and C. stellatoidea presented the highest adherence, whereas C. krusei, C. guilliermondii, and S. cerevisiae adhered less readily. Other species were intermediate in their ability to adhere.


Mutagenic specificity of a novel T4 DNA polymerase mutant.
The in vivo mutational specificity of a novel T4 DNA polymerase mutator mutant, tsM19, was determined. Two genetic tester systems were used to characterize the mutant. Results of our studies indicate that tsM19 promotes transition and transversion mutagenesis and, possibly, frameshift mutagenesis. Central G:C base pairs in runs of three or more consecutive G:C base pairs may be target sites for tsM19-induced transitions.


STAG2 promotes the myelination transcriptional program in oligodendrocytes.
Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelination-related genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelination-promoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.


Non-metric cranial variants in Brazilian skulls.
The incidence of 27 non-metric cranial variants is studied in a sample of 124 skulls from Brazil. The unilateral and bilateral frequencies of the variants are determined. The Brazilian population sample was compared with 28 population samples from different parts of the world.


A review of recent data in the treatment of gallbladder cancer: what we know, what we do, and what should be done.
Gallbladder cancer is now considered a distinct clinical entity, allowing for a separate analysis from that of other malignancies of the biliary tree. Symptoms related to a malignant tumor of the gallbladder include jaundice and abdominal pain, or a palpable abdominal mass that occurs in a late stage of the disease. The majority of patients with operable gallbladder cancer are diagnosed by cholecystectomy performed for presumed benign disease, mostly cholelithiasis, a clinical entity known as incidental gallbladder cancer. Given the poor prognosis if tumor invasion beyond the muscular layer and/or nodal metastasis is found, adjuvant treatments have been implemented, but few data are available to guide treatment decisions in this setting. For advanced disease, a multidisciplinary treatment approach including biliary drainage procedures and palliative support is needed in the management of this aggressive disease. Palliative chemotherapy with a combination of gemcitabine and cisplatin or oxaliplatin is the standard treatment based on the findings of two phase III trials that showed improved overall survival compared to single-agent chemotherapy and best supportive care. Several phase II studies have been reported investigating the role of targeted agents against EGFR, VEGF, HER2, and MEK. International collaboration to enhance our knowledge of gallbladder cancer should be encouraged.


Cross-sectional area of the aditus laryngis and rima glottidis before and after transection of the left recurrent laryngeal nerve in the horse.
The ventral-to-dorsal height of the rima glottidis was measured from lateral pharyngeal radiographs after correction for magnification. The rima glottidis height was used to enlarge accurately endoscopic photographs of 5 horses taken before and after transection of the left recurrent laryngeal nerve. Areas of the rima glottidis and aditus laryngis were measured, using a computerized digitizer. Mean area of the aditus laryngis was 1,908 mm2 before neurectomy and 1,346 mm2 after neurectomy (P = 0.025). Mean area of the rima glottidis was 1,198 mm2 before neurectomy and 805 mm2 after neurectomy (P = 0.025). Mean width of the rima glottidis was 31 mm before neurectomy and 20 mm after neurectomy (P = 0.001). Significant differences were not found between the pre- and postneurectomy heights of the rima glottidis.


The single nucleotide polymorphisms of Kir3.4 gene and their correlation with lone paroxysmal atrial fibrillation in Chinese Han population.
Acetylcholine induced inwardly rectifying current (I(KACh)) is a heteromultimeric complex formed by Kir3.1 and Kir3.4 subunits and plays important roles in the development of atrial fibrillation (AF). AF is a common disorder among Chinese, the frequency of AF is about 0.61%, and in patients with strokes it is 12.1%. We hypothesise that lone paroxysmal AF genetic variation in Kir3.4 may predispose the atria to fibrillation in the Chinese population. We recruited 186 patients with lone paroxysmal AF, and 210 matched controls by age (49.61+/-8.04 years), sex, smoking habit, and left atrial dimension in Zhejiang Province, China. Genotype of Kir3.4 was determined with polymerase chain reaction (PCR) and direct sequencing. The SPSS statistical software was used for chi(2) test. LD and haplotypes were calculated using SHESIS software package. Three synonymous known single nucleotide polymorphisms (SNPs) in Kir3.4 were genotyped, including C171T (rs6590357), G810T (rs7118824) and C834T (rs7118833). We found low levels of linkage disequilibrium (LD) between C171T and G810T (D'=0.272), complete LD between SNPs G810T and C834T (D'=1) in AF patients and controls. The case-control analysis revealed that the frequency of genotype and allele in three SNPs are significantly different between lone paroxysmal AF patients than in control subjects. The odds ratio (OR) for AF 171T and 810T alleles were 1.546 (95% CI 1.015-2.355) and 1.520 (95% CI 1.012-2.284), respectively, when compared with patients without Kir3.4T alleles in these two loci. The OR for AF in patients with C-T genotype were 13.364 (95% CI 5.710-31.278) and 37.135 (95% CI 9.050-152.381) when comparing patients with T-G genotype. Our findings suggest that C171T and G810T SNPs in Kir3.4 gene might be risk factors for lone paroxysmal AF in Chinese population.


Effects of prematurity and retinopathy of prematurity on refractive errors and biometric optic components in school children: results of a tertiary center from Turkey.
To reveal refractive errors, the relationship between refractive errors and optical parameters, and the effect of prematurity and retinopathy of prematurity (ROP) on ocular development in school children with a history of prematurity. Premature children aged 8-12 years were divided into 3 groups as those without ROP (Group 1), with ROP that did not require treatment (Group 2), and with laser-treated ROP (Group 3). Age-matched full-term healthy children were included in the control group. Demographic features were recorded. A detailed ophthalmologic examination was performed. Anterior chamber depth (ACD), trabecular-iris angle (TIA), iris thickness (IT), lens thickness (LT), vitreous body length (VBL), axial length (AL) were measured by ultrasound biomicroscopy (UBM). The results were compared between groups. Group 3 had the lowest best corrected visual acuity (0.81 ± 0.31 SL), the highest rates of myopia (55.9%) and astigmatism (50.0%). In the premature groups, ACD (p < 0.001), TIA (p < 0.001), IT (p = 0.016), VBL (p < 0.001) and AL (p < 0.001) were lower; LT (p < 0.001) was higher than in the control group. As birth weight (BW) and gestational age (GA) increased, ACD, TIA, VBL and AL increased, and LT decreased (p < 0.001). In the group 3, 35.2% anisometropia, 17.6% of esotropia and 5.9% of exotropia were detected. The frequency of myopia, astigmatism, hyperopia and anisometropia is increasing in premature children, especially in cases with laser-treated ROP. Premature cases are characterized by thicker lens, shallower ACD, narrower TIA and shorter AL. Refractive errors, anisometropia, amblyopia and strabismus are important causes of visual impairment in children with laser-treated ROP.


Can muscle protein metabolism be specifically targeted by nutritional support and exercise training in chronic obstructive pulmonary disease?
Chronic obstructive pulmonary disease (COPD) associates with several extra-pulmonary effects. Muscle dysfunction and wasting is one of the most prominent extra-pulmonary effects and contributes to exercise limitation and health related quality of life (HRQoL), morbidity as well as mortality. The loss of muscle mass is characterised by an impaired balance between protein synthesis (anabolism) and protein breakdown (catabolism) which relates to nutritional disturbances, muscle disuse and the presence of a systemic inflammation, among other factors. Current approaches to reverse skeletal muscle dysfunction and wasting attain only modest improvements. The development of new therapeutic strategies aiming at improving skeletal muscle dysfunction and wasting are needed. This requires a better understanding of the underlying molecular pathways responsible for these abnormalities. In this review we update recent research on protein metabolism, nutritional depletion as well as physical (in)activity in relation to muscle wasting and dysfunction in patients with COPD. We also discuss the role of nutritional supplementation and exercise training as strategies to re-establish the disrupted balance of protein metabolism in the muscle of patients with COPD. Future areas of research and clinical practice directions are also addressed.


A novel locally operated master-slave robot system for single-incision laparoscopic surgery.
Single-incision laparoscopic surgery (SILS) provides more cosmetic benefits than conventional laparoscopic surgery but presents operational difficulties. To overcome this technical problem, we have developed a locally operated master-slave robot system that provides operability and a visual field similar to conventional laparoscopic surgery. A surgeon grasps the master device with the left hand, which is placed above the abdominal wall, and holds a normal instrument with the right hand. A laparoscope, a slave robot, and the right-sided instrument are inserted through one incision. The slave robot is bent in the body cavity and its length, pose, and tip angle are changed by manipulating the master device; thus the surgeon has almost the same operability as with normal laparoscopic surgery. To evaluate our proposed system, we conducted a basic task and an ex vivo experiment. In basic task experiments, the average object-passing task time was 9.50 sec (SILS cross), 22.25 sec (SILS parallel), and 7.23 sec (proposed SILS). The average number of instrument collisions was 3.67 (SILS cross), 14 (SILS parallel), and 0.33 (proposed SILS). In the ex vivo experiment, we confirmed the applicability of our system for single-port laparoscopic cholecystectomy. We demonstrated that our proposed robot system is useful for single-incision laparoscopic surgery.


Salivary inflammatory mediator profiling and correlation to clinical disease markers in asthma.
There is a need for a readily available, non-invasive source of biomarkers that predict poor asthma control. We sought to determine if there is an association between the salivary inflammatory profile and disease control in children and adults with asthma. In this cross-sectional study, we collected demographic and clinical information from two independent populations at different sites, resulting in convenience samples of 58 pediatric and 122 adult urban asthmatics. Control was assessed by symptom questionnaire (children) and by Asthma Control Questionnaire and current exacerbation (adults). Saliva was collected in all subjects. We applied principal component analysis to a 10-plex panel of relevant inflammatory markers to characterize marker profiles and determined if profiles were associated with asthma control. There were similar, strong correlations amongst biologically related markers in both populations: eosinophil-related: eotaxin-1/CCL11, RANTES/CCL5, and IL-5 (p<.001); myeloid/innate: IL-1β, IL-6, MCP-1/CCL2, and IL-8/CXCL8 (p<.001). The first three principal components captured ≥74% of variability across all ten analytes in both populations. In adults, the Principal Component 1 score, broadly reflective of all markers, but with greater weight given to myeloid/innate markers, was associated with Asthma Control Questionnaire score and exacerbation. The Principal Component 3 score, reflective of IP-10/CXCL10, was associated with current exacerbation. In children, the Principal Component 1, 2, and 3 scores were associated with recent asthma symptoms. The Principal Component 2 score, reflective of higher eosinophil markers, was inversely correlated with symptoms. The Principal Component 3 score was positively associated with all symptom outcomes. The salivary inflammatory profile is associated with disease control in children and adults with asthma.


Clinical and laboratory indices that enhance the diagnosis of postural tachycardia syndrome.
To identify clinical and laboratory indices that improve the diagnosis of the postural tachycardia syndrome (POTS). We assessed associations of orthostatic intolerance by using multivariate regression analysis. We evaluated autonomic symptoms and autonomic function in 30 patients with POTS, 30 patients with mild orthostatic intolerance, and 19 age- and gender-matched control subjects. Indices of parasympathetic and sympathetic functions were analyzed on the basis of (1) autonomic function tests (head-up tilt), (2) oscillations at respiratory and nonrespiratory frequencies (0.01 to 0.09 Hz) in R-R interval and blood pressure (Wigner distribution), and (3) deterministic component (rescaled range analysis). The four clinical and laboratory indices that independently supported the diagnosis of POTS are as follows: (1) orthostatic heart rate during the first minute of head-up tilt, (2) autonomic deficit (adrenergic autonomic score), (3) loss of spectral powers in R-R interval during head-up tilt at the fifth minute, and (4) severity of orthostatic dizziness, fatigue, palpitations, and shortness of breath. Enhancing the sensitivity and specificity of the diagnosis of POTS should be possible by using these four indices. A hyperadrenergic state and distal neuropathy, affecting adrenergic sympathetic cardiovagal fibers, seem to be involved in the pathophysiology of POTS. Certain features suggest brain-stem dysregulation.


Assessment of liver microcirculation in human cirrhosis.
Alterations in the liver microcirculation were characterized by use of the multiple-indicator dilution technique in 25 cirrhotic patients undergoing hemodynamic evaluation of portal hypertension. Hepatic vein outflow dilution curves were obtained after portal vein or hepatic artery injections of a vascular reference substance (labeled erythrocytes) and of diffusible substances (labeled albumin and sucrose). In 23 of these patients (19 with alcoholic cirrhosis and 4 with postnecrotic cirrhosis), unimodal erythrocytes and albumin curves were obtained; the immediately accessible albumin space ranged from normal values (that were substantially larger than the erythrocyte space) to low values (that were little larger than the erythrocyte space). In parallel with this, the hepatic extraction of indocyanine green decreased and was correlated with the albumin space (r = 0.821, P less than 0.001). The form of labeled sucrose curves showed progressive changes indicating limited diffusion into the interstitial space. In contrast, bimodal curves were found in two patients (with macronodular cirrhosis); a large proportion of all labels appeared simultaneously in the early part of the outflow curves. Model analysis of the unimodal data indicated that the spectrum of findings could best be explained by progressive development of a barrier to exchange by progressive capillarization of the microvascular bed, and the form of the bimodal data suggested that large vessel shunting was occurring. Both changes, in turn, will contribute to the reduced extraction of protein-bound materials in cirrhosis.


5'- and 3'-sequences of satellite tobacco necrosis virus RNA promoting translation in tobacco.
The RNA of satellite tobacco necrosis virus (STNV) is a monocistronic messenger that lacks both a 5' cap and a 3' poly(A) tail. The STNV trailer contains an autonomous translational enhancer domain (TED) that promotes translation in vitro by more than one order of magnitude when combined with the 5'-terminal 173 nt of STNV RNA. We now show that the responsible sequence within the 5' region maps to the first 38 nt of the STNV RNA. Mutational analysis indicated that the primary sequence of the STNV 5' 38 nt and TED is important for translation stimulation in vitro, but did not reveal a role for the complementarity between the two. Translation of chimeric STNV-cat RNAs in tobacco protoplasts showed that TED promotes translation in vivo of RNAs lacking a cap and/or a poly(A) tail. Similar to in vitro, TED-dependent translation in tobacco was stimulated further by the STNV 5' 38 nt.


Turnover of grassland roots in mountain ecosystems revealed by their radiocarbon signature: role of temperature and management.
Root turnover is an important carbon flux component in grassland ecosystems because it replenishes substantial parts of carbon lost from soil via heterotrophic respiration and leaching. Among the various methods to estimate root turnover, the root's radiocarbon signature has rarely been applied to grassland soils previously, although the value of this approach is known from studies in forest soils. In this paper, we utilize the root's radiocarbon signatures, at 25 plots, in mountain grasslands of the montane to alpine zone of Europe. We place the results in context of a global data base on root turnover and discuss driving factors. Root turnover rates were similar to those of a subsample of the global data, comprising a similar temperature range, but measured with different approaches, indicating that the radiocarbon method gives reliable, plausible and comparable results. Root turnover rates (0.06-1.0 y(-1)) scaled significantly and exponentially with mean annual temperatures. Root turnover rates indicated no trend with soil depth. The temperature sensitivity was significantly higher in mountain grassland, compared to the global data set, suggesting additional factors influencing root turnover. Information on management intensity from the 25 plots reveals that root turnover may be accelerated under intensive and moderate management compared to low intensity or semi-natural conditions. Because management intensity, in the studied ecosystems, co-varied with temperature, estimates on root turnover, based on mean annual temperature alone, may be biased. A greater recognition of management as a driver for root dynamics is warranted when effects of climatic change on belowground carbon dynamics are studied in mountain grasslands.


The regulation of the p53-mediated stress response by MDM2 and MDM4.
Exquisite control of the activity of p53 is necessary for mammalian survival. Too much p53 is lethal, whereas too little permits tumorigenesis. MDM2 and MDM4 are structurally related proteins critical for the control of p53 activity during development, homeostasis, and the response to stress. These two essential proteins regulate both the activation of p53 in response to stress and the recovery of cells following resolution of the damage, yet both are oncogenic when overexpressed. Thus, multiple regulatory circuits ensure that their activities are fine-tuned to promote tumor-free survival. Numerous diverse stressors activate p53, and much research has gone into trying to find commonalities between them that would explain the mechanism by which p53 becomes active. It is now clear that although these diverse stressors activate p53 by different biochemical pathways, one common feature is the effort they direct, through a variety of means, toward disrupting the functions of both MDM2 and MDM4. This article provides an overview of the relationship between MDM2 and MDM4, features the various biochemical mechanisms by which p53 is activated through inhibition of their functions, and proposes some emerging areas for investigation of the p53-mediated stress response.


Cerebrovascular pressure reactivity and brain tissue oxygen monitoring provide complementary information regarding the lower and upper limits of cerebral blood flow control in traumatic brain injury: a CAnadian High Resolution-TBI (CAHR-TBI) cohort study.
Brain tissue oxygen tension (PbtO2) and cerebrovascular pressure reactivity monitoring have emerged as potential modalities to individualize care in moderate and severe traumatic brain injury (TBI). The relationship between these modalities has had limited exploration. The aim of this study was to examine the relationship between PbtO2 and cerebral perfusion pressure (CPP) and how this relationship is modified by the state of cerebrovascular pressure reactivity. A retrospective multi-institution cohort study utilizing prospectively collected high-resolution physiologic data from the CAnadian High Resolution-TBI (CAHR-TBI) Research Collaborative database collected between 2011 and 2021 was performed. Included in the study were critically ill TBI patients with intracranial pressure (ICP), arterial blood pressure (ABP), and PbtO2 monitoring treated in any one of three CAHR-TBI affiliated adult intensive care units (ICU). The outcome of interest was how PbtO2 and CPP are related over a cohort of TBI patients and how this relationship is modified by the state of cerebrovascular reactivity, as determined using the pressure reactivity index (PRx). A total of 77 patients met the study inclusion criteria with a total of 377,744 min of physiologic data available for the analysis. PbtO2 produced a triphasic curve when plotted against CPP like previous population-based plots of cerebral blood flow (CBF) versus CPP. The triphasic curve included a plateau region flanked by regions of relative ischemia (hypoxia) and hyperemia (hyperoxia). The plateau region shortened when cerebrovascular pressure reactivity was disrupted compared to when it was intact. In this exploratory analysis of a multi-institution high-resolution physiology TBI database, PbtO2 seems to have a triphasic relationship with CPP, over the entire cohort. The CPP range over which the plateau exists is modified by the state of cerebrovascular reactivity. This indicates that in critically ill TBI patients admitted to ICU, PbtO2 may be reflective of CBF.


Enhancing poly(3-hydroxybutyrate) production in halophilic bacteria through improved salt tolerance.
Polyhydroxyalkanoates (PHA) have emerged as a promising bio-compound in the industrial application due to their potential to replace conventional petroleum-based plastics with sustainable bioplastics. This study focuses on Halomonas sp. YJPS3-3, a halophilic bacterium, and presents a novel approach to enhance PHA production by exploiting its salt tolerance toward PHA biosynthesis. Through gamma irradiation-induced mutants with enhanced salt tolerance from 15% NaCl to 20% NaCl, mutant halo6 showing a significant 11% increase in PHA yield, was achieved. Moreover, the mutants displayed not only higher PHA content but also remarkable cell morphology with elongation. In addition, this research unravels the genetic determinants behind the elevated PHA content and identifies a corresponding shift in fatty acid composition favoring PHA accumulation. This novel mutant obtained from gamma irradiation with enhanced salt tolerance in halophilic bacteria opens up new avenues not only for the bioplastic industry but also for applications in the production of high-value metabolites.


Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems.
Epigenetic control provides a mechanism for the reversible silencing of telomerase expression that occurs as a natural consequence of differentiation. Significant overlap between indirect telomerase regulation pathways and cell cycle checkpoint pathways exist, suggesting that these discrete genetic elements (namely, p21, p53, and hTERT) synergistically cooperate to inhibit tumorigenesis. Mutations in these pathways have been known to contribute to cancer formation. However, the incorporation of epigenetic regulatory mechanisms provides another line of defense against these negative occurrences. These proteins are also implicated in the process of senescence, caused in eukaryotic cell lines by telomere shortening. Although the debate continues, there is significant evidence to classify the process of cellular senescence as an in vitro model for human aging. In addition, the study of stem cells gives information about the down-regulation of hTERT in the aging process. Diseases such as Werner S syndrome, ATM (ataxia telangiectasia mutated kinase), DKC (dyskeratosis congenita), and atherosclerosis have been linked to aberrant telomerase expression and other aging-related tissue malfunctions could be related to the presence of senescent cells changing the cellular microenvironment. Therefore, restoring telomerase activity as a putative therapeutic strategy necessitates further study to elucidate the intricacies linking genetic and epigenetic modulations of hTERT.


Pediatric acquired immunodeficiency syndrome with negative human immunodeficiency virus antibody response by enzyme-linked immunosorbent assay and Western blot.
A 5-month-old white girl having persistent oral candidiasis was brought to medical attention because of acute respiratory distress, pneumonia, and hypoxia that worsened despite supportive care and antibiotics. Bronchial lavage fluid yielded Pneumocystis carinii. The diagnosis of acquired immunodeficiency syndrome (AIDS) was suspected, although enzyme-linked immunosorbent assay (ELISA) and Western blot tests were both negative for human immunodeficiency virus (HIV) antibody. Immunologic evaluation included the following results: a low normal CD4/CD8 ratio 0.88, CD4 lymphocytes 493/microL, and elevated IgA 539 mg/dL and IgM 175 mg/dL with normal IgG 492 mg/dL. Lymphocyte stimulation study results were depressed. Lymphocytes sent for culture were subsequently positive for HIV. The mother was HIV antibody positive by enzyme-linked immunosorbent assay and Western blot but belonged to no high-risk group and was asymptomatic except for chronic diarrhea. The father was HIV antibody negative. The patient was treated with pentamidine and IV gamma-globulin with good clinical response and a rapid decrease of IgM and IgA toward normal values. Subsequent candidal pneumonia and candidal esophagitis were treated successfully with amphotericin B. The patient has received prophylactic IV gamma-globulin infusions for 6 months and remains HIV negative by enzyme-linked immunosorbent assay and Western blot. This case of pediatric AIDS highlights the need to consider HIV infection in the differential diagnosis of any child with physical findings or illnesses suggestive of AIDS-related complex or AIDS, even when HIV serologic findings are negative and parents belong to no high-risk group. Parental testing for HIV antibody is suggested in such cases.


[Potentially precancerous stage of breast cancer].
On the basis of experience with more than 5000 patients, a new classification of potentially precancerous alterations of the breast tissue was undertaken on the basis of more than 200 000 sections. This new classification distinguishes a mastodysplasia minima, a mastodysplasia media and mastodysplasia persevera (lobular and ductular structure). The borderline cases of mastodysplasia media require especially intensive discussion. The histological description is made to serve patient-orientated medicine. On the basis of this classification, potential prestages of breast cancer can be healed when the appropriate inference is made from the exact diagnosis. With advances in technique of breast surgery, subcutaneous mastectomy is to be considered as a possible method of choice. In particular, this also applies as prophylactic therapy in unclear borderline cases, above all in mastodysplasia persevera, and in occasional cases also in mastodysplasia media. The classification of the different degrees of severity of mastodysplasia (as a potential precancerous condition of the breast) has been used successfully for more than six years in a large number of patients.


SRY-box-containing gene 2 regulation of nuclear receptor tailless (Tlx) transcription in adult neural stem cells.
Adult neurogenesis is maintained by self-renewable neural stem cells (NSCs). Their activity is regulated by multiple signaling pathways and key transcription factors. However, it has been unclear whether these factors interplay with each other at the molecular level. Here we show that SRY-box-containing gene 2 (Sox2) and nuclear receptor tailless (TLX) form a molecular network in adult NSCs. We observed that both Sox2 and TLX proteins bind to the upstream region of Tlx gene. Sox2 positively regulates Tlx expression, whereas the binding of TLX to its own promoter suppresses its transcriptional activity in luciferase reporter assays. Such TLX-mediated suppression can be antagonized by overexpressing wild-type Sox2 but not a mutant lacking the transcriptional activation domain. Furthermore, through regions involved in DNA-binding activity, Sox2 and TLX physically interact to form a complex on DNAs that contain a consensus binding site for TLX. Finally, depletion of Sox2 revealed the potential negative feedback loop of TLX expression that is antagonized by Sox2 in adult NSCs. These data suggest that Sox2 plays an important role in Tlx transcription in cultured adult NSCs.


Brain and gonadal aromatase as potential targets of endocrine disrupting chemicals in a model species, the zebrafish (Danio rerio).
Many chemicals in the aquatic environment are able to adversely affect in vitro brain and ovarian aromatase expression/activity. However, it remains to be determined if these substances elicit in vivo effect in fish. With the view to further understanding possible effects of endocrine disrupting chemicals (EDCs) on aromatase function, we first developed methods to measure brain and ovarian aromatase expression/activity in a model species, the zebrafish, and assessed the effect of estradiol (E2) and androstatrienedione (ATD), a steroidal aromatase inhibitor. We showed that CYP19b gene was predominantly expressed in the brain whereas in the ovary CYP19a mRNA level was predominant. Moreover, aromatase activities (AA) were higher in brain than in ovary. In adult zebrafish, E2 treatment had no effect on aromatase expression/activity in brain, whereas at larval stage, E2 strongly triggered CYP19b expression. In the ovaries, E2 led to a complete inhibition of both CYP19a expression and AA. Exposure to ATD led to a total inhibition of both brain and ovarian AA but had no effect on CYP19 transcripts abundance. Together, these results provide relevant knowledge concerning the characterization of aromatase in the zebrafish, and reinforce the idea that brain and ovarian aromatase are promising markers of EDCs in fish and deserve further in vivo studies.


Muscarinic M3 receptor inactivation reveals a pertussis toxin-sensitive contractile response in the guinea pig colon: evidence for M2/M3 receptor interactions.
The role of M2 and M3 receptors in the contractile and phosphoinositide responses elicited to oxotremorine-M was investigated in the guinea pig colon. Under standard conditions, both the contractile and phosphoinositide responses were insensitive to pertussis toxin and irreversibly antagonized by alkylation of M3 receptors with N-(2-chloroethyl)-4-piperidinyl diphenylacetate. After treatment with N-(2-chloroethyl)-4-piperidinyl diphenylacetate, the remaining contractile response was sensitive to pertussis toxin and weakly antagonized by the M2- and M4-selective antagonist AF-DX 116. In contrast, the residual phosphoinositide response was unaffected by pertussis toxin. The pertussis toxin sensitivity of the remaining contractile response suggests that the M2 receptor is mediating the contraction, whereas its weak antagonism by AF-DX 116 suggests that an alternate muscarinic subtype mediates the response. To explain this enigma, we investigated a mathematical model for receptor action based on an interaction between two receptor subtypes (M2 and M3). This model predicts that a response mediated by both the M2 and M3 receptor can be pertussis toxin sensitive yet exhibit an antagonistic profile indicative of an M3 response.


Hard-to-heal peripheral wounds infected with Corynebacterium striatum: a prospective study.
To investigate Corynebacterium striatum as a nosocomial pathogen infecting hard-to-heal peripheral wounds, such as skin wounds, soft tissue abscesses and osteomyelitis. As of 2023, the medical community were alerted against the risk of emerging systemic and central infections; on the other hand literature on peripheral cutaneous regions is still scarce. In this study, two groups of patients with similar lesions which were infected were compared: one group with the presence of the coryneform rod, the other without. In total, Corynebacterium striatum was cultured from 62 patients and 131 samples. Corynebacterium striatum infection correlated well with the presence of: foot ulcer; venous leg ulcer; altered ambulation and/or altered foot loading; peripheral vascular and arterial disease; hospitalisation; malignancy; spinal cord injury; and recent administration of antibiotics (p<0.05 for all associations). Patients with Corynebacterium striatum had a lower overall survival rate compared to patients in the non-Corynebacterium striatum group (28.6 versus 31.6 months, respectively; p=0.0285). Multivariate analysis revealed that Corynebacterium striatum infection was an independent factor for poor prognosis (p<0.0001). In view of the findings of our study, Corynebacterium striatum appears to be an important opportunistic pathogen infecting peripheral tissues and complicating wound healing. Given its numerous and worrying virulence factors (such as multidrug resistance and biofilm production), particular attention should be given to this pathogen by professional wound care providers in nosocomial and outpatient environments.


Secondary closure of an extraction socket using the double-membrane guided bone regeneration technique with immediate implant placement.
Immediate implantation presents challenges regarding site healing, osseointegration, and obtaining complete soft-tissue coverage of the extraction socket, especially in the posterior area. This last issue is addressed herein using the double-membrane (collagen membrane+high-density polytetrafluoroethylene [dPTFE] membrane) technique in two clinical cases of posterior immediate implant placement. An implant was placed immediately after atraumatically extracting the maxillary posterior tooth. The gap between the coronal portion of the fixture and the adjacent bony walls was filled with allograft material. In addition, a collagen membrane (lower) and dPTFE membrane (upper) were placed in a layer-by-layer manner to enable the closure of the extraction socket without a primary flap closure, thus facilitating the preservation of keratinized mucosa. The upper dPTFE membrane was left exposed for 4 weeks, after which the membrane was gently removed using forceps without flap elevation. There was considerable plaque deposition on the outer surface of the dPTFE membrane but not on the inner surface. Moreover, scanning electron microscopy of the removed membrane revealed only a small amount of bacteria on the inner surface of the membrane. The peri-implant tissue was favorable both clinically and radiographically after a conventional dental-implant healing period. Secondary closure of the extraction socket and immediate guided bone regeneration using the double-membrane technique may produce a good clinical outcome after immediate placement of a dental implant in the posterior area.


Role of Polo-like kinase CDC5 in programming meiosis I chromosome segregation.
Meiosis is a specialized cell division in which two chromosome segregation phases follow a single DNA replication phase. The budding yeast Polo-like kinase Cdc5 was found to be instrumental in establishing the meiosis I chromosome segregation program. Cdc5 was required to phosphorylate and remove meiotic cohesin from chromosomes. Furthermore, in the absence of CDC5 kinetochores were bioriented during meiosis I, and Mam1, a protein essential for coorientation, failed to associate with kinetochores. Thus, sister-kinetochore coorientation and chromosome segregation during meiosis I are coupled through their dependence on CDC5.


Posterolateral intertransverse spinal fusion possible in osteoporotic rats with BMP-7 in a higher dose delivered on a composite carrier.
Posterolateral intertransverse process spinal fusion (PLF) was performed in ovariectomized female rats using recombinant human BMP-7 (OP-1) delivered on a composite carrier. To investigate whether BMP-7 collagen on a composite carrier in a higher dose will enhance posterolateral spinal fusion in an estrogen deficiency rat model. Osteoporosis is a systemic disease characterized by bone remodeling skewed in favor of excess bone resorption. This makes new bone formation and fixation of metallic implants difficult. Thus, treating osteoporotic patients who require posterior spinal fusion is challenging. Ovariectomized rats have been used as an osteoporotic model for posterolateral intertransverse process fusion. We have demonstrated in the past that endochondral bone formation in osteoporotic rats is delayed when compared with rats without osteoporosis. We have also shown that OP-1 Putty (BMP-7, collagen, and carboxy-methyl-cellulose) can overcome the effects of osteoporosis in a rat fracture model. However, it has not yet been demonstrated whether BMP-7 collagen composite carrier (Calstrux) can achieve a fusion in a process spinal fusion model in osteoporotic bone. A total of 42 ovariectomized Sprague-Dawley female rats were randomly assigned to 4 control and 2 experimental groups: (1) no Calstrux, no BMP; (2) 400 mg Calstrux alone; (3) 30 microg lactose + 400 mg Calstrux; (4) 90 microg lactose + 400 mg Calstrux; (5) 30 microg rhBMP-7 + 400 mg Calstrux; and (6) 90 microg rhBMP-7 + 400 mg Calstrux. Spinal fusion was evaluated by manual motion testing, microradiographs, computed tomographic scans, DEXA scans, and histology. Ovariectomized rats receiving Calstrux alone or either dose of lactose and Calstrux did not show spinal fusion. Ovariectomized rats receiving 90 microg BMP-7 + 400 mg Calstrux showed significantly higher fusion rates than these control animals. (P < 0.0001). The rats receiving 30 microg BMP-7 + 400 mg Calstrux exhibited only partial fusion. BMP-7, delivered on a composite carrier, is able to overcome the detrimental effects of estrogen deficiency on posterolateral spinal fusion and generate a relatively robust fusion. The effect seems to be dose dependent.


Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.
Chemical or traumatic damage to the liver is frequently associated with aberrant healing (fibrosis) that overrides liver regeneration. The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined. Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration. Nevertheless, it is not known how pro-regenerative angiocrine signals from liver sinusoidal endothelial cells is subverted to promote fibrosis. Here, by combining an inducible endothelial-cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors, CXCR7 and CXCR4 (refs 18, 19, 20, 21), in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells (Cxcr7(iΔEC/iΔEC)) from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signalling in liver sinusoidal endothelial cells counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin(+) hepatic stellate-like cells and enforcing a pro-fibrotic vascular niche. Endothelial-cell-specific ablation of either Fgfr1 (Fgfr1(iΔEC/iΔEC)) or Cxcr4 (Cxcr4(iΔEC/iΔEC)) in mice restored the pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Thus, we demonstrate that in response to liver injury, differential recruitment of pro-regenerative CXCR7-Id1 versus pro-fibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis.


[Neuroticism and suicidal thoughts: a meta-analytic study].
There are conflicting results on the relationship between neuroticism and suicidal ideation in community population. The objectives of this study were to estimate the magnitude and direction of the association between neuroticism and suicide ideation, and to analyze the influence of moderator variables on the effect size. A systematic review and a meta-analysis were carried out. The search for studies was conducted in PubMed/MEDLINE, IME, Lilacs, CINAHL, and EMBASE, until January 2015. A manual search was also carried out and main researchers were contacted. The inclusion criteria were: (a) studies of the association between neuroticism and suicidal ideation; (b) observational and descriptive studies; (c) studies carried out with community population over 18 years; (d) in any geographic region; and (e) written in English, Spanish, French, Portuguese or Italian. The random-effects model was applied to obtain the mean effect size and to explore moderators. Thirteen articles focused on the association between neuroticism and suicide ideation were included in the meta-analysis. The mean effect size was r+ = 0.446 (IC 95%: 0.266-0.595). Publication bias was discarded as a threat against the validity of the results. A predictive model was stablished with two moderator variables: gender and type of self-report to measure neuroticism. Neuroticism can be considered as a risk factor for suicide ideation. This result is important to prevent both suicidal ideation and suicide behavior.


The risk of thromboembolism and need for oral anticoagulation after successful atrial fibrillation ablation.
The aim of this multicenter study was to evaluate the safety of discontinuing oral anticoagulation therapy (OAT) after apparently successful pulmonary vein isolation. Atrial fibrillation (AF) is associated with an increased risk of thromboembolic events (TE) and often requires OAT. Pulmonary vein isolation is considered an effective treatment for AF. We studied 3,355 patients, of whom 2,692 (79% male, mean age 57 +/- 11 years) discontinued OAT 3 to 6 months after ablation (Off-OAT group) and 663 (70% male, mean age 59 +/- 11 years) remained on OAT after this period (On-OAT group). CHADS(2) (congestive heart failure, hypertension, age [75 years and older], diabetes mellitus, and a history of stroke or transient ischemic attack) risk scores of 1 and > or =2 were recorded in 723 (27%) and 347 (13%) Off-OAT group patients and in 261 (39%) and 247 (37%) On-OAT group patients, respectively. During follow-up (mean 28 +/- 13 months vs. 24 +/- 15 months), 2 (0.07%) Off-OAT group patients and 3 (0.45%) On-OAT group patients had an ischemic stroke (p = 0.06). No other thromboembolic events occurred. No Off-OAT group patient with a CHADS(2) risk score of > or =2 had an ischemic stroke. A major hemorrhage was observed in 1 (0.04%) Off-OAT group patient and 13 (2%) On-OAT group patients (p < 0.0001). In this nonrandomized study, the risk-benefit ratio favored the suspension of OAT after successful AF ablation even in patients at moderate-high risk of TE. This conclusion needs to be confirmed by future large randomized trials.


Comparison of two sympatric Pasteuria populations isolated from a tropical vertisol soil.
An isolate of Pasteuria (designated PPMJ) recovered from the root-knot nematode Meloidogyne javanica, was characterized using host preference, spore morphometrics, and serology, and compared with another sympatric Pasteuria isolate (designated PPHC) collected from the cyst nematode, Heterodera cajani. PPMJ spores were larger (x 1.5) than the PPHC spores and had a mean diameter of 3.4 μm after fixation for electron microscopy. The central body of PPMJ spores was about twice as big as the central body of PPHC spores. The host preference tests, based on spore attachment to the nematode cuticle, revealed that Meloidogyne incognita, M. javanica, M. hapla, Pratylenchus coffeae, and Pratylenchus sp. were hosts of PPMJ but not of PPHC. It was found that males of Radopholus similis were hosts of PPHC. Western blot analysis of spore extracts probed with a polyclonal antiserum raised against PPHC spores showed an antigenic ladder which had similarities to lipopolysaccharide; another antiserum revealed differences in the molecular weight of antigens of the different spore isolates. Population diversity can therefore be vastly altered by the maintenance and culture of the bacterium on a particular host. The implications of these results are discussed in relation to the use of Pasteuria as a biological control agent.


Circadian regulation of cardiac muscle function and protein degradation.
The circadian clock plays a fundamental role in physiology. In particular, the heart is a target organ where the clock orchestrates various aspects of cardiac function. At the molecular level, the clock machinery governs daily rhythms of gene expression. Such circadian regulation is in tune with the dynamic nature of heart structure and function, and provides the foundation for chronotherapeutic applications in cardiovascular diseases. In comparison, a regulatory role of the clock in cardiac protein degradation is poorly documented. Sarcomere is the structural and functional unit responsible for cardiac muscle contraction, and sarcomere components are closely regulated by protein folding and proteolysis. Emerging evidence supports a role of the circadian clock in governing sarcomere integrity and function. Particularly, recent studies uncovered a circadian regulation of a core sarcomere component TCAP. It is possible that circadian regulation of the cardiac muscle protein turnover is a key regulatory mechanism underlying cardiac remodeling in response to physiological and environmental stimuli. While the detailed regulatory mechanisms and the molecular links to cardiac (patho)physiology remain to be further studied, therapeutic strategies targeting circadian control in the heart may markedly enhance intervention outcomes against cardiovascular disease.


Metabolomic and transcriptomic profiling reveals the alteration of energy metabolism in oyster larvae during initial shell formation and under experimental ocean acidification.
Marine bivalves secrete calcified shells to protect their soft bodies from predation and damages, which is of great importance for their survival, and for the safety of the coastal ecosystem. In recent years, larval shell formation of marine bivalves has been severely affected by ocean acidification (OA), and previous study indicated that OA might affect such process by disrupting endogenous energy metabolism. Developmental stages from trochophore to D-shape larvae are extremely important for initial shell formation in oyster since a calcified shell was formed to cover the chitin one. In the present study, metabolomic and transcriptomic approaches were employed to investigate the energy metabolism of oyster larvae during initial shell (prodissoconch I, PDI shell) formation and under experimental OA treatment. Totally 230 chemical compounds were identified from the present dataset, most of which were highly expressed in the "middle" stage (early D-shape larvae) which was critical for PDI shell formation since a calcified shell was formed to cover the chitin one. Several compounds such as glucose, glutarylcarnitine (C5), β-hydroxyisovaleroylcarnitine, 5-methylthioadenosine (MTA), myristoleate (14:1n5) and palmitoleate (16:1n7) were identified, which were involved in energy metabolic processes including amino acid oxidation, glycolysis, pentose phosphate pathway and fatty acid metabolism. In addition, mRNA expressions of genes related to protein metabolism, glycolysis, lipid degradation, calcium transport and organic matrix formation activities were significantly down-regulated upon experimental OA. These results collectively suggested that formation of the initial shell in oyster larvae required endogenous energy coming from amino acid oxidation, glycolysis, pentose phosphate pathway and fatty acid metabolism. These metabolic activities could be severely inhibited by experimental OA, which might alter the allocation of endogenous energy. Insufficient endogenous energy supply then suppressed the mobilization of calcium and resulted in a failure or delay in PDI shell formation.


Physical model for absorption of intraocular gas.
To present a physical model for intraocular absorption of an inert gas used as a tamponade. The absorption kinetics of gas in contact with the retinal surface is examined, including the changing geometry of the shrinking gas bubble inside the eye. An analytic solution is derived that predicts how the bubble dimensions change with time, yielding a formula for the lifetime of the gas bubble. Comparison to an experimental measurement shows that the analytic solution accurately replicates the time evolution of the bubble geometry. The result is also compared to an alternative exponential model, which does not predict a finite bubble lifetime. Further experiments are needed to discriminate between the surface absorption and exponential models.


Bayes Forest: a data-intensive generator of morphological tree clones.
Detailed and realistic tree form generators have numerous applications in ecology and forestry. For example, the varying morphology of trees contributes differently to formation of landscapes, natural habitats of species, and eco-physiological characteristics of the biosphere. Here, we present an algorithm for generating morphological tree "clones" based on the detailed reconstruction of the laser scanning data, statistical measure of similarity, and a plant growth model with simple stochastic rules. The algorithm is designed to produce tree forms, i.e., morphological clones, similar (and not identical) in respect to tree-level structure, but varying in fine-scale structural detail. Although we opted for certain choices in our algorithm, individual parts may vary depending on the application, making it a general adaptable pipeline. Namely, we showed that a specific multipurpose procedural stochastic growth model can be algorithmically adjusted to produce the morphological clones replicated from the target experimentally measured tree. For this, we developed a statistical measure of similarity (structural distance) between any given pair of trees, which allows for the comprehensive comparing of the tree morphologies by means of empirical distributions describing the geometrical and topological features of a tree. Finally, we developed a programmable interface to manipulate data required by the algorithm. Our algorithm can be used in a variety of applications for exploration of the morphological potential of the growth models (both theoretical and experimental), arising in all sectors of plant science research.


[Vascular architecture of the vocal cord surfaces. A fluorescence angiography study].
The study reported in this paper was devoted to investigating whether there are differences in the superficial vascularisation of the vocal cords compared with surrounding respiratory mucosa (e.g. false cords). The in-vivo technique employed was fluoresceine angiography. In full agreement with findings in anatomic preparations there was a fine vascular network, consisting of straight vessels running parallel to the surface of the vocal cords in dorsal-ventral direction. In contrast, the superficial vascular pattern of the false cords or other areas of the upper respiratory tract did not follow a linear pattern. Our findings may form the basis for further in-vivo studies of blood vessels in pathological alterations of the vocal cords.


A leukotriene A4 hydrolase-related aminopeptidase from yeast undergoes induced fit upon inhibitor binding.
Vertebrate leukotriene A(4) hydrolases are bifunctional zinc metalloenzymes with an epoxide hydrolase and an aminopeptidase activity. In contrast, highly homologous enzymes from lower organisms only have the aminopeptidase activity. From sequence comparisons, it is not clear why this difference occurs. In order to obtain more information on the evolutionary relationship between these enzymes and their activities, the structure of a closely related leucine aminopeptidase from Saccharomyces cerevisiae that only shows a very low epoxide hydrolase activity was determined. To investigate the molecular architecture of the active site, the structures of both the native protein and the protein in complex with the aminopeptidase inhibitor bestatin were solved. These structures show a more spacious active site, and the protected cavity in which the labile substrate leukotriene A(4) is bound in the human enzyme is partially obstructed and in other parts is more solvent accessible. Furthermore, the enzyme undergoes induced fit upon binding of the inhibitor bestatin, leading to a movement of the C-terminal domain. The main triggers for the domain movement are a conformational change of Tyr312 and a subtle change in backbone conformation of the PYGAMEN fingerprint region for peptide substrate recognition. This leads to a change in the hydrogen-bonding network pulling the C-terminal domain into a different position. Inasmuch as bestatin is a structural analogue of a leucyl dipeptide and may be regarded as a transition state mimic, our results imply that the enzyme undergoes induced fit during substrate binding and turnover.


Alterations in white matter microstructures and cognitive dysfunctions in benign childhood epilepsy with centrotemporal spikes.
Although benign childhood epilepsy with centrotemporal spikes (BECTS) is known to have good prognosis, patients often manifest neuropsychological impairments. This study aimed to investigate cognitive dysfunctions and their relationship with white matter microstructural changes in BECTS patients. Nineteen BECTS and 25 normal subjects aged 7-16 years were included. Neuropsychological performances were assessed by the Wechsler Intelligence Scale for Children III, executive function tests, verbal and visuospatial memory tests, the verbal fluency and Boston naming tests. Diffusion tensor imaging (DTI) was performed to measure the fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivities (MD). The voxel-wise tract-based spatial statistics and region of interest methods were used for DTI, and their correlations with cognitive variables were analyzed. Patients with BECTS had lower intelligence quotient (IQ) scores compared with those of the control group. Higher AD and MD values were found in the left superior longitudinal fasciculus, the retrolenticular part of the internal capsule, posterior thalamic radiation, sagittal stratum and the body of the corpus callosum in BECTS patients compared with controls. Lower performances in verbal IQ, freedom from distractibility and processing speed were correlated with higher AD in the left superior fronto-occipital fasciculus, and lower verbal IQ scores were correlated with decreased FA values in the splenium of the corpus callosum in these patients. White matter microstructural changes predominantly in the left hemisphere might contribute to their cognitive abnormalities especially verbal IQ in BECTS patients.


Incidence of large oesophageal varices in patients with cirrhosis: application to prophylaxis of first bleeding.
Because several studies have suggested that beta blockers are effective in the prophylaxis of first variceal bleeding in cirrhosis, screening for oesophageal varices might be appropriate. We prospectively studied 84 cirrhotic patients without obvious evidence of large oesophageal varices and previous bleeding during a mean follow up of 16 months. At entry to the study 41 patients had no oesophageal varices and in 43 these were grade 1. The subsequent percentages of patients without large oesophageal varices were 74% at one year and 52% at two years. Univariate analysis showed that a longer duration of cirrhosis (p less than 0.05) and grade 1 oesophageal varices at entry (p less than 0.001) were predictive factors for the occurrence of large oesophageal varices, whereas, multivariate analysis showed that the initial size of the oesophageal varices (p less than 0.001), a high initial Child-Pugh score, and a smaller improvement in Child-Pugh score during the study were independent risk factors. Among patients with grades 0 and 1 oesophageal varices at the start of the study the proportions with large oesophageal varices at two years were 31% and 70% respectively. We have calculated that, accepting a maximum risk of first bleeding of 10% without prophylactic treatment, a patient without oesophageal varices should be screened endoscopically every other year, while a patient with grade 1 disease should benefit from one annual upper gastrointestinal endoscopy.


Th0 to Th1 switch of CD4 T cell clones specific from the 16-kDa antigen of Mycobacterium tuberculosis after successful therapy: lack of involvement of epitope repertoire and HLA-DR.
In this study, we have examined the influence of HLA-DR molecules and the structure of the epitope repertoire of the 16-kDa protein of Mycobacterium tuberculosis on the acquisition of the cytokine secretion pattern of CD4 T cell clones, obtained from tuberculous patients before and after anti-mycobacterial therapy. Our data indicate that TB patients have a predominant Th0 response against the 16-kDa protein and its epitopes and that healing, induced by anti-mycobacterial therapy, is associated with a shift toward a predominant Th1 phenotype. Moreover, both HLA-DR molecules restricting the clone specificity and the nature of the recognized epitope do not play any role in the generation of Th0 and Th1 clones. These findings indicate that additional factors, such as the cytokine environment and/or costimulatory molecules, determine the Th phenotype of CD4 T cells during tuberculosis.


Achilles tendon shape and echogenicity on ultrasound among active badminton players.
The relationship between Achilles tendon ultrasound abnormalities, including a spindle shape and heterogeneous echogenicity, is unclear. This study investigated the relationship between these abnormalities, tendon thickness, Doppler flow and pain. Sixty-one badminton players (122 tendons, 36 men, and 25 women) were recruited. Achilles tendon thickness, shape (spindle, parallel), echogenicity (heterogeneous, homogeneous) and Doppler flow (present or absent) were measured bilaterally with ultrasound. Achilles tendon pain (during or after activity over the last week) and pain and function [Victorian Institute of Sport Achilles Assessment (VISA-A)] were measured. Sixty-eight (56%) tendons were parallel with homogeneous echogenicity (normal), 22 (18%) were spindle shaped with homogeneous echogenicity, 16 (13%) were parallel with heterogeneous echogenicity and 16 (13%) were spindle shaped with heterogeneous echogenicity. Spindle shape was associated with self-reported pain (P<0.05). Heterogeneous echogenicity was associated with lower VISA-A scores than normal tendon (P<0.05). There was an ordinal relationship between normal tendon, parallel and heterogeneous and spindle shaped and heterogeneous tendons with regard to increasing thickness and likelihood of Doppler flow. Heterogeneous echogenicity with a parallel shape may be a physiological phase and may develop into heterogeneous echogenicity with a spindle shape that is more likely to be pathological.


The effect of nanomaterials on embryonic stem cell neural differentiation: a systematic review.
Humans' nervous system has a limited ability to repair nerve cells, which poses substantial challenges in treating injuries and diseases. Stem cells are identified by the potential to renew their selves and develop into several cell types, making them ideal candidates for cell replacement in injured neurons. Neuronal differentiation of embryonic stem cells in modern medicine is significant. Nanomaterials have distinct advantages in directing stem cell function and tissue regeneration in this field. We attempted in this systematic review to collect data, analyze them, and report results on the effect of nanomaterials on neuronal differentiation of embryonic stem cells. International databases such as PubMed, Scopus, ISI Web of Science, and EMBASE were searched for available articles on the effect of nanomaterials on neuronal differentiation of embryonic stem cells (up to OCTOBER 2023). After that, screening (by title, abstract, and full text), selection, and data extraction were performed. Also, quality assessment was conducted based on the STROBE checklist. In total, 1507 articles were identified and assessed, and then only 29 articles were found eligible to be included. Nine studies used 0D nanomaterials, ten used 1D nanomaterials, two reported 2D nanomaterials, and eight demonstrated the application of 3D nanomaterials. The main biomaterial in studies was polymer-based composites. Three studies reported the negative effect of nanomaterials on neural differentiation. Neural differentiation is crucial in neurological regenerative medicine. Nanomaterials with different characteristics, particularly those cellular regulating activities and stem cell fate, have much potential in neural tissue engineering. These findings indicate a new understanding of potential applications of physicochemical cues in nerve tissue engineering.


Identification of a human SCARB2 region that is important for enterovirus 71 binding and infection.
We previously identified human scavenger receptor class B, member 2 (SCARB2), as a cellular receptor for enterovirus 71 (EV71). Expression of human SCARB2 (hSCARB2) permitted mouse L929 cells to efficiently bind to virions and to produce both viral proteins and progeny viruses upon EV71 infection. Mouse Scarb2 (mScarb2) exhibited 85.8% amino acid identity and 99.9% similarity to hSCARB2. The expression of mScarb2 in L929 cells conferred partial susceptibility. Very few virions bound to mScarb2-expressing cells. The viral titer in L929 cells expressing mScarb2 was approximately 40- to 100-fold lower than that in L929 cells expressing hSCARB2. Using hSCARB2-mScarb2 chimeric mutants, we attempted to map the region that was important for efficient EV71 infection. L929 cells expressing chimeras that carried amino acids 142 to 204 from the human sequence were susceptible to EV71, while chimeras that carried the mouse sequence in this region were not. Moreover, this region was also critical for binding to virions. The determination of this region in hSCARB2 that is important for EV71 binding and infection greatly contributes to the understanding of virus-receptor interactions. Further studies will clarify the early steps of EV71 infection.


Direct sampled I/Q beamforming for compact and very low-cost ultrasound imaging.
A wide variety of beamforming approaches are applied in modern ultrasound scanners, ranging from optimal time domain beamforming strategies at one end to rudimentary narrowband schemes at the other. Although significant research has been devoted to improving image quality, usually at the expense of beamformer complexity, we are interested in investigating strategies that sacrifice some image quality in exchange for reduced cost and ease in implementation. This paper describes the direct sampled in-phase/quadrature (DSIQ) beamformer, which is one such low-cost, extremely simple, and compact approach. DSIQ beamforming relies on phase rotation of I/Q data to implement focusing. The I/Q data are generated by directly sampling the received radio frequency (RF) signal, rather than through conventional demodulation. We describe an efficient hardware implementation of the beamformer, which results in significant reductions in beamformer size and cost. We present the results of simulations and experiments that compare the DSIQ beamformer to more conventional approaches, namely, time delay beamforming and traditional complex demodulated I/Q beamforming. Results that show the effect of an error in the direct sampling process, as well as dependence on signal bandwidth and system f number (f#) are also presented. These results indicate that the image quality and robustness of the DSIQ beamformer are adequate for low end scanners. We also describe implementation of the DSIQ beamformer in an inexpensive hand-held ultrasound system being developed in our laboratory.


Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance.
Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.


Race and gender variation in response to evoked inflammation.
Race- and gender-variation in innate immunity may contribute to demographic differences in inflammatory and cardiometabolic disease; yet their influence on dynamic responses during inflammatory stress is poorly understood. Our objective was to examine race and gender influence on the response to experimental endotoxemia. The Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) study was designed to investigate regulation of inflammatory and metabolic responses during low-grade endotoxemia (LPS 1 ng/kg intravenously) in healthy individuals (median age 24, IQR=7) of European (EA; n=193, 47% female) and African ancestry (AA; n=101, 59% female). Baseline clinical, metabolic, and inflammatory biomarkers by race and gender were consistent with epidemiological literature; pre-LPS cytokines (e.g. median (IQR) IL-6, 2.7 (2) vs.2.1 (2) pg/ml, P=0.001) were higher in AA than EA. In contrast, acute cytokine responses during endotoxemia were lower in AA than EA (e.g. median (IQR) peak IL-1RA, 30 (38) vs.43 (45) ng/ml P=0.002) as was the induction of hepatic acute-phase proteins (e.g. median (IQR) peak CRP 12.9 (9) vs.17.4 (12) mg/L P=0.005). Further, baseline levels of cytokines were only weakly correlated with peak inflammatory responses (all r(s) <0.2) both in AA and in EA. There were less pronounced and less consistent differences in the response by gender, with males having a higher AUC for CRP response compared to females (median (IQR) AUC: 185 (112) vs. 155 (118), P=0.02). We observed lower levels of evoked inflammation in response to endotoxin in AA compared with EA, despite similar or higher baseline levels of inflammatory markers in AA. Our data also suggest that levels of inflammatory biomarkers measured in epidemiological settings might not predict the degree of acute stress-response or risk of diseases characterized by activation of innate immunity. FDA clinicaltrials.gov registration number NCT00953667.


Protein-RNA complexes and efficient automatic docking: expanding RosettaDock possibilities.
Protein-RNA complexes provide a wide range of essential functions in the cell. Their atomic experimental structure solving, despite essential to the understanding of these functions, is often difficult and expensive. Docking approaches that have been developed for proteins are often challenging to adapt for RNA because of its inherent flexibility and the structural data available being relatively scarce. In this study we adapted the RosettaDock protocol for protein-RNA complexes both at the nucleotide and atomic levels. Using a genetic algorithm-based strategy, and a non-redundant protein-RNA dataset, we derived a RosettaDock scoring scheme able not only to discriminate but also score efficiently docking decoys. The approach proved to be both efficient and robust for generating and identifying suitable structures when applied to two protein-RNA docking benchmarks in both bound and unbound settings. It also compares well to existing strategies. This is the first approach that currently offers a multi-level optimized scoring approach integrated in a full docking suite, leading the way to adaptive fully flexible strategies.


Three-Year Durability of Restorative Neurostimulation Effectiveness in Patients With Chronic Low Back Pain and Multifidus Muscle Dysfunction.
Restorative neurostimulation is a rehabilitative treatment for patients with refractory chronic low back pain (CLBP) associated with dysfunction of the lumbar multifidus muscle resulting in impaired neuromuscular control. The ReActiv8-B randomized, sham-controlled trial provided evidence of the effectiveness and safety of an implanted, restorative neurostimulator. The two-year analysis previously published in this journal demonstrated accrual of clinical benefits and long-term durability. Evaluation of three-year effectiveness and safety in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. Prospective, observational follow-up of the 204 implanted trial participants. Low back pain visual analog scale (VAS), Oswestry Disability Index (ODI), EuroQol quality of life survey, and opioid intake were assessed at baseline, six months, and one, two, and three years after activation. The mixed-effects model repeated measures approach was used to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates. Data were collected from 133 participants, and 16 patients missed their three-year follow-up because of coronavirus disease restrictions but remain available for future follow-up. A total of 62% of participants had a ≥ 70% VAS reduction, and 67% reported CLBP resolution (VAS ≤ 2.5cm); 63% had a reduction in ODI of ≥ 20 points; 83% had improvements of ≥ 50% in VAS and/or ≥ 20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 71% (36/51) participants on opioids at baseline had voluntarily discontinued (49%) or reduced (22%) opioid intake. The attenuation of effectiveness in the imputed (N = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remains favorable, and no lead migrations have been observed to date. At three years, 83% of participants experienced clinically substantial improvements in pain, disability, or both. The results confirm the long-term effectiveness, durability, and safety of restorative neurostimulation in patients with disabling CLBP associated with multifidus muscle dysfunction. The Clinicaltrials.gov registration number for the study is NCT02577354.


A randomized controlled trial of the effectiveness of Housing First in a small Canadian City.
The paper presents two-year findings from a study investigating the effectiveness of Housing First (HF) with assertive community treatment (ACT) in helping individuals with serious mental illness, who are homeless or precariously housed and living in a small city, to become stably housed. The research design was a parallel group non-blinded RCT with participants randomly assigned after the baseline interview to receive HF with ACT (N = 100) or treatment as usual (TAU; N = 101). Participants were interviewed every 3 months over 21/24 months to investigate changes on a range of housing and psychosocial outcomes. The primary outcomes were housing stability (as defined by a joint function of number of days housed and number of moves) and improvement in community functioning. Secondary predicted outcomes were improvements in self-rated physical and mental health status, substance use problems, quality of life, community integration, and recovery. An intent-to-treat analysis was conducted. Compared to TAU participants, HF participants who entered housing did so more quickly (23.30 versus 88.25 days, d = 1.02, 95% CI [0.50-1.53], p < 0.001), spent a greater proportion of time stably housed (Z = 5.30, p < 0.001, OR = 3.12, 95% CI [1.96-4.27]), and rated the quality of their housing more positively (Z = 4.59, p < 0.001, d = 0.43, 95% CI [0.25-0.62]). HF participants were also more likely to be housed continually in the final 6 months (i.e., 79.57% vs. 55.47%), χ2 (2, n = 170) = 11.46, p = .003, Cramer's V = 0.26, 95% CI [0.14-0.42]). HF participants showed greater gains in quality of life, (Z = 3.83, p < 0.001, ASMD = 0.50, 95% CI [0.24-0.75]), psychological integration (Z = 12.89, p < 0.001, pooled ASMD = 0.91, 95% CI [0.77-1.05]), and perceived recovery (Z = 2.26, p = 0.03, ASMD = 0.39, 95% CI [0.05-0.74]) than TAU participants. The study indicates that HF ends homelessness significantly more rapidly than TAU for a majority of individuals with serious mental illness who have a history of homelessness and live in a small city. In addition, compared to TAU, HF produces psychosocial benefits for its recipients that include an enhanced quality of life, a greater sense of belonging in the community, and greater improvements in perceived recovery from mental illness. International Standard Randomized Control Trial Number Register Identifier: ISRCTN42520374 , assigned August 18, 2009.


Effect of the Rho kinase inhibitor Y-27632 on the proteome of hearts with ischemia-reperfusion injury.
Growing attention has been given to the role of the Rho kinase pathway in the development of heart disease and ischemia/reperfusion (I/R) injury. Y-27632 is a Rho kinase inhibitor demonstrated to protect against I/R injury, but the exact mechanism by which it does so remains to be elucidated. The goal of this project was to determine new targets by which Y-27632 can protect the heart against I/R injury. Isolated rat hearts were perfused under aerobic conditions or subjected to I/R in the presence or absence of Y-27632. Administration of Y-27632 (1 μM) before ischemia and during the first 10 min of reperfusion resulted in complete recovery of cardiac function. 2-D electrophoresis followed by MS identified four proteins whose levels were affected by Y-27632 treatment. Lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase were significantly increased in the Y-27632 treated group, while creatine kinase was normalized to control levels. In addition, we found increased level of two different molecular fragments of ATP synthase, which were normalized by Y-27632. This increase suggests that during ischemia ATP synthase is subjected to degradation. The changes in metabolic enzymes' levels and their regulation by Y-27632 suggest that the cardioprotective effect of Y-27632 involves increased energy production.


Absolute risk of breast cancer for Australian women with a family history.
The purpose of the present paper was to estimate the absolute risk of breast cancer over the remainder of a lifetime in Australian women with different categories of family history. Age-specific breast cancer incidence rates were adjusted for screening effects, and rates in those with no family history were estimated using the attributable fraction (AF). Relative risks from a published meta-analysis were applied to obtain incidence rates for different categories of family history, and age-specific incidence was converted to cumulative risk of breast cancer. The risk estimates were based upon Australian population statistics and published relative risks. Breast cancer incidence was from New South Wales women for 1996. The AF was calculated using prevalence of a family history of breast cancer from data on Queensland women. The cumulative absolute risk of breast cancer was calculated from decade and mid-decade ages to age 79 years, not adjusted for competing causes of death. Lifetime risk is approximately 8.6% (1 in 12) for the general population and 7.8% (1 in 13) for those without a family history. Women with one relative affected have lifetime risks of 1 in 6-8 and those with two relatives affected have lifetime risks of 1 in 4-6. The cumulative residual lifetime risk decreases with advancing age; by age 60 years all groups with only one relative affected have well above a 90% probability of not developing breast cancer to age 79 years. These Australian risk statistics are useful for public information and in the clinical setting. Risks given here apply to women with average breast cancer risk from other risk factors.


Evidence-based strategies for reducing cesarean section rates: a meta-analysis.
Canada's cesarean section rate reached an all-time high of 22.5 percent of in-hospital deliveries in 2002 and was associated with potential maternal and neonatal complications. Clinical practice guidelines represent an appropriate mean for reducing cesarean section rates. The challenge now lies in implementing these guidelines. Objectives of this meta-analysis were to assess the effectiveness of interventions for reducing the cesarean section rate and to assess the impact of this reduction on maternal and perinatal mortality and morbidity. The Cochrane Library, EMBASE, and MEDLINE were consulted from January 1990 to June 2005. Additional studies were identified by screening reference lists from identified studies and expert suggestions. Studies involving rigorous evaluation of a strategy for reducing overall cesarean section rates were identified. Randomized controlled trials, controlled before-and-after studies, and interrupted time series studies were evaluated according to Effective Practice and Organisation of Care Group criteria. Among the 10 included studies, a significant reduction of cesarean section rate was found by random meta-analysis (pooled RR = 0.81 [0.75, 0.87]). No evidence of publication bias was identified. Audit and feedback (pooled RR = 0.87 [0.81, 0.93]), quality improvement (pooled RR = 0.74 [0.70, 0.77]), and multifaceted strategies (pooled RR=0.73 [0.68, 0.79]) were effective for reducing the cesarean section rate. However, quality improvement based on active management of labor showed mixed effects. Design of studies showed a higher effect for noncontrolled studies than for controlled studies (pooled RR = 0.76 [0.72, 0.81] vs 0.92 [0.88, 0.96]). Studies including an identification of barriers to change were more effective than other interventions for reducing the cesarean section rate (pooled RR = 0.74 [0.71, 0.78] vs 0.88 [0.82, 0.94]). Among included studies, no significant differences were found for perinatal and neonatal mortality and perinatal and maternal morbidity with respect to the mode of delivery. Only 1 study showed a significant reduction of neonatal and perinatal mortality (p < 0.001). The cesarean section rate can be safely reduced by interventions that involve health workers in analyzing and modifying their practice. Our results suggest that multifaceted strategies, based on audit and detailed feedback, are advised to improve clinical practice and effectively reduce cesarean section rates. Moreover, these findings support the assumption that identification of barriers to change is a major key to success.


An Advanced, Silicon-Based Substrate for Sensitive Nucleic Acids Detection.
Surface substrate and chemical functionalization are crucial aspects for the fabrication of the sensitive biosensor based on microarray technology. In this paper, an advanced, silicon-based substrate (A-MA) allowing enhancement of optical signal for microarray application is described. The substrate consists in a multilayer of Si/Al/SiO₂ layers. The optical signal enhancement is reached by a combination of the mirror effect of Al film and the SiO₂ thickness around 830 nm, which is able to reach the maximum of interference for the emission wavelength of the Cy5 fluorescent label. Moreover, SiO₂ layer is suitable for the immobilization of single-strand DNA through standard silane chemistry, and probe densities of about 2000 F/um² are reached. The microarray is investigated in the detection of HBV (Hepatitis B Virus) pathogen with analytical samples, resulting in a dynamic linear range of 0.05⁻0.5 nM, a sensitivity of about 18000 a.u. nM-1, and a Limit of Detection in the range of 0.031⁻0.043 Nm as a function of the capture probe sequence.


Coexposure to sulfamethoxazole and cadmium impairs development and attenuates transcriptional response in sea urchin embryo.
Among sulfonamides, sulfamethoxazole represents one of the most widely employed. A considerable amount of sulfamethoxazole is introduced into the marine environment after utilization in aquaculture. The cytotoxicity of sulfamethoxazole relies mainly on arylhydroxylamine metabolites and it is associated with the production of reactive oxygen species. Cadmium represents a metal largely employed in several anthropic activities and it is toxic for all living organisms even at low concentrations. Since it is not degraded, cadmium irreversibly accumulates into cells. In order to understand the mechanisms of response to changes in the chemical environment, we investigated by light microscopy observations and RT-qPCR assays the impact of sulfamethoxazole and cadmium in P. lividus sea urchin embryos. During development, embryos were exposed to sulfamethoxazole amount comparable to that usually used in aquaculture procedures and/or sublethal levels of cadmium chloride. Impairment of development and biomarkers for inflammation, detoxification, metal scavenging and cell death were inspected. Even though treatment with sulfamethoxazole apparently did not affect development, it stimulated a remarkable molecular response to oxidative stress. Moreover, combined exposure seriously compromised development and the defense mechanisms to cadmium were blocked. This study leads to the conclusion that coexposure to sulfamethoxazole and cadmium induces neutralizing effects on sea urchin embryos. Thus, in marine areas nearby aquaculture farms, where sulfamethoxazole discharge represents an important environmental contaminant, cadmium occurrence may alter population dynamics of P. lividus.


The positive side of a negative reference: the delay between linguistic processing and common ground.
Interlocutors converge on names to refer to entities. For example, a speaker might refer to a novel looking object as the jellyfish and, once identified, the listener will too. The hypothesized mechanism behind such referential precedents is a subject of debate. The common ground view claims that listeners register the object as well as the identity of the speaker who coined the label. The linguistic view claims that, once established, precedents are treated by listeners like any other linguistic unit, i.e. without needing to keep track of the speaker. To test predictions from each account, we used visual-world eyetracking, which allows observations in real time, during a standard referential communication task. Participants had to select objects based on instructions from two speakers. In the critical condition, listeners sought an object with a negative reference such as not the jellyfish. We aimed to determine the extent to which listeners rely on the linguistic input, common ground or both. We found that initial interpretations were based on linguistic processing only and that common ground considerations do emerge but only after 1000 ms. Our findings support the idea that-at least temporally-linguistic processing can be isolated from common ground.