Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males.
The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve activity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention. 30 young, healthy, sodium loaded, non-obese males were exposed to -15 mmHg LBNP, -30 mmHg LBNP, -15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response. All intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; -15 mmHg: -3.1 ± 0.9 %, -30 mmHg: -2.9 ± 0.6 %, -15 mmHg + aslikiren: -1.8 ± 0.6 %). -15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters. Sympathetic stimulation for 90 min via LBNP at -30 mmHg LBNP compared to -15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.


The Effect of a Resistance Training Session on Physiological and Thermoregulatory Measures of Sub-maximal Running Performance in the Heat in Heat-Acclimatized Men.
The current study examined the acute effects of a lower body resistance training (RT) session on physiological and thermoregulatory measures during a sub-maximal running protocol in the heat in heat-acclimatized men. Ten resistance-untrained men (age 27.4 ± 4.1 years; height 1.78 ± 0.06 m; body mass 76.8 ± 9.9 kg; peak oxygen uptake 48.2 ± 7.0 mL kg-1 min-1) undertook a high-intensity RT session at six-repetition maximum. Indirect muscle damage markers (i.e., creatine kinase [CK], delayed-onset muscle soreness [DOMS], and countermovement jump [CMJ]) were collected prior to, immediately post and 24 and 48 h after the RT session. The sub-maximal running protocol was performed at 70% of the ventilatory threshold, which was conducted prior to and 24 and 48 h following the RT session to obtain physiological and thermoregulatory measures. The RT session exhibited significant increases in DOMS (p < 0.05; effect size [ES]: 1.41-10.53), whilst reduced CMJ (p < 0.05; ES: - 0.79-1.41) for 48 h post-exercise. There were no differences in CK (p > 0.05), although increased with moderate to large ES (0.71-1.12) for 48 h post-exercise. The physiological cost of running was increased for up to 48 h post-exercise (p < 0.05) with moderate to large ES (0.50-0.84), although no differences were shown in thermoregulatory measures (p > 0.05) with small ES (0.33). These results demonstrate that a RT session impairs sub-maximal running performance for several days post-exercise, although thermoregulatory measures are unperturbed despite elevated muscle damage indicators in heat-acclimatized, resistance untrained men. Accordingly, whilst a RT session may not increase susceptibility to heat-related injuries in heat-acclimatized men during sub-maximal running in the heat, endurance sessions should be undertaken with caution for at least 48 h post-exercise following the initial RT session in resistance untrained men.


Analysis of postoperative ultrasonography surveillance after total thyroidectomy in patients with papillary thyroid carcinoma: a multicenter study.
Background In papillary thyroid carcinoma (PTC) patients, postoperative ultrasonography (US) surveillance is recommended at intervals of six or 12 months even though evidence is weak. Purpose To determine the optimal interval of postoperative US surveillance in patients after total thyroidectomy for the treatment of PTC using multicenter data. Material and Methods A total of 1400 patients from seven tertiary hospitals who underwent total thyroidectomy for treatment of PTC were included. Based on a retrospective review of clinical and pathologic results, multiple factors were analyzed according to recurrence/persistence or no recurrence/persistence. In recurrence/persistence group, the interval and number of follow-up US sessions in the initial detection of recurrence/persistence were investigated. Results Of the 1400 patients, 115 (8.2%) showed tumor recurrence/persistence on follow-up US. Of 115 recurrence/persistence cases, 89 (77.4%) were initially detected on US: nodal recurrence/persistence (n = 92), non-nodal recurrence/persistence (n = 22), and both (n = 1). Among the clinical and pathologic factors, only tumor size and N stage were significant predictors for recurrence/persistence. In the recurrence/persistence group, the mean interval and number of follow-up US sessions in the initial detection of recurrence/persistence was 22.3 ± 16.8 months and 2.2 ± 1.9, respectively. Approximately two-thirds of recurrence/persistence cases (76/115, 66.1%) were detected in follow-up US within two years after total thyroidectomy. Conclusion In PTC patients after total thyroidectomy, the optimal interval of the first US follow-up may be one to two years after thyroid surgery, and the appropriate number of postoperative US surveillance sessions within the first five years may be only one or two.


Rehabilitation of a glenohumeral instability utilizing the body blade.
Traditional rehabilitation for shoulder dislocation has a success rate of only 20%. The body blade has been hypothesized to strengthen the muscles stabilizing the shoulder girdle by training the contractile tissues directly and also indirectly affecting the joint and surrounding noncontractile tissues when responding to rapid positional changes and mechanical energy. Shoulder dislocation negatively affects both the active (musculature) and passive (joint and ligaments) stabilizers of the glenohumeral joint. Therefore, the purpose of this case report was to evaluate the efficacy of therapeutic exercise using the body blade in the conservative management of an individual with glenohumeral instability. The patient, an 18-year-old male, dislocated his left shoulder after a wave crashed on top of him. Intervention included therapeutic exercise using the body blade. Measures were taken at examination, re-evaluation (6th visit), and discharge (11th visit). According to the 11-point numeric pain rating scale, worst pain was reduced from 4 to 0. Glenohumeral ROM measures at discharge were all within normal range except external rotation (deficit of 10 degrees), compared to the initial ROM deficits of 10-35% of noninvolved values. Post intervention strength, as assessed by handheld dynamometry, revealed deficits only in scapular retraction compared to the uninvolved side (21% compared to an initial deficit of 39%). Other muscle groups showing deficits from 20% to 40% at initial examination exceeded the comparative strength of the other limb at discharge. The SPADI and WOSI scores were reduced from 13 to 0 and 482 to 46, from initial examination to discharge, respectively. Furthermore 6 months post episode of care the patient reported no recurrent dislocation of the involved shoulder. The success rate of an exercise program with individuals who have dislocated their glenohumeral joint is poor. After 11 visits of physical therapy using the body blade the patient improved in ROM, strength, and function.


Searching for convergent pathways in autism spectrum disorders: insights from human brain transcriptome studies.
Autism spectrum disorder (ASD) is one of the most heritable neuropsychiatric conditions. The complex genetic landscape of the disorder includes both common and rare variants at hundreds of genetic loci. This marked heterogeneity has thus far hampered efforts to develop genetic diagnostic panels and targeted pharmacological therapies. Here, we give an overview of the current literature on the genetic basis of ASD, and review recent human brain transcriptome studies and their role in identifying convergent pathways downstream of the heterogeneous genetic variants. We also discuss emerging evidence on the involvement of non-coding genomic regions and non-coding RNAs in ASD.


Autoimmune mouse antibodies recognize multiple antigens proposed in human immune-mediated hearing loss.
Autoimmune diseased mice with hearing loss will have autoantibodies against the various cochlear antigens proposed in clinical autoimmune inner ear disease. Serum antibodies of patients with hearing loss recognize several proteins that are proposed as possible antigenic targets in the ear. This often leads to a clinical diagnosis of autoimmune inner ear disease, although it is not clear how these antibodies cause inner ear disease. Therefore, to better understand the relationship of autoantibodies and ear disease, an examination was made of serum autoantibodies in the MRL/MpJ-Fas(lpr) autoimmune mouse with hearing loss. Similar antibody patterns in the mouse would provide an animal model in which to investigate potential autoimmune mechanisms of this clinical ear disorder. Sera from MRL/MpJ-Fas(lpr) autoimmune mice and normal C3H mice were tested by the enzyme-linked immunosorbent assay technique for reactivity against various reported cochlear antigens: heat shock protein 70 (bovine, human, bacterial), laminin, heparan sulfate proteoglycan, cardiolipin, and collagen types II and IV. The autoimmune mouse sera showed significantly greater antibody reactivity against all of the antigens when compared with normal mouse sera. Serum antibodies from autoimmune mice recognized several putative autoantigens reported for patients with hearing loss, suggesting that comparable antigen-antibody mechanisms might be operating. However, the recognition of multiple antigens did not identify any one as being the specific target in autoimmune hearing loss. The correlation of antibodies in the MRL/MpJ-Fas(lpr) autoimmune mouse and human studies indicates this animal model should aid further investigations into potential cochlear antigens in autoimmune hearing loss.


Volatile Chemical Emission as a Weapon of Rearguard Action: A Game-Theoretic Model of Contest Behavior.
We use a game-theoretic model to explore whether volatile chemical (spiroacetal) emissions can serve as a weapon of rearguard action. Our basic model explores whether such emissions serve as a means of temporary withdrawal, preventing the winner of the current round of a contest from translating its victory into permanent possession of a contested resource. A variant of this model explores an alternative possibility, namely, that such emissions serve as a means of permanent retreat, attempting to prevent a winner from inflicting costs on a fleeing loser. Our results confirm that the underlying logic of either interpretation of weapons of rearguard action is sound; however, empirical observations on parasitoid wasp contests suggest that the more likely function of chemical weapons is to serve as a means of temporary withdrawal. While our work is centered around the particular biology of contest behavior in parasitoid wasps, it also provides the first contest model to explicitly consider self-inflicted damage costs and thus responds to a recent call by empiricists for theory in this area.


Spatial heterogeneity and the persistence of infectious diseases.
The endemic persistence of infectious diseases can often not be understood without taking into account the relevant heterogeneities of host mixing. Here, we consider spatial heterogeneity, defined as 'patchiness' of the host population. After briefly reviewing how disease persistence is influenced by population size, reproduction number and infectious period, we explore its dependence on the level of spatial heterogeneity. Analysis and simulation of disease transmission in a symmetric meta-population suggest that disease persistence typically becomes worse as spatial heterogeneity increases, although local persistence optima can occur for infections with oscillatory population dynamics. We obtain insight into the dynamics that underlie the observed persistence patterns by studying the infection prevalence correlation between patches and by comparing full-model simulations to results obtained using simplified patch-level descriptions of the interplay between local extinctions and between-patch transmissions. The observed patterns are interpreted in terms of rescue effects for strong spatial heterogeneity and in terms of between-patch coherence and synchronization effects at intermediate and weak levels of heterogeneity.


BRAF, NRAS, and GNAQ Mutations in Conjunctival Melanocytic Nevi.
To evaluate BRAF, NRAS, and GNAQ mutations in surgical specimens of common and blue conjunctival melanocytic nevi. Surgical specimens from 25 conjunctival melanocytic nevi (23 common and 2 blue) of 25 patients were evaluated. All common nevi were analyzed immunohistochemically for the expression of BRAF V600E or NRAS Q61R. One lesion with negative immunoreactivity and for all blue nevi, a hybridization capture-based next-generation sequencing method was employed for mutation analysis. For common nevi, genetic features were compared with clinical and histopathologic findings. Continuous variables (age at excision and largest basal diameter) were compared with a Students's t-test and all categoric variables were compared with Fisher's Exact Test. Of common melanocytic nevi, 9 (39.1%) were immunoreactive for NRASQ61R and 13 (56.5%) were immunoreactive for BRAFV600E. One common nevus, which was immunonegative for both BRAFV600E and NRASQ61R was found to harbor an NRASQ61K mutation by sequence analysis. Patients with NRAS-mutated nevi were more likely to report occurrence of the lesion prior to 18-years old and more likely to have intrinsic cysts. The mean largest basal diameter was 6.0 and 3.5 mm for NRAS- and BRAF-immunoreactive lesions, respectively (P = 0.003). GNAQ mutations were identified in each of the two blue nevi of this study. These findings document that common conjunctival melanocytic nevi have mutually exclusive mutations in BRAF and NRAS. The two conjunctival blue nevi harbored GNAQ mutations. This suggests the driver mutations of conjunctival nevi are similar to those of nevi of the skin. At the molecular level, conjunctival nevi appear more like cutaneous nevi than choroidal nevi.


Systematic interpretation of comutated genes in large-scale cancer mutation profiles.
By high-throughput screens of somatic mutations of genes in cancer genomes, hundreds of cancer genes are being rapidly identified, providing us abundant information for systematically deciphering the genetic changes underlying cancer mechanism. However, the functional collaboration of mutated genes is often neglected in current studies. Here, using four genome-wide somatic mutation data sets and pathways defined in various databases, we showed that gene pairs significantly comutated in cancer samples tend to distribute between pathways rather than within pathways. At the basic functional level of motifs in the human protein-protein interaction network, we also found that comutated gene pairs were overrepresented between motifs but extremely depleted within motifs. Specifically, we showed that based on Gene Ontology that describes gene functions at various specific levels, we could tackle the pathway definition problem to some degree and study the functional collaboration of gene mutations in cancer genomes more efficiently. Then, by defining pairs of pathways frequently linked by comutated gene pairs as the between-pathway models, we showed they are also likely to be codisrupted by mutations of the interpathway hubs of the coupled pathways, suggesting new hints for understanding the heterogeneous mechanisms of cancers. Finally, we showed some between-pathway models consisting of important pathways such as cell cycle checkpoint and cell proliferation were codisrupted in most cancer samples under this study, suggesting that their codisruptions might be functionally essential in inducing these cancers. All together, our results would provide a channel to detangle the complex collaboration of the molecular processes underlying cancer mechanism.


Repeatability and variation of quantitative gait data in subgroups of patients with stroke.
We aimed to determine the repeatability and variation of quantitative gait data in patients with stroke and to compare the subgroups in terms of gait variability. Time-distance and kinematic characteristics of gait were evaluated in 90 inpatients (30 women) with hemiparesis (mean+/-S.D. age 57.7+/-12.5 years and time since stroke 5.99+/-6.46 months). Subgroups were based on "gender", "side of paresis", "lesion type", "motor recovery level", "sensory status", "time since stroke" and "walking velocity". Repeatability was adequate to excellent in all stroke subgroups (ICC range 0.48-0.98). Walking velocity was the most repeatable gait parameter after stroke. Variation in step length was significantly higher in women than in men (CV 16% versus 9%, p<0.05). Slow walkers (walking velocity <0.34 m/s) had a higher variation than fast walkers in step length (CV 12.5% versus 7.5%, p<0.01), single support time (CV 11.9% versus 6.3%, p<0.05), peak hip extensions in stance (CV 11.5% versus 3.7%, p<0.01) and knee flexion in swing (CV 11.8% versus 6.5%, p<0.05). In our stroke patients, their age, time since injury, lesion characteristics, impaired proprioception or level of motor recovery had no effect on gait variability. For better interpretation of quantitative gait data, clinicians should consider that variation in step length, single support time, peak hip extension in stance and knee flexion in swing differs according to walking velocity after stroke.


Health and reproductive experiences of women with an FMR1 premutation with and without fragile X premature ovarian insufficiency.
Recently, research has indicated an increased risk for greater medical and emotional comorbidity and physical health symptoms among women with an FMR1 expansion. However, these studies have generally been limited in their ability to model multiple risk factors associated with these symptoms by small numbers (n = 112-146) of participants. This study used survey methodology to examine the health experiences of 458 adult women with the premutation with and without a history of a fragile X primary ovarian insufficiency (FXPOI) diagnosis. Results suggest similar findings to those reported in the literature with regard to the frequency of medical, emotional, and reproductive experiences of women with the premutation. In addition to expected reproductive differences, women with a diagnosis of FXPOI were also more likely to experience dizziness, nausea, and muscle weakness than women without a diagnosis of FXPOI. Women with and without FXPOI were more likely to have used reproductive assistance and were more likely to have experienced preeclampsia during at least one pregnancy than is reported in the general population. Having comorbid depression and anxiety was predictive of increased medical conditions and increased daily physical health symptoms.


Heavy livestock grazing promotes locust outbreaks by lowering plant nitrogen content.
Current paradigms generally assume that increased plant nitrogen (N) should enhance herbivore performance by relieving protein limitation, increasing herbivorous insect populations. We show, in contrast to this scenario, that host plant N enrichment and high-protein artificial diets decreased the size and viability of Oedaleus asiaticus, a dominant locust of north Asian grasslands. This locust preferred plants with low N content and artificial diets with low protein and high carbohydrate content. Plant N content was lowest and locust abundance highest in heavily livestock-grazed fields where soils were N-depleted, likely due to enhanced erosion. These results suggest that heavy livestock grazing and consequent steppe degradation in the Eurasian grassland promote outbreaks of this locust by reducing plant protein content.


A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids.
Impairment of gut barrier is associated with a fat-rich diet, but mechanisms are unknown. We have earlier shown that dietary fat modifies fecal bile acids in mice, decreasing the proportion of ursodeoxycholic acid (UDCA) vs. deoxycholic acid (DCA). To clarify the potential role of bile acids in fat-induced barrier dysfunction, we here investigated how physiological concentrations of DCA and UDCA affect barrier function in mouse intestinal tissue. Bile acid experiments were conducted in vitro in Ussing chambers using 4- and 20-kDa FITC-labeled dextrans. Epithelial integrity and inflammation were assayed by histology and Western blot analysis for cyclooxygenase-2. LPS was studied in DCA-induced barrier dysfunction. Finally, we investigated in a 10-wk in vivo feeding trial in mice the barrier-disrupting effect of a diet containing 0.1% DCA. DCA disrupted epithelial integrity dose dependently at 1-3 mM, which correspond to physiological concentrations on a high-fat diet. Low-fat diet-related concentrations of DCA had no effect. In vivo, the DCA-containing diet increased intestinal permeability 1.5-fold compared with control (P = 0.016). Hematoxylin-eosin staining showed a clear disruption of the epithelial barrier by 3 mM DCA in vitro. A short-term treatment by DCA did not increase cyclooxygenase-2 content in colon preparations. UDCA did not affect barrier function itself, but it ameliorated DCA-induced barrier disruption at a 0.6 mM concentration. LPS had no significant effect on barrier function at 0.5-4.5 μg/ml concentrations. We suggest a novel mechanism for barrier dysfunction on a high-fat diet involving the effect of hydrophobic luminal bile acids.


The hyaluronate lyase of Staphylococcus aureus - a virulence factor?
The hyaluronate lyase (HL) gene of Staphylococcus aureus 8325-4 (hysA) was inactivated in vitro with the insertion of the erythromycin determinant, ermC, from plasmid pE194. The hysA : : ermC mutation was introduced into S. aureus via a temperature-sensitive shuttle vector, where it underwent homologous recombination with the wild-type (w.t.) allele. The insertion of ermC in the chromosomal hysA locus was confirmed by Southern blot hybridization and the loss of HL activity was demonstrated macroscopically by a plate assay. The importance of HL for pathogenicity was assessed by comparing the virulence of the HL(-) mutant strain to that of the w.t. in an established mouse abscess model of S. aureus infection. A significantly higher cell recovery was obtained from lesions infected with the w.t. strain compared to the lesions infected with the HL(-) strain (P =0.01). Although the lesion areas from both groups were not significantly different (P=0.9) they were of different morphology. A colorimetric assay was used to measure HL activity from culture supernatants of the S. aureus 8325-4 strains w.t., WA250 (agr) and PC1839 (sar) grown in a chemically defined medium. HL activity reached a maximum in the w.t. strain during mid-exponential phase (t=5 h) and while it showed a 16-fold decrease in the agr mutant it increased 35-fold in the sar mutant background. These results strongly suggest that HL is a virulence factor which is important in the early stages of subcutaneous infections.


[Ethical dimension of mental health care within the public health network].
To analyze the meanings of caring for people who seek assistance in mental health, from the perspective of psychologists engaged in their daily activities within public health services. An exploratory qualitative study was conducted in the city of Fortaleza, Northeastern Brazil, in 2006. The sample was composed of eight female informants, all of which were psychologists working in the state public health network. Data was obtained by means of non-directive interviews which were taped and transcribed. Categories were obtained from the discourses based on a hermeneutical approach by means of which an interpretive network was constructed. ANALISYS OF RESULTS: The interpretative network indicated that psychologists recognize their insertion in the field of public health as distinct from the professional field in which they obtained their training and, consequently, as a challenge. The predominant conceptions of care were circumscribed to the technical dimension, although other dimensions, closer to ethical concerns and to those related to respect for the "other" were also identified. In the daily routine of assistance within the public health network, care is perceived as a technical attitude. It involves control and nullification of alterity, being more closely aligned to the traditional models of biomedicine and clinical psychology. However, other practices were observed that overcome this attitude. These emerging practices assume a new configuration, oriented towards affection, dialogue between professionals and those seeking assistance and an ethical commitment forged within a political and socio-cultural perspective.


The Vacuolar Ca2+ ATPase Pump Pmc1p Is Required for Candida albicans Pathogenesis.
Calcium is a critically important secondary messenger of intracellular signal transduction in eukaryotes but must be maintained at low levels in the cytoplasm of resting cells to avoid toxicity. This is achieved by several pumps that actively transport excess cytoplasmic Ca2+ out of the cell across the plasma membrane and into other intracellular compartments. In fungi, the vacuole serves as the major storage site for excess Ca2+, with two systems actively transporting cytoplasmic calcium ions into the vacuole. The H+/Ca2+ exchanger, Vcx1p, harnesses the proton-motive force across the vacuolar membrane (generated by the V-ATPase) to drive Ca2+ transport, while the P-type ATPase Pmc1p uses ATP hydrolysis to translocate Ca2+ into the vacuole. Ca2+-dependent signaling is required for the prevalent human fungal pathogen Candida albicans to endure exposure to the azole antifungals and to cause disease within the mammalian host. The purpose of this study was to determine if the Pmc1p or Vcx1p Ca2+ pumps are required for C. albicans pathogenicity and if these pumps impact antifungal resistance. Our results indicate that Pmc1p is required by C. albicans to transition from yeast to hyphal growth, to form biofilms in vitro, and to cause disease in a mouse model of disseminated infection. Moreover, loss of Pmc1p function appears to enhance C. albicans azole tolerance in a temperature-dependent manner.IMPORTANCE Maintenance of Ca2+ homeostasis is important for fungal cells to respond to a multitude of stresses, as well as antifungal treatment, and for virulence in animal models. Here, we demonstrate that a P-type ATPase, Pmc1p, is required for Candidaalbicans to respond to a variety of stresses, affects azole susceptibility, and is required to sustain tissue invasive hyphal growth and to cause disease in a mouse model of disseminated infection. Defining the mechanisms responsible for maintaining proper Ca2+ homeostasis in this important human pathogen can ultimately provide opportunities to devise new chemotherapeutic interventions that dysregulate intracellular signaling and induce Ca2+ toxicity.


Capturing Aesthetic Experiences With Installation Art: An Empirical Assessment of Emotion, Evaluations, and Mobile Eye Tracking in Olafur Eliasson's "Baroque, Baroque!"
Installation art is one of the most important and provocative developments in the visual arts during the last half century and has become a key focus of artists and of contemporary museums. It is also seen as particularly challenging or even disliked by many viewers, and-due to its unique in situ, immersive setting-is equally regarded as difficult or even beyond the grasp of present methods in empirical aesthetic psychology. In this paper, we introduce an exploratory study with installation art, utilizing a collection of techniques to capture the eclectic, the embodied, and often the emotionally-charged viewing experience. We present results from an investigation of two pieces, both part of Olafur Eliasson's exhibition "Baroque, Baroque" held at the Belvedere museum in Vienna. These were assessed by pre- and post-viewing questionnaires focusing on emotion, meaning-making, and appraisals, in tandem with mobile eye tracking to consider viewers' attention to both installed artworks and/or to the museum environment. The data showed differences in participants' emotional states, appraisals, and visual exploration, which together paint a picture of the aesthetic reactions to the works. These differences also showed how viewers' appraisal strategies, meaning making, and physical actions facilitated relatively more or less deep engagement with, and enjoyment of, the art. The results are discussed in terms of their implications for museum studies, art education, and theory in empirical aesthetics.


Long-term outcomes of surgery followed by radiation therapy for minor salivary gland carcinomas.
Postoperative radiation therapy is often used in patients with high-risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy. Retrospective cohort study. We performed a retrospective analysis of 90 patients treated with curative intent. Median follow-up was 71 months. Fifty-eight patients (64%) had adenoid cystic carcinomas, 22 (24%) had adenocarcinomas, and 10 (11%) had mucoepidermoid cancers. Primary disease site included 39 (43%) sinonasal, 35 (39%) oral cavity, 10 (11%) oropharynx, and six (7%) others. Twenty-seven patients (30%) were treated with intensity-modulated radiation therapy. Eight local, four neck, and 24 distant relapses were detected. Local control rates at 5 and 10 years were 90% and 88%, respectively. Advanced T stage was associated with worse local control. Distant metastasis rates were 24% and 28% at 5 and 10 years, respectively. Tumor stage, histology, perineural invasion, and lymphovascular space invasion were significant predictors of distant metastasis on univariate analysis. However, on multivariate analysis only the American Joint Committee on Cancer stage was significant. Overall survival rates were 76% and 63% at 5 and 10 years, respectively. More advanced T stage and N stage correlated with worse overall survival. Tumor stage remains the best predictor for locoregional and distant disease control of minor salivary gland cancers. Postoperative radiation therapy for high-risk patients results in excellent long-term locoregional disease control. Further work is needed to improve systemic control.


A corrective emotional experience - or just a bit of exercise? The relevance of interpersonal learning in Exercise on prescription.
The objective of the present study was to examine psychological aspects of intra- and interpersonal learning for patients with Type 2 diabetes, hypertension and dyslipidemia treated with Exercise on prescription. The research design consists of a qualitative investigation of 30 patients in Denmark undergoing a community-based exercise treatment at baseline, a post-intervention investigation after four months and a follow-up one year after the start of intervention. The results demonstrated that, for the majority of the participants, interaction under group conditions contributes to maintaining the commitment to exercise. For a corrective emotional experience- a correction of an emotional situation a person could not handle in the past - to occur requires two conditions: the group and the environment must be experienced as sufficiently safe, and there must be feedback to permit reality-testing. However, existential psychological aspects such as fear of dying or the universality of suffering triggered, but could not sustain, a change in health behavior. The article concludes that behavioral change is strengthened by interaction with health personnel and with the training group. These new insights likewise demand an increased focus on the human resources of general practitioners or physiotherapists who handle the training. They should learn about their supportive role for the participants, the regressive urges of the participants and the benefits of promoting group relations.


A human p57(KIP2) transgene is not activated by passage through the maternal mouse germline.
Genomic imprinting results in expression of some autosomal genes from one parental allele only. Human chromosome 11p15, and the syntenic region on mouse distal chromosome 7, contain several imprinted genes, including p57 (KIP2) ( CDKN1C ) and IGF2. These two genes, which are separated by >700 kb, are both implicated in the pathogenesis of Beckwith-Wiedemann syndrome. We have shown previously that an Igf2/H19 transgene is expressed appropriately and can imprint at ectopic chromosomal locations. To investigate the p57 (KIP2) region, we similarly tested the imprinting and function of a 38 kb human genomic fragment containing the p57 (KIP2) gene in transgenic mice. This transgene showed appropriate tissue-specific expression and transgene copy number-dependent expression at ectopic sites. However, the levels of expression are reminiscent of that found for the paternal allele in humans (10%). There was no change in expression levels when the transgene was inherited from the maternal germline. These results suggest that the cis -elements required for enhanced expression of the maternally inherited p57 (KIP2) allele lie at a distance from the gene. This finding has important implications for the role of this gene in the human disease, in particular with respect to the translocation breakpoints identified in some patients.


Effects of a 6-Week Strength Training of the Neck Flexors and Extensors on the Head Acceleration during Headers in Soccer.
The importance of well trained and stable neck flexors and extensors as well as trunk muscles for intentional headers in soccer is increasingly discussed. The neck flexors and extensors should ensure a coupling of trunk and head at the time of ball contact to increase the physical mass hitting the ball and reduce head acceleration. The aim of the study was to analyze the influence of a 6-week strength training program (neck flexors, neck extensors) on the acceleration of the head during standing, jumping and running headers as well as after fatigue of the trunk muscles on a pendulum header. A total of 33 active male soccer players (20.3 ± 3.6 years, 1.81 ± 0.07 m, 75.5 ± 8.3 kg) participated and formed two training intervention groups (IG1: independent adult team, IG2: independent youth team) and one control group (CG: players from different teams). The training intervention consisted of three exercises for the neck flexors and extensors. The training effects were verified by means of the isometric maximum voluntary contraction (IMVC) measured by a telemetric Noraxon DTS force sensor. The head acceleration during ball contact was determined using a telemetric Noraxon DTS 3D accelerometer. There was no significant change of the IMVC over time between the groups (F=2.265, p=.121). Head acceleration was not reduced significantly for standing (IG1 0.4 ± 2.0, IG2 0.1 ± 1.4, CG -0.4 ± 1.2; F = 0.796, p = 0.460), jumping (IG1-0.7 ± 1.4, IG2-0.2 ± 0.9, CG 0.1 ± 1.2; F = 1.272, p = 0.295) and running (IG1-1.0 ± 1.9, IG2-0.2 ± 1.4, CG -0.1 ± 1.6; F = 1.050, p = 0.362) headers as well as after fatigue of the trunk musculature for post-jumping (IG1-0.2 ± 2.1, IG2-0.6 ± 1.4; CG -0.6 ± 1.3; F = 0.184, p = 0.833) and post-running (IG1-0.3 ± 1.6, IG2-0.7 ± 1.2, CG 0.0 ± 1.4; F = 0.695, p = 0.507) headers over time between IG1, IG2 and CG. A 6-week strength training of the neck flexors and neck extensors could not show the presumed preventive benefit. Both the effects of a training intervention and the consequences of an effective intervention for the acceleration of the head while heading seem to be more complex than previously assumed and presumably only come into effect in case of strong impacts.


Dimeric and trimeric derivatives of the azinomycin B chromophore show enhanced DNA binding.
To explore the utility of the azinomycin B chromophore as a platform for the development of major-groove binding small molecules, we have prepared a series of 3-methoxy-5-methylnaphthalene derivatives containing diamine, triamine, and carbohydrate linker moieties. All bis- and tris-azinomycin derivatives are intercalators that display submicromolar binding affinities for calf-thymus DNA, as revealed by viscometry measurements and fluorescent intercalator displacement (FID) assays, respectively. Although the tightest binding ligand 1d (Ka = 2.42 × 107 M-1) has similar affinities for sequence diverse polynucleotides, competition binding studies with methylated phage DNA and known major and minor groove binding small molecules suggest that the tether moiety linking the naphthalene chromophores may occupy the major groove of DNA.


The cost-effectiveness of brief intervention versus brief treatment of Screening, Brief Intervention and Referral to Treatment (SBIRT) in the United States.
To conduct a cost-effectiveness analysis (CEA) comparing the delivery of brief intervention (BI) with brief treatment (BT) within Screening, Brief Intervention and Referral to Treatment (SBIRT) programs. Quasi-experimental differences in observed baseline characteristics between BI and BT patients were adjusted using propensity score techniques. Incremental comparison of costs and health outcomes associated with BI and BT. Health-care settings in four US states participating in Substance Abuse and Mental Health Services Administration SBIRT grant programs. Ninety patients who received BT and 878 who received BI. Per-patient cost of SBIRT, patient demographics and six measures of substance use: proportion using alcohol, proportion using alcohol to intoxication, days of alcohol use, days of alcohol use to intoxication, proportion using drugs and days using drugs. BI and BT were associated with better outcomes. The cost of SBIRT was significantly higher for BT patients ($75.54 versus 16.32, 95% confidence interval, P < 0.01). BT would be cost-effective if the decision-maker had a willingness to pay of $8.90 for a 1 percentage point reduction in the probability of using any alcohol. For the other five outcomes, BT was less effective and more costly, and BI would be a better use of resources. It might be cost-effective to offer brief treatment if the goal is to abstain from alcohol. However, the higher effectiveness of brief treatment for this outcome is associated with considerable uncertainty and, because both brief intervention and brief treatment improve all outcomes, brief treatment does not appear to be a good use of resources.


Hominin life history: reconstruction and evolution.
In this review we attempt to reconstruct the evolutionary history of hominin life history from extant and fossil evidence. We utilize demographic life history theory and distinguish life history variables, traits such as weaning, age at sexual maturity, and life span, from life history-related variables such as body mass, brain growth, and dental development. The latter are either linked with, or can be used to make inferences about, life history, thus providing an opportunity for estimating life history parameters in fossil taxa. We compare the life history variables of modern great apes and identify traits that are likely to be shared by the last common ancestor of Pan-Homo and those likely to be derived in hominins. All great apes exhibit slow life histories and we infer this to be true of the last common ancestor of Pan-Homo and the stem hominin. Modern human life histories are even slower, exhibiting distinctively long post-menopausal life spans and later ages at maturity, pointing to a reduction in adult mortality since the Pan-Homo split. We suggest that lower adult mortality, distinctively short interbirth intervals, and early weaning characteristic of modern humans are derived features resulting from cooperative breeding. We evaluate the fidelity of three life history-related variables, body mass, brain growth and dental development, with the life history parameters of living great apes. We found that body mass is the best predictor of great ape life history events. Brain growth trajectories and dental development and eruption are weakly related proxies and inferences from them should be made with caution. We evaluate the evidence of life history-related variables available for extinct species and find that prior to the transitional hominins there is no evidence of any hominin taxon possessing a body size, brain size or aspects of dental development much different from what we assume to be the primitive life history pattern for the Pan-Homo clade. Data for life history-related variables among the transitional hominin grade are consistent and none agrees with a modern human pattern. Aside from mean body mass, adult brain size, crown and root formation times, and the timing and sequence of dental eruption of Homo erectus are inconsistent with that of modern humans. Homo antecessor fossil material suggests a brain size similar to that of Homo erectus s. s., and crown formation times that are not yet modern, though there is some evidence of modern human-like timing of tooth formation and eruption. The body sizes, brain sizes, and dental development of Homo heidelbergensis and Homo neanderthalensis are consistent with a modern human life history but samples are too small to be certain that they have life histories within the modern human range. As more life history-related variable information for hominin species accumulates we are discovering that they can also have distinctive life histories that do not conform to any living model. At least one extinct hominin subclade, Paranthropus, has a pattern of dental life history-related variables that most likely set it apart from the life histories of both modern humans and chimpanzees.


Birefringence in two-dimensional bulk photonic crystals applied to the construction of quarter waveplates.
We have experimentally measured the birefringence in bulk two-dimensional hexagonal photonic crystals in transparent spectral regions above and below the fundamental band gap. Data is presented for structures with different numbers of layers and two different air-filling fractions. We have used these data to design a photonic crystal quarter waveplate and provide independent experimental demonstrations of its operation.


Reprogramming of fibroblasts from older women with pelvic floor disorders alters cellular behavior associated with donor age.
We aimed to derive induced pluripotent stem cell (iPSC) lines from vaginal fibroblasts from older women with pelvic organ prolapse. We examined the effect of donor age on iPSCs and on the cells redifferentiated from these iPSCs. Vaginal fibroblasts were isolated from younger and older subjects for reprogramming. iPSCs were generated simultaneously using an excisable polycistronic lentiviral vector expressing Oct4, Klf4, Sox2, and cMyc. The pluripotent markers of iPSCs were confirmed by immunocytochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Spectral karyotyping was performed. The ability of the iPSCs to differentiate into three germ layers was confirmed by embryoid body and teratoma formation. Senescence marker (p21, p53, and Bax) expressions were determined by qRT-PCR and Western blot. The iPSCs were redifferentiated to fibroblasts and were evaluated with senescence-associated β-galactosidase (SA) activity and mitotic index using time-lapse dark-field microscopy. iPSCs derived from both the younger and older subjects expressed pluripotency markers and showed normal karyotype and positive teratoma assays. There was no significant difference in expression of senescence and apoptosis markers (p21, p53, and Bax) in iPSCs derived from the younger subject compared with the older subject. Furthermore, fibroblasts redifferentiated from these iPSCs did not differ in SA activity or mitotic index. We report successful derivation of iPSCs from women with pelvic organ prolapse. Older age did not interfere with successful reprogramming. Donor age differences were not observed in these iPSCs using standard senescence markers, and donor age did not appear to affect cell mitotic activity in fibroblasts redifferentiated from iPSCs.


Relationship between gingival bleeding and anaerobic periodontal infection assessed by BANA (N-Benzoyl-DL-Arginine-β-Napthylamide) assay.
Since periodontal diseases are primarily inflammatory in nature, the ability to detect inflammatory lesions in gingival tissue is essential for the diagnosis and monitoring of changes in gingival status. Gingival bleeding has been used as a reliable and objective clinical parameter not only for the evaluation of inflammatory conditions of periodontium, but also in the detection of its activity and progression. The gingival bleeding index (Loe) is based on the presence or absence of gingival bleeding, thereby provides a means of converting observed clinical data into statistical analysis. Periodontitis is widely regarded as a bacterial infection mainly mediated by subgingival plaque. N-benzoyl-DL-arginine β-naphthylamide (BANA) test is a simple chair side test used to detect, the specific enzymatic activity of microorganisms involved in periodontal disease. The objective of this study is to compare the clinical evaluation of the gingival index (GI) with the enzymatic BANA test. A total of 320 sites were selected from 20 patients with generalized chronic periodontitis, based on the presence are absence of gingival bleeding according to GI of Loe. Sub-gingival plaque samples were collected using a sterile curette and the BANA test was performed. The distribution of GI and the intensity of the BANA test for the 320 sites analyzed during the initial examination of patients, with significance determined by the Chi-square test. The results were statistically significant at P ≤ 0.000. There was a direct relationship between positive BANA test results and GI scores, clearly demonstrating the validity of gingival bleeding as a significant diagnostic parameter. The validity of gingival bleeding as a clinical tool not only for the diagnosis of periodontal disease, but also in the detection of its activity and progression could be established by correlating the GI scores (which is based on the presence or absence of bleeding) with the primary etiologic factors (putative periodontal pathogens) assessed by BANA assay.


Synthesis and characterization of a highly strained donor-acceptor nanohoop.
A highly-strained, nitrogen-doped cycloparaphenylene (CPP), aza[6]CPP, was synthesized and then converted to a donor-acceptor nanohoop, N-methylaza[6]CPP, via alkylation of the nitrogen center. The energy levels of the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) for both molecules were then probed by cyclic voltammetry (CV), which revealed that the donor-acceptor nanohoop had a significantly lower LUMO energy relative to [6]CPP and aza[6]CPP. Density functional theory (DFT) revealed that the donor-acceptor nanohoop underwent a redistribution of the frontier molecular orbital (FMO) density such that a significant portion of the LUMO density resided upon the electron-deficient nitrogen-containing ring. This localization of LUMO density caused a large lowering in the LUMO energy of nearly a full electron volt, while the HOMO energy was less affected due to a large centralization of the FMO on the electron-rich phenylene backbone. This ultimately resulted in a net lowering of the HOMO-LUMO energy gap which was observed both experimentally and computationally. In addition, N-methylaza[6]CPP has a significantly lower energy LUMO than N-methylaza[8]CPP, illustrating that the FMO levels of donor-acceptor nanohoops can be tuned by adjusting the hoop size.


An immunofluorescent analysis of lectin binding to normal and regenerating skeletal muscle of rat.
Ten different fluorescein-conjugated lectins of various known sugar specificities were used to study cell surface glycoconjugates of normal and regenerating rat skeletal muscle. In normal muscle, Canavalia ensiformis agglutinin, Triticum vulgaris agglutinin (wheat germ agglutinin, WGA), Ricinus communis agglutinin-I, and Maclura pomifera agglutinin bound strongly to the endomysial region of the myofibers. No binding was observed in the cytoplasm of the myofibers. Other lectins (Dolichos biflorus agglutinin, Griffonia simplifolia agglutinin I and II, Ulex europaeus agglutinin, Arachis hypogaea agglutinin, Glycine max agglutinin) bound very poorly or not at all in the normal muscle. Skeletal muscle degeneration and regeneration was induced by autotransplantation of the extensor digitorum longus muscle. In the transplanted muscles, the endomysial lectin binding of the degenerating myofibers became weak and lacked continuity, indicating a breakdown of the endomysium. Of all the lectins tested, only WGA revealed intense binding in the myogenic zone of regenerating muscle. As the regeneration progressed, this WGA binding became restricted to the new endomysium. In completely regenerated muscle, binding of all lectins was similar to that seen in normal muscle. The specific binding of WGA to the myogenic zone may be important in identifying factors or glycoconjugates, which constitute a favorable environment for skeletal muscle regeneration.


The genetics of Graves' disease.
Graves' disease is a complex autoimmune disorder in which several genetic susceptibility loci and environmental factors are likely to contribute to the development of disease. HLA and the CTLA-4 gene region have been established as susceptibility loci, although the magnitude of their contributions seems to vary between data sets and geographic populations. Genome-wide searches are beginning to identify new loci, including GD-1, GD-2, and GD-3, although these loci have only been found in one data set. Additional loci are likely to be identified via a combination of genome-wide linkage analysis and allelic association analysis of candidate genes.


Evolution of short cognitive test performance in stroke patients with vascular cognitive impairment and vascular dementia: Baseline evaluation and follow-up.
There is limited evidence about the progression of cognitive performance during the post-stroke stage. To assess the evolution of cognitive performance in stroke patients without vascular cognitive impairment (VCI), patients with vascular mild cognitive impairment (MCI), and patients with vascular dementia (VD). A prospective cohort of stroke outpatients from two secondary medical centers in Lima, Peru was studied. We performed standardized evaluations at definitive diagnosis (baseline evaluation), and control follow-ups at 6 and 12 months, including a battery of short cognitive tests: Clinical Dementia Rating (CDR), Addenbrooke's Cognitive Examination (ACE), and INECO Frontal Screening (IFS). 152 outpatients completed the follow-up, showing progressive increase in mean score on the CDR(0.34 to 0.46), contrary to the pattern observed on the ACE and IFS (78.18 to 76.48 and 23.63 to 22.24). The box plot for the CDR test showed that VCI patients had progressive worsening (0.79 to 0.16). Conversely, this trend was not observed in subjects without VCI. The box plot for the ACE and IFS showed that, for the majority of the differentiated stroke types, both non-VCI and VCI patients had progressive worsening. According to both ACE and IFS results during a 1-year follow-up, the cognitive performance of stroke patients worsened, a trend which was particularly consistent in infarction-type stroke patients.


Temperature stability of a dichroic atomic vapor laser lock.
We have investigated the temperature stability of the dichroic atomic vapor laser lock laser frequency lock method. We find that, in general, the lock exhibits significant temperature sensitivity, leading to laser frequency drifts as large as tens of MHz/K. However, for certain configurations of the optical elements of the system, this temperature dependence is reduced to below 1 MHz/K. These temperature-independent points can be found across a broad range of frequencies. We present a numerical model that reproduces the general behavior of the system.


Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.
Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital. Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families. This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema.


Chaperone Hsp27, a novel subunit of AUF1 protein complexes, functions in AU-rich element-mediated mRNA decay.
Controlled, transient cytokine production by monocytes depends heavily upon rapid mRNA degradation, conferred by 3' untranslated region-localized AU-rich elements (AREs) that associate with RNA-binding proteins. The ARE-binding protein AUF1 forms a complex with cap-dependent translation initiation factors and heat shock proteins to attract the mRNA degradation machinery. We refer to this protein assembly as the AUF1- and signal transduction-regulated complex, ASTRC. Rapid degradation of ARE-bearing mRNAs (ARE-mRNAs) requires ubiquitination of AUF1 and its destruction by proteasomes. Activation of monocytes by adhesion to capillary endothelium at sites of tissue damage and subsequent proinflammatory cytokine induction are prominent features of inflammation, and ARE-mRNA stabilization plays a critical role in the induction process. Here, we demonstrate activation-induced subunit rearrangements within ASTRC and identify chaperone Hsp27 as a novel subunit that is itself an ARE-binding protein essential for rapid ARE-mRNA degradation. As Hsp27 has well-characterized roles in protein ubiquitination as well as in adhesion-induced cytoskeletal remodeling and cell motility, its association with ASTRC may provide a sensing mechanism to couple proinflammatory cytokine induction with monocyte adhesion and motility.


Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease.
DNA damage can cause (and result from) oxidative stress and mitochondrial impairment, both of which are implicated in the pathogenesis of Parkinson's disease (PD). We therefore examined the role of mitochondrial DNA (mtDNA) damage in human postmortem brain tissue and in in vivo and in vitro models of PD, using a newly adapted histochemical assay for abasic sites and a quantitative polymerase chain reaction (QPCR)-based assay. We identified the molecular identity of mtDNA damage to be apurinic/apyrimidinic (abasic) sites in substantia nigra dopamine neurons, but not in cortical neurons from postmortem PD specimens. To model the systemic mitochondrial impairment of PD, rats were exposed to the pesticide rotenone. After rotenone treatment that does not cause neurodegeneration, abasic sites were visualized in nigral neurons, but not in cortex. Using a QPCR-based assay, a single rotenone dose induced mtDNA damage in midbrain neurons, but not in cortical neurons; similar results were obtained in vitro in cultured neurons. Importantly, these results indicate that mtDNA damage is detectable prior to any signs of degeneration - and is produced selectively in midbrain neurons under conditions of mitochondrial impairment. The selective vulnerability of midbrain neurons to mtDNA damage was not due to differential effects of rotenone on complex I since rotenone suppressed respiration equally in midbrain and cortical neurons. However, in response to complex I inhibition, midbrain neurons produced more mitochondrial H2O2 than cortical neurons. We report selective mtDNA damage as a molecular marker of vulnerable nigral neurons in PD and suggest that this may result from intrinsic differences in how these neurons respond to complex I defects. Further, the persistence of abasic sites suggests an ineffective base excision repair response in PD.


Expression of vesicular glutamate transporter 1 immunoreactivity in peripheral and central endings of trigeminal mesencephalic nucleus neurons in the rat.
The major neuronal components of the trigeminal mesencephalic nucleus (Vmes) are primary afferent neurons that convey proprioceptive information from the cranioorofacial regions. In the present study, we examined expression of vesicular glutamate transporters (VGLUTs), VGLUT1 and VGLUT2, in the primary afferent neurons of the Vmes (Vmes neurons) in neonatal and adult rats. VGLUT1 immunoreactivity was detected in the cell bodies of Vmes neurons in neonatal rats younger than 11 days old, but not in older rats. However, in situ hybridization signals for VGLUT1 mRNA were detected in both neonatal and adult rats. No VGLUT2 immunoreactivity was detected in Vmes neurons of neonatal or adult rats. VGLUT1 immunoreactivity was also seen in the peripheral sensory endings on the equatorial regions of intrafusal fibers of muscle spindles in the masseter muscles in both neonatal and adult rats. In adult rats injected with cholera toxin B subunit (CTb) into the masseter nerve, central axon terminals of Vmes neurons were identified on masseter motoneurons within the trigeminal motor nucleus (Vm) by transganglionically and retrogradely transported CTb. VGLUT1-immunopositive axon terminals in close apposition to CTb-labeled Vm motoneurons were also detected by dual-immunofluorescence histochemistry for VGLUT1/CTb. Electron microscopy after dual immunolabeling for VGLUT1/CTb by the VGLUT1/immunoperoxidase and CTb/immunogold-silver methods further revealed synaptic contact of VGLUT1- and CTb-immunopositive axon terminals upon CTb-labeled neuronal profiles within the Vm. These data indicate that VGLUT1 is expressed in both the central axon terminals and the peripheral sensory endings of Vmes neurons, although no VGLUT1 immunoreactivity was detectable in the cell bodies of Vmes neurons in adult rats.


Influence of Admission Blood Glucose in Predicting Outcome in Patients With Spontaneous Intracerebral Hematoma.
Background and Aims: Hyperglycemia or elevated blood glucose levels have been associated with poor outcomes in patients with ischemic stroke yet control of hyperglycemia has not resulted in good outcomes. High admission blood glucose (ABG) values have been mitigated by other poor prognosticators like large hematoma volume, intraventricular extension (IVE) of hematoma and poor GCS. The aim of this study was to evaluate the effects of blood glucose levels at admission, on mortality and functional outcomes at discharge and 3 months follow up. Methods: This was a retrospective observational study conducted at a tertiary care. Patients with spontaneous SICH were enrolled from a prospective SICH register maintained at our hospital. Blood glucose values were recorded on admission. Patients with traumatic hematomas, vascular malformations, aneurysms, and coagulation abnormalities were excluded from our study. Results: A total of 510 patients were included in the study. We dichotomised our cohort into two groups, group A with ABG>160 mg/dl and group B with ABG<160 mg/dl. Mean blood glucose levels in these two groups were 220.73 mg/dl and 124.37 mg/dl respectively, with group A having twice the mortality. mRS at discharge and 3 months was better in Group B (p ≤ 0.001) as compared to Group A. Age, GCS, volume of hematoma, ABG, IVE and Hydrocephalus were significant predictors of mortality and poor outcome on univariate analysis with a p < 0.05. The relationship between ABG and mortality (P = 0.249, 95% CI 0.948-1.006) and outcome (P = 0.538, 95% CI 0.997-1.005) failed to reach statistical significance on multivariate logistic regression. Age, Volume of hematoma and GCS were stronger predictors of mortality and morbidity. Conclusion: Admission blood glucose levels was not an independent predictor of mortality in our study when adjusted with age, GCS, and hematoma volume. The effect of high ABG on SICH outcome is probably multifactorial and warrants further research.


Ghrelin secretion in humans - a role for the vagus nerve?
Ghrelin, an orexigenic peptide, is secreted from endocrine cells in the gastric mucosa. Circulating levels rise in the preprandial phase, suggesting an anticipatory or cephalic phase of release, and decline in the postprandial phase, suggesting either the loss of a stimulatory factor or inhibition by factors released when nutrients enter the intestine. We hypothesized that vagal signals are not required for the (i) preprandial increase or (ii) postprandial suppression of ghrelin levels. Further, we wanted to investigate the hypothesis that (iii) glucagon-like peptide-1 might be implicated in the postprandial decline in ghrelin levels. We measured ghrelin levels in plasma from sham-feeding and meal studies carried out in vagotomized individuals and controls, and from a GLP-1 infusion study carried out in fasting healthy young individuals. We find that (i) ghrelin secretion is unchanged during indirect vagal stimulation as elicited by modified sham-feeding in vagotomized individuals and matched controls, (ii) ghrelin secretion is similarly suppressed after meal ingestion in vagotomized individuals and controls, and (iii) infusion of GLP-1 does not lower ghrelin levels. We conclude that for postprandial suppression of circulating ghrelin levels, a circulating factor (but not GLP-1) or short (duodeno-gastric) reflexes seem to be implicated.


Photoelectrically induced free carrier absorption and amplification of light in cadmium sulfide.
It has been demonstrated that it is possible to control the intensity of visible and infrared light being transmitted through cadmium sulfide by controlled variations in photoelectrically induced free charge carrier densities which absorb the transmitted light. The free carrier optical absorption coefficient is extended to fit the case of photoelectrically induced free carrier absorption in semiconductors. This results in a theoretical modulation parameter which predicts the extent to which light transmission can be controlled by induced free carrier absorption. An experimental technique is presented which demonstrates that photoelectrically induced variations in the density of free carriers in CdS can indeed bring about a consequential control of the light transmission. Complete control over the transmission, in addition to light amplification by stimulated absorption, is demonstrated in CdS for both infrared and visible light between 0.6 micro and 4.0 micro. Theoretically computed and experimentally observed values of modulation are in fair agreement, considering the limitation of the theory and the nature of the solid. The observed transmitted wavelength dependence in CdS is discussed on the basis of both the free carrier absorption theory and various photoconductivity mechanisms, and it is shown to be reasonably consistent with modern theory.


Alpha 1-adrenoceptor subtypes linked to different mechanisms for increasing intracellular Ca2+ in smooth muscle.
Receptor-mediated increases in intracellular Ca2+ levels can be caused by release from intracellular organelles and/or influx from the extracellular fluid. Noradrenaline (NA) released from sympathetic nerves acts on alpha 1-adrenoceptors to increase cytosolic Ca2+ and promote smooth muscle contraction. In many cells activation of alpha 1-adrenoceptors causes formation of inositol 1,4,5-trisphosphate which promotes Ca2+ release from intracellular stores. The mechanism by which receptor activation opens cell surface Ca2+ channels is not known, although in some cases it may be secondary to formation of inositol phosphates or release of stored intracellular Ca2+ (ref. 3). However, alpha 1-adrenoceptors have recently been shown to have different pharmacological properties in different tissues, and it has been proposed that different alpha 1-adrenoceptor subtypes may control mobilization of intracellular Ca2+ and gating of extracellular Ca2+ influx. We here report evidence for two subtypes of alpha 1-adrenoceptors which cause contractile responses through different molecular mechanisms. One subtype stimulates inositol phosphate (InsP) formation and causes contractions which are independent of extracellular Ca2+, and the other does not stimulate inositol phosphate formation and causes contractions which require the influx of extracellular Ca2+ through dihydropyridine-sensitive channels. These results suggest that neurotransmitters and hormones may control Ca2+ release from intracellular stores and influx through voltage-gated membrane channels through distinct receptor subtypes.


The conserved 18,000-molecular-weight outer membrane protein of Haemophilus ducreyi has homology to PAL.
Haemophilus ducreyi expresses an 18,000-molecular-weight outer membrane protein that contains a conserved surface-exposed epitope recognized by monoclonal antibody 3B9. Monoclonal antibody 3B9 cross-reacts with proteins of similar molecular weight found in many Haemophilus sp. strains, including P6, a candidate vaccine for Haemophilus influenzae. The gene encoding the 18,000-molecular-weight outer membrane protein was identified by screening a lambdagt11 genomic library with 3B9. The coding sequence of the gene was localized to a 471-bp open reading frame, designated pal (peptidoglycan-associated lipoprotein). Translation of pal predicted a mature polypeptide with a molecular weight of 15,000 that had extensive homology with P6 and Escherichia coli PAL. The predicted signal peptide had features characteristic of a prokaryotic lipoprotein, and processing of PAL was sensitive to globomycin in H. ducreyi. The sequences encoding mature H. ducreyi PAL were subcloned into the vector pRSET B and expressed as a polyhistidine-containing fusion protein that bound 3B9. In Western blot (immunoblot) analysis, serum samples obtained from healthy subjects and patients with chancroid or other genital ulcer diseases contained antibodies to purified PAL. Antibodies that bound to PAL were removed by absorption with a lysate of Haemophilus sp. antigens, suggesting that patients with chancroid do not develop an H. ducreyi-specific antibody response to PAL.


Coevolution of active vision and feature selection.
We show that complex visual tasks, such as position- and size-invariant shape recognition and navigation in the environment, can be tackled with simple architectures generated by a coevolutionary process of active vision and feature selection. Behavioral machines equipped with primitive vision systems and direct pathways between visual and motor neurons are evolved while they freely interact with their environments. We describe the application of this methodology in three sets of experiments, namely, shape discrimination, car driving, and robot navigation. We show that these systems develop sensitivity to a number of oriented, retinotopic, visual-feature-oriented edges, corners, height, and a behavioral repertoire to locate, bring, and keep these features in sensitive regions of the vision system, resembling strategies observed in simple insects.


Osteology of Priocharax and remarkable developmental truncation in a miniature Amazonian fish (Teleostei: Characiformes: Characidae).
Establishing phylogenetic relationships of miniature fishes is challenging in taxa with developmental truncation. Within the Characiformes, developmental truncation appears to be relatively rare, with the Neotropical genus Priocharax being an example. Priocharax includes three miniature species among the smallest of the order and has been hypothesized to belong to the Heterocharacinae. The pronounced reduction in its skeleton, however, prevented a clearer evaluation of its relationships. The present detailed osteological study was designed to address this question and revealed that 21 bones are absent and nine other skeletal structures are simplified in Priocharax when compared to other characids. Comparison of the skeleton of adult Priocharax with early developmental stages of other characids demonstrated that most of the absences and simplifications can be interpreted as developmental truncations. The most striking developmental truncations are in the pectoral girdle, in which the endoskeleton remains entirely cartilaginous. Other interesting truncations are in the ethmoid region of the skull, infraorbital series, and Weberian apparatus, in which the claustrum is absent. Our study also revealed some unusual sexual dimorphisms in the pelvic girdle. Two cladistic analyses were performed to assess the relationships of Priocharax within the Heterocharacinae. The first consisted of a traditional analysis in which all absences and reductions of Priocharax were coded in the same way as in the remaining taxa. This resulted in three equally most parsimonious topologies, all of which have Priocharax as the most basal taxon of the Heterocharacinae. The second analysis incorporated ontogenetic information, and most absences and reductions of Priocharax were reinterpreted as apomorphic conditions and thus, coded differently from similar conditions in outgroups. This resulted in a single phylogenetic hypothesis with Priocharax and Gnathocharax as sister groups based on seven synapomorphies. Our approach demonstrates the importance of developmental studies to better understand morphological evolution of miniaturized, truncated taxa, and to generate hypotheses of their relationships.


Does individual risk moderate the effect of contextual-level protective factors? A latent class analysis of substance use.
The current study investigated how individual risk factors interact with social contextual-level protective factors to predict problematic substance use among a sample of 12th-grade students (n = 8,879, 53% female). Results suggested six latent classes of substance use: (1) Non-Users; (2) Alcohol Experimenters; (3) Alcohol, Tobacco, and Other Drug (ATOD) Experimenters; (4) Current Smokers; (5) Binge Drinkers; and (6) Heavy Users. Binary logistic regression models provided evidence that individual risk, family, school, and community protective factors were associated with membership in the substance use latent classes. However, the significance of interaction terms suggested that these protective influences differed according to the level of individual risk. Adolescents with high levels of individual risk benefited less from a positive family or neighborhood context than adolescents with low levels of individual risk. These findings suggest that the individual risk factors may undermine the protective effect of parental supervision, discipline, and other family factors, as well as protective aspects of cohesive neighborhoods, among these adolescents. Multi-component and adaptive intervention efforts that account for different levels of ATOD use involvement, as well as distinct profiles of risk and protection, are likely to be most effective in preventing problematic substance use.


Clonal clusters and virulence factors of methicillin-resistant Staphylococcus Aureus: Evidence for community-acquired methicillin-resistant Staphylococcus Aureus infiltration into hospital settings in Chennai, South India.
Staphylococcus aureus is one of the major pathogens of nosocomial infections as wells as community-acquired (CA) infections worldwide. So far, large-scale comprehensive molecular and epidemiological characterisation of S. aureus from very diverse settings has not been carried out in India. The objective of this study is to evaluate the molecular, epidemiological and virulence characteristics of S. aureus in both community and hospital settings in Chennai, southern India. S. aureus isolates were obtained from four different groups (a) healthy individuals from closed community settings, (b) inpatients from hospitals, (c) outpatients from hospitals, representing isolates of hospital-community interface and (d) HIV-infected patients to define isolates associated with the immunocompromised. Antibiotic susceptibility testing, multiplex polymerase chain reactions for detection of virulence and resistance determinants, molecular typing including Staphylococcal cassette chromosome mec (SCCmec) and agr typing, were carried out. Sequencing-based typing was done using spa and multilocus sequence typing (MLST) methods. Clonal complexes (CC) of hospital and CA methicillin-resistant S. aureus (MRSA) were identified and compared for virulence and resistance. A total of 769 isolates of S. aureus isolates were studied. The prevalence of MRSA was found to be 7.17%, 81.67%, 58.33% and 22.85% for groups a, b, c and d, respectively. Of the four SCCmec types (I, III, IV and V) detected, SCCmec V was found to be predominant. Panton-Valentine leucocidin toxin genes were detected among MRSA isolates harbouring SCCmec IV and V. A total of 78 spa types were detected, t657 being the most prevalent. 13 MLST types belonging to 9 CC were detected. CC1 (ST-772, ST-1) and CC8 (ST238, ST368 and ST1208) were found to be predominant among MRSA. CA-MRSA isolates with SCCmec IV and V were isolated from all study groups including hospitalised patients and were found to be similar by molecular tools. This shows that CA MRSA has probably infiltrated into the hospital settings.


High efficient multisites genome editing in allotetraploid cotton (Gossypium hirsutum) using CRISPR/Cas9 system.
Gossypium hirsutum is an allotetraploid with a complex genome. Most genes have multiple copies that belong to At and Dt subgenomes. Sequence similarity is also very high between gene homologues. To efficiently achieve site/gene-specific mutation is quite needed. Due to its high efficiency and robustness, the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system has exerted broad site-specific genome editing from prokaryotes to eukaryotes. In this study, we utilized a CRISPR/Cas9 system to generate two sgRNAs in a single vector to conduct multiple sites genome editing in allotetraploid cotton. An exogenously transformed gene Discosoma red fluorescent protein2(DsRed2) and an endogenous gene GhCLA1 were chosen as targets. The DsRed2-edited plants in T0 generation reverted its traits to wild type, with vanished red fluorescence the whole plants. Besides, the mutated phenotype and genotype were inherited to their T1 progenies. For the endogenous gene GhCLA1, 75% of regenerated plants exhibited albino phenotype with obvious nucleotides and DNA fragments deletion. The efficiency of gene editing at each target site is 66.7-100%. The mutation genotype was checked for both genes with Sanger sequencing. Barcode-based high-throughput sequencing, which could be highly efficient for genotyping to a population of mutants, was conducted in GhCLA1-edited T0 plants and it matched well with Sanger sequencing results. No off-target editing was detected at the potential off-target sites. These results prove that the CRISPR/Cas9 system is highly efficient and reliable for allotetraploid cotton genome editing.


Neurobiology of value integration: when value impacts valuation.
Everyday choice options have advantages (positive values) and disadvantages (negative values) that need to be integrated into an overall subjective value. For decades, economic models have assumed that when a person evaluates a choice option, different values contribute independently to the overall subjective value of the option. However, human choice behavior often violates this assumption, suggesting interactions between values. To investigate how qualitatively different advantages and disadvantages are integrated into an overall subjective value, we measured the brain activity of human subjects using fMRI while they were accepting or rejecting choice options that were combinations of monetary reward and physical pain. We compared different subjective value models on behavioral and neural data. These models all made similar predictions of choice behavior, suggesting that behavioral data alone are not sufficient to uncover the underlying integration mechanism. Strikingly, a direct model comparison on brain data decisively demonstrated that interactive value integration (where values interact and affect overall valuation) predicts neural activity in value-sensitive brain regions significantly better than the independent mechanism. Furthermore, effective connectivity analyses revealed that value-dependent changes in valuation are associated with modulations in subgenual anterior cingulate cortex-amygdala coupling. These results provide novel insights into the neurobiological underpinnings of human decision making involving the integration of different values.


Optically stimulated luminescence (OSL) of tooth enamel and its potential use in post-radiation exposure triage.
Optically stimulated luminescence (OSL) properties of dental enamel are discussed with a view to the development of an in vivo dose assessment technique for medical triage following a radiological/nuclear accident or terrorist event. In the OSL technique, past radiation exposure is assessed by stimulating the sample with light of one wavelength and monitoring the luminescence at another wavelength, under the assumption that the luminescence originates from the recombination of radiation-induced charges trapped at metastable defects in the enamel and that the intensity of the luminescence signal is in proportion to the absorbed radiation dose. Several primary findings emerged from this research: (a) sensitivities varied considerably between different teeth and also between fragments of the same tooth, (b) OSL signals were found to decay rapidly during the first 12 h after irradiation and more slowly afterward, (c) the fading rate of the luminescence signal varied between fragments, and (d) blue light stimulation yields greater sensitivity than infra-red stimulation, while the OSL signal obtained with a high-intensity pulsed green-light laser was found not to be correlated with the radiation dose. Significant challenges remain to developing a practical in vivo technique, including the development of calibration procedures and lowering minimum detectable doses.


ER-60 (PDIA3) is highly expressed in a newly established serous ovarian cancer cell line, YDOV-139.
Characterization of a newly established serous ovarian cancer cell line, YDOV-139 was performed and ER-60 (PDIA3), which was highly expressed in YDOV-139, was evaluated as novel biomarker for ovarian cancer. The YDOV-139 cell line was established using ascites samples from a 67-year-old Korean woman with recurrent ovarian cancer, and was characterized with respect to various biological and genetic features. Gene expression profiles were analyzed using cDNA microarrays, and proteomic evaluation was performed by two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption ionization-time of flight peptide mass fingerprinting (MALDI-TOF/PMF). Four candidate markers that were strongly up-regulated in YDOV-139 were validated by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC). The epithelial-like characteristics of YDOV-139 were evident from morphologic studies, and the average population doubling time was 120 h. When transplanted into nude mice, YDOV-139 cells successfully induced tumor masses in all three animals. Chemosensitivity tests showed that gemcitabine had the highest chemosensitivity index against YDOV-139 cells. HLA typing revealed A*24/A*31, B*07/B*35, Cw03*(09)/w*07, and DRB1*01/DRB1*15 alleles. Compared with human ovarian surface epithelial (HOSE) cells, 2,520 genes and 23 protein spots were differentially expressed in YDOV-139. Validation by real-time PCR showed that mRNA expression of LCN2, MDK, SLCO4A1, and ER-60 (PDIA3) were strongly elevated in ovarian cancers. In IHC analysis, ER-60 (PDIA3) was significantly overexpressed in both borderline tumors and invasive ovarian cancers (P<0.001). The molecular characteristics of YDOV-139 may have implications for future ovarian cancer research and ER-60 (PDIA3) should be investigated further as a potential biomarker of ovarian cancer.


Rethinking the environment as a domain of nursing knowledge.
Nurses frequently care for individuals whose problems originate from the environment. Yet the environmental paradigm in nursing is client-oriented and psychosocial and does not adequately explain these conditions. Nursing theory and research in the environmental domain are explored in this article and found to be focused within this limited paradigm. Models and theories from other disciplines and upstream nursing approaches that address multidimensional environmental characteristics are discussed in terms of providing direction for making a paradigm shift leading to a revolution in nursing's environmental consciousness.


Multiscale information storage of linear long-range correlated stochastic processes.
Information storage, reflecting the capability of a dynamical system to keep predictable information during its evolution over time, is a key element of intrinsic distributed computation, useful for the description of the dynamical complexity of several physical and biological processes. Here we introduce a parametric approach which allows one to compute information storage across multiple timescales in stochastic processes displaying both short-term dynamics and long-range correlations (LRC). Our analysis is performed in the popular framework of multiscale entropy, whereby a time series is first "coarse grained" at the chosen timescale through low-pass filtering and downsampling, and then its complexity is evaluated in terms of conditional entropy. Within this framework, our approach makes use of linear fractionally integrated autoregressive (ARFI) models to derive analytical expressions for the information storage computed at multiple timescales. Specifically, we exploit state space models to provide the representation of lowpass filtered and downsampled ARFI processes, from which information storage is computed at any given timescale relating the process variance to the prediction error variance. This enhances the practical usability of multiscale information storage, as it enables a computationally reliable quantification of a complexity measure which incorporates the effects of LRC together with that of short-term dynamics. The proposed measure is first assessed in simulated ARFI processes reproducing different types of autoregressive dynamics and different degrees of LRC, studying both the theoretical values and the finite sample performance. We find that LRC alter substantially the complexity of ARFI processes even at short timescales, and that reliable estimation of complexity can be achieved at longer timescales only when LRC are properly modeled. Then, we assess multiscale information storage in physiological time series measured in humans during resting state and postural stress, revealing unprecedented responses to stress of the complexity of heart period and systolic arterial pressure variability, which are related to the different role played by LRC in the two conditions.


Combined transarterial chemoembolization and arterial administration of Bletilla striata in treatment of liver tumor in rats.
To evaluate and compare the effect of combined transarterial chemoembolization (TACE) and arterial administration of Bletilla striata (a Chinese traditional medicine against liver tumor) versus TACE alone for the treatment of hepatocellular carcinoma (HCC) in ACI rats. Subcapsular implantation of a solid Morris hepatoma 3 924A (2 mm3) in the liver was carried out in 30 male ACI rats. Tumor volume (V1) was measured by magnetic resonance imaging (MRI) on day 13 after implantation. The following different agents of interventional treatment were injected after retrograde catheterization via gastroduodenal artery (on day 14), namely, (A) TACE (0.1 mg mitomycin + 0.1 ml Lipiodol) + Bletilla striata (1.0 mg) (n=10); (B) TACE + Bletilla striata (1.0 mg) + ligation of hepatic artery (n=10), (C) TACE alone (control group, n=10). Tumor volume (V2) was assessed by MRI (on day 13 after treatment) and the tumor growth ratio (V2/V1) was calculated. The mean tumor volume before (V1) and after (V2) treatment was 0.0355 cm3 and 0.2248 cm3 in group A, 0.0374 cm3 and 0.0573 cm3 in group B, 0.0380 cm3 and 0.3674 cm3 in group C, respectively. The mean ratio (V2/V1) was 6.2791 in group A, 1.5324 in group B and 9.1382 in group C. Compared with the control group (group C), group B showed significant inhibition of tumor growth (P<0.01), while group A did not (P>0.05). None of the animals died during implantation or in the postoperative period. Combination of TACE and arterial administration of Bletilla striata plus ligation of hepatic artery is more effective than TACE alone in the treatment of HCC in rats.


Alkaloid variation in New Zealand kōwhai, Sophora species.
Alkaloid contents of leaf and seed samples of eight species of Sophora native to New Zealand, plus Sophora cassioides from Chile are reported. Fifty-six leaf and forty-two seed samples were analysed for alkaloid content by proton nuclear magnetic resonance spectroscopy, which showed major alkaloids as cytisine, N-methyl cytisine and matrine. GC analyses quantified these and identified further alkaloid components. The alkaloids identified were cytisine, sparteine, and matrine-types common to Sophora from other regions of the world. Cytisine, N-methyl cytisine, and matrine were generally the most abundant alkaloids across all species with seeds containing the highest concentrations of alkaloids. However, there was no clear taxonomic grouping based on alkaloid composition. A quantitative analysis of various parts of two Sophora microphylla trees showed that the seeds were the richest source of alkaloids (total 0.4-0.5% DM), followed by leaf and twig (0.1-0.3%) and then bark (0.04-0.06%), with only low amounts (<0.02%) found in the roots. This study represents the most comprehensive phytochemical investigation of New Zealand Sophora species to date and presents data for three species of Sophora for which no prior chemistry has been reported.


Portuguese migration to the Canary Islands: an analysis based on surnames.
As a part of a wider analysis of population and genetic exchange between Spain and Portugal, the long-term pattern of Portuguese immigration to the Canary Islands was studied by means of the frequency of Portuguese surnames. A database of 1,995,833 individuals was obtained from the Spanish National Statistics Institute (2006). Among the 826 most frequent surnames to appear, 79 surnames of Portuguese origin were selected. The distribution of these surnames by municipalities and islands, the Fisher index of diversity, and the Lasker inter-population relationship coefficients R(ij) were considered. These coefficients were inter-correlated and correlated with other variables that could have influenced the distribution of surnames. From the observed distribution of the frequency of surnames, a non-random migration pattern conditioned by economic factors was found. The greatest diversity of surnames existed in cane cultivating areas after the first arrival of Portuguese immigrants. A later dispersion of surnames among islands was correlated with the inter-island geographic distances. In some islands the arrival of new immigrants continued due to their strategic location within the Canary archipelago. The Canary Islands reveal a high frequency and diversity of Portuguese surnames. The results also prove a heterogeneous distribution of these surnames throughout the archipelago. In contrast to the Portuguese archipelagos, some Canary localities have received immigrants continuously because of their economic importance in sugar cane cultivation and strategic geographic location on the maritime routes to Africa and America.


Activated prorenin as a therapeutic target for diabetic nephropathy.
High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between these factors has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in the kidneys include the mesangium and podocytes. The binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of the conversion of prorenin to the active form of prorenin through a conformational change, and the angiotensin II-independent, (pro)renin-receptor-dependent intracellular mitogen-activated protein kinase pathway. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes, the handle region peptide, which binds to the receptor and competitively inhibits prorenin from binding to the receptor, was administered to rats with streptozotocin-induced type I diabetes and to a model of type II diabetes, db/db mice. The handle region peptide significantly inhibited the development of end-organ damage in these diabetic animals, and had a greater benefit than angiotensin-converting enzyme inhibitors in diabetic angiotensin II-type 1a-receptor-deficient mice. In addition, the infusion of the handle region peptide in animals with streptozotocin-induced type I diabetes significantly regressed the nephropathy that had already occurred. These results suggest that prorenin and the (pro)renin receptor play a pivotal role in the pathophysiology of diabetic nephropathy. Receptor-bound prorenin may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in patients with diabetes.


Staphylococcus aureus mutants lacking the LytR-CpsA-Psr family of enzymes release cell wall teichoic acids into the extracellular medium.
The LytR-CpsA-Psr (LCP) proteins are thought to transfer bactoprenol-linked biosynthetic intermediates of wall teichoic acid (WTA) to the peptidoglycan of Gram-positive bacteria. In Bacillus subtilis, mutants lacking all three LCP enzymes do not deposit WTA in the envelope, while Staphylococcus aureus Δlcp mutants display impaired growth and reduced levels of envelope phosphate. We show here that the S. aureus Δlcp mutant synthesized WTA yet released ribitol phosphate polymers into the extracellular medium. Further, Δlcp mutant staphylococci no longer restricted the deposition of LysM-type murein hydrolases to cell division sites, which was associated with defects in cell shape and increased autolysis. Mutations in S. aureus WTA synthesis genes (tagB, tarF, or tarJ2) inhibit growth, which is attributed to the depletion of bactoprenol, an essential component of peptidoglycan synthesis (lipid II). The growth defect of S. aureus tagB and tarFJ mutants was alleviated by inhibition of WTA synthesis with tunicamycin, whereas the growth defect of the Δlcp mutant was not relieved by tunicamycin treatment or by mutation of tagO, whose product catalyzes the first committed step of WTA synthesis. Further, sortase A-mediated anchoring of proteins to peptidoglycan, which also involves bactoprenol and lipid II, was not impaired in the Δlcp mutant. We propose a model whereby the S. aureus Δlcp mutant, defective in tethering WTA to the cell wall, cleaves WTA synthesis intermediates, releasing ribitol phosphate into the medium and recycling bactoprenol for peptidoglycan synthesis.


PRECISE: a domain adaptation approach to transfer predictors of drug response from pre-clinical models to tumors.
Cell lines and patient-derived xenografts (PDXs) have been used extensively to understand the molecular underpinnings of cancer. While core biological processes are typically conserved, these models also show important differences compared to human tumors, hampering the translation of findings from pre-clinical models to the human setting. In particular, employing drug response predictors generated on data derived from pre-clinical models to predict patient response remains a challenging task. As very large drug response datasets have been collected for pre-clinical models, and patient drug response data are often lacking, there is an urgent need for methods that efficiently transfer drug response predictors from pre-clinical models to the human setting. We show that cell lines and PDXs share common characteristics and processes with human tumors. We quantify this similarity and show that a regression model cannot simply be trained on cell lines or PDXs and then applied on tumors. We developed PRECISE, a novel methodology based on domain adaptation that captures the common information shared amongst pre-clinical models and human tumors in a consensus representation. Employing this representation, we train predictors of drug response on pre-clinical data and apply these predictors to stratify human tumors. We show that the resulting domain-invariant predictors show a small reduction in predictive performance in the pre-clinical domain but, importantly, reliably recover known associations between independent biomarkers and their companion drugs on human tumors. PRECISE and the scripts for running our experiments are available on our GitHub page (https://github.com/NKI-CCB/PRECISE). Supplementary data are available at Bioinformatics online.


Factors affecting oral health-related quality of life among pregnant women.
To assess oral health status and to describe the possible factors that could affect the oral health-related quality of life (OHRQoL) among a group of pregnant rural women in South India. A total of 259 pregnant women (mean age 26 +/- 5.5 years) who participated in the cross-sectional study were administered the Oral Health Impact Profile (OHIP-14) questionnaire and were clinically examined for caries and periodontal status. The highest oral impact on quality of life was reported for 'painful mouth' (mean: 1.7) and 'difficulty in eating' (mean: 1.1). On comparing the mean OHIP-14 scores against the various self-reported oral problems, it was seen that the mean OHIP-14 scores were significantly higher among those who reported various oral problems than those who did not. Those with previous history of pregnancies had more severe levels of gingivitis than those who were pregnant for the first time. Also gingival index scores, community periodontal index of treatment needs scores and previous pregnancies was associated with poorer OHRQoL scores. Increased health promotion interventions and simple educational preventive programmes on oral self-care and disease prevention during pregnancy can go a long way in improving oral health and lessening its impact on the quality of life in this important population.


Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.
N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.


Available fluoride in toothpastes used by Brazilian children.
Toothpastes should have a minimum concentration of 1000 ppm of fluoride (F) to control caries and also the active F agent must be chemically free (soluble) in the formulation. Thus, the aim of this study was to evaluate the concentration of soluble F in dentifrices used by 206 Brazilian children. The concentrations of total fluoride (TF), total soluble fluoride (TSF) and fluoride ion were determined. From these analyses, the concentrations of F as sodium monofluorophosphate (MFP) and % of insoluble F were calculated. F was analyzed with an ion specific electrode in duplicates. The majority of dentifrices used (96%) contained F and in 84% of them, TF concentration was according to that declared by the manufacturers. In the F-toothpastes, 78% showed TSF concentration ≥ 1000 ppm, varying from 422.3 to 1432.3 ppm F (mean ± SD of 1017.6 ± 239.4). These findings suggest that most dentifrices used by Brazilian children present available fluoride concentration for caries control.