Prevalence of Mitochondrial ND4 Mutations in 1281 Han Chinese Subjects With Leber's Hereditary Optic Neuropathy.
To investigate the prevalence and spectrum of mitochondrial ND4 mutations in subjects with Leber's hereditary optic neuropathy (LHON). A cohort of 1281 Chinese Han probands and 478 control subjects underwent clinical and genetic evaluation, and sequence analysis of mitochondrial (mt) DNA, as well as enzymatic assay of NADH:ubiquinone oxidoreductase. In this cohort, 503 probands had a family history of optic neuropathy and 778 subjects were sporadic cases. Mutational analysis of ND4 gene identified 149 (102 known and 47 novel) variants. The prevalence of known m.11778G>A mutation was 35.36%. Furthermore, we identified the known m.11696G>A and m.11253T>C mutations and five novel putative LHON-associated mutations. These mutations accounted for 2.74% of cases of LHON subjects. By enzymatic assay, we showed a mild decrease in the activity of NADH:ubiquinone oxidoreductase in mutant cell lines carrying only one putative mtDNA mutation. The low penetrance of optic neuropathy and mild biochemical defects in these pedigrees carrying only m.11696G>A mutation and one putative LHON-associated mutation suggested that the mutation(s) is(are) necessary but is(are) itself(themselves) insufficient to produce a visual failure. Moreover, mtDNAs in 169 probands carrying the LHON-associated mutation(s) were widely dispersed among 13 Eastern Asian haplogroups. In particular, the frequencies of haplogroups D, M8, M10, M11, and H in probands carrying the LHON-associated mtDNA mutation(s) were higher than those in Chinese controls. These results suggested that the ND4 gene is the hot spot for mutations associated with LHON. Thus, these findings may provide valuable information for the further understanding of pathogenic mechanism of LHON.


Rise of the Machines: A Critical Review on the Behavioural Effects of Automating Traditional Gambling Games.
Automated gambling products are now a common feature on many casino floors. Despite their increasing prevalence, little research has considered the impact of converting games traditionally free from technological enhancements to automated versions. This review seeks to illustrate how automation is likely to change the way people engage and experience traditional games based around five prominent modifications: visual and auditory enhancements; illusions of control; cognitive complexity; expedited play; and social customisation. Otherwise known as the "VICES" framework. The inclusion of rich graphics, event-dependent sound and game-play information such as statistics, history, betting options and strategic betting are likely to prolong and entice gambling while encouraging more intense betting. Changes to the social environment due to the asocial nature of automated products is also likely to significantly change the gambling experience. Given the increasing prevalence of these products in the marketplace, it is important to consider the implications of converting traditional products to automated form as technological enhancements have the potential to allow for faster, more intense betting. More research is needed to determine the full impact of automation on player behaviours in order to understand the potential risks associated with technological enhancements to traditional games.


Intravenous fleroxacin versus ceftazidime in the treatment of acute nonpneumococcal lower respiratory tract infections.
Fleroxacin, administered intravenously at a dosage of 400 mg once a day, was compared with ceftazidime, 0.5-2 g three times daily or 1-2 g twice daily, administered for 4-21 days, for treatment of nonpneumococcal lower respiratory tract infections. A total of 319 patients were enrolled and randomized to receive treatment with fleroxacin or ceftazidime in a 2:1 ratio. Of those enrolled, 68 fleroxacin- and 49 ceftazidime-treated patients were included in the efficacy analysis. The most common diagnoses were pneumonia or pneumonitis (47% of the fleroxacin group and 57% of the ceftazidime group) and exacerbation of chronic bronchitis (38% and 33%, respectively). In the fleroxacin group, 59 (88%) of 67 patients were bacteriologic cures, and in the ceftazidime group, 40 (90%) of 49 were bacteriologic cures. It could be concluded with 95% confidence that the bacteriologic outcomes, by infection, for the two groups were equivalent (fleroxacin, 88%; ceftazidime, 90%). The rates of clinical cure were 59 (88%) of 67 for the fleroxacin group and 40 (82%) of 49 in the ceftazidime group, but since the 95% confidence limit around the between-group difference was greater than the stipulated +/- 15%, it could not be concluded that the outcomes were equivalent. The percentage of patients who experienced adverse clinical or laboratory events was similar in the two treatment groups (12% and 13%). The bacteriologic outcomes, by infection, were equivalent for the two treatment groups. Protocol requirements permitting a determination of equivalence of the outcomes for clinical cure were not met, although the rates were similar.


Atmospheric stability of arsines and the determination of their oxidative products in atmospheric aerosols (PM10): evidence of the widespread phenomena of biovolatilization of arsenic.
Biovolatilisation of arsenic as their arsines in the form of AsH(3), and mono-, di and trimethylarsine has often been determined under laboratory conditions. Although environmental point sources such as landfill sites or hot springs have been characterised, only limited knowledge is available on how widespread the formation of volatile methylated arsenic compounds are in the environment. Here we studied the atmospheric stability of the different arsines and quantified their oxidation products in atmospheric particulate matter (PM(10)) in two locations in Argentina. The atmospheric half-life of the arsines range from 19 weeks for AsH(3) to 2 d for trimethylarsine (TMAs) at 20 degrees C in the dark, while during simulated daytime conditions the stability is reduced for all arsines and in particular for the methylated arsines by three orders of magnitude which suggests that TMAs can only be dispersed at night. At both locations the arsenic concentration was in all samples below 1 ng As m(-3), which is considered as rural background for arsenic. The oxidation products, i.e. methylarsonate (MA), dimethylarsinate (DMA) and trimethylarsine oxide (TMAO) were identified by using HPLC-ICP-MS/ES-MS in more than 90% of the 49 PM(10) samples taken from 8 sampling points at the two geographically different locations. TMAO was the predominate organoarsenicals in both locations (66 and 69%, respectively) while DMA was determined to be between 13 and 19% of all organoarsenicals at the two locations. The concentration of the organoarsenicals ranged from 4 to 60 pg As as TMAO m(-3), while the maximum concentration for DMA and MA were 16 and 6 pg As m(-3), respectively. No difference in terms of the concentration or distribution of the organoarsenicals in the PM(10) samples was identified as significant. Since the two locations were different in climate and industrial impact and sampled in different seasons, these data suggest that methylated arsenicals do occur as background chemicals in the environment. Due to the low atmospheric stability of the methylated arsines, it is suggested that biovolatilization of arsenic as methylated arsines is a widespread phenomenon. More studies however are necessary to identify the major sources and determine the flux of the volatilization process in order to determine whether or not the process has environmental significance.


Anticipating the "Silver Tsunami": Prevalence Trajectories and Comorbidity Burden among Older Cancer Survivors in the United States.
Cancer survivors are a growing population, due in large part to the aging of the baby boomer generation and the related "silver tsunami" facing the U.S. health care system. Understanding the impact of a graying nation on cancer prevalence and comorbidity burden is critical in informing efforts to design and implement quality cancer care for this population. Incidence and survival data from 1975 to 2011 were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate current cancer prevalence. SEER-Medicare claims data were used to estimate comorbidity burden. Prevalence projections were made using U.S. Census Bureau data and the Prevalence Incidence Approach Model, assuming constant future incidence and survival trends but dynamic projections of the U.S. In 2016, there were an estimated 15.5 million cancer survivors living in the United States, 62% of whom were 65 years or older. The prevalent population is projected to grow to 26.1 million by 2040, and include 73% of survivors who are 65 years and older. Comorbidity burden was highest in the oldest survivors (those ≥85 years) and worst among lung cancer survivors. Older adults, who often present with complex health needs, now constitute the majority of cancer survivors and will continue to dominate the survivor population over the next 24 years. The oldest adults (i.e., those >75 years) should be priority populations in a pressing cancer control and prevention research agenda that includes expanding criteria for clinical trials to recruit more elderly participants and developing relevant supportive care interventions. Cancer Epidemiol Biomarkers Prev; 25(7); 1029-36. ©2016 AACR.


The effectiveness of a health promotion with group intervention by clinical trial. Study protocol.
The promotion of health and the interventions in community health continue to be one of the pending subjects of our health system. The most prevalent health problems (cardiovascular diseases, cancer, diabetes...) are for the most part related to life habits. We propose a holistic and integral approach as the best option for tackling behavior and its determinants. The research team has elaborated the necessary educational material to realize group teaching, which we call "Health Workshops". The goal of the present study is to evaluate the effectiveness of these Health Workshops in the following terms: Health Related Quality of Life (HRQOL), incorporate and maintain a balanced diet, do physical activity regularly, maintain risk factors such as tension, weight, cholesterol within normal limits and diminish cardiovascular risk. Controlled and random clinical testing, comparing a group of persons who have participated in the Health Workshops with a control group of similar characteristics who have not participated in the Health Workshops.Field of study: the research is being done in Health Centers of the city of Barcelona, Spain. The group is composed of 108 persons that are actually doing the Health Workshops, and 108 that are not and form the control group. They are assigned at random to one group or the other. With Student's t-distribution test to compare the differences between numerical variables or their non parametric equivalent if the variable does not comply with the criteria of normality. (Kolmogorov-Smirnof test). Chi-square test to compare the differences between categorical variables and the Logistic Regression Model to analyze different meaningful variables by dichotomous analysis related to the intervention. The Health Workshop proposed in the present study constitutes an innovative approach in health promotion, placing the emphasis on the person's self responsibility for his/her own health.The rhythm of a weekly session during 8 weeks with recommended activities to put into practice, as well as the support of the group is an opportunity to incorporate healthy habits and make a commitment to self-care. The sheets handed out are a Health Manual that can always be consulted after the workshop ends. Clinical Trials.gov Identifier: NCT01440738.


Certification of herds as free of Mycobacterium paratuberculosis infection: actual pooled faecal results versus certification model predictions.
Dutch dairy herds closed for at least 3 years with no history of paratuberculosis were recruited for a study on herd-certification. One hundred dairy herds were tested for Mycobacterium paratuberculosis at 6-month intervals by pooled faecal culture (five individual animal samples per pool) with solid media. Ninety of the herds completed 9 herd tests and 10 herds dropped out of the study for reasons other than a paratuberculosis diagnosis. Of the 90 herds completing the full study, 61% eventually were found to be M. paratuberculosis-infected. The number of infected herds detected decreased with each round of testing. Assuming that all infected herds had been detected by the ninth herd test, the observed percentage of herds that were truly noninfected (P-free) after each round of testing was calculated. The observed P-free was compared to the predicted P-free based on a previously reported herd-certification model. The P-free predicted by the model was significantly different from the observed P-free. When a single assumption in the model was changed and a diagnostic sensitivity of 40-50% was selected, the predicted P-free closely approximated the observed P-free for the 90 Dutch dairy herds studied. The critical assumption that was changed for Version 2.0 of the model was within-herd infection prevalence for infected but test-negative herds after each round of serial testing. Model Version 1.0 had assumed a 50% decrease in within-herd prevalence but Version 2.0 assumed a stable within-herd prevalence. Culture of pooled faecal samples provides a high-sensitive, high-specific, low-cost test for herd-certification programs.


Keeping the person with dementia and the informal caregiver together: a systematic review of psychosocial interventions.
Social support, relationships, and closeness are emphasized as important by both people with dementia and their informal caregivers. Psychosocial interventions might be helpful to reinforce the relationship between a person with dementia and his or her informal caregiver. Therefore, this review explores what types of psychosocial interventions have been provided for people with dementia and their informal caregivers together, and the effectiveness of these interventions. PubMed, PsychInfo, Cinahl, and references of key papers were searched for studies describing a psychosocial intervention for people with dementia and their informal caregivers together. Psychosocial interventions were defined as focusing primarily on psychological or social factors. A total of seven publications describing six studies were identified as eligible for inclusion in this review. Interventions ranged in focus from skills training to viewing/making art. The methodology of the studies varied, especially regarding the outcome measures used. The results of individual studies were mixed. A narrative synthesis of the included studies is given. Although caregiving dyads emphasize the importance of their relationship, this is mostly not taken into consideration in the design and effect evaluations of the interventions. Improved research is needed on this subject, which focuses on people with dementia living in the community and those living in nursing homes.


Prognosis of treatment response (pathological complete response) in breast cancer.
Pertaining to the female population in the USA, breast cancer is the leading cancer in terms of annual incidence rate and, in terms of mortality, the second most lethal cancer. There are currently no biomarkers available that can predict which breast cancer patients will respond to chemotherapy with both sensitivity and specificity > 80%, as mandated by the latest FDA requirements. In this study, we have developed a prognostic biomarker model (complex mathematical function) that-based on global gene expression analysis of tumor tissue collected during biopsy and prior to the commencement of chemotherapy-can identify with a high accuracy those patients with breast cancer (clinical stages I-III) who will respond to the paclitaxel-fluorouracil-doxorubicin-cyclophosphamide chemotherapy and will experience pathological complete response (Responders), as well as those breast cancer patients (clinical stages I-III) who will not do so (Non-Responders). Most importantly, both the application and the accuracy of our breast cancer prognostic biomarker model are independent of the status of the hormone receptors ER, PR, and HER2, as well as of the ethnicity and age of the subjects. We developed our prognostic biomarker model with 50 subjects [10 responders (R) and 40 non-responders (NR)], and we validated it with 43 unknown (new and different) subjects [10 responders (R) and 33 non-responders (NR)]. All 93 subjects were recruited at five different clinical centers around the world. The overall sensitivity and specificity of our prognostic biomarker model were 90.0% and 91.8%, respectively. The nine most significant genes identified, which comprise the input variables to the mathematical function, are involved in regulation of transcription; cell proliferation, invasion, and migration; oncogenesis; suppression of immune response; and drug resistance and cancer recurrence.


Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70.
The role of cytosolic factors in protein targeting to mitochondria is poorly understood. Here, we show that in mammals, the cytosolic chaperones Hsp90 and Hsp70 dock onto a specialized TPR domain in the import receptor Tom70 at the outer mitochondrial membrane. This interaction serves to deliver a set of preproteins to the receptor for subsequent membrane translocation dependent on the Hsp90 ATPase. Disruption of the chaperone/Tom70 recognition inhibits the import of these preproteins into mitochondria. In yeast, Hsp70 rather than Hsp90 is used in import, and Hsp70 docking is required for the formation of a productive preprotein/Tom70 complex. We outline a novel mechanism in which chaperones are recruited for a specific targeting event by a membrane-bound receptor.


Anaplastic thyroid carcinoma mimicking thyroid abscess.
Anaplastic thyroid carcinoma (ATC) is a particularly fearsome form of thyroid cancer due to its extreme aggressiveness and dismal prognosis. Patients with ATC typically present with a rapidly enlarging neck mass with compressive symptoms. We report a case of ATC, mimicking a thyroid abscess; in a 52-year-old Chinese male with one month history of enlarging neck mass. Ultrasound of the neck was suggestive of a thyroid cyst and fine needle aspiration cytology was negative for malignancy. He presented again 2 weeks later with increased swelling and pain suggestive of right neck abscess. An incision and drainage was performed and histopathology result of a proximal isolated enlarged lymph node biopsied revealed metastatic carcinoma. Subsequent right thyroid wedge biopsy finding 1 month later were confirmatory of ATC.


Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic.
It has been observed that overexpression of some short-hairpin RNAs (shRNAs) can induce acute cytotoxicity. This has raised concerns about the safety of using RNA interference (RNAi) technology as a potential therapeutic tool. We have sought to address this challenge of expression control by developing a mono-cistronic vector for the tissue-specific expression of an shRNA from a liver-derived polymerase (pol) II promoter. This new construct efficiently induces target silencing in hepatoma cells in vitro and in mouse livers in vivo. In order to demonstrate the therapeutic potential and improved safety of this approach, we selected an shRNA targeting the envelope surface antigen (sAg) of hepatitis B virus (HBV), which is among the most toxic when expressed from the commonly used U6 promoter. Packaging it as a double-stranded DNA into an adeno-associated virus (AAV) pseudotype 8 and delivering it at a high particle dose (1 x 10(12)) to HBV transgenic mice resulted in the stable reduction of serum sAg to 85% of starting levels, without any concomitant sign of liver damage. With this improved tolerability, the liver-specific pol II shRNA expression persisted for more than one year after the injection. We conclude that this pol II shRNA expression system combined with a potent delivery vector represents an effective alternative to either U6-based strategies or systems that achieve tissue specificity through the use of additional elements.


Comparison of genome-wide association methods in analyses of admixed populations with complex familial relationships.
Population structure is known to cause false-positive detection in association studies. We compared the power, precision, and type-I error rates of various association models in analyses of a simulated dataset with structure at the population (admixture from two populations; P) and family (K) levels. We also compared type-I error rates among models in analyses of publicly available human and dog datasets. The models corrected for none, one, or both structure levels. Correction for K was performed with linear mixed models incorporating familial relationships estimated from pedigrees or genetic markers. Linear models that ignored K were also tested. Correction for P was performed using principal component or structured association analysis. In analyses of simulated and real data, linear mixed models that corrected for K were able to control for type-I error, regardless of whether they also corrected for P. In contrast, correction for P alone in linear models was insufficient. The power and precision of linear mixed models with and without correction for P were similar. Furthermore, power, precision, and type-I error rate were comparable in linear mixed models incorporating pedigree and genomic relationships. In summary, in association studies using samples with both P and K, ancestries estimated using principal components or structured assignment were not sufficient to correct type-I errors. In such cases type-I errors may be controlled by use of linear mixed models with relationships derived from either pedigree or from genetic markers.


[Acute dystonia in a patient with an elevated clozapine level due to an infection].
Acute dystonia is a side-effect associated with the use of antipsychotics. We describe the case of a 75-year-old patient with late-onset schizophrenia who used clozapine. During a hospital admission due to pneumonia, she developed a form of acute dystonia consisting of a rotational torticollis, which disappeared rapidly after treatment with biperiden. Blood examination showed an increase of the clozapine level, probably due to the infection. This case report shows that acute dystonia, although very rare, can occur during treatment with clozapine; therefore awareness is needed of the circumstances that can alter clozapine levels.


An unknown male increases sexual incentive motivation and partner preference: Further evidence for the Coolidge effect in female rats.
The Coolidge effect is the resumption of copulatory behavior induced by a novel sexual partner that has been reported in several species. The term is also used in males when they resume mating when exposed to an unknown receptive female after they have reached sexual exhaustion. Only few studies have evaluated the Coolidge effect in females. In the present study we further evaluated this possibility using the sexual incentive motivation (SIM) and the partner preference (PP) tests. Ovariectomized rats were hormonally primed and allowed to mate for 1h controlling the sexual interaction (paced mating) or in a condition where they were unable to pace the sexual encounters. In the SIM and PP tests, females were exposed to the male with whom they had mated before (known male) or with an unknown, sexually experienced one (unknown male). Regardless whether they paced the sexual interaction, all females showed clear preference for the unknown male but females that paced the sexual contacts spent more time in the incentive zone of the unknown male than females that could not pace the sexual interaction. Similar results were observed in the PP test. Both groups of females spent more time in the compartment of the previously unknown male than in that of the known one, but received the same amount of sexual stimulation, i.e., mounts, intromissions and ejaculations from both males. No preference was found when the females were tested in the SIM test between an unknown male and a sexually receptive female. The results further support the existence of a Coolidge effect in female rats that is more apparent if they pace the sexual interaction.


Effects of Supplemental Calcium and Vitamin D on Expression of Toll-Like Receptors and Phospho-IKKα/β in the Normal Rectal Mucosa of Colorectal Adenoma Patients.
Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/β (pIKKα/β), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/β expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/β. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/β expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707-16. ©2018 AACR.


Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19.
The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation. In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed. The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related). A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).


Correlation of quantified contrast-enhanced sonography with in vivo tumor response.
The purpose of our study was to establish in vivo criteria for monitoring tumor treatment response using 3-dimensional (3D) volumetric gray scale, power Doppler, and contrast-enhanced sonography. Twelve mice were implanted with Lewis lung carcinoma cells on their hind limbs and categorized to 4 groups: control, chemotherapy, radiation therapy, and chemoradiation. A high-frequency ultrasound system with a 40-MHz probe was used to image the tumors. Follow-up contrast-enhanced sonography was performed on days 7 and 14 of treatment with two 50-microL boluses of a perflutren microbubble contrast agent injected into the tail vein. The following contrast-enhanced sonographic criteria were quantified: time to peak, peak intensity, alpha (microvessel cross-sectional area), and beta (microbubble velocity). Three-dimensional power Doppler images were also obtained after the acquisition of contrast data. On day 15, the tumors were excised for immunohistochemical analysis with CD31 fluorescent staining. The tumor size and 3D power Doppler vascular index showed no statistically significant correlation with microvascular density in all examined groups. Among all of the analyzed contrast-enhanced sonographic parameters, relative alpha showed the strongest correlation with the histologic microvessel density (Pearson r = 0.93; P < .01) and an independent association with the histologic data in a multiple regression model (beta = .93; R(2) = 0.86; P < .01). Of the various examined sonographic parameters, alpha has the strongest correlation with histologic microvessel density and may be the parameter of choice for the noninvasive monitoring of tumor angiogenic response in vivo.


Awake Craniotomy Anesthesia: A Comparison of the Monitored Anesthesia Care and Asleep-Awake-Asleep Techniques.
Commonly used sedation techniques for an awake craniotomy include monitored anesthesia care (MAC), using an unprotected airway, and the asleep-awake-asleep (AAA) technique, using a partially or totally protected airway. We present a comparative analysis of the MAC and AAA techniques, evaluating anesthetic management, perioperative outcomes, and complications in a consecutive series of patients undergoing the removal of an eloquent brain lesion. Eighty-one patients underwent awake craniotomy for an intracranial lesion over a 9-year period performed by a single-surgeon and a team of anesthesiologists. Fifty patients were treated using the MAC technique, and 31 were treated using the AAA technique. A retrospective analysis evaluated anesthetic management, intraoperative complications, postoperative outcomes, pain management, and complications. The MAC and AAA groups had similar preoperative patient and tumor characteristics. Mean operative time was shorter in the MAC group (283.5 minutes vs. 313.3 minutes; P = 0.038). Hypertension was the most common intraoperative complication seen (8% in the MAC group vs. 9.7% in the AAA group; P = 0.794). Intraoperative seizure occurred at a rate of 4% in the MAC group and 3.2% in the AAA group (P = 0.858). Awake cases were converted to general anesthesia in no patients in the MAC group and in 1 patient (3.2%) in the AAA group (P = 0.201). No cases were aborted in either group. The mean hospital length of stay was 3.98 days in the MAC group and 3.84 days in the AAA group (P = 0.833). Both the MAC and AAA sedation techniques provide an efficacious and safe method for managing awake craniotomy cases and produce similar perioperative outcomes, with the MAC technique associated with shorter operative time.


Interface Immobilization Chemistry of cRGD-based Peptides Regulates Integrin Mediated Cell Adhesion.
The interaction of specific surface receptors of the integrin family with different extracellular matrix-based ligands is of utmost importance for the cellular adhesion process. A ligand consists of an integrin-binding group, here cyclic RGDfX, a spacer molecule that lifts the integrin-binding group from the surface and a surface anchoring group. c(-RGDfX-) peptides are bound to gold nanoparticle structured surfaces via polyproline, polyethylene glycol or aminohexanoic acid containing spacers of different lengths. Although keeping the integrin-binding c(-RGDfX-) peptides constant for all compounds, changes of the ligand's spacer chemistry and length reveal significant differences in cell adhesion activation and focal adhesion formation. Polyproline-based peptides demonstrate improved cell adhesion kinetics and focal adhesion formation compared with common aminohexanoic acid or polyethylene glycol spacers. Binding activity can additionally be improved by applying ligands with two head groups, inducing a multimeric effect. This study gives insights into spacer-based differences in integrin-driven cell adhesion processes and remarkably highlights the polyproline-based spacers as suitable ligand-presenting templates for surface functionalization.


Green tea decoction improves glucose tolerance and reduces weight gain of rats fed normal and high-fat diet.
Green tea containing polyphenols exerts antidiabetic and antiobesity effects, but the mechanisms involved are not fully understood. In this study, we first analyzed and compared polyphenol compounds [epigallocatechin gallate (EGCG), epigallocatechin (EGC)] in decoction of green tea leaves versus usual green tea extracts. Second, the effects of acute (30 min) or chronic (6 weeks) oral administration of green tea decoction (GTD) on intestinal glucose absorption were studied in vitro in Ussing chamber, ex vivo using isolated jejunal loops and in vivo through glucose tolerance tests. Finally, we explore in rat model fed normal or high-fat diet the effects of GTD on body weight, blood parameters and on the relative expression of glucose transporters SGLT-1, GLUT2 and GLUT4. GTD cooked for 15 min contained the highest amounts of phenolic compounds. In fasted rats, acute administration of GTD inhibited SGLT-1 activity, increased GLUT2 activity and improved glucose tolerance. Similarly to GTD, acute administration of synthetic phenolic compounds (2/3 EGCG+1/3 EGC) inhibited SGLT-1 activity. Chronic administration of GTD in rat fed high-fat diet reduced body weight gain, circulating triglycerides and cholesterol and improved glucose tolerance. GTD-treated rats for 6 weeks display significantly reduced SGLT-1 and increased GLUT2 mRNA levels in the jejunum mucosa. Moreover, adipose tissue GLUT4 mRNA levels were increased. These results indicate that GTD, a traditional beverage rich in EGCG and EGC reduces intestinal SGLT-1/GLUT2 ratio, a hallmark of regulation of glucose absorption in enterocyte, and enhances adipose GLUT4 providing new insights in its possible role in the control of glucose homeostasis.


Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel NaV1.7.
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100- to 1000-fold selective over other NaV family members, including NaV1.4 expressed in muscle and NaV1.5 expressed in the heart, as well as TTX-resistant NaV channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple NaV1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective NaV1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain.


Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia.
Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors. Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (-550 H/L and -221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course. Of the 133 patients, 28% experienced severe neutropenia and 10% experienced febrile neutropenia. No associations were found between exon polymorphisms and febrile neutropenia. However, patients with the H/H promoter genotype, associated with high MBL levels, experienced significantly more febrile neutropenia than patients with the H/L and L/L genotypes (20% versus 13% versus 5%). Moreover, patients with the HYA haplotype encountered significantly more febrile neutropenia than patients without this high MBL-producing haplotype (16% versus 4%). In the subgroup with wild-type exon polymorphisms (A/A), patients with the high MBL promoter phenotype had the highest incidence of febrile neutropenia, regardless of known risk factors. Patients with high MBL2 promoter genotypes and haplotypes seem more at risk for developing febrile neutropenia. If confirmed, these preliminary findings may contribute to more individualized approaches of irinotecan treatment.


Dosage Compensation in the African Malaria Mosquito Anopheles gambiae.
Dosage compensation is the fundamental process by which gene expression from the male monosomic X chromosome and from the diploid set of autosomes is equalized. Various molecular mechanisms have evolved in different organisms to achieve this task. In Drosophila, genes on the male X chromosome are upregulated to the levels of expression from the two X chromosomes in females. To test whether a similar mechanism is operating in immature stages of Anopheles mosquitoes, we analyzed global gene expression in the Anopheles gambiae fourth instar larvae and pupae using high-coverage RNA-seq data. In pupae of both sexes, the median expression ratios of X-linked to autosomal genes (X:A) were close to 1.0, and within the ranges of expression ratios between the autosomal pairs, consistent with complete compensation. Gene-by-gene comparisons of expression in males and females revealed mild female bias, likely attributable to a deficit of male-biased X-linked genes. In larvae, male to female ratios of the X chromosome expression levels were more female biased than in pupae, suggesting that compensation may not be complete. No compensation mechanism appears to operate in male germline of early pupae. Confirmation of the existence of dosage compensation in A. gambiae lays the foundation for research into the components of dosage compensation machinery in this important vector species.


Dietary restriction mitigates age-related accumulation of DNA damage, but not all changes in mouse corneal epithelium.
The cornea protects the anterior eye and accounts for two thirds of the eyes refractive capacity. The homeostasis of corneal epithelium is thought to be maintained by putative stem cells residing in the epithelial basal layer. As a tissue constantly exposed to environmental stress, the cornea is hypothesised to accumulate persistent DNA damage events with time in stem cell populations. Recently, telomere associated DNA damage foci (TAFs) have been suggested as a marker for persistent DNA damage which can be used to detect senescent cells during ageing. Dietary restriction (DR) is the only known non-genetic intervention that is able to increase both life and health span among various animal species. The aim of this study was to analyse changes in corneal properties with age and under 16 months of DR. We employed immunofluorescence staining for ɣH2A.X together with telomere fluorescence in situ hybridisation (immuno-FISH) on mouse corneas from young, old ad libitum (AL) fed as well as dietary restricted (DR) mice. Our data show that the central corneas of old mice had significantly more general and telomere-associated DNA damage compared to young mice while DR treatment was able to reduce the amount of DNA damage significantly. We also found that the thickness of the peripheral region of the cornea, where the putative stem cells may reside, decreased with age regardless of whether the animals underwent DR treatment or not. Number of bullae, which indicates corneal edema, accumulated in old corneas in the central area and DR treatment mitigated the formation of these bullae. Moreover, the protein levels of the stem cell marker TAp63 decreased with age only in the central but not the peripheral region of the cornea. This finding suggests that epithelial progenitors might be better maintained in the peripheral than the central cornea during ageing. Together with the finding that the peripheral corneal showed no increase in DNA damage during age, we speculate that in mice, like humans, the putative stem cells reside in the peripheral cornea.


Impact of external price referencing on medicine prices - a price comparison among 14 European countries.
This study aims to examine the impact of external price referencing (EPR) on on-patent medicine prices, adjusting for other factors that may affect price levels such as sales volume, exchange rates, gross domestic product (GDP) per capita, total pharmaceutical expenditure (TPE), and size of the pharmaceutical industry. Price data of 14 on-patent products, in 14 European countries in 2007 and 2008 were obtained from the Pharmaceutical Price Information Service of the Austrian Health Institute. Based on the unit ex-factory prices in EURO, scaled ranks per country and per product were calculated. For the regression analysis the scaled ranks per country and product were weighted; each country had the same sum of weights but within a country the weights were proportional to its sales volume in the year (data obtained from IMS Health). Taking the scaled ranks, several statistical analyses were performed by using the program "R", including a multiple regression analysis (including variables such as GDP per capita and national industry size). This study showed that on average EPR as a pricing policy leads to lower prices. However, the large variation in price levels among countries using EPR confirmed that the price level is not only driven by EPR. The unadjusted linear regression model confirms that applying EPR in a country is associated with a lower scaled weighted rank (p=0.002). This interaction persisted after inclusion of total pharmaceutical expenditure per capita and GDP per capita in the final model. The study showed that for patented products, prices are in general lower in case the country applied EPR. Nevertheless substantial price differences among countries that apply EPR could be identified. Possible explanations could be found through a correlation between pharmaceutical industry and the scaled price ranks. In conclusion, we found that implementing external reference pricing could lead to lower prices.


Genes Encoding Recognition of the Cladosporium fulvum Effector Protein Ecp5 Are Encoded at Several Loci in the Tomato Genome.
The molecular interactions between tomato and Cladosporium fulvum have been an important model for molecular plant pathology. Complex genetic loci on tomato chromosomes 1 and 6 harbor genes for resistance to Cladosporium fulvum, encoding receptor like-proteins that perceive distinct Cladosporium fulvum effectors and trigger plant defenses. Here, we report classical mapping strategies for loci in tomato accessions that respond to Cladosporium fulvum effector Ecp5, which is very sequence-monomorphic. We screened 139 wild tomato accessions for an Ecp5-induced hypersensitive response, and in five accessions, the Ecp5-induced hypersensitive response segregated as a monogenic trait, mapping to distinct loci in the tomato genome. We identified at least three loci on chromosomes 1, 7 and 12 that harbor distinct Cf-Ecp5 genes in four different accessions. Our mapping showed that the Cf-Ecp5 in Solanum pimpinellifolium G1.1161 is located at the Milky Way locus. The Cf-Ecp5 in Solanum pimpinellifolium LA0722 was mapped to the bottom arm of chromosome 7, while the Cf-Ecp5 genes in Solanum lycopersicum Ontario 7522 and Solanum pimpinellifolium LA2852 were mapped to the same locus on the top arm of chromosome 12. Bi-parental crosses between accessions carrying distinct Cf-Ecp5 genes revealed putative genetically unlinked suppressors of the Ecp5-induced hypersensitive response. Our mapping also showed that Cf-11 is located on chromosome 11, close to the Cf-3 locus. The Ecp5-induced hypersensitive response is widely distributed within tomato species and is variable in strength. This novel example of convergent evolution could be used for choosing different functional Cf-Ecp5 genes according to individual plant breeding needs.


A reward increases running-wheel performance without changing cell proliferation, neuronal differentiation or cell death in the dentate gyrus of C57BL/6 mice.
Exercise is one of the best-known stimulators of adult hippocampal neurogenesis, but it is not known if voluntary changes in the intensity of exercise are accompanied by changes in neurogenesis. In this study we investigated whether a reward influences the performance in a running wheel and the rate of cell proliferation, neuronal differentiation and cell death in C57BL/6 mice. Mice had free access to a running wheel during the first week of the experiment. In the second week, animals were rewarded for their performance and compared to normal voluntary running and control mice. A reward significantly increased the performance by 78% when compared to the non-rewarded performance of the first week. The performance of the non-rewarded runners remained relatively constant. Fourteen days of exercise significantly increased cell proliferation by 27% and the number of doublecortin immunoreactive cells by 46%. A reward and the associated increase of performance did not modulate proliferation, cell death or the number of cells entering the neuronal lineage. We suggest that, in C57BL/6 mice, either exercise increases adult hippocampal neurogenesis to a ceiling value, which is reached by a performance at or below the level achieved by voluntary wheel running, or that a possible positive effect of increased running-wheel activity is balanced by stress resulting from rewarded running, which is no longer performed on a strictly voluntary basis.


Single-molecule analysis of DNA replication in Xenopus egg extracts.
The recent advent in single-molecule imaging and manipulation methods has made a significant impact on the understanding of molecular mechanisms underlying many essential cellular processes. Single-molecule techniques such as electron microscopy and DNA fiber assays have been employed to study the duplication of genome in eukaryotes. Here, we describe a single-molecule assay that allows replication of DNA attached to the functionalized surface of a microfluidic flow cell in a soluble Xenopus leavis egg extract replication system and subsequent visualization of replication products via fluorescence microscopy. We also explain a method for detection of replication proteins, through fluorescently labeled antibodies, on partially replicated DNA immobilized at both ends to the surface.


What do nonprofit hospitals reward? An examination of CEO compensation in nonprofit hospitals.
Nonprofit hospital chief executive officer (CEO) compensation has received considerable attention in light of nonprofits' tax-favored status as well as the high costs of hospital care. Past studies have found that hospital financial performance is a significant determinant of CEO pay but nonprofit performance, including quality and charity care, are not. Using post-ACA data, we re-examine whether a variety of hospital performance measures are important determinants of nonprofit hospital CEO compensation. We found mixed evidence with respect to the significance of the association between financial performance and uncompensated care and CEO compensation. Among the other nonprofit performance measures, patient satisfaction was significantly associated with CEO compensation, but other measures were not significant determinants of CEO compensation. Our results suggest nonprofit hospitals balance their financial health against their mission when setting CEO incentives. Additional policy targeting transparency in hospital CEO compensation may be warranted to help policymakers understand the specific factors used by hospital boards to incentivize CEOs.


Exit and Entry Screening Practices for Infectious Diseases among Travelers at Points of Entry: Looking for Evidence on Public Health Impact.
A scoping search and a systematic literature review were conducted to give an insight on entry and exit screening referring to travelers at points of entry, by analyzing published evidence on practices, guidelines, and experiences in the past 15 years worldwide. Grey literature, PubMed. and Scopus were searched using specific terms. Most of the available data identified through the systematic literature review concerned entry screening measures at airports. Little evidence is available about entry and exit screening measure implementation and effectiveness at ports and ground crossings. Exit screening was part of the World Health Organisation's (WHO) temporary recommendations for implementation in certain points of entry, for specific time periods. Exit screening measures for Ebola Virus Disease (EVD) in the three most affected West African countries did not identify any cases and showed zero sensitivity and very low specificity. The percentages of confirmed cases identified out of the total numbers of travelers that passed through entry screening measures in various countries worldwide for Influenza Pandemic (H1N1) and EVD in West Africa were zero or extremely low. Entry screening measures for Severe Acute Respiratory Syndrome (SARS) did not detect any confirmed SARS cases in Australia, Canada, and Singapore. Despite the ineffectiveness of entry and exit screening measures, authors reported several important concomitant positive effects that their impact is difficult to assess, including discouraging travel of ill persons, raising awareness, and educating the traveling public and maintaining operation of flights from/to the affected areas. Exit screening measures in affected areas are important and should be applied jointly with other measures including information strategies, epidemiological investigation, contact tracing, vaccination, and quarantine to achieve a comprehensive outbreak management response. Based on review results, an algorithm about decision-making for entry/exit screening was developed.


Ethical aspects of personality disorders.
To review recent literature around the controversial diagnosis of personality disorder, and to assess the ethical aspects of its status as a medical disorder. The diagnostic currency of personality disorder as a psychiatric/medical disorder has a longstanding history of ethical and social challenges through critiques of the medicalization of deviance. More recently controversies by reflexive physicians around the inclusion of the category in the forthcoming revisions of International Classification of Diseases and Diagnostic and Statistical Manual of Mental Disorders classifications reflect the problems of value-laden criteria, with the diagnostic category being severely challenged from within psychiatry as well as from without. The clinical diagnostic criteria for extremely value-laden psychiatric conditions such as personality disorder need to be analyzed through the lens of values-based medicine, as well as through clinical evidence, as the propensity for political and sociolegal appropriation of the categories can render their clinical and diagnostic value meaningless.


Extending the honey bee venome with the antimicrobial peptide apidaecin and a protein resembling wasp antigen 5.
Honey bee venom is a complex mixture of toxic proteins and peptides. In the present study we tried to extend our knowledge of the venom composition using two different approaches. First, worker venom was analysed by liquid chromatography-mass spectrometry and this revealed the antimicrobial peptide apidaecin for the first time in such samples. Its expression in the venom gland was confirmed by reverse transcription PCR and by a peptidomic analysis of the venom apparatus tissue. Second, genome mining revealed a list of proteins with resemblance to known insect allergens or venom toxins, one of which showed homology to proteins of the antigen 5 (Ag5)/Sol i 3 cluster. It was demonstrated that the honey bee Ag5-like gene is expressed by venom gland tissue of winter bees but not of summer bees. Besides this seasonal variation, it shows an interesting spatial expression pattern with additional production in the hypopharyngeal glands, the brains and the midgut. Finally, our immunoblot study revealed that both synthetic apidaecin and the Ag5-like recombinant from bacteria evoke no humoral activity in beekeepers. Also, no IgG4-based cross-reactivity was detected between the honey bee Ag5-like protein and its yellow jacket paralogue Ves v 5.


The new bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD) remains the most common severe complication of preterm birth. A number of recent animal models and clinical studies provide new information about pathophysiology and treatment. The epidemiology of BPD continues to demonstrate that birth weight and gestational age are most predictive of BPD. Correlations of BPD with chorioamnionitis are clouded by the complexity of the fetal exposures to inflammation. Excessive oxygen use in preterm infants can increase the risk of BPD but low saturation targets may increase death. Numerous recent trials demonstrate that many preterm infants can be initially stabilized after delivery with continuous positive airway response (CPAP) and then be selectively treated with surfactant for respiratory distress syndrome. The growth of the lungs of the infant with BPD through childhood remains poorly characterized. Recent experiences in neonatology suggest that combining less invasive care strategies that avoid excessive oxygen and ventilation, decrease postnatal infections, and optimize nutrition may decrease the incidence and severity of BPD.


Assessing uncertainties in land cover projections.
Understanding uncertainties in land cover projections is critical to investigating land-based climate mitigation policies, assessing the potential of climate adaptation strategies and quantifying the impacts of land cover change on the climate system. Here, we identify and quantify uncertainties in global and European land cover projections over a diverse range of model types and scenarios, extending the analysis beyond the agro-economic models included in previous comparisons. The results from 75 simulations over 18 models are analysed and show a large range in land cover area projections, with the highest variability occurring in future cropland areas. We demonstrate systematic differences in land cover areas associated with the characteristics of the modelling approach, which is at least as great as the differences attributed to the scenario variations. The results lead us to conclude that a higher degree of uncertainty exists in land use projections than currently included in climate or earth system projections. To account for land use uncertainty, it is recommended to use a diverse set of models and approaches when assessing the potential impacts of land cover change on future climate. Additionally, further work is needed to better understand the assumptions driving land use model results and reveal the causes of uncertainty in more depth, to help reduce model uncertainty and improve the projections of land cover.


Epidemiology of anxiety disorders: from surveys to nosology and back.
On the basis of epidemiological survey findings, anxiety disorders are the most prevalent mental disorders around the world and are associated with significant comorbidity and morbidity. Such surveys rely on advances in psychiatric nosology and may also contribute usefully to revisions of the nosology. There are a number of questions at the intersection of psychiatric epidemiology and nosology. This review addresses the following: What is the prevalence of anxiety disorders and how do we best explain cross-national differences in prevalence estimates? What are the optimal diagnostic criteria for anxiety disorders, and how can epidemiological data shed light on this question? What are the comorbidities of anxiety disorders, and how do we best understand the high comorbidities seen in these conditions? What is the current treatment gap for anxiety disorders, and what are the implications of current understandings of psychiatric epidemiology and nosology for policy-making relevant to anxiety disorders? Here, we emphasize that anxiety disorders are the most prevalent of the psychiatric conditions, and that rather than merely contrasting cross-national prevalence in anxiety disorders, it is more productive to delineate cross-national themes that emerge about the epidemiology of these conditions. We discuss that optimizing diagnostic criteria for anxiety disorders is an iterative process to which epidemiological data can make a crucial contribution. Additionally, high comorbidity in anxiety disorders is not merely artefactual; it provides key opportunities to explore pathways to mental disorders and to intervene accordingly. Finally, work on the epidemiology and nosology of anxiety disorders has provided a number of important targets for mental health policy and for future integrative work to move between bench and bedside, as well as between clinic and community.


Heritable variation in maternally derived yolk androgens, thyroid hormones and immune factors.
Maternal reproductive investment can critically influence offspring phenotype, and thus these maternal effects are expected to be under strong natural selection. Knowledge on the extent of heritable variation in the physiological mechanisms underlying maternal effects is however limited. In birds, resource allocation to eggs is a key mechanism for mothers to affect their offspring and different components of the egg may or may not be independently adjusted. We studied the heritability of egg components and their genetic and phenotypic covariation in great tits (Parus major), using captive-bred full siblings of wild origin. Egg mass, testosterone (T) and androstenedione (A4) hormone concentrations showed moderate heritability, in agreement with earlier findings. Interestingly, yolk triiodothyronine hormone (T3), but not its precursor, thyroxine hormone (T4), concentration was heritable. An immune factor, albumen lysozyme, showed moderate heritability, but yolk immunoglobulins (IgY) did not. The genetic correlation estimates were moderate but statistically nonsignificant; a trend for a positive genetic correlation was found between A4 and egg mass, T and lysozyme and IgY and lysozyme, respectively. Interestingly, phenotypic correlations were found only between A4 and T, and T4 and T3, respectively. Given that these egg components are associated with fitness-related traits in the offspring (and mother), and that we show that some components are heritable, it opens the possibility that natural selection may shape the rate and direction of phenotypic change via egg composition.


Deciphering AP-1 function in tumorigenesis: fra-ternizing on target promoters.
Multi-gene families of transcription factors pose a formidable challenge to molecular and functional analysis. Dissecting distinct functions for individual family members requires a combination of approaches in different cellular and animal models. The AP-1 transcription factor complex serves as a paradigm for understanding the dynamics of transcriptional regulation. Knockout, knockdown and transgenic strategies, inducible alleles, mutational analysis, chemical genetics, etc.; researchers have applied all the tricks of the trade to understand how AP-1 works. AP-1 refers to a mixture of dimers formed between members of the Jun, Fos and ATF families. The complexity of the AP-1 biological functions reflects the wide combinatorial diversity of its components. AP-1 has been linked to cancer and neoplastic transformation ever since the first jun and fos genes were cloned as cellular homologues of viral oncogenes twenty years ago. Because of the oncogenic or tumor suppressive activity exhibited by distinct Jun and Fos nuclear proteins depending on the cell context and the genetic background of the tumor, the AP-1 complex has been called a "double-edged sword" in tumorigenesis. The cumulating results over the last decade are finally leading to the identification of specific functions for individual AP-1 components and their contribution to neoplastic disease. Here, we focus on the Fra-1 protein in tumorigenesis, which offers an illustrative example of this helter-skelter voyage.


Early Initiation of Antiretroviral Therapy Can Functionally Control Productive HIV-1 Infection in Humanized-BLT Mice.
Recent reports showed that functional control of HIV-1 infection for a prolonged time is possible by early antiretroviral therapy (ART); however, its underlying mechanism needs to be studied with a suitable animal model. Recently, humanized-BLT (bone marrow, liver, and thymus) mouse (hu-BLT) was shown to be an excellent model for studying HIV-1 infection. We thus tested the feasibility of studying functional control of HIV-1 infection using hu-BLT mice. Animals in 3 treatment groups (Rx-6h, Rx-24h, and Rx-48h) and untreated group were infected with HIV-1, followed by ART initiation at 6, 24, or 48 hours postinfection and continued daily for 2 weeks. Three weeks after stopping ART, CD8 T cells were depleted from all animals. Plasma viral load was monitored weekly using droplet digital polymerase chain reaction. Percentage of CD4 and CD8 T cells were measured by flow cytometry. In situ hybridization and droplet digital polymerase chain reaction were used to detect viral RNA (vRNA) and DNA. Although control animals had high viremia throughout the study, all Rx-6h animals had undetectable plasma viral load after ART cessation. After CD8 T-cell depletion, viremia increased and CD4 T cells decreased in all animals except the Rx-6h group. Viral DNA was detected in spleens of all animals and a few vRNA cells were detected by in situ hybridization in 1 of 3 Rx-6h animals. Early ART did not act as prophylaxes but, rather, can control HIV-1 productive infection and prevented CD4 T-cell depletion in hu-BLT mice. This mouse model can be used to elucidate the mechanism for functional control of HIV-1.


Potential environmental benefits of prospective genetic changes in broiler traits.
A system approach-based Life Cycle Assessment (LCA) framework, combined with a simple mechanistic model of bird energy balance was used to predict the potential effects of 15 y prospective broiler breeding on the environmental impacts of the standard UK broiler production system. The year 2014 Ross 308 genotype was used as a baseline, and a future scenario was specified from rates of genetic improvement predicted by the industry. The scenario included changes in the traits of growth rate (reducing the time to reach a target weight 2.05 kg from 34 d to 27 d), body lipid content, carcass yield, mortality and the number of chicks produced by a breeder hen. Diet composition was adjusted in order to accommodate the future nutrient requirements of the birds following the genetic change. The results showed that predicted changes in biological performance due to selective breeding could lead to reduced environmental impacts of the broiler production chain, most notably in the Eutrophication Potential (by 12%), Acidification Potential (by 10%) and Abiotic Resource Use (by 9%) and Global Warming Potential (by 9%). These reductions were mainly caused by the reduced maintenance energy requirement and thus lower feed intake, resulting from the shorter production cycle, together with the increased carcass yield. However, some environmental benefits were limited by the required changes in feed composition (e.g., increased inclusion of soy meal and vegetable oil) as a result of the changes in bird nutrient requirements. This study is the first one aiming to link the mechanistic animal modeling approach to predicted genetic changes in order to produce quantitative estimates of the future environmental impacts of broiler production. Although a more detailed understanding on the mechanisms of the potential changes in bird performance and their consequences on feeding and husbandry would be still be needed, the modeling framework produced in this study provides a starting point for predictions of the effects of prospective genetic progress.


Bee-honey and yogurt: a novel mixture for treating patients with vulvovaginal candidiasis during pregnancy.
To evaluate the clinical and mycological cure rates of a novel mixture consisting of Bee-honey and yogurt compared to local antifungal agents for treating patients with vulvo-vaginal candidiasis (VVC) during pregnancy. This is a prospective comparative study which included 129 patients with VVC during pregnancy. The participants were allocated into study group (n = 82) who received a mixture of Bee-honey and yogurt vaginally and control group (n = 47) who received local anti-fungal agents. The Chi-square test was used to evaluate the clinical and mycological cure rates and the side-effects of both modes of therapy. The clinical cure rate was significantly higher in the study than the control group (87.8 vs. 72.3%, respectively) while the mycological cure rate was higher in the control than the study group (91.5 vs. 76.9%, respectively). Both types of therapy were favorably tolerated by most of the patients. Side effects were reported only in 24.3 and 29.7% of patients in group I and II, respectively (p < 0.05). The mixture of Bee-honey and yogurt produced a high clinical cure rate and a reasonable mycological cure rate. It can be used as a complementary or an alternative to antifungal agents especially in patients with VVC during pregnancy.


Towards a new generation of agricultural system data, models and knowledge products: Design and improvement.
This paper presents ideas for a new generation of agricultural system models that could meet the needs of a growing community of end-users exemplified by a set of Use Cases. We envision new data, models and knowledge products that could accelerate the innovation process that is needed to achieve the goal of achieving sustainable local, regional and global food security. We identify desirable features for models, and describe some of the potential advances that we envisage for model components and their integration. We propose an implementation strategy that would link a "pre-competitive" space for model development to a "competitive space" for knowledge product development and through private-public partnerships for new data infrastructure. Specific model improvements would be based on further testing and evaluation of existing models, the development and testing of modular model components and integration, and linkages of model integration platforms to new data management and visualization tools.


A novel algorithm for view and illumination invariant image matching.
The challenges in local-feature-based image matching are variations of view and illumination. Many methods have been recently proposed to address these problems by using invariant feature detectors and distinctive descriptors. However, the matching performance is still unstable and inaccurate, particularly when large variation in view or illumination occurs. In this paper, we propose a view and illumination invariant image-matching method. We iteratively estimate the relationship of the relative view and illumination of the images, transform the view of one image to the other, and normalize their illumination for accurate matching. Our method does not aim to increase the invariance of the detector but to improve the accuracy, stability, and reliability of the matching results. The performance of matching is significantly improved and is not affected by the changes of view and illumination in a valid range. The proposed method would fail when the initial view and illumination method fails, which gives us a new sight to evaluate the traditional detectors. We propose two novel indicators for detector evaluation, namely, valid angle and valid illumination, which reflect the maximum allowable change in view and illumination, respectively. Extensive experimental results show that our method improves the traditional detector significantly, even in large variations, and the two indicators are much more distinctive.


Effect of the quality of health care on permanent inability secondary to femoral fractures due to occupational accidents.
To construct and validate an indicator for evaluating the quality of care for femoral fractures, and to assess the contribution of the quality of health care as a determinant of partial permanent inability secondary to femoral fractures due to occupational accidents. The study was conducted from January to December 1995 at Mexican Institute of Social Security. The instrument was designed with experts' contribution along different stages and validated using implicit criteria and factorial analysis. A case-control study was then conducted to evaluate the contribution of the quality of care to inability secondary to femoral fractures. Cases were 108 active workers with permanent inability secondary to femoral fracture; controls were 94 active workers with fracture of femur but no permanent inability. Logistic regression modeling was used to establish the association between quality of care and partial permanent inability, adjusting by relevant variables. The ultimate indicator of quality of care consisted of the following: Timely care, presurgical management, surgical management, and fracture complications. A final score over 229 points meant that the worker had received good quality of care. Workers getting 229 or less points had received poor quality of care. Forty-eight (44%) cases and 66 (70%) controls received good quality of medical care. The likelihood of partial permanent inability was almost three times higher among workers given poor quality of care (OR 2.95; 95% CI 1.5-5.5). According to the multivariate model, predictors of partial permanent inability were: Having exposed or epiphysiary fractures, being re-submitted to surgery, having less than 90 days of rehabilitation care, and receiving deficient medical care. The constructed instrument was validated. The level of the quality of care received by workers is a determining factor for the generation of partial permanent inability. In workers having femoral fractures, it is important to consider timely medical care and early rehabilitation, to reduce the high incidence and prevalence of this medical problem in Mexico. The English version of this paper is available too at: http://www.insp.mx/salud/index.html.


Antennal-expressed ammonium transporters in the malaria vector mosquito Anopheles gambiae.
The principal Afrotropical malaria vector mosquito, Anopheles gambiae remains a significant threat to human health. In this anthropophagic species, females detect and respond to a range of human-derived volatile kairomones such as ammonia, lactic acid, and other carboxylic acids in their quest for blood meals. While the molecular underpinnings of mosquito olfaction and host seeking are becoming better understood, many questions remain unanswered. In this study, we have identified and characterized two candidate ammonium transporter genes, AgAmt and AgRh50 that are expressed in the mosquito antenna and may contribute to physiological and behavioral responses to ammonia, which is an important host kairomone for vector mosquitoes. AgAmt transcripts are highly enhanced in female antennae while a splice variant of AgRh50 appears to be antennal-specific. Functional expression of AgAmt in Xenopus laevis oocytes facilitates inward currents in response to both ammonium and methylammonium, while AgRh50 is able to partially complement a yeast ammonium transporter mutant strain, validating their conserved roles as ammonium transporters. We present evidence to suggest that both AgAmt and AgRh50 are in vivo ammonium transporters that are important for ammonia sensitivity in An. gambiae antennae, either by clearing ammonia from the sensillar lymph or by facilitating sensory neuron responses to environmental exposure. Accordingly, AgAmt and AgRh50 represent new and potentially important targets for the development of novel vector control strategies.


On the spatial orientation of the transverse irradiance profile of partially coherent beams.
On the basis of the irradiance-moments formalism, four matrices are proposed whose elements, defined for any partially coherent field, are closely related with the second-order measurable parameters handled in the ISO standard 11146. These matrices are shown to exhibit a number of properties concerning the orientation of the transverse profile of a partially coherent beam. This behavior is described by the rotation of the principal axes of the field around its propagation axis. In addition, these matrices provide information about the spatial structure of the field (beam spread product and orbital part of the angular momentum). A new overall parameter is introduced in terms of the above matrices, which remains invariant under rotation of the Cartesian coordinate axes and upon propagation through rotationally-symmetric first-order optical systems.


Influence of platelet reactivity on BARC classification in East Asian patients undergoing percutaneous coronary intervention. Results of the ACCEL-BLEED study.
An increasing body of data suggests that East Asian patients have differing risk profiles for both thrombophilia and bleeding compared with Western population. This study was designed to evaluate the relationship of bleeding to platelet function in East Asians undergoing percutaneous coronary intervention (PCI). Patients who had undergone uneventful PCI (n= 301) were prospectively enrolled and bleeding events were evaluated during dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Platelet function was measured during hospitalisation and at 30-day follow-up by light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. During 30-day follow-up, 29.2 % of patients (n= 88) experienced post-discharge Bleeding Academic Research Consortium (BARC) complications (24.6 % and 7.0 % of BARC type 1 and 2, respectively). Patients presenting with acute myocardial infarction had fewer episodes of type 1 BARC bleeding (odds ratio: 0.41; 95 % confidence interval: 0.22 to 0.76; p= 0.005). The cut-off of low platelet reactivity (LPR) (20 µM ADP-induced platelet aggregation ≤ 46.1 %; platelet reactivity index ≤ 45.1 %) was the independent determinant of type 2 BARC bleeding (odds ratio: 3.55 and 4.44; p= 0.009 and 0.002, respectively). The first 30-day BARC bleeding episodes were associated with an increased rate of subsequent premature DAPT discontinuation during one-year follow-up (4.7 % vs 11.4 %; odds ratio: 2.60; 95 % confidence interval: 1.04 to 6.50; p= 0.035). In conclusion, among East Asians, mild bleeding episodes are common early after PCI and are associated with premature DAPT discontinuation. Type 2 BARC bleeding episodes are associated with LPR cut-offs measured at 30 days post-discharge.


Looking at neurodevelopment through a big data lens.
The formation of the human brain, which contains nearly 100 billion neurons making an average of 1000 connections each, represents an astonishing feat of self-organization. Despite impressive progress, our understanding of how neurons form the nervous system and enable function is very fragmentary, especially for the human brain. New technologies that produce large volumes of high-resolution measurements-big data-are now being brought to bear on this problem. Single-cell molecular profiling methods allow the exploration of neural diversity with increasing spatial and temporal resolution. Advances in human genetics are shedding light on the genetic architecture of neurodevelopmental disorders, and new approaches are revealing plausible neurobiological mechanisms underlying these conditions. Here, we review the opportunities and challenges of integrating large-scale genomics and genetics for the study of brain development.


The Link between Potassium and Mild Cognitive Impairment in Mexican-Americans.
Recent evidence suggests that increasing dietary intake of minerals reduces the risk of dementia. This study aimed to examine the relationship between potassium and diagnosis of mild cognitive impairment (MCI) in a sample of older Mexican-Americans from rural and urban populations. The sample was formed of a total of 139 participants with MCI and 371 normal controls from two independent cohorts: a rural cohort (Facing Rural Obstacles to Healthcare Now through Intervention, Education and Research [Project FRONTIER]) and an urban cohort (the Health and Aging Brain among Latino Elders [HABLE] study). Serum electrolytes examined were sodium and potassium. Age and education were entered in the model as covariates. Across both cohorts, the Project FRONTIER (OR = 3.1; p = 0.01) and the HABLE Project (OR = 2.0; p = 0.04), the results indicated that serum potassium levels significantly increased the risk of diagnosis of MCI. Our finding suggested a link between serum potassium levels and a diagnosis of MCI in Mexican-Americans. The results of this study support a previous research which has suggested that the risk factors for MCI may vary by ethnicity.


ER stress and UPR in familial amyotrophic lateral sclerosis.
The primary mechanism by which mutations in Cu, Zn-superoxide dismutase (SOD1) contribute to progressive motor neuron loss in familial amyotrophic lateral sclerosis (FALS) remains unknown. Misfolded protein aggregates, ubiquitin-proteasome system impairment and neuronal apoptosis mediated by death receptor or mitochondrial-dependent pathways are implicated in mutant SOD1-induced toxicity. Recent evidence from cellular and transgenic rodent models of FALS proposes activation of a third apoptotic pathway linked to sustained endoplasmic reticulum (ER) stress. Here, we review the emerging role of ER stress and the unfolded protein response (UPR) in the pathogenesis of mutant SOD1-linked FALS. The UPR observed in FALS rodents is described which encompasses induction of key ER-resident chaperones during presymptomatic disease, leading to activation of stress transducers and pro-apoptotic molecules by late stage disease. Importantly, mutant SOD1 co-aggregates with UPR components and recruits to the ER, suggesting a direct adverse effect on ER function. By contrast, the opposing neuroprotective effects of wild-type SOD1 overexpression on UPR signalling are also highlighted. In addition, the potential impact of neuronal Golgi apparatus (GA) fragmentation and subsequent disturbances in intracellular protein trafficking on motor neuron survival in FALS is also discussed. We propose that ER stress and UPR may be coupled to GA dysfunction in mutant SOD1-mediated toxicity, promoting ER-initiated cell death signalling in FALS.


Fluorescence-based reporter for gauging cyclic di-GMP levels in Pseudomonas aeruginosa.
The increased tolerance toward the host immune system and antibiotics displayed by biofilm-forming Pseudomonas aeruginosa and other bacteria in chronic infections such as cystic fibrosis bronchopneumonia is of major concern. Targeting of biofilm formation is believed to be a key aspect in the development of novel antipathogenic drugs that can augment the effect of classic antibiotics by decreasing antimicrobial tolerance. The second messenger cyclic di-GMP is a positive regulator of biofilm formation, and cyclic di-GMP signaling is now regarded as a potential target for the development of antipathogenic compounds. Here we describe the development of fluorescent monitors that can gauge the cellular level of cyclic di-GMP in P. aeruginosa. We have created cyclic di-GMP level reporters by transcriptionally fusing the cyclic di-GMP-responsive cdrA promoter to genes encoding green fluorescent protein. We show that the reporter constructs give a fluorescent readout of the intracellular level of cyclic di-GMP in P. aeruginosa strains with different levels of cyclic di-GMP. Furthermore, we show that the reporters are able to detect increased turnover of cyclic di-GMP mediated by treatment of P. aeruginosa with the phosphodiesterase inducer nitric oxide. Considering that biofilm formation is a necessity for the subsequent development of a chronic infection and therefore a pathogenicity trait, the reporters display a significant potential for use in the identification of novel antipathogenic compounds targeting cyclic di-GMP signaling, as well as for use in research aiming at understanding the biofilm biology of P. aeruginosa.


DNA polymerase β variant Ile260Met generates global gene expression changes related to cellular transformation.
Maintenance of genomic stability is essential for cellular survival. The base excision repair (BER) pathway is critical for resolution of abasic sites and damaged bases, estimated to occur 20,000 times in cells daily. DNA polymerase β (Pol β) participates in BER by filling DNA gaps that result from excision of damaged bases. Approximately 30% of human tumours express Pol β variants, many of which have altered fidelity and activity in vitro and when expressed, induce cellular transformation. The prostate tumour variant Ile260Met transforms cells and is a sequence-context-dependent mutator. To test the hypothesis that mutations induced in vivo by Ile260Met lead to cellular transformation, we characterized the genome-wide expression profile of a clone expressing Ile260Met as compared with its non-induced counterpart. Using a 1.5-fold minimum cut-off with a false discovery rate (FDR) of <0.05, 912 genes exhibit altered expression. Microarray results were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and revealed unique expression profiles in other clones. Gene Ontology (GO) clusters were analyzed using Ingenuity Pathways Analysis to identify altered gene networks and associated nodes. We determined three nodes of interest that exhibited dysfunctional regulation of downstream gene products without themselves having altered expression. One node, peroxisome proliferator-activated protein γ (PPARG), was sequenced and found to contain a coding region mutation in PPARG2 only in transformed cells. Further analysis suggests that this mutation leads to dominant negative activity of PPARG2. PPARG is a transcription factor implicated to have tumour suppressor function. This suggests that the PPARG2 mutant may have played a role in driving cellular transformation. We conclude that PPARG induces cellular transformation by a mutational mechanism.


Oral iron supplementation after blood donation: a randomized clinical trial.
Although blood donation is allowed every 8 weeks in the United States, recovery of hemoglobin to the currently accepted standard (12.5 g/dL) is frequently delayed, and some donors become anemic. To determine the effect of oral iron supplementation on hemoglobin recovery time (days to recovery of 80% of hemoglobin removed) and recovery of iron stores in iron-depleted ("low ferritin," ≤26 ng/mL) and iron-replete ("higher ferritin," >26 ng/mL) blood donors. Randomized, nonblinded clinical trial of blood donors stratified by ferritin level, sex, and age conducted in 4 regional blood centers in the United States in 2012. Included were 215 eligible participants aged 18 to 79 years who had not donated whole blood or red blood cells within 4 months. One tablet of ferrous gluconate (37.5 mg of elemental iron) daily or no iron for 24 weeks (168 days) after donating a unit of whole blood (500 mL). Time to recovery of 80% of the postdonation decrease in hemoglobin and recovery of ferritin level to baseline as a measure of iron stores. The mean baseline hemoglobin levels were comparable in the iron and no-iron groups and declined from a mean (SD) of 13.4 (1.1) g/dL to 12.0 (1.2) g/dL after donation in the low-ferritin group and from 14.2 (1.1) g/dL to 12.9 (1.2) g/dL in the higher-ferritin group. Compared with participants who did not receive iron supplementation, those who received iron supplementation had shortened time to 80% hemoglobin recovery in both the low-ferritin (mean, 32 days, interquartile range [IQR], 30-34, vs 158 days, IQR, 126->168) and higher-ferritin groups (31 days, IQR, 29-33, vs 78 days, IQR, 66-95). Median time to recovery to baseline ferritin levels in the low-ferritin group taking iron was 21 days (IQR, 12-84). For participants not taking iron, recovery to baseline was longer than 168 days (IQR, 128->168). Median time to recovery to baseline in the higher-ferritin group taking iron was 107 days (IQR, 75-141), and for participants not taking iron, recovery to baseline was longer than 168 days (IQR, >168->168). Recovery of iron stores in all participants who received supplements took a median of 76 days (IQR, 20-126); for participants not taking iron, median recovery time was longer than 168 days (IQR, 147->168 days; P < .001). Without iron supplements, 67% of participants did not recover iron stores by 168 days. Among blood donors with normal hemoglobin levels, low-dose iron supplementation, compared with no supplementation, reduced time to 80% recovery of the postdonation decrease in hemoglobin concentration in donors with low ferritin (≤26 ng/mL) or higher ferritin (>26 ng/mL). clinicaltrials.gov Identifier: NCT01555060.


Temperature-Induced Lattice Relaxation of Perovskite Crystal Enhances Optoelectronic Properties and Solar Cell Performance.
Hybrid organic-inorganic perovskite crystals have recently become one of the most important classes of photoactive materials in the solar cell and optoelectronic communities. Albeit improvements have focused on state-of-the-art technology including various fabrication methods, device architectures, and surface passivation, progress is yet to be made in understanding the actual operational temperature on the electronic properties and the device performances. Therefore, the substantial effect of temperature on the optoelectronic properties, charge separation, charge recombination dynamics, and photoconversion efficiency are explored. The results clearly demonstrated a significant enhancement in the carrier mobility, photocurrent, charge carrier lifetime, and solar cell performance in the 60 ± 5 °C temperature range. In this temperature range, perovskite crystal exhibits a highly symmetrical relaxed cubic structure with well-aligned domains that are perpendicular to a principal axis, thereby remarkably improving the device operation. This finding provides a new key variable component and paves the way toward using perovskite crystals in highly efficient photovoltaic cells.


Brain glucose sensing in homeostatic and hedonic regulation.
Glucose homeostasis as well as homeostatic and hedonic control of feeding is regulated by hormonal, neuronal, and nutrient-related cues. Glucose, besides its role as a source of metabolic energy, is an important signal controlling hormone secretion and neuronal activity, hence contributing to whole-body metabolic integration in coordination with feeding control. Brain glucose sensing plays a key, but insufficiently explored, role in these metabolic and behavioral controls, which when deregulated may contribute to the development of obesity and diabetes. The recent introduction of innovative transgenic, pharmacogenetic, and optogenetic techniques allows unprecedented analysis of the complexity of central glucose sensing at the molecular, cellular, and neuronal circuit levels, which will lead to a new understanding of the pathogenesis of metabolic diseases.


Perceptions and experiences of adolescents, parents and school administrators regarding adolescent-parent communication on sexual and reproductive health issues in urban and rural Uganda.
Evidence suggests that in spite of some adolescents being sexually active, many parents do not discuss sex-related issues with them due to lack of age-appropriate respectful vocabulary and skills. The likelihood of parent-adolescent communication improving sexual and reproductive health outcomes appears plausible. The desire to understand parent-adolescent communication and how to improve it for promotion of healthy sexual behaviours inspired this research. The paper is meant to describe perceptions of adolescents, parents and school administrators about parent-adolescent communication on sexual issues; describe the content of such communication and identify factors that influence this communication. The study was done among two urban and two rural secondary school students in their second year of education. Data were collected from 11 focus group discussions and 10 key Informants Interviews. Data management, analysis and interpretation followed thematic analysis principles. Illuminating verbatim quotations are used to illustrate findings. Parental warmth and acceptability of children was perceived by parents to be foundational for a healthy adolescent- parent communication. Perceptions of adolescents tended to point to more open and frequent communication with mothers than fathers and to cordial relationships with mothers. Fathers were perceived by adolescents to be strict, intimidating, unapproachable and unavailable. While adolescents tended to generally discuss sexual issues with mothers, male adolescents communicated less with anyone on sex, relationships and condoms. Much of the parent-adolescent communication was perceived to focus on sexually transmitted infections and body changes. Discussions of sex and dating with adolescents were perceived to be rare. Common triggers of sexuality discussions with female adolescents were; onset of menstruation and perceived abortion in the neighbourhood. Discussion with male adolescents, if it occurred was perceived to be triggered by parental suspicion of having female 'friends' or coming home late. Peers at school and mass media were perceived to the main source of sexuality information. Communication on sexuality issues between parents and their adolescent children was infrequent and critical elements like sex and specifics of protection against undesirable sexual behaviour consequences were avoided. Peers, schools and mass media should be creatively harnessed to improve parent-adolescent communication about sexuality issues.


Nocturnal hypoxia and arrhythmias in patients with impaired left ventricular function.
To document the incidence of hypoxic episodes in a series of patients with impaired left ventricular function, and to correlate the occurrence of hypoxia with severity of arrhythmia. 34 patients with breathlessness and clinical evidence of left ventricular dysfunction. Simultaneous overnight finger oximetry and electrocardiographic monitoring. High grade arrhythmias (Lown grade > III) occurred in 20/34 (59%) of patients, and frequent dips in oxygen saturation were noticed (mean dip frequency 4.8/h, range 0.1-20.0). 20/34 (59%) of patients had episodic hypoxaemia, including 13/34 (38%) with a classical Cheyne Stokes pattern. There was a correlation between dip frequency and the presence of high grade arrhythmias (those with high grade arrhythmia had mean (SD) 6.7 (5.5) dips/h v 2.2 (3.4) in those without, p < 0.01); there was also a correlation between the presence of arrhythmias and episodic hypoxaemia (episodic hypoxaemia in those with high grade arrhythmias occurred in 17/20 (85%) v 3/14 (21%) of those without arrhythmias, p < 0.002). There was no correlation between the presence of high grade arrhythmias or dip frequency and the extent of left ventricular impairment, which was present in all patients (mean (SD) ejection fraction 26% (13%)). Noticeable abnormalities of nocturnal oxygen saturation occur in patients with impaired left ventricular function, and these are associated with high grade arrhythmias. Interventions that limit desaturation may have valuable anti-arrhythmic effects.


Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis.
This study aimed to characterize the single-dose pharmacokinetic (PK) and pharmacodynamic (PD) profile of rivaroxaban 15 mg administered before and after dialysis in subjects with end-stage renal disease (ESRD), and to compare this profile in subjects with ESRD to that in healthy control subjects (creatinine clearance ≥80 ml/min). This was an open-label, single-dose, single-center, parallel-group study of rivaroxaban in ESRD subjects who had been clinically stable on maintenance hemodialysis for ≥3 months. In 8 subjects with ESRD, a 15-mg dose of rivaroxaban was administered 2 ± 0.5 h before a hemodialysis session and repeated 7-14 days later at 3 h after a 4-h hemodialysis session. Eight healthy control subjects, matched for age, sex, and body mass index, received one 15-mg rivaroxaban dose. Compared to healthy subjects, area under the rivaroxaban plasma concentration versus time curve (AUC) increased by 56% following post-dialysis administration. Assuming similar bioavailability between groups, this reflects an approximate 35% decrease in overall drug clearance in ESRD subjects. Pre-dialysis dosing resulted in only 5% lowering of AUC versus post-dialysis dosing, confirming the minimal impact of dialysis on the PK of rivaroxaban. PD effects, as assessed by change in prothrombin time, percent factor Xa inhibition, and anti-Xa activity, were generally concordant with observed changes in plasma PK. Changes in PK and PD parameters in chronic dialysis patients were generally comparable to changes observed previously in patients with moderate-to-severe renal impairment who were not undergoing dialysis, and support use of a 15-mg dose in this patient population.


A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus.
Filamentous fungi rely heavily on the secretory pathway, both for the delivery of cell wall components to the hyphal tip and the production and secretion of extracellular hydrolytic enzymes needed to support growth on polymeric substrates. Increased demand on the secretory system exerts stress on the endoplasmic reticulum (ER), which is countered by the activation of a coordinated stress response pathway termed the unfolded protein response (UPR). To determine the contribution of the UPR to the growth and virulence of the filamentous fungal pathogen Aspergillus fumigatus, we disrupted the hacA gene, encoding the major transcriptional regulator of the UPR. The DeltahacA mutant was unable to activate the UPR in response to ER stress and was hypersensitive to agents that disrupt ER homeostasis or the cell wall. Failure to induce the UPR did not affect radial growth on rich medium at 37 degrees C, but cell wall integrity was disrupted at 45 degrees C, resulting in a dramatic loss in viability. The DeltahacA mutant displayed a reduced capacity for protease secretion and was growth-impaired when challenged to assimilate nutrients from complex substrates. In addition, the DeltahacA mutant exhibited increased susceptibility to current antifungal agents that disrupt the membrane or cell wall and had attenuated virulence in multiple mouse models of invasive aspergillosis. These results demonstrate the importance of ER homeostasis to the growth and virulence of A. fumigatus and suggest that targeting the UPR, either alone or in combination with other antifungal drugs, would be an effective antifungal strategy.