Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers.
Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.


Psychometric properties of the Brunel Mood Scale in Chinese adolescents and adults.
Building on the work of Terry and colleagues (Terry, P. C., Lane, A. M., Lane, H. J., & Keohane, L. (1999). Development and validation of a mood measure for adolescents. Journal of Sports Sciences, 17, 861-872; Terry, P. C., Lane, A. M., & Fogarty, G. J. (2003). Construct validity of the Profile of Mood States-Adolescents for use with adults. Psychology of Sport & Exercise, 4, 125-139.), the present study examined the validity and internal consistency reliability of the Chinese version of the Brunel Mood Scale (BRUMS-C) among 2,548 participants, comprising adolescent athletes (n = 520), adult athletes (n = 434), adolescent students (n = 673), and adult students (n = 921). Both adolescent and adult athletes completed the BRUMS-C before, during, or after regular training and both adolescent and adult students completed the BRUMS-C in a classroom setting. Confirmatory factor analyses (CFAs) provided support for the factorial validity of a 23-item six-factor model, with one item removed from the hypothesised measurement model. Internal consistency reliabilities were satisfactory for all subscales across each of the four samples. Criterion validity was supported with strong relationships between the BRUMS-C, abbreviated POMS, and Chinese Affect Scale consistent with theoretical predictions. Multi-sample CFAs showed the BRUMS-C to be invariant at the configural, metric, strong, and structural levels for all samples. Furthermore, latent mean difference analyses showed that athletes reported significantly higher levels of fatigue than students while maintaining almost the same levels of vigour, and adolescent students reported significantly higher levels of depressed mood than the other three samples.


Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status. We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2; 95% CI, 0.53 to 2.72; P = .66; (P)INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87; 95% CI, 0.64 to 1.16; P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11; 95% CI, 0.001 to 0.832; P = .027; (P)INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92; 95% CI, 0.60 to 1.42; P = .71). Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.


Bending and Twisting Lattice Tilt in Strained Core-Shell Nanowires Revealed by Nanofocused X-ray Diffraction.
We have investigated strained GaAs-GaInP core-shell nanowires using transmission electron microscopy and nanofocused scanning X-ray diffraction. Nominally identical growth conditions for each sample were achieved by using nanoimprint lithography to create wafer-scale arrays of Au seed particles. However, we observe large individual differences, with neighboring nanowires showing either straight, bent, or twisted morphology. Using scanning X-ray diffraction, we reconstructed and quantified the bending and twisting of the nanowires in three dimensions. In one nanowire, we find that the shell lattice is tilted with respect to the core lattice, with an angle that increases from 2° at the base to 5° at the top. Furthermore, the azimuthal orientation of the tilt changes by 30° along the nanowire axis. Our results demonstrate how strained core-shell nanowire growth can lead to a rich interplay of composition, lattice mismatch, bending and lattice tilt, with additional degrees of complexity compared with thin films.


Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.
Stargazer, an ataxic and epileptic mutant mouse, lacks functional AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate) receptors on cerebellar granule cells. Stargazin, the mutated protein, interacts with both AMPA receptor subunits and synaptic PDZ proteins, such as PSD-95. The interaction of stargazin with AMPA receptor subunits is essential for delivering functional receptors to the surface membrane of granule cells, whereas its binding with PSD-95 and related PDZ proteins through a carboxy-terminal PDZ-binding domain is required for targeting the AMPA receptor to synapses. Expression of a mutant stargazin lacking the PDZ-binding domain in hippocampal pyramidal cells disrupts synaptic AMPA receptors, indicating that stargazin-like mechanisms for targeting AMPA receptors may be widespread in the central nervous system.


Selective interactions of cells with crystal surfaces. Implications for the mechanism of cell adhesion.
In this study we have characterized the mode of cell adhesion to calcite and calcium (R,R)-tartrate tetrahydrate crystals. The use of crystals as adhesion substrata was motivated by their well-established chemical nature and structurally defined surfaces. We show that calcite binds A6 Xenopus laevis epithelial cells rapidly and efficiently, most likely via surface-adsorbed proteins. Surface topology had only a limited effect on the adhesive interactions. Calcium (R,R)-tartrate tetrahydrate crystals exhibits two chemically equivalent, yet structurally distinct faces that differ mainly in the surface distribution of their lattice water molecules and charges. However, despite the gross similarity between the two faces striking differences were noted in their adhesive behavior. One of the faces was highly adhesive for cells, leading to protein-independent attachment and spreading followed by cell death. In contrast, cell adhesion to the other surface of tartrate was slow (> 24 h) and apparently mediated by RGD-containing protein(s). It was further shown that the latter face of tartrate crystals could be "conditioned" by long (24 h) incubation with serum-containing medium, after which it becomes highly adhesive. The results presented here indicate that crystal surfaces may serve as excellent, structurally defined, substrata for cell adhesion, that cell binding may occur directly or via RGD-containing proteins and that cell adhesion may be dramatically modulated by variations in surface structure. The implications of the results to the mechanism of cell-substratum adhesion are discussed.


Chaetoglobosin A preferentially induces apoptosis in chronic lymphocytic leukemia cells by targeting the cytoskeleton.
Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B cells. One of the major challenges in treatment of CLL is the achievement of a complete remission to prevent relapse of disease originating from cells within lymphoid tissues and subsequent chemoresistance. In search for novel drugs that target CLL cells in protective microenvironments, we performed a fungal extract screen using cocultures of primary CLL cells with bone marrow-derived stromal cells. A secondary metabolite produced by Penicillium aquamarinium was identified as Chaetoglobosin A (ChA), a member of the cytochalasan family that showed preferential induction of apoptosis in CLL cells, even under culture conditions that mimic lymphoid tissues. In vitro testing of 89 CLL cases revealed effective targeting of CLL cells by ChA, independent of bad prognosis characteristics, like 17p deletion or TP53 mutation. To provide insight into its mechanism of action, we showed that ChA targets filamentous actin in CLL cells and thereby induces cell-cycle arrest and inhibits membrane ruffling and cell migration. Our data further revealed that ChA prevents CLL cell activation and sensitizes them for treatment with PI3K and BTK inhibitors, suggesting this compound as a novel potential drug for CLL.


Temporal trails of natural selection in human mitogenomes.
Mildly deleterious mutations initially contribute to the diversity of a population, but later they are selected against at high frequency and are eliminated eventually. Using over 1,500 complete human mitochondrial genomes along with those of Neanderthal and Chimpanzee, I provide empirical evidence for this prediction by tracing the footprints of natural selection over time. The results show a highly significant inverse relationship between the ratio of nonsynonymous-to-synonymous divergence (d(N)/d(S)) and the age of human haplogroups. Furthermore, this study suggests that slightly deleterious mutations constitute up to 80% of the mitochondrial amino acid replacement mutations detected in human populations and that over the last 500,000 years these mutations have been gradually removed.


Sensory information from a slipping object elicits a rapid and automatic shoulder response.
Humans have the remarkable ability to hold, grasp, and manipulate objects. Previous work has reported rapid and coordinated reactions in hand and shoulder muscles in response to external perturbations to the arm during object manipulation; however, little is known about how somatosensory feedback of an object slipping in the hand influences responses of the arm. We built a handheld device to stimulate the sensation of slipping at all five fingertips. The device was integrated into an exoskeleton robot that supported it against gravity. The setup allowed us to decouple somatosensory stimulation in the fingers from forces applied to the arm, two variables that are highly interdependent in real-world scenarios. Fourteen participants performed three experiments in which we measured their arm feedback responses during slip stimulation. Slip stimulations were applied horizontally in one of two directions, and participants were instructed to either follow the slip direction or move the arm in the opposite direction. Participants showed shoulder muscle responses within ∼67 ms of slip onset when following the direction of slip but significantly slower responses when instructed to move in the opposite direction. Shoulder responses were modulated by the speed but not the distance of the slip. Finally, when slip stimulation was combined with mechanical perturbations to the arm, we found that sensory information from the fingertips significantly modulated the shoulder feedback responses. Overall, the results demonstrate the existence of a rapid feedback system that stabilizes handheld objects.NEW & NOTEWORTHY We tested whether the sensation of an object slipping from the fingers modulates shoulder feedback responses. We found rapid shoulder feedback responses when participants were instructed to follow the slip direction with the arm. Shoulder responses following mechanical joint perturbations were also potentiated when combined with slipping. These results demonstrate the existence of fast and automatic feedback responses in the arm in reaction to sensory input to the fingertips that maintain grip on handheld objects.


Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease.
The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.


Long-term effects of neonicotinoid insecticides on ants.
The widespread prophylactic usage of neonicotinoid insecticides has a clear impact on non-target organisms. However, the possible effects of long-term exposure on soil-dwelling organisms are still poorly understood especially for social insects with long-living queens. Here, we show that effects of chronic exposure to the neonicotinoid thiamethoxam on black garden ant colonies, Lasius niger, become visible before the second overwintering. Queens and workers differed in the residue-ratio of thiamethoxam to its metabolite clothianidin, suggesting that queens may have a superior detoxification system. Even though thiamethoxam did not affect queen mortality, neonicotinoid-exposed colonies showed a reduced number of workers and larvae indicating a trade-off between detoxification and fertility. Since colony size is a key for fitness, our data suggest long-term impacts of neonicotinoids on these organisms. This should be accounted for in future environmental and ecological risk assessments of neonicotinoid applications to prevent irreparable damages to ecosystems.


The dual regulator Sufu integrates Hedgehog and Wnt signals in the early Xenopus embryo.
Hedgehog (Hh) and Wnt proteins are important signals implicated in several aspects of embryonic development, including the early development of the central nervous system. We found that Xenopus Suppressor-of-fused (XSufu) affects neural induction and patterning by regulating the Hh/Gli and Wnt/β-catenin pathways. Microinjection of XSufu mRNA induced expansion of the epidermis at the expense of neural plate tissue and caused enlargement of the eyes. An antisense morpholino oligonucleotide against XSufu had the opposite effect. Interestingly, both gain- and loss-of-function experiments resulted in a posterior shift of brain markers, suggesting a biphasic effect of XSufu on anteroposterior patterning. XSufu blocked early Wnt/β-catenin signaling, as indicated by the suppression of XWnt8-induced secondary axis formation in mRNA-injected embryos, and activation of Wnt target genes in XSufu-MO-injected ectodermal explants. We show that XSufu binds to XGli1 and Xβ-catenin. In Xenopus embryos and mouse embryonic fibroblasts, Gli1 inhibits Wnt signaling under overexpression of β-catenin, whereas β-catenin stimulates Hh signaling under overexpression of Gli1. Notably, endogenous Sufu is critically involved in this crosstalk. The results suggest that XSufu may act as a common regulator of Hh and Wnt signaling and contribute to intertwining the two pathways.


Evaluation of the alkaline comet assay and urinary 3-methyladenine excretion for monitoring DNA damage in melanoma patients treated with dacarbazine and tamoxifen.
To develop, using dacarbazine as a model, reliable techniques for measuring DNA damage and repair as pharmacodynamic endpoints for patients receiving chemotherapy. A group of 39 patients with malignant melanoma were treated with dacarbazine 1 g/m(2) i.v. every 21 days. Tamoxifen 20 mg daily was commenced 24 h after the first infusion and continued until 3 weeks after the last cycle of chemotherapy. DNA strand breaks formed during dacarbazine-induced DNA damage and repair were measured in individual cells by the alkaline comet assay. DNA methyl adducts were quantified by measuring urinary 3-methyladenine (3-MeA) excretion using immunoaffinity ELISA. Venous blood was taken on cycles 1 and 2 for separation of peripheral blood lymphocytes (PBLs) for measurement of DNA strand breaks. Wide interpatient variation in PBL DNA strand breaks occurred following chemotherapy, with a peak at 4 h (median 26.6 h, interquartile range 14.75-40.5 h) and incomplete repair by 24 h. Similarly, there was a range of 3-MeA excretion with peak levels 4-10 h after chemotherapy (median 33 nmol/h, interquartile range 20.4-48.65 nmol/h). Peak 3-MeA excretion was positively correlated with DNA strand breaks at 4 h (Spearman's correlation coefficient, r=0.39, P=0.036) and 24 h (r=0.46, P=0.01). Drug-induced emesis correlated with PBL DNA strand breaks (Mann Whitney U-test, P=0.03) but not with peak 3-MeA excretion. DNA damage and repair following cytotoxic chemotherapy can be measured in vivo by the alkaline comet assay and by urinary 3-MeA excretion in patients receiving chemotherapy.


Drosophila methionine sulfoxide reductase A (MSRA) lacks methionine oxidase activity.
Mouse, human, and E. coli methionine sulfoxide reductase A (MSRA) stereospecifically catalyze both the reduction of S-methionine sulfoxide to methionine and the oxidation of methionine to S-methionine sulfoxide. Calmodulin has 9 methionine residues, but only Met77 is oxidized by MSRA, and this is completely reversed when MSRA operates in the reductase direction. Given the powerful genetic tools available for Drosophila, we selected this model organism to identify the in vivo calmodulin targets regulated by redox modulation of Met77. The active site sequences of mammalian and Drosophila MSRA are identical, and both contain two cysteine residues in their carboxy terminal domains. We produced recombinant Drosophila MSRA and studied its biochemical and biophysical properties. The enzyme is active as a methionine sulfoxide reductase, but it cannot function as a methionine oxidase. The first step in the mammalian oxidase reaction is formation of a sulfenic acid at the active site, and the second step is the reaction of the sulfenic acid with a carboxy terminal domain cysteine to form a disulfide bond. The third step regenerates the active site through a disulfide exchange reaction with a second carboxy terminal domain cysteine. Drosophila MSRA carries out the first and second steps, but it cannot regenerate the active site in the third step. Thus, unlike the E. coli and mammalian enzymes, Drosophila MSRA catalyzes only the reduction of methionine sulfoxide and not the oxidation of methionine.


Renal and Splenic Infarction in a Patient with Familial Hypercholesterolemia and Previous Cerebral Infarction.
BACKGROUND This is a case report of a male patient who presented with a history of right flank pain based on renal infarction. Initially the symptoms were misdiagnosed as acute pyelonephritis. CASE REPORT A 47-year-old male with a history of familial hypercholesterolemia and cerebral infarction presented at the Emergency Department with a 3-day history of acute right-sided flank pain. Physical examination revealed hypertension, subfebrile temperature, and costovertebral angle tenderness. Blood tests were unremarkable except for renal impairment, a high C-reactive protein level of 215 mg/L (normal <8 mg/dL) and an elevated lactate dehydrogenase (LDH) of 1289 U/L (normal <248 U/L). Renal ultrasonography was normal. He was admitted with a presumed diagnosis of acute pyelonephritis and treated accordingly. However, 2 days later, we rejected this diagnosis as the urine culture was sterile. Based on the acute onset of symptoms and the initial high LDH, renal infarction was suspected. A computed tomography scan confirmed right-sided partial renal and splenic infarctions likely due to spreading emboli from atherosclerosis of the descending aorta. CONCLUSIONS Acute renal infarction is often missed or delayed as a diagnosis because patients often present with flank pain that can resemble more frequently encountered conditions such as pyelonephritis and nephrolithiasis. Renal infarction should be considered in cases with acute flank pain accompanied by (low-grade) fever, high LDH level, increased C-reactive protein level, hypertension, and renal impairment, especially in those patients with an increased risk of thromboembolism.


Urinary Tract Infection: Which Conformation of the Bacterial Lectin FimH Is Therapeutically Relevant?
Frequent antibiotic treatment of urinary tract infections has resulted in the emergence of antimicrobial resistance, necessitating alternative treatment options. One such approach centers around FimH antagonists that block the bacterial adhesin FimH, which would otherwise mediate binding of uropathogenic Escherichia coli to the host urothelium to trigger the infection. Although the FimH lectin can adopt three distinct conformations, the evaluation of FimH antagonists has mainly been performed with a truncated construct of FimH locked in one particular conformation. For a successful therapeutic application, however, FimH antagonists should be efficacious against all physiologically relevant conformations. Therefore, FimH constructs with the capacity to adopt various conformations were applied. By examining the binding properties of a series of FimH antagonists in terms of binding affinity and thermodynamics, we demonstrate that depending on the FimH construct, affinities may be overestimated by a constant factor of 2 orders of magnitude. In addition, we report several antagonists with excellent affinities for all FimH conformations.


Multiple scattering tomography.
Multiple scattering represents a challenge for numerous modern tomographic imaging techniques. In this Letter, we derive an appropriate line integral that allows for the tomographic reconstruction of angular resolved scattering distributions, even in the presence of multiple scattering. The line integral is applicable to a wide range of imaging techniques utilizing various kinds of probes. Here, we use x-ray grating interferometry to experimentally validate the framework and to demonstrate additional structural sensitivity, which exemplifies the impact of multiple scattering tomography.


Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths.
Liver cancer and liver cirrhosis are common causes of death in China, where chronic lifelong hepatitis B infection is a major cause of both diseases. To help determine whether smoking is a cofactor for the development of liver cancer, we ascertained retrospectively the smoking habits of 36,000 adults who had died from liver cancer (cases) and 17,000 who had died from cirrhosis (controls) in 24 Chinese cities and 74 rural counties. Calculations of the smoker vs. nonsmoker risk ratios (RR) for liver cancer mortality were standardised for age and locality. Among adult men (aged 35+) there was a 36% excess risk of death from liver cancer among smokers (smoker vs. nonsmoker standardised risk ratio [RR] =1.36, with 95% confidence interval [CI] 1.29-1.43, 2p<0.00001; attributable fraction 18%). In the general male population this indicates absolute risks of death from liver cancer before age 70 of about 4% in smokers and 3% in nonsmokers (in the absence of other causes). Most liver cancer, however, occurs among the 10-12% of men with haematological evidence of chronic hepatitis B infection, so among them the corresponding risks would be about 33% in smokers and 25% in nonsmokers. The RR was approximately independent of age, was similar in urban and rural areas, was not significantly related to the age when smoking started but was significantly (p<0.001) greater for cigarette smokers than for smokers of other forms of tobacco. Among men who smoked only cigarettes, the RR was significantly (p<0.001 for trend) related to daily consumption, with a greater hazard among those who smoked 20/day (RR 1.50, 95% CI 1.39-1.62) than among those who smoked fewer (mean 10/day: RR=1.32, 95% CI 1.23-1.41). Smoking was also associated with a significant excess of liver cancer death in women (RR 1.17, 95% CI 1.06-1.29, 2p=0.003; attributable fraction 3%), but fewer women (17%) than men (62%) were smokers, and their cigarette consumption per smoker was lower. Among women who smoked only cigarettes, there was a significantly greater hazard among those who smoked at least 20/day (mean 22/day: RR=1.45, 95% CI 1.18-1.79) than among those who smoked fewer (mean 8/day: RR=1.09, 95% CI 0.94-1.25). These associations indicate that tobacco is currently responsible for about 50,000 liver cancer deaths each year in China, chiefly among men with chronic HBV infection.


Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene.
The refractoriness of prostate cancer to androgen suppression is the landmark of clinically aggressive disease. In this study, the androgen-dependent LNCaP prostate cancer cells were transfected with the mutated c-Ha-ras gene from the T24 human bladder cancer. The derivative clone overexpressing T24-ras (LNCaP(T24-ras)) proliferated in androgen-depleted medium and showed increased growth. Protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells were tested in the presence of phenylacetate to document a possible relationship with the drug-induced inhibition of cell proliferation. Phenylacetate is a differentiation inducer that down-regulates in vitro the expression of the myc oncogene and activates the human peroxisome proliferator-activated nuclear receptor involved in cell growth regulation. The drug inhibited protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells; IC50 values were 3.1 and 3.3 mM, respectively, compared with controls. The drug reduced the cellular levels of endogenous farnesyl-PP (mean IC50 = 3.5 mM) and inhibited activation of the p21ras downstream target, p42(MAPK)/ERK2. LNCaP(T24-ras) was more sensitive than the parental line to both growth inhibition (mean IC50 = 3.01 and 7.1 mM, respectively) and apoptosis by phenylacetate. Exogenous farnesyl- and geranylgeranyl-PP indeed reduced the effects of the drug on proliferation and apoptosis in LNCaP(T24-ras) cells. In conclusion, the inhibition of protein isoprenylation and p21ras farnesylation by phenylacetate resulted in increased chemosensitivity of the androgen-independent LNCaP(T24-ras) cells compared with LNCaP, and this effect might contribute to the pharmacological activity of the drug.


Trochanteric micropuncture: treatment for gluteus medius tendinopathy.
Lateral hip pain along with tenderness of the greater trochanter has been associated with greater trochanteric pain syndrome. Radiographically, this has been associated with gluteus medius pathology on magnetic resonance imaging. This has led some surgeons to conclude that abductor pathology is a primary cause of lateral hip pain. Failure of conservative treatment in the setting of gluteus medius pathology may lead to surgical intervention. In some patients a focal tear of the gluteus medius cannot be visualized and likely represents more diffuse tendinopathy. In these patients we propose micropuncture of the greater trochanter. Similar procedures have shown effectiveness in the elbow and shoulder by eliciting a healing response. Our experience suggests that trochanteric micropuncture at the insertion of the gluteus medius tendon can be effectively performed endoscopically for gluteus medius tendinopathy.


Multiportal endoscopic approaches to the central skull base: a cadaveric study.
There has been marked evolution in techniques in skull base surgery including the development of minimally invasive endoscopic supraorbital, transnasal, and more recently, transorbital approaches. These have been typically described as isolated, rather than concerted approaches. It is possible that rather than using these approaches alone, they could be combined with transnasal approaches to provide improved manipulation angles, shorter working distances, and optimal visualization of the pathology. The primary objective of this study is therefore to determine whether these pathways can be combined in "multiportal" approaches to further improve the surgeon's ability to access and manipulate pathology in the central anterior cranial fossa. A study was performed on five cadaver heads. Each cadaver underwent an expanded endoscopic binasal approach with clivectomy, bilateral precaruncular transorbital approaches, and bilateral supraorbital craniotomies through an eyebrow incision. A total of 25 procedures were performed. Five endonasal, 10 transorbital, and 10 supraorbital procedures were performed using 0- and 45-degree 4-mm rigid endoscopes. Measurements were obtained from the nasal spine and anterior lacrimal crest to the pituitary gland (PG), optic chiasm (OC), and ipsilateral cavernous carotid artery (IpsiCavCa). Measurements from the anterior border of the orbital roof through the supraorbital approach to the PG and OC were also performed. Photographs were taken to demonstrate these approaches and angles of visualization. The precaruncular transorbital approach provided a uniformly shorter distance to the PG, OC, and IpsiCavCa compared with the endoscopic transnasal approach. The difference in the mean distances between these two approaches in the left and right sides were 2.38 cm (P=.000) and 2.56 cm (P=.000), respectively. The supraorbital approach to the PG and OC was shorter than the transnasal by a mean difference of 1.92 cm (P=.000) and 1.99 cm (P=.000) on the right and left side, respectively. There was no significant difference in the mean distances to the PG and the OC between the transorbital and supraorbital approaches. Use of these approaches in tandem provided an extra working port by which structures above and below the target organ were better visualized and more easily dissected with two-handed microsurgical techniques than through a single approach. The precaruncular transorbital approach provided rapid, direct, coplanar access to the clivus, sella, and suprasellar/parasellar regions. The supraorbital minicraniotomy augmented access to the planum sphenoidale, sella, tuberculum sella, and suprasellar regions. These approaches provided shorter working distances, improved visualization, and working angles that offer more direct access to the pituitary gland, suprasellar region, clivus, medial and lateral cavernous sinus than the endoscopic transnasal approach alone. The combination of endoscopic approaches to the central anterior skull base significantly improved instrument access, particularly to lateral targets, as well as better visualization of the vital structures in these regions. These ports provide the surgeon with a more expansive surgical field and improved the ability to perform two-handed microsurgical dissections.


Vitamin D Supplementation in Patients with Chronic Low Back Pain: An Open Label, Single Arm Clinical Trial.
Vitamin-D deficiency may possibly be related to chronic low back pain (CLBP). The study is aimed to assess the impact of vitamin-D supplementation on pain intensity, functional disability, and vitamin-D levels in patients with CLBP. Single arm open-label study. Outpatient pain clinic of a tertiary care hospital. Sixty-eight eligible patients (CLBP for = 3 months, pain score = 50 on visual analogue scale (VAS) and plasma 25-Hydroxyvitamin D3 levels < 30 ng/mL) were enrolled. Patients were supplemented with 60,000 IU of oral vitamin-D3 given every week for 8 weeks. Efficacy parameters included pain intensity and functional disability measured by VAS and modified Oswestry disability questionnaire (MODQ) scores at baseline, 2, 3, and 6 months post-supplementation. Plasma 25(OH) D3 levels were measured at baseline and 8 weeks. Baseline mean (SD) vitamin-D levels were 12.8 (5.73) ng/mL and increased to 36.07 (12.51) post supplementation (P < 0.01). Forty-five (66%) patients attained normal levels (> 29 ng/mL) post supplementation. Significant reduction in VAS was observed at 2, 3, and 6 months [61 (19), 45 (19), 36 (18)] as compared to 81 (19) at baseline (P = 0.001 at all-time intervals). A significant improvement in the functional ability was also observed at 2, 3, and 6 months [36 (12), 31 (13), and 26 (10)] as compared to baseline 45 (16) (P = 0.001 at all-time intervals). Vitamin-D supplementation in deficient CLBP patients may lead to improvement in pain intensity and functional ability apart from normalization of the levels. Future controlled clinical trials are required to confirm the hypothesis.Key words: Vitamin D, deficiency, screening, low back pain, chronic, supplementation.


Nanoporous membranes for medical and biological applications.
Synthetic nanoporous materials have numerous potential biological and medical applications that involve sorting, sensing, isolating, and releasing biological molecules. Nanoporous systems engineered to mimic natural filtration systems are actively being developed for use in smart implantable drug delivery systems, bioartificial organs, and other novel nano-enabled medical devices. Recent advances in nanoscience have made it possible to precisely control the morphology as well as physical and chemical properties of the pores in nanoporous materials that make them increasingly attractive for regulating and sensing transport at the molecular level. In this work, an overview of nanoporous membranes for biomedical applications is given. Various in vivo and in vitro membrane applications, including biosensing, biosorting, immunoisolation, and drug delivery, are presented. Different types of nanoporous materials and their fabrication techniques are discussed with an emphasis on membranes with ordered pores. Desirable properties of membranes used in implantable devices, including biocompatibility and antibiofouling behavior, are discussed. The use of surface modification techniques to improve the function of nanoporous membranes is reviewed. Despite the extensive research carried out in fabrication, characterization, and modeling of nanoporous materials, there are still several challenges that must be overcome in order to create synthetic nanoporous systems that behave similarly to their biological counterparts.


A systematic review of randomized controlled trials of mHealth interventions against non-communicable diseases in developing countries.
The reasons of deaths in developing countries are shifting from communicable diseases towards non-communicable diseases (NCDs). At the same time the number of health care interventions using mobile phones (mHealth interventions) is growing rapidly. We review studies assessing the health-related impacts of mHealth on NCDs in low- and middle-income countries (LAMICs). A systematic literature search of three major databases was performed in order to identify randomized controlled trials (RCTs) of mHealth interventions. Identified studies were reviewed concerning key characteristics of the trial and the intervention; and the relationship between intervention characteristics and outcomes was qualitatively assessed. The search algorithms retrieved 994 titles. 8 RCTs were included in the review, including a total of 4375 participants. Trials took place mostly in urban areas, tested different interventions (ranging from health promotion over appointment reminders and medication adjustments to clinical decision support systems), and included patients with different diseases (diabetes, asthma, hypertension). Except for one study all showed rather positive effects of mHealth interventions on reported outcome measures. Furthermore, our results suggest that particular types of mHealth interventions that were found to have positive effects on patients with communicable diseases and for improving maternal care are likely to be effective also for NCDs. Despite rather positive results of included RCTs, a firm conclusion about the effectiveness of mHealth interventions against NCDs is not yet possible because of the limited number of studies, the heterogeneity of evaluated mHealth interventions and the wide variety of reported outcome measures. More research is needed to better understand the specific effects of different types of mHealth interventions on different types of patients with NCDs in LaMICs.


Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele.
To determine whether memory loss is detectable before the symptomatic presentation of mild cognitive impairment (MCI) in those at greater genetic risk for Alzheimer disease (AD) based upon presence or absence of the e4 allele of APOE. Participants were age 50 years or older who responded to newspaper advertisements. A total of 212 cognitively normal individuals of known APOE genotype were initially enrolled in a match paradigm that included e4 homozygotes, e3/4 heterozygotes, and e4 noncarriers in a 1:1:2 ratio (53 sets). Of the original 212 individually matched participants, 180 completed at least two epochs of testing including 45 APOE e4/4 homozygotes, 42 APOE e3/4 heterozygotes, and 93 APOE e4 noncarriers, mean age 60 (+/-6.2) years. Of these, four developed MCI or AD during the follow-up period and were excluded from analysis. Longitudinal neuropsychological study included two verbal (Auditory Verbal Learning Test [AVLT], Selective Reminding Test [SRT]) and two visual (Complex Figure Test [CFT], Visual Retention Test) memory tests. Multiple measures on both verbal memory tests showed poorer performance over a mean interval of 33 months in e4 carriers than noncarriers: AVLT total learning, long term delayed recall; SRT free and cued recall. Among those age 50 to 59 years, AVLT long term delayed recall, SRT free and cued recall, and CFT recall declined more in APOE e4 carriers. No differences were found in the domains of language, spatial skills, or executive function. Memory declined in APOE e4 carriers before the symptomatic presentation of MCI in a cohort whose mean age was 60 years over a median period of 33 months. The decline began prior to age 60.


26th Lauriston S. Taylor Lecture: developing mechanistic data for incorporation into cancer and genetic risk assessments: old problems and new approaches.
The theme that runs through this 26th Taylor Lecture is the question of how can data on the mechanism of induction of genetic alterations by radiations and chemicals be used to support the development of risk estimates, particularly at low exposure levels. The premise is that chromosomal alterations are involved in the development of tumors and birth defects, and that data generated for genetic alterations can be interpreted in terms of these adverse health outcomes. The general conclusions are that chromosomal alterations can be induced by ionizing radiations by a single energy loss event in a target of the size of a DNA molecule and that aberrations generally result from misrepair or failure to repair the induced lesions (generally assumed to be double-strand breaks). Chromosomal alterations induced by chemicals are produced almost exclusively by replication errors on a damaged DNA template. Thus, cell cycle stage and DNA repair and replication fidelity will be influential on overall sensitivity to aberration induction. These same features are also important in considerations of genetic susceptibility-alterations in cell cycle control or DNA repair or replication fidelity can alter sensitivity. The differences in mechanism of induction of chromosomal aberrations by ionizing radiation and chemicals is most important when considering cells at risk and comparative sensitivities among species and cell types. Models of cancer induction have gradually evolved from initiation, promotion, and progression models to multistep genetic models to the most recent one of six acquired characteristics. This evolution has passed the level of concentration of research from single gene, single cell to multiple genes (pathways), and whole tissues. The latter areas of concentration are ideal for addressing with the new genomics, proteomics, and computational modeling approaches. The attention is still on the role of genetic alterations in cancer and hereditary effects and the mechanism of their formation--it is the approaches to address these that are changing.


'Living stones' reveal alternative petal identity programs within the core eudicots.
Petals, defined as the showy laminar floral organs in the second floral whorl, have been shown to be under similar genetic control in distantly related core eudicot model organisms. On the basis of these findings, it is commonly assumed that the petal identity program regulated by B-class MADS-box gene homologs is invariant across the core eudicot clade. However, the core eudicots, which comprise >70% of angiosperm species, exhibit numerous instances of petal and sepal loss, transference of petal function between floral whorls, and recurrent petal evolution. In the face of these complex patterns of perianth evolution, the concept of a core eudicot petal identity program has not been tested. We therefore examined the petal identity program in the Caryophyllales, a core eudicot clade in which perianth differentiation into sepals and petals has evolved multiple times. Specifically, we analyzed the expression patterns of B- and C-class MADS-box homologs for evidence of a conserved petal identity program between sepal-derived and stamen-derived petaloid organs in the 'living stone' family Aizoaceae. We found that neither sepal-derived nor stamen-derived petaloid organs exhibit gene expression patterns consistent with the core eudicot petal identity program. B-class gene homologs are not expressed during the development of sepal-derived petals and are not implicated in petal identity in stamen-derived petals, as their transient expression coincides with early expression of the C-class homolog. We therefore provide evidence for petal development that is independent of B-class genes and suggest that different genetic control of petal identity has evolved within this lineage of core eudicots. These findings call for a more comprehensive understanding of perianth variation and its genetic causes within the core eudicots--an endeavor that will have broader implications for the interpretation of perianth evolution across angiosperms.


Psychological health and HIV transmission among female sex workers: a systematic review and meta-analysis.
Current HIV prevention interventions for female sex workers (FSWs) have tended to target the cognitive factors in changing their behaviors, yet little attention has been paid to the psychological factors that influence the behavior of women in sex work. This review aimed to explore the associations between the psychological health of FSWs and HIV risk. A total of eight studies published in English before July 2013 were identified and reviewed. FSWs had reported psychological issues, including depression, suicidal thoughts as well as lower quality of life, and the pooled prevalence of probable depression was as high as 62.4%. The majority of studies showed that higher scores in psychological health problems were associated with increased HIV risk behavior, in particular inconsistent condom use, or sexually transmitted infections. Among the five studies which measured symptoms of depression, four documented that higher depression scores were significantly associated with inconsistent condom use among FSWs with their clients and/or partners. Meta-analysis using a fixed-effects model was performed to examine the association between depression and inconsistent condom use and found that higher scores in depression were significantly associated with inconsistent condom use (odds ratio = 2.57, p < .001). This review contends that future HIV preventive interventions should take psychological health of FSWs into consideration.


Effects of hydrogen peroxide-induced oxidative damage on outflow facility and washout in pig eyes.
Previous studies show that hydrogen peroxide (H2O2) is present in the aqueous humor of many species and is capable of affecting outflow facility in animal model experiments. To study the hypothesis that oxidative damage to the outflow pathway may play a role in the pathogenesis of primary open-angle glaucoma, 3 mM H2O2 with 20 mM 3-aminotriazole and 1 mM carmustine (BCNU) in Dulbecco's phosphate-buffered saline (DPBS) was perfused into enucleated pig eyes at constant pressure. Baseline and experimental perfusions were done at two different pressures (7.5 and 30 mm Hg) to study the effect of pressure on the response to oxidative damage. Outflow facility in the baseline experiments (with DPBS only) was observed to increase nonlinearly with time during the perfusions, but could be linearized if plotted as a function of the volume perfused. Thus, a term "volumetric washout" (W) was introduced and defined as the fractional rate of change of outflow facility with respect to the volume perfused. This quantity was found to be independent of pressure in the baseline studies. Perfusion of H2O2 and inhibitors increased W at 7.5 mm Hg but decreased W at 30 mm Hg. These results indicate that oxidative damage increases outflow facility at normal pressure but decreases it at elevated pressure, suggesting that elevated pressure may increase the susceptibility of the outflow pathway to this form of insult.


[Inhibitory effect of angiotensin II receptor antagonist on the contraction and growth of hepatic stellate cells].
This study aimed to investigate the effects of angiotensin II (ANG II) and its receptor antagonist (losartan) on the contraction and growth of HSCs. HSCs were isolated from Sprague Dawley rat and cultured at various conditions as follows: control, pretreatment of 10(-5) M ANG II, pretreatment of 10(-5) M endothelin, and pretreatment of 10(-5) M ANG II and 10(-6) M losartan. We conducted morphologic analysis with cellular area and length by image analysis system to estimate cell growth in each group. In addition, we measured the change of intracellular calcium currents via electrophysiological methods to evaluate the contractile effect of ANG II and losartan on HSCs. At the fifth day of incubation, the mean cellular area of ANG II-pretreated group and ANG II with losartan-pretreated group were 704.68+/-22.6 micro m2 and 332.90+/-32.6 micro m2, respectively. This difference was statistically significant (p<0.05). ANG II induced an increase in the intracellular calcium current by 22.0+/-3.0% compared with basal current level (p<0.05). However, when losartan was pretreated, ANG II did not cause a significant increase in calcium current (3.1+/-0.8%, p>0.05). ANG II accelerates the contraction and growth of HSCs, while its receptor blocker, losartan, inhibits the contraction and growth of HSCs.


Mechanisms of enveloped virus entry into cells.
Enveloped animal viruses enter their host cells by a process of membrane fusion. This fusion can occur at the cell plasma membrane or within the endocytic vacuolar system, depending on the characteristics of the virus fusion protein. Examples of both pathways of viral entry are detailed in this review. Semliki Forest virus (SFV) is presented as a well-studied prototype of those viruses which use endocytic uptake in order to infect cells. Fusion of endocytosed SFV is specifically triggered by the acidic pH present within the endocytic pathway, which causes specific conformational changes in the SFV spike protein. While the overall features of endocytic uptake are similar for all viruses which use this pathway, the mechanism by which the viruses then cause fusion appears to differ significantly between them. The best understood fusion mechanism is that of influenza virus, for which sequences involved in pH-dependent fusion can be correlated with the crystallographic structure of the spike protein. In contrast to these pH-dependent virus systems, the entry of human immunodeficiency virus (HIV) into cells occurs by a pH-independent fusion mechanism probably involving fusion at the plasma membrane. The data to date on HIV fusion, endocytosis and entry are summarized as an example of this pathway.


Stable biochemically micro-patterned hydrogel layers control specific cell adhesion and allow long term cyclic tensile strain experiments.
Poly(dimethylsiloxane) can be covalently coated with ultrathin NCO-sP(EO-stat-PO) hydrogel layers which permit covalent binding of cell adhesive moieties, while minimizing unspecific cell adhesion on non-functionalized areas. We applied long term uniaxial cyclic tensile strain (CTS) and revealed (a) the preservation of protein and cell-repellent properties of the NCO-sP(EO-stat-PO) coating and (b) the stability and bioactivity of a covalently bound fibronectin (FN) line pattern. We studied the adhesion of human dermal fibroblast (HDFs) on non-modified NCO-sP(EO-stat-PO) coatings and on the FN. HDFs adhered to FN and oriented their cell bodies and actin fibers along the FN lines independently of the direction of CTS. This mechanical long term stability of the bioactive, patterned surface allows unraveling biomechanical stimuli for cellular signaling and behavior to understand physiological and pathological cell phenomenon. Additionally, it allows for the application in wound healing assays, tissue engineering, and implant development demanding spatial control over specific cell adhesion.


Assessment of renal blood flow with contrast ultrasonography.
Sonicated albumin microspheres, a digitalizing ultrasound system, and a mathematical model for flow were used to determine whether blood flow in the canine kidney could be assessed with contrast ultrasound. Albunex ultrasound contrast microspheres were injected into the aorta while ultrasound images of the kidney and aorta were recorded simultaneously. Ultrasound data were obtained during contrast injections at 93 different renal blood flow rates in nine dogs. Contrast dose was calibrated to ultrasound system response for both aortic and renal images. A linear relationship between microbubble concentration used and pixel intensity was established (r = 0.89 for aortic images and r = 0.91 for renal images). Renal blood flow was manipulated from baseline by means of a hydraulic renal artery occluder and by intravenous dopamine or fenoldopam infusion. Blood flow calculated with contrast ultrasonography was compared with direct measurement obtained with an electromagnetic flow probe at each flow rate. Direct measurement correlated with rates calculated with contrast ultrasonography (r = 0.84, 95% confidence limits from 0.75 to 0.90). Overall, calculations tended to overestimate absolute flow measurements, and overestimation of flow tended to be greater during pharmacologically manipulated flow rates. We conclude the changes and trends in renal blood flow can be serially assessed in vivo with contrast ultrasonography, but technical limitations of present commercial ultrasounds systems preclude absolute quantification at this time.


Adenocarcinoma of the urinary bladder.
We report 40 patients seen over a 15-year period with a histological diagnosis of adenocarcinoma of the bladder; 18 patients had primary adenocarcinoma of the bladder, arising either from the urachus or from glandular metaplasia of the urothelium, and the other 22 had secondary lesions representing invasion from adjacent structures, notably prostate, colon and ovary. In this latter group symptoms related to the primary lesion were variable. The distinction between primary and secondary neoplasm is an important one and was rarely made on the basis of endoscopic or clinical findings alone. Urachal tumours were more common in females, whereas primary and secondary vesical adenocarcinomas were more common in males. The urachal tumours also occurred in a younger age group. Most of the adenocarcinomas, urachal or primary, were already advanced at the time of diagnosis. All tumours were palpable bimanually after resection and were at least T2 or T3. In the urachal carcinomas the results of partial cystectomy were disappointing because of the high rate of local recurrence and death from metastases. Primary non-urachal vesical adenocarcinoma carried an even poorer prognosis if non-radical surgery was carried out. The mean survival was 13 months. Radiotherapy was not effective in urachal and primary adenocarcinomas as these tumours are generally radioresistant. The treatment of secondary adenocarcinoma was governed by the primary site of the tumour. Radical surgery combined with chemotherapy and radiotherapy appeared to give the longest survival in the colonic tumours. Patients with prostatic cancer had a poorer survival rate than those with the same stage tumour but without bladder involvement, with renal failure secondary to obstructive uropathy being the commonest cause of death.


Pulmonary targeting with biodegradable salbutamol-loaded nanoparticles.
Aerosol therapy using particulate drug carriers has become an increasingly attractive method to deliver therapeutic or diagnostic compounds to the lung. Polymeric nanoparticles are widely investigated carriers in nanomedicine. The targeted and controlled release of drugs from nanoparticles for pulmonary delivery, however, is a research field that has been so far rather unexploited. Therefore, the objective of this study was to compare the pulmonary absorption and distribution characteristics of salbutamol after aerosolization as solution or entrapped into novel polymeric nanoparticles in an isolated rabbit lung model (IPL). Physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, stability of nanoparticles to nebulization, as well as pulmonary drug absorption and distribution after nebulization in the IPL were investigated. Salbutamol-loaded poly(D,L-lactide-co-glycolide) (PLGA) and poly(vinyl sulfonate-co-vinyl alcohol)-graft-poly(D,L-lactide-co-glycolide) (VS(72)-10) nanoparticles were prepared by a modified solvent displacement technique with a mean particle size of approximately 120 nm and a polydispersity index below 0.150. VS(72)-10 nanoparticles showed a more negative zeta-potential of -54.2 +/- 3.3 mV compared to PLGA nanoparticles (-36.5 +/- 2.6 mV). Salbutamol encapsulation efficiency was 25.2 +/- 4.9% and 63.4 +/- 3.5% for PLGA and VS(72)-10 nanoparticles, respectively. After nebulization utilizing the MicroSprayer physicochemical properties of salbutamol-loaded VS(72)-10 nanoparticles were virtually unchanged, whereas nebulized salbutamol-loaded PLGA nanoparticles showed a significant increase in mean particle size and polydispersity. In vitro release studies demonstrated a sustained release of the encapsulated salbutamol from VS(72)-10 nanoparticles. In parallel, a sustained salbutamol release profile was observed after aerosol delivery of these particles to the IPL as reflected by a lower salbutamol recovery in the perfusate (40.2 +/- 5.8%) when compared to PLGA nanoparticles (55.2 +/- 9.1%) and salbutamol solution (62.8 +/- 7.1%). The current study suggests that inhalative delivery of biodegradable nanoparticles may be a viable approach for the treatment of respiratory diseases.


The Outcome and Patterns of Traumatic Brain Injury in the Paediatric Population of a Developing Country Secondary to TV Trolley Tip-Over.
Television (TV) trolley tip-over incidences are common and can cause significant morbidity and mortality in children. This study was aimed at analyzing the pattern and outcomes of head injuries resulting from TV trolley tip-over. We conducted a medical chart review of children with TV trolley tip-over head injuries from January 2009 to April 2016. We collected data on demographics, the mechanism of injury, clinical and radiological features of the injury, and outcomes. Outcomes were measured by means of the Glasgow Outcome Scale (GOS) at 6 months (except in 1 case). A descriptive analysis was carried out using SPSS v19. Twenty-two children were included in the study (median age 23.5 months). Sixteen children were male. Most of the children (n = 16) were aged 12-35 months. The median Glasgow Coma Scale score on admission was 15. The median Rotterdam Score for the patients was 2.0. Common symptoms upon admission were vomiting, irritability, scalp laceration, and bruises. Median length of hospital stay was 3 days. Skull bone fractures were present in 12 children. Other CT findings included contusions, extradural and subdural haematomas, intraventricular haemorrhage, and pneumocranium. Surgical intervention was required in 4 cases. Although most of the patients made a good recovery (GOS = 5), 1 patient developed a mild disability and another died in hospital. TV trolley tip-over is most common in toddlers and can lead to significant head injury and mortality. This can be avoided by parental supervision and adjustments in the household.


The risk of stable partnerships: associations between partnership characteristics and unprotected anal intercourse among men who have sex with men and transgender women recently diagnosed with HIV and/or STI in Lima, Peru.
Partnership type is an important factor associated with unprotected anal intercourse (UAI) and subsequent risk for HIV and sexually transmitted infections (STI). We examined the association of partnership type with UAI among men who have sex with men (MSM) and male-to-female transgender women (TGW) in Lima, Peru, recently diagnosed with HIV and/or STI. We report data from a cross-sectional analysis of MSM and TGW recently diagnosed with HIV and/or STI in Lima, Peru between 2011 and 2012. We surveyed participants regarding UAI with up to their three most recent sexual partners according to partner type. Multivariable Generalized Estimate Equating (GEE) models with Poisson distribution were used to estimate prevalence ratios (PR) for UAI according to partner type. Among 339 MSM and TGW recently diagnosed with HIV and/or STI (mean age: 30.6 years, SD 9.0), 65.5% self-identified as homosexual/gay, 16.0% as bisexual, 15.2% as male-to-female transgender, and 3.3% as heterosexual. Participants provided information on 893 recent male or TGW partners with whom they had engaged in insertive or receptive anal intercourse: 28.9% stable partners, 56.4% non-stable/non-transactional partners (i.e. casual or anonymous), and 14.7% transactional partners (i.e. transactional sex client or sex worker). Unprotected anal intercourse was reported with 41.3% of all partners. In multivariable analysis, factors associated with UAI included partnership type (non-stable/non-transactional partner APR 0.73, [95% CI 0.59-0.91], transactional partner APR 0.53 [0.36-0.78], p<0.05) and the number of previous sexual encounters with the partner (>10 encounters APR 1.43 [1.06-1.92], p<0.05). UAI was more commonly reported for stable partners and in partnerships with >10 sexual encounters, suggesting UAI is more prevalent in partnerships with a greater degree of interpersonal commitment. Further research assessing partner-level factors and behavior is critical for improving HIV and/or STI prevention efforts among Peruvian MSM and TGW.


Goal representations and motivational drive in schizophrenia: the role of prefrontal-striatal interactions.
The past several years have seen a resurgence of interest in understanding the psychological and neural bases of what are often referred to as "negative symptoms" in schizophrenia. These aspects of schizophrenia include constructs such as asociality, avolition (a reduction in the motivation to initiate or persist in goal-directed behavior), and anhedonia (a reduction in the ability to experience pleasure). We believe that these dimensions of impairment in individuals with schizophrenia reflect difficulties using internal representations of emotional experiences, previous rewards, and motivational goals to drive current and future behavior in a way that would allow them to obtain desired outcomes, a deficit that has major clinical significance in terms of functional capacity. In this article, we review the major components of the systems that link experienced and anticipated rewards with motivated behavior that could potentially be impaired in schizophrenia. We conclude that the existing evidence suggests relatively intact hedonics in schizophrenia, but impairments in some aspects of reinforcement learning, reward prediction, and prediction error processing, consistent with an impairment in "wanting." As of yet, there is only indirect evidence of impairment in anterior cingulate and orbital frontal function that may support value and effort computations. However, there are intriguing hints that individuals with schizophrenia may not be able to use reward information to modulate cognitive control and dorsolateral prefrontal cortex function, suggesting a potentially important role for cortical-striatal interactions in mediating impairment in motivated and goal-directed behavior in schizophrenia.


A Pilot Study to Adapt a Trauma-Informed, Mindfulness-Based Yoga Intervention for Justice-Involved Youth.
The purpose of the present study was to adapt and pilot a trauma-informed, mindfulness-based yoga (TIMBY) intervention focused on enhancing self-regulation among youth in the Georgia Department of Juvenile Justice system. In this article we (1) describe the process by which we systematically adapted an evidence-based protocol specifically for this population, (2) describe the nature of and rationale for those adaptations, (3) present some preliminary qualitative findings based on interviews with youth participants, and (4) briefly summarize how the adapted protocol will be evaluated in the subsequent feasibility trial. The iterative drafting and revision process involved modifications to a well-established, protocolized Trauma-Informed Yoga program and was identified by the project advisory board and t h rough formal interviews with intervention staff. Qualitative interviews were conducted with youth participants concerning intervention impact, credibility, and satisfaction. Several needed modifications were identified so that the intervention would be contextually appropriate for justice-involved youth. Thirty youth were enrolled in the pilot study: 77% we re Non - Hispanic Black/African-American, 18% were Non-Hispanic White, and 5% were Hispanic White. The average age was 16.45 years (range 14-20). The youth consistently reported satisfaction with the sessions and positive beliefs about how the sessions were helping them with a range of physical and psychological/ emotional challenges. Adaptations to the protocol in the present study highlight how mindfulness-based interventions for justice-involved youth need to consider what is both developmentally suitable for youth and appropriate in a justice setting. A feasibility study using this revised TIMBY protocol is underway at four Georgia Department of Juvenile Justice facilities to formally identify the barriers and facilitators to implementation for the present study and a future, larger-scale trial.


Stable bis(trifluoromethyl)nickel(III) complexes.
Organometallic Ni(III) intermediates have been proposed in several Nickel-catalyzed cross-coupling reactions, yet no isolated bis(hydrocarbyl)Ni(III) complexes have been reported to date. Herein we report the synthesis and detailed characterization of stable organometallic Ni(III) complexes that contain two trifluoromethyl ligands and are supported by tetradentate N-donor ligands (R)N4 (R = Me or tBu). Interestingly, the corresponding Ni(II) precursors undergo facile oxidation, including aerobic oxidation, to generate uncommonly stable organometallic Ni(III) complexes that exhibit limited reactivity.


Diabetes Learning in Virtual Environments: Testing the Efficacy of Self-Management Training and Support in Virtual Environments (Randomized Controlled Trial Protocol).
Ongoing self-management improves outcomes for those with Type 2 diabetes (T2D); however, there are many barriers to patients receiving assistance in this from the healthcare system and peers. Findings from our pilot study showed that a virtual diabetes community on the Internet with real-time interaction among peers with T2D-and with healthcare professionals-is feasible and has the potential to influence clinical and psychosocial outcomes. The purpose of this article is to present the protocol for the Diabetes Learning in Virtual Environments (LIVE) trial. Diabetes LIVE is a two-group, randomized controlled trial to compare effects of a virtual environment and traditional Web site on diet and physical activity. Our secondary aims will determine the effects on metabolic outcomes; effects of level of engagement and social network formation in LIVE on behavioral outcomes; potential mediating effects of changes in self-efficacy; and diabetes knowledge, diabetes-related distress, and social support on behavior change and metabolic outcomes. We will enroll 300 subjects at two sites (Duke University/Raleigh-Durham, NC and New York University/New York, NY) who have T2D and do not have serious complications or comorbidities. Those randomly assigned to the intervention group have access to the LIVE site where they can find information, synchronous classes with diabetes educators, and peer support to enhance self-management. Those in the control group have access to the same informational and educational content in a traditional asynchronous Web format. Measures of self-management, clinical outcomes, and psychosocial outcomes are assessed at baseline and 3, 6, 12, and 18 months. Should LIVE prove effective in improved self-management of diabetes, similar interventions could be applied to other prevalent chronic diseases. Innovative programs such as LIVE have potential for improving healthcare access in an easily disseminated alternative model of care that potentially improves the reach of self-management training and support.


Cushing syndrome: maybe not so uncommon of an endocrine disease.
Cushing syndrome (CS) is the result of extended exposure to excessive glucocorticoids from endogenous or exogenous sources. Traditionally, the most common cause of endogenous CS is a pituitary adenoma (Cushing disease). Less common causes are adrenocortical tumors and extrapituitary adrenocorticotropin-producing neoplasias. This review provides updated information regarding the potential for increased prevalence of CS in specific patient populations. Here the authors provide to family physicians clinical guidance for recognition of CS by presenting a case, discussing the advantages/disadvantages of the diagnostic tests, and discussing information about the treatment options. CS is expected to have an incidence of 10 to 15 people per million; however, studies of patients with diabetes, obesity, hypertension, and osteoporosis found a high prevalence of CS among these populations. The clinical manifestations of CS range from the distinctive clinical features (purple striae, facial plethora, proximal myopathy) to common conditions such as hypertension, obesity, and diabetes. Clinical practice guidelines recommend biochemical tests to screen patients for CS; however, the sensitivity and specificity of these tests vary, so a careful analysis must be performed to avoid misdiagnosis. CS is challenging to diagnose. Nevertheless, with a systematic approach to testing patients and an increased awareness of the high-risk patient populations, the disease can be identified in a timely manner.


The physiology and clinical utility of anti-Mullerian hormone in women.
BACKGROUND The measurement of circulating anti-Müllerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. AMH has been suggested to predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause, and to indicate iatrogenic damage to the ovarian follicle reserve. It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of polycystic ovary syndrome (PCOS). METHODS This paper is a summary of presentations at a European Society of Human Reproduction and Embryology campus workshop on AMH, with literature cited until September 2013. Published peer-reviewed medical literature about AMH was searched through MEDLINE and was subjected to systematic review and critical assessment by the panel of authors. RESULTS Physiologically, recent data confirm that AMH is a follicular gatekeeper limiting follicle growth initiation, and subsequently estradiol production from small antral follicles prior to selection. AMH assays continue to evolve and technical issues remain; the absence of an international standard is a key issue. The dynamics of circulating AMH levels throughout life can be split into several distinct phases, with a peak in the early 20s before a decline to the menopause, with a strong and positive correlation with non-growing follicle recruitment. There is a more complex rise during childhood and adolescence, which is likely to be more reflective of different stages of follicle development. AMH shows limited short-term variability, but the influence of states such as prolonged oral contraceptive use need to be considered in clinical assessment. There are only very limited data on relationships between AMH and natural fertility at different stages of reproductive life, and while it has a relationship to age at menopause the marked variability in this needs further exploration. AMH may be useful in assessing the need for fertility preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve. Long-term follow-up of patients to ascertain fully the value of post-cancer serum AMH in predicting long-term ovarian function is required. There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation. AMH can also identify 'poor responders', but it seems inappropriate at present to withhold IVF purely on this basis. Women with PCOS show markedly raised AMH levels, due to both the increased number of small antral follicles and intrinsic characteristics of those granulosa cells, and this may contribute to anovulation. The value of AMH in the diagnosis of PCOS remains controversial, but it may replace AFC in the future. CONCLUSIONS For the first time in female reproductive biology, it is possible to measure the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity. An international standard for AMH and improved assay validity are urgently needed to maximize the clinical utility of this very promising biomarker of ovarian function in a large array of clinical situations, both in childhood and adulthood.


Angiotensin II-induced arterial thickening, fibrosis and stiffening involves elevated arginase function.
Arterial stiffness (AS) is an independent risk factor for cardiovascular morbidity/mortality. Smooth muscle cell (SMC) proliferation and increased collagen synthesis are key features in development of AS. Arginase (ARG), an enzyme implicated in many cardiovascular diseases, can compete with nitric oxide (NO) synthase for their common substrate, L-arginine. Increased arginase can also provide ornithine for synthesis of polyamines via ornithine decarboxylase (ODC) and proline/collagen via ornithine aminotransferase (OAT), leading to vascular cell proliferation and collagen formation, respectively. We hypothesized that elevated arginase activity is involved in Ang II-induced arterial thickening, fibrosis, and stiffness and that limiting its activity can prevent these changes. We tested this by studies in mice lacking one copy of the ARG1 gene that were treated with angiotensin II (Ang II, 4 weeks). Studies were also performed in rat aortic Ang II-treated SMC. In WT mice treated with Ang II, we observed aortic stiffening (pulse wave velocity) and aortic and coronary fibrosis and thickening that were associated with increases in ARG1 and ODC expression/activity, proliferating cell nuclear antigen, hydroxyproline levels, and collagen 1 protein expression. ARG1 deletion prevented each of these alterations. Furthermore, exposure of SMC to Ang II (1 μM, 48 hrs) increased ARG1 expression, ARG activity, ODC mRNA and activity, cell proliferation, collagen 1 protein expression and hydroxyproline content. Treatment with ABH prevented these changes. Arginase 1 is crucially involved in Ang II-induced SMC proliferation and arterial fibrosis and stiffness and represents a promising therapeutic target.


Examining drinking game harms as a function of gender and college student status.
Drinking game (DG) participation among young adults is widespread. Because heavy alcohol consumption is commonly associated with playing DGs, this activity presents a health risk for those who play. In the present study, we explored the most common negative DG consequences experienced by young adults and how DG consequences differed by gender and college status. Participants were young adult drinking gamers (N = 1,600; age 18-25; Mage = 22.6; 47% men; 41% noncollege students; 77% White) recruited from Amazon's Mechanical Turk. They completed an online anonymous survey which included items on the Brief Young Adult Alcohol Consequences Questionnaire that were modified to measure DG consequences experienced in the past month. Over half of the participants reported experiencing a hangover, saying/doing embarrassing things, having less energy, and feeling sick as a result of playing DGs. Using IRT analysis, we also found differential item functioning (DIF) on several items across gender and college status. We then created a short-form version of the DG consequences measure that excluded items demonstrating DIF, and based on this modified measure, we examined differences in severity of negative DG consequences as a function of gender and college status. Controlling for age, college status, DG frequency/consumption, and alcohol use on non-DG occasions, we found that men experienced slightly more DG consequences than women. Similar findings emerged for college students compared to noncollege students. This study is an important first step toward understanding who is most at risk for experiencing certain types of negative DG consequences and how researchers/practitioners could measure this construct. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Selective Pressure Promotes Tetracycline Resistance of Chlamydia Suis in Fattening Pigs.
In pigs, Chlamydia suis has been associated with respiratory disease, diarrhea and conjunctivitis, but there is a high rate of inapparent C. suis infection found in the gastrointestinal tract of pigs. Tetracycline resistance in C. suis has been described in the USA, Italy, Switzerland, Belgium, Cyprus and Israel. Tetracyclines are commonly used in pig production due to their broad-spectrum activity and relatively low cost. The aim of this study was to isolate clinical C. suis samples in cell culture and to evaluate their antibiotic susceptibility in vitro under consideration of antibiotic treatment on herd level. Swab samples (n = 158) identified as C. suis originating from 24 farms were further processed for isolation, which was successful in 71% of attempts with a significantly higher success rate from fecal swabs compared to conjunctival swabs. The farms were divided into three treatment groups: A) farms without antibiotic treatment, B) farms with prophylactic oral antibiotic treatment of the whole herd consisting of trimethoprime, sulfadimidin and sulfathiazole (TSS), or C) farms giving herd treatment with chlortetracycline with or without tylosin and sulfadimidin (CTS). 59 isolates and their corresponding clinical samples were selected and tested for the presence or absence of the tetracycline resistance class C gene [tet(C)] by conventional PCR and isolates were further investigated for their antibiotic susceptibility in vitro. The phenotype of the investigated isolates was either classified as tetracycline sensitive (Minimum inhibitory concentration [MIC] < 2 μg/ml), intermediate (2 μg/ml ≤ MIC < 4 μg/ml) or resistant (MIC ≥ 4 μg/ml). Results of groups and individual pigs were correlated with antibiotic treatment and time of sampling (beginning/end of the fattening period). We found clear evidence for selective pressure as absence of antibiotics led to isolation of only tetracycline sensitive or intermediate strains whereas tetracycline treatment resulted in a greater number of tetracycline resistant isolates.


Abdominal wall haematoma in cardioembolic stroke due to enoxaparine therapy: a report of two cases.
Abdominal wall haematomas are uncommon and often misdiagnosed entities. Most of the time the haematoma is produced by rupture of the epigastric vessels, deep circumflex iliac artery or tear in the rectus or lateral oblique muscle. Predisposing factors such as arteriosclerosis of vessels, old age, straining while urinating and coughing and use of anticoagulant agents make bleeding more likely. Here, two uncommon cases who experienced cardioembolic stroke are described. The patients were given enoxaparin sodium urgently, administered to the stomach area subcutaneously. They presented with abdominal masses, periumbilical and inguinal ecchymosis. Their haemoglobin levels dropped. Abdominal CT scan and ultrasonography revealed rectus sheath and internal abdominal oblique muscle haematomas. The patients were treated conservatively. This report concerns this rare condition, often misdiagnosed in unconscious patients, that has not been reported as being due to cardiogenic brain embolism in the literature to date.


Thiostrepton-resistant mutants of Thermus thermophilus.
Ribosomal protein L11 and its associated binding site on 23S rRNA together comprise one of the principle components that mediate interactions of translation factors with the ribosome. This site is also the target of the antibiotic thiostrepton, which has been proposed to act by preventing important structural transitions that occur in this region of the ribosome during protein synthesis. Here, we describe the isolation and characterization of spontaneous thiostrepton-resistant mutants of the extreme thermophile, Thermus thermophilus. All mutations were found at conserved positions in the flexible N-terminal domain of L11 or at conserved positions in the L11-binding site of 23S rRNA. A number of the mutant ribosomes were affected in in vitro EF-G-dependent GTP hydrolysis but all showed resistance to thiostrepton at levels ranging from high to moderate. Structure probing revealed that some of the mutations in L11 result in enhanced reactivity of adjacent rRNA bases to chemical probes, suggesting a more open conformation of this region. These data suggest that increased flexibility of the factor binding site results in resistance to thiostrepton by counteracting the conformation-stabilizing effect of the antibiotic.


Association between body mass index, sexually transmitted infections, and contraceptive compliance.
Recent studies have examined the relationship between body mass index (BMI) and sexual behaviors, but little information exists on this relationship among racially diverse, low-income women using objectively measured clinical data. The purpose of this study was to examine the association between BMI and sexual behaviors, rates of sexually transmitted infections (STIs) and unintended pregnancy, and contraceptive adherence among adolescent and young adult women. As part of a larger study, 1,015 Hispanic (54.2%), Black (18.6%) and White (24.8%) women aged 16 to 24 years seeking family planning services at publicly funded reproductive health clinics provided data on their baseline sexual behaviors, and contraceptive use and pregnancy history over 12 months. Objective clinical data were available from medical records at baseline (i.e., height, weight, and Papanicolaou [Pap] smear results), and over a 12-month period (i.e., STI results). Multivariable analyses were used to compare sexual behaviors, STI rates, contraceptive compliance, and unintended pregnancy rates between obese, overweight, and normal weight participants after adjusting for age, race/ethnicity, and other confounders. Overall, 423 (36.6%), 304 (26.3%), and 288 (24.9%) participants were classified as normal weight, overweight, and obese, respectively. No statistically significant association was observed between BMI and sexual behaviors, STI rates (overweight odds ratio [OR] 0.67; 95% confidence interval [95% CI] [0.4, 1.08]; obese OR 0.68; 95% CI [0.42, 1.10]); contraceptive compliance (overweight OR 0.89; 95% CI [0.69, 1.16]; obese OR 0.89; 95% CI 0.68, 1.16]), or unintended pregnancy (overweight OR 1.08 95% CI [0.73, 1.60]; obese OR 1.09; 95% CI [0.72, 1.63]). STI history and contraceptive compliance did not vary by BMI. Therefore, all women should receive equal contraceptive counseling (including condoms) to reduce the risk of unplanned pregnancy and STIs.


Adult UVR exposure changes with life stage - a 14-year follow-up study using personal electronic UVR dosimeters.
Over a period spanning 14 years (1999-2001, 2006 and 2012), 31 volunteers participated in sun behaviour studies with the same protocol wearing a personal, electronic wrist-borne UVR dosimeter and completed sun exposure diaries resulting in a total of 15 946 measurements days (126 days per person per year). The participants individually maintained their UVR dose level and behaviour over the years. No statistically significant differences were seen from year to year in the "estimated annual UVR dose", the "mean UVR dose per day", the "mean percentage of ambient UVR", "days sunbathing to get a tan", "days with intermittent exposure" or in "sunburn episodes". The 20 participants still active in the labour market used sunscreen on more days in 2012 than in 1999 (p = 0.019) and with a significantly higher SPF (sun protecting factor (p < 0.001)) resulting in significantly fewer days with risk behaviour without sunscreen applied in 2012 than in 2006 (p < 0.001) and 1999 (p < 0.003). This was in contrast to the 11 participants who retired during the study period. The retired group received a non-significant 45% higher UV dose in 2012 than in 1999 (p = 0.054). In an additional study, nine 30-year-old indoor workers (high school students in the 1999 study) had changed their sun exposure pattern and had fewer days sunbathing (p = 0.008) and fewer risk behaviour days without sunscreen applied in 2012 than in 1999 (p = 0.002). Conclusion: The participants still active in the labour market maintained their sun exposure behaviour over a 14-year period. The retirees had a higher UVR dose and riskier exposure behaviour after retirement, while the high school students had changed to less risky sun behaviour on becoming indoor workers.


Medical management and monitoring of the hyperthyroid cat: a survey of UK general practitioners.
Feline hyperthyroidism is commonly diagnosed in general practice. This study assessed the opinions and experiences of UK general practitioners (GPs) regarding the management of feline hyperthyroidism. This included an evaluation of preferred treatment modalities and the monitoring of medically treated cats in relation to thyroxine (T4) level, co-morbid disease and adverse drug reactions. Six hundred and three GPs completed an online questionnaire comprising 34 questions. Oral medication was the most commonly preferred treatment option (65.7% of respondents), followed by thyroidectomy (27.5%) and then radioiodine (5.5%). When cost of treatment was eliminated as a consideration factor, significantly more respondents selected radioiodine (40.5%, P <0.001). Concerning target total T4 levels during medical management, 48.4% aimed for the lower half of the reference interval (RI), 32.3% anywhere within RI, 13.1% within the top half of RI and 0.5% above the RI; 3.4% evaluated efficacy by physical assessment only. In the presence of chronic kidney disease (CKD) respondents were significantly more likely to target total T4 levels within the upper half of the RI (40.3%) or above it (9.8%) when compared with targets for routine cases (P <0.001). Assessment for unmasking of CKD after initiating treatment or for hypertension was not consistently performed. Variability in monitoring strategies may result in CKD and hypertension remaining undetected, inadequate suppression of T4 levels in cats with concurrent CKD and delayed recognition of potentially significant haematological abnormalities.


A Rehabilitation-Internet-of-Things in the Home to Augment Motor Skills and Exercise Training.
Although motor learning theory has led to evidence-based practices, few trials have revealed the superiority of one theory-based therapy over another after stroke. Nor have improvements in skills been as clinically robust as one might hope. We review some possible explanations, then potential technology-enabled solutions. Over the Internet, the type, quantity, and quality of practice and exercise in the home and community can be monitored remotely and feedback provided to optimize training frequency, intensity, and progression at home. A theory-driven foundation of synergistic interventions for walking, reaching and grasping, strengthening, and fitness could be provided by a bundle of home-based Rehabilitation Internet-of-Things (RIoT) devices. A RIoT might include wearable, activity-recognition sensors and instrumented rehabilitation devices with radio transmission to a smartphone or tablet to continuously measure repetitions, speed, accuracy, forces, and temporal spatial features of movement. Using telerehabilitation resources, a therapist would interpret the data and provide behavioral training for self-management via goal setting and instruction to increase compliance and long-term carryover. On top of this user-friendly, safe, and conceptually sound foundation to support more opportunity for practice, experimental interventions could be tested or additions and replacements made, perhaps drawing from virtual reality and gaming programs or robots. RIoT devices continuously measure the actual amount of quality practice; improvements and plateaus over time in strength, fitness, and skills; and activity and participation in home and community settings. Investigators may gain more control over some of the confounders of their trials and patients will have access to inexpensive therapies.


Demographic heterogeneity, cohort selection, and population growth.
Demographic heterogeneity--variation among individuals in survival and reproduction--is ubiquitous in natural populations. Structured population models address heterogeneity due to age, size, or major developmental stages. However, other important sources of demographic heterogeneity, such as genetic variation, spatial heterogeneity in the environment, maternal effects, and differential exposure to stressors, are often not easily measured and hence are modeled as stochasticity. Recent research has elucidated the role of demographic heterogeneity in changing the magnitude of demographic stochasticity in small populations. Here we demonstrate a previously unrecognized effect: heterogeneous survival in long-lived species can increase the long-term growth rate in populations of any size. We illustrate this result using simple models in which each individual's annual survival rate is independent of age but survival may differ among individuals within a cohort. Similar models, but with nonoverlapping generations, have been extensively studied by demographers, who showed that, because the more "frail" individuals are more likely to die at a young age, the average survival rate of the cohort increases with age. Within ecology and evolution, this phenomenon of "cohort selection" is increasingly appreciated as a confounding factor in studies of senescence. We show that, when placed in a population model with overlapping generations, this heterogeneity also causes the asymptotic population growth rate lambda to increase, relative to a homogeneous population with the same mean survival rate at birth. The increase occurs because, even integrating over all the cohorts in the population, the population becomes increasingly dominated by the more robust individuals. The growth rate increases monotonically with the variance in survival rates, and the effect can be substantial, easily doubling the growth rate of slow-growing populations. Correlations between parent and offspring phenotype change the magnitude of the increase in lambda, but the increase occurs even for negative parent-offspring correlations. The effect of heterogeneity in reproductive rate on lambda is quite different: growth rate increases with reproductive heterogeneity for positive parent-offspring correlation but decreases for negative parent-offspring correlation. These effects of demographic heterogeneity on lambda have important implications for population dynamics, population viability analysis, and evolution.


Durability and Clinical Outcomes of Transcatheter Aortic Valve Replacement for Failed Surgical Bioprostheses.
Valve-in-valve transcatheter aortic valve replacement (TAVR) is an option when a surgical valve demonstrates deterioration and dysfunction. This study reports 3-year results following valve-in-valve with self-expanding TAVR. The CoreValve US Expanded Use Study is a prospective, nonrandomized, single-arm study that evaluates safety and effectiveness of TAVR in extreme risk patients with symptomatic failed surgical biologic aortic valves. Study end points include all-cause mortality, need for valve reintervention, hemodynamic changes over time, and quality of life through 3 years. Patients were stratified by presence of preexisting surgical valve prosthesis-patient mismatch. From March 2013 to May 2015, 226 patients deemed extreme risk (STS-PROM [Society of Thoracic Surgeons Predicted Risk of Mortality] 9.0±7%) had attempted valve-in-valve TAVR. Preexisting surgical valve prosthesis-patient mismatch was present in 47.2% of the cohort. At 3 years, all-cause mortality or major stroke was 28.6%, and 93% of patients were in New York Heart Association I or II heart failure. Valve performance was maintained over 3 years with low valve reintervention rates (4.4%), an improvement in effective orifice area over time and a 2.7% rate of severe structural valve deterioration. Preexisting severe prosthesis-patient mismatch was not associated with 3-year mortality but was associated with significantly less improvement in quality of life at 3-year follow-up (P=0.01). Self-expanding TAVR in patients with failed surgical bioprostheses at extreme risk for surgery was associated with durable hemodynamics and excellent clinical outcomes. Preexisting surgical valve prosthesis-patient mismatch was not associated with mortality but did limit patient improvement in quality of life over 3-year follow-up. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01675440.


Sleeping birds do not respond to predator odour.
During sleep animals are relatively unresponsive and unaware of their environment, and therefore, more exposed to predation risk than alert and awake animals. This vulnerability might influence when, where and how animals sleep depending on the risk of predation perceived before going to sleep. Less clear is whether animals remain sensitive to predation cues when already asleep. We experimentally tested whether great tits are able to detect the chemical cues of a common nocturnal predator while sleeping. We predicted that birds exposed to the scent of a mammalian predator (mustelid) twice during the night would not go into torpor (which reduces their vigilance) and hence would not reduce their body temperature as much as control birds, exposed to the scent of another mammal that does not represent a danger for the birds (rabbit). As a consequence of the higher body temperature birds exposed to the scent of a predator are predicted to have a higher resting metabolic rate (RMR) and to lose more body mass. In the experiment, all birds decreased their body temperature during the night, but we did not find any influence of the treatment on body temperature, RMR, or body mass. Our results suggest that birds are not able to detect predator chemical cues while sleeping. As a consequence, antipredatory strategies taken before sleep, such as roosting sites inspection, may be crucial to cope with the vulnerability to predation risk while sleeping.


Catheter-based renal denervation reduces atrial nerve sprouting and complexity of atrial fibrillation in goats.
Atrial fibrillation (AF) leads to structural and neural remodeling in the atrium, which enhances AF complexity and perpetuation. Renal denervation (RDN) can reduce renal and whole-body sympathetic activity. Aim of this study was to determine the effect of sympathetic nervous system modulation by RDN on atrial arrhythmogenesis. Eighteen goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. Percutaneous catheter-based RDN was performed in 8 goats (RDN-AF). Ten goats undergoing a sham procedure served as control (SHAM-AF). AF was induced and maintained by burst pacing for 6 weeks. High-resolution mapping was used to record epicardial conduction patterns of the right and left atrium. RDN reduced tyrosine hydroxylase-positive sympathetic nerve staining and resulted in lower transcardiac norepinephrine levels. This was associated with reduced expression of nerve growth factor-β, indicating less atrial nerve sprouting. Atrial endomysial fibrosis content was lower and myocyte diameter was smaller in RDN-AF. Median conduction velocity was higher (75 ± 9 versus 65 ± 10 cm/s, P = 0.02), and AF cycle length was shorter in RDN-AF compared with SHAM-AF. Left atrial AF complexity (4.8 ± 0.8 fibrillation waves/AF cycle length versus 8.5 ± 0.8 waves/AF cycle length, P = 0.001) and incidence of breakthroughs (2.0 ± 0.3 versus 4.3 ± 0.5 waves/AF cycle length, P = 0.059) were lower in RDN-AF compared with SHAM-AF. Blood pressure was normal and not significantly different between the groups. RDN reduces atrial sympathetic nerve sprouting, structural alterations, and AF complexity in goats with persistent AF, independent of changes in blood pressure.


Identification of a specialized adenylyl cyclase that may mediate odorant detection.
The mammalian olfactory system may transduce odorant information via a G protein-mediated adenosine 3',5'-monophosphate (cAMP) cascade. A newly discovered adenylyl cyclase, termed type III, has been cloned, and its expression was localized to olfactory neurons. The type III protein resides in the sensory neuronal cilia, which project into the nasal lumen and are accessible to airborne odorants. The enzymatic activity of the type III adenylyl cyclase appears to differ from nonsensory cyclases. The large difference seen between basal and stimulated activity for the type III enzyme could allow considerable modulation of the intracellular cAMP concentration. This property may represent one mechanism of achieving sensitivity in odorant perception.


Effect of the Cognitive-Behavioral Prevention Program on Levels of Depression Symptoms Among Working Adolescents in Turkey.
The current study was conducted to determine the effect of the Cognitive-Behavioral Prevention Program (CBPP) on levels of depression symptoms, ability to cope with stress, and automatic negative thought patterns among working adolescents in Turkey. The CBPP was conducted once per week for eight sessions and then once per month for six sessions. Data were collected using the Beck Depression Inventory, Automatic Thoughts Questionnaire, and Rosenbaum's Learned Resourcefulness Schedule. Observations were made prior to administration of the CBPP, upon conclusion of the program, and at 6 and 12 months. Chi-square and t tests were used for data analysis. Mean age of participants was 15.85, and they worked a mean 10.84 hours per day. After taking part in the CBPP, participants displayed a decrease in levels of depression symptoms, an increase in their ability to cope with stress, and diminished automatic negative thoughts (all p = 0.001), thus indicating that they benefited from the program and its effectiveness continued through 12-month follow up. [Journal of Psychosocial Nursing and Mental Health Services, 54(7), 43-51.].