The antiplaque efficacy of propolis-based herbal toothpaste: A crossover clinical study.
In recent years, herbal products have been suggested as an economic, safe and probably effective alternative for prevention and control of various oral diseases. But still there are some products which need to be evaluated. Of lately, Propolis is one such product. To assess and compare the efficacy of herbal dentifrice containing Propolis with Miswak and Colgate total toothpastes in controlling plaque formation. A double blind, randomized, crossover study design was conducted among thirty healthy dental students. After oral prophylaxis all subjects were given a washout product for one week period. Subjects were then made to brush with (washout product) for 1 minute followed by 1 minute brushing with assigned test product. The baseline MGMPI plaque scores were recorded. Subjects were then refrained from oral hygiene for 24 hours, and were recalled to be re-disclosed and re-measured for plaque formation. This procedure was repeated according to crossover design after a washout period of (2 week). Statistical tests used were Krukalwallis and Wilcoxon sign rank test. There was a significant difference in 24 hour score between the test products evaluated. When the change from baseline to 24 hours was analyzed, the test product Propolis resulted in a consistently and significantly (p < 0.05) lower MGMPI mean scores than the Colgate Total and Miswak toothpastes. Propolis was found to be safe and effective in reducing plaque accumulation when compared to Miswak and Colgate total toothpaste.


Precision feeding can significantly reduce lysine intake and nitrogen excretion without compromising the performance of growing pigs.
This study was developed to assess the impact on performance, nutrient balance, serum parameters and feeding costs resulting from the switching of conventional to precision-feeding programs for growing-finishing pigs. A total of 70 pigs (30.4±2.2 kg BW) were used in a performance trial (84 days). The five treatments used in this experiment were a three-phase group-feeding program (control) obtained with fixed blending proportions of feeds A (high nutrient density) and B (low nutrient density); against four individual daily-phase feeding programs in which the blending proportions of feeds A and B were updated daily to meet 110%, 100%, 90% or 80% of the lysine requirements estimated using a mathematical model. Feed intake was recorded automatically by a computerized device in the feeders, and the pigs were weighed weekly during the project. Body composition traits were estimated by scanning with an ultrasound device and densitometer every 28 days. Nitrogen and phosphorus excretions were calculated by the difference between retention (obtained from densitometer measurements) and intake. Feeding costs were assessed using 2013 ingredient cost data. Feed intake, feed efficiency, back fat thickness, body fat mass and serum contents of total protein and phosphorus were similar among treatments. Feeding pigs in a daily-basis program providing 110%, 100% or 90% of the estimated individual lysine requirements also did not influence BW, body protein mass, weight gain and nitrogen retention in comparison with the animals in the group-feeding program. However, feeding pigs individually with diets tailored to match 100% of nutrient requirements made it possible to reduce (P<0.05) digestible lysine intake by 26%, estimated nitrogen excretion by 30% and feeding costs by US$7.60/pig (-10%) relative to group feeding. Precision feeding is an effective approach to make pig production more sustainable without compromising growth performance.


Maternal dietary intake in twin pregnancies: does it diminish towards term?
We tested the hypothesis that energy intake among women with twin pregnancies decreases in late gestation, as the uterus enlarges and they become increasingly uncomfortable. We asked women to recall dietary intake for the previous 24 hours, every 2 weeks from around 29 weeks of gestation, using a photographic atlas and other strategies to estimate portion size. Eighty women provided data at around 29, 31, 33 and 35 weeks of gestation. We calculated total energy intake, and energy intake from carbohydrate, fat and protein. Data were log transformed to reduce skewness. Using mixed effects linear regression models, we found minimal evidence that total energy intake changed over this time period, either before or after adjustment for potential confounding factors (95% confidence interval for relative change per week: -1.4%, 0.6%). There was weak evidence of a small decline in carbohydrate intake over time, both before and after controlling for energy intake. We cannot exclude change in energy intake or diet composition before 29 weeks or after 35 weeks of twin gestation.


In vivo Imaging of the Cerebral Endothelial Glycocalyx in Mice.
Endothelial glycocalyx refers to the proteoglycan or glycoprotein layer of vessel walls and has critical physiological functions. Cerebral glycocalyx may have additional functions considering the blood-brain barrier and other features. However, the assessment of it has only been performed ex vivo, which includes processes presumably damaging the glycocalyx layer. Here we visualize and characterize the cerebral endothelial glycocalyx in vivo. We visualized and quantified the cerebral endothelial glycocalyx in vivo under a 2-photon microscope by tagging glycocalyx and vessel lumen with wheat germ agglutinin lectin and dextran, respectively. The radial intensity was analyzed to measure the thickness of the cerebral endothelial glycocalyx in each vessel type. Cerebral arteries and capillaries have an intact endothelial glycocalyx, but veins and venules do not. The thickness of the glycocalyx layer in pial arteries, penetrating arteries, and capillaries was different; however, it was not correlated with the vessel diameter within each vessel type. We characterized the distribution of the cerebral endothelial glycocalyx in vivo. Compared to the results from ex vivo studies, the layer is thicker, indicating that the layer may be damaged in ex vivo systems. We also observed an inhomogeneous cerebral endothelial glycocalyx distribution that might reflect the functional heterogeneity of the vessel type.


Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.
Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.


Image scoring in great apes.
'Image scoring' occurs when person A monitors the giving behaviour of person B towards person C. We tested for 'image scoring' in chimpanzees, bonobos, gorillas, and orangutans. Subjects passively observed two types of incident: (i) a 'nice' person gave grapes to a human beggar, and (ii) a 'nasty' person refused to give. The subject witnessed both incidents in succession (but was unable to obtain the grapes). Shortly after, the ape had an opportunity to approach one or both human actors (nice/nasty), both of whom were now sitting side-by-side holding grapes. However, neither human offered their grapes if approached. The subject's expectation of which human was more likely to offer food was measured by comparing the proportion of time that subjects spent near each person. Chimpanzees (n=17) spent significantly more time at the 'nice' window compared to 'nasty'. Also, preference for 'nasty' declined as trials progressed. Results for other apes were not significant.


P2-Na(x)VO2 system as electrodes for batteries and electron-correlated materials.
Layered oxides are the subject of intense studies either for their properties as electrode materials for high-energy batteries or for their original physical properties due to the strong electronic correlations resulting from their unique structure. Here we present the detailed phase diagram of the layered P2-Na(x)VO(2) system determined from electrochemical intercalation/deintercalation in sodium batteries and in situ X-ray diffraction experiments. It shows that four main single-phase domains exist within the 0.5≤x≤0.9 range. During the sodium deintercalation (intercalation), they differ from one another in the sodium/vacancy ordering between the VO(2) slabs, which leads to commensurable or incommensurable superstructures. The electrochemical curve reveals that three peculiar compositions exhibit special structures for x = 1/2, 5/8 and 2/3. The detailed structural characterization of the P2-Na(1/2)VO(2) phase shows that the Na(+) ions are perfectly ordered to minimize Na(+)/Na(+) electrostatic repulsions. Within the VO(2) layers, the vanadium ions form pseudo-trimers with very short V-V distances (two at 2.581 Å and one at 2.687 Å). This original distribution leads to a peculiar magnetic behaviour with a low magnetic susceptibility and an unexpected low Curie constant. This phase also presents a first-order structural transition above room temperature accompanied by magnetic and electronic transitions. This work opens up a new research domain in the field of strongly electron-correlated materials. From the electrochemical point of view this system may be at the origin of an entire material family optimized by cationic substitutions.


Monoclonal anti-acetylcholine receptor antibodies with differing capacities to induce experimental autoimmune myasthenia gravis.
To study the characteristics of the individual autoantibodies that are important in the development of an autoimmune disease, we produced 26 anti-acetylcholine receptor (anti-AChR) monoclonal antibodies (mcAb) and studied the experimental autoimmune myasthenia gravis (EAMG) induced by a number of them. The mcAb reactive with mammalian acetylcholine receptor (M-AChR) exhibited a wide range of dissociation rates from in situ M-AChR of motor endplates. All anti-M-AChR mcAb were capable of producing at least some degree of histopathologic change at the endplate indicative of EAMG, but their potencies varied markedly. One mcAb induced, even at large doses, only minor macrophage invasion without clinical or electromyographic effect. Others induced severe EAMG, and even death, at 1/200th the dose. Low potency was associated with high rate of mcAb dissociation from antigen. High potency was associated with intermediate avidity, not high avidity. These observations suggest that in EAMG, and perhaps in myasthenia gravis, the characteristics of the individual antibodies making up the autoimmune response can determine the severity of the autoimmune disease.


Opposite biases in salience-based selection for the left and right posterior parietal cortex.
Visual selection is determined in part by the saliency of stimuli. We assessed the brain mechanisms determining attentional responses to saliency. Repetitive transcranial magnetic stimulation (rTMS) was applied to the left and right posterior parietal cortices (PPC) immediately before participants were asked to identify a compound letter. rTMS to the right PPC disrupted the guidance of attention toward salient stimuli, whereas rTMS to the left PPC affected the ability to bias selection away from salient stimuli. We conclude that right and left PPC have opposite roles in biasing selection to and from salient stimuli in the environment.


High glucose upregulates connective tissue growth factor expression in human vascular smooth muscle cells.
Connective tissue growth factor (CTGF) is a potent profibrotic factor, which is implicated in fibroblast proliferation, angiogenesis and extracellular matrix (ECM) synthesis. It is a downstream mediator of some of the effects of transforming growth factor beta (TGFbeta) and is potentially induced by hyperglycemia in human renal mesangial cells. However, whether high glucose could induce the CTGF expression in vascular smooth muscle cells (VSMCs) remains unknown. Therefore, this study was designed to test whether high glucose could regulate CTGF expression in human VSMC. The effect of modulating CTGF expression on VSMC proliferation and migration was further investigated. Expression of CTGF mRNA was up-regulated as early as 6 hours in cultured human VSMCs after exposed to high glucose condition, followed by ECM components (collagen type I and fibronectin) accumulation. The upregulation of CTGF mRNA appears to be TGFbeta-dependent since anti-TGFbeta antibody blocks the effect of high glucose on CTGF gene expression. A small interference RNA (siRNA) targeting CTGF mRNA (CTGF-siRNA) effectively suppressed CTGF up-regulation stimulated by high glucose up to 79% inhibition. As a consequence of decreased expression of CTGF gene, the deposition of ECM proteins in the VSMC was also declined. Moreover, CTGF-siRNA expressing vector partially inhibited the high glucose-induced VSMC proliferation and migration. Our data suggest that in the development of macrovascular complications in diabetes, CTGF might be an important factor involved in the patho-physiological responses to high glucose in human VSMCs. In addition, the modulatory effects of CTGF-siRNA during this process suggest that specific targeting CTGF by RNA interference could be useful in preventing intimal hyperplasia in diabetic macrovascular complications.


Photoionization-Induced Emission of Tunable Few-Cycle Midinfrared Dispersive Waves in Gas-Filled Hollow-Core Photonic Crystal Fibers.
We propose a scheme for the emission of few-cycle dispersive waves in the midinfrared using hollow-core photonic crystal fibers filled with noble gas. The underlying mechanism is the formation of a plasma cloud by a self-compressed, subcycle pump pulse. The resulting free-electron population modifies the fiber dispersion, allowing phase-matched access to dispersive waves at otherwise inaccessible frequencies, well into the midinfrared. Remarkably, the pulses generated turn out to have durations of the order of two optical cycles. In addition, this ultrafast emission, which occurs even in the absence of a zero dispersion point between pump and midinfrared wavelengths, is tunable over a wide frequency range simply by adjusting the gas pressure. These theoretical results pave the way to a new generation of compact, fiber-based sources of few-cycle midinfrared radiation.


H3Africa AWI-Gen Collaborative Centre: a resource to study the interplay between genomic and environmental risk factors for cardiometabolic diseases in four sub-Saharan African countries.
Africa is experiencing a rapid increase in adult obesity and associated cardiometabolic diseases (CMDs). The H3Africa AWI-Gen Collaborative Centre was established to examine genomic and environmental factors that influence body composition, body fat distribution and CMD risk, with the aim to provide insights towards effective treatment and intervention strategies. It provides a research platform of over 10 500 participants, 40-60 years old, from Burkina Faso, Ghana, Kenya and South Africa. Following a process that involved community engagement, training of project staff and participant informed consent, participants were administered detailed questionnaires, anthropometric measurements were taken and biospecimens collected. This generated a wealth of demographic, health history, environmental, behavioural and biomarker data. The H3Africa SNP array will be used for genome-wide association studies. AWI-Gen is building capacity to perform large epidemiological, genomic and epigenomic studies across several African counties and strives to become a valuable resource for research collaborations in Africa.


General principles for the treatment of non-infectious uveitis.
Ocular inflammatory disorders constitute a sight-threatening group of diseases that might be managed according to their severity. Their treatment guidelines experience constant changes with new agents that improve the results obtained with former drugs. Nowadays we can make use of a five step protocol in which topical, periocular and systemic corticosteroids remain as the main therapy for non infectious uveitis. In addition, immunosuppresive drugs can be added in order to enhance the anti-inflammatory effects and to develop the role of corticosteroid-saving agents. These can be organized in four other steps: Cyclosporine and Methotrexate in a second one; Azathioprine, Mycophenolate Mofetil and Tacrolimus in a third step; biological anti-TNF drugs in fourth position; and a theoretical last one with Cyclophosphamide and Chlorambucil. In the present review we go through the main characteristics and complications of all these treatments and make a rational of this five-step treatment protocol for non infectious posterior uveitis.


Comparison of isocaloric very low carbohydrate/high saturated fat and high carbohydrate/low saturated fat diets on body composition and cardiovascular risk.
It is speculated that high saturated fat very low carbohydrate diets (VLCARB) have adverse effects on cardiovascular risk but evidence for this in controlled studies is lacking. The objective of this study was to compare, under isocaloric conditions, the effects of a VLCARB to 2 low saturated fat high carbohydrate diets on body composition and cardiovascular risk. Eighty three subjects, 48 +/- 8 y, total cholesterol 5.9 +/- 1.0 mmol/L, BMI 33 +/- 3 kg/m2 were randomly allocated to one of 3 isocaloric weight loss diets (6 MJ) for 8 weeks and on the same diets in energy balance for 4 weeks: Very Low Fat (VLF) (CHO:Fat:Protein; %SF = 70:10:20; 3%), High Unsaturated Fat (HUF) = (50:30:20; 6%), VLCARB (4:61:35; 20%) Percent fat mass loss was not different between diets VLCARB -4.5 +/- 0.5, VLF-4.0 +/- 0.5, HUF -4.4 +/- 0.6 kg). Lean mass loss was 32-31% on VLCARB and VLF compared to HUF (21%) (P < 0.05). LDL-C increased significantly only on VLCARB by 7% (p < 0.001 compared with the other diets) but apoB was unchanged on this diet and HDL-C increased relative to the other 2 diets. Triacylglycerol was lowered by 0.73 +/- 0.12 mmol/L on VLCARB compared to -0.15 +/- 0.07 mmol/L on HUF and -0.06 +/- 0.13 mmol/L on VLF (P < 0.001). Plasma homocysteine increased 6.6% only on VLCARB (P = 0.026). VLCARB lowered fasting insulin 33% compared to a 19% fall on HUF and no change on VLF (P < 0.001). The VLCARB meal also provoked significantly lower post prandial glucose and insulin responses than the VLF and HUF meals. All diets decreased fasting glucose, blood pressure and CRP (P < 0.05). Isocaloric VLCARB results in similar fat loss than diets low in saturated fat, but are more effective in improving triacylglycerols, HDL-C, fasting and post prandial glucose and insulin concentrations. VLCARB may be useful in the short-term management of subjects with insulin resistance and hypertriacylglycerolemia.


Predicting the effect of ozone on vegetation via linear non-threshold (LNT), threshold and hormetic dose-response models.
The nature of the dose-response relationship in the low dose zone and how this concept may be used by regulatory agencies for science-based policy guidance and risk assessment practices are addressed here by using the effects of surface ozone (O3) on plants as a key example for dynamic ecosystems sustainability. This paper evaluates the current use of the linear non-threshold (LNT) dose-response model for O3. The LNT model has been typically applied in limited field studies which measured damage from high exposures, and used to estimate responses to lower concentrations. This risk assessment strategy ignores the possibility of biological acclimation to low doses of stressor agents. The upregulation of adaptive responses by low O3 concentrations typically yields pleiotropic responses, with some induced endpoints displaying hormetic-like biphasic dose-response relationships. Such observations recognize the need for risk assessment flexibility depending upon the endpoints measured, background responses, as well as possible dose-time compensatory responses. Regulatory modeling strategies would be significantly improved by the adoption of the hormetic dose response as a formal/routine risk assessment option based on its substantial support within the literature, capacity to describe the entire dose-response continuum, documented explanatory dose-dependent mechanisms, and flexibility to default to a threshold feature when background responses preclude application of biphasic dose responses. The processes of ozone hazard and risk assessment can be enhanced by incorporating hormesis into their principles and practices.


Colonic epithelial miR-31 associates with the development of Crohn's phenotypes.
Crohn's disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. We performed small RNA sequencing of adult colon tissue from CD and NIBD controls. Colonic epithelial cells and immune cells were isolated from colonic tissues, and microRNA-31 (miR-31) expression was measured. miR-31 expression was measured in colonoid cultures generated from controls and patients with CD. We performed small RNA-sequencing of formalin-fixed paraffin-embedded colon and ileum biopsies from treatment-naive pediatric patients with CD and controls and collected data on disease features and outcomes. Small RNA-sequencing and microRNA profiling in the colon revealed 2 distinct molecular subtypes, each with different clinical associations. Notably, we found that miR-31 expression was a driver of these 2 subtypes and, further, that miR-31 expression was particularly pronounced in epithelial cells. Colonoids revealed that miR-31 expression differences are preserved in this ex vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery were associated with worse disease outcome as measured by need for an end ileostomy and recurrence of disease in the neoterminal ileum. In pediatric patients, lower miR-31 expression at the time of diagnosis was associated with future development of fibrostenotic ileal CD requiring surgeryCONCLUSIONS. These findings represent an important step forward in designing more effective clinical trials and developing personalized CD therapies. This work was supported by CCF Career Development Award (SZS), R01-ES024983 from NIEHS (SZS and TSF), 1R01DK104828-01A1 from NIDDK (SZS and TSF), P01-DK094779-01A1 from NIDDK (SZS), P30-DK034987 from NIDDK (SZS), 1-16-ACE-47 ADA Pathway Award (PS), UNC Nutrition Obesity Research Center Pilot & Feasibility Grant P30DK056350 (PS), CCF PRO-KIIDS NETWORK (SZS and PS), UNC CGIBD T32 Training Grant from NIDDK (JBB), T32 Training Grant (5T32GM007092-42) from NIGMS (MH), and SHARE from the Helmsley Trust (SZS). The UNC Translational Pathology Laboratory is supported, in part, by grants from the National Cancer Institute (3P30CA016086) and the UNC University Cancer Research Fund (UCRF) (PS).


Genotyping and DNA microarray based characterization of Staphylococcus aureus isolates from rabbit carcasses.
Staphylococcus aureus can cause staphylococcal food poisoning. Although the organism is frequently detected on rabbit carcasses, little is known about the characteristics of S. aureus strains contaminating rabbit meat. In this study, 137 S. aureus isolates originating from 137 rabbit carcasses were spa typed and characterized by DNA microarray. The isolates were assigned to CC5, CC7, CC8, CC15, CC96, CC101, CC121, and ST890, and to 13 spa types (t056, t085, t091, t160, t179, t681, t741, t745, t1190, t1773, t4770, t8456, t14871). Enterotoxin genes detected included sea, sed, sej, and ser. In addition, the egc operon, encoding the newly described staphylococcal enterotoxins SEG/SEI/SElM/SElN/SElO/SElU, was found in all isolates except those of t091. While none of the examined isolates presented genes conferring methicillin, vancomycin, or aminoglycoside resistance, we frequently detected blaZ/I/R conferring resistance to penicillin. The isolates represented a heterogeneous group assigned to clonal lineages detected among humans and animals, with two spa types exclusively associated with rabbit meat (t4770, t8456).


Impact of parturition on maternal cardiovascular and neuronal integrity in a high risk cohort - a prospective cohort study.
To better understand the profound multisystem changes in maternal physiology triggered by parturition, in particular in the underexplored neuronal system, by deploying a panel of pre- vs post-delivery maternal serum biomarkers, most notably the neuronal cytoskeleton constituent neurofilament light chain (NfL). This promising fluid biomarker is not only increasingly applied to investigate disease progression in numerous brain diseases, particularly in proteopathies, but also in detection of traumatic brain injury or monitoring neuroaxonal injury after ischemic stroke. The study was nested within a prospective cohort study of pregnant women at risk of developing preeclampsia at the University Hospital of Basel. Paired ante- and postpartum levels of progesterone, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin (CT-proAVP), and NfL were measured in 56 women with complete clinical data. Placental delivery significantly decreased all placental markers: progesterone 4.5-fold, PlGF 2.2-fold, and sFlt-1 1.7-fold. Copeptin and MR-proANP increased slightly (1.4- and 1.2-fold, respectively). Unexpectedly, NfL levels (median [interquartile range]) increased significantly post-partum: 49.4 (34.7-77.8) vs 27.7 (16.7-31.4) pg/ml (p < 0.0001). Antepartum NfL was the sole independent predictor of NfL peri-partum change; mode of delivery, duration of labor, clinical characteristics and other biomarkers were all unrelated. Antepartum NfL levels were themselves independently predicted only by maternal age. Parturition per se increases maternal serum NfL levels, suggesting a possible impact of parturition on maternal neuronal integrity.


Sub-optimal CD4 recovery on long-term suppressive highly active antiretroviral therapy is associated with favourable outcome.
To examine risk factors for sub-optimal CD4 recovery on suppressive highly active antiretroviral therapy (HAART) and assess long-term clinical and immunological outcomes. Retrospective analysis of 286 HIV-positive patients from a university clinic who initiated HAART with CD4 count <350 cells/microL between January 1996 and July 2006 and achieved > or =52 weeks of viral suppression (VS). Sub-optimal and optimal CD4 count recovery were defined by gains of <150 and > or =150 cells/microL during the first year of VS, respectively. Risk factors were analysed by multivariate logistic regression and markers of immune maturation and activation were evaluated prospectively for a sub-group of patients with prolonged (>5 years) VS. One hundred and two (36%) patients had sub-optimal CD4 recovery. Male gender, lower pre-HAART viral load, HAART toxicity and use of opportunistic infection (OI) prophylaxis were independent risk factors on multivariate analysis (P<0.05). Outcomes of duration of VS on HAART (4 years), new OI events (1%) and mortality (5%) were similar between groups. Markers of immune maturation and activation were higher among patients with sub-optimal CD4 recovery (P<0.05). Among HIV-positive patients with long-term VS, sub-optimal CD4 recovery was common but morbidity and mortality remained low. In addition, persistent CD4 T-cell activation appeared to blunt long-term CD4 gains.


Human immunodeficiency virus type 1 coreceptors participate in postentry stages in the virus replication cycle and function in simian immunodeficiency virus infection.
Primate lentiviruses use chemokine coreceptors in addition to the CD4 receptor to initiate virus infection. Simian immunodeficiency virus (SIV) productively infects human cells expressing CD4 and the human allele of the chemokine coreceptor CCR-5 as efficiently as it infects macaque cells expressing human CD4, suggesting that SIV can function with either a simian or a human coreceptor in conjunction with human CD4. In the same macaque cells expressing human CD4, the replication of human immunodeficiency virus type 1 (HIV-1) is blocked at several stages of infection; some isolates are restricted prior to reverse transcription, while others, including some macrophage-tropic and primary isolates, are restricted at a step after reverse transcription but prior to migration of the preintegration complex to the nucleus. Both blocks in HIV-1 replication can be relieved by either expression of the appropriate human coreceptor (CCR-5 or CXCR-4) or expression of SIV gene products in cis with the HIV-1 envelope as a chimera between SIV and HIV-1 (SHIV). Thus, a virus with a SIV core and HIV-1 envelope can efficiently infect macaque cells expressing human CD4, presumably by interacting with the simian coreceptor, whereas a virus with an HIV-1 core and an HIV-1 envelope requires expression of the human allele of the coreceptor for productive infection of these cells. These studies suggest that there are interactions among the coreceptor, the viral envelope, and another viral gene product that govern postentry steps of virus replication. These data are consistent with the hypothesis that such interactions may be required for translocation of the virus core to the nucleus. Moreover, the differential abilities of SIV and HIV-1 to function in these processes with heterologous primate coreceptors may have implications for cross-species transmission.


The effect of beliefs about alcohol's acute effects on alcohol priming and alcohol-induced impairments of inhibitory control.
Acute alcohol administration can lead to a loss of control over drinking. Several models argue that this 'alcohol priming effect' is mediated by the effect of alcohol on inhibitory control. Alternatively, beliefs about how alcohol affects behavioural regulation may also underlie alcohol priming and alcohol-induced inhibitory impairments. Here two studies examine the extent to which the alcohol priming effect and inhibitory impairments are moderated by beliefs regarding the effects of alcohol on the ability to control behaviour. In study 1, following a priming drink (placebo or .5g/kg of alcohol), participants were provided with bogus feedback regarding their performance on a measure of inhibitory control (stop-signal task; SST) suggesting that they had high or average self-control. However, the bogus feedback manipulation was not successful. In study 2, before a SST, participants were exposed to a neutral or experimental message suggesting acute doses of alcohol reduce the urge to drink and consumed a priming drink and this manipulation was successful. In both studies craving was assessed throughout and a bogus taste test which measured ad libitum drinking was completed. Results suggest no effect of beliefs on craving or ad lib consumption within either study. However, within study 2, participants exposed to the experimental message displayed evidence of alcohol-induced impairments of inhibitory control, while those exposed to the neutral message did not. These findings do not suggest beliefs about the effects of alcohol moderate the alcohol priming effect but do suggest beliefs may, in part, underlie the effect of alcohol on inhibitory control.


Improving measles incidence inference using age-structured serological data.
Measles is a target for elimination in all six WHO regions by 2020, and over the last decade, there has been considerable progress towards this goal. Surveillance is recognised as a cornerstone of elimination programmes, allowing early identification of outbreaks, thus enabling control and preventing re-emergence. Fever-rash surveillance is increasingly available across WHO regions, and this symptom-based reporting is broadly used for measles surveillance. However, as measles control increases, symptom-based cases are increasingly likely to reflect infection with other diseases with similar symptoms such as rubella, which affects the same populations, and can have a similar seasonality. The WHO recommends that cases from suspected measles outbreaks be laboratory-confirmed, to identify 'true' cases, corresponding to measles IgM titres exceeding a threshold indicative of infection. Although serological testing for IgM has been integrated into the fever-rash surveillance systems in many countries, the logistics of sending in every suspected case are often beyond the health system's capacity. We show how age data from serologically confirmed cases can be leveraged to infer the status of non-tested samples, thus strengthening the information we can extract from symptom-based surveillance. Applying an age-specific confirmation model to data from three countries with divergent epidemiology across Africa, we identify the proportion of cases that need to be serologically tested to achieve target levels of accuracy in estimated infected numbers and discuss how this varies depending on the epidemiological context. Our analysis provides an approach to refining estimates of incidence leveraging all available data, which has the potential to improve allocation of resources, and thus contribute to rapid and efficient control of outbreaks.


Geographical Distribution of Cacao swollen shoot virus Molecular Variability in Côte d'Ivoire.
The discovery of new outbreaks caused by Cacao swollen shoot virus (CSSV) in Côte d'Ivoire in 2003, when this disease seemed to have been eradicated since the end of the 1950s in that country, casts doubt on the sustainability of Ivorian cocoa production. The aims of this study were, first, to carry out a molecular characterization of CSSV isolates from the main outbreaks in Côte d'Ivoire; second, determine their phylogenetic position in relation to isolates already discovered in Togo and Ghana; and, finally, study their geographical distribution to understand the dispersal of the virus. Additionally, this study was intended to enable the implementation and validation of a polyvalent molecular diagnosis assay for CSSV. Sequences analyses, corresponding to a fragment located at the 5' end of open reading frame (ORF)3 of the CSSV genome, revealed three new CSSV groups (D, E, and F) distinct from the A, B, and C groups already identified in Togo. Only group B was detected in all the outbreaks, whereas groups A and C were not identified in Côte d'Ivoire. In addition, a polymerase chain reaction diagnostic using the ORF3A F/R primer pair was polyvalent, because it enabled the detection of CSSV in 90% of the plots in all the cocoa regions analyzed by this study.


A search for ceramide binding proteins using bifunctional lipid analogs yields CERT-related protein StarD7.
Ceramides are central intermediates of sphingolipid metabolism with dual roles as mediators of cellular stress signaling and mitochondrial apoptosis. How ceramides exert their cytotoxic effects is unclear and their poor solubility in water hampers a search for specific protein interaction partners. Here, we report the application of a photoactivatable and clickable ceramide analog, pacCer, to identify ceramide binding proteins and unravel the structural basis by which these proteins recognize ceramide. Besides capturing ceramide transfer protein (CERT) from a complex proteome, our approach yielded CERT-related steroidogenic acute regulatory protein D7 (StarD7) as novel ceramide binding protein. Previous work revealed that StarD7 is required for efficient mitochondrial import of phosphatidylcholine (PC) and serves a critical role in mitochondrial function and morphology. Combining site-directed mutagenesis and photoaffinity labeling experiments, we demonstrate that the steroidogenic acute regulatory transfer domain of StarD7 harbors a common binding site for PC and ceramide. While StarD7 lacks robust ceramide transfer activity in vitro, we find that its ability to shuttle PC between model membranes is specifically affected by ceramides. Besides demonstrating the suitability of pacCer as a tool to hunt for ceramide binding proteins, our data point at StarD7 as a candidate effector protein by which ceramides may exert part of their mitochondria-mediated cytotoxic effects.


Genome-wide association studies for complex traits: consensus, uncertainty and challenges.
The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.


Probiotic yogurt Affects Pro- and Anti-inflammatory Factors in Patients with Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) is an irregular response of immune system accompanied with different inflammatory manifestations including alterations in cytokines. Probiotics are non-pathogenic organisms with probable effects in various conditions such as inflammation. The present study hypothesized whether oral intake of bifidobacterium and lactobacillus in form of probiotic yogurt may represent an immunomodulatory effect in IBD patients. Overally, 210 patients in remission phase and 95 healthy people were recruited. Patients were randomly divided into two groups of either 250 grams of probiotic yogurt (PI) or 250 grams of plain yogurt (PC) daily for 8 weeks. The healthy control group (HG) also received probiotic yogurt as noted. The serum levels of cytokines TNF-α, IL-6, IL-1β, IL-10 and CRP levels were measured at baseline and at termination time. A significant difference was observed between intervention groups of PI and PC with HG group (p < 0.05). After the intervention, serum levels of IL-1β, TNF-α and CRP were significantly decreased in PI group compared to their baseline values and intervention groups. The serum levels of IL-6 and IL-10 increased significantly after the intervention compared to baseline values and PC levels (all p-values < 0.05). Intestinal homeostasis is a balance between pro and anti-inflammatory responses of intestinal immunocytes and could be maintained by probiotics.


Assessment of Regeneration of Bone in the Extracted Third Molar Sockets Augmented Using Xenograft (CollaPlugTN Zimmer) in Comparison with the Normal Healing on the Contralateral Side.
Alveolar bone resorption is a significant clinical problem. Bone loss in third molar region following extraction or surgical removal not only leads to periodontal problems in second molar region but also it may lead to some serious problems like increased incidence of angle fractures. In order to reduce the risks following third molar surgery, the socket should be augmented with bone grafts. In recent days guided tissue regeneration is the most accepted and successful technique followed many authors and its efficacy has been proved. Based upon our clinical experience, the use of bio absorbable collagen wound dressing such as CollaPlugTN has achieved quick healing and more primary wound coverage. Amongst the graft materials collagen is preferable due to its high biocompatibility and hemostatic ability. This study was done to assess the regeneration of bone in the extracted third molar sockets using xenograft (CollaPlugTN-Zimmer) which was compared with the normal healing on the contra lateral side. The assessment was done to analyze post-operative healing complications and to compare the bone density formed between control site and implant site radiologically. On this basis of this study, the use of collaplugTN appears to be beneficial to the patient in postoperative wound healing and also for better bone formation. The use of this material was advantageous because of its simplicity of application cost effectiveness and availability. There is enhanced wound healing and early bone formation.


Mild Clinical Course of COVID-19 in 3 Patients Receiving Therapeutic Monoclonal Antibodies Targeting C5 Complement for Hematologic Disorders.
BACKGROUND Patients receiving immunosuppressive therapies might be more susceptible to COVID-19. Conversely, an exaggerated inflammatory response to the SARS-CoV-2 infection might be blunted by certain forms of immunosuppression, which could be protective. Indeed, there are data from animal models demonstrating that complement may be a part of the pathophysiology of coronavirus infections. There is also evidence from an autopsy series demonstrating complement deposition in the lungs of patients with COVID-19. This raises the question of whether patients on anti-complement therapy could be protected from COVID-19. CASE REPORT Case 1 is a 39-year-old woman with an approximately 20-year history of paroxysmal nocturnal hemoglobinuria (PNH), who had recently been switched from treatment with eculizumab to ravulizumab prior to SARS-CoV-2 infection. Case 2 is a 54-year-old woman with a cadaveric renal transplant for lupus nephritis, complicated by thrombotic microangiopathy, who was maintained on eculizumab, which she started several months before she developed the SARS-CoV-2 infection. Case 3 is a 60-year-old woman with a 14-year history of PNH, who had been treated with eculizumab since 2012, and was diagnosed with COVID-19 at the time of her scheduled infusion. All 3 patients had a relatively mild course of COVID-19. CONCLUSIONS We see no evidence of increased susceptibility to SARS-CoV-2 in these patients on anti-complement therapy, which might actually have accounted for the mild course of infection. The effect of anti-complement therapy on COVID-19 disease needs to be determined in clinical trials.


Fast intra-fractional image-guidance with 6D positioning correction reduces delivery uncertainty for stereotactic radiosurgery and radiotherapy.
The purpose of this study is to analyze intra-fractional positioning uncertainty for stereotactic radiotherapy and radiosurgery of cranial tumors. Specifically, we wish to determine the use of intra-fractional image guided patient positioning verification is necessary during delivery of "frameless" stereotactic radiotherapy and radiosurgery (SRT/SRS) and non-coplanar radiation beams, and if positioning uncertainty is associated with overall treatment time. Orthogonal radiographic treatment verification data was extracted for 288 patients and 1344 fractions, and were analyzed with respect to 3D translational and angular corrections once during treatment delivery of SRT/SRS. We find that positioning corrections greater than 2 mm are required for approximately 6% of beams, and that the magnitude of the translational corrections was significantly associated with the delay time between beams (p=0.003). Further, we find that the maximum angular and translational deviations were associated (p<0.001). We conclude that a subgroup of SRT/SRS patients may have considerable positioning error unless this is monitored and corrected during treatment, and that keeping the imaging and delivery times below approximately 5 min is beneficial towards clinically relevant geographical errors. In case longer time-delays than 5 min occurs, the treatment staff should consider acquiring a new set of radiographs in order to verify the patient's position, assuming this technically feasible to be performed quickly.


Serum troponin I levels in hyperthyroid cats before and after treatment with radioactive iodine.
A raised concentration of serum cardiac troponin I (cTnI) is a sensitive marker of cardiac myocyte injury in the cat and assays developed for its measurement in human patients have been validated in the cat. Raised levels have been associated with a number of cardiac insults including hypertrophic cardiomyopathy and trauma. Hyperthyroidism is a common disease of older cats and excess thyroid hormone is known to produce significant cardiovascular effects in this species. This study evaluated the effect of treatment for hyperthyroidism with radioactive iodine on cTnI concentration, assessed the association between thyroxin levels and glomerular filtration rate (GFR) and cTnI concentration in cats treated for hyperthyroidism and described changes in echocardiographic parameters following treatment. Prior to the treatment serum cTnI was measured and echocardiography performed, thyroxin, cTnI, and echocardiography were then repeated at various time points following radioisotope therapy. The results show that higher thyroxin levels were significantly (P=0.002) associated with a higher likelihood of the cat presenting with detectable levels of cTnI. No significant association was found between GFR and presence of detectable levels of cTnI. Furthermore the results indicate that the effects of hyperthyroidism on echocardiographic parameters appear considerably less in this study than in previous studies and that the main outcome of treatment on these parameters is a significant reduction in fractional shortening (P=0.006). These results suggest that chronic exposure to excess thyroid hormone may induce myocyte damage of sufficient severity to raise serum cTnI concentration in a proportion of cats that resolves following establishment of a euthyroid state.


Drugs targeting 5-hydroxytryptamine receptors in acute treatments of migraine attacks. A review of new drugs and new administration forms of established drugs.
The development of sumatriptan, more than 20 years ago, added substantially to the characterization of 5-hydroxytryptamine (5-HT) receptors and their relevance to acute migraine therapy. Recently, 5-HT1F receptor agonists, with no vascular effects, have shown efficacy in the treatment of migraines. This evaluation reviews the recent advances in acute migraine therapy targeting the 5-HT receptor. Specifically, the authors review the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of 5-HT1F receptor agonists and new formulations of sumatriptan and dihydroergotamine (DHE). Lasmiditan, a non-vascular acting 5-HT1F receptor agonist, is effective in migraine but causes central nervous system-related adverse events, which may considerably limit its clinical use. The efficacy of transdermal sumatriptan is too low for general use in migraine. Intranasal sumatriptan powder could be a step forward compared with oral sumatriptan, but comparative trials are needed. Orally inhaled DHE has a very quick systemic absorption but the onset of effect in migraine is relatively slow with a maximum effect after 2 h. In contrast, orally inhaled DHE results in a low incidence of recurrence. None of these reviewed treatments are likely to fulfill patients' expectations, and the advancement of acute migraine drugs should likely depend on different mechanisms from current 5-HT-related drugs.


Class III treatment using facial mask: stability after 10 years.
Early Class III malocclusion treatment may not have long-term stability due to mandibular growth. Although some features of this malocclusion point to a better prognosis, it is practically impossible for the orthodontist to foresee cases that require new intervention. Many patients need retreatment, whether compensatory or orthodontic-surgical. The present study reports the case of a Class III patient treated at the end of the mixed dentition with the use of a face mask followed by conventional fixed appliances. The case remains stable 10 years after treatment completion. It was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO) as a requirement for the title of certified by the BBO.


Sulforaphane Bioavailability and Chemopreventive Activity in Men Presenting for Biopsy of the Prostate Gland: A Randomized Controlled Trial.
Previous studies suggest compounds such as sulforaphane (SFN) derived from cruciferous vegetables may prevent prostate cancer development and progression. This study evaluated the effect of broccoli sprout extract (BSE) supplementation on blood histone deacetylase (HDAC) activity, prostate RNA gene expression, and tissue biomarkers (histone H3 lysine 18 acetylation (H3K18ac), HDAC3, HDAC6, Ki67, and p21). A total of 98 men scheduled for prostate biopsy were allocated into either BSE (200 µmol daily) or a placebo in our double-blind, randomized controlled trial. We used nonparametric tests to evaluate the differences of blood HDAC activity and prostate tissue immunohistochemistry biomarkers between treatment groups. Further, we performed RNA-Seq analysis on the prostate biopsies and identified 40 differentially expressed genes correlated with BSE treatment, including downregulation of two genes previously implicated in prostate cancer development, AMACR and ARLNC1. Although urine and plasma SFN isothiocyanates and individual SFN metabolites were statistically higher in the treatment group, our results did not show a significant difference in HDAC activity or prostate tissue biomarkers. This study indicates BSE supplementation correlates with changes in gene expression but not with several other prostate cancer biomarkers. More research is required to fully understand the chemopreventive effects of BSE supplementation on prostate cancer.


2-cysteine peroxiredoxins and thylakoid ascorbate peroxidase create a water-water cycle that is essential to protect the photosynthetic apparatus under high light stress conditions.
Different peroxidases, including 2-cysteine (2-Cys) peroxiredoxins (PRXs) and thylakoid ascorbate peroxidase (tAPX), have been proposed to be involved in the water-water cycle (WWC) and hydrogen peroxide (H2O2)-mediated signaling in plastids. We generated an Arabidopsis (Arabidopsis thaliana) double-mutant line deficient in the two plastid 2-Cys PRXs (2-Cys PRX A and B, 2cpa 2cpb) and a triple mutant deficient in 2-Cys PRXs and tAPX (2cpa 2cpb tapx). In contrast to wild-type and tapx single-knockout plants, 2cpa 2cpb double-knockout plants showed an impairment of photosynthetic efficiency and became photobleached under high light (HL) growth conditions. In addition, double-mutant plants also generated elevated levels of superoxide anion radicals, H2O2, and carbonylated proteins but lacked anthocyanin accumulation under HL stress conditions. Under HL conditions, 2-Cys PRXs seem to be essential in maintaining the WWC, whereas tAPX is dispensable. By comparison, this HL-sensitive phenotype was more severe in 2cpa 2cpb tapx triple-mutant plants, indicating that tAPX partially compensates for the loss of functional 2-Cys PRXs by mutation or inactivation by overoxidation. In response to HL, H2O2- and photooxidative stress-responsive marker genes were found to be dramatically up-regulated in 2cpa 2cpb tapx but not 2cpa 2cpb mutant plants, suggesting that HL-induced plastid to nucleus retrograde photooxidative stress signaling takes place after loss or inactivation of the WWC enzymes 2-Cys PRX A, 2-Cys PRX B, and tAPX.


Counterfeit anti-infective drugs.
The production of counterfeit or substandard anti-infective drugs is a widespread and under-recognised problem that contributes to morbidity, mortality, and drug resistance, and leads to spurious reporting of resistance and toxicity and loss of confidence in health-care systems. Counterfeit drugs particularly affect the most disadvantaged people in poor countries. Although advances in forensic chemical analysis and simple field tests will enhance drug quality monitoring, improved access to inexpensive genuine medicines, support of drug regulatory authorities, more open reporting, vigorous law enforcement, and more international cooperation with determined political leadership will be essential to counter this threat.


Awareness and interest in osteopathic manipulative treatment in allopathic medical students.
Osteopathic manipulative treatment (OMT) is utilized by clinicians to diagnose and treat a variety of musculoskeletal conditions including acute and chronic pain, and other medical conditions. Previous studies have examined attitudes of allopathic (MD) residents toward OMT and have implemented residency-based curricula; however, literature is lacking on the attitudes of MD students toward OMT. The objective of this study was to determine MD students' familiarity with OMT and to evaluate their interest in an elective osteopathic curriculum. A 15-item online survey was electronically sent to 600 MD students at a large allopathic academic medical center. The survey assessed familiarity with OMT, interest in OMT and in participating in an OMT elective, educational format preference, and interest in pursuing primary care. Educational demographics were also collected. Descriptive statistics and Fisher's exact test were utilized for categorical variables, and nonparametric tests were utilized for the ordinal and continuous variables. A total of 313 MD students submitted responses (response rate=52.1 %), of which 296 (49.3 %) responses were complete and utilized for analysis. A total of 92 (31.1 %) students were aware of OMT as a modality in treating musculoskeletal disorders. Among the respondents who indicated "very interested" in learning a new pain treatment modality, the majority: (1) observed OMT in a prior clinical or educational setting (85 [59.9 %], p=0.02); (2) had a friend or family member treated by a DO physician (42 [71.2 %], p=0.01); (3) were pursuing a primary care specialty (43 [60.6 %], p=0.02); or (4) interviewed at an osteopathic medical school (47 [62.7 %], p=0.01). Among those interested in developing some OMT competency, the majority: (1) were pursuing a primary care specialty (36 [51.4 %], p=0.01); (2) applied to osteopathic schools (47 [54.0], p=0.002); or (3) interviewed at an osteopathic medical school (42 [56.8 %], p=0.001). A total of 230 (82.1 %) students were somewhat or very interested in a 2-week elective course in OMT; among all respondents, hands-on labs were the preferred method for delivery of OMT education (272 [94.1 %]). The study found a strong interest in an OMT elective by MD students. These results will inform OMT curriculum development aimed at interested MD students and residents in order to provide them with OMT-specific theoretical and practical knowledge.


MAGNETIC RESONANCE IMAGING OF INTRACRANIAL INFLAMMATORY CONDITIONS IN DOGS: SENSITIVITY OF SUBTRACTION IMAGES VERSUS PRE- AND POST-GADOLINIUM T1-WEIGHTED IMAGE PAIRS.
Ante mortem diagnosis of canine meningoencephalitis is usually based on the results of neurologic examination, cerebrospinal fluid analysis and magnetic resonance (MR) imaging. It has been hypothesized that subtraction MR imaging may increase the sensitivity of MR for intracranial inflammatory lesions compared to conventional post-gadolinium T1-weighted imaging. Sensitivity of pre- and post-gadolinium (C-/C+) image pairs and dynamic subtraction (DS) images was compared in a retrospective diagnostic accuracy study of 52 dogs with inflammatory cerebrospinal fluid and 67 dogs with idiopathic epilepsy. Series of transverse C-/C+ and DS images were reviewed independently for signs of abnormal enhancement affecting the pachymeninges, leptomeninges or intra-axial structures. Sensitivity of C-/C+ image pairs and DS images was 48% (95% CI: 35-61%) and 65% (95% CI: 52-77%), respectively (P = 0.01). Intra-axial lesions were observed more frequently than meningeal lesions in both C-/C+ (43% vs. 31%) and DS images (61% vs. 22%). The difference in sensitivities of C-/C+ and DS series was entirely due to increased sensitivity of DS images for intra-axial lesions. Eight (12%) dogs with epilepsy had evidence of intra-axial gadolinium accumulation affecting the cerebral cortex in DS images. This finding may represent a false-positive result or a true sign of pathology, possibly associated with a leaky blood-brain barrier in areas of the brain affected by neovascularization secondary to repeated seizures. Results suggest that DS imaging has higher sensitivity than comparison of pre- and post-gadolinium image pairs for inflammatory intra-axial lesions.


Stress in romantic relationships and adolescent depressive symptoms: Influence of parental support.
It is well known that stressful life events can play a role in the development of adolescent depressive symptoms; however, there has been little research on romantic stress specifically. The relationship between romantic stress and depressive symptoms is particularly salient in adolescence, as adolescence often involves the onset of dating. This and other stressors are often dealt with in the context of the family. The present study examined the relationship between romantic stress and depressive symptoms both concurrently and prospectively, controlling for preexisting depressive symptoms. We then explored whether support from parents buffers the negative effects of romantic stress on depressive symptoms. In addition, the study sought to determine whether the benefits of support vary by parent and child gender. A community sample of 375 adolescents completed self-report measures of parental support (both maternal and paternal), romantic stress, and depressive symptoms. A behavioral measure of maternal support was also obtained. For boys and girls, romantic stress at age 15 predicted depressive symptoms at ages 15 and 18, even when controlling for age 13 depressive symptoms. Perceived maternal support buffered the stress-depressive symptom relationship for both genders at age 15, even when controlling for age 13 depressive symptoms. Higher perceived paternal support was associated with lower adolescent depressive symptoms; however, it did not have a buffering effect. These results have implications for the development of effective family-centered methods to prevent the development of depressive symptoms in adolescents.


Plants use macronutrients accumulated in leaf-cutting ant nests.
Leaf-cutting ants (Atta spp.) are known for their extensive defoliation in neo-tropical forests and savannahs. Debate about the costs and benefits of their activities has been largely dominated by their detrimental effects on agriculture and agroforestry. However, the large accumulation of nutrients and changes in soil properties near their nests might benefit plants growing near them. Here, we test whether trees use nutrients that accumulate in debris piles near, or refuse chambers within, leaf-cutting ant nests. At two tropical sites (a moist tropical forest site in Panama and a savannah site in Brazil), we fed leaves labelled with the stable isotope 15N to two species of leaf-cutting ants (Atta colombica and Atta laevigata) and traced the stable isotope label in plants surrounding the two nests. Thus, we show that plants in both sites access resources associated with Atta nests. In addition, leaf tissue of trees near the nests labelled with 15N had significantly higher calcium concentrations than those of distal, unlabelled conspecifics. It has been documented that calcium is a limiting macronutrient in tropical forests and savannahs. Atta may thus play an important ecological role through their long-distance transport, redistribution and concentration of critical macronutrients.


Viral adaptation to host immune responses occurs in chronic hepatitis B virus (HBV) infection, and adaptation is greatest in HBV e antigen-negative disease.
Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.


A lab-on-chip ultrasonic platform for real-time and nondestructive assessment of extracellular matrix stiffness.
Extracellular matrix (ECM) mechanical stiffness and its dynamic change is one of the main cues that directly affects the differentiation and proliferation of normal cells as well as the progression of disease processes such as fibrosis and cancer. Recent advancements in biomaterials have enabled a wide range of polymer matrices that could mimic the ECM of different tissues for a wide range of in vitro basic research and drug discovery. However, most of the technologies utilized to quantify the stiffness of such ECM are either destructive or expensive, and therefore are unsuitable for the in situ, long-term monitoring of variations in ECM stiffness for on-chip cell culture applications. This work demonstrates a novel noninvasive on-chip platform for characterization of ECM stiffness in vitro, by monitoring ultrasonic wave attenuation through the targeted material. The device is composed of a pair of millimeter scale ultrasonic transmitter and receiver transducers with the test medium placed in between them. The transmitter generates an ultrasonic wave that propagates through the material, triggers the piezoelectric receiver and generates a corresponding electrical signal. The characterization reveals a linear (r2 = 0.86) decrease in the output voltage of the piezoelectric receiver with an average sensitivity of -15.86 μV kPa-1 by increasing the stiffnesses of hydrogels (from 4.3 kPa to 308 kPa made with various dry-weight concentrations of agarose and gelatin). The ultrasonic stiffness sensing is also demonstrated to successfully monitor dynamic changes in a simulated in vitro tissue by gradually changing the polymerization density of an agarose gel, as a proof-of-concept towards future use for 3D cell culture and drug screening. In situ long-term ultrasonic signal stability and thermal assessment of the device demonstrates its high robust performance even after two days of continuous operation, with negligible (<0.5 °C) heating of the hydrogel in contact with the piezoelectric transducers. In vitro biocompatibility assessment of the device with mammary fibroblasts further assures that the materials used in the platform did not produce a toxic response and cells remained viable under the applied ultrasound signals in the device.


Restricting carbohydrates to fight head and neck cancer-is this realistic?
Head and neck cancers (HNCs) are aggressive tumors that typically demonstrate a high glycolytic rate, which results in resistance to cytotoxic therapy and poor prognosis. Due to their location these tumors specifically impair food intake and quality of life, so that prevention of weight loss through nutrition support becomes an important treatment goal. Dietary restriction of carbohydrates (CHOs) and their replacement with fat, mostly in form of a ketogenic diet (KD), have been suggested to accommodate for both the altered tumor cell metabolism and cancer-associated weight loss. In this review, I present three specific rationales for CHO restriction and nutritional ketosis as supportive treatment options for the HNC patient. These are (1) targeting the origin and specific aspects of tumor glycolysis; (2) protecting normal tissue from but sensitizing tumor tissue to radiation- and chemotherapy induced cell kill; (3) supporting body and muscle mass maintenance. While most of these benefits of CHO restriction apply to cancer in general, specific aspects of implementation are discussed in relation to HNC patients. While CHO restriction seems feasible in HNC patients the available evidence indicates that its role may extend beyond fighting malnutrition to fighting HNC itself.


Temporal trends in disability evaluation and retirement in the Army, Navy, and Marine Corps: 2005-2011.
Surveillance of trends in disability is necessary to determine the burden of disability on the U.S. military, the most common types of disability conditions, and the prevalence of combat exposures in the disability population. Previous studies of disability in the U.S. military have focused on a particular service or condition rather than examining the epidemiology of disability in the military overall. This study's objective is to describe rates of disability evaluation and retirement in U.S. Army, Navy, and Marine Corps. A cross-sectional study of 126,170 service members evaluated for disability discharge from the U.S. military in fiscal years 2005-2011 was conducted. Crude and standardized rates of disability evaluation and retirement were calculated per 10,000 service members by year of disability, demographic characteristics, and type of disability evaluation or retirement. Temporal trends in the prevalence of combat-related disability in the disability evaluated and retired population were also examined. Rates of disability evaluation and retirement were highest among female, enlisted, and active duty service members. Overall rates of disability evaluation significantly decreased, while rates of disability retirement increased. Rates of psychiatric disability evaluation and retirement significantly increased in all services during the same time period from 2005 to 2011. Combat-related disability evaluations and retirements have substantially increased in all services particularly among psychiatric disability cases. Psychiatric disability, combat-related disability, and disability retirement continue to increase in the military, despite observed decreases in the rates of disability the Department of Defense since 2005.


On brain atlas choice and automatic segmentation methods: a comparison of MAPER & FreeSurfer using three atlas databases.
Several automatic image segmentation methods and few atlas databases exist for analysing structural T1-weighted magnetic resonance brain images. The impact of choosing a combination has not hitherto been described but may bias comparisons across studies. We evaluated two segmentation methods (MAPER and FreeSurfer), using three publicly available atlas databases (Hammers_mith, Desikan-Killiany-Tourville, and MICCAI 2012 Grand Challenge). For each combination of atlas and method, we conducted a leave-one-out cross-comparison to estimate the segmentation accuracy of FreeSurfer and MAPER. We also used each possible combination to segment two datasets of patients with known structural abnormalities (Alzheimer's disease (AD) and mesial temporal lobe epilepsy with hippocampal sclerosis (HS)) and their matched healthy controls. MAPER was better than FreeSurfer at modelling manual segmentations in the healthy control leave-one-out analyses in two of the three atlas databases, and the Hammers_mith atlas database transferred to new datasets best regardless of segmentation method. Both segmentation methods reliably identified known abnormalities in each patient group. Better separation was seen for FreeSurfer in the AD and left-HS datasets, and for MAPER in the right-HS dataset. We provide detailed quantitative comparisons for multiple anatomical regions, thus enabling researchers to make evidence-based decisions on their choice of atlas and segmentation method.


Autophagy in cell death: an innocent convict?
The visualization of autophagosomes in dying cells has led to the belief that autophagy is a nonapoptotic form of programmed cell death. This concept has now been evaluated using cells and organisms deficient in autophagy genes. Most evidence indicates that, at least in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. This review summarizes the evidence linking autophagy to cell survival and cell death, the complex interplay between autophagy and apoptosis pathways, and the role of autophagy-dependent survival and death pathways in clinical diseases.


Computational study of fluorescence scattering by silver nanoparticles.
We study the nature of fluorescence scattering by a radiating fluorophore placed near a metal nanoparticle with the finite-difference time-domain method. Angle-resolved light-scattering distributions are contrasted with those that result when ordinary plane waves are scattered by the nanoparticle. For certain sized nanoparticles and fluorophore dipoles oriented parallel to the metal surface, we find that the highest scattered fluorescence emission is directed back toward the fluorophore, which is very different from plane-wave scattering. The largest enhancements of far-field radiation are found when the dipole is oriented normal to the surface. We also examined the effect of the fluorophore on the near field around the particle. The fields can be enhanced or quenched compared to the isolated fluorophore and exhibit strong dependence on fluorophore orientation, as well as interesting spatial variations around the nanoparticle.


Exploiting chemistry and molecular systems for quantum information science.
The power of chemistry to prepare new molecules and materials has driven the quest for new approaches to solve problems having global societal impact, such as in renewable energy, healthcare and information science. In the latter case, the intrinsic quantum nature of the electronic, nuclear and spin degrees of freedom in molecules offers intriguing new possibilities to advance the emerging field of quantum information science. In this Perspective, which resulted from discussions by the co-authors at a US Department of Energy workshop held in November 2018, we discuss how chemical systems and reactions can impact quantum computing, communication and sensing. Hierarchical molecular design and synthesis, from small molecules to supramolecular assemblies, combined with new spectroscopic probes of quantum coherence and theoretical modelling of complex systems, offer a broad range of possibilities to realize practical quantum information science applications.


Identification of Haemophilus influenzae Rd transformation genes using cassette mutagenesis.
Genes required for natural transformation of Haemophilus influenzae Rd were identified by a cassette mutagenesis protocol consisting of the following steps: random insertional mutagenesis, phenotypic screening, sequencing of genome sequence tags from the DNA flanking the insertion in the selected mutants and comparison of genome sequence tags to genomic sequence data. The cassette mutagenesis screen for transformation genes resulted in five distinct mutant classes, two of which have been identified in previous studies. Insertions in the three newly identified loci interrupted genes with predicted protein products homologous to a type IV pilin-like protein biogenesis operon, drug-efflux transporters and a phospholipid-biosynthesis enzyme. The most significant finding of this screen is the requirement for type IV pilin-like proteins in genetic transformation of H. influenzae. These surface structures are utilized for DNA uptake in a number of Gram-positive and Gram-negative bacteria, and appear to be the common component among the systems for DNA binding.


Will nonlinear peculiar velocity and inhomogeneous reionization spoil 21 cm cosmology from the epoch of reionization?
The 21 cm background from the epoch of reionization is a promising cosmological probe: line-of-sight velocity fluctuations distort redshift, so brightness fluctuations in Fourier space depend upon angle, which linear theory shows can separate cosmological from astrophysical information. Nonlinear fluctuations in ionization, density, and velocity change this, however. The validity and accuracy of the separation scheme are tested here for the first time, by detailed reionization simulations. The scheme works reasonably well early in reionization (≲40% ionized), but not late (≳80% ionized).


Comparative proteomic analysis of different stages of breast cancer tissues using ultra high performance liquid chromatography tandem mass spectrometer.
Breast cancer is the fifth most prevalent cause of death among women worldwide. It is also one of the most common types of cancer among Malaysian women. This study aimed to characterize and differentiate the proteomics profiles of different stages of breast cancer and its matched adjacent normal tissues in Malaysian breast cancer patients. Also, this study aimed to construct a pertinent protein pathway involved in each stage of cancer. In total, 80 samples of tumor and matched adjacent normal tissues were collected from breast cancer patients at Seberang Jaya Hospital (SJH) and Kepala Batas Hospital (KBH), both in Penang, Malaysia. The protein expression profiles of breast cancer and normal tissues were mapped by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The Gel-Eluted Liquid Fractionation Entrapment Electrophoresis (GELFREE) Technology System was used for the separation and fractionation of extracted proteins, which also were analyzed to maximize protein detection. The protein fractions were then analyzed by tandem mass spectrometry (LC-MS/MS) analysis using LC/MS LTQ-Orbitrap Fusion and Elite. This study identified the proteins contained within the tissue samples using de novo sequencing and database matching via PEAKS software. We performed two different pathway analyses, DAVID and STRING, in the sets of proteins from stage 2 and stage 3 breast cancer samples. The lists of molecules were generated by the REACTOME-FI plugin, part of the CYTOSCAPE tool, and linker nodes were added in order to generate a connected network. Then, pathway enrichment was obtained, and a graphical model was created to depict the participation of the input proteins as well as the linker nodes. This study identified 12 proteins that were detected in stage 2 tumor tissues, and 17 proteins that were detected in stage 3 tumor tissues, related to their normal counterparts. It also identified some proteins that were present in stage 2 but not stage 3 and vice versa. Based on these results, this study clarified unique proteins pathways involved in carcinogenesis within stage 2 and stage 3 breast cancers. This study provided some useful insights about the proteins associated with breast cancer carcinogenesis and could establish an important foundation for future cancer-related discoveries using differential proteomics profiling. Beyond protein identification, this study considered the interaction, function, network, signaling pathway, and protein pathway involved in each profile. These results suggest that knowledge of protein expression, especially in stage 2 and stage 3 breast cancer, can provide important clues that may enable the discovery of novel biomarkers in carcinogenesis.


Porous Ti6Al4V scaffold directly fabricating by rapid prototyping: preparation and in vitro experiment.
Three-dimensional (3D) fiber deposition (3DF), a rapid prototyping technology, was successfully directly applied to produce novel 3D porous Ti6Al4V scaffolds with fully interconnected porous networks and highly controllable porosity and pore size. A key feature of this technology is the 3D computer-controlled fiber depositing of Ti6Al4V slurry at room temperature to produce a scaffold, consisting of layers of directionally aligned Ti6Al4V fibers. In this study, the Ti6Al4V slurry was developed for the 3D fiber depositing process, and the parameters of 3D fiber depositing were optimized. The experimental results show how the parameters influence the structure of porous scaffold. The potential of this rapid prototyping 3DF system for fabricating 3D Ti6Al4V scaffolds with regular and reproducible architecture meeting the requirements of tissue engineering and orthopedic implants is demonstrated.


Interaction between vascular factors and the APOE ε4 allele in predicting rate of progression in Alzheimer's disease.
Vascular factors have been shown to affect the rate of Alzheimer's disease (AD) progression. However, the effect of the APOE ε4 allele on rate of progression has been ambiguous. Little research to date has examined an interaction between vascular factors and the APOE ε4 allele in predicting decline among AD patients. 216 participants with incident AD from a population of elderly persons in Cache County, Utah, were followed for a mean of 3.3 years and 4.2 follow-up visits. A history of vascular risk factors and conditions and anti-hypertensive use was assessed at the diagnostic visit. Linear mixed effects models tested interactions between the vascular factors, APOE ε4, and time as predictors of clinical progression on the Mini-Mental State Exam (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Multiple comparisons were corrected using the Holm-Bonferroni method. There was a 3-way interaction between stroke, APOE ε4 and time in predicting MMSE decline (LR χ² = 10.32, 2 df, p = 0.006). For the CDR-SB, there were 3-way interactions between the APOE ε4, time and either myocardial infarction (LR χ² = 17.83, 2 df, p = 0.0001) or stroke (LR χ² = 11.48, 2 df, p = 0.003. Results suggest a complex relationship between the APOE ε4 and vascular factors in predicting cognitive and functional progression. Among individuals with a history of stroke or myocardial infarction at baseline, progression of AD is influenced by APOE ε4 carrier status and varies by time after AD diagnosis.


Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment.
Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer. Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m(2) intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m(2) on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review. Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [>/= grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups. Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.


A Rapid High-Performance LC-MS/MS Method for Therapeutic Drug Monitoring of Voriconazole, Posaconazole, Fluconazole, and Itraconazole in Human Serum.
To achieve therapeutic efficacy and prevent toxicity simultaneously, therapeutic drug monitoring has been increasingly adopted for antifungal agents with narrow therapeutic indexes. We herein report the development and validation of an accurate, simple, fast, and cost-effective clinical test with high-performance LC-MS/MS to simultaneously quantify voriconazole, posaconazole, fluconazole, and itraconazole in human serum. Mixed with extraction solution and internal standard, 100 μL serum samples were centrifuged for protein precipitation. Diluted supernatant was injected onto a Phenomenex® Luna C8 (2) 50 × 2 mm (3 μm) column and was analyzed with a Prominence Shimadzu high-performance liquid chromatography (HPLC) system coupled with a SCIEX QTRAP 4000 mass spectrometer in a positive ionization mode with multiple reaction monitoring. The total analytical run time was 3 min. The assay is linear for voricoanzole (0.01-10 μg/mL), posaconazole (0.02-40 μg/mL), fluconazole (0.2-200 μg/mL), and itraconazole (0.02-20 μg/mL). The intraday CVs ranged from 1.9% to 3.8% (n = 20); the interday CVs ranged from 2.7% to 5.4% (n = 20). Method comparison study (n = 39 or 40) demonstrated good correlation with reference laboratories (R >0.99) with average biases ranging from -7.2% to 17.5%. The recoveries for each analyte were above 90%, and matrix effects ranged from 95% to 112%. The method is acceptable for routine therapeutic drug monitoring of these antifungal agents in clinical laboratories for better therapeutic outcome.


Direct imaging of heteroatom dopants in catalytic carbon nano-onions.
The hollow core, concentric graphitic shells, and large surface area of the carbon nano-onion (CNO) make these carbon nanostructures promising materials for highly efficient catalytic reactions. Doping CNOs with heteroatoms is an effective method of changing their physical and chemical properties. In these cases, the configurations and locations of the incorporated dopant atoms must be a key factor dictating catalytic activity, yet determining a structural arrangement on the single-atom length scale is challenging. Here we present direct imaging of individual nitrogen and sulfur dopant atoms in CNOs, using an aberration-corrected scanning transmission electron microscopy (STEM) approach, combined with electron energy loss spectroscopy (EELS). Inspection of the statistics of dopant configuration and location in sulfur-, nitrogen-, and co-doped samples reveals dopant atoms to be more closely situated to defects in the graphitic shells for co-doped samples, than in their singly doped counterparts. Correlated with an increased activity for the oxygen reduction reaction in the co-doped samples, this suggests a concerted mechanism involving both the dopant and defect.


Selective extraction of proteins and other macromolecules from biological samples using molecular imprinted polymers.
The accurate determination of intact macromolecules in biological samples, such as blood, plasma, serum, urine, tissue and feces is a challenging problem. The increased interest in macromolecules both as candidate drugs and as biomarkers for diagnostic purposes means that new method development approaches are needed. This review charts developments in the use of molecularly imprinted polymers first for small-molecular-mass compounds then for proteins and other macromolecules. Examples of the development of molecularly imprinted polymers for macromolecules are highlighted. The two main application areas to date are sensors and separation science, particularly SPE. Examples include peptides and polypeptides, lysozyme, hemoglobin, ovalbumin, bovine serum albumin and viruses.


The role of p27 in endometrial carcinoma.
The cyclin-dependent kinase inhibitor p27 has been shown to mediate cell growth arrest in response to various environmental stimuli. p27 protein levels have shown prognostic value in several different types of cancer. We examined the prognostic value of p27 protein expression in endometrial cancer, the most common gynecologic malignancy. A total of 95 paraffin-embedded tumor blocks were obtained and stained via immunohistochemical techniques with a monoclonal antibody against p27. Ten high-power fields were evaluated per slide with at least 1000 cells per slide and two slides per specimen evaluated by two reviewers for nuclear and cytoplasmic staining. The specimens were evaluated for associations with age, stage, grade, and histology. Statistical analysis was performed using the Student t test, chi(2) Kaplan-Meier, and likelihood ratios to assess the data and to generate P values. A total of 91 patients met inclusion criteria for statistical analysis. Fifty-three patients were stage I, 13 stage II, 14 stage III and 11 stage IV with a positive stain (>50% of cells) for p27 obtained in 32.1, 23.1, 35.7, and 36.4%, respectively (Student t test P = 0.77). Survival data were available on 24 advanced stage patients. p27 protein immunostaining showed no association with patient survival. We also found no association of p27 staining with age or histology. Notably, we found a trend in increasing staining with increase in grade, particularly with stage I patients. Also, there was an association of the nuclear and cytoplasmic staining and stage (P = 0.05), but it had no correlation with patient survival. Our study showed decreased p27 protein staining in endometrial cancers compared to normal endometrial cells. We found that p27 protein staining shows no association with stage, age, or histology and is not prognostic for survival in advanced endometrial cancers. However, there may be a trend associated with increased p27 protein staining with advanced grades of tumors.


'Stealth' nanoparticles evade neural immune cells but also evade major brain cell populations: Implications for PEG-based neurotherapeutics.
Surface engineering to control cell behavior is of high interest across the chemical engineering, drug delivery and biomaterial communities. Defined chemical strategies are necessary to tailor nanoscale protein interactions/adsorption, enabling control of cell behaviors for development of novel therapeutic strategies. Nanoparticle-based therapies benefit from such strategies but particle targeting to sites of neurological injury remains challenging due to circulatory immune clearance. As a strategy to overcome this barrier, the use of stealth coatings can reduce immune clearance and prolong circulatory times, thereby enhancing therapeutic capacity. Polyethylene glycol (PEG) is the most widely-used stealth coating and facilitates particle accumulation in the brain. However, once within the brain, the mode of handling of PEGylated particles by the resident immune cells of the brain itself (the 'microglia') is unknown. This is a critical question as it is well established that microglia avidly sequester nanoparticles, limiting their bioavailability and posing a major translational barrier. If PEGylation can be proved to promote evasion of microglia, then this information will be of high value in developing tailored nanoparticle-based therapies for neurological applications. Here, we have conducted the first comparative study of uptake of PEGylated particles by all the major (immune and non-immune) brain cell types. We prove for the first time that PEGylated nanoparticles evade major brain cell populations - a phenomenon which will enhance extracellular bioavailability. We demonstrate changes in protein coronas around these particles within biological media, and discuss how surface chemistry presentation may affect this process and subsequent cellular interactions.


Cost-Effectiveness Analysis of the Diagnosis and Treatment of Primary Aldosteronism in Japan.
Approximately 10% of cases of hypertension in Japan are caused by primary aldosteronism (PA), amounting to about 4 million patients in total. Primary aldosteronism due to unilateral aldosterone hypersecretion is potentially curable by adrenalectomy. The clinical benefits of identifying and treating PA have been reported internationally, but its cost-effectiveness is unclear. We examined whether diagnosing and treating hidden PA in hypertensive population was cost-effective compared with suboptimal treatment. Our hypothetical patient was a 50-year-old man diagnosed with stage I-III hypertension. We established a Markov decision model based on plausible clinical pathways and prognoses of PA. We applied cost-effectiveness analysis comparing a comprehensive diagnostic strategy for PA (measurement of plasma aldosterone/renin ratio, 2 loading tests, imaging, and selective adrenal venous sampling) with a suboptimal strategy to manage hypertension by medication unless the typical signs of PA or other complication were manifest. Outcome measures were expected costs, expected effectiveness, and incremental cost-effectiveness ratio. The robustness of the findings was established by one-way and scenario sensitivity analyses. The comprehensive PA diagnostic strategy increased the expected costs by 64 004 JPY and expected life-years by 0.013 compared with standard treatment. The incremental cost-effectiveness ratio for the diagnosis of PA was 4 923 385 JPY per year. Our findings were sensitive to the outcomes of screening and treatment, and the costs of continuous or periodic medication for hypertension and the treatment of stroke and its complications.


Trade-offs, spatial heterogeneity, and the maintenance of microbial diversity.
Specialization and concomitant trade-offs are assumed to underlie the non-neutral coexistence of lineages. Trade-offs across heterogeneous environments can promote diversity by preventing competitive exclusion. However, the importance of trade-offs in maintaining diversity in natural microbial assemblages is unclear, as trade-offs are frequently not detected in artificial evolution experiments. Stressful conditions associated with patches of heavy-metal enriched serpentine soils provide excellent opportunities for examining how heterogeneity may foster genetic diversity. Using a spatially replicated design, we demonstrate that rhizobium bacteria symbiotic with legumes inhabiting contrasting serpentine and nonserpentine soils exhibit a trade-off between a genotype's nickel tolerance and its ability to replicate rapidly. Furthermore, we detected adaptive divergence in rhizobial assemblages across soil type heterogeneity at multiple sites, suggesting that this trade-off may promote the coexistence of phenotypically distinct bacterial lineages. Trade-offs and adaptive divergence may be important factors maintaining the tremendous diversity within natural assemblages of bacteria.


A Growing Social Divide in Body Mass Index, Strength, and Fitness of Swedish Male Conscripts.
The aim of the study was to monitor trends in socioeconomic inequalities in body mass index (BMI), cardiorespiratory fitness (CRF), and muscular strength over several decades in a population of Swedish males aged 18-19 years. The cohort consists of 1.5 million young men attending military conscript examinations from late 1968 to 2005. Parental education was used as a marker for socioeconomic conditions in the conscripts' families of origin. Changing gradient in BMI, CRF, and muscular strength in sons of parents with higher and lower educational attainment was evaluated during four periods covering 36 years. Over the course of the obesity epidemic, BMI remained higher in conscripts with lesser (vs. higher) parental education. Moreover, the absolute difference in obesity prevalence between groups showed a continuous increase, from .6% to 3.9%, indicating growing inequalities. Regarding fitness, lower CRF was consistently associated with less parental education, but with no clear secular trend in the magnitude of the difference. Finally, social differences in muscular strength changed in direction, from lower strength among conscripts with higher parental education in the initial observation period to lower strength associated with lower parental education in the final decade studied. Among Swedish conscripts entering adulthood, social gradients in BMI and obesity widened continuously between 1968 and 2005. An apparent reversal of the earlier gradient in muscular strength in young men may be related to societal trends in occupational and leisure-time physical activity over the observation period. This cohort is being continually monitored through national registries for obesity-related comorbidities in later life.


Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066).
Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4(+) TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/10(6) PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes.


Electric field control of terahertz polarization in a multiferroic manganite with electromagnons.
All-electrical control of a dynamic magnetoelectric effect is demonstrated in a classical multiferroic manganite DyMnO3, a material containing coupled antiferromagnetic and ferroelectric orders. Because of intrinsic magnetoelectric coupling with electromagnons a linearly polarized terahertz light rotates upon passing through the sample. The amplitude and the direction of the polarization rotation are defined by the orientation of ferroelectric domains and can be switched by static voltage. These experiments allow the terahertz polarization to be tuned using the dynamic magnetoelectric effect.


Parents' perceptions of food intolerance in primary school children.
In a study of about 7000 children, parents' perceptions were used to examine the prevalence of food intolerance, the types of food implicated, the association of intolerance with diseases, and the social background of those identified as being food intolerant. One hundred and ninety two children (3%) were perceived as being food intolerant, with a further 105 (2%) being classed as intolerant under a less stringent definition of intolerance. For 128 (67%) of these children a doctor was consulted. The pattern of food avoided was very similar in children for whom the decision to exclude certain foods was made by health staff and in those for whom the parents themselves made decisions about their child's diet. A strong association was seen between the mother's level of education and the child being perceived as being food intolerant. Between 20% and 30% of children with a disease associated with food intolerance--for example, eczema--had currently or previously avoided some types of food. The results of this study emphasise the need to develop criteria to tackle the growing demand for National Health Service treatment by parents who believe their child to be food intolerant.