Safety of the insect repellent N,N-diethyl-M-toluamide (DEET) in pregnancy.
The safety of daily application of N, N-diethyl-m-toluamide (DEET) (1.7 g of DEET/day) in the second and third trimesters of pregnancy was assessed as part of a double-blind, randomized, therapeutic trial of insect repellents for the prevention of malaria in pregnancy (n = 897). No adverse neurologic, gastrointestinal, or dermatologic effects were observed for women who applied a median total dose of 214.2 g of DEET per pregnancy (range = 0-345.1 g). DEET crossed the placenta and was detected in 8% (95% confidence interval = 2.6-18.2) of cord blood samples from a randomly selected subgroup of DEET users (n = 50). No adverse effects on survival, growth, or development at birth, or at one year, were found. This is the first study to document the safety of DEET applied regularly in the second and third trimesters of pregnancy. The results suggest that the risk of DEET accumulating in the fetus is low and that DEET is safe to use in later pregnancy.


Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies.
Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.


Interleukin-6 trans-signaling inhibition prevents oxidative stress in a mouse model of early diabetic retinopathy.
Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of visual disability and blindness in diabetic patients. Chronic hyperglycemia leads to increased oxidative stress and inflammation in the retina, resulting in microvascular damage. Our recent in vitro studies have demonstrated that inhibition of interleukin-6 (IL-6) trans-signaling significantly reduces oxidative stress in retinal endothelial cells. The purpose of this study was to further explore the relationship between IL-6 trans-signaling and oxidative stress using a streptozotocin (STZ) induced mouse model of early diabetic retinopathy. Diabetes was induced in eight week-old male C57BL/6J mice using STZ injections. sgp130Fc (mouse sgp130Fc protein) treatment was used for inhibition of IL-6 trans-signaling. Studies were conducted to evaluate the effects of IL-6 trans-signaling on oxidative balance at the systemic and retinal level. Decreased antioxidant capacity and increased oxidative stress was observed in diabetic mice, which returned to near-normal levels with sgp130Fc treatment. Similarly, superoxide levels, lipid peroxidation, and markers of oxidative DNA damage were increased in the diabetic retina, and these effects were abrogated by sgp130Fc treatment. Inhibition of IL-6 trans-signaling also restored normal expression of catalase and endothelial nitric oxide synthase in mouse retinas. Inhibition of IL-6 trans-signaling significantly reduces diabetes-induced oxidative damage at the systemic level and in the retina. These findings provide further evidence for the role of IL-6 trans-signaling in diabetes-mediated oxidative stress.


Nanoscale Tungsten-Microbial Interface of the Metal Immobilizing Thermoacidophilic Archaeon Metallosphaera sedula Cultivated With Tungsten Polyoxometalate.
Inorganic systems based upon polyoxometalate (POM) clusters provide an experimental approach to develop artificial life. These artificial symmetric anionic macromolecules with oxidometalate polyhedra as building blocks were shown to be well suited as inorganic frameworks for complex self-assembling and organizing systems with emergent properties. Analogously to mineral cells based on iron sulfides, POMs are considered as inorganic cells in facilitating prelife chemical processes and displaying "life-like" characteristics. However, the relevance of POMs to life-sustaining processes (e.g., microbial respiration) has not yet been addressed, while iron sulfides are very well known as ubiquitous mineral precursors and energy sources for chemolithotrophic metabolism. Metallosphaera sedula is an extreme metallophilic and thermoacidophilic archaeon, which flourishes in hot acid and respires by metal oxidation. In the present study we provide our observations on M. sedula cultivated on tungsten polyoxometalate (W-POM). The decomposition of W-POM macromolecular clusters and the appearance of low molecular weight W species (e.g., WO) in the presence of M. sedula have been detected by electrospray ionization mass spectrometry (ESI-MS) analysis. Here, we document the presence of metalloorganic assemblages at the interface between M. sedula and W-POM resolved down to the nanometer scale using scanning and transmission electron microscopy (SEM and TEM) coupled to electron energy loss spectroscopy (EELS). High-resolution TEM (HR-TEM) and selected-area electron diffraction (SAED) patterns indicated the deposition of redox heterogeneous tungsten species on the S-layer of M. sedula along with the accumulation of intracellular tungsten-bearing nanoparticles, i.e., clusters of tungsten atoms. These results reveal the effectiveness of the analytical spectroscopy coupled to the wet chemistry approach as a tool in the analysis of metal-microbial interactions and microbial cultivation on supramolecular self-assemblages based on inorganic metal clusters. We discuss the possible mechanism of W-POM decomposition by M. sedula in light of unique electrochemical properties of POMs. The findings presented herein highlight unique metallophilicity in hostile environments, extending our knowledge of the relevance of POMs to life-sustaining processes, understanding of the transition of POMs as inorganic prebiotic model to life-sustainable material precursors and revealing biogenic signatures obtained after the decomposition of an artificial inorganic compound, which previously was not associated with any living matter.


A genome-by-environment interaction classifier for precision medicine: personal transcriptome response to rhinovirus identifies children prone to asthma exacerbations.
To introduce a disease prognosis framework enabled by a robust classification scheme derived from patient-specific transcriptomic response to stimulation. Within an illustrative case study to predict asthma exacerbation, we designed a stimulation assay that reveals individualized transcriptomic response to human rhinovirus. Gene expression from peripheral blood mononuclear cells was quantified from 23 pediatric asthmatic patients and stimulated in vitro with human rhinovirus. Responses were obtained via the single-subject gene set testing methodology "N-of-1-pathways." The classifier was trained on a related independent training dataset (n = 19). Novel visualizations of personal transcriptomic responses are provided. Of the 23 pediatric asthmatic patients, 12 experienced recurrent exacerbations. Our classifier, using individualized responses and trained on an independent dataset, obtained 74% accuracy (area under the receiver operating curve of 71%; 2-sided P = .039). Conventional classifiers using messenger RNA (mRNA) expression within the viral-exposed samples were unsuccessful (all patients predicted to have recurrent exacerbations; accuracy of 52%). Prognosis based on single time point, static mRNA expression alone neglects the importance of dynamic genome-by-environment interplay in phenotypic presentation. Individualized transcriptomic response quantified at the pathway (gene sets) level reveals interpretable signals related to clinical outcomes. The proposed framework provides an innovative approach to precision medicine. We show that quantifying personal pathway-level transcriptomic response to a disease-relevant environmental challenge predicts disease progression. This genome-by-environment interaction assay offers a noninvasive opportunity to translate omics data to clinical practice by improving the ability to predict disease exacerbation and increasing the potential to produce more effective treatment decisions.


First Report of the Occurrence and Resistance to Mefenoxam of Peronospora belbahrii, Causal Agent of Downy Mildew of Basil (Ocimum basilicum) in Israel.
Downy mildew in basil was first reported from Uganda in 1933 (4). In 2004, it was reported from Italy (3) and, thereafter, from other countries around the world. In Israel, the disease was first observed in November 2011 in two greenhouses located in the northern part of the Jordan Valley. Within a month, second and third outbreaks of the disease occurred simultaneously near the southwest and southeast borders of Israel, 250 km from the initial disease outbreak. By the summer of 2012, the disease had appeared throughout the country, causing major economic damage. The causal agent, identified as Peronospora belbahrii (see below), produced chlorotic lesions on leaf blades with sporangia developing on the lower leaf surfaces. Lesions gradually turn necrotic, and infected leaves abscised. Sporangia were dark purple, oval, 30.4 ± 2.9 μm long × 21.4 ± 1.7 μm wide. Sporangiophores emerged from stomatal openings in a saturated atmosphere, were hyaline, 400 to 600 μm long, dichotomously branched, with three to five branches per sporangiophore, and bore a single sporangium on each branchlet tip. Oospores, seldom seen, were brown, round, and 46.2 ± 2.8 μm in diameter. Sporangia germinated directly, each producing a single germ tube that penetrated the periclinal wall of epidermal cells. PCR assays using sporangia and infected leaves as the template, and specific BAZ primers (1), produced a 134-bp band typical of P. belbahrii (1,2). Twenty isolates, collected from 12 locations in Israel from December 2011 to September 2012, were all sensitive to mefenoxam as the isolates did not cause symptoms on 15-leaf, potted basil plants (cv. Peri, Volcani Center, Israel) that were sprayed with 10 μg mefenoxam/ml (Ridomil Gold 48%, Syngenta, Basel, Switzerland) prior to inoculation. However, one isolate collected in early October 2012 from a severely infected plant in a greenhouse at Rehov in Bet-Shaan Valley, in which the plants had been treated with mefenoxam, was resistant to mefenoxan, showing abundant sporulation on leaves of potted basil plants that had been sprayed with 1,000 μg of mefenoxam/ml prior to inoculation. To our knowledge, this is the first report of the occurrence of downy mildew in basil in Israel. This is also the first global report of resistance to mefenoxam in P. belbahrii. References: (1) L. Belbahri et al. Mycol. Res. 109:1276, 2005. (2) R. Djalali et al. Mycol. Progress 11:961, 2012. (3) A. Garibaldi et al., Plant Dis. 89:683, 2004. (4) C. G. Hansford. Rev. Appl. Mycol. 12:421, 1933.


First clinical experiences of concurrent bleeding control and intracranial pressure monitoring using a hybrid emergency room system in patients with multiple injuries.
The outcomes of multiple injury patients with concomitant torso hemorrhage and traumatic brain injury (TBI) are very poor. The hybrid emergency room system (HERS) is a trauma management system designed to complete resuscitation, computed tomography (CT), surgery, angioembolization, and intracranial pressure (ICP) monitoring all in one trauma resuscitation room without patient transfer. We aimed to review the outcomes of polytrauma patients who underwent concurrent bleeding control and ICP monitoring using the HERS. In this retrospective observational study, we enrolled patients who underwent concurrent bleeding control and ICP monitoring using the HERS between August 2011 and June 2018. Initial data on vital signs, Injury Severity Score (ISS), probability of survival (Ps) calculated by the Trauma and Injury Severity Score (TRISS), intervention type, 28-day mortality, and Extended Glasgow Outcome Scale at 6 months after injury were collected. Continuous variables were expressed as the median (25th and 75th percentiles) and categorical variables as numbers (%). Ten patients were included in the analysis. The injury severity of the patients was as high as an ISS of 58 (50-64) and TRISS Ps of 0.15 (0.02-0.36). Seven of the 10 (70%) patients had hemodynamic instability within 30 min from arrival. The recorded durations from arrival to events were CT examination 9 (6-16) min, bleeding control procedure 29 (22-42) min, and neurosurgical intervention 39 (31-53) min. Four of the 10 patients (40%) survived to discharge, and two of them (20%) were able to live independently at 6 months after injury. The concurrent performance of bleeding control procedure and ICP monitoring would be feasible in HERS settings among polytrauma patients with exsanguinating hemorrhage and TBI.


Antimicrobial evaluation of red, phytoalexin-rich sorghum food biocolorant.
Sorghum (Sorghum bicolor) extract is traditionally used as red biocolorant in West Africa to colour foods, among which wagashi, a soft cheese. This biocolorant is a source of the phytoalexin apigeninidin and phenolic acids, and users claim that it has preservative effects next to its colouring properties. If such a claim can be scientifically substantiated, it adds a valuable functional property to this natural red colorant, thereby increasing its potential applications in the food industry. Hence, the present study evaluated the antimicrobial properties of dye sorghum extracts using challenge tests in broth and wagashi as a model of a popular food application. The alkaline extract and hot aqueous extract were used for dyeing wagashi by 87.7% and 12.3% of the traders, respectively. The dyeing procedure is perceived as a preservation strategy, and is also a means to maximise the revenues. However, results demonstrated that the application of sorghum biocolorant on wagashi had no inhibitory effect on the growth of fungi (Penicillium chrysogenum, Cladosporium macrocarpum) and Escherichia coli O157:H7. Furthermore, sorghum biocolorant in broth had no effect on growth of Listeria monocytogenes and Escherichia coli O157:H7. Consequently, the commonly used extracts for colouring soft West-African cheese did not show a preservative effect. In addition, dyeing did not affect the physico-chemical properties of wagashi. Still, the red colour hampered visual detection of microbial growth, thus clarifying the preservative effect reported by users.


Primary spontaneous pneumothorax: a cohort study of VATS with talc poudrage.
Video-assisted thoracoscopic surgery (VATS) is an increasingly common treatment for recurrent or persistent primary spontaneous pneumothorax (PSP). Surgery usually involves diffuse treatment of the pleura and possible targeted therapy to areas of bullous disease. The purpose of this large cohort study was to examine incidence of recurrence after VATS and identify predictors of outcome. Patients undergoing VATS for PSP at a single centre between 2000 and 2012 were prospectively enrolled. All patients underwent talc poudrage. Targeted surgical techniques were used based on presence of air leak and Vanderschueren's stage. Patients had clinical and radiological follow-up for at least 2 years (median 8.5 years). 1415 patients with PSP underwent VATS with talc poudrage. The most frequent indications were recurrent pneumothorax (92.2%) and persistent air leak (6.5%). The complication rate was 2.0% of which 1.7% was prolonged air leak. There was no mortality. Median length of stay was 5 days. Recurrent pneumothorax occurred in 26 patients (1.9%). At the time of surgery, 592 patients smoked (43%) and they had a significantly higher incidence of recurrence (24/575, 4.2%) than non-smokers (2/805, 0.2%), p<0.001. The incidence of recurrence in those undergoing bullae suturing (3.8%, n=260) was significant higher than those undergoing poudrage alone (0.3%, p=0.036). The marked difference in recurrence between smokers and non-smokers suggests this as an important predictor of outcome. This study demonstrates a low incidence of recurrence and complications for patients with PSP undergoing VATS with talc poudrage. Talc poudrage requires prospective comparison with pleurectomy and mechanical abrasion.


Evaluation of Liver Biomarkers as Prognostic Factors for Outcomes to Yttrium-90 Radioembolization of Primary and Secondary Liver Malignancies.
The objective of this study was to examine indicators of liver function and inflammation for prognostic value in predicting outcomes to yttrium-90 radioembolization (RE). In a retrospective analysis, markers of liver function and inflammation, biomarkers required to stage liver function and inflammation, and data regarding survival, tumor response, and progression after RE were recorded. Univariate regression models were used to investigate the prognostic value of liver biomarkers in predicting outcome to RE as measured by survival, tumor progression, and radiographic and biochemical tumor response. Markers from all malignancy types were analyzed together. A subgroup analysis was performed on markers from patients with metastatic colorectal cancer. A total of 31 patients received RE from 2004 to 2014. Median survival after RE for all malignancies combined was 13.6 months (95% CI: 6.7-17.6 months). Results from an exploratory analysis of patient data suggest that liver biomarkers, including albumin concentrations, international normalized ratio, bilirubin concentrations, and the model for end-stage liver disease score, possess prognostic value in predicting outcomes to RE.


The effect of cinacalcet on intraoperative findings in tertiary hyperparathyroidism patients undergoing parathyroidectomy.
Tertiary hyperparathyroidism (3HPTH) patients who undergo parathyroidectomy (PTX) are often managed with calcium lowering medications such as cinacalcet (Sensipar) before surgery. Here, we assess how cinacalcet treatment influences intraoperative parathyroid hormone (IOPTH) kinetics and surgical findings in 3HPTH patients undergoing PTX. We reviewed retrospectively 113 patients 3HPTH who underwent PTX, 14 of whom were taking cinacalcet and 112 who were not taking the drug. IOPTH levels fitted to linear curves versus time were used to evaluate the role of cinacalcet. Cinacalcet did not correlate with rates of cure (P = .41) or recurrence (P = .54). Patients taking cinacalcet experienced a steeper decrease in IOPTH compared with those not taking the medication (P = .005). Cinacalcet treatment was associated with an increase in rate of hungry bones (P = .04). Weights of the heaviest glands resected (P = .02) and preoperative PTH levels (P = .0004) were greater among patients taking cinacalcet. Perioperative cinacalcet treatment in patients with 3HPTH alters IOPTH kinetics by causing a steeper decrease in IOPTH, but does not require modification of the standard IOPTH protocol. Although cinacalcet use does not adversely affect cure rates, it is associated with greater preoperative PTH and an increased incidence of hungry bones, hence serving as an indicator of more severe disease. Cinacalcet does not need to be held before operation.


Surgical Approach for Long-term Survival of Patients With Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis of 434 Patients.
OBJECTIVES To examine the outcomes of a hepatectomy for intrahepatic cholangiocarcinoma (IHC) and to clarify the prognostic impact of a lymphadenectomy and the surgical margin. Large series of patients who were surgically treated for IHC are scarce. Thus, prognostic factors and long-term survival after resection of IHC remain uncertain. DESIGN Prospective study of patients who were surgically treated for IHC. Clinicopathologic, operative, and long-term survival data were analyzed. SETTING Prospectively collected data of all consecutive patients with pathologically confirmed IHC who had undergone liver resection with a curative intent at 1 of 16 tertiary referral centers were entered into a multi-institutional registry. PATIENTS All consecutive patients who underwent a hepatectomy with a curative intent for IHC (1990-2008) were identified from a multi-institutional registry. RESULTS A total of 434 patients were included in the analysis. Most patients underwent a major or extended hepatectomy (70.0%) and a systematic lymphadenectomy (62.2%). The incidence of lymph node metastases (overall, 36.9%) increased with increased tumor size, with 24.4% of patients with a small IHC (diameter ≤3 cm) having N1 disease. Almost one-third of patients required an additional major procedure to obtain a R0 resection in 84.6% of the cases. In these patients, the median time of survival was 39 months, and the 5-year survival rate was 39.8%. Lymph node metastases (hazard ratio, 2.21; P < .001), multiple tumors (hazard ratio, 1.50; P = .009), and an elevated preoperative cancer antigen 19.9 level (hazard ratio, 1.62; P = .006) independently predicted an adverse prognosis. Conversely, survival was not influenced by the width of a negative resection margin (P = .61). The potential survival benefit of a lymphadenectomy was assessed with the therapeutic value index, which was calculated to be 5.9 points. CONCLUSIONS Survival rates after a hepatectomy with a curative intent for IHC at tertiary referral centers exceed the survival rates reported in most study series in single institutions, which strengthens the value of an aggressive approach to radical resection. Lymph node metastases and multiple tumors are associated with decreased survival rates, but they should not be considered selection criteria that prevent other patients from undergoing a potentially curative resection. Lymphadenectomy should be considered for all patients.


Ectopic Adrenocorticotropic Hormone-Secreting Pituitary Adenomas: An Underestimated Entity.
The diagnosis of Cushing disease is based on endocrinological pa-rameters, with no single test being specific. In some patients, dynamic thin-slice sellar magnetic resonance imaging fails to detect a pituitary tumor. The purpose of this study is to investigate the role of ectopic pituitary adenoma in this situation. In a retrospective chart review, 5 patients (6%) with ectopic adenomas were identified in 83 consecutive patients undergoing transsphenoidal surgery for adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas by 1 surgeon. In all 5 patients (all female, 32-41 years of age), an exclusively extrasellar ACTH-secreting adenoma was excised. Three adenomas were located in the cavernous sinus, 1 in the sphenoid sinus, and 1 in the ethmoidal cells. Histologically, none of the tumors showed signs of aggressiveness. Three of the 5 adenomas specifically expressed somatostatin receptor 5. In 4 patients with Cushing disease, postoperative remission was obtained, with 1 recurrence after 14 months. In the patient with Nelson syndrome, ACTH decreased from >800 to <80 pg/mL. Three patients underwent previous surgery elsewhere, including 1 hypophysectomy. In this case, the ectopic adenoma (positive for somatostatin receptor 5) in the ethmoidal cells turned out to be positive on gallium 68 DOTATATE positron emission tomography/computed tomography. The incidence of primarily ectopic ACTH-secreting adenomas in this series was 6%. In cases of negative MRI findings, an ectopic ACTH-secreting adenoma should be taken into account. 68 Ga DOTATATE positron emission tomography/computed tomography may identify ectopic pituitary adenomas. Hypophysectomy should always be avoided in primary surgery for CD.


[The compartment syndrome].
The compartment syndrome is in fact secondary to intracompartmental hypertension which creates ischemia of the muscles, nerves, vessels, and anterior tibial and peroneal arteries in the leg. Described in the 19th century, the clinical picture is better known when progressing either in the acute form or in the chronic form. Diagnosis depends basically on the measurement of intramuscular pressure; treatment, at least initially, apart from subcutaneous aponeurotic decompression, also calls for hyperbaric oxygen therapy. The latter is particularly indicated in those cases bordering on surgical and medical treatment, for preventing deterioration and improving muscular possibilities in the post-surgical period. At the present time, the physiopathology of the condition is still poorly understood. The whiplash syndrome was well described by Martorelli and is due to rupture of the muscular veins of the calf. The clinical picture is often ambiguous and can suggest underlying phlebitis. The triad of symptoms --pain, disability and ecchymosis-- generally enables a diagnosis to be made, with treatment consisting primarily of immobilization. As for Bywaters' syndrome (crush syndrome), it is still very topical. The original description of the clinical picture by Bywaters during the bombardment of London in 1942 has been replaced by the picture resulting from large scale accidents that are part of modern society. The picture is still highly dramatic and if untreated progresses to acute renal insufficiency. Treatment has certainly changed and hyperbaric therapy (administered at two or three atmospheres) is a valid adjuvant to basic treatment and modifies the progress of the phenomenon with entirely satisfactory results.


Changes in H3K27ac at Gene Regulatory Regions in Porcine Alveolar Macrophages Following LPS or PolyIC Exposure.
Changes in chromatin structure, especially in histone modifications (HMs), linked with chromatin accessibility for transcription machinery, are considered to play significant roles in transcriptional regulation. Alveolar macrophages (AM) are important immune cells for protection against pulmonary pathogens, and must readily respond to bacteria and viruses that enter the airways. Mechanism(s) controlling AM innate response to different pathogen-associated molecular patterns (PAMPs) are not well defined in pigs. By combining RNA sequencing (RNA-seq) with chromatin immunoprecipitation and sequencing (ChIP-seq) for four histone marks (H3K4me3, H3K4me1, H3K27ac and H3K27me3), we established a chromatin state map for AM stimulated with two different PAMPs, lipopolysaccharide (LPS) and Poly(I:C), and investigated the potential effect of identified histone modifications on transcription factor binding motif (TFBM) prediction and RNA abundance changes in these AM. The integrative analysis suggests that the differential gene expression between non-stimulated and stimulated AM is significantly associated with changes in the H3K27ac level at active regulatory regions. Although global changes in chromatin states were minor after stimulation, we detected chromatin state changes for differentially expressed genes involved in the TLR4, TLR3 and RIG-I signaling pathways. We found that regions marked by H3K27ac genome-wide were enriched for TFBMs of TF that are involved in the inflammatory response. We further documented that TF whose expression was induced by these stimuli had TFBMs enriched within H3K27ac-marked regions whose chromatin state changed by these same stimuli. Given that the dramatic transcriptomic changes and minor chromatin state changes occurred in response to both stimuli, we conclude that regulatory elements (i.e. active promoters) that contain transcription factor binding motifs were already active/poised in AM for immediate inflammatory response to PAMPs. In summary, our data provides the first chromatin state map of porcine AM in response to bacterial and viral PAMPs, contributing to the Functional Annotation of Animal Genomes (FAANG) project, and demonstrates the role of HMs, especially H3K27ac, in regulating transcription in AM in response to LPS and Poly(I:C).


Tuning pacemaker frequency of individual dopaminergic neurons by Kv4.3L and KChip3.1 transcription.
The activity of dopaminergic (DA) substantia nigra (SN) neurons is essential for voluntary movement control. An intrinsic pacemaker in DA SN neurons generates their tonic spontaneous activity, which triggers dopamine release. We show here, by combining multiplex and quantitative real-time single-cell RT- PCR with slice patch-clamp electrophysiology, that an A-type potassium channel mediated by Kv4.3 and KChip3 subunits has a key role in pacemaker control. The number of active A-type potassium channels is not only tightly associated with the pacemaker frequency of individual DA SN neurons, but is also highly correlated with their number of Kv4.3L (long splice variant) and KChip3.1 (long splice variant) mRNA molecules. Consequently, the variation of Kv4alpha and Kv4beta subunit transcript numbers is sufficient to explain the full spectrum of spontaneous pacemaker frequencies in identified DA SN neurons. This linear coupling between Kv4alpha as well as Kv4beta mRNA abundance, A-type channel density and pacemaker frequency suggests a surprisingly simple molecular mechanism for how DA SN neurons tune their variable firing rates by transcriptional control of ion channel genes.


High prevalence of multiple human papillomavirus infection in Japanese patients with invasive uterine cervical cancer.
Multiple human papillomavirus (HPV) infection of the uterine cervix has been suggested as a risk factor for persistent HPV infection, resulting in the development of invasive cervical cancer. The aim of this study was to reveal the actual state of multiple HPV infection in Japanese patients with invasive cervical cancer. Sixty fresh-frozen invasive cervical cancer tissues were examined for genotyping of HPV. The presence of HPV genotypes was determined with an HPV-DNA array, which can discriminate 25 different HPV genotypes with high sensitivity and specificity. Among 60 samples, 59 (96.7%) were positive for HPV. The three common genotypes were HPV-16 (83.3%), HPV-18 (45.0%) and HPV-52 (28.3%). Multiple HPV infection was observed in 47 of 60 samples (78.3%), among which 42 were infected with more than one high-risk genotype (70.0%). Multiple high-risk HPV infection was significantly more prevalent in patients below 40 years old (14/15, 93.3%) than in patients 40 years of age and over (28/45, 62.2%). The HPV-DNA array is the preferred method to detect HPV genotypes. Multiple HPV infection in Japanese patients with invasive cervical cancer seemed to be more frequent than reported in the literature.


Collection and validation of data in the United Kingdom Atomic Energy Authority mortality study.
The United Kingdom Atomic Energy Authority mortality study investigated the relation between mortality and recorded exposure to ionising radiation among employees working at the authority's seven establishments between 1946 and 1979. This report examines the design of the study and methods of data collection and validation. The completeness of the study population was deemed to be unsatisfactory at two establishments, where records of employment before 1965 had been destroyed. Assessment of the magnitude of the deficit led to the conclusion that the data from these establishments were too incomplete for inclusion in the mortality analysis. At the other establishments validation showed that the data collected were accurate and unbiased. Certain characteristics of the 39 546 employees included in the mortality analysis were identified which were relevant in interpreting the findings.


Cannabis and Cannabinoids on Treatment of Inflammation: A Patent Review.
The inflammatory process is a physiological response to a vast number of harmful stimulus that takes place in order to restore homeostasis. Many drugs used in pharmacotherapy are effective to control inflammatory responses, however, there is a range of adverse effects attributed to steroidal and non-steroidal anti-inflammatory drugs (NSAIDs). In this sense, herbal medicine and derivatives have gained more attention because of their effectiveness and safety, showing the importance of medicinal plants, especially the Cannabis genus and the cannabinoid derivatives. The aim of this prospection was to identify data related to patents involving Cannabis and cannabinoids for the treatment of inflammation. To do so, a search for patents was conducted to evaluate the anti-inflammatory activity of Cannabis and cannabinoids. Four specialized databases for patent research were consulted using the terms "cannabis", "cannabidiol", "cannabinoids" and "THC" associated with "inflammation". A total of 370 patents were found, of which 17 patents met the inclusion criteria. Although reports show synergistic effects of the plant components, patents involving Cannabis and cannabinoids focus on isolated substances (CBD e THC). However, patents related to Cannabis and cannabinoids are promising for future use of the plant or its derivatives on the treatment of inflammation.


Does supervision improve health worker productivity? Evidence from the Upper East Region of Ghana.
To assess whether supervision of primary health care workers improves their productivity in four districts of Northern Ghana. We conducted a time-use study during which the activities of health workers were repeatedly observed and classified. Classification included four categories: direct patient care; documentation and reporting; staff development and facility operations; and personal time. These data were supplemented by a survey of health workers during which patterns of supervision were assessed. We used logistic regression models with health facility fixed effects to test the hypothesis that supervision increases the amount of time spent providing direct patient care (productivity). We further investigated whether these effects depend on whether or not supervision is supportive. Direct patient care accounted for <25% of observations. In bivariate analyses, productivity was higher among midwives and in facilities with a high volume of care. Supervisory visits were frequent in those four districts, but only a minority of health workers felt supported by their supervisors. Having been supervised within the last month was associated with a significantly higher proportion of time spent on direct patient care (OR = 1.57). The effects of supervision on productivity further depended on whether the health workers felt supported by their supervisors. Supportive supervision was associated with increased productivity. Investments in supervision could help maximize the output of scarce human resources in primary health care facilities. Time-use studies represent an objective approach in monitoring the productivity of health workers and evaluating the impact of health-system interventions on human resources.


The fate of manuscripts rejected by The Journal of Bone and Joint Surgery (American Volume).
Of the many manuscripts that are submitted to The Journal of Bone and Joint Surgery (American Volume) (JBJS-A) for publication, the majority are not accepted. However, little is known about the outcome of these rejected submissions. To determine the fate of studies rejected by JBJS-A, we conducted a follow-up investigation of all clinical and basic science manuscripts that were submitted to The Journal between January 2004 and June 2005 but were not accepted. For each rejected manuscript, data were extracted on a wide variety of scientific and nonscientific characteristics, which were plausibly related to subsequent publication. PubMed searches were conducted to determine which manuscripts achieved full publication within five years, and logistic regression was used to identify the factors associated with publication. To further elucidate the factors associated with publication, a survey was administered to the corresponding author of each rejected manuscript. At five years following rejection by JBJS-A, 75.8% (696 of 918) of manuscripts had reached full publication. In the multivariate analysis, factors associated with a higher likelihood of subsequent publication included grade of initial review by JBJS-A (p = 0.029), disclosure of a for-profit or nonprofit conflict of interest (p = 0.028 and 0.027, respectively), and a greater number of prior publications in frequently cited orthopaedic journals by the corresponding author (p < 0.0001). Manuscripts were less likely to reach full publication if the corresponding author was from Asia or the Middle East (p = 0.004) or was a woman (p = 0.003). Among survey respondents who indicated that their study had not yet reached full publication, the most commonly cited reason was lack of time (reported by 51.4% of respondents [thirty-eight of seventy-four]). Most manuscripts (75.8%) not accepted by JBJS-A were published elsewhere within five years of rejection. The factors predictive of subsequent publication were primarily investigator-related as opposed to study-related. Given this low threshold for eventual publication, readers are encouraged to use criteria other than inclusion in the PubMed database to identify high-quality papers.


Capacitated location of collection sites in an urban waste management system.
Urban waste management is becoming an increasingly complex task, absorbing a huge amount of resources, and having a major environmental impact. The design of a waste management system consists in various activities, and one of these is related to the location of waste collection sites. In this paper, we propose an integer programming model that helps decision makers in choosing the sites where to locate the unsorted waste collection bins in a residential town, as well as the capacities of the bins to be located at each collection site. This model helps in assessing tactical decisions through constraints that force each collection area to be capacitated enough to fit the expected waste to be directed to that area, while taking into account Quality of Service constraints from the citizens' point of view. Moreover, we propose an effective constructive heuristic approach whose aim is to provide a good solution quality in an extremely reduced computational time. Computational results on data related to the city of Nardò, in the south of Italy, show that both exact and heuristic approaches provide consistently better solutions than that currently implemented, resulting in a lower number of activated collection sites, and a lower number of bins to be used.


Loss of transcription factor AP-2gamma/TFAP2C impairs branching morphogenesis of the murine mammary gland.
Extensive development of the mammary gland occurs during puberty, when rising levels of ovarian hormones induce the formation of highly proliferative terminal end buds (TEBs) at the tips of mammary ducts. TEBs consist of an outer layer of cap cells and of inner body cells. TEBs invade the adipose stroma and bifurcate while extending the ducts to generate an arborized ductal network. We show that in murine mammary glands transcription factor AP-2gamma is strongly expressed in the cap cell layer and in a subset of body cells of TEBs. To decipher AP-2gamma functions during mammary development we generated AP-2gamma-deficient mice. Their mammary glands displayed impaired ductal branching and elongation. Cellular proliferation within TEBs was reduced. Although estrogen receptor was expressed, exogenously administered ovarian hormones could not restore normal development. Therefore, AP-2gamma is functionally involved in branching morphogenesis of the mammary epithelium, possibly by controlling genetic processes downstream of ovarian hormones.


The pupillary light response reflects exogenous attention and inhibition of return.
Here we show that the pupillary light response reflects exogenous (involuntary) shifts of attention and inhibition of return. Participants fixated in the center of a display that was divided into a bright and a dark half. An exogenous cue attracted attention to the bright or dark side of the display. Initially, the pupil constricted when the bright, as compared to the dark, side of the display was cued, reflecting a shift of attention toward the exogenous cue. Crucially, this pattern reversed about 1 s after cue presentation. This later-occurring, relative dilation (when the bright side was cued) reflected disengagement from the previously attended location, analogous to the behavioral phenomenon of inhibition of return. Indeed, we observed a reliable correlation between "pupillary inhibition" and behavioral inhibition of return. Our results support the view that inhibition of return results from habituation to (or short-term depression of) visual input. We conclude that the pupillary light response is a complex eye movement that reflects how we selectively parse and interpret visual input.


Isolation of Specific Genomic Regions and Identification of Their Associated Molecules by Engineered DNA-Binding Molecule-Mediated Chromatin Immunoprecipitation (enChIP) Using the CRISPR System and TAL Proteins.
Comprehensive understanding of genome functions requires identification of molecules (proteins, RNAs, genomic regions, etc.) bound to specific genomic regions of interest in vivo. To perform biochemical and molecular biological analysis of specific genomic regions, we developed engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) to purify genomic regions of interest. In enChIP, specific genomic regions are tagged for biochemical purification using engineered DNA-binding molecules, such as transcription activator-like (TAL) proteins and a catalytically inactive form of the clustered regularly interspaced short palindromic repeats (CRISPR) system. enChIP is a comprehensive approach that emphasizes non-biased search using next-generation sequencing (NGS), microarrays, mass spectrometry (MS), and other methods. Moreover, this approach is not restricted to cultured cell lines and can be easily extended to organisms. In this review, we discuss applications of enChIP to elucidating the molecular mechanisms underlying genome functions.


The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells.
Androgen ablation therapy is the most common strategy for suppressing prostate cancer progression; however, tumor cells eventually escape androgen dependence and progress to an androgen-independent phase. The androgen receptor (AR) plays a pivotal role in this transition. To address this transition mystery in prostate cancer, we established an androgen-independent prostate cancer cell line (LNCaPdcc), by long-term screening of LNCaP cells in androgen-deprived conditions, to investigate changes of molecular mechanisms before and after androgen withdrawal. We found that LNCaPdcc cells displayed a neuroendocrine morphology, less aggressive growth, and lower expression levels of cell cycle-related factors, although the cell cycle distribution was similar to parental LNCaP cells. Notably, higher protein expression of AR, phospho-Ser(81)-AR, and PSA in LNCaPdcc cells were observed. The nuclear distribution and protein stability of AR increased in LNCaPdcc cells. In addition, cell proliferation results exhibited the biphasic nature of the androgen (R1881) effect in two cell lines. On the other hand, LNCaPdcc cells expressed higher levels of Her2, phospho-Tyr(1221/1222)-Her2, ErbB3, and ErbB4 proteins than parental LNCaP cells. These two cell lines exhibited distinct responses to Her2 activation (by heregulin treatment) on Her2 phosphorylation and Her2 inhibition (by AG825 or Herceptin treatments) on proliferation. In addition, the Her2 inhibitor more effectively caused AR degradation and diminished AR Ser(81) phosphorylation in LNCaPdcc cells. Taken together, our data demonstrate that Her2 plays an important role in the support of AR protein stability in the transition of androgen requirement in prostate cancer cells. We hope these findings will provide novel insight into the treatment of hormone-refractory prostate cancer.


Bioterrorism and invasive species.
The risk of dispersing invasive species, especially human pathogens, through acts of bioterrorism, cannot be neglected. However, that risk appears quite low in comparison with the risk of dispersing animal pathogens that could dramatically burden the agricultural economy of food animal producing countries, such as Australia and countries in Europe and North and South America. Although it is not directly related to bioterrorism, the intentional release of non-native species, particularly undesired companion animals or wildlife, may also have a major economic impact on the environment and, possibly, on animal and human health, in the case of accidental release of zoonotic agents.


Gene flow between sexual and asexual strains of parasitic wasps: a possible case of sympatric speciation caused by a parthenogenesis-inducing bacterium.
Sympatric speciation is strictly defined as the emergence of two species from a population in which mating has been random with respect to the place of birth of the mating partners. Mathematical models have shown that sympatric speciation is possible, but very few examples have been documented in nature. In this article, we demonstrate that arrhenotokous and thelytokous strains of a parasitic wasp, Neochrysocharis formosa, speciated sympatrically through infection by a symbiotic bacterium Rickettsia for the following reasons: First, Rickettsia infection was detected in all of the thelytokous strains collected throughout Japan. Second, the arrhenotokous and thelytokous strains have been collected sympatrically. Third, crossing experiments between the two strains did not result in fertilized offspring. In addition, the two strains were genetically isolated at the nuclear and mitochondrial genes. Fourth, the two strains showed a sister relationship in nuclear 28S rRNA gene. Finally, thelytokous females treated with antibiotics produced Rickettsia-free male offspring of the same reproductive form as arrhenotokous females indicating that the thelytokous strain could have speciated sympatrically from an individual of the arrhenotokous strain.


Assessing the effectiveness of low vision rehabilitation in children: an observational study.
To evaluate the change in visual functioning (VF) using the L. V. Prasad-Functional Vision Questionnaire II (LVP-FVQ II) following multidisciplinary low vision rehabilitation (LVR) services in children with low vision (LV). Children with LV referred for the first time to the Centre for Sight Enhancement were administered the LVP-FVQ II at baseline and at 3 to 4 months' follow-up to assess the outcomes of LVR. Participants' responses to the LVP-FVQ II at baseline and follow-up were transformed into interval-level estimates of VF using Rasch analysis. Cohen's d values (effect size) were used to estimate the magnitude of change in VF. A total of 183 participants completed the rehabilitation (mean age, 11.9 years; male, 57%). More than one-half of the participants had retinal disorders (55%) and most were moderately visually impaired (<20/60-20/200, 76.5%). Using the LVP-FVQ II, significant improvement in VF after rehabilitation was recorded (P < 0.0001) and the increase in VF (SD) was 1.20 (1.82) logits. Using Cohen's d, the magnitude of the improvement in LVR intervention at follow-up was found to be 0.75, indicating nearly large treatment effect. Ours is the first study to provide strong evidence that LVR services result in nearly large and significant improvements in the overall VF in children with LV, regardless of the cause of LV. These results should encourage eye care professionals to refer children with LV to LVR services. Further investigation is needed to determine if the improvement in VF can be sustained over a longer duration (>4 months).


Developmental dyslexia, neural timing and hemispheric lateralisation.
Approximately 5% of 8-10-year-olds experience exceptional difficulties learning to read (developmental dyslexia). This usually has a congenital basis; it runs in families, and affects 4 times as many boys as girls. Dyslexics typically show impairment both in phonemic segmentation (the subdivision of speech beyond the natural syllabic level) and in sequencing small visual symbols. Both these skills draw upon the ability of the nervous system to time sensory events precisely. A specific magnocellular cell type which expresses a distinctive surface antigen plays a crucial role in these functions. The development of this cell line is probably congenitally impaired in dyslexics. Visually they have lowered flicker and motion sensitivity, and disorder of the magnocellular layers of the Lateral Geniculate Nucleus can be seen post mortem. Likewise they have lowered sensitivity to changes in frequency and amplitude of sounds, hence impaired discrimination of speech sounds. These disorders are associated with abnormal hemispheric lateralisation in these subjects, e.g. dyslexics show reduction or reversal of the usual left > right asymmetry of the planum temporale. Many of these characteristics of impaired magnocellular function and reversed hemispheric asymmetry are found not only in dyslexic children but also in developmental dysphasics, autistics, high schizotypes and schizophrenics. I will speculate therefore that normal magnocellular development promotes normal hemispheric asymmetry and that impaired magnocellular development is responsible for a spectrum of problems associated with impaired hemispheric specialisation, ranging from the mildest, dyslexia, to the most severe, schizophrenia.


Evaluation of Two Techniques for Viral Load Monitoring Using Dried Blood Spot in Routine Practice in Vietnam (French National Agency for AIDS and Hepatitis Research 12338).
Background. Although it is the best method to detect early therapeutic failure, viral load (VL) monitoring is still not widely available in many resource-limited settings because of difficulties in specimen transfer, personnel shortage, and insufficient laboratory infrastructures. Dried blood spot (DBS) use, which was introduced in the latest World Health Organization recommendations, can overcome these difficulties. This evaluation aimed at validating VL measurement in DBS, in a laboratory without previous DBS experience and in routine testing conditions. Methods. Human immunodeficiency virus (HIV)-infected adults were observed in a HIV care site in Hanoi, and each patient provided 2 DBS cards with whole blood spots and 2 plasma samples. Viral load was measured in DBS and in plasma using the COBAS Ampliprep/TaqMan and the Abbott RealTime assays. To correctly identify those with VL ≥ 1000 copies/mL, sensitivity and specificity were estimated. Results. A total of 198 patients were enrolled. With the Roche technique, 51 plasma VL were ≥1000 copies/mL; among these, 28 presented a VL in DBS that was also ≥1000 copies/mL (sensitivity, 54.9; 95% confidence interval [CI], 40.3-68.9). On the other hand, all plasma VL < 1000 copies/mL were also <1000 copies/mL in DBS (specificity, 100; 95% CI, 97.5-100). With the Abbott technique, 45 plasma VL were ≥1000 copies/mL; among these, 42 VL in DBS were also ≥1000 copies/mL (sensitivity, 93.3%; 95% CI, 81.7-98.6); specificity was 94.8 (95% CI, 90.0-97.7). Conclusions. The Abbott RealTime polymerase chain reaction assay provided adequate VL results in DBS, thus allowing DBS use for VL monitoring.


The role of extracellular potassium in the epileptogenic transformation of recurrent GABAergic inhibition.
Epileptiform burst-firing can occur in hippocampal area CA1 where recurrent excitation is relatively weak and recurrent inhibition strong. Recent observations suggest that recurrent inhibition can transform into recurrent excitation because of collapse of the chloride gradient. Here we assess the role of potassium in this epileptogenic transformation. Extracellular field potential recordings, combined with either intracellular recordings from pyramidal neurons or extracellular potassium concentration recordings, were made in vitro from isolated CA1 minislices cut from the rat hippocampus and in vivo from area CA1 in urethane-anesthetized rats. Burst responses were evoked by 5-Hz alveus stimulation. The 5-Hz alveus stimulation in vitro caused a transient period of burst responses that was associated with a transient increase in synaptic input in stratum oriens and a transient shift of the reversal potential of the synaptic potential. These changes were related to the transient increase in extracellular potassium concentration in stratum oriens. Observations in vivo confirmed the relation between bursting and extracellular potassium concentration in stratum oriens. Use-dependent increase of extracellular potassium concentration in stratum oriens facilitates the collapse of the chloride gradient in the basal dendrites and transforms gamma-aminobutyric acid (GABA)ergic inhibition into GABAergic excitation, giving rise to burst firing. Improvement of intracellular chloride homeostasis or extracellular potassium homeostasis could reduce epileptogenicity.


Knowledge, moral claims and the exercise of power in global health.
A number of individuals and organizations have considerable influence over the selection of global health priorities and strategies. For some that influence derives from control over financial resources. For others it comes from expertise and claims to moral authority-what can be termed, respectively, epistemic and normative power. In contrast to financial power, we commonly take for granted that epistemic and normative forms of power are legitimate. I argue that we should not; rather we should investigate the origins of these forms of power, and consider under what circumstances they are justly derived.


Jugular venous reflux and white matter abnormalities in Alzheimer's disease: a pilot study.
To determine whether jugular venous reflux (JVR) is associated with cerebral white matter changes (WMCs) in individuals with Alzheimer's disease (AD), we studied 12 AD patients 24 mild cognitive impairment (MCI) patients, and 17 elderly age- and gender-matched controls. Duplex ultrasonography and 1.5T MRI scanning was applied to quantify cerebral WMCs [T2 white matter (WM) lesion and dirty-appearing-white-matter (DAWM)]. Subjects with severe JVR had more frequently hypertension (p = 0.044), more severe WMC, including increased total (p = 0.047) and periventricular DAWM volumes (p = 0.008), and a trend for increased cerebrospinal fluid volumes (p = 0.067) compared with the other groups. A significantly decreased (65.8%) periventricular DAWM volume (p = 0.01) in the JVR-positive AD individuals compared with their JVR-negative counterparts was detected. There was a trend for increased periventricular and subcortical T2 WMC lesion volumes in the JVR-positive AD individuals compared with their JVR-negative counterparts (p = 0.073). This phenomenon was not observed in either the control or MCI groups. In multiple regression analysis, the increased periventricular WMC lesion volume and decreased DAWM volume resulted in 85.7% sensitivity and 80% specificity for distinguishing between JVR-positive and JVR-negative AD patients. These JVR-WMC association patterns were not seen in the control and MCI groups. Therefore, this pilot study suggests that there may be an association between JVR and WMCs in AD patients, implying that cerebral venous outflow impairment might play a role in the dynamics of WMCs formation in AD patients, particularly in the periventricular regions. Further longitudinal studies are needed to confirm and validate our findings.


Vitamins and bone health: beyond calcium and vitamin D.
Osteoporosis is a major health disorder associated with an increased risk of fracture. Nutrition is among the modifiable factors that influence the risk of osteoporosis and fracture. Calcium and vitamin D play important roles in improving bone mineral density and reducing the risk of fracture. Other vitamins appear to play a role in bone health as well. In this review, the findings of studies that related the intake and/or the status of vitamins other than vitamin D to bone health in animals and humans are summarized. Studies of vitamin A showed inconsistent results. Excessive, as well as insufficient, levels of retinol intake may be associated with compromised bone health. Deficiencies in vitamin B, along with the consequent elevated homocysteine level, are associated with bone loss, decreased bone strength, and increased risk of fracture. Deficiencies in vitamins C, E, and K are also associated with compromised bone health; this effect may be modified by smoking, estrogen use or hormonal therapy after menopause, calcium intake, and vitamin D. These findings highlight the importance of adequate nutrition in preserving bone mass and reducing the risk of osteoporosis and fractures.


A transcriptional network in polycystic kidney disease.
Mutations in cystic kidney disease genes represent a major genetic cause of end-stage renal disease. However, the molecular cascades controlling the expression of these genes are still poorly understood. Hepatocyte Nuclear Factor 1beta (HNF1beta) is a homeoprotein predominantly expressed in renal, pancreatic and hepatic epithelia. We report here that mice with renal-specific inactivation of HNF1beta develop polycystic kidney disease. We show that renal cyst formation is accompanied by a drastic defect in the transcriptional activation of Umod, Pkhd1 and Pkd2 genes, whose mutations are responsible for distinct cystic kidney syndromes. In vivo chromatin immunoprecipitation experiments demonstrated that HNF1beta binds to several DNA elements in murine Umod, Pkhd1, Pkd2 and Tg737/Polaris genomic sequences. Our results uncover a direct transcriptional hierarchy between HNF1beta and cystic disease genes. Interestingly, most of the identified HNF1beta target gene products colocalize to the primary cilium, a crucial organelle that plays an important role in controlling the proliferation of tubular cells. This may explain the increased proliferation of cystic cells in MODY5 patients carrying autosomal dominant mutations in HNF1beta.


Apolipoprotein E co-localizes with newly formed amyloid beta-protein (Abeta) deposits lacking immunoreactivity against N-terminal epitopes of Abeta in a genotype-dependent manner.
Different types of amyloid beta-protein (Abeta)-containing plaques occur in brains of Alzheimer's disease (AD) patients. Diffuse plaques seen during early stages of AD differ from neuritic plaques in later stages both with respect to the length of the Abeta peptides and the presence of other proteins, e.g., apolipoprotein-E (apoE). Since apoE is involved in Abeta transport and clearance, and the epsilon4-allele of the apolipoprotein-E gene (APOE) is a major risk factor for sporadic AD, it is plausible to speculate that apoE plays a pathophysiological role in the initiation of Abeta deposition. To address the issue of whether binding of apoE to Abeta is involved in initial Abeta deposition, we studied the human medial temporal lobe of 60 autopsy cases encompassing the full spectrum of AD-related pathology. In temporal lobe regions, which become involved for the first time at a given stage of beta-amyloidosis, all plaques represent newly formed plaques, and these were studied with immunohistochemical methods. ApoE was present in 36 cases, and was frequently co-localized with newly formed Abeta deposits detectable with anti-Abeta(42) but not with antibodies raised against N-terminal epitopes of Abeta. In 10 additional cases, immunoreactivity against apoE was completely lacking in newly formed plaques, which, at the same time, displayed immunoreactivity against N-terminal epitopes of Abeta. The failure of N-terminal epitopes of Abeta to co-localize with apoE in newly formed plaques indicates that these deposits presumably contain apoE-Abeta complexes, in which the N-terminal epitopes of Abeta are often concealed after complexing with apoE, thus preventing subsequent binding of antibodies. Moreover, apoE-positive newly formed plaques were seen more frequently in APOE epsilon4/4 cases than in non-APOE epsilon4/4 individuals, thereby underlining the potentially crucial role of apoE for the development of Abeta deposits.


Elephant trunks form joints to squeeze together small objects.
Wild African elephants are voracious eaters, consuming 180 g of food per minute. One of their methods for eating at this speed is to sweep food into a pile and then pick it up. In this combined experimental and theoretical study, we elucidate the elephant's unique method of picking up a pile of food by compressing it with its trunk. To grab the smallest food items, the elephant forms a joint in its trunk, creating a pillar up to 11 cm tall that it uses to push down on food. Using a force sensor, we show the elephant applies greater force to smaller food pieces, in a manner that is required to solidify the particles into a lump solid, as calculated by Weibullian statistics. Elephants increase the height of the pillar with the force required, achieving up to 28% of the applied force using the self-weight of the pillar alone. This work shows that elephants are capable of modulating the force they apply to granular materials, taking advantage of their transition from fluid to solid. In the future, heavy robotic manipulators may also form joints to compress and lift objects together.


Visuospatial deficits in schizophrenia: central executive and memory subsystems impairments.
Object and spatial visual working memory are impaired in schizophrenic patients. It is not clear if the impairments reside in each memory subsystem alone or also in the central executive component that coordinates these processes. In order to elucidate which memory component is impaired, we developed a paradigm with single spatial and object working memory tasks and dual ones with two different delays (5 and 30 s). Fifteen schizophrenic patients and 14 control subjects performed these tests. Schizophrenic patients had a poorer performance compared to normal controls in all tasks and in all time delays. Both schizophrenics and controls performed significantly worse in the object task than in the spatial task. The performance was even worse in the dual task compared to the singles ones in schizophrenic patients but not in controls. These data suggest that visuospatial performance deficits in schizophrenia are due to both visuospatial memory subsystems impairments and central executive ones. The pattern of deficits observed points to a codification or evocation deficit and not to a maintenance one.


Effects of expectancies and coping on pain-induced motivation to smoke.
The prevalence of tobacco smoking among persons with recurrent pain is approximately twice that observed in the general population. Smoking has been associated with the development and exacerbation of several chronically painful conditions. Conversely, there is both experimental and cross-sectional evidence that pain is a potent motivator of smoking. A recent study provided the first evidence that laboratory-induced pain could elicit increased craving and produce shorter latencies to smoke (Ditre & Brandon, 2008). To further elucidate interrelations between pain and smoking, and to identify potential targets for intervention, in the current study, we tested whether several constructs derived from social-cognitive theory influence the causal pathway between pain and increased motivation to smoke. Smokers (N = 132) were randomly assigned to 1 of 4 conditions in this 2 x 2 between-subjects experimental design. Results indicated that manipulations designed to (a) challenge smoking-related outcome expectancies for pain reduction and (b) enhance pain-related coping produced decreased urge ratings and increased latencies to smoke, relative to controls. An unexpected interaction effect revealed that although each manipulation was sufficient to reduce smoking urges, the combination was neither additive nor synergistic. These findings were integrated with those of the extant literature to conceptualize and depict a causal pathway between pain and motivation to smoke as moderated by smoking-related outcome expectancies and mediated by the use of pain coping behaviors.


A versatile tool for conditional gene expression and knockdown.
Drug-inducible systems allowing the control of gene expression in mammalian cells are invaluable tools for genetic research, and could also fulfill essential roles in gene- and cell-based therapy. Currently available systems, however, often have limited in vivo functionality because of leakiness, insufficient levels of induction, lack of tissue specificity or prohibitively complicated designs. Here we describe a lentiviral vector-based, conditional gene expression system for drug-controllable expression of polymerase (Pol) II promoter-driven transgenes or Pol III promoter-controlled sequences encoding small inhibitory hairpin RNAs (shRNAs). This system has great robustness and versatility, governing tightly controlled gene expression in cell lines, in embryonic or hematopoietic stem cells, in human tumors xenotransplanted into nude mice, in the brain of rats injected intraparenchymally with the vector, and in transgenic mice generated by infection of fertilized oocytes. These results open up promising perspectives for basic or translational research and for the development of gene-based therapeutics.


Site reactivity in the free radicals induced damage to leucine residues: a theoretical study.
Several recent computational studies have tried to explain the observed selectivity in radical damage to proteins. In this work we use Density Functional Theory and Transition State Theory including tunnelling corrections, reaction path degeneracy, the effect of diffusion, and the role of free radicals to get further insights into this important topic. The reaction between a leucine derivative and free radicals of biological significance, in aqueous and lipid media, has been investigated. Both thermochemical and kinetic analyses, in both hydrophilic and hydrophobic environments, have been carried out. DPPH, ˙OOH, ˙OOCH3, ˙OOCH2Cl, ˙OOCHCl2 and ˙OOCHCH2 radicals do not react with the target molecule. The reactions are proposed to be kinetically controlled. The leucine gamma site was the most reactive for the reactions with ˙N3, ˙OOCCl3, ˙OCH3, ˙OCH2Cl, and ˙OCHCl2 radicals, with rate constants equal to 1.97 × 10(5), 3.24 × 10(4), 6.68 × 10(5), 5.98 × 10(6) and 8.87 × 10(8) M(-1) s(-1), respectively, in aqueous solution. The ˙Cl, ˙OH and ˙OCCl3 radicals react with leucine at the beta, gamma, and delta positions at rates close to the diffusion limit with the alpha position which is the slowest path and the most thermodynamically favored. The presented results confirm that the Bell-Evans-Polanyi principle does not apply for the reactions between amino acid residues and free radicals. Regarding the influence of the environment on the reactivity of the studied series of free radicals towards leucine residues, it is concluded that hydrophilic media slightly lower the reactivity of the studied radicals, compared to hydrophobic ones, albeit the trends in reactivity are very similar.


G6PD deficiency at Sumba in Eastern Indonesia is prevalent, diverse and severe: implications for primaquine therapy against relapsing Vivax malaria.
Safe treatment of Plasmodium vivax requires diagnosis of both the infection and status of erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity because hypnozoitocidal therapy against relapse requires primaquine, which causes a mild to severe acute hemolytic anemia in G6PD deficient patients. Many national malaria control programs recommend primaquine therapy without G6PD screening but with monitoring due to a broad lack of G6PD deficiency screening capacity. The degree of risk in doing so hinges upon the level of residual G6PD activity among the variants present in any given area. We conducted studies on Sumba Island in eastern Indonesia in order to assess the potential threat posed by primaquine therapy without G6PD screening. We sampled 2,033 residents of three separate districts in western Sumba for quantitative G6PD activity and 104 (5.1%) were phenotypically deficient (<4.6U/gHb; median normal 10U/gHb). The villages were in two distinct ecosystems, coastal and inland. A positive correlation occurred between the prevalence of malaria and G6PD deficiency: 5.9% coastal versus inland 0.2% for malaria (P<0.001), and 6.7% and 3.1% for G6PD deficiency (P<0.001) at coastal and inland sites, respectively. The dominant genotypes of G6PD deficiency were Vanua Lava, Viangchan, and Chatham, accounting for 98.5% of the 70 samples genotyped. Subjects expressing the dominant genotypes all had less than 10% of normal enzyme activities and were thus considered severe variants. Blind administration of anti-relapse primaquine therapy at Sumba would likely impose risk of serious harm.


A fast species redistribution approach to accelerate the kinetic Monte Carlo simulation for heterogeneous catalysis.
The first-principles kinetic Monte Carlo (kMC) simulation has been demonstrated as a reliable multiscale modeling approach in silico to disclose the interplay among all the elementary steps in a complex reaction network for heterogeneous catalysis. Heterogeneous catalytic systems frequently contain fast surface diffusion processes of some adsorbates while the elementary steps in it would be much slower than those in fast diffusion. Consequently, the kMC simulation for these systems is easily trapped in the sub-basins of a super basin on a potential energy surface due to the continuous and repeated sampling of these fast processes, which would significantly increase the total accessible simulation time and even make it impossible to get the reasonable simulation results using the kMC simulation. In this work, we present an improved fast species redistribution (FSR) method for the kMC simulation to overcome the stiffness problem resulting from the low-barrier surface diffusion to accelerate the heterogeneous catalytic kMC simulation. Taking CO oxidations on Pt(111) and Pt(100) as examples, we demonstrate that the FSR approach can properly reproduce the results of an equivalent first-principles microkinetic model simulation with more reasonable reaction rates. The improved kMC simulation based on the FSR method can accurately incorporate the effect of the fast diffusion of species on the surface and provide several orders of magnitude of acceleration compared to the standard kMC simulation.


CAVE and fishtank virtual-reality displays: a qualitative and quantitative comparison.
We present the results from a qualitative and quantitative user study comparing fishtank virtual-reality (VR) and CAVE displays. The results of the qualitative study show that users preferred the fishtank VR display to the CAVE system for our scientific visualization application because of perceived higher resolution, brightness and crispness of imagery, and comfort of use. The results of the quantitative study show that users performed an abstract visual search task significantly more quickly and more accurately on the fishtank VR display system than in the CAVE. The same study also showed that visual context had no significant effect on task performance for either of the platforms. We suggest that fishtank VR displays are more effective than CAVEs for applications in which the task occurs outside the user's reference frame, the user views and manipulates the virtual world from the outside in, and the size of the virtual object that the user interacts with is smaller than the user's body and fits into the fishtank VR display. The results of both studies support this proposition.


GATA-2 regulates granulocyte-macrophage progenitor cell function.
The zinc finger transcription factor GATA-2 has been implicated in the regulation of hematopoietic stem cells. Herein, we explored the role of GATA-2 as a candidate regulator of the hematopoietic progenitor cell compartment. We showed that bone marrow from GATA-2 heterozygote (GATA-2(+/-)) mice displayed attenuated granulocyte-macrophage progenitor function in colony-forming cell (CFC) and serial replating CFC assays. This defect was mapped to the Lin(-)CD117(+)Sca-1(-)CD34(+)CD16/32(high) granulocyte-macrophage progenitor (GMP) compartment of GATA-2(+/-) marrow, which was reduced in size and functionally impaired in CFC assays and competitive transplantation. Similar functional impairments were obtained using a RNA interference approach to stably knockdown GATA-2 in wild-type GMP. Although apoptosis and cell-cycle distribution remained unperturbed in GATA-2(+/-) GMP, quiescent cells from GATA-2(+/-) GMP exhibited altered functionality. Gene expression analysis showed attenuated expression of HES-1 mRNA in GATA-2-deficient GMP. Binding of GATA-2 to the HES-1 locus was detected in the myeloid progenitor cell line 32Dcl3, and enforced expression of HES-1 expression in GATA-2(+/-) GMP rectified the functional defect, suggesting that GATA-2 regulates myeloid progenitor function through HES-1. These data collectively point to GATA-2 as a novel, pivotal determinant of GMP cell fate.


[Survival benefit with intraarterial techniques in hepatocellular carcinoma].
The two intraarterial techniques used in the treatment of hepatocellular carcinoma (HCC) are the transarterial chemoembolization (TACE) and radioembolization (RE). TACE includes various procedures whose objective is to expose tumor cells to a chemotherapy agent and induce acute ischemia in the tumor. The survival benefit obtained by adding a chemotherapy agent or lipiodol to simple particle embolization has not been demonstrated in 2 meta-analyses, which suggests that the antitumor effect is primarily ischemic. RE is a form of brachytherapy that consists of an intraarterial injection of microspheres loaded with yttrium 90 as the source of radiation, a pure beta emitter with a mean tissue penetration of 2mm. TACE is performed in several sessions every 4-8 weeks, while RE is generally a single procedure. The guidelines adopted by the main research societies support the use of TACE for the palliative treatment of patients with intermediate stage HCC. This is a level 1 recommendation based on the positive results of 2 randomized clinical trials and 3 meta-analyses and on several uncontrolled studies with thousands of patients with unresectable HCC. Survival in clinical practice studies is heterogeneous due to the heterogeneity of the treated population. The survival rate varies from 8% to 26% at 5 years, and the median is 16-40 months in the early stage and 15-27 months in the intermediate stage. TACE with drug-eluting beads (DEB-TACE) has not shown superiority versus conventional TACE in terms of improved survival or tumor response, but it decreases the severe chemotherapy-related adverse events. One of its advantages is the standardization of the procedure, while its primary disadvantage is the onset of biliary complications when used nonselectively. There is level 2 evidence to support the use of RE in HCC, evidence that comes from patient cohorts with consistent results and case-control studies. The treated population includes mainly patients with unresectable tumors, who are considered suboptimal candidates for TACE or are progressing toward this condition, and those for whom TACE was directly contraindicated by the presence of portal vein thrombosis. Consequently, these patients tend to have large or extensively bilobar tumors and other factors for a poor prognosis. The overall survival reported for patients in the intermediate and advanced stages is 16-18 months and 7-17 months, respectively. A number of retrospective studies have reported comparable survival for patients treated with TACE and RE in the same institution; however, these results should be interpreted as a generator of ideas and not as an equivalent efficacy test. Although the combination of systemic agents such as sorafenib with intraarterial techniques is attractive, the results to date are not encouraging. In the only available randomized trial that compared the combination of a continuous regimen of sorafenib started before the first session of DEB-TACE versus DEB-TACE alone, neither the time to progression nor the overall survival were significantly different between the 2 groups. TACE and RE are contraindicated in cases of decompensated cirrhosis. TACE is also contraindicated for patients with considerable tumor burden in whom the procedure cannot be performed selectively and in patients with portal vein invasion.


Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production.
Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε (Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet 45: 531-536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol 24: 377-384, 2013). DGKε is unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgke knockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgke null mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2 are impaired in Dgke null kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2 supplementation was able to rescue motility defects of Dgke knockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgke in the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.


Increasing damage to tumor blood vessels during motexafin lutetium-PDT through use of low fluence rate.
Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug-light intervals and thus deliver illumination while plasma concentrations of photosensitizer are high, creating a prominent vascular response. In this study, the effects of light fluence rate on PDT response were investigated using motexafin lutetium (10 mg/kg) in combination with 730 nm light and a 180-min drug-light interval. At 180 min, the plasma level of photosensitizer was 5.7 ng/microl compared to 3.1 ng/mg in RIF tumor, and PDT-mediated vascular effects were confirmed by a spasmodic decrease in blood flow during illumination. Light delivery at 25 mW/cm(2) significantly improved long-term tumor responses over that at 75 mW/cm(2). This effect could not be attributed to oxygen conservation at low fluence rate, because 25 mW/cm(2) PDT provided little benefit to tumor hemoglobin oxygen saturation. However, 25 mW/cm(2) PDT did prolong the duration of ischemic insult during illumination and was correspondingly associated with greater decreases in perfusion immediately after PDT, followed by smaller increases in total hemoglobin concentration in the hours after PDT. Increases in blood volume suggest blood pooling from suboptimal vascular damage; thus the smaller increases after 25 mW/cm(2) PDT provide evidence of more widespread vascular damage, which was accompanied by greater decreases in clonogenic survival. Further study of low fluence rate as a means to improve responses to PDT under conditions designed to predominantly damage vasculature is warranted.


Catastrophic Mortality, Allee Effects, and Marine Protected Areas.
For many species, reproductive failure may occur if abundance drops below critical Allee thresholds for successful breeding, in some cases impeding recovery. At the same time, extreme environmental events can cause catastrophic collapse in otherwise healthy populations. Understanding what natural processes and management strategies may allow for persistence and recovery of natural populations is critical in the face of expected climate change scenarios of increased environmental variability. Using a spatially explicit continuous-size fishery model with stochastic dispersal parameterized for abalone-a harvested species with sedentary adults and a dispersing larval phase-we investigated whether the establishment of a system of marine protected areas (MPAs) can prevent population collapse, compared with nonspatial management when populations are affected by mass mortality from environmental shocks and subject to Allee effects. We found that MPA networks dramatically reduced the risk of collapse following catastrophic events (75%-90% mortality), while populations often continued to decline in the absence of spatial protection. Similar resilience could be achieved by closing the fishery immediately following mass mortalities but would necessitate long periods without catch and therefore economic income. For species with Allee effects, the use of protected areas can ensure persistence following mass mortality events while maintaining ecosystem services during the recovery period.


Modification of the existing maximum residue level for triclopyr in kiwi.
In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Arysta LifeScience Benelux submitted a request to the competent national authority in Greece to modify the existing maximum residue levels (MRLs) for the active substance triclopyr in kiwi fruits. The data submitted in support of the request were found to be sufficient to derive an MRL proposal for kiwi fruits. Adequate analytical methods for enforcement are available to control the residues of triclopyr in the plant matrix under consideration (i.e. high acid content commodity) at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of triclopyr according to the reported agricultural practice is unlikely to present a risk to consumer health.


Intra-chromosomal heterogeneity between the four 16S rRNA gene copies in the genus Veillonella: implications for phylogeny and taxonomy.
Among the seven species characterized within the genus Veillonella, three (Veillonella dispar, Veillonella parvula and Veillonella atypica) have so far been isolated from human flora and during infectious processes. Sequencing and analysis of 16S rDNA (rrs) has been described as the best method for identification of Veillonella strains at the species level since phenotypic characteristics are unable to differentiate between species. rrs sequencing for the three species isolated from humans showed more than 98 % identity between them. Four rrs copies were found in the reference strains and in all the clinical isolates studied. The sequences of each rrs were determined for the clinical strain ADV 360.1, and they showed a relatively high level of heterogeneity (1.43 %). In the majority of cases, polymorphic positions corresponded to nucleotides allowing differentiation between the three species isolated from humans. Moreover, variability observed between rrs copies was higher than that between 16S rDNA sequences of V. parvula and V. dispar. Phylogenetic analysis showed that polymorphism between rrs copies affected the position of strain ADV 360.1 in the tree. Variable positions occurred in stems and loops belonging to variable and hypervariable regions of the 16S rRNA secondary structure but did not change the overall structure of the 16S rRNA. PCR-RFLP experiments performed on 27 clinical isolates of Veillonella sp. suggested that inter-rrs heterogeneity occurs widely among the members of the genus VEILLONELLA: These results, together with the lack of phenotypic criteria for species differentiation, give preliminary arguments for unification of V. dispar and V. parvula.


Ranking analysis of F-statistics for microarray data.
Microarray technology provides an efficient means for globally exploring physiological processes governed by the coordinated expression of multiple genes. However, identification of genes differentially expressed in microarray experiments is challenging because of their potentially high type I error rate. Methods for large-scale statistical analyses have been developed but most of them are applicable to two-sample or two-condition data. We developed a large-scale multiple-group F-test based method, named ranking analysis of F-statistics (RAF), which is an extension of ranking analysis of microarray data (RAM) for two-sample t-test. In this method, we proposed a novel random splitting approach to generate the null distribution instead of using permutation, which may not be appropriate for microarray data. We also implemented a two-simulation strategy to estimate the false discovery rate. Simulation results suggested that it has higher efficiency in finding differentially expressed genes among multiple classes at a lower false discovery rate than some commonly used methods. By applying our method to the experimental data, we found 107 genes having significantly differential expressions among 4 treatments at <0.7% FDR, of which 31 belong to the expressed sequence tags (ESTs), 76 are unique genes who have known functions in the brain or central nervous system and belong to six major functional groups. Our method is suitable to identify differentially expressed genes among multiple groups, in particular, when sample size is small.


The Zur of Xanthomonas campestris is involved in hypersensitive response and positively regulates the expression of the hrp cluster via hrpX but not hrpG.
In bacteria, Zur is a key regulator for zinc homeostasis. Our previous work has shown that, in the phytopathogen Xanthomonas campestris pv. campestris, in addition to regulating zinc homeostasis, Zur is essential for full virulence. Here, we demonstrate that the X. campestris pv. campestris Zur is involved in hypersensitive response (HR) and positively regulates the transcription of hrpA to hrpF operons and hrpX but not hrpG. Constitutively expressing hrpX but not hrpG in the zur mutant could bypass the requirement of Zur for the expression of hrpA to hrpF operons and the induction of wild-type HR, indicating that Zur controls the expression of hrp cluster via hrpX. Promoter-gusA reporter and semiquantitative reverse-transcription polymerase chain reaction analyses revealed that HrpG controls the expression of hrpX and HrpX regulates the expression of all the six hrp operons (hrpA to hrpF) in X. campestris pv. campestris.


Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes.
Schizophrenia is a serious psychotic disorder with high heritability. Several common genetic variants, rare copy number variants and ultra-rare gene-disrupting mutations have been linked to disease susceptibility, but there is still a large gap between the estimated and explained heritability. Since several studies have indicated brain myelination abnormalities in schizophrenia, we aimed to examine whether variants in myelination-related genes could be associated with risk for schizophrenia. We established a set of 117 myelination genes by database searches and manual curation. We used a combination of GWAS (SCZ_N = 35,476; CTRL_N = 46,839), exome chip (SCZ_N = 269; CTRL_N = 336) and exome sequencing data (SCZ_N = 2,527; CTRL_N = 2,536) from schizophrenia cases and healthy controls to examine common and rare variants. We found that a subset of lipid-related genes was nominally associated with schizophrenia (p = 0.037), but this signal did not survive multiple testing correction (FWER = 0.16) and was mainly driven by the SREBF1 and SREBF2 genes that have already been linked to schizophrenia. Further analysis demonstrated that the lowest nominal p-values were p = 0.0018 for a single common variant (rs8539) and p = 0.012 for burden of rare variants (LRP1 gene), but none of them survived multiple testing correction. Our findings suggest that variation in myelination-related genes is not a major risk factor for schizophrenia.


Indian craniometric variability and affinities.
Recently published craniometric and genetic studies indicate a predominantly indigenous ancestry of Indian populations. We address this issue with a fuller coverage of Indian craniometrics than any done before. We analyse metrical variability within Indian series, Indians' sexual dimorphism, differences between northern and southern Indians, index-based differences of Indian males from other series, and Indians' multivariate affinities. The relationship between a variable's magnitude and its variability is log-linear. This relationship is strengthened by excluding cranial fractions and series with a sample size less than 30. Male crania are typically larger than female crania, but there are also shape differences. Northern Indians differ from southern Indians in various features including narrower orbits and less pronounced medial protrusion of the orbits. Indians resemble Veddas in having small crania and similar cranial shape. Indians' wider geographic affinities lie with "Caucasoid" populations to the northwest, particularly affecting northern Indians. The latter finding is confirmed from shape-based Mahalanobis-D distances calculated for the best sampled male and female series. Demonstration of a distinctive South Asian craniometric profile and the intermediate status of northern Indians between southern Indians and populations northwest of India confirm the predominantly indigenous ancestry of northern and especially southern Indians.


Quality of Life of Persons Affected by Leprosy in an Endemic District, West Bengal, India.
Leprosy still remains a public health problem in India. Stigma and associated psychosocial problems are common in leprosy and may affect the quality of life (QoL). This study aimed to assess the QoL of the person affected by leprosy living in Purulia district, West Bengal. A cross-sectional study was conducted among 358 persons affected by leprosy above the age of 18 years and who were reporting at tertiary leprosy referral hospital, Purulia, West Bengal, from April to July 2017. The World Health Organization QoL (WHOQOL-BREF) scale was used to measure the QoL and the scale had four domain; physical health, psychological health, social relationship, and environmental health. Of the 358 respondents, 41% were female, 60% were aged between 18 and 45 years, and 58% were literate. Half of the participants (55%) were farmer and labor, and 75% of the participants' family income was below Rs. 5000 per month. One hundred and forty-four (40%) participants had physical disability. There was a highly significant difference seen among the person affected by leprosy between those with visible deformity and no deformity in four domains. The participants with visible deformity had lower QoL than the person without deformity. The study observed that the person affected by leprosy with visible deformity had lower QoL. Early detection and management would prevent the deformity and might improve the QoL of persons affected by leprosy.


Elevated p53 and p21waf1 mRNA expression in blood lymphocytes from lung cancer patients with chemoresistance.
Clinical and experimental studies suggest that alteration of the expression level of the p53 gene and other damage responsive genes may be associated with chemoresistance in cancer patients. The present study evaluated the differences of the basal levels of lymphocytic p53 and p21waf1 mRNA expression collected before receiving cisplatin-based chemotherapy between 48 chemo-ineffective lung cancer patients and 39 chemo-effective lung cancer patients using an optimized semi-quantitative multiplex reverse transcriptase-polymerase chain reaction (RT-PCR). The data indicated that the mean mRNA level of p53 gene in chemo-ineffective patients (0.66) was 26.9% higher than that of the chemo-effective patients (0.52) with statistical significance (P=0.03), and a significantly higher level of p21waf1 mRNA expression in the chemo-ineffective patients (P=0.03) was also observed. In addition, by the multiplex long quantitative PCR analysis, we demonstrated that chemo-ineffective and chemo-effective patients have similar amounts of UV damage on their p53 gene of lymphocyte DNA through equal UV treatment. Our results suggest that elevated levels of p53/p21waf1 mRNA in blood lymphocytes collected before chemotherapy may predict the chemoresponses of lung cancer patients.


Risk factors for breast cancer in Turkish women with early pregnancies and long-lasting lactation--a case-control study.
A hospital-based case-control study was carried out among 504 women with breast cancer and 610 controls to analyse the risk factors for breast cancer in Turkey. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each risk factor were obtained from logistic regression analysis. Risk factors for breast cancer were found to be long-term lactation (> or = 5 years versus never OR 0.31, 95% CI 0.12-0.79), young age at menarche (< 15 years versus > or = 15 OR 1.72, 95% CI 1.30-2.28), late age at first full-term pregnancy (> or = 30 versus < 20 OR 2.86, 95% CI 1.32-6.21), oral contraceptive use (ever versus never OR 1.51, 95% CI 1.10-2.08), positive family history (positive versus negative OR 2.81, 95% CI 1.35-5.82), and menstrual irregularity (yes versus no OR 1.61, 95% CI 1.05-2.49). The results of the present study will lead to a better understanding of the risk factors for breast cancer in a developing country.


A change in temperature modulates defence to yellow (stripe) rust in wheat line UC1041 independently of resistance gene Yr36.
Rust diseases are of major importance in wheat production worldwide. With the constant evolution of new rust strains and their adaptation to higher temperatures, consistent and durable disease resistance is a key challenge. Environmental conditions affect resistance gene performance, but the basis for this is poorly understood. Here we show that a change in day temperature affects wheat resistance to Puccinia striiformis f. sp tritici (Pst), the causal agent of yellow (or stripe) rust. Using adult plants of near-isogenic lines UC1041 +/- Yr36, there was no significant difference between Pst percentage uredia coverage in plants grown at day temperatures of 18°C or 25°C in adult UC1041 + Yr36 plants. However, when plants were transferred to the lower day temperature at the time of Pst inoculation, infection increased up to two fold. Interestingly, this response was independent of Yr36, which has previously been reported as a temperature-responsive resistance gene as Pst development in adult UC1041 -Yr36 plants was similarly affected by the plants experiencing a temperature reduction. In addition, UC1041 -Yr36 plants grown at the lower temperature then transferred to the higher temperature were effectively resistant and a temperature change in either direction was shown to affect Pst development up to 8 days prior to inoculation. Results for seedlings were similar, but more variable compared to adult plants. Enhanced resistance to Pst was observed in seedlings of UC1041 and the cultivar Shamrock when transferred to the higher temperature. Resistance was not affected in seedlings of cultivar Solstice by a temperature change in either direction. Yr36 is effective at 18°C, refining the lower range of temperature at which resistance against Pst is conferred compared to previous studies. Results reveal previously uncharacterised defence temperature sensitivity in the UC1041 background which is caused by a change in temperature and independently of Yr36. This novel phenotype is present in some cultivars but absent in others, suggesting that Pst defence may be more stable in some cultivars than others when plants are exposed to varying temperatures.