Prospects for comparing European hospitals in terms of quality and safety: lessons from a comparative study in five countries.
Being able to compare hospitals in terms of quality and safety between countries is important for a number of reasons. For example, the 2011 European Union directive on patients' rights to cross-border health care places a requirement on all member states to provide patients with comparable information on health-care quality, so that they can make an informed choice. Here, we report on the feasibility of using common process and outcome indicators to compare hospitals for quality and safety in five countries (England, Portugal, The Netherlands, Sweden and Norway). The cross-country comparison identified the following seven challenges with respect to comparing the quality of hospitals across Europe: different indicators are collected in each country; different definitions of the same indicators are used; different mandatory versus voluntary data collection requirements are in place; different types of organizations oversee data collection; different levels of aggregation of data exist (country, region and hospital); different levels of public access to data exist; and finally, hospital accreditation and licensing systems differ in each country. Our findings indicate that if patients and policymakers are to compare the quality and safety of hospitals across Europe, then further work is urgently needed to agree the way forward. Until then, patients will not be able to make informed choices about where they receive their health care in different countries, and some governments will remain in the dark about the quality and safety of care available to their citizens as compared to that available in neighbouring countries.


Computed tomography-guided fine-needle aspirate and tissue-core biopsy of intrathoracic lesions in thirty dogs and cats.
Medical records and computed tomography (CT) images were reviewed retrospectively for 30 animals (27 dogs, two cats, one cougar) in which CT-guided intrathoracic fine-needle aspirates (FNA) (12), core biopsies (10) or both (8) were performed. Sample interpretation was listed as diagnostic or nondiagnostic and nonneoplasia or neoplasia. Diagnostic results were inconclusive in 35% FNA and 17% biopsies. FNA and biopsy interpretations were in agreement in seven patients, one nonneoplasia, and six neoplasia. A clinical diagnosis was made in 65% FNA and 83% biopsies. When 18 patients with confirmed diagnoses were used, overall accuracy for diagnosis was 92% for FNA and biopsy and the sensitivity for neoplasia was 91% using fine needle aspirate and 80% using biopsy. Complications seen on CT images were noted in 43% of patients, four pneumothorax, five pulmonary hemorrhage, and four with both. No clinical manifestations were noted and treatment was not necessary. Significant correlation was noted between complications and penetration of aerated lung, but not with lesion location, type of disease, method of sampling, width of mass and depth of aerated lung penetrated. CT-guided sampling is relatively safe and useful in the diagnosis of intra-thoracic lesions, especially neoplasia. FNA samples are nondiagnostic more often than biopsy samples. Sub-clinical pneumothorax and hemorrhage are common when aerated lung is penetrated.


Fumarase is involved in DNA double-strand break resection through a functional interaction with Sae2.
One of the most severe forms of DNA damage is the double-strand break (DSB). Failure to properly repair the damage can cause mutation, gross chromosomal rearrangements and lead to the development of cancer. In eukaryotes, homologous recombination (HR) and non-homologous end joining (NHEJ) are the main DSB repair pathways. Fumarase is a mitochondrial enzyme which functions in the tricarboxylic acid cycle. Intriguingly, the enzyme can be readily detected in the cytosolic compartment of all organisms examined, and we have shown that cytosolic fumarase participates in the DNA damage response towards DSBs. In human cells, fumarase was shown to be involved in NHEJ, but it is still unclear whether fumarase is also important for the HR pathway. Here we show that the depletion of cytosolic fumarase in yeast prolongs the presence of Mre11 at the DSBs, and decreases the kinetics of repair by the HR pathway. Overexpression of Sae2 endonuclease reduced the DSB sensitivity of the cytosolic fumarase depleted yeast, suggesting that Sae2 and fumarase functionally interact. Our results also suggest that Sae2 and cytosolic fumarase physically interact in vivo. Sae2 has been shown to be important for the DSB resection process, which is essential for the repair of DSBs by the HR pathway. Depletion of cytosolic fumarase inhibited DSB resection, while the overexpression of cytosolic fumarase or Sae2 restored resection. Together with our finding that cytosolic fumarase depletion reduces Sae2 cellular amounts, our results suggest that cytosolic fumarase is important for the DSB resection process by regulating Sae2 levels.


Can the process of experimentation lead to greater happiness?
We argue that the self-experimentation espoused by Roberts as a means of generating new ideas, particularly in the area of mood, may be confounded by the experimental procedure eliciting those affective changes. We further suggest that ideas might be better generated through contact with a broad range of people, rather than in isolation.


Transcriptional profiling of the rat nucleus accumbens after modest or high alcohol exposure.
Alcohol use disorder is a chronic relapsing brain disorder and a global health issue. Prolonged high alcohol consumption increases the risk for dependence development, a complex state that includes progressive alterations in brain function. The molecular mechanisms behind these changes remain to be fully disclosed, but several genes show altered expression in various regions of the rat brain even after modest alcohol exposure. The present study utilizes whole-transcriptome sequencing (RNA-seq) to investigate expression changes in the brain nucleus accumbens (NAc), an area of particular interest in addictive disorders, of alcohol consuming rats. The impact on gene expression after eight weeks of moderate voluntary alcohol consumption or voluntary consumption combined with forced excessive exposure was explored in two separate experiments. The results point to a lack of strong and consistent expression alterations in the NAc after alcohol exposure, suggesting that transcriptional effects of alcohol are weak or transient, or occur primarily in brain regions other than NAc.


Advances in Understanding How Heavy Metal Pollution Triggers Gastric Cancer.
With the development of industrialization and urbanization, heavy metals contamination has become a major environmental problem. Numerous investigations have revealed an association between heavy metal exposure and the incidence and mortality of gastric cancer. The mechanisms of heavy metals (lead, cadmium, mercury, chromium, and arsenic) contamination leading to gastric cancer are concluded in this review. There are four main potential mechanisms: (1) Heavy metals disrupt the gastric mucosal barrier by decreasing mucosal thickness, mucus content, and basal acid output, thereby affecting the function of E-cadherin and inducing reactive oxygen species (ROS) damage. (2) Heavy metals directly or indirectly induce ROS generation and cause gastric mucosal and DNA lesions, which subsequently alter gene regulation, signal transduction, and cell growth, ultimately leading to carcinogenesis. Exposure to heavy metals also enhances gastric cancer cell invasion and metastasis. (3) Heavy metals inhibit DNA damage repair or cause inefficient lesion repair. (4) Heavy metals may induce other gene abnormalities. In addition, heavy metals can induce the expression of proinflammatory chemokine interleukin-8 (IL-8) and microRNAs, which promotes tumorigenesis. The present review is an effort to underline the human health problem caused by heavy metal with recent development in order to garner a broader perspective.


Contemporary concepts of pain surgery.
Pain surgery is one of the historic foundations of neurological surgery. The authors present a review of contemporary concepts in surgical pain management, with reference to past successes and failures, what has been learned as a subspecialty over the past 50 years, as well as a vision for current and future practice. This subspecialty confronts problems of cancer pain, nociceptive pain, and neuropathic pain. For noncancer pain, ablative procedures such as dorsal root entry zone lesions and rhizolysis for trigeminal neuralgia (TN) should continue to be practiced. Other procedures, such as medial thalamotomy, have not been proven effective and require continued study. Dorsal rhizotomy, dorsal root ganglionectomy, and neurotomy should probably be abandoned. For cancer pain, cordotomy is an important and underutilized method for pain control. Intrathecal opiate administration via an implantable system remains an important option for cancer pain management. While there are encouraging results in small case series, cingulotomy, hypophysectomy, and mesencephalotomy deserve further detailed analysis. Electrical neuromodulation is a rapidly changing discipline, and new methods such as high-frequency spinal cord stimulation (SCS), burst SCS, and dorsal root ganglion stimulation may or may not prove to be more effective than conventional SCS. Despite a history of failure, deep brain stimulation for pain may yet prove to be an effective therapy for specific pain conditions. Peripheral nerve stimulation for conditions such as occipital neuralgia and trigeminal neuropathic pain remains an option, although the quality of outcomes data is a challenge to these applications. Based on the evidence, motor cortex stimulation should be abandoned. TN is a mainstay of the surgical treatment of pain, particularly as new evidence and insights into TN emerge. Pain surgery will continue to build on this heritage, and restorative procedures will likely find a role in the armamentarium. The challenge for the future will be to acquire higher-level evidence to support the practice of surgical pain management.


Simultaneous clock recovery and dispersion, OSNR monitoring for 112-Gbit/s NRZ-DQPSK using frequency down-conversion electro-optical phase-locked loop.
A cost effective clock recovery scheme simultaneously providing signal performance monitoring is proposed for high speed electrical time domain multiplexing (ETDM) transmission systems to release the bandwidth requirement on the involved electrical devices. In the scheme, we first convert the clock frequency down in the optical domain using electroptic modulation, and then extract the clock with a phase locked loop (PLL) after photo-detection. All the devices involved are operated at frequencies lower than half of the symbol rate. Furthermore, we use a quadrature phase detector in the PLL to create a monitor signal which characterizes the transmitted signal performance in terms of optical-to-noise ratio (OSNR) and accumulated chromatic dispersion (ACD). This scheme is applied to a 112-Gbit/s none-return-to-zero (NRZ) differential quadrature phase shift keying (DQPSK) system. Experimental results show that the clock can be recovered in a dispersion range of -40 to 40 ps/nm, and the evaluated OSNR, over a range of 18~36 dB, has a deviation smaller than 1 dB compared to the measured one based on the optical spectrum method. The bit error ratio remains below 10(-9) for 12 hours in the back-to-back case and 2 hours after transmission over 100-km standard single mode fiber (SSMF).


Long chain fatty acids alter the interactive binding of ligands to the two principal drug binding sites of human serum albumin.
A wide variety of drugs bind to human serum albumin (HSA) at its two principal sites, namely site I and site II. A number of reports indicate that drug binding to these two binding sites are not completely independent, and that interactions between ligands of these two discrete sites can play a role. In this study, the effect of the binding of long-chain fatty acids on the interactive binding between dansyl-L-asparagine (DNSA; site I ligand) and ibuprofen (site II ligand) at pH6.5 was examined. Binding experiments showed that the binding of sodium oleate (Ole) to HSA induces conformational changes in the molecule, which, in turn, changes the individual binding of DNSA and ibuprofen, as well as the mode of interaction between these two ligands from a 'competitive-like' allosteric interaction in the case of the defatted HSA conformer to a 'nearly independent' binding in the case of non-defatted HSA conformer. Circular dichroism measurements indicated that ibuprofen and Ole are likely to modify the spatial orientation of DNSA at its binding site. Docking simulations suggest that the long-distance electric repulsion between DNSA and ibuprofen on defatted HSA contributes to a 'competitive-like' allosteric interaction, whereas extending the distance between ligands and/or increasing the flexibility or size of the DNSA binding site in fatted HSA evokes a change in the interaction mode to 'nearly independent' binding. The present findings provide further insights into the structural dynamics of HSA upon the binding of fatty acids, and its effects on drug binding and drug-drug interactions that occur on HSA.


Spatio-temporal theory of lasing action in optically-pumped rotationally excited molecular gases.
We investigate laser emission from optically-pumped rotationally excited molecular gases confined in a metallic cavity. To this end, we have developed a theoretical framework able to accurately describe, both in the spatial and temporal domains, the molecular collisional and diffusion processes characterizing the operation of this class of lasers. The effect on the main lasing features of the spatial variation of the electric field intensity and the ohmic losses associated to each cavity mode are also included in our analysis. Our simulations show that, for the exemplary case of methyl fluoride gas confined in a cylindrical copper cavity, the region of maximum population inversion is located near the cavity walls. Based on this fact, our calculations show that the lowest lasing threshold intensity corresponds to the cavity mode that, while maximizing the spatial overlap between the corresponding population inversion and electric-field intensity distributions, simultaneously minimizes the absorption losses occurring at the cavity walls. The dependence of the lasing threshold intensity on both the gas pressure and the cavity radius is also analyzed and compared with experiment. We find that as the cavity size is varied, the interplay between the overall gain of the system and the corresponding ohmic losses allows for the existence of an optimal cavity radius which minimizes the intensity threshold for a large range of gas pressures. The theoretical analysis presented in this work expands the current understanding of lasing action in optically-pumped far-infrared lasers and, thus, could contribute to the development of a new class of compact far-infrared and terahertz sources able to operate efficiently at room temperature.


Distinctive actions of interleukin-13 and interleukin-4 on growth of hematopoietic progenitors.
We examined the effects of interleukin (IL)-13 and IL-4 on growth of hematopoietic progenitors from 5-fluorouracil (5-FU)-treated mice, using an in vitro culture system. IL-13 or IL-4 alone failed to support colony formation by enriched marrow cells. IL-4 but not IL-13 in combination with IL-11 yielded a significant number of colonies. Neither IL-4 nor IL-13 affected colony formation supported by IL-3. When tested with two-factor combinations, IL-4 but not IL-13 suppressed the formation of colonies including multilineage colonies in the absence of IL-11. The inhibitory effects of IL-4 were not lineage-specific. Delayed addition experiments demonstrated that IL-4 is inhibitory in the early stage of colony formation. Effects of IL-4 on colony formation by pooled blast cells derived from 5-day culture of post-5-FU marrow cells was not evident. These findings indicate that IL-4 but not IL-13 is a negative regulator of hematopoietic progenitors, suggesting distinctive roles for IL-4 and IL-13 in early hematopoiesis.


Old-School Chemotherapy in Immunotherapeutic Combination in Cancer, A Low-cost Drug Repurposed.
Cancer immunotherapy has proven to be a potent treatment modality. Although often successful in generating antitumor immune responses, cancer immunotherapy is frequently hindered by tumor immune-escape mechanisms. Among immunosuppressive strategies within the tumor microenvironment, suppressive immune regulatory cells play a key role in promoting tumor progression through inhibiting the effector arm of the immune response. Targeting these suppressive cells can greatly enhance antitumor immune therapies, hence augmenting a highly effective therapeutic antitumor response. Several approaches are being tested to enhance the effector arm of the immune system while simultaneously inhibiting the suppressor arm. Some of these approaches are none other than traditional drugs repurposed as immune modulators. Cyclophosphamide, an old-school chemotherapeutic agent used across a wide range of malignancies, was found to be a potent immune modulator that targets suppressive regulatory immune cells within the tumor microenvironment while enhancing effector cells. Preclinical and clinical findings have confirmed the ability of low doses of cyclophosphamide to selectively deplete regulatory T cells while enhancing effector and memory cytotoxic T cells within the tumor microenvironment. These immune effects translate to suppressed tumor growth and enhanced survival, evidence of antitumor therapeutic efficacy. This article discusses the reincarnation of cyclophosphamide as an immune modulator that augments novel immunotherapeutic approaches. Cancer Immunol Res; 4(5); 377-82. ©2016 AACR.


CO2 emissions from land-use change affected more by nitrogen cycle, than by the choice of land-cover data.
The high uncertainty in land-based CO2 fluxes estimates is thought to be mainly due to uncertainty in not only quantifying historical changes among forests, croplands, and grassland, but also due to different processes included in calculation methods. Inclusion of a nitrogen (N) cycle in models is fairly recent and strongly affects carbon (C) fluxes. In this study, for the first time, we use a model with C and N dynamics with three distinct historical reconstructions of land-use and land-use change (LULUC) to quantify LULUC emissions and uncertainty that includes the integrated effects of not only climate and CO2 but also N. The modeled global average emissions including N dynamics for the 1980s, 1990s, and 2000-2005 were 1.8 ± 0.2, 1.7 ± 0.2, and 1.4 ± 0.2 GtC yr(-1) , respectively, (mean and range across LULUC data sets). The emissions from tropics were 0.8 ± 0.2, 0.8 ± 0.2, and 0.7 ± 0.3 GtC yr(-1) , and the non tropics were 1.1 ± 0.5, 0.9 ± 0.2, and 0.7 ± 0.1 GtC yr(-1) . Compared to previous studies that did not include N dynamics, modeled net LULUC emissions were higher, particularly in the non tropics. In the model, N limitation reduces regrowth rates of vegetation in temperate areas resulting in higher net emissions. Our results indicate that exclusion of N dynamics leads to an underestimation of LULUC emissions by around 70% in the non tropics, 10% in the tropics, and 40% globally in the 1990s. The differences due to inclusion/exclusion of the N cycle of 0.1 GtC yr(-1) in the tropics, 0.6 GtC yr(-1) in the non tropics, and 0.7 GtC yr(-1) globally (mean across land-cover data sets) in the 1990s were greater than differences due to the land-cover data in the non tropics and globally (0.2 GtC yr(-1) ). While land-cover information is improving with satellite and inventory data, this study indicates the importance of accounting for different processes, in particular the N cycle.


Sickle cell disease in western Sudan: genetic epidemiology and predictors of knowledge attitude and practices.
To investigate the epidemiology of sickle cell disease (SCD) and determinants of knowledge, attitudes and practices (KAP) towards SCD in western Kordofan State, Sudan. A community-based, descriptive, cross-sectional study was conducted in three towns. Three hundred and seventy-two households were polled, and blood samples for haemoglobin phenotyping were collected from 1116 individuals. Sociodemographic, socio-economic and KAP data were collected using investigator-administered questionnaires. Descriptive, frequency distribution and multiple regression analyses were performed. About 50.9% of the study population were Misseriya tribes. Consanguineous marriages were reported by 67.5% of the households. The highest percentage of homozygous SCD was 2.8% among children under 5 years of age. About 24.9% were carriers of HbS allele (HbAS). HbS allele frequency was highest in children aged 5-11 years (18.3%, CI: 13.7-22.9%) and lowest in males >15 years old (12.0%, CI: 6.1-17.9%). The average HbS frequency across all age groups was 14.5% (95% CI: 12.2-16.8%). The most frequent β-globin gene cluster haplotype was the Cameroon (30.8%), followed by the Benin (21.8%), the Senegal (12.8%) and the Bantu (2.2%) haplotypes. About 17.0% of all-cause child deaths were due to SCD. The estimated change in log odds of having the SS genotype per year increase in age was (-) 0.0058 (95% CI -0.0359, 0.0242). This represents a non-statistically significant 2.9% increase in 5-year mortality for individuals with the SS genotype relative to those with AS and AA genotypes. About 46.9% of the households had poor knowledge, 26.1% had satisfactory knowledge, and 26.9% had good knowledge about sickle cell disease. Mothers' and fathers' educational levels were significant predictors of good knowledge about SCD (P < 0.05). About 48.0% had a satisfactory attitude towards sickle cell disease while 30.7% had poor attitude and only 21.3 showed good attitudes. Poor knowledge about SCD and low socio-economic status were the strongest positive predictors of poor attitude and practices towards SCD (P < 0.01). Sickle cell disease is a major health problem in West Kordofan, Sudan. Knowledge, attitude and practices towards the disease are not satisfactory. The development of public health programs is highly recommended to control and manage SCD in western parts of Sudan.


Pregabalin alleviates clinical signs of syringomyelia-related central neuropathic pain in Cavalier King Charles Spaniel dogs: a randomized controlled trial.
We aimed to assess the efficacy and benefit-risk profile of pregabalin (PGN) to reduce the clinical signs of central neuropathic pain (CNeP) as reflected by scratching episodes in dogs with symptomatic syringomyelia (SM). Randomized, double-blind, placebo-controlled crossover study. A total of 12 client-owned Cavalier King Charles Spaniels (age, 1.1-7.4 years, bodyweight, 8.2-10.8 kg) with magnetic resonance imaging-confirmed SM and clinical signs of CNeP. Dogs were randomized to either PGN 150 mg or placebo for 25 days, followed by 48 hour washout period before crossover to the alternate phase of 25 days. The primary outcome was defined as number of scratching events during 10 minutes of video-recorded physical activity. Treatment effect was estimated using a generalized estimation equation model. Benefit-risk and quality of life assessments were obtained through owner interviews focusing on potential adverse events. The treatment effect estimate was an 84% (95% confidence interval = 75-89%) reduction in mean number of scratching events relative to baseline compared with placebo (p < 0.0001). Owner-assessed satisfactory quality of life was status quo and rated as 'good' or 'could not be better' in six/11 dogs and improved in four/11 dogs. The most prevalent adverse events were increased appetite in nine/12 dogs and transient ataxia in nine/12 dogs. There was one dog withdrawn by the owner 7 days after crossover to PGN owing to persistent ataxia. No dogs needed rescue analgesia during the trial. PGN is superior to placebo in the reduction of clinical signs of SM-related CNeP in dogs. At a dose range of 13-19 mg kg-1 orally twice daily, the encountered adverse events were acceptable to all but one owner.


Results of a randomized trial of HERMES-assisted versus non-HERMES-assisted laparoscopic antireflux surgery.
Speech recognition technology is a recent development in minimally invasive surgery. This study was designed to assess the impact of HERMES on operating room efficiency and user satisfaction. Patients undergoing laparoscopic antireflux operations by surgeons experienced in minimally invasive surgery were randomized to HERMES-assisted or standard laparoscopic operations. The variables of interest were circulating nurse's time spent adjusting devices that are voice-controlled by HERMES, number of adjustments to devices requested, and surgeon and nurse satisfaction measured on a scale from 1 (dissatisfied) to 10 (satisfied). A total of 30 cases were studied. In the non-HERMES cases, nurses were interrupted to make device adjustments an average of 15.3 times per case versus 0.33 times per case in the with-HERMES cases (p < 0.01). The interruptions during the non-HERMES cases averaged 4.35 min per case versus 0.16 min per case in the with-HERMES cases (p = 0.03). Average satisfaction scores for HERMES operations as opposed to non-HERMES operations were 9.2 versus 5.3 for nurses (p < 0.01) and 9.0 versus 5.1 for surgeons (p < 0.01). Physician and nurse acceptance of HERMES was very high because of the smoother interruption-free environment.


Modulation of cerebral endothelial cell function by TGF-β in glioblastoma: VEGF-dependent angiogenesis versus endothelial mesenchymal transition.
Glioblastoma are among the most angiogenic tumors. The molecular mechanisms that control blood vessel formation by endothelial cells (EC) in glioblastoma remain incompletely understood. Transforming growth factor-β (TGF-β) is a key regulatory cytokine that has proinvasive and stemness-maintaining autocrine properties in glioblastoma and confers immunosuppression to the tumor microenvironment. Here we characterize potential pro- and anti-angiogenic activities of TGF-β in the context of glioblastoma in vitro, using human brain-derived microvascular endothelial cells (hCMEC/D3) and glioblastoma-derived endothelial cells (GMEC) as model systems. We find that TGF-β induces vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) mRNA expression and protein release in a TGF-β receptor (TβR) II / activin-like kinase (ALK)-5-dependent manner under normoxia and hypoxia, defining potential indirect proangiogenic activity of TGF-β in glioblastoma. In parallel, exogenous TGF-β has also inhibitory effects on EC properties and induces endothelial-mesenchymal transition (EndMT) in hCMEC and GMEC. Accordingly, direct inhibition of endogenous TGF-β/ALK-5 signalling increases EC properties such as tube formation, von-Willebrand factor (vWF) and claudin (CLDN) 5 expression. Yet, the supernatant of TGF-β-stimulated hCMEC and GMEC strongly promotes EC-related gene expression and tube formation in a cediranib-sensitive manner. These observations shed light on the complex pro- and anti-angiogenic pathways involving the cross-talk between TGF-β and VEGF/PLGF signalling in glioblastoma which may involve parallel stimulation of angiogenesis and EndMT in distinct target cell populations.


Herpes simplex virus type 1 amplicon vectors for the infectious delivery and expression of genomic DNA loci.
A wide range of viral gene transfer technologies has been developed for gene therapy and functional genetic purposes. Different viral vectors vary in transgene capacity, range of infectivity and stability of expression. It is now becoming increasingly apparent that there are distinct advantages in using a complete genomic locus as a transgene to produce physiological levels of tissue-specific, sustained expression. However, the number of vector systems capable of delivering complete genomic loci is limited. The development of the infectious bacterial artificial chromosome system, a herpes simplex virus type 1-based vector that provides efficient infectious delivery and expression of bacterial artificial chromosome or P1-based artificial chromosome clone inserts, is reviewed. This system currently represents the leading technology capable of infectious delivery and expression of complete genomic DNA loci above 100 kb.


Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming.
Progesterone promotes differentiation coupled to proliferation and prosurvival in the breast, but inhibits estrogen-driven growth in the reproductive tract and ovaries. Herein, it is demonstrated, using progesterone receptor (PR) isoform-specific ovarian cancer model systems, that PR-A and PR-B promote distinct gene expression profiles that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target gene p21 (CDKN1A) are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15 (CDKN2B). Chromatin immunoprecipitation (ChIP) assays performed on PR isoform-specific cells demonstrated that while each isoform is recruited to the same PRE-containing region of the p21 promoter in response to progestin, only PR-B elicits active chromatin marks. Overexpression of constitutively active FOXO1 in PR-A-expressing cells conferred robust ligand-dependent upregulation of the PR-B target genes GZMA, IGFBP1, and p21, and induced cellular senescence. In the presence of endogenous active FOXO1, PR-A was phosphorylated on Ser294 and transactivated PR-B at PR-B target genes; these events were blocked by the FOXO1 inhibitor (AS1842856). PR isoform-specific regulation of the FOXO1/p21 axis recapitulated in human primary ovarian tumor explants treated with progestin; loss of progestin sensitivity correlated with high AKT activity. This study indicates FOXO1 as a critical component for progesterone signaling to promote cellular senescence and reveals a novel mechanism for transcription factor control of hormone sensitivity.


The antiatherogenic, renal protective and immunomodulatory effects of purslane, pumpkin and flax seeds on hypercholesterolemic rats.
Atherosclerosis remains one of the leading causes of death all over the world. Flax, pumpkin and purslane seeds are rich sources of unsaturated fatty acids, antioxidants and fibers, known to have antiatherogenic activities. This study was to examine the efficiency of using either flax/pumpkin or purslane/pumpkin seed mixture (components of ω-3 and ω-6) on hyperlipidemia, kidney function and as immunomodulators in rats fed high cholesterol diets. 40 male albino rats were divided into four groups: control group, hypercholesterolemic rats, fed the balanced diet supplemented with cholesterol at a dose level of 2 g/100 g diet; the other two groups of animals fed the same previous hypercholesterolemic diet supplemented with either flax/pumpkin seed mixture or pumpkin/purslane seed mixture at ratio of (5/1) (ω-3 and ω-6). The present study showed that 2% cholesterol administration caused a significant increase in total cholesterol, total lipids, and triacylglycerol in both serum and liver. Serum phospholipids, LDL-C, and atherogenic index AI also significantly increased compared to control group. Cholesterol-enriched diet significantly increased serum urea, creatinine, sodium and potassium levels as well as significantly increased serum IgG and IgM compared to healthy control. Consumption of flax/pumpkin or purslane/pumpkin seed mixtures by hypercholesterolemic rats resulted in a significantly decrement in lipid parameters and significant improvement in IgG and IgM levels as compared with hypercholesterolemic rats. Our results suggests that both flax/pumpkin and purslane/pumpkin seed mixtures had anti-atherogenic hypolipidemic and immunmodulator effects which were probably mediated by unsaturated fatty acids (including alpha linolenic acid) present in seed mixture.


Thyrotropin concentration predicts outcome in critical illness.
Concentrations of thyrotropin, total thyroxine, total tri-iodothyronine and cortisol were measured on admission to an intensive care unit in 200 consecutive patients who did not receive dopamine. Thyrotropin concentration was subnormal (< 0.4 mU.l-1) in 25 patients (12%) and increased (> 5.0 mU.l-1) in 27 (13%). Mortality in these groups differed 22-fold (88% and 4% respectively) despite comparable APACHE II outcome predictions (51% and 32%). Thyrotropin concentration correlated positively with total thyroxine concentration (r = 0.46, p < 0.001) and negatively with cortisol concentration (r = -0.56, p < 0.001). In 15 of the patients with increased thyrotropin concentration on admission, repeat measurements were made on recovery and were normal in 13. The high frequency of abnormal thyrotropin concentrations casts doubt on the assumption of euthyroidism in critical illness. Admission thyrotropin concentration is of prognostic value in critically ill patients.


Computed tomography in the elderly. 3. Affective disorder.
Clinical and computed tomographic (CT) data on a consecutive series of 41 elderly patients with affective disorders are presented, and comparisons made with a group of 50 healthy controls. In both groups ventricular size increased with age, but only in the controls was there an age correlation with sulcal widening. Using clinical and radiological criteria, the prevalence of cerebrovascular disease in the patient group was 12 per cent. A sub-group of patients with enlarged ventricles emerged, whose first depression began later in life, and who at the time of this study were older and showed more "endogenous" features than the remainder. It is suggested that this provides further evidence that organic cerebral factors may have aetiological significance in some depressions of old age.


PDZ domain-mediated protein interactions: therapeutic targets in neurological disorders.
Protein-protein interactions are critical for cellular functioning, and their deregulation is involved in several diseases. Targeting these protein interacting domains could be a promising approach in drug designing. One such domain, the PDZ domain is encoded by several proteins of the nervous system in particular at the postsynaptic density site of neurons where they contribute to signal transduction pathways and neurotransmission. Since PDZ domains have well-defined binding sites, often corresponding to short amino acid motifs at the C-termini of target partner proteins, they provide promising targets for drug discovery. Viruses are art master in manipulating the signaling machinery of the cell they infect. Some of them such as rabies virus which promotes neuron survival by disrupting peculiar PDZ complexes can serve as a source of inspiration for the design of new neuroprotective drugs. This review highlights PDZ-mediated protein interactions in nervous system and their therapeutic potential.


[High protein and vitamin cereal bars: enzymatic and vitamins C and E stability during storage].
Cereal-based products have become an excellent vehicle for delivering tasty functional food ingredients to busy consumers. One emerging trends is food products formulates with soy protein because of its proven health benefits. Because of the potential usefulness of these products, it was considered of interest to determine the stability of cereal bars based on soy protein, wheat germ and oat, enriched with vitamin C (ascorbic acid) and E (acetate of a-tocopherol 50%), during the storage. Three films with different properties of barrier (A: PET/PEBD; B: PETMET/PEBD; C: PET/PEBD/ALIPEBD) were used as packing and the cereal bars were stored at temperature (25 +/- 2 degrees C) and relative humidity ambient (56%) for six months. The stability of vitamin C, vitamin E and, its lipase and peroxidase activity was verified. During the study, the cereal bars packed in three tested films presented retention in the vitamin C lesser that 50%. However, packing structuralized with aluminum (C) leaf provided to minor speed of reaction during the storage, k = 0.00437 (-day), and greater time of half-life (146 days). The vitamin E (acetate of a-tocopherol) in the cereal bars presented a little variation during the storage. It had a significant (p < or = 0.05) increase in the peroxidase activity at 90 days of storage in the packages tested, while that the lipase activity demonstrated no significant increase during the period studied.


Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice.
The antinociceptive effects of various cannabinoids, alone and in combination with opiates, were evaluated in antinociceptive tests in mice. The cannabinoids tested produce marked antinociceptive effects after i.t. administration to mice. The rank order of potency for the drugs using the tail-flick test was levonantradol greater than CP-55,940 = CP-56,667 greater than 11-hydroxy-delta 9-THC greater than delta 9-THC greater than delta 8-THC; dextronantradol was inactive at a dose of 25 micrograms/mouse. Respective ED50 values in the tail-flick test were 0.4, 12.3, 4.2, 15, 45 and 72 micrograms/mouse. Although pretreatment with morphine somewhat enhanced the effects of delta 9-THC, pretreatment of the mice with naloxone (1 mg/kg s.c. or 1 micrograms/mouse i.t.) failed to block the antinociceptive effects of the cannabinoids, indicating that the cannabinoid-induced antinociception does not occur due to direct interaction with the opiate receptor. Pretreatment of mice with 3.13 micrograms/mouse and 6.25 micrograms/mouse of delta 9-THC shifted the ED50 of morphine to 0.15 and 0.05 micrograms/mouse, respectively (a 4-and a 12-fold shift). The shifts in the dose-response curve of the morphine were parallel. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of the combination of 6.25 micrograms of delta 9-THC with morphine. The AD50 for naloxone blockade of the drug combination was 0.24 (0.06-0.94) mg/kg s.c. and the pA2 was 7.7 (6.7-8.9). The pA2 for naloxone blockade of the dimethylsulfoxide-morphine combination was 6.9 (5.7-8.1).(ABSTRACT TRUNCATED AT 250 WORDS)


Higher-order sensorimotor circuit of the brain's global network supports human consciousness.
Consciousness is a mental characteristic of the human mind, whose exact neural features remain unclear. We aimed to identify the critical nodes within the brain's global functional network that support consciousness. To that end, we collected a large fMRI resting state dataset with subjects in at least one of the following three consciousness states: preserved (including the healthy awake state, and patients with a brain injury history (BI) that is fully conscious), reduced (including the N1-sleep state, and minimally conscious state), and lost (including the N3-sleep state, anesthesia, and unresponsive wakefulness state). We also included a unique dataset of subjects in rapid eye movement sleep state (REM-sleep) to test for the presence of consciousness with minimum movements and sensory input. To identify critical nodes, i.e., hubs, within the brain's global functional network, we used a graph-theoretical measure of degree centrality conjoined with ROI-based functional connectivity. Using these methods, we identified various higher-order sensory and motor regions including the supplementary motor area, bilateral supramarginal gyrus (part of inferior parietal lobule), supragenual/dorsal anterior cingulate cortex, and left middle temporal gyrus, that could be important hubs whose degree centrality was significantly reduced when consciousness was reduced or absent. Additionally, we identified a sensorimotor circuit, in which the functional connectivity among these regions was significantly correlated with levels of consciousness across the different groups, and remained present in the REM-sleep group. Taken together, we demonstrated that regions forming a higher-order sensorimotor integration circuit are involved in supporting consciousness within the brain's global functional network. That offers novel and more mechanism-guided treatment targets for disorders of consciousness.


Continuous flash suppression modulates cortical activity in early visual cortex.
A salient visual stimulus can be rendered invisible by presenting it to one eye while flashing a mask to the other eye. This procedure, called continuous flash suppression (CFS), has been proposed as an ideal way of studying awareness as it can make a stimulus imperceptible for extended periods of time. Previous studies have reported robust suppression of cortical activity in higher visual areas during CFS, but the role of primary visual cortex (V1) is still controversial. In this study, we resolve this controversy on the role of V1 in CFS and also begin characterizing the computational processes underlying CFS. Early visual cortical activity was measured with functional magnetic resonance imaging while human subjects viewed stimuli composed of target and mask, presented to the same or different eyes. Functional MRI responses in early visual cortex were smaller when target and mask were in different eyes compared with the same eye, not only for the lowest contrast target rendered invisible by CFS, but also for higher contrast targets, which were visible even when presented to the eye opposite the mask. We infer that CFS is based on modulating the gain of neural responses, akin to reducing target contrast.


Diaphragm and lubricant gel acceptance, skills and patterns of use among women in an effectiveness trial in Southern Africa.
We examined diaphragm and gel-related skills, patterns of use, and problems, among women who participated in the MIRA study, a multisite phase III diaphragm trial in Zimbabwe and South Africa. We evaluated whether baseline characteristics were associated with the ability to correctly insert/remove the diaphragm prior to randomisation by means of multivariate logistic regression modeling. Employing face-to-face interviews with intervention arm participants, patterns of use and comfort using the products were measured at Month 3 and Exit, and reported problems with the products were assessed quarterly. At baseline, 72.5% of women correctly inserted/removed the diaphragm within one attempt, and this skill was most strongly associated with the Johannesburg study site. At exit, over 90% of intervention women were very comfortable inserting, wearing, cleaning and removing the diaphragm; however, 31.8% reported usual removal of the diaphragm before the prescribed six hours after sex. During the 12-24 month follow-up period there were only 133 (<1%) reported problems with the diaphragm and gel over 14,544 follow-up visits. Diaphragm skills were easily acquired and few problems were reported during the course of the trial. Reviving the diaphragm as a contraceptive option or as a reusable microbicide delivery mechanism seems feasible in these settings.


Estimating the probability of the presence of a signal of interest in multiresolution single- and multiband image denoising.
We develop three novel wavelet domain denoising methods for subband-adaptive, spatially-adaptive and multivalued image denoising. The core of our approach is the estimation of the probability that a given coefficient contains a significant noise-free component, which we call "signal of interest." In this respect, we analyze cases where the probability of signal presence is 1) fixed per subband, 2) conditioned on a local spatial context, and 3) conditioned on information from multiple image bands. All the probabilities are estimated assuming a generalized Laplacian prior for noise-free subband data and additive white Gaussian noise. The results demonstrate that the new subband-adaptive shrinkage function outperforms Bayesian thresholding approaches in terms of mean-squared error. The spatially adaptive version of the proposed method yields better results than the existing spatially adaptive ones of similar and higher complexity. The performance on color and on multispectral images is superior with respect to recent multiband wavelet thresholding.


Apparent bacteriophage-binding region of an Escherichia coli K-12 outer membrane protein.
The 325-residue OmpA protein is one of the major outer membrane proteins of Escherichia coli. It serves as the receptor for several T-even-like phages and is required for the action of certain colicins and for the stabilization of mating aggregates in conjugation. We have isolated two mutant alleles of the cloned ompA gene which produce a protein that no longer functions as a phage receptor. Bacteria possessing the mutant proteins were unable to bind the phages, either reversibly or irreversibly. However, both proteins still functioned in conjugation, and one of them conferred colicin L sensitivity. DNA sequence analysis showed that the phage-resistant, colicin-sensitive phenotype exhibited by one mutant was due to the amino acid substitution Gly leads to Arg at position 70. The second mutant, which contained a tandem duplication, encodes a larger product with 8 additional amino acid residues, 7 of which are a repeat of the sequence between residues 57 and 63. In contrast to the wild-type OmpA protein, this derivative was partially digested by pronase when intact cells were treated with the enzyme. The protease removed 64 NH2-terminal residues, thereby indicating that this part of the protein is exposed to the outside. It is argued that the phage receptor site is most likely situated around residues 60 to 70 of the OmpA protein and that the alterations characterized have directly affected this site.


Bone fragility and osteoporosis in children and young adults.
Osteoporosis is a metabolic bone disorder which increases fragility fracture risk. Elderly individuals, especially postmenopausal women, are particularly susceptible to osteoporosis. Although rare, osteoporosis in children and young adults is becoming increasingly evident, highlighting the need for timely diagnosis, management and follow-up. Early-onset osteoporosis is defined as the presence of a low BMD (Z-score of ≤ -2.0 in individuals aged < 20 years; T-score of ≤ -2.5 in those aged between 20 to 50 years) accompanied by a clinically significant fracture history, or the presence of low-energy vertebral compression fractures even in the absence of osteoporosis. Affected children and young adults should undergo a thorough diagnostic workup, including collection of clinical history, radiography, biochemical investigation and possibly bone biopsy. Once secondary factors and comorbidities are excluded, genetic testing should be considered to determine the possibility of an underlying monogenic cause. Defects in genes related to type I collagen biosynthesis are the commonest contributors of primary osteoporosis, followed by loss-of-function variants in genes encoding key regulatory proteins of canonical WNT signalling (specifically LRP5 and WNT1), the actin-binding plastin-3 protein (encoded by PLS3) resulting in X-linked osteoporosis, and the more recent sphingomyelin synthase 2 (encoded by SGMS2) which is critical for signal transduction affecting sphingomyelin metabolism. Despite these discoveries, genetic causes and underlying mechanisms in early-onset osteoporosis remain largely unknown, and if no causal gene is identified, early-onset osteoporosis is deemed idiopathic. This calls for further research to unravel the molecular mechanisms driving early-onset osteoporosis that consequently will aid in patient management and individualised targeted therapy.


Classification of response regulators based on their surface properties.
The two-component signal transduction system is a ubiquitous signaling module present in most prokaryotic and some eukaryotic systems. Two conserved components, a histidine protein kinase (HPK) protein and a response regulator (RR) protein, function as a biological switch, sensing and responding to changes in the environment, thereby eliciting a specific response. Extensive studies have classified the HPK and RR proteins using primary sequence characteristics, domain identity, domain organization, and biological function. We propose that structural analysis of the surface properties of the highly conserved receiver domain of RRs can be used to build on previous classification methods. Our studies of the OmpR subfamily RRs in Bacillus subtilis and Escherichia coli reveal a notable correlation between the RR receiver domain surface classification and previous classification of cognate HPK proteins. We have extended these studies to analyze the receiver domains of all predicted RR proteins in the marine-dwelling bacterium Vibrio vulnificus.


Etiology of Neuromuscular Fatigue After Repeated Sprints Depends on Exercise Modality.
To compare neuromuscular fatigue induced by repeated-sprint running vs cycling. Eleven active male participants performed 2 repeated-maximal-sprint protocols (5×6 s, 24-s rest periods, 4 sets, 3 min between sets), 1 in running (treadmill) and 1 in cycling (cycle ergometer). Neuromuscular function, evaluated before (PRE); 30 s after the first (S1), the second (S2), and the last set (LAST); and 5 min after the last set (POST5) determined the knee-extensor maximal voluntary torque (MVC); voluntary activation (VA); single-twitch (Tw), high- (Db100), and low- (Db10) frequency torque; and maximal muscle compound action potential (M-wave) amplitude and duration of vastus lateralis. Peak power output decreased from 14.6 ± 2.2 to 12.4 ± 2.5 W/kg in cycling (P < .01) and from 21.4 ± 2.6 to 15.2 ± 2.6 W/kg in running (P < .001). MVC declined significantly from S1 in running but only from LAST in cycling. VA decreased after S2 (~-7%, P < .05) and LAST (~-9%, P < .01) set in repeated-sprint running and did not change in cycling. Tw, Db100, and Db10/Db100 decreased to a similar extent in both protocols (all P < .001 post-LAST). Both protocols induced a similar level of peripheral fatigue (ie, low-frequency peripheral fatigue, no changes in M-wave characteristics), while underlying mechanisms probably differed. Central fatigue was found only after running. Findings about neuromuscular fatigue resulting from RS cycling cannot be transferred to RS running.


CK1δ/GSK3β/FBXW7α axis promotes degradation of the ZNF322A oncoprotein to suppress lung cancer progression.
Overexpression of Cys2His2 zinc-finger 322A (ZNF322A) oncogenic transcription factor is associated with lung tumorigenesis. However, the mechanism of ZNF322A overexpression remains poorly understood. Here, we discover that protein stability of ZNF322A is regulated by coordinated phosphorylation and ubiquitination through the CK1δ/GSK3β/FBXW7α axis. CK1δ and GSK3β kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7α leading to ZNF322A protein destruction. Overexpression of FBXW7α induces ZNF322A protein degradation, thereby blocks ZNF322A transcription activity and suppresses ZNF322A-induced tumor growth and metastasis in vitro and in vivo. Clinically, overexpression of ZNF322A correlates with low FBXW7α or defective CK1δ/GSK3β-mediated phosphorylation in lung cancer patients. Multivariate Cox regression analysis indicates that patients with ZNF322A high/FBXW7 low expression profile can be used as an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of ZNF322A oncoprotein destruction regulated by the CK1δ/GSK3β/FBXW7α axis. Deregulation of this signaling axis results in ZNF322A overexpression and promotes cancer progression.


Postpartum GAD is a risk factor for postpartum MDD: the course and longitudinal relationships of postpartum GAD and MDD.
The objective was to examine the course and longitudinal associations of generalized anxiety disorder (GAD) and major depressive disorder (MDD) in mothers over the postpartum 2 years. Using a prospective naturalistic design, 296 mothers recruited from a large community pool were assessed for GAD and MDD at 3, 6, 10, 14, and 24 months postpartum. Structured clinical interviews were used for diagnoses, and symptoms were assessed using self-report questionnaires. Logistic regression analyses were used to examine diagnostic stability and longitudinal relations, and latent variable modeling was employed to examine change in symptoms. MDD without co-occurring GAD, GAD without co-occurring MDD, and co-occurring GAD and MDD, displayed significant stability during the postpartum period. Whereas MDD did not predict subsequent GAD, GAD predicted subsequent MDD (in the form of GAD + MDD). Those with GAD + MDD at 3 months postpartum were significantly less likely to be diagnosis free during the follow-up period than those in other diagnostic categories. At the symptom level, symptoms of GAD were more trait-like than those of depression. Postpartum GAD and MDD are relatively stable conditions, and GAD is a risk factor for MDD but not vice versa. Given the tendency of MDD and GAD to be persistent, especially when comorbid, and the increased risk for MDD in mothers with GAD, as well as the potential negative effects of cumulative exposure to maternal depression and anxiety on child development, the present findings clearly highlight the need for screening and treatment of GAD in addition to MDD during the postpartum period.


Safety in chiropractic practice. Part II: Treatment to the upper neck and the rate of cerebrovascular incidents.
Circumstances surrounding cerebrovascular accidents after cervical manipulation need further clarification. In particular, more information is needed on the importance of specific techniques. To estimate the occurrence of cerebrovascular incidents (CVI) after chiropractic treatment to the cervical spine in relation to both the estimated number of treatments given to the upper and lower cervical spine and the techniques used. Retrospective data were collected from questionnaires covering the period 1978-1988 inclusive; in a second survey, chiropractors provided information obtained through inspection of their own case records. All 226 practicing members of the Danish Chiropractors' Association in 1989 (response rate 54%) and a random sample of 40 chiropractors (response rate 72.5%) from the same population were invited to participate in the study. Survey 1: Estimated proportion of consultations that involved treatment to the cervical spine, number and clinical particulars of CVI. Survey 2: proportion of treatment sessions on a specific day that included the neck, upper/lower neck and the type of treatment (nonrotation or rotation techniques) preferred. Among the respondents, the reported incidence of CVI between 1981 and 1988 was about one for every 120,000 cervical treatment sessions, and SMT to the upper neck was about four times more commonly associated with CVI than treatment of the lower neck. Rotation procedures to the upper cervical spine were almost twice as often linked to CVI as nonrotation procedures of that area. Although there seems to be a link between upper cervical rotation manipulative techniques and cerebrovascular incidents, treatment to the lower neck and the use of other techniques are implicated as well.


Oxidative stress, obesity, and breast cancer risk: results from the Shanghai Women's Health Study.
Increased reactive oxygen species may exhaust the antioxidant capability of human defense systems, leading to oxidative stress and cancer development. Urinary F2-isoprostanes, secondary end products of lipid peroxidation, are more accurate markers of oxidative stress than other available biomarkers. No prospective study has investigated whether levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP) and its metabolite 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (15-F(2t)-IsoPM) are related to breast cancer risk. We conducted a nested case-control study within the Shanghai Women's Health Study, a population-based cohort study of 74,942 Chinese women between 40 and 70 years of age. Prediagnostic urinary 15-F(2t)-IsoP and 15-F(2t)-IsoPM were measured by gas chromatography mass spectrometry for 436 breast cancer cases and 852 individually matched controls. Urinary excretion of isoprostanes was not significantly different between cases and controls. However, among overweight women, levels of isoprostanes were positively associated with breast cancer risk, which became stronger with increasing body mass index (BMI). Among women with a BMI > or = 29, the odds ratio (OR) increased to 10.27 (95% CI, 2.41 to 43.80) for the highest compared with the lowest tertile of 15-F(2t)-IsoPM (P for trend = .003; P for interaction = .0004). In contrast, 15-F(2t)-IsoP and 15-F(2t)-IsoPM were inversely associated with breast cancer risk among nonoverweight women. Among women with a BMI < or = 23, breast cancer risk was reduced with increasing 15-F(2t)-IsoP levels in a dose-response manner (P for trend = .006), with an OR of 0.46 (95% CI, 0.26 to 0.80) for the highest tertile versus the lowest (P for interaction = .006). Our results suggest that the role of oxidative stress in breast cancer development may depend on adiposity.


Diarrhea in young children from low-income countries leads to large-scale alterations in intestinal microbiota composition.
Diarrheal diseases continue to contribute significantly to morbidity and mortality in infants and young children in developing countries. There is an urgent need to better understand the contributions of novel, potentially uncultured, diarrheal pathogens to severe diarrheal disease, as well as distortions in normal gut microbiota composition that might facilitate severe disease. We use high throughput 16S rRNA gene sequencing to compare fecal microbiota composition in children under five years of age who have been diagnosed with moderate to severe diarrhea (MSD) with the microbiota from diarrhea-free controls. Our study includes 992 children from four low-income countries in West and East Africa, and Southeast Asia. Known pathogens, as well as bacteria currently not considered as important diarrhea-causing pathogens, are positively associated with MSD, and these include Escherichia/Shigella, and Granulicatella species, and Streptococcus mitis/pneumoniae groups. In both cases and controls, there tend to be distinct negative correlations between facultative anaerobic lineages and obligate anaerobic lineages. Overall genus-level microbiota composition exhibit a shift in controls from low to high levels of Prevotella and in MSD cases from high to low levels of Escherichia/Shigella in younger versus older children; however, there was significant variation among many genera by both site and age. Our findings expand the current understanding of microbiota-associated diarrhea pathogenicity in young children from developing countries. Our findings are necessarily based on correlative analyses and must be further validated through epidemiological and molecular techniques.


Telomere length: a review of methods for measurement.
The exciting discovery that telomere shortening is associated with many health conditions and that telomere lengths can be altered in response to social and environmental exposures has underscored the need for methods to accurately and consistently quantify telomere length. The purpose of this article is to provide a comprehensive summary that compares and contrasts the current technologies used to assess telomere length. Multiple methods have been developed for the study of telomeres. These techniques include quantification of telomere length by terminal restriction fragmentation-which was one of the earliest tools used for length assessment-making it the gold standard in telomere biology. Quantitative polymerase chain reaction provides the advantage of being able to use smaller amounts of DNA, thereby making it amenable to epidemiology studies involving large numbers of people. An alternative method uses fluorescent probes to quantify not only mean telomere lengths but also chromosome-specific telomere lengths; however, the downside of this approach is that it can only be used on mitotically active cells. Additional methods that permit assessment of the length of a subset of chromosome-specific telomeres or the subset of telomeres that demonstrate shortening are also reviewed. Given the increased utility for telomere assessments as a biomarker in physiological, psychological, and biobehavioral research, it is important that investigators become familiar with the methodological nuances of the various procedures used for measuring telomere length. This will ensure that they are empowered to select an optimal assessment approach to meet the needs of their study designs. Gaining a better understanding of the benefits and drawbacks of various measurement techniques is important not only in individual studies, but also to further establish the science of telomere associations with biobehavioral phenomena.


Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.
Tumour necrosis factor alpha (TNF alpha) is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy. In support of this hypothesis, we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha (cA2). We now report the results of a four-centre, randomised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis. The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, an amalgam of six clinical, observational, and laboratory variables. Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time, compared with 11 of 25 patients treated with low-dose cA2 (p = 0.0083) and 19 of 24 patients treated with high-dose cA2 (p < 0.0001). Over half of the high-dose cA2 patients responded by the more stringent 50% Paulus criteria at this time (p = 0.0005). The magnitude of these responses was impressive, with maximum mean improvements in individual disease-activity assessments, such as tender or swollen-joint counts and in serum C-reactive protein, exceeding 60% for patients on high-dose treatment. There were two severe adverse events. 1 patient on 1 mg/kg cA2 developed pneumonia ("possibly" treatment-related) and 1 on 10 mg/kg had a fracture ("probably not" treatment-related). The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis.


Detection of soluble ST2 in human follicular fluid and luteinized granulosa cells.
Follicular fluid (FF) contains various cytokines that are involved with folliculogenesis, some of which have been shown to be associated with oocyte quality and the implantation potential of a resulting embryo. Several IL-1 family members have previously been identified in FF. This study investigates a newly identified member of the family, IL-33, and its receptor ST2, comparing values to those of FF Granulocyte-Colony Stimulating Factor (G-CSF)--a known predictor of Assisted Reproductive Technology (ART) success. FF was collected from patients undergoing in vitro fertilisation/intra-cytoplasmic sperm injection (IVF/ICSI) at oocyte retrieval to analyse IL-33 and sST2 expression in human follicles. sST2, but not IL-33, is highly increased in the FF compared to plasma levels (up to 7.9-fold), with higher levels in larger follicles (p<0.05). Furthermore, we identify that human luteinised granulosa cells are one possible source of the FF sST2, as these cells express and secrete sST2 when cultured ex vivo. FF associated with oocytes which when fertilised develop into good quality embryos have higher sST2 levels than those which are graded average (p<0.01). These embryos were transferred to the patient and levels of FF sST2 compared between successful and unsuccessful ICSI cycles. However unlike G-CSF, sST2 levels cannot be used to predict cycle outcome.


Adhesion of platelets to artificial surfaces: effect of red cells.
Adhesion of platelets to several polymer- and protein-coated glass surfaces has been studied in vitro. The apparatus consists of a cylindrical probe rotating in a test tube containing the platelet medium and allows close control of fluid shear and mass transport. Suspensions of washed pig platelets constitute the basic platelet medium, and can be modified by adding back red cells and plasma proteins. Adhesion is measured via 51Cr-labeling of platelets. In the absence of red cells, identical low levels of adhesion were seen on all surfaces and saturation was reached within 2 min. In the presence of red cells, adhesion was greater. Saturation on all surfaces except fibrinogen and collagen again occurred within 2 min. The adhesion levels on polymer surfaces and glass were indistinguishable, while those on albumin were lower and those on fibrinogen were higher. Collagen was the most reactive surface. It did not equilibrate within 15 min., and kinetic data indicated a platelet diffusivity strongly dependent on hematocrit. These effects were attributed to rotational and translational motion of the red cells causing increased diffusion and surface-platelet collision energy.


Dating app use among rural men who have sex with men and its relationship to HIV prevention and risk behaviors: a mixed-methods analysis.
Men who have sex with men (MSM) in rural areas have limited access to HIV prevention and education resources. Given the growing usage of mobile dating apps among the wider MSM population, this research sought to explore their use among MSM in rural areas and their potential for delivering HIV prevention information. Participants were recruited from different areas of the rural Southern USA. This mixed-methods study consisted of an online survey (n=85) and follow-up qualitative phone interviews with 20 survey respondents. The survey assessed dating app use, sexual behaviors, and pre-exposure prophylaxis (PrEP) awareness, usage, and attitudes among MSM in the rural, Southern USA. Interviews explored perceptions of dating apps and their potential value as a source of health and HIV prevention information. Among survey respondents, 74% had used a dating app, with Grindr being the most frequently used app. Of individuals who were in a relationship, 41% had met their current partner online. Using a dating app was associated with having a greater number of sexual partners. Three-quarters of participants had heard of PrEP, but only 7% had ever received a prescription for it and less than one-third reported that it would be easy to get PrEP if they wanted it. Dating app users were more likely than non-app users to have more positive attitudes toward taking PrEP and interest in taking PrEP. In qualitative interviews, respondents expressed support for integrating HIV prevention information into dating apps. Dating app usage is high among rural MSM. Individuals who use these apps have more sexual partners and also are more interested in PrEP for HIV prevention, suggesting that this is an ideal group to target for PrEP education and interventions. This could be especially beneficial for MSM in rural areas, as most have difficulty accessing PrEP and PrEP education.


High viral load of human bocavirus correlates with duration of wheezing in children with severe lower respiratory tract infection.
Human bocavirus (HBoV) is a newly discovered parvovirus and increasing evidences are available to support its role as an etiologic agent in lower respiratory tract infection (LRTI). The objective of this study is to assess the impact of HBoV viral load on clinical characteristics in children who were HBoV positive and suffered severe LRTI. Lower respiratory tract aspirates from 186 hospitalized children with severe LRTI were obtained by bronchoscopy. HBoVs were detected by real-time PCR and other 10 infectious agents were examined using PCR and/or direct fluorescent assay. Thirty-one patients (24.6%) were tested positive for HBoV in the respiratory tract aspirates. Fifteen samples had a high viral load (>10(4) copies/mL) and the other sixteen samples had a low viral load (<10(4) copies/mL). The duration of presented wheezing and hospitalization was longer in children with high viral load of HBoV than that in children with low viral load. The days of wheezing showed a correlation with viral load of HBoV. We confirmed that HBoV was frequently detected in patients with severe LRTI. Wheezing was one of the most common symptoms presented by patients with positive HBoV. A high HBoV viral load could be an etiologic agent for LRTI, which led to more severe lower respiratory tract symptom, longer duration of wheezing and hospitalization.


Methods for comparison of cost data.
Researchers are increasingly interested in examining costs of care, and large administrative and clinical databases have made relevant data readily available. Because a few patients incur high costs relative to most patients, the distribution of cost data is often skewed. How robust are the usual methods of cost analysis against the skewed distribution of cost data? To determine the methods commonly used for comparing cost data, describe their limitations, and provide an alternate method of analysis. Review of statistical methods used in studies of medical costs published in medical journals between January 1991 and January 1996. Description of a Z-score method appropriate for testing the equality of mean costs between two log-normal samples; and reanalysis of published two-sample comparison results done by using the Z-score method. For two-sample comparisons, three methods were commonly used: the Student t-test on untransformed costs, the Wilcoxon test on untransformed costs, and the Student t-test on log-transformed costs. The t-test on untransformed costs ignores the skewness in cost data, the Wilcoxon test ignores unequal variances, and the t-test on log-transformed costs tests the wrong null hypothesis unless variances in the log-scale are equal. Eleven articles included two-sample tests and had enough information to allow reanalysis of the data using the Z-score method. These articles described a total of 23 Wilcoxon tests and 24 t-tests on untransformed costs. Most results did not change on reanalysis, but six results changed enough to alter conclusions. Specifically, reanalysis of data for which one Wilcoxon test had shown statistically significant results showed nonsignificant results; reanalysis of data for which two Wilcoxon tests had shown nonsignificant results showed statistically significant results. In articles that used t-tests on untransformed costs, two statistically significant results became nonsignificant on reanalysis and one nonsignificant result became statistically significant on reanalysis. The methods commonly used to compare costs of two groups have limitations. Some limitations may change some conclusions, and the direction of the change cannot be predicted. The Z-score method is designed to adjust for skewness in cost data and is appropriate for comparing means of log-normally distributed cost data.


Integration of simian virus 40 into cellular DNA occurs at or near topoisomerase II cleavage hot spots induced by VM-26 (teniposide).
Inhibition of DNA topoisomerase II in simian virus 40 (SV40)-infected BSC-1 cells with a topoisomerase II poison, VM-26 (teniposide), resulted in rapid conversion of a population of the SV40 DNA into a high-molecular-weight form. Characterization of this high-molecular-weight form of SV40 DNA suggests that it is linear, double stranded, and a recombinant with SV40 DNA sequences covalently joined to cellular DNA. The majority of the integrants contain fewer than two tandem copies of SV40 DNA. Neither DNA-damaging agents, such as mitomycin and UV, nor the topoisomerase I inhibitor camptothecin induced detectable integration in this system. In addition, the recombination junctions within the SV40 portion of the integrants correlate with VM-26-induced, topoisomerase II cleavage hot spots on SV40 DNA. These results suggest a direct and specific role for topoisomerase II and possibly the enzyme-inhibitor-DNA ternary cleavable complex in integration. The propensity of poisoned topoisomerase II to induce viral integration also suggests a role for topoisomerase II in a pathway of chromosomal DNA rearrangements.


Risk factor-based screening compared to universal screening for gestational diabetes mellitus in marginalized Burman and Karen populations on the Thailand-Myanmar border: An observational cohort.
Background: Gestational diabetes mellitus (GDM) contributes to maternal and neonatal morbidity. As data from marginalized populations remains scarce, this study compares risk-factor-based to universal GDM screening in a low resource setting. Methods: This is a secondary analysis of data from a prospective preterm birth cohort. Pregnant women were enrolled in the first trimester and completed a 75g oral glucose tolerance test (OGTT) at 24-32 weeks' gestation. To define GDM cases, Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO trial) criteria were used. All GDM positive cases were treated. Sensitivity and specificity of risk-factor-based selection for screening (criteria: age ≥30y, obesity (Body mass index (BMI) ≥27.5kg/m 2), previous GDM, 1 st degree relative with diabetes, previous macrosomia (≥4kg), previous stillbirth, or symphysis-fundal height ≥90th percentile) was compared to universal screening using the OGTT as the gold standard. Adverse maternal and neonatal outcomes were compared by GDM status. Results: GDM prevalence was 13.4% (50/374) (95% CI: 10.3-17.2). Three quarters of women had at least one risk factor (n=271 women), with 37/50 OGTT positive cases correctly identified: sensitivity 74.0% (59.7-85.4) and specificity 27.8% (3.0-33.0). Burman women (self-identified) accounted for 29.1% of the cohort population, but 38.0% of GDM cases. Percentiles for birthweight (p=0.004), head circumference (p=0.002), and weight-length ratio (p=0.030) were higher in newborns of GDM positive compared with non-GDM mothers. 21.7% (75/346) of newborns in the cohort were small-for-gestational age (≤10 th percentile). In Burman women, overweight/obese BMI was associated with a significantly increased adjusted odds ratio 5.03 (95% CI: 1.43-17.64) for GDM compared with normal weight, whereas in Karen women, the trend in association was similar but not significant (OR 2.36; 95% CI 0.95-5.89). Conclusions: Risk-factor-based screening missed one in four GDM positive women. Considering the benefits of early detection of GDM and the limited additional cost of universal screening, a two-step screening program was implemented.


A Novel Missense Mutation in the ALDH13 Gene Causes Anophthalmia in Two Unrelated Iranian Consanguineous Families.
Anophthalmia or microphthalmia (A/M) is a rare group of congenital/developmental ocular malformations, characterized by absent or small eye within the orbit affecting one or both eyes. It has complex etiology with chromosomal, monogenic with high heterogeneity, and environmental causes. We performed genome SNP-array analysis followed by autozygosity mapping and sequencing in the members of two families in which three individuals are suffering from severe bilateral anophthalmia. The genetic analysis revealed a novel missense c.709G>A mutation in exon 7 of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), causing a substitution of glycine (Gly) to arginine (Arg) at residue 237. This study consolidates the importance of ALDH1A3 gene screening in autosomal recessive anophthalmia. This variation may also be suggestive of a founder effect in the southeastern area of Iran.


Neoadjuvant Chemotherapy Reinforces Antitumour T cell Response in Urothelial Urinary Bladder Cancer.
Evidence indicates that neoadjuvant chemotherapy (NAC) may promote antitumour immune responses by activating T cells. The tumour-draining sentinel node (SN) is a key site to study tumour-specific T cell activation, being the primary immunological barrier against the tumour. In this prospective study, we set out to elucidate the effects of NAC on T cell subsets in the SNs of patients with muscle-invasive urothelial bladder cancer. We found that CD8+ effector T (Teff) cell exhaustion was reduced after NAC treatment, while cytotoxicity was increased. Additionally, in complete responders (CR patients), these cells were functionally committed effectors, as displayed by epigenetic analysis. In CD4+ Teffs, NAC treatment was associated with increased clonal expansion of tumour-specific SN-derived cells, as demonstrated by a specific cell reactivity assay. In contrast, we observed an attenuating effect of NAC on regulatory T cells (Tregs) with a dose-dependent decrease in Treg frequency and reduced effector molecule expression in the remaining Tregs. In addition, multicolour flow cytometry analysis revealed that CR patients had higher Teff to activated Treg ratio, promoting antitumoural T cell activation. These results suggest that NAC reinforces the antitumour immune response by activating the effector arm of the T cell compartment and diminishing the influence of suppressive Tregs. PATIENT SUMMARY: In this report, we analysed the effect of chemotherapy on immune cell subsets of 40 patients with advanced bladder cancer. We found that chemotherapy has a positive effect on immune effector T cells, whereas an opposite, diminishing effect was observed for immune-suppressive regulatory T cells. We conclude that chemotherapy reinforces the antitumour immune response in bladder cancer patients.


Pigment epithelium-derived factor suppresses adipogenesis via inhibition of the MAPK/ERK pathway in 3T3-L1 preadipocytes.
We previously reported that circulating levels of pigment epithelium-derived factor (PEDF), a newly identified adipokine, are increased in patients with type 2 diabetes, correlating with body mass index. However, the role of PEDF in adipogenesis remains elusive. In the present study, we have investigated the effects and mechanisms of PEDF on adipocyte differentiation in 3T3-L1 preadipocytes. Differentiation of 3T3-L1 preadipocytes was induced in the presence or absence of human recombinant PEDF protein. The effects of PEDF on adipogenic gene expression, mitotic clonal expansion (MCE), and MAPK activation were investigated. Physiological concentrations of human PEDF protein inhibited adipocyte differentiation, evidenced by decreased lipid accumulation, downregulation of adipocyte markers, and inhibition of master adipogenic transcription factors such as C/EBP-alpha and PPARgamma. The antiadipogenic effects of PEDF were observed only when PEDF was added to the cells on day 0, but not on day 3 during differentiation, suggesting that PEDF targets some early adipogenic events. Similarly, overexpression of PEDF by adenovirus attenuated adipocyte differentiation. Further studies revealed that PEDF, or U-0126, a specific MAPK/ERK inhibitor, sequentially inhibited the early activation of ERK and MCE. Moreover, PEDF attenuated expression and the phosphorylation of C/EBP-beta at Thr(188), an essential step for transcriptional activation of C/EBP-beta. In addition, PEDF expression was decreased significantly in the first 24 h during adipocyte differentiation, suggesting that downregulation of PEDF may be essential for the initiation of MCE and adipogenesis. We conclude that PEDF inhibits adipogenesis in 3T3-L1 preadipocytes partially because of inhibition of the MAPK/ERK signaling pathway and MCE.


Effects of transverse and frontal plane knee laxity on hip and knee neuromechanics during drop landings.
Varus-valgus (LAX(VV)) and internal-external (LAX(IER)) rotational knee laxity have received attention as potential contributing factors in anterior cruciate ligament injury. This study compared persons with above-and below-average LAX(VV) and LAX(IER) values on hip and knee neuromechanics during drop jump landings. People with greater LAX(VV) and LAX(IER) values will have greater challenges controlling frontal and transverse plane knee motions, as evidenced by greater joint excursions, joint moments, and muscle activation levels during the landing phase. Descriptive laboratory study. Recreationally active participants (52 women and 44 men) between 18 and 30 years old were measured for LAX(VV) and LAX(IER) and for their muscle activation and transverse and frontal plane hip and knee kinetics and kinematics during the initial landing phase of a drop jump. The mean value was obtained for each sex, and those with above-average values on LAX(VV) and LAX(IER) (LAX(HIGH) = 17 women, 16 men) were compared with those with below-average values (LAX(LOW) = 18 women, 17 men). Women with LAX(HIGH) verus LAX(LOW) were initially positioned in greater hip adduction and knee valgus and also produced more prolonged internal hip adduction and knee varus moments as they moved toward greater hip adduction and internal rotation as the landing progressed. These patterns in LAX(HIGH) women were accompanied by greater prelanding and postlanding muscle activation amplitudes. Men with LAX(HIGH) versus LAX(LOW) also demonstrated greater hip adduction motion and produced greater internal hip internal rotation and knee varus and internal rotation moments. Participants with greater LAX(VV) and LAX(IER) landed with greater hip and knee transverse and frontal plane hip and knee motions. People (especially, women) with increased frontal and transverse plane knee laxity demonstrate motions associated with noncontact anterior cruciate ligament injury mechanisms.


An investigation into the use of music as potential auditory enrichment for moloch gibbons (Hylobates moloch).
The use of music as enrichment has rarely been explored in zoos, despite evidence that music has a positive effect on a range of laboratory housed animals. In this study of moloch gibbons, Hylobates moloch, at Howletts Wild Animal Park (Kent, England), instrumental classical music was played to eight individuals in two family groups. Music was played 7 hr a day during three of six study weeks for each group, alternating with control weeks in which no music was played. In focal watches, data were recorded on a measure of activity, brachiation, and on two rates of affiliative behavior, giving and receiving grooming. In addition, to assess potential impacts on emotional state, data were recorded on self-scratching and self-grooming, two widely used indices of anxiety or stress. Analyses were carried out for each individual separately, as previous studies of primates indicate animals may differ in their response to enrichment. Results revealed little evidence for effects of music on gibbons' behavior. During the music compared to control weeks, the adult male from one group showed higher rates of self-scratching and higher durations of both self-grooming and grooming others. The adult female from the same group was groomed more during the music weeks than control weeks. For the six other animals, no significant differences in behaviors were seen between music and control conditions. Our findings suggest music may not be an effective enrichment for captive gibbons, and further highlight the importance of considering individual differences when assessing the effects of potential enrichment.


An approach to identifying incident breast cancer cases using Medicare claims data.
This study developed and evaluated a method for ascertaining a newly diagnosed breast cancer case using multiple sources of data from the Medicare claims system. Predictors of an incident case were operationally defined as codes for breast cancer-related diagnoses and procedures from hospital inpatient, hospital outpatient, and physician claims. The optimal combination of predictors was then determined from a logistic regression model using 1992 data from the linked SEER registries-Medicare claims data base and a sample of noncancer controls drawn from the SEER areas. While the ROC curve demonstrates that the model can produce levels of sensitivity and specificity above 90%, the positive predictive value is comparatively low (67-70%). This low predictive value is largely the result of the model's limitation in distinguishing recurrent and secondary malignancies from incident cases and possibly from the model identifying true incident cases not identified by SEER. Nevertheless, the logistic regression approach is a useful method for ascertaining incident cases because it allows for greater flexibility in changing the performance characteristics by selecting different cut-points depending on the application (e.g., high sensitivity for registry validation, high specificity for outcomes research). It also allows us to make specific adjustments to population based estimates of breast cancer incidence with claims.


Special Forces Medical Sergeant/Special Operations Independent Duty Corpsman Candidates: Large Animal Module.
Medical care provided by Special Operations Forces (SOF) combat medics is vital for establishing communication with local populations. In many of these communities, livestock hold a valuable position within the social, political, and cultural structure. The West Virginia University (WVU) Special Forces Medical Sergeant/Special Operations Independent Duty Corpsman (SFMS/SOIDC) Large Animal Module is designed to provide a foundational experience in livestock husbandry and veterinary procedures to SOF combat medic candidates. This study was conducted to determine the participants' base knowledge of food animal production and to evaluate if the program content was sufficient for increasing their knowledge of the subject matter. A quasi-experimental design utilizing pre-test and post-test instruments was used. The validity of the testing instruments was established by a panel of subject matter experts and the instruments' reliability was determined by a split-half analysis using SPSS® statistical software. The difference between the pre-test and post-test examinations were compared for 66 candidates who were assigned to WVU Health Sciences Center for the applied medical experience program and 46 counterparts assigned to other institutions by a match pair analysis. Seventy-five percent of the subjects had no previous livestock exposure, and only 7% had previously participated in the 4-H program or Future Farmers of America (FFA). The average improvement in scores, pre-test versus post-test, was significantly greater for those that attended the module (18.5 versus 0.9). Few SFMS/SOIDC candidates have prior knowledge of livestock husbandry practices. The large animal module successfully provides education on livestock husbandry practice to participants. Knowledge of livestock production can assist SOF medics in establishing rapport with indigenous populations while on mission.


Overnourishing pregnant adolescent ewes preserves perirenal fat deposition in their growth-restricted fetuses.
Overnourishing the adolescent sheep promotes rapid maternal growth at the expense of the gravid uterus. The growth of the placenta is impaired and results in the premature delivery of low-birthweight lambs. The present study details fetal adipose tissue development in these growth-restricted pregnancies. Singleton pregnancies were established by embryo transfer and, thereafter, adolescent ewes were offered a high (H; n = 12) or moderate (M; n = 14) level of a complete diet until necropsy on Day 131 of gestation. Fetal weight was lower (P < 0.001) in H compared with M groups. High maternal intake preserved brain and perirenal fat weight (P < 0.003), whereas relative weights of the heart, lungs, spleen and liver were unaltered. High nutrient intake resulted in significantly elevated maternal plasma concentrations of insulin, leptin, prolactin and glucose, no significant changes in fetal insulin, leptin or non-esterified fatty acids and attenuated fetal prolactin concentrations. Irrespective of nutritional intake, maternal plasma leptin, prolactin and glucose concentrations were negatively correlated with fetal weight and were positively correlated with fetal perirenal fat proportion (all P < 0.01). The mRNA expression for leptin, prolactin receptor and uncoupling protein (UCP) 1 in fetal perirenal fat was equivalent between groups, but, irrespective of maternal nutrition, UCP1 mRNA levels were negatively correlated with fetal weight (P < 0.01). Thus, overnourishing pregnant adolescent sheep preserves fat deposition in their growth-restricted fetuses, which may have implications for neonatal thermogenesis and for programming of postnatal adiposity.


Anticipatory neural dynamics of spatial-temporal orienting of attention in younger and older adults.
Spatial and temporal expectations act synergistically to facilitate visual perception. In the current study, we sought to investigate the anticipatory oscillatory markers of combined spatial-temporal orienting and to test whether these decline with ageing. We examined anticipatory neural dynamics associated with joint spatial-temporal orienting of attention using magnetoencephalography (MEG) in both younger and older adults. Participants performed a cued covert spatial-temporal orienting task requiring the discrimination of a visual target. Cues indicated both where and when targets would appear. In both age groups, valid spatial-temporal cues significantly enhanced perceptual sensitivity and reduced reaction times. In the MEG data, the main effect of spatial orienting was the lateralised anticipatory modulation of posterior alpha and beta oscillations. In contrast to previous reports, this modulation was not attenuated in older adults; instead it was even more pronounced. The main effect of temporal orienting was a bilateral suppression of posterior alpha and beta oscillations. This effect was restricted to younger adults. Our results also revealed a striking interaction between anticipatory spatial and temporal orienting in the gamma-band (60-75 Hz). When considering both age groups separately, this effect was only clearly evident and only survived statistical evaluation in the older adults. Together, these observations provide several new insights into the neural dynamics supporting separate as well as combined effects of spatial and temporal orienting of attention, and suggest that different neural dynamics associated with attentional orienting appear differentially sensitive to ageing.


Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome.
The ongoing Zika virus epidemic in the Americas and the observed association with both fetal abnormalities (primary microcephaly) and adult autoimmune pathology (Guillain-Barré syndrome) has brought attention to this neglected pathogen. While initial case studies generated significant interest in the Zika virus outbreak, larger prospective epidemiology and basic virology studies examining the mechanisms of Zika viral infection and associated pathophysiology are only now starting to be published. In this review, we analyze Zika fetal neuropathogenesis from a comparative pathology perspective, using the historic metaphor of "TORCH" viral pathogenesis to provide context. By drawing parallels to other viral infections of the fetus, we identify common themes and mechanisms that may illuminate the observed pathology. The existing data on the susceptibility of various cells to both Zika and other flavivirus infections are summarized. Finally, we highlight relevant aspects of the known molecular mechanisms of flavivirus replication.


Association of Biomarker Cutoffs and Endoscopic Outcomes in Crohn's Disease: A Post Hoc Analysis From the CALM Study.
CALM was a randomized phase 3 trial in patients with Crohn's disease (CD) that demonstrated improved endoscopic outcomes when treatment was escalated based on cutoffs for inflammatory biomarkers, fecal calprotectin (FC), C-reactive protein (CRP), and CD Activity Index (CDAI) remission vs CDAI response alone. The purpose of this post hoc analysis of CALM was to identify drivers of treatment escalation and evaluate the association between biomarker cutoff concentrations and endoscopic end points. The proportion of patients achieving CD Endoscopic Index of Severity (CDEIS) <4 and no deep ulcers 48 weeks after randomization was evaluated according to CRP <5 mg/L or ≥5 mg/L and FC <250 μg/g or ≥250 μg/g. Subgroup analyses were performed according to disease location, and sensitivity analyses were conducted in patients with elevated CRP and/or FC at baseline. The association between endoscopic end points and biomarker cutoffs was performed using χ 2 test. The proportion of patients who achieved the primary end point CDEIS <4 and no deep ulcers was significantly greater for those with FC <250 µg/g (74%; P < 0.001), with an additive effect for CRP <5 mg/L. The association of FC <250 µg/g with improved endoscopic outcomes was independent of disease location, although the greatest association was observed for ileocolonic disease. Fecal calprotectin <250 µg/g, CRP <5 mg/L, and CDAI <150 gave a sensitivity/specificity of 72%/63% and positive/negative predictive values of 86%/42% for CDEIS <4 and no deep ulcers 48 weeks after randomization. This post hoc analysis of CALM demonstrated that a cutoff of FC <250 µg/g is a useful surrogate marker for mucosal healing in CD.


LYAR potentiates rRNA synthesis by recruiting BRD2/4 and the MYST-type acetyltransferase KAT7 to rDNA.
Activation of ribosomal RNA (rRNA) synthesis is pivotal during cell growth and proliferation, but its aberrant upregulation may promote tumorigenesis. Here, we demonstrate that the candidate oncoprotein, LYAR, enhances ribosomal DNA (rDNA) transcription. Our data reveal that LYAR binds the histone-associated protein BRD2 without involvement of acetyl-lysine-binding bromodomains and recruits BRD2 to the rDNA promoter and transcribed regions via association with upstream binding factor. We show that BRD2 is required for the recruitment of the MYST-type acetyltransferase KAT7 to rDNA loci, resulting in enhanced local acetylation of histone H4. In addition, LYAR binds a complex of BRD4 and KAT7, which is then recruited to rDNA independently of the BRD2-KAT7 complex to accelerate the local acetylation of both H4 and H3. BRD2 also helps recruit BRD4 to rDNA. By contrast, LYAR has no effect on rDNA methylation or the binding of RNA polymerase I subunits to rDNA. These data suggest that LYAR promotes the association of the BRD2-KAT7 and BRD4-KAT7 complexes with transcription-competent rDNA loci but not to transcriptionally silent rDNA loci, thereby increasing rRNA synthesis by altering the local acetylation status of histone H3 and H4.


Comparison of the effects of artificial and natural barriers on large African carnivores: implications for interspecific relationships and connectivity.
1. Physical barriers contribute to habitat fragmentation, influence species distribution and ranging behaviour, and impact long-term population viability. Barrier permeability varies among species and can potentially impact the competitive balance within animal communities by differentially affecting co-occurring species. The influence of barriers on the spatial distribution of species within whole communities has nonetheless received little attention. 2. During a 4-year period, we studied the influence of a fence and rivers, two landscape features that potentially act as barriers on space use and ranging behaviour of lions Panthera leo, spotted hyenas Crocuta crocuta, African wild dogs Lycaon pictus and cheetahs Acinonyx jubatus in Northern Botswana. We compared the tendencies of these species to cross the barriers using data generated from GPS-radio collars fitted to a total of 35 individuals. Barrier permeability was inferred by calculating the number of times animals crossed a barrier vs. the number of times they did not cross. Finally, based on our results, we produced a map of connectivity for the broader landscape system. 3. Permeability varied significantly between fence and rivers and among species. The fence represented an obstacle for lions (permeability = 7.2%), while it was considerably more permeable for hyenas (35.6%) and wild dogs and cheetahs (≥ 50%). In contrast, the rivers and associated floodplains were relatively permeable to lions (14.4%) while they represented a nearly impassable obstacle for the other species (<2%). 4. The aversion of lions to cross the fence resulted in a relatively lion-free habitat patch on one side of the fence, which might provide a potential refuge for other species. For instance, the competitively inferior wild dogs used this refuge significantly more intensively than the side of the fence with a high presence of lions. 5. We showed that the influence of a barrier on the distribution of animals could potentially result in a broad-scale modification of community structure and ecology within a guild of co-occurring species. As habitat fragmentation increases, understanding the impact of barriers on species distributions is thus essential for the implementation of landscape-scale management strategies, the development and maintenance of corridors and the enhancement of connectivity.