Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation.
During states of low carbohydrate intake, mammalian ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial enzyme coenzyme A (CoA) transferase [succinyl-CoA:3-oxoacid CoA transferase (SCOT), encoded by nuclear Oxct1] is required for oxidation of ketone bodies and that germline SCOT-knockout (KO) mice die within 48 h of birth because of hyperketonemic hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during starvation in the adult. Although transgene-mediated restoration of myocardial CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic hypoglycemia in the neonatal period, mice lacking CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal CoA transferase deficiency exhibit increased cerebral glycolysis and glucose oxidation, and, while these neonatal mice exhibit modest hyperketonemia, they do not develop hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1(+/-) mice demonstrates that global diminution of ketone body oxidation yields hyperketonemia, but hypoglycemia emerges only during a protracted state of low carbohydrate intake. Together, these data suggest that, at the tissue level, ketone bodies are not a required energy substrate in the newborn period or during starvation, but rather that integrated ketone body metabolism mediates adaptation to ketogenic nutrient states.


Mechanical Anisotropy and Surface Roughness in Additively Manufactured Parts Fabricated by Stereolithography (SLA) Using Statistical Analysis.
In this study, the degree of mechanical anisotropy was investigated through tensile testing of specimens built in different orientations and designed according to the ASTM D638 standard. The mechanical properties that were evaluated include Young's modulus, ultimate tensile strength (UTS), and percentage elongation. Additionally, physical properties, such as mean surface roughness (Ra), density and dimension of the cross-sectional area, were also measured. These properties were then compared with the available standard data to see how SLA performs comparing to the traditional manufacturing methods. The obtained modulus of elasticity and UTS values of the printed samples were 2481 ± 50 MPa and 51.9 ± 1.3 MPa respectively, which were very similar to the standard data (2550 and 52 MPa, respectively) as provided by the material suppliers. The percentage elongation values (4.8% ± 0.4%) were a bit lower than the expected value of 6%. However, the surfaces of all the printed samples were quite smooth, with a surface roughness range of 2.28 ± 0.59 µm. A design of experiments was created to study the influence of the independent variables such as build orientation and angular orientation on the mechanical properties. Extensive statistical analysis, using the Taguchi method and analysis of variance (ANOVA), was performed to examine the effect of these independent variables on the mechanical properties. The SLA printed parts can be classified as isotropic since the build orientation and the angular orientation did not have a statistically significant impact on the mechanical properties. The effect of aging on the mechanical properties was also evaluated and it shows that the specimens that had been aged for a longer time resulted in superior mechanical properties. For example, the UTS increased from 24 to 54 MPa when the sample aligned parallel to the XY plane was aged from 1 week to 6 months, respectively. This significant increase implies that aging has a substantial effect on the mechanical properties of the parts fabricated by stereolithography. The resin used for this study, Visijet Sl Clear, produced very consistent mechanical properties in different directions.


Effect of Food Emulsifiers on Aroma Release.
This study aimed to determine the influence of different emulsifiers or xanthan-emulsifier systems on the release of aroma compounds. Solid-phase microextraction (SPME) and GC-MS were used to study the effects of varying concentrations of xanthan gum, sucrose fatty acid ester, Tween 80 and soybean lecithin on the release of seven aroma compounds. The effects of the emulsifier systems supplemented with xanthan gum on aroma release were also studied in the same way. The results showed varying degrees of influence of sucrose fatty acid ester, soybean lecithin, Tween 80 and xanthan gum on the release of aroma compounds. Compared with other aroma compounds, ethyl acetate was more likely to be conserved in the solution system, while the amount of limonene released was the highest among these seven aroma compounds. In conclusion, different emulsifiers and complexes showed different surface properties that tend to interact with different aroma molecules. The present studies showed that the composition and structure of emulsifiers and specific interactions between emulsifiers and aroma molecules have significant effects on aroma release.


Pancreatic calcification: a report of 45 cases.
Forty-five cases of pancreatic calcification are reported, and it is shown that in Western Nigeria this malady afflicts younger people than in Europe and the United States of America. Males and females seem about equally affected in Western Nigeria, whereas it predominantly affects males in France, Britain, and North America. Diabetes mellitus was the commonest complication in this series, and brought many patients to the doctor. In this series chronic relapsing pancreatitis was a rare cause; there was no history of alcoholism; and protein malnutrition was thought to be responsible for pancreatic calcification in over 90% of the patients.


Nonfocal Symptoms in Patients with Transient Ischemic Attack and Association with Stroke Risk.
Patients with transient ischemic attack(TIA)occasionally showed nonfocal symptoms, such as decreased consciousness, amnesia and non-rotatory dizziness. This study intended to evaluate the effect of nonfocal symptoms on the prognosis of patients with TIA. Data from the prospective hospital-based TIA database of the First Affiliated Hospital of Zhengzhou University were analyzed. The predictive outcome was stroke occurrence at 1 year. Cumulative risks of stroke in patients with and without nonfocal symptoms were estimated with Kaplan-Meier models. We studied 1384 patients with TIA (842 men; mean age, 56±13 years), including 450 (32.5%) with nonfocal symptoms. In the first year after TIA, stroke occurred in 168(12.1%) patients. There was no difference in the risk of stroke between patients with both focal and nonfocal symptoms and patients with focal symptoms alone (11.8% vs 12.4%, log-rank; P=0.691). The occurrence of nonfocal symptoms did not increase the risk of stroke at one-year follow-up compared to the occurrence of focal symptoms alone.


[Clinical characteristics of late manifestations of recurrent depressive psychoses].
A total of 70 patients with recurrent depression manifested at the age over 45 were under investigation. Major clinical types of depressions were: adynamic, anxious, senesto-hypochondric, combined depressive-paranoic, endoreactive. Major types of the course of these disorders were: stereotype phases (cliché type), and polymorphic endogenous episodes. The impact of ageing factor increased with age, hence the modification of depressive phases, and changed interrelations of the types in different age periods, increased recurrence rates, shortened remissions and their worsening due to persisting residual depression.


Rehabilitation and follow-up issues in drug abusers managed at the Neuropsychiatric Hospital, Abeokuta, Nigeria.
The authors report on sixty two (62) patients treated at the drug abuse unit of the Neuropsychiatric Hospital, Aro, Abeokuta, Nigeria over a 17-month period (June 1985-October 1986). Drugs mainly abused were marijuana (53.5%, alcohol (28.2%) and hard drugs (mainly heroin and cocaine) which accounted for 14.3%. All the patients went through a programme of assessment, detoxification, individual counselling, group psychotherapy and rehabilitation. Their length of stay in the hospital was (mean +/- SD) 64 + 44 days. Factors that militated against successful rehabilitation were the severity of the patients' illness at presentation, unemployment coupled with poor educational status and distance from the hospital of patient's normal abode. Sixty seven percent had defaulted 6 months after discharge from the hospital. Non-defaulters at 2 months performed well on some parameters assessed. Possible ways of ensuring proper rehabilitation and follow-up of this group of patients are discussed.


Formation of alginate microspheres produced using emulsification technique.
This study investigated the formative process of alginate microspheres produced using an emulsification technique. The alginate microspheres were produced by cross-linking alginate globules dispersed in a continuous organic phase using various calcium salts: calcium chloride, calcium acetate, calcium lactate and calcium gluconate. The size, shape, drug content and Ca2+ content of the microspheres were evaluated. The tack, viscosity and pH of the calcium salt solution and percentage of Ca2+ partitioned into the organic phase were determined. Microscopic examination of the test emulsion at various stages of the emulsification process was also carried out. The propensity of cross-linking reaction was found to be dependent on successful collision between alginate and calcium salt globules. Examination of the characteristics of microspheres indicated that the formed microsphere was a resultant product of alginate globule clustering. The growth propensity of microspheres was promoted by the higher rate and extent of cross-linkage which was governed by the pH, tack and/or Ca2+ content of the cross-linking solution, as well as the dissociation constant and diffusivity of the calcium salt. Overall, the amount of free Ca2+ cross-linked with alginate in the formed microspheres was in the following order: calcium acetate > calcium chloride + calcium acetate > calcium chloride + calcium gluconate; calcium chloride + calcium lactate > calcium chloride. In microencapsulation by emulsification, the mean size of the microspheres produced can be modified by varying the tack, pH and Ca2+ content of the cross-linking solution and through the use of a combination of calcium salts. The shape of the microspheres produced was, nonetheless, unaffected by the physicochemical properties of the cross-linking solution.


Developing a suitability index for land uses and agricultural land covers: a case study in Turkey.
This study was aimed at determining the land-use and land-cover (LULC) potentials of a southeastern Mediterranean area (Antakya, Turkey) of 36 816 ha for a total of 23 different LULC types: nine horticultural crops, nine field crops and five non-agricultural lands. Land evaluation was carried out by using a combination of SENOL Land Evaluation System and ILSEN computer program adapted to Turkey from FAO land evaluation principles. Our assessment resulted in the identification of nine physiographical units, 27 different soil series, and 110 land mapping units. Nearly 49% of the study area was determined as suitable for agricultural land cover types, and 35% for non-agricultural land use types. A map showing potential suitability of LULC was derived for the study area. The quantification of LULC suitability assists decision makers in ensuring that lands are used according to their capacities to satisfy human needs for present and future generations, thus sustaining ecological and economic productivity of natural resources.


[Usefulness of preemptive anticoagulation in patients with suspected pulmonary embolism].
The usefulness of anticoagulation in patients with suspected non-massive pulmonary embolism (PE) is uncertain. We recently published a decision analysis model suggesting a benefit for preemptive anticoagulation in patients with an intermediate or high probability of PE, even with short diagnostic delays (0-3 h). In case of a low probability of PE, the decision to treat or not could partly rely on the expected diagnostic delay. Once the diagnosis is confirmed, achieving rapidly therapeutic anticoagulation levels decreases future thrombotic complications.


[The perception of hypertensive elderly patients regarding their health needs].
Considering the prevalence of arterial hypertension among the elderly, the present study analyzes their perception of health needs, in a qualitative way, from focal groups with elderly users of Family Health Units. Data analysis was performed according to the hermeneutic-dialectical perspective and resulted in three nuclei of meaning: recognizing the possibility of having access to basic health care together with the desire to consume services of greater complexity and understanding the shortcomings of the State; attachment and welcoming as fundamental elements in the feelings of support and security and autonomy permeated by the tranquility to deal with the disease and the difficulties imposed by conditions inherent to the subjects' life style. Therefore, it is understood that the Family Health Strategy has been complying with its role in terms of the access to the healthcare system and regarding the professional-user attachment. However, health care continues to be centered on the disease rather than the individual.


Preoperative weight loss with a very-low-energy diet: quantitation of changes in liver and abdominal fat by serial imaging.
A very-low-energy diet (VLED) can result in substantial, rapid weight loss and is increasingly prescribed before obesity surgery to minimize risk and difficulty by reducing liver size and abdominal adiposity. Despite its growing popularity, a VLED in this setting has received little attention. The aim of this study was to investigate the efficacy and acceptability of a preoperative VLED. In a prospective observational study, 32 subjects (n = 19 men and 13 women) with a mean (+/-SD) age of 47.5 +/- 8.3 y and a body mass index (in kg/m(2)) of 47.3 +/- 5.3 consumed a VLED for 12 wk. Primary outcomes included changes in liver volume (LV) and in visceral and subcutaneous adipose tissue (VAT/SAT). Changes in body weight, anthropometric measures, and biochemical variables were also recorded, and compliance with, acceptability of, and side effects of treatment were assessed. Changes in LV and VAT/SAT area were measured by computed tomography and magnetic resonance imaging at baseline and weeks 2, 4, 8, and 12. Mean (+/-SD) LV, VAT/SAT, and body weight decreased significantly (P < 0.001 for all). The degree of LV reduction was directly related to the reduction in relative body weight (r = 0.54, P = 0.001) and initial LV (r = 0.43, P = 0.015). Eighty percent of the reduction in LV occurred between weeks 0 and 2 (P < 0.001). Reductions in body weight and VAT were uniform over the 12-wk period. Attrition was 14%. Acceptability was adequate but waned over time, and mild transitory side effects occurred. Given the observed early reduction in LV and the progressive reduction in VAT, we suggest that the minimum duration for a preoperative VLED be 2 wk. Ideally, the duration should be 6 wk to achieve maximal LV reduction and significant reductions in VAT and body weight without compromising compliance and acceptability.


Hypertension Prevalence Among Adults Aged 18 and Over: United States, 2017-2018.
Hypertension is a major risk factor for cardiovascular disease. Lowering blood pressure has been shown to decrease the incidences of stroke, heart attack, and heart failure (1,2). This report provides 2017-2018 U.S. hypertension prevalence estimates using the 2017 American College of Cardiology and American Heart Association definition of hypertension (3) and new guidelines, which redefine hypertension by lowering the previous threshold levels of 140/90 mmHg to 130/80 mmHg (4). This change categorizes a greater percentage of people as having hypertension.


Amplification of ERBB2 (HER2) in embryonal rhabdomyosarcoma: A potential treatment target in rare cases?
The ERBB2 gene encodes a receptor tyrosine kinase also known as HER2. The gene is amplified and overexpressed in one-fifth of breast carcinomas; patients with such tumors benefit from targeted treatment with trastuzumab or other drugs blocking the receptor. In addition, ERBB2 has been shown to be amplified and/or overexpressed in a variety of other malignancies. Notably, both alveolar and embryonal rhabdomyosarcoma (RMS), especially in children, often show increased expression of ERBB2. Although high-level amplification of the gene has not been described in RMS, its frequent expression at the cell surface of RMS cells has been exploited for chimeric antigen receptor T-cell (CAR T)-based treatment strategies. We here describe two cases of pediatric, fusion-negative embryonal RMS with high-level amplification of the ERBB2 gene. One patient is currently treated with conventional chemotherapy for a recently detected standard risk RMS, whereas the other patient died from metastatic disease. Both tumors displayed focal amplicons (210 and 274 Kb, respectively) in chromosome band 17q12, with proximal and distal borders corresponding to those typically seen in breast cancer. In both tumors, the ERBB2 amplicon correlated with high expression at the RNA and protein levels. Thus, breast cancer-like ERBB2 amplification is a very rare, but recurrent feature of pediatric RMS, and should be exploited as an alternative treatment target.


Development of a terbium complex-based luminescent probe for imaging endogenous hydrogen peroxide generation in plant tissues.
A highly sensitive Tb(3+) complex-based luminescent probe, N,N,N(1),N(1)-[2,6-(3'-aminomethyl-1'-pyrazolyl)-4-(3'',4''-diaminophenoxy)methylene-pyridine] tetrakis(acetate)-Tb(3+) (BMTA-Tb(3+)), has been designed and synthesized for the recognition and detection of hydrogen peroxide (H(2)O(2)) in aqueous solutions. This probe is almost nonluminescent because the Tb(3+) luminescence is effectively quenched by the electron-rich moiety, diaminophenyl, on the basis of the photoinduced electron transfer (PET) mechanism. In the presence of peroxidase, the probe can react with H(2)O(2) to cause the cleavage of the diaminophenyl ether, which affords a highly luminescent Tb(3+) complex, N,N,N(1),N(1)-[2,6-bis(3'-aminomethyl-1'-pyrazolyl)-4-hydroxymethyl-pyridine] tetrakis(acetate)-Tb(3+) (BHTA-Tb(3+)), accompanied by a 39-fold increase in luminescence quantum yield with the increase of luminescence lifetime from 1.95 to 2.76 ms. The dose-dependent luminescence enhancement of the probe shows a good linearity with a detection limit of 3.7 nM for H(2)O(2), which is approximately 14-fold lower than those of the commonly used fluorescent probes. The probe was used for the time-resolved luminescence imaging detection of the oligosaccharide-induced H(2)O(2) generation in tobacco leaf epidermal tissues. On the basis of the probe, a background-free time-resolved luminescence imaging method for detecting H(2)O(2) in complicated biological systems was successfully established.


Effect of irrigation salinity and ecotype on the growth, physiological indicators and seed yield and quality of Salicornia europaea.
The euhalophyte species Salicornia europaea is cultivated for oilseed and as a fodder crop in various parts of the world. In saline coastal environments it possesses great potential for the subsistence of the most disadvantaged farmers. We investigated the effect of salinity levels in irrigation water on the germination capacity, shoot biomass and seed productivity as well as diverse quality traits (nitrogen content in shoots and seeds and fatty acids, in seeds) and physiological traits (stable carbon and nitrogen isotopes and ion content) of two accessions collected in the United Arab Emirates (UAE). The three salinity levels tested were irrigation with fresh water (0.3 dS m-1), brackish water (25 dS m-1) and sea water (40 dS m-1). In addition, a hypersaline condition (80 dS m-1) was also tested for germination. The best germination rates were achieved with seeds exposed to fresh and brackish water, while imbibition with sea water decreased germination by half and hypersaline water inhibited it almost totally. However, the best irrigation regime in terms of biomass and seed yield involved brackish water. Moreover, rising salinity in the irrigation increased the stable isotope composition of carbon (δ13C) and nitrogen (δ15N), together with the Na+ and K+ of shoots and seeds, and the lipid levels of seeds, while the total nitrogen content and the profile of major fatty acids of seeds did not change. Differences between the two ecotypes existed for growth and seed yield with the best ecotype exhibiting lower δ13C and higher K+ in both shoots and seeds, lower Na+ and higher δ15N in shoots, and lower N in seeds, together with differences in major fatty acids. Physiological mechanisms behind the response to irrigation salinity and the ecotypic differences are discussed in terms of photosynthetic carbon and nitrogen metabolism.


External rhinoplasty approach to transsphenoidal hypophysectomy.
The external rhinoplasty approach is a modification of the well recognized transseptal transsphenoidal hypophysectomy technique first introduced by Cushing in 1910. Our approach has been used successfully in 75 cases over a six year period, demonstrating its efficacy and safety. It provides a simple, reliable, rapid technique for exposing the septum and the floor of the nose with excellent exposure to the sphenoid sinus and pituitary gland. There has been no loss of nasal tip projection or other cosmetic deformity.


Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation.
Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL) in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA) or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs) activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80+, CD68+, and Ly6C+ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1) mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate that PlGF plays an important role in liver inflammation, angiogenesis, and fibrosis by promoting hepatic macrophage recruitment and activation, and suggest that blockage of PlGF could be a promising novel therapy for chronic fibrotic liver diseases.


Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8+ T cells compared with women with BRCA wild-type disease during the early disease course.
Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8+ T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed cell death protein 1 (PD-1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45+ PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post-diagnosis. CD8+ T cells among viable CD45+ PBMCs and CTLA-4+/CD8+ T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post-diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM-3 expression on Tregs was associated with poor progression-free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8+ T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post-diagnosis decade.


ABCB4 mediates diet-induced hypercholesterolemia in laboratory opossums.
High-responding opossums are susceptible to developing hypercholesterolemia on a high-cholesterol diet, but low-responding opossums are resistant. The observation of low biliary cholesterol and low biliary phospholipids in high responders suggested that the ABCB4 gene affects response to dietary cholesterol. Two missense mutations (Arg29Gly and Ile235Leu) were found in the ABCB4 gene of high responders. High responders (ATHH strain) were bred with low responders (ATHE or ATHL strain) to produce F1 and F2 progeny in two different genetic crosses (KUSH6 and JCX) to determine the effect of ABCB4 allelic variants on plasma cholesterol concentrations after a dietary challenge. Pedigree-based genetic association analyses consistently implicated a variant in ABCB4 or a closely linked locus as a major, but not the sole, genetic contributor to variation in the plasma cholesterol response to dietary cholesterol. High responders, but not low responders, developed liver injury as indicated by elevated plasma biomarkers of liver function, probably reflecting damage to the canalicular membrane by bile salts because of impaired phospholipid secretion. Our results implicate ABCB4 as a major determinant of diet-induced hypercholesterolemia in high-responding opossums and suggest that other genes interact with ABCB4 to regulate lipemic response to dietary cholesterol.


Norovirus genotypes implicated in two oyster-related illness outbreaks in Ireland.
We investigated norovirus (NoV) concentrations and genotypes in oyster and faecal samples associated with two separate oyster-related outbreaks of gastroenteritis in Ireland. Quantitative analysis was performed using real-time quantitative reverse transcription polymerase chain reaction and phylogenetic analysis was conducted to establish the NoV genotypes present. For both outbreaks, the NoV concentration in oysters was >1000 genome copies/g digestive tissue and multiple genotypes were identified. In faecal samples, GII.13 was the only genotype detected for outbreak 1, whereas multiple genotypes were detected in outbreak 2 following the application of cloning procedures. While various genotypes were identified in oyster samples, not all were successful in causing infection in consumers. In outbreak 2 NoV GII.1 was identified in all four faecal samples analysed and NoV GII concentrations in faecal samples were >108 copies/g. This study demonstrates that a range of NoV genotypes can be present in highly contaminated oysters responsible for gastroenteritis outbreaks.


Peripheral venous catheter related complications are common among paediatric and neonatal patients.
The aims of this study were to describe the characteristics of peripheral venous catheters (PVCs), including dwell time and reasons for removal, and explore predictors for PVC-related complications. We included PVCs in 2032 children - 484 neonatal and 1548 paediatric - from 12 inpatient units. Data were retrieved from the patient record system, and predictors for complications were explored using logistic regression analyses. Just over one-third (35.4%) of the PVCs were removed due to complications, in particular infiltration and occlusion (51.9 and 48.4/1000 PVC days, respectively). PVC survival time was shorter in neonatal than paediatric patients (4 versus 5 days), and infiltration was more frequent in neonatal patients (92.8 versus 38.7/1000 PVC days). Infiltration was associated with younger age (odds ratio 0.97) for neonatal patients and with younger age (OR 0.96), insertion in the bend of the arm (OR 1.48) or ankle (OR 2.81) for paediatric patients. Occlusion was, both for neonatal and paediatric patients, associated with longer dwell time (OR 1.32 and 1.22 respectively), insertion in the ankle (OR 5.00 and 3.51) or foot (OR 3.47 and 1.99). PVC-related complications, particularly infiltration and occlusion, were more common in hospitalised children but decreased with the child's age.


TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury.
Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits. Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn (SDH) but inhibits LTP in hippocampus. The opposite changes in synaptic plasticity may contribute to chronic pain and memory deficits, respectively. However, the structural and molecular bases of these alterations of synaptic plasticity are unclear. Here, we show that the complexity of excitatory synaptic connectivity and brain-derived neurotrophic factor (BDNF) expression are enhanced in SDH but reduced in the hippocampus in neuropathic pain and the opposite changes depend on tumor necrosis factor-alpha/tumor necrosis factor receptor 1 signaling and microglial activation. The region-dependent synaptic alterations may underlie chronic neuropathic pain and memory deficits induced by peripheral nerve injury.


Periorbital skeletal augmentation to improve blepharoplasty and midfacial results.
Narrow palpebral fissures, short lower lids, and full cheeks are hallmarks of youthful periorbita. The presence of these features is predicated on a convex upper midface skeleton. Faces whose midface skeletons are flat or concave do not manifest these youthful attributes, tend to age prematurely, and are prone to lower lid malposition after blepharoplasty. Augmentation of the infraorbital rim with alloplastic implants can provide convexity to the deficient upper midface skeleton. Suspension of the cheek soft tissues (subperiosteal midface lift) on this now supportive framework narrows the palpebral fissure, shortens the lower lid, and gives fullness to the cheek. The addition of lateral canthopexy to skeletal augmentation and subperiosteal midface lift can restore lower lid position when previous blepharoplasty has resulted in lower lid malposition in patients with deficient midface skeletons. This concept has been utilized in 87 patients (65 female, 22 male) over the last 7 years. Of these 87 patients, four patients (5 percent) required revision surgery to correct implant malposition or prominence. Three patients (3 percent) required implant removal to treat infection. Implants were later replaced in two of these three patients. Augmentation of the infraorbital rim with alloplastic implants provides convexity to the upper midface skeleton. Together with lower lid and midface soft-tissue suspension, it creates or restores youthful periorbital aesthetics.


Proteomic Characterization Reveals a Molecular Portrait of Nasopharyngeal Carcinoma Differentiation.
Nasopharyngeal carcinoma (NPC) is categorized into three different differentiated subtypes by World Health Organization (WHO). Based on an earlier comparative proteomic database of the three histological subtypes, the study was to deepen our understanding of molecular mechanisms associated with NPC differentiation through bio-information mining. Among the three subtypes were 194 differentially expressed proteins (DEPs) of 725 identified proteins. Two DEPs, heat shock protein family B (small) member 1 (HSPB1) and keratin 5 (KRT5), were validated in a series of NPC tissue samples by using immunohistochemistry. Quantified protein families including keratins, S100 proteins (S100s) and heat shock proteins exhibited characteristic expression alterations. Comparisons of predicted bio-function activation states among different subtypes, including formation of cellular protrusion, metastasis, cell death, and viral infections, were conducted. Canonical pathway analysis inferred that Rho GTPases related signaling pathways regulated the motility and invasion of dedifferentiated NPC. In conclusion, the study explored the proteomic characteristics of NPC differentiation, which could deepen our knowledge of NPC tumorigenesis and allow the development of novel targets of therapeutic and prognostic value in NPC.


Managing pulmonary nontuberculous mycobacterial infection. time for a patient-centered approach.
The incidence of nontuberculous mycobacteria is increasing worldwide. However, the evidence base for clinical management comprises mostly expert opinion, case series, and few randomized clinical trials. Most currently recommended treatment regimens entail prolonged use of multiple antimicrobial agents associated with multiple self-limited and persistent potential adverse effects, including irreversible impairments of hearing, vision, and kidney function. Yet, little is known about how treatment impacts an individual patient's overall health status. Current treatment guidelines, although of undoubted value, are constrained by these limitations. Here we call for new studies that reassess recommendations for medical management of pulmonary nontuberculous mycobacteria infections, in particular Mycobacterium avium-intracellulare complex and Mycobacterium abscessus complex. We propose pragmatic, person-centered outcome measures that might be used in clinical assessments and new research studies, including patient-reported experience measures and patient-reported outcome measures. This will enable patients and their health-care providers to make clinical management decisions that derive from a realistic view of what they can hope to achieve from treatment.


Profile of Patients with Active Tuberculosis Admitted to a Respiratory Intensive Care Unit in a Tertiary Care Center of North India.
There is a paucity of literature regarding outcome of critically ill patients with tuberculosis (TB) from India. Herein, we describe our experience of patients with active TB admitted to a Respiratory Intensive Care Unit (RICU) of a tertiary care hospital. This was a retrospective analysis of all the patients admitted with active TB. The baseline clinical, demographic, ICU parameters and mortality were recorded. A multivariate logistic regression analysis was performed to identify factors predicting mortality. A total 3630 patients were admitted to the ICU during the study period; of these, 63 (1.7%) patients (mean [standard deviation (SD)] age 37.3 [19] years, 55.6% females) were admitted with active TB. Fifty-seven patients were mechanically ventilated (56, invasive and 1, noninvasive) for a mean (SD) duration of 7.5 (9.1) days. Respiratory failure was the most common indication for mechanical ventilation. TB-related acute respiratory distress syndrome was seen in 18 (28.6%) patients. There were 28 deaths (44.4%) during the study period. On a multivariate logistic regression analysis, a high baseline Acute Physiology and Chronic Health Evaluation II (APACHE II) score (odds ratio [OR] [95 confidence interval (CI)], 1.12 [1.02-1.23]) and delta Sequential Organ Failure Assessment (SOFA) (OR [95 CI], 1.39 [1.00-1.94]) were the independent predictors of mortality. TB was an uncommon cause of ICU admission even in a high TB burden country. Critically ill patients with TB had high mortality. A higher APACHE II score and delta SOFA were independent predictors of ICU mortality.


Minimum intervention dentistry approach to managing early childhood caries: a randomized control trial.
A pragmatic randomized control trial was undertaken to compare the minimum intervention dentistry (MID) approach, based on the atraumatic restorative treatment procedures (MID-ART: Test), against the standard care approach (Control) to treat early childhood caries in a primary care setting. Consenting parent/child dyads were allocated to the Test or Control group using stratified block randomization. Inclusion and exclusion criteria were applied. Participants were examined at baseline and at follow-up by two calibrated examiners blind to group allocation status (κ = 0.77), and parents completed a questionnaire at baseline and follow-up. Dental therapists trained in MID-ART provided treatment to the Test group and dentists treated the Control group using standard approaches. The primary outcome of interest was the number of children who were referred for specialist pediatric care. Secondary outcomes were the number of teeth treated, changes in child oral health-related quality of life and dental anxiety and parental perceptions of care received. Data were analyzed on an intention to treat basis; risk ratio for referral for specialist care, test of proportions, Wilcoxon rank test and logistic regression were used. Three hundred and seventy parents/carers were initially screened; 273 children were examined at baseline and 254 were randomized (Test = 127; Control = 127): mean age = 3.8 years, SD 0.90; 59% male, mean dmft = 4.9, SD 4.0. There was no statistically significant difference in age, sex, baseline caries experience or child oral health-related quality of life between the Test and Control group. At follow-up (mean interval 11.4 months, SD 3.1 months), 220 children were examined: Test = 115, Control = 105. Case-notes review of 231 children showed Test = 6 (5%) and Control = 53 (49%) were referred for specialist care, P < 0.0001. More teeth were filled in the Test group (mean = 2.93, SD 2.48) than in the Control group (mean = 1.54, SD 2.20), Wilcoxon's test, P < 0.0001. Logistic regression, after controlling for age and baseline caries experience, showed a higher risk of referral by allocation to control group, OR 32.6, 95% CI 10.8-98.4, P < 0.0001. The MID-ART approach reduced significantly the likelihood of referral for specialist care, and more children and teeth were provided with treatment.


Monofunctional platinum-DNA adducts are strong inhibitors of transcription and substrates for nucleotide excision repair in live mammalian cells.
To overcome drug resistance and reduce the side effects of cisplatin, a widely used antineoplastic agent, major efforts have been made to develop next generation platinum-based anticancer drugs. Because cisplatin-DNA adducts block RNA polymerase II unless removed by transcription-coupled excision repair, compounds that react similarly but elude repair are desirable. The monofunctional platinum agent pyriplatin displays antitumor activity in mice, a cytotoxicity profile in cell cultures distinct from that of cisplatin, and a unique in vitro transcription inhibition mechanism. In this study, we incorporated pyriplatin globally or site specifically into luciferase reporter vectors to examine its transcription inhibition profiles in live mammalian cells. Monofunctional pyriplatin reacted with plasmid DNA as efficiently as bifunctional cisplatin and inhibited transcription as strongly as cisplatin in various mammalian cells. Using repair-defective nucleotide excision repair (NER)-, mismatch repair-, and single-strand break repair-deficient cells, we show that NER is mainly responsible for removal of pyriplatin-DNA adducts. These findings reveal that the mechanism by which pyriplatin generates its antitumor activity is very similar to that of cisplatin, despite the chemically different nature of their DNA adducts, further supporting a role for monofunctional platinum anticancer agents in human cancer therapy. This information also provides support for the validity of the proposed mechanism of action of cisplatin and provides a rational basis for the design of more potent platinum anticancer drug candidates using a monofunctional DNA-damaging strategy.


Urinary-type plasminogen activator (uPA) expression and uPA receptor localization are regulated by alpha 3beta 1 integrin in oral keratinocytes.
Expression of urinary-type plasminogen activator (uPA) and its receptor (uPAR) is correlated with matrix proteolysis, cell adhesion, motility, and invasion. To evaluate the functional link between adhesion and proteolysis in gingival keratinocytes (pp126), cells were treated with immobilized integrin antibodies to induce integrin clustering. Clustering of alpha(3) and beta(1) integrin subunits, but not alpha(2), alpha(5), alpha(6), or beta(4), enhanced uPA secretion. Bead-immobilized laminin-5 and collagen I, two major alpha(3)beta(1) ligands, also induced uPA expression. Coordinate regulation of the serpin plasminogen activator inhibitor 1 was also apparent; however, a net increase in uPA activity was predominant. alpha(3)beta(1) integrin clustering induced extracellular signal-regulated kinase 1/2 phosphorylation, and both uPA induction and extracellular signal-regulated kinase activation were blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059. Integrin aggregation also promoted a dramatic redistribution of uPAR on the cell surface to sites of clustered alpha(3)beta(1) integrins. Co-immunoprecipitation of beta(1) integrin with uPAR provided further evidence that protein-protein interactions between uPAR and beta(1) integrin control uPAR distribution. As a functional consequence of uPA up-regulation and uPA-mediated plasminogen activation, the globular domain of the laminin-5 alpha(3) subunit, a major pp126 matrix protein, was proteolytically processed from a 190-kDa form to a 160-kDa species. Laminin-5 containing the 160-kDa alpha(3) subunit efficiently nucleates hemidesmosome formation and reduces cell motility. Together, these data suggest that multivalent aggregation of the alpha(3)beta(1) integrin regulates proteinase expression, matrix proteolysis, and subsequent cellular behavior.


Evolution of Orthonectida body plan.
Orthonectida is an enigmatic group of animals with still uncertain phylogenetic position. Orthonectids parasitize various marine invertebrates. Their life cycle comprises a parasitic plasmodium and free-living males and females. Sexual individuals develop inside the plasmodium; after egress from the host they copulate in the external environment, and the larva, which has developed inside the female infects a new host. In a series of studied orthonectid species simplification of free-living sexual individuals can be clearly traced. The number of longitudinal and transverse muscle fibers is gradually reduced. In the nervous system, simplification is even more pronounced. The number of neurons constituting the ganglion is dramatically reduced from 200 in Rhopalura ophiocomae to 4-6 in Intoshia variabili. The peripheral nervous system undergoes gradual simplification as well. The morphological simplification is accompanied with genome reduction. However, not only genes are lost from the genome, it also undergoes compactization ensured by extreme reduction of intergenic distances, short intron sizes, and elimination of repetitive elements. The main trend in orthonectid evolution is simplification and miniaturization of free-living sexual individuals coupled with reduction and compactization of the genome.


The biosynthetic incorporation of selenomethionine and telluromethionine into pyrrolidone carboxyl peptidase (PYRase) from S. aureus.
Heavy-atom derivatives of PYRase proteins prepared in the past have been unsuitable for x-ray diffraction analysis. Thus, we propose utilizing unnatural metalloid-containing amino acids as an alternative to heavy-atom derivatization. Selenomethionine-containing proteins analyzed by multiwavelength anomalous diffraction provides a facile means of addressing the phase problem, whose solution is necessary to determine protein structures by X-ray Crystallography [Hendrickson, et al., 1991 and references therein]. Telluromethionine-containing proteins offer the same investigational potential, and additionally allow further simplification of the data collection technique by requiring only traditional methods of phase analysis [Boles et al., 1995 and references therein]. We sought to introduce the required Se and Te atoms into Staphylococcus aureus Pyrrolidone Carboxyl Peptidase (PYRase) via selenomethionine (SeMet) and telluromethionine (TeMet). Complete incorporation of SeMet into S. aureus PYRase was succeeded with little change in enzymatic properties. Incomplete incorporation (75%) of TeMet was accomplished in preparing TeMet-PYRase, however, representing the highest incorporation to date of a tellurium-containing amino acid. Enzymatic properties remained unchanged when TeMet was incorporated. We report herein the biosynthetic substitution and expression, protein purification and comparative biochemistry of SeMet-PYRase and TeMet-PYRase.


Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation.
Recent studies support the hypothesis that soluble oligomers of amyloid beta-peptide (Abeta) rather than mature amyloid fibrils are the earliest effectors of synaptic compromise in Alzheimer's disease. We took advantage of an amyloid precursor protein-overexpressing cell line that secretes SDS-stable Abeta oligomers to search for inhibitors of the pathobiological effects of natural human Abeta oligomers. Here, we identify small molecules that inhibit formation of soluble Abeta oligomers and thus abrogate their block of long-term potentiation (LTP). Furthermore, we show that cell-derived Abeta oligomers can be separated from monomers by size exclusion chromatography under nondenaturing conditions and that the isolated, soluble oligomers, but not monomers, block LTP. The identification of small molecules that inhibit early Abeta oligomer formation and rescue LTP inhibition offers a rational approach for therapeutic intervention in Alzheimer's disease and highlights the utility of our cell-culture paradigm as a useful secondary screen for compounds designed to inhibit early steps in Abeta oligomerization under biologically relevant conditions.


Idiopathic flexible flatfoot in the adolescent.
In summary, factors to consider in treatment are (1) the patient's age; (2) the flexibility of the condition; (3) the severity of deformity; (4) the presence of equinus; (5) abnormal shoe wear; and (6) the symptoms. When a child presents with severe flexible flatfoot one should rule out an underlying neuromuscular disorder and perform a complete biomechanical evaluation to ascertain any rotational or angular conditions of the legs that might influence the treatment. If a child is in group 1 (ages 4 to 7), a Helfet heel seat with a medial plantar wedge is usually adequate treatment. In the group II (ages 8 to 12) adolescent with flexible flatfoot, more control of the calcaneal eversion is needed. This is obtained by using a device constructed from a plaster mold taken while the foot is in neutral position. This UCBL type of device must usually extend to the metatarsal heads and be elevated on the medial and lateral sides. The group III (ages 13 to 17) adolescent usually has the additional problem of a forefoot varus, which must be controlled using a forefoot post. It is also not unusual to have to add additional wedging inside the heel of the shoe to invert the heel.


Amphibian neural crest cell migration on purified extracellular matrix components: a chondroitin sulfate proteoglycan inhibits locomotion on fibronectin substrates.
The ability of purified extracellular matrix components to promote the initial migration of amphibian neural crest (NC) cells was quantitatively investigated in vitro. NC cells migrated avidly on fibronectin (FN), displaying progressively more extensive dispersion at increasing amounts of material incorporated in the substrate. In contrast, dispersion on laminin substrates was optimal at low protein concentrations but strongly reduced at high concentrations. NC cells were unable to migrate on substrates containing a high molecular mass chondroitin sulfate proteoglycan (ChSP). When proteolytic peptides, representing isolated functional domains of the FN molecule, were tested as potential migration substrates, the cell binding region of the molecule (105 kD) was found to be as active as the intact FN. A 31-kD heparin-binding fragment also stimulated NC cell migration, whereas NC cells dispersed to a markedly lower extent on the isolated collagen-binding domain (40 kD), or the latter domain linked to the NH2-terminal part of the FN molecule. Migration on the intact FN was partially inhibited by antibodies directed against the 105- and 31-kD fragments, respectively; dispersion was further decreased when the antibodies were used in combination. Addition of the ChSP to the culture medium dramatically perturbed NC cell migration on substrates of FN, as well as of 105- or 31-kD fragments. However, preincubation of isolated cells or substrates with ChSP followed by washing did not affect NC cell movement. The use of substrates consisting of different relative amounts of ChSP and the 105-kD peptide revealed that ChSP counteracted the motility-promoting activity of the 105-kD FN fragment in a concentration-dependent manner also when bound to the substrate. Our results indicate that NC cell migration on FN involves two separate domains of the molecule, and that ChSP can modulate the migratory behavior of NC cells moving along FN-rich pathways and may therefore influence directionally and subsequent localization of NC cells in the embryo.


Distributed rewiring model for complex networking: The effect of local rewiring rules on final structural properties.
The study of complex networks has become an important subject over the last decades. It has been shown that these structures have special features, such as their diameter, or their average path length, which in turn are the explanation of some functional properties in a system such as its fault tolerance, its fragility before attacks, or the ability to support routing procedures. In the present work, we study some of the forces that help a network to evolve to the point where structural properties are settled. Although our work is mainly focused on the possibility of applying our ideas to Information and Communication Technologies systems, we consider that our results may contribute to understanding different scenarios where complex networks have become an important modeling tool. Using a discrete event simulator, we get each node to discover the shortcuts that may connect it with regions away from its local environment. Based on this partial knowledge, each node can rewire some of its links, which allows modifying the topology of the entire underlying graph to achieve new structural properties. We proposed a distributed rewiring model that creates networks with features similar to those found in complex networks. Although each node acts in a distributed way and seeking to reduce only the trajectories of its packets, we observed a decrease of diameter and an increase in clustering coefficient in the global structure compared to the initial graph. Furthermore, we can find different final structures depending on slight changes in the local rewiring rules.


The Nurr1 Activator 1,1-Bis(3'-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor κB.
NR4A family orphan nuclear receptors are an important class of transcription factors for development and homeostasis of dopaminergic neurons that also inhibit expression of inflammatory genes in glial cells. The identification of NR4A2 (Nurr1) as a suppressor of nuclear factor κB (NF-κB)-related neuroinflammatory genes in microglia and astrocytes suggests that this receptor could be a target for pharmacologic intervention in neurologic disease, but compounds that promote this activity are lacking. Selected diindolylmethane compounds (C-DIMs) have been shown to activate or inactivate nuclear receptors, including Nurr1, in cancer cells and also suppress astrocyte inflammatory signaling in vitro. Based upon these data, we postulated that C-DIM12 [1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane] would suppress inflammatory signaling in microglia by a Nurr1-dependent mechanism. C-DIM12 inhibited lipopolysaccharide (LPS)-induced expression of NF-κB-regulated genes in BV-2 microglia including nitric oxide synthase (NOS2), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2), and the effects were attenuated by Nurr1-RNA interference. Additionally, C-DIM12 decreased NF-κB activation in NF-κB-GFP (green fluorescent protein) reporter cells and enhanced nuclear translocation of Nurr1 primary microglia. Chromatin immunoprecipitation assays indicated that C-DIM12 decreased lipopolysaccharide-induced p65 binding to the NOS2 promoter and concurrently enhanced binding of Nurr1 to the p65-binding site. Consistent with these findings, C-DIM12 also stabilized binding of the Corepressor for Repressor Element 1 Silencing Transcription Factor (CoREST) and the Nuclear Receptor Corepressor 2 (NCOR2). Collectively, these data identify C-DIM12 as a modulator of Nurr1 activity that results in inhibition of NF-κB-dependent gene expression in glial cells by stabilizing nuclear corepressor proteins, which reduces binding of p65 to inflammatory gene promoters.


Zinc-α2-glycoprotein as an inhibitor of amine oxidase copper-containing 3.
Zinc-α2-glycoprotein (ZAG) is a major plasma protein whose levels increase in chronic energy-demanding diseases and thus serves as an important clinical biomarker in the diagnosis and prognosis of the development of cachexia. Current knowledge suggests that ZAG mediates progressive weight loss through β-adrenergic signalling in adipocytes, resulting in the activation of lipolysis and fat mobilization. Here, through cross-linking experiments, amine oxidase copper-containing 3 (AOC3) is identified as a novel ZAG binding partner. AOC3-also known as vascular adhesion protein 1 (VAP-1) and semicarbazide sensitive amine oxidase (SSAO)-deaminates primary amines, thereby generating the corresponding aldehyde, H2O2 and NH3. It is an ectoenzyme largely expressed by adipocytes and induced in endothelial cells during inflammation. Extravasation of immune cells depends on amine oxidase activity and AOC3-derived H2O2 has an insulinogenic effect. The observations described here suggest that ZAG acts as an allosteric inhibitor of AOC3 and interferes with the associated pro-inflammatory and anti-lipolytic functions. Thus, inhibition of the deamination of lipolytic hormone octopamine by AOC3 represents a novel mechanism by which ZAG might stimulate lipolysis. Furthermore, experiments involving overexpression of recombinant ZAG reveal that its glycosylation is co-regulated by oxygen availability and that the pattern of glycosylation affects its inhibitory potential. The newly identified protein interaction between AOC3 and ZAG highlights a previously unknown functional relationship, which may be relevant to inflammation, energy metabolism and the development of cachexia.


Prospective associations with physiological, psychosocial and educational outcomes of meeting Australian 24-Hour Movement Guidelines for the Early Years.
Several countries have released movement guidelines for children under 5 that incorporate guidelines for sleep, physical activity and sedentary behavior. This study examines prospective associations of preschool children's compliance with the 24-Hour Australian movement guidelines (sleep, physical activity, screen time) and physiological, psychosocial and educational outcomes during primary school. Data were from the Healthy Active Preschool and Primary Years Study (Melbourne, Australia; n = 471; 3-5 years; 2008/9). Follow-ups occurred at 3 (2011/12; 6-8 years), 6 (2014/15; 9-11 years) and 7 (2016; 10-12 years) years post baseline. Multiple regression models assessed associations between compliance with guidelines at baseline and later outcomes. Children were 4.6 years at baseline (53% boys; 62% high socio-economic families). Most children met physical activity (89%) and sleep (93%) guidelines; 23% met screen-time guidelines; and 20% met all guidelines at baseline. Meeting all of the three guidelines was associated with lower BMI z-scores at 9-11 years of age (b = - 0.26, 95%CI -0.47, - 0.05). Meeting physical activity guidelines was associated with higher total body bone mineral density (b = 0.64, 95%CI 0.15, 1.13), and total body bone mineral content (b = 183.19, 95%CI 69.92, 296.46) at 10-12 years of age. Meeting sleep guidelines was associated with better reading (b = 37.60, 95%CI 6.74, 68.46), spelling (b = 34.95, 95%CI 6.65, 63.25), numeracy (b = 39.09, 95%CI 11.75, 66.44), language (b = 44.31, 95%CI 11.77, 76.85) and writing (b = 25.93, 95%CI 0.30, 51.57) at 8-9 years of age. No associations were evident for compliance with screen-time guidelines or for psychosocial outcomes. Compliance with different movement behavior guidelines was associated with different outcomes. Strategies to support children in meeting all of the guidelines are warranted to maximize health and educational outcomes. Future research investigating dose-response associations, and potential mechanisms, is necessary.


[Expression of augmenter of liver regeneration in hepatic tumor cells and its clinical significance].
To investigate the effects of augmenter of liver regeneration (ALR) on the proliferation of hepatocytes and hepatic tumor cells and the expression of ALR in herpatocellular carcinoma (HCC). Primary rat hepatocytes, QGY and HepG2 cells were cultured separately with ALR from different species. Cell proliferation was detected by their 3H-TdR uptake. The expression of ALR was examined in 9 normal hepatic tissues and 21 HCC cases using immunohistochemistry method. Different ALRs could stimulate the proliferation of HepG2 and QGY cells in a dose-dependent way in vitro, but all ALR had no influence in the proliferation of primary rat hepatocytes. The expression of ALR was absent in normal hepatic tissues, but present in all HCC hepatic tissues. However, the expression of ALR had no relationship with the differentiation and size of the carcinomas. ALR might play an important role in the occurrence and development of HCC.


Association of mucosal-associated invariant T cells with different disease phases of polymyalgia rheumatica.
Although T cells are thought to be involved in the pathogenesis of PMR, whether innate-like T cells are involved in the process remains unknown. The serum levels of 27 cytokines/chemokines in patients with PMR were measured by a multiplex immunoassay (Bio-Plex Assay). The cytokine-producing capacity of T and innate-like T cells was assessed by intracellular cytokine staining and flow cytometry. The frequency and activated status of T and innate-like T cells were investigated by flow cytometry and their associations with clinical parameters were assessed. The levels of inflammatory cytokines were associated with disease activity in PMR. The cytokine-producing capacity by CD8+ T and innate-like T cells was associated with disease activity. The frequency of HLA-DR+ CD38+ cells among CD8+ T cells was increased in patients with active disease. The frequencies of HLA-DR+ CD38+ cells among CD4+ T, mucosal-associated invariant T (MAIT) and γδ T cells were higher in patients with inactive disease. The frequency of HLA-DR+ CD38+ MAIT cells was associated with the PMR activity score and CRP levels in patients in remission. The inflammatory cytokine-producing capacity and expression of activation markers of CD8+ T and innate-like T cells were associated with the disease activity of PMR. MAIT cell activation in patients in remission may contribute to the subclinical activity of the disease.


Malliavin weight sampling for computing sensitivity coefficients in Brownian dynamics simulations.
We present a method for computing parameter sensitivities and response coefficients in Brownian dynamics simulations. The method involves tracking auxiliary variables (Malliavin weights) in addition to the usual particle positions, in an unperturbed simulation. The Malliavin weights sample the derivatives of the probability density with respect to the parameters of interest and are also interesting dynamical objects in themselves. Malliavin weight sampling is simple to implement, applies to equilibrium or nonequilibrium, steady state or time-dependent systems, and scales more efficiently than standard finite difference methods.


Asynchronous bidirectional replication of polyoma virus DNA.
The structure of polyoma virus replicative intermediates isolated from infected 3T6 cells was analyzed by two-dimensional agarose gel electrophoresis (Sundin and Varshavsky, Cell 21:103-114, 1980) and quantitative electron microscopy (Krauss and Benbow, J. Virol. 38:815-825, 1981). DNA replication was initiated at a single site (ori) in essentially all of the replicative intermediates. Most of the early replicative intermediates were formed by unidirectional synthesis in the direction of early transcription. Most mid- and late replicative intermediates contained two replication forks which had traveled unequal distances from the origin. Asynchronous initiation of the two growing forks was postulated to account for these observations.


[Molecular and genetic polymorphism of cultivated soybean detected by AP-PCR, SSRP and SSR].
Molecular-genetic polymorphism of cultivated soybean from different geographic regions was analysed using three PCR methods (AP-PCR, SSRP and ISSR). The dendrogram of phenogenetic relationship was constructed on the base of obtained data. The allocation of varieties are in a good agreement with pedigree information. Main parameters such as polymorphism level, expected heterozygosity, and marker index were calculated. It was shown that ISSR is the method of choice for the differentiation of soybean varieties.


Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer.
A sensitive and acceptable screening regimen for women at high risk for breast cancer is essential. Contrast-enhanced magnetic resonance imaging (MRI) of the breast is highly sensitive for diagnosis of breast cancer but has variable specificity. To summarize the sensitivity, specificity, likelihood ratios, and posttest probability associated with adding MRI to annual mammography screening of women at very high risk for breast cancer. English-language literature search of the MEDLINE, EMBASE, and Cochrane databases from January 1995 to September 2007, supplemented by hand searches of pertinent articles. Prospective studies published after 1994 in which MRI and mammography (with or without additional tests) were used to screen women at very high risk for breast cancer. Methods and potential biases of studies were assessed by 2 reviewers, and data were extracted and entered into 2 x 2 tables that compared American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) scores of MRI plus mammography, mammography alone, or MRI alone with results of breast tissue biopsies. Eleven relevant, prospective, nonrandomized studies that ranged from small single-center studies with only 1 round of patient screening to large multicenter studies with repeated rounds of annual screening were identified. Characteristics of women that varied across study samples included age range, history of breast cancer, and BRCA1 or BRCA2 mutation status. Studies used dynamic contrast-enhanced MRI with axial or coronal plane images (European studies) or sagittal images (North American studies) that were usually interpreted without knowledge of mammography results. The summary negative likelihood ratio and the probability of a BI-RADS-suspicious lesion (given negative test findings and assuming a 2% pretest probability of disease) were 0.70 (95% CI, 0.59 to 0.82) and 1.4% (CI, 1.2% to 1.6%) for mammography alone and 0.14 (CI, 0.05 to 0.42) and 0.3% (CI, 0.1% to 0.8%) for the combination of MRI plus mammography, using a BI-RADS score of 4 or higher as the definition of positive. Differences in patient population, center experience, and criteria for positive screening results led to between-study heterogeneity. Data on patients with nonfamilial high risk were limited, and no data were available on recurrence or survival. Screening with both MRI and mammography might rule out cancerous lesions better than mammography alone in women who are known or likely to have an inherited predisposition to breast cancer.


Cellular Immunobiology and Molecular Mechanisms in Alloimmunity-Pathways of Immunosuppression.
Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.


Exploring underutilization of videophones in hospice settings.
The aim of this study was to evaluate hospice providers' attitudes and perceptions regarding videophone technology in settings where the technology was introduced but underutilized. Specifically, the project seeks to provide an in-depth understanding of attitudes and perceptions that may lead to failure of a telehealth implementation in the hospice setting in the context of the technology acceptance model. Two hospice agencies were selected as a purposive sample. Both agencies had acquired videophones that were meant to be integrated into care delivery but ultimately were underutilized or never used. Interviews with staff were conducted over the telephone. The interview guide was constructed to capture staff perceptions and attitudes concerning videophone technology. Interviews were audiotaped and transcribed for content analysis. A total of 17 (n = 17) participants (2 hospice administrators, 1 hospice management staff, 10 nurse case managers, and 4 social workers) were interviewed. Participants found videophones to be useful in hospice care but expressed specific practical challenges, such as lack of equipment reliability, lack of human resources, and lack of clarity pertaining to caregiver eligibility criteria. While perceived usefulness of videophones was high among respondents, practical concerns can be interpreted as lack of perceived ease of use. Findings indicate that the Technology Acceptance Model (TAM) provides a good framework for an understanding of telehealth underutilization. Staff perceived that videophones were useful, but they were discouraged by their perception that the videophones were not reliable or easy to use and by their uncertainty about the cases that they were best suited for. Lessons learned are integrated into a randomized clinical trial currently under development.


The effect of diurnal variation on total plasma calcium concentration in normal subjects.
In 12 normal subjects plasma calcium and phosphorus concentrations were estimated during a normal working day. In the individual subjects fluctuations from the fasting values occurred during the period of study, but at no time during that period did the mean values differ significantly from the fasting plasma calcium or phosphorus concentrations. In three of the subjects the study was repeated while fasting during a normal working day. In these subjects the fluctuations in both plasma calcium and phosphorus concentrations were less than during a normal day while taking meals, and there was evidence of a diurnal variation in the plasma phosphorus concentration.


Interpersonal determinants of eating behaviours in Dutch older adults living independently: a qualitative study.
Eating behaviour of older adults is influenced by a complex interaction of determinants. Understanding the determinants of a specific target group is important when developing targeted health-promoting strategies. The aim of this study was to explore interpersonal determinants of eating behaviours in older adults living independently in a specific neighbourhood in the Netherlands. In the neighbourhood of interest, populated by relatively many older adults, fifteen semi-structured interviews were conducted with independently living older adults (aged 76.9 ± 6.4y). Interviews were complemented with observations among the target group: three occasions of grocery shopping and three collective eating occasions in the neighbourhood. A thematic approach was used to analyse the qualitative data. When we asked the older adults unprompted why they eat what they eat, the influence of interpersonal determinants did not appear directly; respondents rather mentioned individual (e.g. habits) and environmental factors (e.g. food accessibility). Key findings regarding interpersonal factors were: 1) Behaviours are shaped by someone's context; 2) Living alone influences (determinants of) eating behaviour via multiple ways; 3) There is a salient norm that people do not interfere with others' eating behaviour; 4) Older adults make limited use of social support (both formal and informal) for grocery shopping and cooking, except for organised eating activities in the neighbourhood. In this particular neighbourhood, many facilities (e.g. shops at walking distance) are present, and events (e.g. dinners) are organised with and for the target group, which likely impact (determinants of) their behaviours. The study showed that older adults do not directly think of interpersonal factors influencing their eating behaviour, but rather of individual or environmental factors. However, multiple interpersonal factors did appear in the interviews and observations. Moreover, neighbourhood-specific factors seem to play a role, which underlines the need to understand the specific (social) setting when developing and implementing intervention programmes. Insights from this study can assist in developing health-promoting strategies for older adults, taking into account the context of the specific neighbourhood.


Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review.
Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.


Detection of a circadian enhancer in the mDbp promoter using prokaryotic transposon vector-based strategy.
In mammals, the expression of 5-10% of genes occurs with circadian fluctuation in various organs and tissues. This cyclic transcription is thought to be directly or indirectly regulated through circadian transcriptional/translational feedback loops consisting of a set of clock genes. Among the clock genes in mammals, expression of the Dbp mRNA robustly oscillates both in vivo and in culture cells. Here, we present circadian enhancer detection strategy using prokaryotic transposon system. The mDbp promoter drives reporter gene expression in robust circadian cycles in rat-1 fibroblasts. To identify the circadian enhancer generating this robust rhythm, we developed a prokaryotic transposon-based enhancer detecting vector for in vitro transposition. Using this system, we identified a strong circadian enhancer region containing the CATGTG sequence in the 5' flanking region of the mDbp gene; this enhancer region is critical for the ability of the mDbp promoter to drive robust oscillation in living cells. This enhancer is classified as a CANNTG type non-canonical E-box. These findings strongly suggest that CANNTG-type non-canonical E-boxes may contribute, at least in part, to the regulation of robust circadian gene expression. Furthermore, these data may help explain the wider effects of the CLOCK/BMAL1 complex in control of clock output genes.


Development of a family caregiver needs-assessment scale for end-of-life care for senility at home (FADE).
This study aimed to develop a "family caregiver needs-assessment scale for end-of-life care for senility at home" (FADE) and examine its reliability and validity. A draft item pool was developed based on a literature review, and simplified to 30 items in four domains. Next, the item pool was reviewed by four visiting nurses and four researchers and refined to 15 items. A cross-sectional study was then conducted using a self-reported questionnaire. Questionnaires were sent to 2703 visiting nurses. The survey questions included participants' basic demographic information, the importance of each item according to a modified scale, basic demographics for cases of death by senility at home, satisfaction with each item of the modified scale in an example case, and assessment of the case using the Japanese version of the Support Team Assessment Schedule (STAS-J). Internal consistency was assessed using Cronbach's alpha. Construct validity was confirmed using confirmatory factor analysis, and correlation between the new scale and the STAS-J was used to assess criterion-related validity. In total, 461 visiting nurses provided valid responses. The exploratory and confirmatory factor analyses identified 12 items from two factors: "Needs for adaptation to senility bereavement" and "Needs for essential skills in supporting a dignified death by senility." The final model showed appropriate index values: standardized root mean residual = 0.057, Tucker-Lewis index = 0.920, Akaike information criterion = 191.6, and Bayesian information criterion = 298.2. Cronbach's alpha for the entire scale was 0.908, and was above 0.840 for each factor. The correlation coefficient between STAS-J and the entire scale was 0.259-0.427 (p<0.001). The FADE scale showed acceptable internal consistency and concurrent validity. The scale can help clarify issues and desires that present themselves at home related to adaptation to senility bereavement and essential skills in supporting a dignified death by senility. Addressing these issues and desires is expected to reduce caregivers' anxiety and burden, and means the older adults under their care may be respected and enabled to live with dignity and peace.


When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?
Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations. In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters. In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups. According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.


Deletions of chromosome 4 occur early during the pathogenesis of colorectal carcinoma.
Allelic losses at one or both arms of chromosome 4 are frequent in several tumor types, but information about colorectal carcinoma is limited. We have previously defined 4 nonoverlapping regions of frequent deletions in several tumor types. In an effort to more precisely locate the putative tumor suppressor gene(s) on chromosome 4 involved in the multistage pathogenesis of colorectal carcinomas, we performed loss of heterozygosity (LOH) studies using 19 polymorphic microsatellite markers. After precise microdissection of archival surgical cases, we determined LOH in DNA obtained from 23 colorectal adenocarcinomas, 20 colorectal adenomas, and from corresponding histologically normal-appearing colonic epithelial samples adjacent to the tumors and at the resection margins. We observed localized deletions of chromosome 4 at multiple regions in both carcinomas and adenomas. We identified deletions at 4 previously identified regions: R1 at 4q33-34 (18%-33%), R2 at 4q25-26 (45%-65%), R3 at 4p15.1-15.3 (35%-47%), and R4 at 4p16.3 (40%-49%). Six of fifteen (40%) cases examined with deletions of chromosome 4 in either adenocarcinomas or adenomas had loss of the same parental alleles in adjacent histologically normal epithelium but not in epithelial samples from the surgical resection margins. The deletions, which commenced on the short arm of chromosome 4 (regions R3 and/or R4), were more extensive in adenocarcinomas, intermediate in length in adenomas, and least extensive in histologically normal epithelium. Our results suggest that there may be multiple putative tumor suppressor genes located on both arms of chromosome 4 whose inactivation are important early events in the pathogenesis of colorectal carcinoma.


A brief experimental alcohol beverage-tailored program for adolescents.
The objective of this study was to develop and test a brief, experimental alcohol preventive intervention matched to the use of specific alcohol beverages among adolescents. A total of 232 high school students who drank within the last year participated in this study. Participants were randomly assigned to either the experimental intervention or a minimal intervention control. Four-month postintervention data are reported. Overall multivariate analyses of covariance (MANCOVAs) were significant (p's < .05) on risk factors (influenceability, perceived severity, perceived susceptibility and perceived peer prevalence) for three of six beverages (beer, wine and distilled spirits), with a fourth, malt liquor, approaching significance (p = .06). These tests showed intervention adolescents experiencing less risk for alcohol use than control adolescents. In addition, whereas the overall MANCOVA for malt liquor use was not significant, univariate analyses were significant for 30-day frequency (F = 5.69, 1/195 df, p = .01) and 30-day quantity of malt liquor use (F = 4.03, 1/195 df, p = .04) with intervention adolescents showing less consumption than control adolescents. A post hoc analysis examining differential intervention effects using preintervention drug use as a factor (i.e., 30-day cigarette or marijuana use) showed a significant overall factorial MANCOVA interaction (F = 6.90, 4/189 df, p = .000), with drug-using intervention adolescents consuming cigarettes and marijuana less frequently than drug-using control adolescents at postintervention. The findings of this study suggest the brief, beverage-tailored intervention reduced certain risk factors mediating individual alcohol beverage use and consumption of malt liquor (4 months after intervention) and may have reduced the frequency of cigarette and marijuana use among those already using drugs.


The effect of typing frequency and speed on the incidence of upper extremity cumulative trauma disorder.
Typing in the work setting, with its emphasis on speed, force and repetitive movements and its tendency to be performed under less than optimum conditions has been one of the major causes of upper extremity cumulative trauma disorder (CTD). This disorder, also known as overuse syndrome, is a chronic condition believed to result from habitual overuse of the digits, hands or arms. The objective of this study was to examine the relationship between typing habits, specifically the influence of typing frequency, speed and style, on the incidence of injury. One hundred Israeli female typists aged between 20 and 60 years with no prior history of orthopedic or neurological disease participated in the study. Data collection took place at the work setting and consisted of a clinical evaluation of the upper extremities and trunk, a typing test, and a questionnaire which included questions concerning demographic information, occupational history, and upper extremity usage in the home and at work. Subjects were asked whether they had suffered from pain or other symptoms in the upper extremity (shoulder, arm, forearm, elbow or hand) on more than three occasions in the last year or on one occasion lasting more than a week. Subjects who answered no to this question were designated as 'non-sufferers'. Those who answered yes to the question were designated 'sufferers'. The 100 women who participated in the study represented a wide range of ages and educational levels. The variables describing on-the-job performance showed a wide range of values. Similar variability was found in the anthropometric variables. On the basis of the subjective criterion, 40 of the women belonged to the group labeled 'sufferers'. The remaining 60 subjects belonged to the group of 'non-sufferers'. The Odd's ratio test (OR), a common statistical procedure for risk factor estimation, was used to determine threshold levels associated with the development of CTD. Age, hours worked per week, typing speed, and years worked as a typist were variables in which at least one cut-off value generated a significant OR. The delineation of factors associated with typists who are classified as 'sufferers' establishes a portrait of the typical worker at risk for the development of CTD and provides insight into ways in which employers, clinicians and workers themselves could reduce the risk of CTD.


Purification and initial characterization of human placental trophoblast interferon induced by polyriboinosinic.polyribocytidylic acid.
Human placental trophoblast interferon (tro-IFN), induced in trophoblast cultures by a superinduction procedure, was purified to a homogeneous product with retention of biological activity. The problems associated with isolation from serum-containing medium were overcome by a combination of Blue Sepharose affinity chromatography and reversed-phase HPLC (RP-HPLC) on Separon SGX C-18. This two-step purification procedure yielded tro-IFN with a specific activity of 3.4 x 10(7) international units/mg of protein. The overall recovery of interferon activity was 66.7%. The purified tro-IFN was shown to be a glycoprotein with an Mr of 24K on native and SDS-PAGE. Its antiviral activity was stable at pH 2.0 at 37 degrees C but was sensitive to heat at 56 degrees C for 1 h and was neutralized by antibodies to human IFN-beta.


Nasal and cloacal bacteria in free-ranging desert tortoises from the western United States.
Aerobic bacteria were collected from three free-ranging desert tortoise (Gopherus agassizii) populations in the eastern Mojave Desert (Arizona, Utah; USA) from 1989 to 1993, and from two free-ranging populations in the central Sonoran Desert (Arizona, USA) from 1990 to 1994. Six species of nasal bacteria and 18 species of cloacal bacteria were identified. At least one potential pathogen was found in the nasal cavity (Pasteurella testudinis), and at least two potential pathogens in the cloaca (Pseudomonas spp., Salmonella spp.).


Comparison of Two-Talker Attention Decoding from EEG with Nonlinear Neural Networks and Linear Methods.
Auditory attention decoding (AAD) through a brain-computer interface has had a flowering of developments since it was first introduced by Mesgarani and Chang (2012) using electrocorticograph recordings. AAD has been pursued for its potential application to hearing-aid design in which an attention-guided algorithm selects, from multiple competing acoustic sources, which should be enhanced for the listener and which should be suppressed. Traditionally, researchers have separated the AAD problem into two stages: reconstruction of a representation of the attended audio from neural signals, followed by determining the similarity between the candidate audio streams and the reconstruction. Here, we compare the traditional two-stage approach with a novel neural-network architecture that subsumes the explicit similarity step. We compare this new architecture against linear and non-linear (neural-network) baselines using both wet and dry electroencephalogram (EEG) systems. Our results indicate that the new architecture outperforms the baseline linear stimulus-reconstruction method, improving decoding accuracy from 66% to 81% using wet EEG and from 59% to 87% for dry EEG. Also of note was the finding that the dry EEG system can deliver comparable or even better results than the wet, despite the latter having one third as many EEG channels as the former. The 11-subject, wet-electrode AAD dataset for two competing, co-located talkers, the 11-subject, dry-electrode AAD dataset, and our software are available for further validation, experimentation, and modification.


Classification of Mental Stress Levels using EEG Connectivity and Convolutional Neural Networks.
Classifying mental stress is important as it helps in identifying the type and severity of stress, which can inform the most appropriate treatment or intervention. In this study, we propose utilizing electroencephalography (EEG) signals with convolutional neural networks (CNNs) to classify four mental states: rest, control-alert, stress and stress mitigation. The mental stress state was induced using Stroop color word test (SCWT) with time constrains and was then mitigated using 16 Hz Binaural beat stimulation (BBs). We quantified the four mental states using the reaction time (RT) to stimuli, accuracy of target detection, subjective score, and functional connectivity images of EEG estimated by Phase Locking Value (PLV). Our results show that, the SCWT reduced the accuracy of target detection by 70% with (F= 24.56, p = .00001), and the BBs improved the accuracy by 28% (F= 4.54, p = .00470). The functional connectivity network showed different patterns between the frontal/occipital and parietal regions, under the four mental states. The proposed CNNs with PLV images differentiated between the four mental states with highest classification performance at beta frequency band with 80.95% accuracy, 80.36% sensitivity, 94.75% specificity, 83.63% precision and 81.96% F-score. The overall results suggest that 16 Hz BBs can be used as an effective method to mitigate stress and the proposed CNNs with EEG-PLV images as a promising method for classifying different mental states.


A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma.
Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice. To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 μg) or switch to FP/FOR (1000/40 μg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 μg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. In phase 1, FP/FOR (1000/40 μg) (n = 126) was noninferior to FP/SAL (1000/100 μg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 μg) (n = 52) was noninferior to FP/FOR (1000/40 μg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007). In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.


Implementation of an On-Line lsokinetic Analysis System.
A cost effective and efficient means of obtaining torque, work, and power measurements for a large group of subjects was needed. As a solution to this problem, an Apple 111 microcomputer was interfaced to a Cybex II isokinetic dynamometer. This system provided instantaneous values for the three parameters listed above as well as additional options for filekeeping and data manipulation. Intraclass reliability coefficients for the parameters of torque, work, and power ranged from r = 0.991 to r = 0.999. It was concluded that a microcomputer support system is, in view of its time saving qualities and relative cost, an economical and efficient means of providing meaningful information for clinical analysis of patients. J Orthop Sports Phys Ther 1982;4(1):36-38.


Understanding the complex relationships underlying hot flashes: a Bayesian network approach.
The mechanism underlying hot flashes is not well-understood, primarily because of complex relationships between and among hot flashes and their risk factors. We explored those relationships using a Bayesian network approach based on a 2006 to 2015 cohort study of hot flashes among 776 female residents, 45 to 54 years old, in the Baltimore area. Bayesian networks were fit for each outcome (current hot flashes, hot flashes before the end of the study, hot flash severity, hot flash frequency, and age at first hot flashes) separately and together with a list of risk factors (estrogen, progesterone, testosterone, body mass index and obesity, race, income level, education level, smoking history, drinking history, and activity level). Each fitting was conducted separately on all women and only perimenopausal women, at enrollment and 4 years after enrollment. Hormone levels, almost always interrelated, were the most common variable linked to hot flashes; hormone levels were sometimes related to body mass index, but were not directly related to any other risk factors. Smoking was also frequently associated with increased likelihood of severe symptoms, but not through an antiestrogenic pathway. The age at first hot flashes was related only to race. All other factors were either not related to outcomes or were mediated entirely by race, hormone levels, or smoking. These models can serve as a guide for design of studies into the causal network underlying hot flashes.