Role of thyroid hormone in the morphological differentiation and maturation of astrocytes: temporal correlation with synthesis and organization of actin.
Morphological changes and the molecular mechanisms associated with the maturation of astrocytes were studied under normal and thyroid hormone-deficient conditions using long-term (30 days) primary cultures derived from the neonatal rat brain. Immunocytochemical staining of cells with a monoclonal antibody specific to glial fibrillary acidic protein demonstrated for the first time that, similar to their maturation in vivo, astrocytes maintained in normal serum-containing medium can undergo complete maturation involving two distinct stages of morphological differentiation (from radial glia to flat polygonal cells with epithelioid morphology and then to mature process-bearing cells with stellate morphology). Deficiency of thyroid hormone delays the first step and totally blocks the second stage of differentiation in the maturation process. Comparative staining of normal and thyroid hormone-deficient astrocytes with filamentous actin-specific fluorescein isothiocyanate-phalloidin and quantitation of the various forms of intracellular actin using an improved DNase I assay demonstrated that maturation of astroglial cells is associated with characteristic alterations in the level of cytoskeletal and noncytoskeletal filamentous (F) actin. In particular, the maintenance of the epithelioid form of the hypothyroid astrocytes is associated with a progressive increase in the level of cytoskeletal F-actin and a concomitant decline in the level of non-cytoskeletal F-actin. Quantitation of actin mRNA by Northern blot analysis and studies on the rate of actin synthesis at various stages of differentiation showed that the initial transformation into the epithelioid form is associated with an increase in the rate of synthesis of actin and the expression of its mRNA, while the final transformation into the nature process-bearing form is correlated with a decline in these parameters. The results indicates that thyroid hormone plays an obligatory role in promoting the differentiation and maturation of astrocytes, and that during this process the hormone regulates the expression of actin and its intracellular organization in a way conducive to morphological differentiation.


Absorption to reflection transition in selective solar coatings.
The optimum transition wavelength between high absorption and low emissivity for selective solar absorbers has been calculated in several prior treatises for an ideal system, where the emissivity is exactly zero in the infrared. However, no real coating can achieve such a low emissivity across the entire infrared with simultaneously high absorption in the visible. An emissivity of even a few percent radically changes the optimum wavelength separating the high and low absorption spectral bands. This behavior is described and calculated for AM0 and AM1.5 solar spectra with an infrared emissivity varying between 0 and 5%. With an emissivity of 5%, solar concentration of 10 times the AM1.5 spectrum the optimum transition wavelength is found to be 1.28 µm and have a 957K equilibrium temperature. To demonstrate typical absorptions in optimized solar selective coatings, a four-layer sputtered Mo and SiO₂ coating with absorption of 5% across the infrared is described experimentally and theoretically.


Vitamin D status and its relation to age and body mass index.
While numerous studies have examined 25(OH)-vitamin D(3) (25-D) concentrations and their relation to parathyroid hormone (PTH) levels there is only limited information on the interrelation between 25-D, 1,25(OH)(2)-vitamin D(3) (1,25-D) and PTH. It was the aim of this study to assess the vitamin D endocrine system and its relation to age and body mass index (BMI). This cross-sectional study comprised a convenience sample of 483 adults which attended the endocrinology outpatient service of a university hospital in the years 2002-2004. The mean concentrations of 25-D, 1,25-D, calcium and PTH were 21.0 +/- 10.6 ng/ml, 47.9 +/- 21.7 pg/ml, 9.48 +/- 0.48 mg/dl and 51.0 +/- 27.2 pg/ml, respectively. 25-D was related (p < 0.01) to BMI, age, PTH and 1,25-D. After correction for 25-D, we found no relation between BMI and 1,25-D. PTH was related (p < 0.01) to serum calcium, BMI, age and 1,25-D (p = 0015). There was a seasonal variation in both, 25-D and 1,25-D serum concentrations: 25-D levels were lowest in January and increased until July while the nadir and zenith of 1,25-D were found in April and October, respectively. Since BMI was negatively related to 25-D the prevalence of 25-D deficiency (<8.8 ng/ml) increased from 8.8% in subjects with BMI <30 kg/m(2) to 15.0% in subjects with BMI >30 kg/m(2). BMI, age and season should be taken into account when assessing a patients vitamin D status and more aggressive vitamin D supplementation should be considered for obese subjects.


Protein-tyrosine phosphatase 1B (PTP1B) deficiency confers resistance to transforming growth factor-β (TGF-β)-induced suppressor effects in hepatocytes.
Transforming growth factor-β (TGF-β) plays a dual role in hepatocytes, mediating both tumor suppressor and promoter effects. The suppressor effects of the cytokine can be negatively regulated by activation of survival signals, mostly dependent on tyrosine kinase activity. The aim of our work was to study the role of the protein-tyrosine phosphatase 1B (PTP1B) on the cellular responses to TGF-β, using for this purpose immortalized neonatal hepatocytes isolated from both PTP1B(+/+) and PTP1B(-/-) mice. We have found that PTP1B deficiency conferred resistance to TGF-β suppressor effects, such as apoptosis and growth inhibition, correlating with lower Smad2/Smad3 activation. Both responses were recovered in the presence of the general tyrosine kinase inhibitor genistein. PTP1B(-/-) cells showed elevated NF-κB activation in response to TGF-β. Knockdown of the NF-κB p65 subunit increased cell response in terms of Smads phosphorylation and apoptosis. Interestingly, these effects were accompanied by inhibition of Smad7 up-regulation. In addition, lack of PTP1B promoted an altered NADPH oxidase (NOX) expression pattern in response to TGF-β, strongly increasing the NOX1/NOX4 ratio, which was reverted by genistein and p65 knockdown. Importantly, NOX1 knockdown inhibited nuclear translocation of p65, promoted Smad phosphorylation, and decreased Smad7 levels. In summary, our results suggest that PTP1B deficiency confers resistance to TGF-β through Smad inhibition, an effect that is mediated by NOX1-dependent NF-κB activation, which in turn, increases the level of the Smad inhibitor Smad7 and participates in a positive feedback loop on NOX1 up-regulation.


Hepatitis C virus genotypes distribution and transmission risk factors in Luxembourg from 1991 to 2006.
To analyze the Hepatitis C virus (HCV) genotype distribution and transmission risk factors in a population of unselected patients in Luxembourg. Epidemiological information (gender, age and transmission risks) were collected from 802 patients newly diagnosed for hepatitis C and living in Luxembourg, among whom 228 patients referred from prison. Genotyping using 5'noncoding (5'NC) sequencing was performed. We compared categorical data using the Fisher's exact F-test and odds ratios (OR) were calculated for evaluating association of HCV genotype and risk factors. The sex ratio was predominantly male (2.2) and individuals aged less than 40 years represented 49.6% of the population. Genotype 1 was predominant (53.4%) followed by genotype 3 (33%). Among risk factors, intravenous drug usage (IVDU) was the most frequently reported (71.4%) followed by medical-related transmission (17.6%) including haemophilia, transfusion recipients and other nosocomial reasons. Genotype 3 was significantly associated to IVDU (OR = 4.84, P < 0.0001) whereas genotype 1 was significantly associated with a medical procedure (OR = 2.42, P < 0.001). The HCV genotype distribution from inmate patients differed significantly from the rest of the population (Chi-square test with four degrees of freedom, P < 0.0001) with a higher frequency of genotype 3 (46.5% vs 27.5%) and a lower frequency of genotype 1 and 4 (44.7% vs 56.8% and 5.3% vs 9.6%, respectively). IVDU was nearly exclusively reported as a risk factor in prison. We report the first description of the HCV genotype distribution in Luxembourg. The repartition is similar to other European countries, with one of the highest European prevalence rates of genotype 3 (33%). Since serology screening became available in 1991, IVDU remains the most common way of HCV transmission in Luxembourg.


Low yield of residual vulvar carcinoma and dysplasia upon re-excision for close or positive margins.
The objectives of this study are to determine the utility of re-excision after a primary diagnosis of vulvar carcinoma by assessing the frequency of residual carcinoma found upon re-excision and to quantitate the wound breakdown and carcinoma recurrence rates. We reviewed 1122 cases of VIN or vulvar carcinoma. Women who underwent re-excisional procedures, as part of their initial surgical treatment were identified. Associations between the margin status of the original excisional sample and histology of re-excision, as well as association between the depth of invasion upon initial excision and histology of re-excision were analyzed with Chi-square tests. We identified 84 evaluable patients, 72 with stage I disease, 4 with stage II, and 7 with stage III disease. Upon the initial excisional procedure, 33 patients (39%) had carcinoma-positive margins, 27 patients had VIN-positive margins (32%) and 24 patients (28%) had negative margins (>1mm). Upon re-excision, 1/24 (4%) patients with negative margins, 2/27 (7%) patients with VIN-positive margins, and 11/33 (33%) patients with carcinoma-positive margins were found to have carcinoma in the re-excision specimens (p<0.0001, χ(2)=31). Deeper tumor invasion of the initial excisional specimen (1-12mm) was associated with a higher chance of finding carcinoma upon re-excision (range 18-42%, depending on depth of invasion) (p=0.015, χ(2)=19). Nineteen patients (23%) had vulvar wound breakdown post re-excision. Twelve patients (15%) experienced recurrences. The yield of micro- or invasive carcinoma at re-excision is low, with a high wound breakdown rate. Re-excision should be considered for patients with margins positive for carcinoma, especially for women with deep invasion, while women with VIN or close but clear margins may be followed.


Chiral Pool Meets Chiral Catalysis: Eight-Step Convergent Total Synthesis of Anticancer Natural Lipid Mycalol.
An exemplary blend of chiral pool with chiral catalysis is exhibited in an eight-step (longest) convergent asymmetric total synthesis of mycalol, which is a promising anticancer natural lipid from a marine source. The polyhydroxy lipid is constructed by using four blocks, and two of which are derived from the chiral pool (d-mannitol and d-gluconolactone) and the other two by chiral catalysis (Sharpless epoxidation and Keck allylation). Alkylation and metathesis were used to knit the blocks in an excellent display of a modular convergent eight-step synthesis. The modular excess will enable rapid analogue generation as revealed by the convenient synthesis of 4-epi-mycalol similarly in an eight-step sequence.


Effects of Early and Current Environmental Enrichment on Behavior and Growth in Pigs.
Enriched environments are known to beneficially affect the behavior of pigs, as compared with barren pens. The influence of enrichment may, however, depend on pigs' early life housing experiences. The aim of this study was to investigate the long-term effects of early and later life environmental enrichment on behavior and growth in pigs with different coping styles. Pigs were housed in either barren pens or in larger pens enriched with rooting substrates from birth, and half of them experienced a housing switch, i.e., a loss or gain of enrichment, at 7 weeks of age, creating four treatment groups. Home pen behavior and body weight were recorded until 19 weeks of age. Pigs were classified as reactive or proactive based on a backtest at 2 weeks of age. Enrichment increased time spent exploring, chewing, and play and decreased oral manipulation of penmates and pen-directed exploring and chewing. Behavior of pigs that switched from barren to enriched pens or vice versa reflected not only their actual environment, but also their early life housing. As early and later life enrichment affected most behaviors in opposite directions, effects of enrichment, or lack thereof, after the switch were more pronounced in pigs that had experienced a different early life condition. For instance, pigs experiencing an upgrade from barren to enriched pens seemed to "catch-up" by showing more exploration and play. Conversely, pigs exposed to a downgrade displayed more oral manipulation of penmates than ones kept barren throughout, which particularly held for pigs with a reactive coping style. Effects of early life and current housing on several other behaviors depended on coping style too. Pigs housed in enriched conditions appeared better able to cope with weaning than barren housed pigs, as they gained more weight and had higher feed intake post-weaning. Barren housed pigs had a lower body weight than enriched pigs just before the switch, after which growth was mainly determined by actual housing, with enriched kept pigs having a higher feed intake and body weight. Thus, not only current housing conditions, but also a (mis)match with the early life environment may affect behavior and growth of pigs.


Fundamental relationships between blood pressure and cerebral blood flow in humans.
Cerebral blood flow responses to transient blood pressure challenges are frequently attributed to cerebral autoregulation (CA), yet accumulating evidence indicates vascular properties like compliance are also influential. We hypothesized that middle cerebral blood velocity (MCAv) dynamics during or following a transient blood pressure perturbation can be accurately explained by the windkessel mechanism. Eighteen volunteers underwent blood pressure manipulations, including bilateral thigh-cuff deflation and sit-to-stand maneuvers under normocapnic and hypercapnic (5% CO2) conditions. Pressure-flow recordings were analyzed using a windkessel analysis approach that partitions the frequency-dependent resistance and compliance contributions to MCAv dynamics. The windkessel was typically able to explain more than 50% of the MCAv variance, as indicated by R(2) values for both the flow recovery and postrecovery phase. The most consistent predictors of MCAv dynamics under the control condition were the windkessel capacitive gain and high-frequency resistive gain. However, there were significant interindividual variations in the composition of windkessel predictors. Hypercapnia consistently reduced the capacitive gain and enhanced the low-frequency (0.04-0.20 Hz) resistive gain for both thigh-cuff deflation and sit-to-stand trials. These findings indicate that 1) MCAv dynamics during acute transient hypotension challenges are dominated by cerebrovascular windkessel properties independent of CA; 2) there is significant heterogeneity in windkessel properties between individuals; and 3) hemodynamic effects of hypercapnia during transient blood pressure challenges primarily reflect changes in windkessel properties rather than pure CA impairment.


Valence photoionization dynamics in circular dichroism of chiral free molecules: the methyl-oxirane.
The dynamical behavior of circular dichroism for valence photoionization processes in pure enantiomers of randomly oriented methyl-oxirane molecules has been studied by circularly polarized synchrotron radiation. Experimental results of the dichroism coefficient obtained for valence photoionization processes as a function of photon energy have been compared with theoretical values predicted by state-of-the-art ab initio density-functional theory. The circular dichroism measured at low electron kinetic energies was as large as 11%. Trends in the experimental dynamical behavior of the dichroism coefficients D(i)(omega) have been observed. Agreement between experimental and theoretical results permits unambiguous identification of the enantiomer and of the individual orbitals.


Gene-specific vulnerability to imprinting variability in human embryonic stem cell lines.
Disregulation of imprinted genes can be associated with tumorigenesis and altered cell differentiation capacity and so could provide adverse outcomes for stem cell applications. Although the maintenance of mouse and primate embryonic stem cells in a pluripotent state has been reported to disrupt the monoallelic expression of several imprinted genes, available data have suggested relatively higher imprint stability in the human equivalents. Identification of 202 heterozygous loci allowed us to examine the allelic expression of 22 imprinted genes in 22 human embryonic stem cell lines. Half of the genes examined (IPW, H19, MEG3, MEST isoforms 1 and 2, PEG10, MESTIT1, NESP55, ATP10A, PHLDA2, IGF2) showed variable allelic expression between lines, indicating vulnerability to disrupted imprinting. However, seven genes showed consistent monoallelic expression (NDN, MAGEL2, SNRPN, PEG3, KCNQ1, KCNQ1OT1, CDKN1C). Furthermore, four genes known to be monoallelic or to exhibit polymorphic imprinting in later-developing human tissues (TP73, IGF2R, WT1, SLC22A18) were always biallelic in hESCs. MEST isoform 1, PEG10, and NESP55 showed an association between the variability observed in interline allelic expression status and the DNA methylation of previously identified regulatory regions. Our results demonstrate gene-specific differences in the stability of imprinted loci in human embryonic stem cells and identify disrupted DNA methylation as one potential mechanism. We conclude the prudence of including comprehensive imprinting analysis in the continued characterization of human embryonic stem cell lines.


Methionine derivatives diminish sulphide damage to colonocytes--implications for ulcerative colitis.
Bacterial production of anionic sulphide is increased in the colon of ulcerative colitis and sulphides can cause metabolic damage to colonocytes. To assess the reversal of the damaging effect of sulphide to isolated colonocytes by methionine and methionine derivatives. Isolated colonocytes were prepared from rat colons and 12 human colectomy specimens. In cell suspensions 14CO2/acetoacetate generation was measured from [1-14C]-butyrate (5.0 mmol/l) in the presence of 0-2.0 mmol/l sodium hydrogen sulphide. The effect of 5.0 mmol/l L-methionine, S-adenosylmethionine 1,4 butane disulphonate and DL-methionine-S-methylsulphonium chloride on sulphide inhibited oxidation was observed. In rat colonocytes sodium hydrogen sulphide dose dependently reduced oxidative metabolite formation from n-butyrate, an action reversed in order of efficacy by S-adenosylmethionine 1,4 butane disulphonate > DLmethionine-S-methyl-sulphonium chloride > L-methionine. In human colonocytes S-adenosylmethionine 1,4 butane disulphonate most significantly improved 14CO2 production (p = < 0.005) suppressed by sodium hydrogen sulphide. Sulphide toxicity in colonocytes is reversible by methyl donors. The efficiency of sulphide detoxification may be an important factor in the pathogenesis and treatment of ulcerative colitis for which S-adenosylmethionine 1,4 butane disulphonate may be of therapeutic value.


[Gastrointestinal stromal tumor in young pregnant woman: case report].
Female patient, 28 years old, with a gestation of 14 weeks, natural and from Ilo-Moquegua. Came with a time of disease 4 days with hematemesis, melena, epigastric pain and syncope. Background of colonic resection for peritonitis due to trauma 20 years ago; upper gastrointestinal bleeding three years ago; paternal grandparents died of gastric cancer; chronic gastritis diagnosed from 19 year old. In laboratory studies hemoglobin of 9.2. In the upper gastrointestinal endoscopy was found absence of active upper gastrointestinal bleeding, a large tumor in proximal body toward greater curvature and posterior wall, 8 cm in diameter approximately, lobed appearance, with most of the mucosal surface unscathed is evidence, areas of ulceration of 2-3 mm covered with fibrin (biopsies taken), hard consistency, tent sign (positive) and cushionsign (negative). Imaging studies such as MRI or CT were not possible due to the pregnancy. In the complete abdominal ultrasound only grade I hepatic steatosis was reported. The results of endoscopic biopsy showed cell proliferation ofepithelioid characteristics with atypia. Immunohistochemistry was performed indicating CD117 (positive), CD 34 (negative), Ki 67 (positive 1%). The final diagnosis was a gastrointestinal stromal tumor epithelioid type with mitotic rate lower of 1%. Finally, surgical resection of the tumor was performed in which addition of 3 implants was found up to 1 cm in diameter in pancreatic peritoneum covering surface. We present the case as this is an unusual presentation of this tumor.


Rages--what are they and who has them?
The purpose of this study was to examine rages and define their associated clinical and diagnostic conditions systematically. Children's severe anger outbursts, sometimes called "rages," have been associated with many disorders, including mania, "severe mood dysregulation," and oppositional defiant/conduct disorder. Although reactive aggression has been studied extensively, there are almost no data on this important and disabling clinical phenomenon. A total of 130 different 5-12 year olds were hospitalized over 151 consecutive admissions were evaluated diagnostically with information from parents, children, doctors, nursing staff, and teachers. Rages were operationally defined as agitated/angry behaviors requiring seclusion or medication because the child could not be verbally redirected to "time out." Rage behaviors were categorized as they occurred with the specially designed Children's Agitation Inventory. Hypotheses were that rages would be associated with prior treatment failure, and that children with rages would have the most co-morbidities, including learning/language disorders. We did not expect narrow-phenotype bipolar disorder to be specifically associated with rages. Of 130 children, 71 (54.6%) were admitted for rages. Preadmission rages and admission taking an atypical antipsychotic significantly predicted the subsequent number of in-hospital rages. Attention-deficit/hyperactivity disorder with learning/language disorder significantly predicted the occurrence and number of rages. Bipolar disorder was the referring diagnosis in 17/49 (34.7%) admissions with rages and 15/102 (14.7%) of admissions without rages (odds ratio [OR] 3.05, confidence interval [CI] 1.36, 6.80). However, a consensus diagnosis of bipolar disorder occurred in 5 (9.1%) of the sample with rages and 5 (5.8%) in the rest of admissions. Psychiatrically hospitalized children with multiple rages have complex, chronic neuropsychiatric disorders and have failed prior conventional treatment. One third of children with rages had been given a bipolar diagnosis prior to admission. However, only 9% of children with rages were given that diagnosis after careful observation.


Epigenetic mechanisms in Alzheimer's disease.
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders affecting elderly people (over 65 years old). Only a small percentage (less than 5%) of the disease is consistent with the Mendelian form of inheritance. The rest, named as Late Onset Alzheimer's Disease (more than 95%), is characterized as a complex multi-factorial disorder, missing familial traits. Although some genes have been implicated in the pathogenesis and the risk of developing sporadic AD, they only account for the minority of LOAD cases. Thus, over the past few years emerging data suggest a potential role of epigenetic mechanisms and chromatin remodeling on neurodegenerative processes leading to dementia. Alterations on the epigenomic machinery cause aberrant DNA methylation and histone acetylation. Therefore, these changes trigger alterations on the transcriptional level of genes involved in the pathogenesis of AD, such as APP. In this review we summarize recent advances on synaptic dysfunction and cognitive decline caused by common epigenetic modifications. We also discuss potential treatment strategies targeting on the epigenetic machinery.


Dynamical modeling the effect of glucagon-like peptide on glucose-insulin regulatory system based on mice experimental observation.
As an emerging global epidemic, type 2 diabetes mellitus (T2DM) represents one of the leading causes of morbidity and mortality worldwide. Existing evidences demonstrated that glucagon-like peptide-1 (GLP-1) modulate the glucose regulatory system by enhancing the β-cell function. However, the detailed process of GLP-1 in glycaemic regulator for T2DM remains to be clarified. Thus, in this study, we propose an Institute of Cancer Research (ICR) mice high fat and cholesterol dietary experimental data-driven mathematical model to investigate the secretory effect of GLP-1 on the dynamics of glucose-insulin regulatory system. Specifically, we develop a mathematical model of GLP-1 dynamics as part of the interaction model of β-cell, insulin, and glucose dynamics. The parameter estimation and data fitting are in agreement with the data in mice experiments In addition, uncertainty quantification is performed to explore the possible factors that influence the pathways leading to the pathological state. Model analyses reveal that the high fat or high cholesterol diet stimulated GLP-1 plays an important role in the dynamics of glucose, insulin and β cells in short-term. These results show that enhanced GLP-1 may mitigate the dysregulation of glucose-insulin regulatory system via promoting the β cells function and stimulating secretion of insulin, which offers an in-depth insights into the mechanistic of hyperglycemia from dynamical approach and provide the theoretical basis for GLP-1 served as a potential clinical targeted drug for treatment of T2DM.


Dysregulation of renal transient receptor potential melastatin 6/7 but not paracellin-1 in aldosterone-induced hypertension and kidney damage in a model of hereditary hypomagnesemia.
Hyperaldosteronism, important in hypertension, is associated with electrolyte alterations, including hypomagnesemia, through unknown mechanisms. To test whether aldosterone influences renal Mg(2+) transporters, (transient receptor potential melastatin (TRPM) 6, TRPM7, paracellin-1) leading to hypomagnesemia, hypertension and target organ damage and whether in a background of magnesium deficiency, this is exaggerated. Aldosterone effects in mice selectively bred for high-normal (MgH) or low (MgL) intracellular Mg(2+) were studied. Male MgH and MgL mice received aldosterone (350 μg/kg per day, 3 weeks). SBP was elevated in MgL. Aldosterone increased blood pressure and albuminuria and increased urinary Mg(2+) concentration in MgH and MgL, with greater effects in MgL. Activity of renal TRPM6 and TRPM7 was lower in vehicle-treated MgL than MgH. Aldosterone increased activity of TRPM6 in MgH and inhibited activity in MgL. TRPM7 and paracellin-1 were unaffected by aldosterone. Aldosterone-induced albuminuria in MgL was associated with increased renal fibrosis, increased oxidative stress, activation of mitogen-activated protein kinases and nuclear factor-NF-κB and podocyte injury. Mg(2+) supplementation (0.75% Mg(2+)) in aldosterone-treated MgL normalized plasma Mg(2+), increased TRPM6 activity and ameliorated hypertension and renal injury. Hence, in a model of inherited hypomagnesemia, TRPM6 and TRPM7, but not paracellin-1, are downregulated. Aldosterone further decreased TRPM6 activity in hypomagnesemic mice, a phenomenon associated with hypertension and kidney damage. Such effects were prevented by Mg(2+) supplementation. Amplified target organ damage in aldosterone-induced hypertension in hypomagnesemic conditions is associated with dysfunctional Mg(2+)-sensitive renal TRPM6 channels. Novel mechanisms for renal effects of aldosterone and insights into putative beneficial actions of Mg(2+), particularly in hyperaldosteronism, are identified.


Laboratory and imaging studies used by French rheumatologists to evaluate patients with early arthritis.
To conduct a practice survey of laboratory and imaging studies used by French rheumatologists to identify the cause of recent-onset arthritis. We selected a random sample of 210 rheumatologists, who were asked to recruit all patients with recent-onset arthritis (at least one joint involved, for less than one year) during a 2 week period, and to record laboratory and imaging studies performed. Results were analyzed in the overall group, in diagnostic subgroups, and in clinical presentation subgroups. The 119 rheumatologists who participated recruited 104 patients. Investigations done in 50% to 75% of patients were blood cell counts; erythrocyte sedimentation rate; serum assays of C-reactive protein, rheumatoid factors, antinuclear antibodies; and hand radiographs. Investigations in 50% to 74% of patients were serum ASAT/ALAT, creatinine, and uric acid; and foot radiographs. Finally, 25% to 49% of patients were tested for proteinuria; antikeratin antibodies; hepatitis B, hepatitis C, and Lyme serologies; creatine phosphokinase; blood iron; HLA-B27; and radiographs of chest and pelvis. No differences were found between investigations in patients with suspected rheumatoid arthritis and/or undifferentiated arthritis and those in other patients. In contrast, suspected diagnoses and presence of extraarticular manifestations classically associated with specific diseases modified the selection of investigations. Although considerable variability occurred, our study suggests that a limited panel of laboratory and imaging studies is performed in at least 25% of patients with recent-onset arthritis, regardless of clues suggesting a specific diagnosis.


[Clinical and pathological analysis of intravenous leiomyomatosis].
To investigate the clinical and biological characteristics of intravenous leiomyomatosis and the treatment methods, as well as their effect on prognosis. The clinical and pathologic data of 7 patients with intravenous leiomyomatosis of the uterus admitted to our hospital from June 1992 to June 2003 were analyzed retrospectively. All the cases were followed up. All the patients complained of pelvic mass. Three of them had enlarged uterus which was over 12 gestational week, 2 of them had prolonged menstruation and hypermenorrhea, 1 of them presented with postmenopausal bleeding. B-ultrasound examination showed 4 leiomyomas, 1 sarcoma of uterus, and 3 ovarian tumors. No intravenous leiomyomatosis within uterus was diagnosed preoperatively. A resection of the mass and a total abdominal hysterectomy with bilateral salpingo-oophorectomy were performed in 4 cases. Intravenous leiomyomatosis has special and quasi-malignant biological behavior. The prognosis can be improved if the disease could be correctly diagnosed during the operation and treated with combined modality therapy and intensively followed up after operation.


Prevalence of prehypertension and hypertension and associated risk factors among Turkish adults: Trabzon Hypertension Study.
To estimate the prevalence, awareness and control of prehypertension (preHT) and hypertension (HT) as defined by JNC-7 criteria in the Trabzon Region and its associations with demographic factors (age, sex, obesity, marital status, reproductive history in women and level of education), socioeconomic factors (household income and occupation), family history of selected medical conditions (diabetes, hypertension, obesity and cardiovascular disease), lifestyle factors (smoking habits, physical activity and alcohol consumption) in the adult population. In this cross-sectional survey, a sample of households was systematically selected from the central province of Trabzon and its nine towns. A total of 4809 adult subjects (2601 women and 2208 men) were included in the study. Demographic and socioeconomic factors, family history of selected medical conditions, and lifestyle factors were obtained for all participants. Systolic blood pressure (BP) and diastolic BP levels were measured for all subjects. The persons included in the questionnaire were invited to the local medical centers for blood examination between 08:00-10:00 following 12 hours of fasting. The levels of serum glucose (FBG), total cholesterol (Total-C), high density cholesterol (HDL-C), low density cholesterol (LDL-C) and triglycerides were measured with autoanalyzer. Definition and classification of HT was performed according to guidelines from the US JNC-7 report. Prevalence, awareness, treatment and control of HT were assessed. The prevalences of HT and preHT were 44.0% (46.1% in women and 41.6% in men) and 14.5% (12.6% in women and 16.8% in men), respectively. Overall, only 41% of the hypertensive individuals had been previously diagnosed. Furthermore, 54.5% of the hypertensive subjects were being treated with antihypertensive drugs (AHD), but only 24.3% of treated subjects had their BP adequately controlled. Among all hypertensive subjects (known and newly diagnosed), only 5.43% had their BP under control. The prevalence of HT increased with age, being highest in the 60- to 69-year-old age group (84.4%) but lower again in the 70+ age group. Interestingly, the prevalence was 16.9% in the 20-to 29-year old age group. HT was associated positively with marital status, parity, cessation of cigarette smoking, and negatively with level of education, alcohol consumption, current cigarette use, and physical activity. Multinomial logistic regression analysis revealed that HT were significantly associated with age, male gender, BMI, low education level, nonsmoking, positive family history of selected medical conditions, occupation, and parity. The Trabzon Hypertension Study data indicated that HT is very common and is an important health problem in the adult population of Trabzon. Patients who are unaware of their status and treated uncontrolled hypertensives are at high risk of early cardiovascular morbidity and mortality. To control preHT and HT, effective public health education and urgent precautions are needed. The precautions include serious health education, a well-balanced diet and increasing physical activity.


The virus's tooth: cyanophages affect an African flamingo population in a bottom-up cascade.
Trophic cascade effects occur when a food web is disrupted by loss or significant reduction of one or more of its members. In East African Rift Valley lakes, the Lesser Flamingo is on top of a short food chain. At irregular intervals, the dominance of their most important food source, the cyanobacterium Arthrospira fusiformis, is interrupted. Bacteriophages are known as potentially controlling photoautotrophic bacterioplankton. In Lake Nakuru (Kenya), we found the highest abundance of suspended viruses ever recorded in a natural aquatic system. We document that cyanophage infection and the related breakdown of A. fusiformis biomass led to a dramatic reduction in flamingo abundance. This documents that virus infection at the very base of a food chain can affect, in a bottom-up cascade, the distribution of end consumers. We anticipate this as an important example for virus-mediated cascading effects, potentially occurring also in various other aquatic food webs.


Structure-fragmentation relationship and rapid dereplication of Buxus steroidal alkaloids by electrospray ionization-quadrupole time-of-flight mass spectrometry.
Tandem mass spectrometric studies of natural products revealed the identification of key fragments which can be helpful for their rapid dereplication in plant extracts utilizing a liquid chromatography/tandem mass spectrometry (LC/MS/MS) approach, particularly for the thermally labile compounds. The knowledge of the collision-induced dissociation (CID) fragmentation pattern of the molecule is essentially required prior to the analysis by LC/MS/MS. The fragmentation patterns of eleven Buxus steroidal alkaloids were studied by using a positive ion electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QqTOF-MS/MS) hybrid instrument. Chromatographic separation of a Buxus papillosa extract was achieved using a capillary HPLC system coupled with the mass instrument. ESI-QqTOF-MS (positive ion mode) showed the presence of several characteristic fragments which can be used to rapidly identify various classes of Buxus steroidal alkaloids. The presence of a cyclopropane ring in the cycloartenol skeleton and the hydroxyl group at C-10 was found to effect on the fragmentation pattern and afford characteristic peaks. This study distinguishes between different types of Buxus steroidal alkaloids based on logical fragmentation pathways. This strategy was successfully applied in LC/ESI-QqTOF-MS/MS analysis of Buxus papillosa extract to investigate and characterize Buxus steroidal alkaloids and 14 compounds were identified as steroidal alkaloids. The knowledge of the fragmentation pattern was used for the rapid identification of this bioactive group of biosynthetically unique steroidal alkaloids in complex plant extracts of Buxus species, especially in the absence of any reference material, by combining key fragments, exact mass measurements and relative abundances of diagnostic fragment ions.


Age-related macular degeneration-susceptibility single nucleotide polymorphisms in a han chinese control population.
Our study aimed to detect the frequency of age-related macular degeneration (AMD)-susceptibility single nucleotide polymorphisms (SNPs) in control subjects of Han Chinese in a population-based study. A total of 419 subjects of Han Chinese without AMD were recruited from our population-based Nantong Eye Study. Nine AMD-susceptibility SNPs were genotyped. The allele/genotype frequencies were compared with the data from the literature and NCBI Reference Assembly. The call rates of genotyping were > 98%. All tested SNPs except for HTRA1 rs11200638 were in Hardy-Weinberg Equilibrium (HWE). The allele distributions of some AMD-susceptibility SNPs were different from the records for the Chinese population in the National Center for Biotechnology Information (NCBI) Reference Assembly. Compared to those in a Caucasian population, the frequency of minor alleles of CFH rs800292 (48% vs. 19.2%) and HTRA1 rs11200638 were much higher (47% vs. 25%), while the frequency of minor alleles of CFH rs1061170 (9% vs. 35%), CX3CR1 rs3732379 (3% vs. 21%), CX3CR1 rs3732378 (3% vs. 11%) and SERPING1 rs2511989 (11% vs. 48%) were much lower in the Han Chinese population. Minor differences were observed in the frequency of minor alleles of CFB rs4151667, C2 rs547154 and TLR3 rs3775291. The allele/genotype frequencies of CFH rs1061170 and HTRA1 rs11200638, two well-confirmed AMD-susceptible SNPs, were close to each other in the Han Chinese and Japanese population. The distribution of AMD-susceptibility SNPs shows ethnicity specificity. Substantial differences of the SNPs' distribution were noted from study to study, even within the same ethnic group. The genotype data will be used for longitudinal observation of AMD onset in the follow-up of the cohort.


Polymeric nanoparticles as cancer-specific DNA delivery vectors to human hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the third most deadly cancer in the US, with a meager 5-year survival rate of <20%. Such unfavorable numbers are closely related to the heterogeneity of the disease and the unsatisfactory therapies currently used to manage patients with invasive HCC. Outside of the clinic, gene therapy research is evolving to overcome the poor responses and toxicity associated with standard treatments. The inadequacy of gene delivery vectors, including poor intracellular delivery and cell specificity, are major barriers in the gene therapy field. Herein, we described a non-viral strategy for effective and cancer-specific DNA delivery to human HCC using biodegradable poly(beta-amino ester) (PBAE) nanoparticles (NPs). Varied PBAE NP formulations were evaluated for transfection efficacy and cytotoxicity to a range of human HCC cells as well as healthy human hepatocytes. To address HCC heterogeneity, nine different sources of human HCC cells were utilized. The polymeric NPs composed of 2-((3-aminopropyl)amino) ethanol end-modified poly(1,5-pentanediol diacrylate-co-3-amino-1-propanol) ('536') at a 25 polymer-to-DNA weight-to-weight ratio led to high transfection efficacy to all of the liver cancer lines, but not to hepatocytes. Each individual HCC line had a significantly higher percentage of exogenous gene expression than the healthy liver cells (P<0.01). Notably, this biodegradable end-modified PBAE gene delivery vector was not cytotoxic and maintained the viability of hepatocytes above 80%. In a HCC/hepatocyte co-culture model, in which cancerous and healthy cells share the same micro-environment, 536 25 w/w NPs specifically transfected cancer cells. PBAE NP administration to a subcutaneous HCC mouse model, established with one of the human lines tested in vitro, confirmed effective DNA transfection in vivo. PBAE-based NPs enabled high and preferential DNA delivery to HCC cells, sparing healthy hepatocytes. These biodegradable and liver cancer-selective NPs are a promising technology to deliver therapeutic genes to liver cancer.


A synthetic peptide corresponding to the extracellular loop 2 region of claudin-4 protects against Clostridium perfringens enterotoxin in vitro and in vivo.
Clostridium perfringens enterotoxin (CPE) action starts when the toxin binds to claudin receptors. Claudins contain two extracellular loop domains, with the second loop (ECL-2) being slightly smaller than the first. CPE has been shown to bind to ECL-2 in receptor claudins. We recently demonstrated that Caco-2 cells (a naturally CPE-sensitive enterocyte-like cell line) can be protected from CPE-induced cytotoxicity by preincubating the enterotoxin with soluble full-length recombinant claudin-4 (rclaudin-4), which is a CPE receptor, but not with recombinant nonreceptor claudins, such as rclaudin-1. The current study evaluated whether a synthetic peptide corresponding to the claudin-4 ECL-2 sequence can similarly inhibit CPE action in vitro and in vivo. Significant protection of Caco-2 cells was also observed using either rclaudin-4 or the claudin-4 ECL-2 peptide in both a preincubation assay and a coincubation assay. This inhibitory effect was specific, since rclaudin-1 and a synthetic peptide based on the claudin-1 ECL-2 offered no protection to Caco-2 cells. However, the claudin-4 ECL-2 peptide was unable to neutralize cytotoxicity if CPE had already bound to Caco-2 cells. When the study was repeated in vivo using a rabbit small intestinal loop assay, preincubation or coincubation of CPE with the claudin-4 ECL-2 peptide significantly and specifically inhibited the development of CPE-induced luminal fluid accumulation and histologic lesions in rabbit small intestinal loops. No similar in vivo protection from CPE was afforded by the claudin-1 ECL-2 peptide. These results suggest that claudin-4 ECL-2 peptides should be further investigated for their potential therapeutic application against CPE-associated disease.


2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
Many developments have occurred since the publication of the widely-used 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used, per present standards of the CCS. The total cardiovascular disease Framingham Risk Score (FRS), modified for a family history of premature coronary disease, is recommended for risk assessment. Low-density lipoprotein cholesterol remains the primary target of therapy. However, non-high density lipoprotein cholesterol has been added to apolipoprotein B as an alternate target. There is an increased emphasis on treatment of higher risk patients, including those with chronic kidney disease and high risk hypertension. The primary panel has recommended a judicious use of secondary testing for subjects in whom the need for statin therapy is unclear. Expanded information on health behaviours is presented and is the backbone of risk reduction in all subjects. Finally, a systematic approach to statin intolerance is advocated to maximize appropriate use of lipid-lowering therapy. This document presents the recommendations and principal conclusions of this process. Along with associated Supplementary Material that can be accessed online, this document will be part of a program of knowledge translation. The goal is to increase the appropriate use of evidence-based cardiovascular disease event risk assessment in the management of dyslipidemia as a fundamental means of reducing global risk in the Canadian population.


Elevated Serum Complement C1q Levels After Traumatic Brain Injury and Its Association with Poor Prognosis.
Complement C1q is implicated in neuroinflammation. We intended to discern the relationship between serum C1q levels and severity in addition to prognosis following traumatic brain injury (TBI). In this prospective, observational study, serum C1q levels were quantified in 188 TBI patients and 188 healthy controls. Glasgow coma scale (GCS) and Rotterdam computed tomography (CT) classification were used as clinical and radiological indicators of severity. Patients with extended Glasgow outcome scale (GOSE) score of 1-4 at 6 months after trauma were considered to have a poor outcome. Multiple logistic regression model was built to ascertain the independent association of serum C1q levels with 6-month poor outcome. Receiver operating characteristic (ROC) curve was configured for analysis of prognostic capability with respect to serum C1q levels. TBI patients exhibited substantially higher serum C1q levels than controls (median, 223.9 mg/l versus 75.4 mg/l). Serum C1q levels of patients were tightly correlated with GCS score (r = -0.671), Rotterdam CT classification (r = 0.604) and GOSE score (r = -0.581). An area under the ROC curve was yielded of 0.793 (95% confidence interval = 0.728-0.849), and serum C1q levels above 345.5 mg/l discriminated the risk of 6-month poor outcome with 59.6% sensitivity and 92.6% specificity. Serum C1q levels above 345.5 mg/l retained as an independent predictor for 6-month poor outcome with odds ratio of 4.922 (95% confidence interval = 1.552-15.606; P = 0.017). Elevated serum C1q levels are closely correlated with traumatic severity and independently predicted the risk of long-term poor prognosis after TBI.


Self-assembled periodic sub-wavelength structures by femtosecond laser direct writing.
Self-assembled, sub-wavelength periodic structures are induced in fused silica by a tightly focused, linearly polarized, femtosecond laser beam. Two different types of periodic structures, the main one with period (Lambda(E)) in the direction of the laser beam polarization and the second with period (Lambda(k)) in the direction of the light propagation, are identified from the cross-sectional images of the modified regions using scanning electron microscopy. We demonstrate the spatial coherence of these nanogratings in the plane perpendicular to the beam propagation direction. The range of effective pulse energy which could produce nanogratings narrows when the pulse repetition rate of writing laser increases. The period Lambda(E) is proportional to the wavelength of the writing laser and period Lambda(k) in the head of the modified region remains approximately the wavelength of light in fused silica.


Pathophysiology, prevention and management of chronic kidney disease in the hypertensive patient with diabetes mellitus.
The authors concisely review the main clinical issues arising in the management of the hypertensive patient with type 2 diabetes, in whom chronic kidney disease is prevalent and heralds increased cardiovascular morbidity and mortality. Special attention is paid to the clinical meaning, relevance and limits of albumin excretion and glomerular filtration rate, the two widely used markers of reduced kidney function during the course of chronic diseases like diabetes and hypertension. The main therapeutic strategies involving blood pressure and glycemic control, treatment of dyslipidemia and improvement of lifestyle are discussed from the viewpoint of a general practitioner dealing with the clinical complexity of these patients.


Endogenous gut signals and metabolites control daily food intake.
Parabiotic pairs of inbred Lewis rats had two different types of crossed intestinal surgery performed. In the one-way surgery, food was lost from the duodenum of one rat in a pair into a 30 cm segment of upper small intestine of its partner. The unabsorbed intestinal chyme returned to the lower duodenum of the first rat. In the second surgery, food was lost from the lower jejunum of one rat into the upper ileum of its partner. The lower gut of the first rat received no further food stimulus while the ileum, cecum and colon of its partner were doubly stimulated. As a result of these two surgeries, the rat in each pair that lost food into its partner's intestine showed a 40-60 percent increase in daily food intake while its partner reduced its intake by an equivalent 40-60 percent regardless of whether the food was lost into the upper or lower small intestine. The large and sustained changes in daily food intake did not correlate significantly with body weight or with the wet weight of the fat, liver or heart at sacrifice. Therefore, daily significant changes in body or organ weight were not necessary to produce large changes in daily food intake. Instead, some combination of endogenous signals from the gut, of plasma levels of absorbed nutrients or of endogenous signals generated by the subsequent metabolism of absorbed nutrients in peripheral tissues must control daily food intake.


Using the Theoretical Domains Framework to Identify Barriers and Enablers to Implementing a Virtual Tertiary-Regional Telemedicine Rounding and Consultation for Kids (TRaC-K) Model: Qualitative Study.
Inequities in access to health services are a global concern and a concern for Canadian populations living in rural areas. Rural children hospitalized at tertiary children's hospitals have higher rates of medical complexity and experience more expensive hospitalizations and more frequent readmissions. The 2 tertiary pediatric hospitals in Alberta, Canada, have already been operating above capacity, but the pediatric beds at regional hospitals are underused. Such imbalance could lead to poor patient safety and increased readmission risk at tertiary pediatric hospitals and diminish the clinical exposure of regional pediatric health care providers, erode their confidence, and compel health systems to further reduce the capacity at regional sites. A Telemedicine Rounding and Consultation for Kids (TRaC-K) model was proposed to enable health care providers at Alberta Children's Hospital to partner with their counterparts at Medicine Hat Regional Hospital to provide inpatient clinical care for pediatric patients who would otherwise have to travel or be transferred to the tertiary site. The aim of this study is to identify perceived barriers and enablers to implementing the TRaC-K model. This study was guided by the Theoretical Domains Framework (TDF) and used qualitative methods. We collected qualitative data from 42 participants from tertiary and regional hospitals through 31 semistructured interviews and 2 focus groups. These data were thematically analyzed to identify major subthemes within each TDF domain. These subthemes were further aggregated and categorized into barriers or enablers to implementing the TRaC-K model and were tabulated separately. Our study identified 31 subthemes in 14 TDF domains, ranging from administrative issues to specific clinical conditions. We were able to merge these subthemes into larger themes and categorize them into 4 barriers and 4 enablers. Our findings showed that the barriers were lack of awareness of telemedicine, skills to provide virtual clinical care, unclear processes and resources to support TRaC-K, and concerns about clear roles and responsibilities. The enablers were health care providers' motivation to provide care closer to home, supporting system resource stewardship, site and practice compatibility, and motivation to strengthen tertiary-regional relationships. This systematic inquiry into the perceived barriers and enablers to the implementation of TRaC-K helped us to gain insights from various health care providers' and family members' perspectives. We will use these findings to design interventions to overcome the identified barriers and harness the enablers to encourage successful implementation of TRaC-K. These findings will inform the implementation of telemedicine-based interventions in pediatric settings in other parts of Canada and beyond. RR2-10.1186/s12913-018-3859-2.


Simulation of the influence of different factors on the motor nerve condition velocity measurement. Part 1: Normal conditions.
The result of a motor nerve conduction velocity measurement is dependent of a row of factors which will influence the measurement. These factors have been tested extensively in healthy volunteers. However, under pathological conditions it is not known to what degree the reported velocities are influenced by biological and technical factors. In an attempt to broaden our knowledge on the matter, a model was made to test different factors under varying conditions. Part I describes the model and reports results from calculations on simulated normal nerves. The results are in concert with results from healthy volunteers. Part II reports on results in pathological conducting nerves. The effect of the different factors affecting the nerve conduction velocities are shown. A simulation of doing a measurement twice and reporting the average showed a marked decrease of the variability in the reported nerve conduction velocity. This was more effective than eliminating any of the other factors influencing the measured conduction velocity.


The roles of copper transporters in cisplatin resistance.
Platinum-based antitumor agents have been effective in the treatments of many human malignancies but the ultimate success of these agents is often compromised by development of drug resistance. One mechanism associated with resistance to platinum drugs is reduced intracellular accumulation owing to impaired drug intake, enhanced outward transport, or both. Mechanisms for transporting platinum drugs were not known until recent demonstrations that import and export transporters involved in maintenance copper homeostasis are also involved in the transport of these drugs. Ctr1, the major copper influx transporter, has been convincingly demonstrated to transport cisplatin and its analogues, carboplatin, and oxaliplatin. Evidence also suggests that the two copper efflux transporters ATP7A and ATP7B regulate the efflux of cisplatin. These observations are intriguing, because conventional thinking of the inorganic physiologic chemistry of cisplatin and copper is quite different. Hence, understanding the underlying mechanistic aspects of these transporters is critically important. While the mechanisms by which hCtr1, ATP7A and ATP7B transport copper ions have been studied extensively, very little is known about the mechanisms by which these transporters shuffle platinum-based antitumor agents. This review discusses the identification of copper transporters as platinum drug transporters, the structural-functional and mechanistic aspects of these transporters, the mechanisms that regulate their expression, and future research directions that may eventually lead to improved efficacy of platinum-based-based drugs in cancer chemotherapy through modulation of their transporters' activities.


Description and predictors of hospital costs of oesophageal cancer during the first year following diagnosis in Northern Ireland.
The cost-effectiveness of novel interventions in the treatment of cancer is well researched; however, relatively little attention is paid to the cost of many aspects of routine care. Oesophageal cancer is the ninth most common cancer in the UK and sixth most common cause of cancer death. It usually presents late and has a poor prognosis. The hospital costs incurred by oesophageal cancer patients diagnosed in Northern Ireland in 2005 (n = 198) were determined by review of medical records. The average cost of hospital care per patient in the 12 months from presentation was £7847. Variations in total hospital costs by age at diagnosis, gender, cancer stage, histological type, mortality at 1 year, co-morbidity count and socio-economic status were analysed using multiple regression analyses. Higher costs were associated with earlier stages of cancer and cancer stage remained a significant predictor of costs after controlling for cancer type, patient age and mortality at 1 year. Thus, although early detection of cancer usually improves survival, this would mean increased costs in the first year. Deprivation achieved borderline significance with those from more deprived areas having lower resource consumption relative to the more affluent.


Photoprotective activity of a cream containing lyophilized aqueous extract of Lepidium meyenii (MACA) against ultraviolet irradiation on mouse skin.
To evaluate the photoprotective activity of a cream with lyophilized aqueous extract of maca (LEM) against ultraviolet (UV) irradiation in the skin of mice. An experimental study was carried out on 35 BALB/c mice. Treatment was applied topically on the dorsum of the animals, which were subsequently irradiated with ultraviolet B rays, and then we measured the thickness in microns (μm) of histological samples of the skin of the mice. Seven groups were assigned, divided into non-irradiated: Blank (G1) and irradiated with UV light: no treatment (G2); with commercial sunscreen with sun protection factor (SPF) 30 (G3); cream (placebo) (G4); LEM at 15% in water (G5); LEM cream at 5% (G6); and LEM cream at 15% (G7). In vitro SPF was determined using the Mansur method. Absorbance readings were taken in an ultraviolet- visible spectrophotometer (UV-VIS) and SPFs were determined for the following formulations: LEM cream at 5%, benzophenone-4 (BZF-4) and commercial sunscreen SPF 30. Mouse skin thickness in microns (μm) was 27.28 in G2; 18.31 in G3; 27.33 in G4; 19.51 in G5 and 18.04 in G6. There was no significant difference between the group not exposed to radiation (G1) and the 15% LEM cream group (G7), both had the lowest thicknesses (12.76 and 14.20 μm, respectively). The SPF of LEM cream at 15% was 5.480 ± 0.020. The formulation with LEM cream showed photoprotective activity against UV irradiation, alkaloids were the phytochemical components mostly found and the formulation was compatible with the active principle (LEM).


Radial basis function-sparse partial least squares for application to brain imaging data.
Magnetic resonance imaging (MRI) data is an invaluable tool in brain morphology research. Here, we propose a novel statistical method for investigating the relationship between clinical characteristics and brain morphology based on three-dimensional MRI data via radial basis function-sparse partial least squares (RBF-sPLS). Our data consisted of MRI image intensities for multimillion voxels in a 3D array along with 73 clinical variables. This dataset represents a suitable application of RBF-sPLS because of a potential correlation among voxels as well as among clinical characteristics. Additionally, this method can simultaneously select both effective brain regions and clinical characteristics based on sparse modeling. This is in contrast to existing methods, which consider prespecified brain regions because of the computational difficulties involved in processing high-dimensional data. RBF-sPLS employs dimensionality reduction in order to overcome this obstacle. We have applied RBF-sPLS to a real dataset composed of 102 chronic kidney disease patients, while a comparison study used a simulated dataset. RBF-sPLS identified two brain regions of interest from our patient data: the temporal lobe and the occipital lobe, which are associated with aging and anemia, respectively. Our simulation study suggested that such brain regions are extracted with excellent accuracy using our method.


Preparation, structure, and versatile reactivity of pseudocyclic benziodoxole triflate, new hypervalent iodine reagent.
A new pseudocyclic triflate derivative of benziodoxole (IBA-OTf) was prepared and characterized by X-ray analysis. This highly electrophilic reagent readily reacts with various organic substrates to give the corresponding products in good yields. Furthermore, IBA-OTf can be used as a catalyst with m-chloroperoxybenzoic acid as the terminal oxidant.


Removal of Fecal Indicators, Pathogenic Bacteria, Adenovirus, Cryptosporidium and Giardia (oo)cysts in Waste Stabilization Ponds in Northern and Eastern Australia.
Maturation ponds are used in rural and regional areas in Australia to remove the microbial loads of sewage wastewater, however, they have not been studied intensively until present. Using a combination of culture-based methods and quantitative real-time PCR, we assessed microbial removal rates in maturation ponds at four waste stabilization ponds (WSP) with (n = 1) and without (n = 3) baffles in rural and remote communities in Australia. Concentrations of total coliforms, E. coli, enterococci, Campylobacter spp., Salmonella spp., F+ RNA coliphage, adenovirus, Cryptosporidium spp. and Giardia (oo) cysts in maturation ponds were measured at the inlet and outlet. Only the baffled pond demonstrated a significant removal of most of the pathogens tested and therefore was subjected to further study by analyzing E. coli and enterococci concentrations at six points along the baffles over five sampling rounds. Using culture-based methods, we found a decrease in the number of E. coli and enterococci from the initial values of 100,000 CFU per 100 mL in the inlet samples to approximately 1000 CFU per 100 mL in the outlet samples for both bacterial groups. Giardia cysts removal was relatively higher than fecal indicators reduction possibly due to sedimentation.


Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women.
Among Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment. To determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among patients of Ashkenazi Jewish ancestry with breast cancer. In this cohort study, genomic DNA of women from 12 major cancer centers with a first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish and participated in the New York Breast Cancer Study (NYBCS) from 1996 to 2000 was sequenced for known and candidate breast cancer genes. Data analysis was performed from July 10, 2014, to March 10, 2017. Genomic DNA from all 1007 NYBCS probands was sequenced for 23 known and candidate breast cancer genes using BROCA, a targeted multiplexed gene panel. Of the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN). Of all inherited predispositions to breast cancer in the NYBCS, 73.8% (104 of 142) were due to a BRCA1 or BRCA2 founder allele, 4.9% (7 of 142) to another BRCA1 or BRCA2 mutation, and 21.8% (31 of 142) to a mutation in another gene. Overall, 14.1% (142 of 1007) of Ashkenazi Jewish patients with breast cancer in the NYBCS carried a germline mutation responsible for their disease: 11.0% (111 of 1007) in BRCA1 or BRCA2, and 3.1% (31 of 1007) in CHEK2 or another breast cancer gene. Of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer and 54 patients (48.6%) did not. Comprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer.


Fear of the unexpected: hippocampus mediates novelty-induced return of extinguished fear in rats.
Several lines of evidence indicate an important role for the hippocampus in the recovery of fear memory after extinction. For example, hippocampal inactivation prevents the renewal of fear to an extinguished conditioned stimulus (CS) when it is presented outside the extinction context. Renewal of extinguished responding is accompanied by associative novelty (an unexpected occurrence of a familiar CS in a familiar place), the detection of which may require the hippocampus. We therefore examined whether the hippocampus also mediates the recovery of extinguished fear caused by other unexpected events, including presenting a familiar CS in a novel context or presenting a novel cue with the CS in a familiar context (e.g., external disinhibition). Rats underwent Pavlovian fear conditioning and extinction using an auditory CS and freezing behavior served as the index of conditioned fear. In Experiment 1, conditioned freezing to the extinguished CS was renewed in a novel context and this was eliminated by intra-hippocampal infusions of the GABAA agonist, muscimol, prior to the test. In Experiment 2, muscimol inactivation of the hippocampus reduced the external disinhibition of conditioned freezing that occurred when a novel white noise accompanied the extinguished tone CS. Collectively, these results suggest that the hippocampus mediates the return of fear when extinguished CSs are unexpected, or when unexpected stimuli accompany CS presentation. Ultimately, a violation of expectations about when, where, and with what other stimuli an extinguished CS will occur may form the basis of spontaneous recovery, renewal, and external disinhibition.


Expander Eye Prosthesis Assisting Ocular Rehabilitation in Child with Eye Loss.
This clinical report describes the ocular rehabilitation of a child, initially using an acrylic expander and subsequently the conventional prosthesis. A two-month-old anophthalmic female patient was referred to Araçatuba Dental School, for rehabilitation with ocular prosthesis. The treatment chosen was the manufacturing of expander prostheses changed periodically until the socket reached an adequate size, so that a definitive ocular prosthesis could be installed. The acrylic expander remained in patient's anophthalmic socket for 60 days in order to restore its volume. After this period, ocular prosthesis was installed and replaced according to facial growth. It can be observed that the expander prostheses increased the anophthalmic cavity and provided patient's adaptation for using an ocular prosthesis. The ocular prosthesis set the face aesthetic balance which eventually reflects positively on psychological and social development of the child.


Assessing the need for hot meals: a descriptive Meals on Wheels study.
According to recent literature, delivering chilled Meals on Wheels to seniors increases food quality and safety. The purpose of this study was to determine the acceptability and/or feasibility of a cook-chill delivery system for participants in the Maimonides Geriatric Centre Meals on Wheels program in Montreal, Quebec. The authors also evaluated whether the meal was eaten upon delivery, documented where the meal was stored if consumption was delayed, determined what cooking/heating appliances were used and if the recipients were capable of heating up their meals, and assessed preferences for receiving chilled versus hot meals. Upon receiving the meal, 89% of the 60 seniors did not eat it immediately. Those who ate the meal later stored it in the refrigerator. All had some appliance available to heat the delivered meal; 55% used a microwave. Approximately 75% did not object to receiving meals chilled. The majority of recipients did not require delivery of hot meals, as most delayed consuming the meal until later in the day. Other meal-delivery program planners can use these findings when deciding if a cook-chill system is appropriate for their client populations.


Physical inactivity as a policy problem: applying a concept from policy analysis to a public health issue.
Despite the recent rapid development of policies to counteract physical inactivity (PI), only a small number of systematic analyses on the evolution of these policies exists. In this article we analyze how PI, as a public health issue, "translates" into a policy-making issue. First, we discuss why PI has become an increasingly important public health issue during the last two decades. We then follow Guy Peters and conceptualize PI as a "policy problem" that has the potential to be linked to policy instruments and policy impact. Analysis indicates that PI is a policy problem that i) is chronic in nature; ii) involves a high degree of political complexity; iii) can be disaggregated into smaller scales; iv) is addressed through interventions that can be difficult to "sell" to the public when their benefits are not highly divisible; v) cannot be solved by government spending alone; vi) must be addressed through a broad scope of activities; and vii) involves interdependencies among both multiple sectors and levels of government.We conclude that the new perspective on PI proposed in this article might be useful and important for i) describing and mapping policies to counteract PI in different contexts; ii) evaluating whether or not existing policy instruments are appropriate to the policy problem of PI, and iii) explaining the factors and processes that underlie policy development and implementation. More research is warranted in all these areas. In particular, we propose to focus on comparative analyses of how the problem of PI is defined and tackled in different contexts, and on the identification of truly effective policy instruments that are designed to "solve" the PI policy problem.


Effect of steroid on mitochondrial oxidative stress enzymes, intestinal microflora, and bacterial translocation in rats subjected to temporary liver inflow occlusion.
Protective effects of steroids against ischemia-reperfusion (I/R) injury are well known, but there is little information about the influence of temporary inflow occlusion on intestinal barrier function or bacterial translocation. The aim of this experimental study was to investigate the effects on liver, kidney, spleen, ileal mitochondrial stress enzymes, and bacterial translocation of methylprednisolone (MP) in rats undergoing temporary liver inflow occlusion. Twenty-seven pathogen-free Wistar albino rats were randomized into three groups: group A: I/R (n = 10); group B: I/R + MP (n = 10); and group C: sham (n = 7). Rats in groups A and B were subjected to 20 minutes of portal vein and hepatic artery occlusion with 3 mg/kg MP injected into group B animals intraperitoneally during the occlusion. Twenty-two hours later, all rats were sacrificed to measure mitochondrial oxidative stress enzymes in liver, kidney, spleen, and ileum. We evaluated intestinal bacterial counts, intestinal mucosal histopathology, bacterial translocation to mesenteric lymph nodes (MLN), liver, spleen, and kidney. Decreased levels of malondialdehyde and increased levels of glutathione were observed in all examined tissues of group B compared to those of group A rats. Statistically significant increases in the intestinal counts of Klebsiella spp and Proteus spp and of bacterial translocation to liver, kidney, spleen, and MLN were measured in group B with respect to group A.


Gene Expression Under the Influence: Transcriptional Profiling of Ethanol in the Brain.
Sensitivity to ethanol intoxication, propensity to drink ethanol and vulnerability to develop alcoholism are all influenced by genetic factors. Conversely, exposure to ethanol or subsequent withdrawal produce gene expression changes, which, in combination with environmental variables, may participate in the emergence of compulsive drinking and relapse. The present review offers an integrated perspective on brain gene expression profiling in rodent models of predisposition to differential ethanol sensitivity or consumption, in rats and mice subjected to acute or chronic ethanol exposure, as well as in human alcoholics. The functional categories over-represented among differentially expressed genes suggest that the transcriptional effects of chronic ethanol consumption contribute to the neuroplasticity and neurotoxicity characteristic of alcoholism. Importantly, ethanol produces distinct transcriptional changes within the different brain regions involved in intoxication, reinforcement and addiction. Special emphasis is put on recent profiling studies that have provided some insights into the molecular mechanisms potentially mediating genome-wide regulation of gene expression by ethanol. In particular, current evidence for a role of transcription factors, chromatin remodeling and microRNAs in coordinating the expression of large sets of genes in animals predisposed to excessive ethanol drinking or exposed to protracted abstinence, as well as in human alcoholics, is presented. Finally, studies that have compared ethanol with other drugs of abuse have highlighted common gene expression patterns that may play a central role in drug addiction. The availability of novel technologies and a focus on mechanistic approaches are shaping the future of ethanol transcriptomics.


The pathogenesis of emphysema: the elastase:antielastase hypothesis 30 years later.
Thirty years ago the concept of the elastase:antielastase hypothesis was introduced. Neutrophil elastase:A1PI balance was found to be critical, predisposing patients deficient in A1PI to panacinar emphysema; however, the causative elastases in common cigarette-induced pulmonary emphysema are unclear. Several members of the serine, cysteine, and metalloproteinase families have been identified in inflammatory and resident lung cells. We propose to use gene-targeted mice, deficient in individual elastases to determine the relative contribution of candidate elastases to cigarette-smoking-related emphysema. This does not guarantee that humans will respond to cigarette smoke with the same array of elastases as mice. However, these studies may guide labor intensive therapeutic trials with specific proteinase inhibitors and ultimately lead to rational therapy.


Volatile fingerprints of beef cooking methods using sol-gel-based solid-phase microextraction (SPME) and direct analysis in real-time mass spectrometry (DART-MS).
The aroma profile of food is a complex mixture of volatile compounds that constitutes a major component of the overall eating experience. The food service industry and chefs therefore constantly seek ways to investigate and thereby enhance the aroma profile. Oven cooking, sous vide and pan fry are three cooking methods of beef commonly practised by chefs. Near real-time analysis of volatile compounds from these three cooking methods will provide insight into respective volatile fingerprints and help improve cooking techniques. Volatile compounds from three beef cooking methods were captured using an in-house sol-gel based solid phase microextraction (SPME) method and analysed using direct analysis in real-time mass spectrometry (DART-MS). A volatile organic compound (VOC) standard was used to demonstrate successful implementation of the sol-gel coating technique. Volatile features discriminating the three cooking methods were shortlisted and statistically assessed by univariate and multivariate analyses. The VOC standard was successfully adsorbed by the sol-gel method and detected by DART-MS. Hierarchical cluster analysis clearly demarcated three beef cooking methods based on their volatile fingerprints. Out of 65 significant features differentiating the cooking methods, 50 were at highest concentrations from pan-fry cooking only, followed by 14 with highest concentrations from oven cooking followed by pan frying. Sous vide followed by pan frying showed lowest concentrations of almost all volatile features. The sol-gel-based solid-phase microextraction technique combined with DART-MS was successful in differentiating beef cooking methods based on their volatile fingerprints. A workflow for rapid assessment of the volatile profile from beef cooking methods was established, providing a baseline to further explore volatile profiles from other key ingredients.


Catalytic Transformation of Triglycerides to Biodiesel with SiO2-SO3H and Quaternary Ammonium Salts in Toluene or DMSO.
SiO2-SO3H, with a surface area of 115 m2·g-1, pore volumes of 0.38 cm3·g-1 and 1.32 mmol H+/g, was used as a transesterification catalyst. Triglycerides of waste cooking oil reacted with methanol in refluxing toluene to yield mixtures of diglycerides, monoglycerides and fatty acid methyl esters (FAMEs) in the presence of 20% (w/w) catalyst/oil using the hydrophilic sulfonated silica (SiO2-SO3H) catalyst alone or with the addition of 10% (w/w) co-catalyst/oil [(Bun4N)(BF4) or Aliquat 336]. The addition of the ammonium salts to the catalyst lead to a decrease in the amounts of diglycerides in the products, but the concentrations of monoglycerides increased. Mixtures of (Bun4N)(BF4)/catalyst were superior to catalyst alone or Aliquat 336/catalyst for promoting the production of mixtures with high concentrations of FAMEs. The same experiments were repeated using DMSO as the solvent. The use of the more polar solvent resulted in excellent conversion of the triglycerides to FAME esters with all three-catalyst media. A simplified mechanism is presented to account for the experimental results.


Challenges and Approaches to Quantitative Therapy Response Assessment in Glioblastoma Multiforme Using the Novel Apoptosis Positron Emission Tomography Tracer F-18 ML-10.
Evaluation of cancer-therapy efficacy at early time points is necessary for realizing the goal of delivering maximally effective treatment. Molecular imaging with carefully selected tracers and methodologies can provide the means for realizing this ability. Many therapies are aimed at inducing apoptosis in malignant tissue; thus, the ability to quantify apoptosis in vivo may be a fruitful approach. Apoptosis rate changes occur on a fast time scale, potentially allowing correspondingly rapid decisions regarding therapy value. However, quantification of tissue status based on apoptosis imaging is complicated by this time scale and by the spatial heterogeneity of the process. Using the positron emission tomography (PET) tracer 2-(5-fluoro-pentyl)-2-methyl-malonic acid (F-18 ML-10), we present methods of voxelwise analysis yielding quantitative measures of apoptosis changes, parametric apoptosis change images, and graphical representation of apoptotic features. A method of deformable registration to account for anatomic changes between scan time points is also demonstrated. Overall apoptotic rates deduced from imaging depend on tumor density and the specific rate of apoptosis, a situation resulting in an ambiguity in the source of observed image-based changes. The ambiguity may be resolved through multimodality imaging. An example of intracellular sodium magnetic resonance imaging coupled with F-18 ML-10 PET is provided.


Ethical precepts for medical volunteerism: including local voices and values to guide RHD surgery in Rwanda.
At the invitation of the Rwandan Government, Team Heart, a team of American healthcare professionals, performs volunteer rheumatic heart disease (RHD) surgery in Rwanda every year, and confronts ethical concerns that call for cultural sensitivity. This article describes how five standard bioethical precepts are applied in practice in medical volunteerism related to RHD surgery in Rwanda. The content for the applied precepts stems from semiscripted, transcribed conversations with the authors, two Rwandan cardiologists, a Rwandan nurse and a Rwandan premedical student. The conversations revealed that the criteria for RHD surgical selection in Rwanda are analogous to the patient-selection process involving material scarcity in the USA. Rwandan notions of benefit and harm focus more attention on structural issues, such as shared benefit, national reputation and expansion of expertise, than traditional Western notions. Harm caused by inadequate patient follow-up remains a critical concern. Gender disparities regarding biological and social implications of surgical valve choices impact considerations of justice. Individual agency remains important, but not central to Rwandan concepts of justice, transparency and respect, particularly regarding women. The Rwandan understanding of standard bioethical precepts is substantively similar to the traditionally recognised interpretation with important contextual differences. The communal importance of improving the health of a small number of individuals may be underestimated in previous literature. Moreover, openness and the incorporation of Rwandan stakeholders in difficult ethical choices and long-term contributions to indigenous medical capacity appear to be valued by Rwandans. These descriptions of applied precepts are applicable to different medical missions in other emerging nations following a similar process of inclusion.


Bee flowers drive macroevolutionary diversification in long-horned bees.
The role of plant-pollinator interactions in the rapid radiation of the angiosperms have long fascinated evolutionary biologists. Studies have brought evidence for pollinator-driven diversification of various plant lineages, particularly plants with specialized flowers and concealed rewards. By contrast, little is known about how this crucial interaction has shaped macroevolutionary patterns of floral visitors. In particular, there is currently no empirical evidence that floral host association has increased diversification in bees, the most prominent group of floral visitors that essentially rely on angiosperm pollen. In this study, we examine how floral host preference influenced diversification in eucerine bees (Apidae, Eucerini), which exhibit large variations in their floral associations. We combine quantitative pollen analyses with a recently proposed phylogenetic hypothesis, and use a state speciation and extinction probabilistic approach. Using this framework, we provide the first evidence that multiple evolutionary transitions from host plants with accessible pollen to restricted pollen from 'bee-flowers' have significantly increased the diversification of a bee clade. We suggest that exploiting host plants with restricted pollen has allowed the exploitation of a new ecological niche for eucerine bees and contributed both to their colonization of vast regions of the world and their rapid diversification.


Proximal segment histology of resected bowel in Hirschsprung's disease predicts postoperative bowel function.
The authors present an overview of 101 patients operated for Hirschsprung's disease by Rehbein procedure. Special attention is directed to the histomorphological findings in the proximal segment of the resected bowel specimens. A strong link was confirmed between these specific features and postoperative bowel function. A histologically regular proximal bowel segment generally predicted good postoperative bowel function with a constipation rate of 10.5%. In patients with intestinal neuronal dysplasia (IND) of the proximal segment the overall clinical result remained unchanged, although the constipation rate rose to 17.8%. Postoperative bowel function was seriously affected in cases characterized by proximal segment hypoganglionosis with a constipation rate of 23.1% and an additional 7.7% with encopresis. Finally, the distinct group of children with aganglionosis of the proximal segment followed a complicated postoperative course with secondary bowel resections and recurrent episodes of enterocolitis. In addition, the authors state their general observation that histological findings become less important whenever a more extensive resection than left hemicolectomy is required. Discussing the results, guidelines are given to further patient treatment once the particular proximal segment histology is diagnosed.


"If He Were a Terrorist, You Would Have Caught Him Already": The Experience of Divorce Denial Among Intimate Partner Violence Survivors.
This study aimed to advance knowledge about separation abuse-and, specifically, divorce denial-and its implications for the well-being of survivors, by applying the conservation of resources (COR) theory. Data were collected from 15 Israeli female survivors of intimate partner violence who were denied divorce over a period lasting between 1 and 12 years. The findings revealed the participants' perceived detrimental effects of divorce denial on their well-being through multiple losses-in terms of autonomy, spiritual and relational, institutional, and financial resources. These findings suggest the need to assess and address the effects of resource loss in separation abuse interventions.


Pubic rami fractures in the elderly--a neglected injury?
To evaluate the patient characteristics and natural history of pubic rami fractures in geriatric patients, with a special focus on the frequency of concomitant posterior pelvic ring lesions and the percentage of secondarily operated patients as a result of conservative treatment failure. Retrospective cohort study. Patients were treated in a university hospital that is equivalent to a level I Trauma centre. We analysed 132 consecutive patients (113 women, 19 men), >65 years old, presenting with low energy-trauma pubic rami fractures at our emergency department from January 2009 to December 2011. Mean age of patients was 84 years (range 66-100). Women were affected six times more frequently than men. Almost 30% of patients lost their previous independence permanently owing to the injury. Ninety eight percent of previously independent patients (community dwellers) required temporary hospital care for a median duration of 39 days (interquartile range [IQR] 28-52). One-year mortality was 18.5%. A concomitant posterior pelvic ring lesion was identified by computed tomography in 54% of patients. In 4% of the patients secondary operative fracture stabilisation was performed. Pubic rami fractures are frequently associated with concomitant posterior pelvic ring injuries, making these injuries more unstable than generally assumed. Based on this fact and the long duration of hospital stay, more aggressive management of these injuries may be considered. The principle aims in this patient population are satisfying pain management, early mobilisation, conservation of independence and return to previous place of residence.


Identification of an N-terminal glycogen synthase kinase 3 phosphorylation site which regulates the functional localization of polycystin-2 in vivo and in vitro.
PKD2 is mutated in 15% of patients with autosomal dominant polycystic kidney disease. Polycystin-2 (PC2), the PKD2 protein, is a non-selective Ca(2+)-permeable cation channel which may function at the cell surface and ER. Nevertheless, the factors that regulate the dynamic translocation of PC2 between the ER and other compartments are not well understood. Constitutive phosphorylation of PC2 at a single C-terminal site (Ser(812)) has been previously reported. As we were unable to abolish phospholabelling of PC2 in HEK293 cells by site-directed mutagenesis of Ser(812) or all five predicted phosphorylation sites in the C-terminus, we hypothesized that PC2 could also be phosphorylated at the N-terminus. In this paper, we report the identification of a new phosphorylation site for PC2 within its N-terminal domain (Ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (GSK3). The consensus recognition sequence for GSK3 (Ser(76)/Ser(80)) is evolutionarily conserved down to lower vertebrates. In the presence of specific GSK3 inhibitors, the lateral plasma membrane pool of endogenous PC2 redistributes into an intracellular compartment in MDCK cells without any change in primary cilia localization. Finally, co-injection of wild-type but not a S76A/S80A mutant PKD2 capped mRNA could rescue the cystic phenotype induced by an antisense morpholino oligonucleotide to pkd2 in zebrafish pronephric kidney. We conclude that surface localization of PC2 is regulated by phosphorylation at a unique GSK3 site in its N-terminal domain in vivo and in vitro. This site is functionally significant for the maintenance of normal glomerular and tubular morphology.


Urinary glycosaminoglycan excretion in patients with primary nocturnal enuresis.
The aim of this study was to determine whether primary nocturnal enuresis (PNE) leads to alterations in glycosaminoglycan (GAG) excretion. Twenty subjects (mean age 8.7 years, M/F 15/5) with PNE were included in the study. Twenty-two healthy subjects were selected as a control group (mean age 8.7 years, M/F 14/8). Urinary GAG excretion was measured using a modified dimethylmethylene blue (DMD) assay of 24-hour urine. The mean urinary GAG content was 33.9 mg/g and 23.8 mg/g creatinine in patients with PNE and controls, respectively; patients with PNE thus had a higher mean GAG excretion than did age-matched controls (p < 0.05). The association between GAG level and enuresis frequency bordered on significance (p = 0.068). GAG excretion in patients with PNE was significantly higher than in normal children, suggesting that measurement of urinary GAG may be useful in evaluating physiopathological conditions of the bladder wall. Further studies are needed to confirm this finding.


Photoastigmatic refractive keratectomy in myopes. Nidek US Investigators Group.
Photoastigmatic refractive keratectomy (PARK) was studied in a multi-center clinical trial. The Nidek EC-5000 excimer laser was evaluated for its effect on refraction, visual acuity, and safety measures as part of a U.S. Food and Drug Administration (FDA) regulated study. Eight U.S. centers enrolled adults with eyes having refractive astigmatism up to 4.00 D and a myopic spherical equivalent refraction up to -8.00 D. Results are reported for 749 eyes of 486 patients with at least 6 months follow-up. The rectangular beam scanning Nidek EC-5000 used a 5.5-mm-diameter treatment zone, a 7.0-mm-diameter peripheral blend zone, and a 40 Hz pulse rate for surface treatment of myopic astigmatism. Nomogram corrections to machine settings were required to achieve the desired results. Preoperative average spherical equivalent refraction of -4.90+/-1.74 D was reduced to -0.02+/-0.79 D at 6 months. Refractive stability was established at 3 months. Over 62% of eyes were within +/-0.50 D of desired correction at 6 months, with over 86% within +/-1.00 D. Uncorrected visual acuity improved by an average of 10 Snellen lines; over 64% of eyes saw 20/20 or better uncorrected and over 93% saw 20/40 or better uncorrected at 6 and 12 months. PARK treatment effectively reduced astigmatism with little average axis error or magnitude error. Corneal haze and safety concerns were minimal. Photoastigmatic refractive keratectomy using the Nidek EC-5000 excimer laser provided significant reduction of myopia and astigmatism, with minimal complications.


Questionnaire-based study to assess the association between management practices and mastitis within tie-stall and free-stall dairy housing systems in Switzerland.
Prophylactic measures are key components of dairy herd mastitis control programs, but some are only relevant in specific housing systems. To assess the association between management practices and mastitis incidence, data collected in 2011 by a survey among 979 randomly selected Swiss dairy farms, and information from the regular test day recordings from 680 of these farms was analyzed. The median incidence of farmer-reported clinical mastitis (ICM) was 11.6 (mean 14.7) cases per 100 cows per year. The median annual proportion of milk samples with a composite somatic cell count (PSCC) above 200,000 cells/ml was 16.1 (mean 17.3) %. A multivariable negative binomial regression model was fitted for each of the mastitis indicators for farms with tie-stall and free-stall housing systems separately to study the effect of other (than housing system) management practices on the ICM and PSCC events (above 200,000 cells/ml). The results differed substantially by housing system and outcome. In tie-stall systems, clinical mastitis incidence was mainly affected by region (mountainous production zone; incidence rate ratio (IRR) = 0.73), the dairy herd replacement system (1.27) and farmers age (0.81). The proportion of high SCC was mainly associated with dry cow udder controls (IRR = 0.67), clean bedding material at calving (IRR = 1.72), using total merit values to select bulls (IRR = 1.57) and body condition scoring (IRR = 0.74). In free-stall systems, the IRR for clinical mastitis was mainly associated with stall climate/temperature (IRR = 1.65), comfort mats as resting surface (IRR = 0.75) and when no feed analysis was carried out (IRR = 1.18). The proportion of high SSC was only associated with hand and arm cleaning after calving (IRR = 0.81) and beef producing value to select bulls (IRR = 0.66). There were substantial differences in identified risk factors in the four models. Some of the factors were in agreement with the reported literature while others were not. This highlights the multifactorial nature of the disease and the differences in the risks for both mastitis manifestations. Attempting to understand these multifactorial associations for mastitis within larger management groups continues to play an important role in mastitis control programs.


[Paget's disease and metastatic epithelioma on the same bone. 11 new cases and review of the literature].
The authors collected observations concerning 11 newly histologically proved cases of a combination of Paget's disease and carcinoma metastatic to bone on the same bone from members of the French Rheumatology Society. The most frequent locations can be specified from their analysis and an analysis of 26 detailed cases from the literature, i.e. pelvis, femur, rachis, tibia, humerus, and the cancers most frequently involved--prostate, bronchi, kidney, breast and intestine. The most usual histological appearance is osteolytic, except in the case of prostatic carcinoma. The metastasis reveals the presence of cancer in 2 cases out of 3, whereas Paget's disease is most often already diagnosed. A histological examination is necessary because of the risk of non recognition of such metastases or of confusion with sarcomatous degeneration. It does not appear to be exceptional to find Paget's disease in combination with a metastasis on the same bone. Although six of the cases concern metastases only located at sites of Paget's disease, an analysis of all the cases does not seem to indicate that Paget bone is more exposed to metastases than normal bone, since both diseases in fact locate preferentially at the same sites on the skeleton.


Improved localisation for 2-hydroxyglutarate detection at 3T using long-TE semi-LASER.
2-hydroxyglutarate (2-HG) has emerged as a biomarker of tumour cell IDH mutations that may enable the differential diagnosis of glioma patients. At 3 Tesla, detection of 2-HG with magnetic resonance spectroscopy is challenging because of metabolite signal overlap and a spectral pattern modulated by slice selection and chemical shift displacement. Using density matrix simulations and phantom experiments, an optimised semi-LASER scheme (TE = 110 ms) improves localisation of the 2-HG spin system considerably compared to an existing PRESS sequence. This results in a visible 2-HG peak in the in vivo spectra at 1.9 ppm in the majority of IDH mutated tumours. Detected concentrations of 2-HG were similar using both sequences, although the use of semi-LASER generated narrower confidence intervals. Signal overlap with glutamate and glutamine, as measured by pairwise fitting correlation was reduced. Lactate was readily detectable across glioma patients using the method presented here (mean CLRB: (10±2)%). Together with more robust 2-HG detection, long TE semi-LASER offers the potential to investigate tumour metabolism and stratify patients in vivo at 3T.


Upper small intestine microbiome in obesity and related metabolic disorders: A new field of investigation.
The study of the gut microbiome holds great promise for understanding and treating metabolic diseases, as its functions and derived metabolites can influence the metabolic status of the host. While research on the fecal microbiome has provided valuable insights, it tells us only part of the story. This limitation arises from the substantial variations in microorganism distribution throughout the gastrointestinal tract due to changes in physicochemical conditions. Thus, relying solely on the fecal microbiome may not be sufficient to draw comprehensive conclusions about metabolic diseases. The proximal part of the small intestine, particularly the jejunum, indeed, serves as the crucial site for digestion and absorption of nutrients, suggesting a potential role of its microbiome in metabolic regulation. Unfortunately, it remains relatively underexplored due to limited accessibility. This review presents current evidence regarding the relationships between the microbiome in the upper small intestine and various phenotypes, focusing on obesity and type 2 diabetes, in both humans and rodents. Research on humans is still limited with variability in the population and methods used. Accordingly, to better understand the role of the whole gut microbiome in metabolic diseases, studies exploring the human microbiome in different niches are needed.