Industrial effluent treatment with immersed MBRs: treatability and cost.
A comprehensive OPEX analysis for both municipal and industrial wastewaters has been conducted encompassing energy, critical component (membrane) replacement, chemicals consumption, waste disposal and labour. The analysis was preceded by a review of recent data on industrial effluent treatability with reference to published chemical oxygen demand (COD) removal data for four effluent types: food and beverage, textile, petroleum and landfill leachate. Outcomes revealed labour costs to be the most significant of those considered, contributing 50% of the OPEX for a 10,000 m3/day capacity municipal wastewater treatment works. An analysis of the OPEX sensitivity to 12 individual parameters (labour cost, flux, electrical energy cost, membrane life, feed COD, membrane cost, membrane air-scour rate, chemicals cost, waste disposal cost, mixed liquor suspended solids (MLSS) concentration, recirculation ratio, and transmembrane pressure) revealed OPEX to be most sensitive to labour effort and/or costs for all scenarios considered other than a large (100,000 m3/day capacity) works, for which flux and electrical energy costs were found to be slightly more influential. It was concluded that for small- to medium-sized plants cost savings are best made through improving the robustness of plants to limit manual intervention necessitated by unforeseen events, such as electrical/mechanical failure, foaming or sludging.


Blinded and unblinded hypohydration similarly impair cycling time trial performance in the heat in trained cyclists.
Knowledge of hydration status may contribute to hypohydration-induced exercise performance decrements; therefore, this study compared blinded and unblinded hypohydration on cycling performance. Fourteen trained, nonheat-acclimated cyclists (age: 25 ± 5 yr; V̇o2peak: 63.3 ± 4.7 ml·kg-1·min-1; cycling experience: 6 ± 3 yr) were pair matched to blinded (B) or unblinded (UB) groups. After familiarization, subjects completed euhydrated (B-EUH; UB-EUH) and hypohydrated (B-HYP; UB-HYP) trials in the heat (31°C); 120-min cycling preload (50% Wpeak) and a time trial (~15 min). During the preload of all trials, 0.2 ml water·kg body mass-1 was ingested every 10 min, with additional water provided during EUH trials to match sweat losses. To blind the B group, a nasogastric tube was inserted in both trials and used to provide water in B-EUH. The preload induced similar ( P = 0.895) changes in body mass between groups (B-EUH: -0.6 ± 0.5%; B-HYP: -3.0 ± 0.5%; UB-EUH: -0.5 ± 0.3%; UB-HYP -3.0 ± 0.3%). All variables responded similarly between B and UB groups ( P ≥ 0.558), except thirst ( P = 0.004). Changes typical of hypohydration (increased heart rate, rating of perceived exertion, gastrointestinal temperature, serum osmolality and thirst, and decreased plasma volume; P ≤ 0.017) were apparent in HYP by 120 min. Time trial performance was similar between groups ( P = 0.710) and slower ( P ≤ 0.013) with HYP for B (B-EUH: 903 ± 89 s; B-HYP: 1,008 ± 121 s; -11.4%) and UB (UB-EUH: 874 ± 108 s; UB-HYP: 967 ± 170 s; -10.1%). Hypohydration of ~3% body mass impairs time trial performance in the heat, regardless of knowledge of hydration status. NEW & NOTEWORTHY This study demonstrates, for the first time, that knowledge of hydration status does not exacerbate the negative performance consequences of hypohydration when hypohydration is equivalent to ~3% body mass. This is pivotal for the interpretation of the many previous studies that have not blinded subjects to their hydration status and suggests that these previous studies are not likely to be confounded by the overtness of the methods used to induce hypohydration.


Influence of Socio-Economic Factors and Region of Birth on the Risk of Preeclampsia in Sweden.
To investigate the association between socio-economic factors and the risk of preeclampsia in Sweden, specifically investigating if this relationship is confounded by maternal region of birth. All singleton births between 1999 and 2009 in an ethnically diverse area in southern Sweden, totaling 46,618 pregnancies, were included in this study. The data on maternal pregnancy outcomes were retrieved from a regional birth register and socio-economic variables from Statistics Sweden. The risk ratios for preeclampsia were calculated for educational level and household disposable income, adjusting for maternal region of birth, maternal age, body mass index, parity, and smoking. Low income levels were associated with a higher risk for preeclampsia, adjusted risk ratio (aRR) = 1.25 (95% confidence interval [CI]: 0.99, 1.59) and aRR = 1.36 (95% CI: 1.10, 1.68) for the two lowest quintiles, respectively, compared to the highest. There was an educational gradient in preeclampsia risk, although not all categories reached statistical significance: aRR = 1.16, (95% CI: 0.89-1.50) for low educational attainment and aRR = 1.23 (95% CI: 1.08, 1.41) for intermediate educational attainment compared to women with highest education. The socio-economic gradient remained after adjusting for region of birth. There was a lower risk for preeclampsia for women born in Asia, aRR = 0.60 (95% CI: 0.47, 0.75), regardless of socio-economic position. An increased risk for preeclampsia was seen for women with measures of lower socio-economic position, even in a universal, government-funded healthcare setting. The relationship was not explained by region of birth, indicating that the excess risk is not due to ethnically differential genetic pre-disposition but rather due to modifiable factors.


Intractable anemia among hemodialysis patients: a sign of suboptimal management or a marker of disease?
Most incident hemodialysis (HD) patients who initiate dialysis therapy with anemia usually can achieve a hemoglobin (Hb) level of 11 g/dL or greater (> or =110 g/L) within a few months of the initiation of recombinant human erythropoietin (EPO) therapy. However, patients unable to achieve this level may be at greater risk for adverse outcomes. Whether intractable anemia is a modifiable problem or a marker for other conditions is unclear. This question was addressed in a cohort of 130,544 incident HD patients from 1996 to 2000 who were administered EPO regularly. Medicare claims data were used to determine demographic characteristics, comorbidities, hospitalizations, and related events. Patients who did not achieve an Hb level of 11 g/dL or greater (> or =110 g/L; n = 19,096; 14.6%) during months 4 to 9 after dialysis therapy initiation were compared with those who did. Patients unable to achieve an Hb level of 11 g/dL (110 g/L) were younger and more often of nonwhite race. In addition, these patients had more comorbid conditions; experienced more hospitalizations with longer stays, more infectious hospitalizations, and more catheter insertions; and were administered more blood transfusions. EPO was administered in higher and increasing doses during the years of study among patients with intractable anemia compared with those with an Hb level of 11 g/dL or greater (> or =110 g/L), likely denoting increasing attempts to correct anemia over the years. It is apparent that incident HD patients unable to achieve an Hb level of 11 g/dL or greater (> or =110 g/L) have a greater disease burden. The independent association of intractable anemia with such future outcomes as cardiovascular events and hospitalizations remains to be determined.


Mitochondrial DNA sequencing of a wet-collection syntype demonstrates the importance of type material as genetic resource for lantern shark taxonomy (Chondrichthyes: Etmopteridae).
After initial detection of target archival DNA of a 116-year-old syntype specimen of the smooth lantern shark, Etmopterus pusillus, in a single-stranded DNA library, we shotgun-sequenced additional 9 million reads from this same DNA library. Sequencing reads were used for extracting mitochondrial sequence information for analyses of mitochondrial DNA characteristics and reconstruction of the mitochondrial genome. The archival DNA is highly fragmented. A total of 4599 mitochondrial reads were available for the genome reconstruction using an iterative mapping approach. The resulting genome sequence has 12 times coverage and a length of 16 741 bp. All 37 vertebrate mitochondrial loci plus the control region were identified and annotated. The mitochondrial NADH2 gene was subsequently used to place the syntype haplotype in a network comprising multiple E. pusillus samples from various distant localities as well as sequences from a morphological similar species, the shortfin smooth lantern shark Etmopterus joungi. Results confirm the almost global distribution of E. pusillus and suggest E. joungi to be a junior synonym of E. pusillus. As mitochondrial DNA often represents the only available reference information in non-model organisms, this study illustrates the importance of mitochondrial DNA from an aged, wet collection type specimen for taxonomy.


Effect of nilvadipine on the cerebral ischemia-induced impairment of spatial memory and hippocampal apoptosis in rats.
We investigated the effects of nilvadipine and amlodipine on the cerebral ischemia-induced impairment of spatial memory in 8-arm radial maze performance and hippocampal CA1 apoptosis in rats. Single cerebral ischemia impaired memory without inducing apoptosis. In these rats, neither nilvadipine nor amlodipine at 3.2 mg/kg, i.p. improved the impaired memory. On the other hand, repeated cerebral ischemia (10 min ischemia x 2, 1 h interval) impaired spatial memory and induced hippocampal apoptosis 7 days after the final occlusion/reperfusion. Moreover, repeated ischemia increased the apoptotic cell number, an effect observed after 3 days and peaked after 7 days. However, mRNA expression of the apoptosis-related early oncogene bax and CPP 32 (caspase-3) was observed after 24 h. In these rats, nilvadipine, but not amlodipine, significantly improved memory, concomitantly decreased hippocampal apoptosis, and suppressed both bax and CPP 32 expression. These results suggest that nilvadipine improved the memory impairment in repeated ischemia by reducing bax and CPP 32 expression and suppressing the induction of apoptosis in the hippocampus. Nilvadipine may have a neuroprotective effect and could be a useful pharmacotherapeutic agent for cerebrovascular dementia.


Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma.
Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.


MiR-143-3p regulates early cartilage differentiation of BMSCs and promotes cartilage damage repair through targeting BMPR2.
The aim of this study was to explore the role of microRNA-143-3p (miR-143-3p) in cartilage injury, and to investigate the possible underlying mechanism. A chondrogenic differentiation cell model was established in bone marrow mesenchymal stem cells (BMSCs). The mRNA expression levels of runt-related transcription factor 2 (RUNX2), miR-143-3p and bone morphogenetic protein 2 (BMPR2) in BMSCs were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) after 0 d, 5 d and 10 d, respectively. Mesenchymal stem cells (MSCs) were transfected with miR-143-3p mimics and its control in accordance with the liposome method. Alcian blue colorimetric assay was used to evaluate proteoglycan deposition of MSCs. Meanwhile, qRT-PCR and Western blot were performed to analyze the expression levels of ACAN and COL2A1. Luciferase reporter gene assay was applied to verify the binding status of miR-143-3p and BMPR2 3'UTR. Also, proteoglycan deposition and the expression of ACAN and COL2A1 were detected after simultaneous transfection of miR-143-3p mimics and BMPR2 overexpression plasmid. 0 d, 5 d and 10 d after inducing cartilage differentiation, the mRNA expression levels of RUNX2 and BMPR2 were markedly increased. However, the expression level of miR-143-3p was significantly decreased with the prolongation of induction period. After transfection with miR-143-3p mimics, the level of miR-143-3p in MSCs was remarkably increased. Alcian blue colorimetric assay and staining assay showed that the deposition of proteoglycans in the mimics group was significantly lower than that of the control group. Meanwhile, after overexpressing miR-143-3p, the levels of cartilage differentiation marker proteins including ACAN and COL2A1 were remarkably reduced. Luciferase report gene assay indicated that miR-143-3p could negatively regulate BMPR2 by binding to its 3'UTR. In addition, overexpression of BMPR2 could strikingly reverse the above effects of overexpressed miR-143-3p. During chondrogenic differentiation, the level of miR-143-3p was decreased. Moreover, miR-143-3p could regulate the differentiation process by targeting BMPR2 in BMSCs.


Principles of CO2/erbium laser safety.
There are a variety of potential hazards with laser technology. A review of the literature. To summarize the potential hazards of CO2 and erbium laser technologies and the safety guidelines and equipment developed to minimize them. Laser hazards can be divided into the following categories: mechanical, environmental, macrobiologic, microbiologic, and iatrogenic. At the conclusion of this learning activity, the reader should be able to discuss the mechanical, environmental, macrobiologic, microbiologic, and iatrogenic hazards of resurfacing laser technology, the literature cited to support current safety guidelines, and the equipment developed to promote laser safety.


[Apolipoprotein(a) phenotypes as markers of genetic susceptibility for cardiovascular risk in occupational medicine].
Several agents (e.g. chemical or physical) present in the work environment may be harmful for the cardiovascular system. Recent studies on the cardiovascular diseases linked to hyperlipidemia have demonstrated a strong correlation between high lipoprotein(a) [Lp(a)] levels and Coronary Heart Disease (CHD). In particular, the severity of this pathological condition correlates well with the molecular weight (MW) of the apolipoprotein(a) [apo(a)] isoforms supporting Lp(a) (low MW = high risk; high MW = low risk), which are characterized by a high degree of individual variability. Since apo(a) isoforms are genetically determined, a genetic predisposition for CHD has been identified, i.e. the apo(a) phenotype is considered a marker of genetic susceptibility for cardiovascular risk. After a brief presentation of the main occupational cardiovascular risk factors (e.g. carbon disulfide, carbon monoxide, noise, psycho-physical stress) and of the most updated theories on atherogenesis, the present review proposes to utilize the measurement of the plasmatic Lp(a) level to screen for occupational cardiovascular risk susceptibility. Apo(a) phenotype characterization of workers with medium-high Lp(a) levels is then suggested. Our proposal may be realized by means of simple and relatively unexpensive laboratory methods.


Observations of fracture of the anconeal process of the ulna of swine.
Fractures of the anconeal process of 5 pigs ranging in age from 4 to 8 months were studied radiographically and histologically. Clinically, animals with a fracture of the anconeal process had a "tight," restricted gait. In pigs at 4.5 months of age, a radiolucent line through the base of the anconeal process was composed of fibrocartilage, fibrous connective tissue, and hyaline cartilage. Subperiosteal proliferation of woven bone was located along the cranial surface of the olecranon, adjacent to the base of the anconeal process. In older animals, the radiolucent line through the anconeal process contained variable amounts of fibrous connective tissue and fibrocartilage. The proliferation of subperiosteal bone at the base of the anconeal process formed a "buttress callus" which retained a radiolucent area between the callus and the proximal surface of the anconeal process. The latter region of radiolucency was continuous with the transversely oriented line that traversed the base of the anconeal process.


Socioeconomic disadvantage and disease-specific mortality in Asia: systematic review with meta-analysis of population-based cohort studies.
That socioeconomic deprivation has shown a correlation with disease-specific mortality in Western societies is well documented. However, it is unclear whether these findings are also apparent in Asian societies. Accordingly, we conducted the first systematic review and meta-analysis of studies from Asia that have reported on the association between socioeconomic position and adult mortality risk. Relevant studies were identified through an electronic search of databases. Studies were included if they had published quantitative estimates of the association between socioeconomic status (SES) and mortality in a general population-based sample. The pooled multiple-adjusted relative risks for mortality in the lowest SES group relative to the highest SES group were studied. Random effects meta-analyses were computed. A total of 29 cohort studies from 10 Asian countries were identified, comprising 1 370 023 individuals and 71 818 total deaths. The three markers of SES most widely used (education, income, occupation) were inversely related to mortality outcomes under consideration (all-causes, cardiovascular disease, cancer). For instance, the pooled relative risks of low education compared with high education were: 1.40 (95% CI 1.29 to 1.52) for all-cause mortality, 1.66 (1.23 to 2.25) for cardiovascular mortality and 1.16 (1.07 to 1.27) for cancer mortality. There was some evidence that the age of cohort members at study induction, the gross national product of the country from which the cohort was drawn and geographical region modified the association between SES and mortality. Concordant with findings from Western societies, socioeconomic disadvantage is associated with total and cause-specific mortality in Asia.


HIV-1 viral protein R (Vpr) induces fatty liver in mice via LXRα and PPARα dysregulation: implications for HIV-specific pathogenesis of NAFLD.
HIV patients develop hepatic steatosis. We investigated hepatic steatosis in transgenic mice expressing the HIV-1 accessory protein Vpr (Vpr-Tg) in liver and adipose tissues, and WT mice infused with synthetic Vpr. Vpr-Tg mice developed increased liver triglyceride content and elevated ALT, bilirubin and alkaline phosphatase due to three hepatic defects: 1.6-fold accelerated de novo lipogenesis (DNL), 45% slower fatty acid ß-oxidation, and 40% decreased VLDL-triglyceride export. Accelerated hepatic DNL was due to coactivation by Vpr of liver X receptor-α (LXRα) with increased expression of its lipogenic targets Srebp1c, Chrebp, Lpk, Dgat, Fasn and Scd1, and intranuclear SREBP1c and ChREBP. Vpr enhanced association of LXRα with Lxrα and Srebp1c promoters, increased LXRE-LXRα binding, and broadly altered hepatic expression of LXRα-regulated lipid metabolic genes. Diminished hepatic fatty acid ß-oxidation was associated with decreased mRNA expression of Pparα and its targets Cpt1, Aox, Lcad, Ehhadh, Hsd10 and Acaa2, and blunted VLDL export with decreased expression of Mttp and its product microsomal triglyceride transfer protein. With our previous findings that Vpr circulates in HIV patients (including those with undetectable plasma HIV-1 RNA), co-regulates the glucocorticoid receptor and PPARγ and transduces hepatocytes, these data indicate a potential role for Vpr in HIV-associated fatty liver disease.


Flexible focusing pattern realization of centimeter-scale planar super-oscillatory lenses in parallel fabrication.
Planar super-oscillatory lenses (SOLs) can exert far-field foci beyond the diffraction limit free from the contribution of evanescent waves. However, the reported design methods of SOLs are always complicated and divergent, leading to a poor control over the desired focusing patterns. Furthermore, the existing device sizes of SOLs are mainly within hundreds of micrometers accompanied by a subwavelength-scale feature size. Here, we propose a general optimization design model for realizing flexible focusing patterns, e.g. multifocal and achromatic contours. Additionally, a novel design called the chromatic-customized SOL fighting against the dispersion rule of traditional diffractive optical elements (DOEs) is also demonstrated based on the proposed flexible algorithm. The diameters for all the SOLs reach 12 mm with 30 μm minimum feature size, which can be easily fabricated by employing the conventional optical lithography technique. Such centimeter-scale, light weight and low-cost lenses reveal new capacities of arbitrarily customized optical patterns in various interdisciplinary fields including parallel particle trapping, full-color high-resolution imaging, and compact spectral imaging.


Remote monitoring or close encounters? Ethical considerations in priority setting regarding telecare.
The proportion of elderly in society is growing rapidly, leading to increasing health care costs. New remote monitoring technologies are expected to lower these costs by reducing the number of close encounters with health care professionals, for example the number of visits to health care centres. In this paper, I discuss issues of priority setting raised by this expectation. As a starting-point, I analyse the recent debate on principles for priority setting in Sweden. The Swedish debate illustrates that developing an approach to priority setting is an ongoing process. On the basis of this analysis, I conclude that several different ethical principles, and specifications of these principles, can be appealed to for giving priority--over close encounters--to a large-scale introduction of remote monitoring technologies in health care services to elderly people, but also that many specifications can be appealed to against giving such priority. I propose that given the different views on principles, it is necessary to develop fair procedures of deliberation on these principles and their application, in particular in order to reach agreement on exactly how much resources should be allocated to remote monitoring and how much to close encounters. I also present a few points to consider in a large-scale introduction of remote monitoring.


[Motivation for the choice of complementary and mainstream medicine. Patients' behavior in a pluralistic medical system].
The reasons for choosing between various therapeutic possibilities depend in part on rational and in part on emotional factors. This project dealt with the systematic verification of some decision factors most of which were known already. The project was divided in a qualitative and a quantitative part. The qualitative segment was based on semistructured interviews with patients of general practitioners or of naturopaths. This procedure is often used in ethnological research. It identified and evaluated the main motives for the individual choices of therapies by the patients. The quantitative part of the study was carried out by a procedure often used in social sciences, namely by strictly structured telephone interviews of several thousand policyholders of the health insurance fund Helvetia. The aim of this part of the study was to verify the findings of the qualitative study and to investigate the possible significance of additional sociological factors for the choice between different therapies. The conclusions drawn from the abundance of data show that a widespread use of complementary medicine is a reality. Both parts of the project came to the same conclusions. The patients use complementary medicine in a very pragmatic way, be it alternately, be it in parallel but not necessarily in addition to mainstream medicine. The behavior of the patients is very complex, depends on many factors, and can neither be predicted nor easily influenced, not even by an additional free insurance for complementary medicine which was offered to one of the subgroups of the study (in conjunction with J. Sommer's project 'A Randomized Experiment Studying the Effect of Including Complementary Medicine in the Mandatory Benefit Package of Health Insurance Funds in Switzerland'). The interpretation of the telephone interviews concerning the significance of some of the registered sociological factors turned out to be difficult. The project aimed primarily at illustrating the use of complementary medicine and at characterizing its users.


Actinobacillus actinomycetemcomitans induces apoptosis in human monocytic THP-1 cells.
It has previously been reported that the murine macrophage cell line J774.1 and the human oral epithelial cell line KB undergo apoptosis as a result of Actinobacillus actinomycetemcomitans infection. Recent studies have demonstrated that apoptosis regulation is modulated by multiple phosphorylation of several different protein kinases, including the major subtypes of the mitogen-activated protein kinase (MAPK) family. The MAPK family promotes cell survival and/or proliferation in response to growth factor stimulation, or apoptosis in response to various stress stimuli. The primary objective of the present investigation was to clarify whether human immune cells undergo apoptosis following A. actinomycetemcomitans infection and, if so, to establish the involvement of the MAPK family. Human monocytic THP-1 cells were infected with A. actinomycetemcomitans in microtubes. Lactate dehydrogenase release into the culture supernatant and DNA fragmentation in the cells were monitored. DNA fragmentation was also identified by agarose gel electrophoresis. Cell death following A. actinomycetemcomitans infection occurred by apoptosis, shown by an increase in the proportion of fragmented DNA and the typical ladder pattern of DNA fragmentation indicative of apoptosis. Furthermore, p38 MAPK activity and tumour necrosis factor alpha (TNF-alpha) levels increased following A. actinomycetemcomitans infection. In contrast, cell death and TNF-alpha levels in infected cells decreased upon addition of a p38 inhibitor or an anti-TNF-alpha antibody. However, exogenous TNF-alpha could not induce apoptosis in uninfected THP-1 cells. Interestingly, p38 MAPK activity diminished in the presence of anti-TNF-alpha antibody. These findings indicated that A. actinomycetemcomitans infection induces apoptosis in THP-1 cells and that p38 MAPK activity is directly involved in apoptosis. TNF-alpha may play an indirect role in apoptosis via enhanced p38 MAPK activity. A. actinomycetemcomitans-induced apoptosis of human immune cells may be important in terms of initiation and progression of periodontal diseases.


A model for treating avian aspergillosis: serum and lung tissue kinetics for Japanese quail (Coturnix japonica) following single and multiple aerosol exposures of a nanoparticulate itraconazole suspension.
Aspergillosis is frequently reported in parrots, falcons and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but administration requires repeated oral dosing and the safety margin is narrow. We describe lung tissue and serum pharmacokinetics of a nanoparticulate ITRA suspension administered to Japanese quail by aerosol exposure. Aerosolized ITRA (1 and 10% suspension) administered over 30 min did not induce adverse clinical reactions in quail upon single or 5-day repeated doses. High lung concentrations, well above the inhibitory levels for A. fumigatus, of 4.14 ± 0.19 μg/g and 27.5 ± 4.58 μg/g (mean ± SEM, n = 3), were achieved following single-dose inhalation of 1% and 10% suspension, respectively. Upon multiple dose administration of 10% suspension, mean lung concentrations reached 104.9 ± 10.1 μg/g. Drug clearance from the lungs was slow with terminal half-lives of 19.7 h and 35.8 h following inhalation of 1% and 10% suspension, respectively. Data suggest that lung clearance is solubility driven. Lung concentrations of hydroxy-itraconazole reached 1-2% of the ITRA lung tissue concentration indicating metabolism in lung tissue. Steady, but low, serum concentrations of ITRA could be measured after multiple dose administration, reaching less than 0.1% of the lung tissue concentration. This formulation may represent a novel, easy to administer treatment modality for fungal lung infection, preventing high systemic exposure. It may also be useful as metaphylaxis to prevent the outbreak of aspergillosis in colonized animals.


Selective dopamine D3 receptor antagonist YQA14 inhibits morphine-induced behavioral sensitization in wild type, but not in dopamine D3 receptor knockout mice.
Increasing preclinical evidence demonstrates that dopamine D3 receptor (D3R) antagonists are a potential option for the treatment of drug addiction. The reinstatement of the addiction can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. YQA14 is a novel D3R antagonist that has exhibited pharmacotherapeutic efficacy in reducing cocaine and amphetamine reward and relapse to drug seeking in mice. In this study we investigated the effects of YQA14 on morphine-induced context-specific locomotor sensitization in mice. We showed that repeated injection of YQA14 (6.25-25 mg/kg every day ip) prior to morphine (10 mg/kg every day sc) not only inhibited the acquisition, but also significantly attenuated the expression of morphine-induced locomotor sensitization. Furthermore, in the expression phase, one single injection of YQA14 (6.25-25 mg/kg, ip) dose-dependently inhibited the expression of morphine-induced behavioral sensitization. Moreover, YQA14 inhibited the expression of morphine-induced behavioral sensitization in wild mice (WT), but not in D3R knockout (D3R-/-) mice in the expression phase. In addition, D3R-/- mice also displayed the reduction in the expression phase compared with WT mice. In summary, this study demonstrates that blockade or knockout of the D3R inhibits morphine-induced behavior sensitization, suggesting that D3R plays an important role in the pathogenesis and etiology of morphine addiction, and it might be a potential target for clinical management of opioid addiction.


Tyrosine kinase inhibitors rechallenge in solid tumors: a review of literature and a case description with lenvatinib in thyroid cancer.
In the last decade tyrosine kinase inhibitors (TKIs) have been employed for a wide range of hematological and solid tumors and today they represent a valid therapeutic option for different neoplasms. Among them, both sorafenib and lenvatinib were approved for the treatment of radioactive iodine (RAI) refractory differentiated thyroid carcinoma (DTC). Unfortunately, in some cases the efficacy of TKIs is limited by the onset of drug resistance after the initial response. Areas covered: We report the case of a patient with a RAI refractory advanced DTC, treated with lenvatinib after surgery, multiple RAI administrations, traditional chemotherapy, and sorafenib. During treatment with lenvatinib, a noticeable response was detected by sequential computed tomography scans but, after 27 months, tumor progression became evident and led to lenvatinib interruption. In absence of any active treatment, a further disease progression was documented, and lenvatinib was re-administered obtaining a new objective response. Starting from this case report, we review available reports about the rechallenge with TKIs in solid tumors, discussing the possible mechanisms underlying the efficacy of this approach. Expert commentary: Rechallenge with TKIs in solid tumors could be a therapeutic option in subjects with advanced and metastatic DTC who experience a progressive disease after initial response to lenvatinib.


The Replisomes Remain Spatially Proximal throughout the Cell Cycle in Bacteria.
The positioning of the DNA replication machinery (replisome) has been the subject of several studies. Two conflicting models for replisome localization have been proposed: In the Factory Model, sister replisomes remain spatially co-localized as the replicating DNA is translocated through a stationary replication factory. In the Track Model, sister replisomes translocate independently along a stationary DNA track and the replisomes are spatially separated for the majority of the cell cycle. Here, we used time-lapse imaging to observe and quantify the position of fluorescently labeled processivity-clamp (DnaN) complexes throughout the cell cycle in two highly-divergent bacterial model organisms: Bacillus subtilis and Escherichia coli. Because DnaN is a core component of the replication machinery, its localization patterns should be an appropriate proxy for replisome positioning in general. We present automated statistical analysis of DnaN positioning in large populations, which is essential due to the high degree of cell-to-cell variation. We find that both bacteria show remarkably similar DnaN positioning, where any potential separation of the two replication forks remains below the diffraction limit throughout the majority of the replication cycle. Additionally, the localization pattern of several other core replisome components is consistent with that of DnaN. These data altogether indicate that the two replication forks remain spatially co-localized and mostly function in close proximity throughout the replication cycle. The conservation of the observed localization patterns in these highly divergent species suggests that the subcellular positioning of the replisome is a functionally critical feature of DNA replication.


Black sesame pigment: DPPH assay-guided purification, antioxidant/antinitrosating properties, and identification of a degradative structural marker.
An improved purification procedure leading to black sesame ( Sesamum Indicum L.) pigment was developed involving fat removal by treatment of ground black sesame seeds with dichloromethane followed by an optimized hydrolytic protocol with 6 M HCl, at 100 °C, overnight. The black pigment thus obtained displayed good antioxidant efficiency by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical assay (82% reduction at 0.5 mg/mL), good ferric ion-reducing capacity (61 μM Trolox equivalent concentration at 0.5 mg/mL), and potent antinitrosating properties (74% inhibition of 2,3-diaminonaphthalene (DAN) nitrosation at gastric pH at 2.5 mg/mL). A synthetic pigment obtained by oxidative polymerization of coniferyl alcohol (polyconiferyl alcohol, PCA), the putative biosynthetic precursor to the sesame pigment, was characterized as a reference standard. FT IR spectra of the purified sesame pigment and PCA supported the structural similarity. HPLC analysis of degradation products by alkaline hydrogen peroxide of purified black sesame pigment showed the formation of vanillic acid (VA) as the main isolable fragment. Similar yields of VA were obtained by degradation of PCA. A positive correlation between VA yields and DPPH activity was determined in samples of different purities. It is suggested that VA is a structural marker of black sesame pigment, confirming the biosynthetic origin from coniferyl alcohol and pointing to the o-methoxyphenol motif as the key factor accounting for the potent antioxidant properties of the pigment.


Molecular biology of the androgen receptor.
Androgen receptor (AR) is a member of the steroid hormone receptor family of molecules. AR primarily is responsible for mediating the physiologic effects of androgens by binding to specific DNA sequences that influence transcription of androgen-responsive genes. The three-dimensional structure of the AR ligand-binding domain has shown it is similar to other steroid hormone receptors and that ligand binding alters the protein conformation to allow binding of coactivator molecules that amplify the hormone signal and mediate transcriptional initiation. However, AR also undergoes intramolecular interactions that regulate its interactions with coactivators and influence its activity. A large number of naturally occurring mutations of the human AR gene have provided important information about AR molecular structure and intermolecular interactions. AR is also a critical mediator of prostate cancer promotion, conferring growth signals to prostate cancer cells throughout the natural history of the disease. Late-stage prostate cancer, unresponsive to hormonal deprivation, sustains AR signaling through a diverse array of molecular strategies. Variations in the AR gene may also confer genetic predisposition to prostate cancer development and severity. Further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.


Nutritional modulators of ulcerative colitis: clinical efficacies and mechanistic view.
Ulcerative colitis (UC) is an inflammation-associated disease of the colon and rectum. The onset and progress of the disease are directly influenced by the nature of the intestinal microflora, the intestinal barrier function, and the immunological responses of the host. The epithelial invasion of pathogenic bacteria due to excess contact and/or barrier dysfunction is related to inflammation mediated by intestinal immune responses. Although the etiology of UC is not clearly understood, recent studies have shown a rising incidence of UC worldwide, and this phenomenon is more prominent in Asian countries and in Asian immigrants in Western countries. The increased prevalence of UC also contributes to an increased risk of developing colorectal cancer. Environmental factors, including changes in dietary habits, have been suggested as major risk factors of UC. A systematic review showed a negative association between UC risk and vegetable intake, whereas total fat, omega-6 fatty acids and meat intake were positively associated with an increased risk of UC. Individual dietary factors and energy balance have been suggested as having important roles in inducing changes in the microbial population and intestinal barrier integrity and in regulating inflammatory immune responses, directly or indirectly. Excess energy intake is now known to increase pathogenic microbial populations. Likewise, the application of appropriate probiotics may reverse the pathogenic progression of the disease. In the meantime, dietary anti-inflammatory compounds, including omega-3 fatty acids and other phytochemicals, may directly suppress inflammatory responses in the course of UC development. In this review, the increased prevalence of UC and its management are interpreted from the standpoint of nutritional modulation to regulate the intestinal microflora population, intestinal epithelium permeability, and inflammatory responses.


Gene structure and organization of the human beta-secretase (BACE) promoter.
The first step in the generation of the amyloid-beta peptide (Abeta) deposited in the brains of patients with Alzheimer's disease (AD) is the processing of the larger Abeta precursor protein (APP) by an integral membrane aspartyl protease named the beta-site APP-cleaving enzyme (BACE). We present the genomic organization of the BACE gene. BACE mRNAs are synthesized as nine exons and eight introns from a 30.6 kb region of chromosome 11q23.2-11q23.3. Regulation of BACE may play an important role in regulating the levels of Abeta produced and is therefore likely to play an important role in AD. Herein, we report the cloning and detailed analysis of 3765 nucleotides of the promoter region of BACE and 364 nucleotides of the 5' untranslated region of the BACE mRNA (5' UTR). Characteristic "CAAT" and "TATA" boxes are absent within 1.5 kb of the transcription start site (TSS). The promoter region and 5' UTR contain multiple transcription factor binding sites, such as activator protein (AP)1, AP2, cAMP response element binding protein (CREB), estrogen responsive element (ERE), glucocorticoid responsive element (GRE), "GC" box, nuclear factor (NF)-kappaB, signal transducer and activator of transcription (STAT)1, stimulating protein (SP)1, metal-regulatory elements, and possible Zeste binding sites. Limited interspecies similarity was observed between the human sequence and corresponding genomic DNA from the rat and mouse sequences, but several transcription factor-binding sites are conserved. Thus, the BACE gene contains basal regulatory elements, inducible features and sites for regulated activity by various transcription factors. These results identify the important regions for functional analysis of the binding domains and neuron-specific expression (1). Such a study will allow us to further examine the possible role of changes in the promoter of BACE in AD pathogenesis.


Functional impact of cancer-associated cohesin variants on gene expression and cellular identity.
Cohesin is a ring-shaped protein complex that controls dynamic chromosome structure. Cohesin activity is important for a variety of biological processes, including formation of DNA loops that regulate gene expression. The precise mechanisms by which cohesin shapes local chromosome structure and gene expression are not fully understood. Recurrent mutations in cohesin complex members have been reported in various cancers, though it is not clear whether many cohesin sequence variants have phenotypes and contribute to disease. Here, we utilized CRISPR/Cas9 genome editing to introduce a variety of cohesin sequence variants into murine embryonic stem cells and investigate their molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription, including altered expression of gene encoding lineage-specifying developmental regulators. Altered gene expression was also observed at insulated neighborhoods, where cohesin-mediated DNA loops constrain potential interactions between genes and enhancers. Furthermore, some cohesin variants altered the proliferation rate and differentiation potential of murine embryonic stem cells. This study provides a functional comparison of cohesin variants found in cancer within an isogenic system, revealing the relative roles of various cohesin perturbations on gene expression and maintenance of cellular identity.


Locally stable brain states predict suppression of epileptic activity by enhanced cognitive effort.
Cognitive effort is known to play a role in healthy brain state organization, but little is known about its effects on pathological brain dynamics. When cortical stimulation is used to map functional brain areas prior to surgery, a common unwanted side effect is the appearance of afterdischarges (ADs), epileptiform and potentially epileptogenic discharges that can progress to a clinical seizure. It is therefore desirable to suppress this activity. Here, we analyze electrocorticography recordings from 15 patients with epilepsy. We show that a cognitive intervention in the form of asking an arithmetic question can be effective in suppressing ADs, but that its effectiveness is dependent upon the brain state at the time of intervention. By applying novel techniques from network analysis to quantify brain states, we find that the spatial organization of ADs with respect to coherent brain regions relates to the success of the cognitive intervention: if ADs are mainly localized within a single stable brain region, a cognitive intervention is likely to suppress the ADs. These findings show that cognitive effort is a useful tactic to modify unstable pathological activity associated with epilepsy, and suggest that the success of therapeutic interventions to alter activity may depend on an individual's brain state at the time of intervention.


Inactivation of p16INK4a by CpG hypermethylation is not a frequent event in colorectal cancer.
Gene promoter hypermethylation is common in colorectal cancer and is associated with transcriptional silencing. However, the clinicopathological significance of p16(INK4a) gene silencing with hypermethylation is unknown. Therefore, the aim of this study was to analyze loss of p16 expression and its relationship to hypermethylation in sporadic colorectal cancer. Tissue from 426 colorectal cancers underwent histological analysis. Immunohistochemistry was performed for p16 expression. Fresh tumor DNA was analyzed for microsatellite instability (MSI) and the presence of K-ras mutations. In addition, DNA was bisulphite-modified and analyzed for p16(INK4a) promoter methylation by methylation-specific PCR. There were 25% of tumors with p16(INK4a) promoter hypermethylation. These tumors were associated with older patients, right-sidedness, MSI and were poorly differentiated, mucinous, and had intraepithelial and peritumoral lymphocytes and a Crohn's-type lymphocytic reaction (P < 0.05). However, only right-sidedness was significant on multivariate analysis (P < 0.001). Only 8.1% of tumors did not express p16, and this was associated with hypermethylation (P < 0.05). p16(INK4a) promoter methylation, although common in colorectal cancer, does not result in a clinicopathologically distinct subgroup of tumors and infrequently results in transcriptional silencing. This suggests that p16(INK4a) gene inactivation does not have an important role in the pathogenesis of sporadic colorectal cancer.


Can a core outcome set improve the quality of systematic reviews?--a survey of the Co-ordinating Editors of Cochrane Review Groups.
Missing outcome data or the inconsistent reporting of outcome data in clinical research can affect the quality of evidence within a systematic review. A potential solution is an agreed standardized set of outcomes known as a core outcome set (COS) to be measured in all studies for a specific condition. We investigated the amount of missing patient data for primary outcomes in Cochrane systematic reviews, and surveyed the Co-ordinating Editors of Cochrane Review Groups (CRGs) on issues related to the standardization of outcomes in their CRG's reviews. These groups are responsible for the more than 7,000 protocols and full versions of Cochrane Reviews that are currently available, and the several hundred new reviews published each year, presenting the world's largest collection of standardized systematic reviews in health care. Using an unselected cohort of Cochrane Reviews, we calculated and presented the percentage of missing patient data for the primary outcome measure chosen for each review published by each CRG. We also surveyed the CRG Co-ordinating Editors to see what their policies are with regards to outcome selection and outcomes to include in the Summary of Finding (SoF) tables in their Cochrane Reviews. They were also asked to list the main advantages and challenges of standardizing outcomes across all reviews within their CRG. In one fifth of the 283 reviews in the sample, more than 50% of the patient data for the primary outcome was missing. Responses to the survey were received from 90% of Co-ordinating Editors. Thirty-six percent of CRGs have a centralized policy regarding which outcomes to include in the SoF table and 73% of Co-ordinating Editors thought that a COS for effectiveness trials should be used routinely for a SoF table. The reliability of systematic reviews, in particular meta-analyses they contain, can be improved if more attention is paid to missing outcome data. The availability of COSs for specific health conditions might help with this and the concept has support from the majority of Co-ordinating Editors in CRGs.


Aging and urinary control: Alterations in the brain-bladder axis.
Age-associated alterations in bladder control affect millions of older adults, with a heavy burden added to families both economically and in quality of life. Therapeutic options are limited with poor efficacy in older adults, lending to a growing need to address the gaps in our current understanding of urinary tract aging. This review summarizes the current knowledge of age-associated alterations in the structure and function of the brain-bladder axis and identifies important gaps in the field that have yet to be addressed. Urinary aging is associated with decreased tissue responsiveness, decreased control over the voiding reflex, signaling dysfunction along the brain-bladder axis, and structural changes within the bladder wall. Studies are needed to improve our understanding of how age affects the brain-bladder axis and identify genetic targets that correlate with functional outcomes.


Safety of abatacept compared with other biologic and conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: data from an observational study.
To assess the risks of malignancies, infections and autoimmune diseases in patients with rheumatoid arthritis (RA) treated with abatacept compared with other biologic (b) disease-modifying antirheumatic drugs (DMARDs) or conventional synthetic (cs)DMARDs, in a US-wide observational RA cohort METHODS: Data were reviewed from patients (≥ 18 years) with RA who were registered with FORWARD, the National Databank for Rheumatic Diseases, and who initiated abatacept, other bDMARDs or csDMARDs between 2005 and 2015. Patients who switched treatment during the study could be allocated to more than one group. The incidence rates (IRs) by treatment were calculated for malignancies, hospitalized infections and autoimmune diseases identified by six monthly questionnaires and medical records. The hazard ratios (HRs) (95% confidence intervals [CIs]) for all outcomes with abatacept compared with other bDMARDs or csDMARDs were determined using marginal structural models adjusted for clinical confounders. In the study sample, 1496 initiated abatacept, 3490 initiated another bDMARD and 1520 initiated a csDMARD. The risk of malignancies with abatacept was not statistically significant versus other bDMARDs (HR [95% CI)] 1.89 [0.93, 3.84]) or versus csDMARDs (HR [95% CI] 0.93 [0.20, 4.27]). Patients receiving abatacept versus other bDMARDs were at a lower risk of hospitalized infections (HR [95% CI] 0.37 [0.18, 0.75]); the risk versus csDMARDs was lower with wide CIs (HR [95% CI] 0.31 [0.09, 1.05]). The relative risks for psoriasis were similar between treatment groups (HR [95% CI] 1.46 [0.76, 2.81] and HR [95% CI] 2.05 [0.59, 7.16] for abatacept versus other bDMARDs and versus csDMARDS, respectively). The IR (95% CI) of severe infusion/injection reactions was lower with abatacept compared with other bDMARDs (1.57 [1.11, 2.17] vs 2.31 [1.87, 2.82] per 100 patient-years, respectively). In this analysis, abatacept was well tolerated and did not result in an overall increased risk of malignancies, infections or autoimmune diseases compared with other bDMARDs or csDMARDs.


Fast sampling with Gaussian scale-mixture priors in high-dimensional regression.
We propose an efficient way to sample from a class of structured multivariate Gaussian distributions. The proposed algorithm only requires matrix multiplications and linear system solutions. Its computational complexity grows linearly with the dimension, unlike existing algorithms that rely on Cholesky factorizations with cubic complexity. The algorithm is broadly applicable in settings where Gaussian scale mixture priors are used on high-dimensional parameters. Its effectiveness is illustrated through a high-dimensional regression problem with a horseshoe prior on the regression coefficients. Other potential applications are outlined.


Adverse childhood experiences and obesity: Systematic review of behavioral interventions for women.
Studies have demonstrated a relationship between adverse childhood experiences (ACEs) and adult obesity. Group interventions addressing the psychosocial sequelae of ACES using a trauma-informed approach for adults are well described in the literature. There is also a significant body of literature on the efficacy and proposed structure of interventions addressing weight reduction in adults. However, it is unknown how often interventions addressing attainment of a healthy weight incorporate a specific focus on adult women with a history of ACEs, including childhood abuse and trauma. A systematic review of the literature was conducted using standard approaches. Two additional reviews used broadened inclusion criteria to identify and include group-level interventions that addressed intended outcomes other than obesity. Studies that examined the link between ACEs and obesity as a primary outcome and that provided a description of any potential mediating variables were also identified. The current literature search was conducted as the first step in a multifaceted approach to the development of a set of proposed research protocol designs for an Office on Women's Health-sponsored trauma-informed healthy weight pilot intervention for obese women with a history of ACEs. No articles describing interventions for the treatment of obesity or overweight women with a history of ACEs were identified. Eleven articles describing ACE-related interventions and 15 studies identifying mediators were reviewed. Intervention studies for women with ACEs, other than psychotherapy, are limited. Significant mediators to be considered include anxiety symptoms and internalizing behaviors. Specific recommendations for interventions are provided. (PsycINFO Database Record


Genetics of mammalian sex chromosomes.
The great strides made during the past two years in the whole field of mammalian cytogenetics have, in particular, enlarged our knowledge of the role of the mammalian sex chromosomes. The following summary briefly lists the most recent discoveries in the mouse, where genetic findings have played a relatively greater role than in the other species of mammals. The male-determining property of the mammalian Y chromosome, established earlier in mouse and man, has been further confirmed by the finding of an XXY mouse, which was detected by genetic means and has been studied cytologically. This animal is a fully viable, phenotypically normal, though sterile, male. Since various doubts concerning detectability of the XXY type have been removed by the discovery of this animal, it can be concluded that the occurrence of XXY in the mouse is extremely rare. It has been shown that the X chromosome of the mouse, when it is involved in certain chromosomal rearrangements, has the power to produce variegated-type position effects, a phenomenon formerly not observed in any animal except Drosophila. The fact that the X chromosome is involved in all four of the known cases of V-type position effect in the mouse indicates that it is strongly heterochromatic, while there may be little heterochromatin on the autosomes. Recent findings have shown that the presence of two X chromosomes is necessary for the expression of the position effect in one of them. This fact, when related to various cytological findings in other species, permits the hypothesis that, in mammals, genic balance requires the action of one X in a manner which precludes realization of its heterochromatic potentialities, so that only any additional X's present assume the properties characteristic of heterochromatin. A variety of different findings sheds light on the mechanisms that may lead to the occurrence of individuals with abnormal numbers of sex chromosomes. The XXY mouse proves, by virtue of its sex-linked marker genes, that nondisjunction can occur in the first meiotic division of a normal male (a proof not previously provided by human cases of XXY, which could have been of different origin). However, first-meiotic nondisjunction is apparently very rare in males, and there is not yet any evidence that it ever occurs in females. Data from numerous types of crosses involving five sex-linked markers yield the following results: no cases of X(M)X(M)Y or OX(P) have occurred to date; X(M)X(P)Y << X(M)O; OX(P) << X(M)O (where the superscripts M and P designate maternal and paternal derivation, respectively, of the X). The total frequency of XO individuals can be increased by irradiation shortly after fertilization. This treatment has yielded, in addition to X(M)O, several animals of the OX(P) constitution, a type that has not yet been found to occur spontaneously. The various findings on spontaneous and induced frequencies of mice with abnormal numbers of sex chromosomes lead to the conclusion that XO individuals are most often the result of events occurring after fertilization. Specifically, it is suggested that there exists a relatively high probability of loss of the paternally contributed sex chromosome some time between fertilization and the first cleavage(32).


Low intracranial compliance increases the impact of intracranial volume insults to the traumatized brain: a microdialysis study in a traumatic brain injury rodent model.
The vulnerability of the brain is considered to be increased after trauma. The present study was undertaken to determine whether intracranial volume insults in the posttraumatic period led to increased metabolic disturbances if intracranial compliance was decreased. A weight drop technique with a brain compression of 1.5 mm was used for injury. Intracranial compensatory volume was decreased 60 microl by placing rubber film between the dura mater and the bone. Intracranial volume insults were induced using the Bolus injection technique. Microdialysis was used to measure interstitial lactate, pyruvate, hypoxanthine, and glycerol. Fifty-two rats were allocated to trauma and sham groups with 0 to 3 layers of rubber film with and without intracranial volume insults. In the groups with reduced intracranial volume exposed to intracranial volume insults, the time course of metabolic markers showed higher increases and slower recovery rates than for the other groups. Reduced intracranial volume or intracranial volume insults alone did not cause any changes compared with controls. These results support the hypothesis that decreased intracranial compliance increases the vulnerability of the brain for secondary volume insults even with intracranial pressure at low levels between the insults. This finding has important clinical implications in that it stresses the need to identify patients with low intracranial compliance so that their treatment can be optimized.


Towards an open and synergistic framework for mapping global land cover.
Global land-cover datasets are key sources of information for understanding the complex inter-actions between human activities and global change. They are also among the most critical variables for climate change studies. Over time, the spatial resolution of land cover maps has increased from the kilometer scale to 10-m scale. Single-type historical land cover datasets, including for forests, water, and impervious surfaces, have also been developed in recent years. In this study, we present an open and synergy framework to produce a global land cover dataset that combines supervised land cover classification and aggregation of existing multiple thematic land cover maps with the Google Earth Engine (GEE) cloud computing platform. On the basis of this method of classification and mosaicking, we derived a global land cover dataset for 6 years over a time span of 25 years. The overall accuracies of the six maps were around 75% and the accuracy for change area detection was over 70%. Our product also showed good similarity with the FAO and existing land cover maps.


Self-reported history of anorexia nervosa and current quality of life: findings from a community-based study.
To evaluate the impact of a lifetime history of anorexia nervosa (AN) on current quality of life (QoL) and eating disorder (ED) symptomatology. 3,034 participants from a randomly selected sample of households in the Australian population were interviewed for current ED symptoms and QoL (SF-36). 89 participants (2.9 %) reported a history of AN, 73 of whom were female. These participants scored lower on six of the eight subscales on the SF-36, including all of the mental health subscales, and were more likely to report binge eating and extreme weight or shape concerns than participants who did not report a history of AN. On the other hand, participants who reported a history of AN were less likely to be overweight. None of the participants who reported a history of AN met current criteria for AN; however, one met criteria for bulimia nervosa non-purging subtype and four met criteria for binge eating disorder. The endorsement of current ED symptoms was found to moderate the impact of a history of AN on scores of the social functioning and role limitations due to emotional health SF-36 subscales, such that participants who reported a history of AN scored lower on these subscales if they also reported current ED symptoms. A history of AN has a deleterious impact on current QoL, despite remittance from the disorder. This may be explained in part by the presence of certain ED symptoms, including objective binge eating and the persistence of extreme weight and shape concerns.


Mechanisms underlying the effects of caloric restriction on hypertension.
Hypertension is a major risk factor for cardiovascular disease (CVD) as well as a major contributor to all-cause mortality and disability worldwide. The pathophysiology of hypertension is highly attributed to a dysfunctional endothelium and vascular remodeling. Despite the wide use of pharmacological therapies that modulate these pathways, a large percentage of patients continue to have uncontrolled hypertension, and the use of non-pharmacological interventions is increasingly investigated. Among these, caloric restriction (CR) appears to be a promising nutritional intervention for the management of hypertension. However, the mechanisms behind this effect are not yet fully understood, although an evolving view supports a significant impact of CR on vascular structure and function, specifically at the level of vascular endothelial cells, vascular smooth muscle cells along with their extracellular matrix (ECM). Accumulating evidence suggests that CR promotes endothelium-dependent vasodilation through activating eNOS and increasing nitric oxide (NO) levels through multiple cascades involving modulation of oxidative stress, autophagy, and inflammation. Indeed, CR diminishes phenotypic shift, and suppresses proliferation and migration of VSMCs via pathways involving NO and mTOR. By regulating transforming growth factor-β and matrix metalloproteinases, CR appears to reduce ECM and collagen deposition in vascular walls. Here, we offer a detailed discussion of how these mechanisms contribute to CR's influence on reducing blood pressure. Such mechanisms could then provide a valuable foundation on which to base new therapeutic interventions for hypertension.


Neuroprotective properties of Melissa officinalis after hypoxic-ischemic injury both in vitro and in vivo.
Brain ischemia initiates several metabolic events leading to neuronal death. These events mediate large amount of damage that arises after some neurodegenerative disorders as well as transient brain ischemia. Melissa officinalis is considered as a helpful herbal plant in the prevention of various neurological diseases like Alzheimer that is related with oxidative stress. We examined the effect of Melissa officinalis on hypoxia induced neuronal death in a cortical neuronal culture system as in vitro model and transient hippocampal ischemia as in vivo model. Transient hippocampal ischemia was induced in male rats by tow vessel-occlusion for 20 min. After reperfusion, the histopathological changes and the levels inflammation, oxidative stress status, and caspase-3 activity in hippocampus were measured. Cytotoxicity assays showed a significant protection of a 10 μg/ml dose of Melissa against hypoxia in cultured neurons which was confirmed by a conventional staining (P<0.05). Melissa treatment decrease caspase3 activity (P<0.05) and TUNEL-positive cells significantly (P<0.01). Melissa oil has also inhibited malon dialdehyde level and attenuated decrease of Antioxidant Capacity in the hippocampus. Pro-inflammatory cytokines TNF-α, IL-1β and HIF-1α mRNA levels were highly increased after ischemia and treatment with Melissa significantly suppressed HIF-1α gene expression (P<0.05). Results showed that Melissa officinalis could be considered as a protective agent in various neurological diseases associated with ischemic brain injury.


A rare case of Hoffa's fat pad herniation in a young patient: dynamic ultrasound and MRI diagnosis.
Hoffa's fat pad (HFP) is part of the knee structure interposed between the joint capsule and the synovium. Recent studies have classified infrapatellar fat pad (IFP) disorders on a pathogenesis-based classification: traumatic disorders, post-traumatic disorders, lesions secondary to adjacent disorders. Masses or pseudo-masses may also be found within the IFP, however these alterations are much less frequent. Diagnostic imaging plays an important role in the diagnosis of masses and pseudo-masses of IFP and the first choice exam is a dynamic ultrasound study. We presented a rare case of Hoffa's fat pad herniation through the joint capsule, in a young child without history of knee injuries that has never been described before in the literature.


When Good Guys Turn Bad: Bone Marrow's and Hematopoietic Stem Cells' Role in the Pathobiology of Diabetic Complications.
Diabetes strongly contributes to the development of cardiovascular disease, the leading cause of mortality and morbidity in these patients. It is widely accepted that hyperglycemia impairs hematopoietic stem/progenitor cell (HSPC) mobilization from the bone marrow (BM) by inducing stem cell niche dysfunction. Moreover, a recent study demonstrated that type 2 diabetic patients are characterized by significant depletion of circulating provascular progenitor cells and increased frequency of inflammatory cells. This unbalance, potentially responsible for the reduction of intrinsic vascular homeostatic capacity and for the establishment of a low-grade inflammatory status, suggests that bone BM-derived HSPCs are not only victims but also active perpetrators in diabetic complications. In this review, we will discuss the most recent literature on the molecular mechanisms underpinning hyperglycemia-mediated BM dysfunction and differentiation abnormality of HSPCs. Moreover, a section will be dedicated to the new glucose-lowering therapies that by specifically targeting the culprits may prevent or treat diabetic complications.


Age-related changes of NA(+), K(+) - ATPase, Ca(+2) - ATPase and Mg(+2) - ATPase activities in rat brain synaptosomes.
Cerebral metabolism of glucose, one of the determinants of tissue ATP level, is crucial for central nervous system function. The activity of P-type pumps, namely Na(+), K(+) - ATPase, Ca(+2) - ATPase and Mg (+2) - ATPase were examined in brain synaptosomes of 5 - day, 3 - month and 18 - month - old rats to determine if changes in enzyme activity related to aging are potentially associated with alterations in glucose homeostasis. Activities of all the ATPases studied in isolated brain synaptosomes were expressed in micromol of Pi liberated from ATP by 1 mg of synaptosome protein during one hour. Serum glucose concentration was measured by the glucose oxidase method and insulin level was estimated by the RIA. Our results demonstrate that 18 - month - old rats are characterized by hyperglycemia and hyperinsulinemia. Their serum glucose concentration was significantly increased approx. 62.3% and 135.8 % as compared to 3 - month - old rats and 5 - day, newborn rats, respectively. An enormous increase in serum insulin concentration in the old, hyperglycemic rats was observed concomitantly. As a result of these changes the insulin - to - glucose ratio in the old rats was greatly increased approx. (270% and 230%) compared to young, mature and newborn rats. Hyperglycemia and hyperinsulinemia occurring in the old rats, had a different impact on activities of the ATPases tested. Our results have revealed that Na(+), K(+) - ATPase activity remains almost unchanged with age, the activity of Ca(+2) - ATPase decreases, whereas that of Mg(+2) - ATPase increases significantly in old, insulin resistant rats. In conclusion it seems that changes in activity of different P - type pumps may differ with aging and that adaptation of specific ATPases to internal environment alterations is not identical.


Lamellar Liquid Crystals of In-Plane Lying Rod-Like Mesogens with Designer Side-Chains: The Case of Sliding versus Locked Layers.
The dimensionality of self-assembled nanostructures plays an essential role for their properties and applications. Herein, an understanding of the transition from weakly to strongly coupled layers in soft matter systems is provided involving in-plane organized π-conjugated rods. For this purpose, bolaamphiphilic triblock molecules consisting of a rigid biphenyl core, polar glycerol groups at the ends, and a branched (swallow-tail) or linear alkyl or semiperfluoroalkyl chain in lateral position have been synthesized and investigated. Besides weakly coupled lamellar isotropic (LamIso ), lamellar nematic (LamN ) and sliding lamellar smectic phases (LamSm ), a sequence of three distinct types of strongly coupled (correlated) lamellar smectic phases with either centered (c2mm) or non-centered rectangular (p2mm) lattice and an intermediate oblique lattices (p2) were observed depending on chain length, chain branching and degree of chain fluorination. This new sequence is explained by the strengthening of the layer coupling and the competition between energetic packing constraints and the entropic contribution of either longitudinal or tangential fluctuations. This example of directed side chain engineering of small generic model compounds provides general clues for morphological design of two-dimensional and three-dimensionally coupled lamellar systems involving larger π-conjugated molecular rods and molecular or supramolecular polymers, being of actual interest in organic electronics and nanotechnology.


Exposure to domestic violence between parents: a perspective from Tehran, Iran.
Women may bear the brunt of domestic violence, but children are also inflicted by the consequences of violence between their parents. We sought to evaluate the lifetime prevalence of exposure to physical violence between parents among some senior secondary school students in Tehran. The study was conducted on senior secondary school students in all 19 educational districts of the Iranian capital, Tehran, in the academic year of 2005-06 using a multi-stage sampling. Data were collected via a self-administered questionnaire. A total of 1,495 students participated in this survey, with the prevalence estimated at 22.8%. More than half of the subjects had witnessed domestic violence between their parents; the prevalence of exposure among the girls was twice that among the boys. The most frequent act of violence was beating the partner with bare hands and the perpetrators of the violent acts were predominantly the fathers. Exposure was long-lasting; and in those with more than one exposure, the mean duration of exposure was 5.1 years. The most prevalent rates of exposure to domestic violence came from Educational Districts 15 and 10. The fact that a considerable portion of the teenagers in the present study had witnessed physical violence between their parents bears testimony to the high frequency of this form of violence in Tehran households. It is noteworthy that the socio-economic status of the families and parental divorce and estrangement increased the likelihood of exposure to domestic violence in our series.


Generation of V-point polarization singularity lattices.
V-points normally do not occur in generic light fields as compared to C-points and L-lines. In structured optical fields, simultaneous existence of C-points, V-points and L-lines can be engineered in lattice forms. But lattices consisting only of V-points have not been realized so far. In this paper we demonstrate creation of lattices of V-point polarization singularities with translational periodicity. These lattice structures are obtained by the interference of four (six) linearly polarized plane waves arranged in symmetric umbrella geometry. The state of polarization of each beam is controlled by an S-waveplate. Since in a periodic lattice of polarization singularities the net charge in a unit cell is zero, the lattices are populated with positive and negative index V-point singularities. All the first order degenerate states of V-point singularities can be realized in the same setup by selective excitation of the S-waveplate.


The two phenylalanines in the GFFKR motif of the integrin alpha6A subunit are essential for heterodimerization.
The membrane-proximal domain of the integrin alpha subunit contains a conserved motif of five amino acid residues, GFFKR. We deleted this motif from the human alpha6A subunit and found that in COS-7 cells this mutant cannot associate with the beta1 subunit and is retained in the endoplasmic reticulum. Point mutations in the GFFKR motif of the glycine residue or the two highly charged amino acids, or deletion of the lysine and arginine residues, had no effect on the ability of alpha6 to interact with beta1 and to be expressed at the cell surface. In contrast, by replacing either of the two phenylalanines with alanine, or by deletion of both of these residues, alpha6 was incapable of associating with beta1. The alpha6 point mutants that associated with beta1 were expressed in K562 cells and their responsiveness to integrin-activating factors was determined. None of these transfectants bound spontaneously to laminin-1, but binding could be induced by either PMA or the stimulating anti-beta1 antibody TS2/16 to the same extent as that of the wild-type transfectant. The ability of these mutants to initiate focal-contact formation in CHO cells plated on laminin-1 substrates also appeared to be unaltered. Thus the behaviour of alpha6 mutants involving the glycine, lysine or arginine residues was indistinguishable from that of wild-type alpha6 both in inside-out and outside-in signalling. In contrast, deletion of the cytoplasmic domain of alpha6 C-terminal of the GFFKR motif resulted in a loss of responsiveness of alpha6beta1 to PMA stimulation and formation of focal contacts on laminin-1. However, this mutant was targeted to focal contacts formed by other integrins, even when they had not bound ligand. Together, these results suggest that the two phenylalanine residues of the GFFKR motif provide a site for interaction of the alpha6A subunit with beta1, whereas the cytoplasmic domain C-terminal of this motif is involved in the regulation of bidirectional signalling via alpha6Abeta1.


Differing effects of ursodeoxycholic or chenodeoxycholic acid on biliary cholesterol saturation and bile acid metabolism in man. A dose-response study.
A dose-response study comparing ursodeoxycholic and chenodeoxycholic acid was carried out in six men with asymptomatic radiolucent gallstones present in well-visualizing gallbladders. The study tested the effects of a low (averaging 6 mg/kg/day) or medium dose (averaging 11 mg/kg/day) of each bile acid on the cholesterol saturation of bile as well as on bile acid metabolism, as inferred from biliary and fecal bile acid composition. Ursodeoxycholic acid, at low or medium doses, induced bile desaturation in most patients, whereas chenodeoxycholic acid did not. Despite the greater desaturation efficacy of ursodeoxycholic acid, biliary bile acids became less enriched with the administered bile acid during ursodeoxycholic acid treatment than during chenodeoxycholic acid treatment. Both bile acids were nearly completely 7-dehydroxylated to lithocholic acid by colonic bacteria, but biliary lithocholic increased only slightly (and similarly) with each bile acid. Fecal bile acid composition suggested that administered ursodeoxycholic acid suppressed endogenous bile acid synthesis much less than chenodeoxycholic acid. The results indicate that ursodeoxycholic acid and chenodeoxycholic acid have similar but not identical effects on bile acid metabolism, but that for a given dose, ursodeoxycholic acid is a more potent desaturating agent than chenodeoxycholic acid. The results suggest that cholesterol gallstone dissolution with ursodeoxycholic acid should occur with a dose of 8-10 mg/kg in most nonobese patients.


Effect of immunosuppressive agents on the immunogenicity and efficacy of an immunotoxin in mice.
Immunotoxins (ITs) are potent cytotoxic agents used in the treatment of cancer, autoimmune disease, and graft-versus-host disease. Results from clinical trials demonstrate that many IT-treated patients, especially those with an intact immune system, develop anti-IT antibodies that may prohibit repeated IT dosing. We, therefore, evaluated a panel of novel immunosuppressive (IS) agents for their ability to inhibit the antitoxin immune response in mice receiving multiple courses of a ricin A chain (RTA)-containing IT and also assessed whether this suppression would result in an increase in IT-mediated antitumor activity. The results indicate that a 3-day pretreatment, plus one additional boost 2 weeks later, of a combination of hCTLA4Ig + anti-CD40L, virtually eliminated the anti-RTA response in normal mice receiving six weekly injections of an IT. When tested in BCL1 tumor-bearing mice, the concomitant use of a combination of hCTLA4Ig + anti-CD40L and six doses of the IT resulted in a 1.5-fold increase in tumor cell killing, as compared with treatment with IT alone. We conclude that a combination of IS + IT therapy should facilitate the administration of multiple courses of IT, as well as enhance its antitumor activity.


The usual Interstitial pneumonia pattern in autoimmune rheumatic diseases.
Usual Interstitial Pneumonia (UIP) is characterized by progression of lung parenchyma that may be observed in various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis and connective tissue diseases. From a diagnostic point of view, a UIP pattern related to ARDs may display imaging and pathological features able to distinguish it from that related to IPF, such as the "straight-edge" sign at HRCT and lymphoplasmacytic infiltrates at histologic specimens. Multidisciplinary approach (MDD), involving at least pulmonologist, rheumatologist and radiologist, is fundamental in the differential diagnosis process, but MDD is also required in the evaluation of severity, progression and response to treatment, that is based on the combination of changes in symptoms, pulmonary function trends, and, in selected patients, serial CT evaluation. Differently from IPF, in patients with ARDs both functional evaluation and patient-reported outcomes may be affected by systemic involvement and comorbidities, including musculoskeletal manifestations of disease. Finally, in regards to pharmacological treatment, immunosuppressants have been considered the cornerstone of therapy, despite the lack of solid evidence in most cases; recently, antifibrotic drugs were also proposed for the treatment of progressive fibrosing ILDs other than IPF. In ARD-ILD, the therapeutic choice should balance the need for the control of systemic and lung involvements with the risk of adverse events from multi-morbidities and -therapies. Purpose of this review is to summarize the definition, the radiological and morphological features of the UIP pattern in ARDs, together with risk factors, diagnostic criteria, prognostic evaluation, monitoring and management approaches of the UIP-ARDs.


Physical development and sexual orientation in men and women: an analysis of NATSAL-2000.
In the present study, three physical development characteristics-weight, height, and age of menarche-were examined for their relation to sexual orientation. Participants were men and women comprising the National Survey of Sexual Attitudes and Lifestyles-2000 (N > 11,000). Participants completed self-report measures of sexual orientation, height, weight, and, for women, age of menarche. Results indicated that gay/bisexual men were significantly shorter and lighter than heterosexual men. There were no significant differences between lesbians and heterosexual women in height, weight, and age of puberty. The results add to literature suggesting that, relative to heterosexual men, gay/bisexual men may have different patterns of growth and development because of early biological influences (e.g., exposure to atypical levels of androgens prenatally). However, the present results do not support a number of studies suggesting that lesbian/bisexual women are taller and heavier than heterosexual women.


Study of white matter at the centrum semiovale level with magnetic resonance spectroscopy and diffusion tensor imaging in cerebral small vessel disease.
White matter lesion (WML) in magnetic resonance imaging is commonly observed in patients with cerebral small vessel disease (SVD), but the pathological mechanism of WML in SVD is still unclear. We observed the metabolism and microscopic anatomy of white matter in SVD patients. Twelve subjects clinically diagnosed with SVD and 6 normal control subjects were examined with magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI). The white matter at the centrum semiovale level was selected as the region of interest (ROI). The ROI metabolism parameters, including N-acetyl-l-aspartic acid (NAA), creatine (Cr), and choline (Cho) were measured by MRS. Microscopic parameters such as mean diffusion (MD) and fractional anisotropy (FA) in ROI were obtained by DTI. Compared with the normal control group, bilateral MD values in the SVD group were significantly elevated, whereas bilateral FA values in SVD were decreased, but the difference was not statistically significant. Additionally, NAA/Cho, Cho/Cr, and NAA/Cr showed no significant statistical differences. Our study suggests that the mechanisms of the SVD cognitive impairment are related to damage of the white matter structures rather than to brain metabolism.


Isolation of a new canine cytochrome P450 CDNA from the cytochrome P450 2C subfamily (CYP2C41) and evidence for polymorphic differences in its expression.
Two members of the canine cytochrome P4502C subfamily [CYP2C21 and CYP2C41 (sequence has been submitted to Genbank with accession number AF016248)] were cloned from three beagle liver cDNA libraries. The two canine CYP2C cDNAs exhibited 70% nucleotide and amino acid identity as well as 74-83% nucleotide and 67-76% amino acid identity with the human CYP2Cs. Canine CYP2C41 is more homologous to the human CYP2Cs than CYP2C21. The two canine CYP2C cDNAs exhibited a slightly lower nucleotide and amino acid identity (66-77%) with the rat P450CYPs, 2C11 and 2C12. Reverse transcription-polymerase chain reaction-based restriction enzyme tests for CYP2C21 and 2C41 mRNAs as well as polymerase chain reaction-based tests for genomic DNA were developed. CYP2C21 cDNA was present in the livers of all dogs tested (N = 9), but CYP2C41 was present in only 1 of the 9 (11%). Genomic tests found that the gene coding for CYP2C21 was also present in all dogs tested (N = 25), of which 15 were beagles and 10 mixed breeds. In contrast, the gene coding for CYP2C41 was present in only 16% (4 out of 25) of the dogs. An even distribution of the CYP2C41 gene was found between the sexes and between beagles and mixed breeds. This unique polymorphism in the canine CYP2C subfamily may be a source of variability in the metabolic clearance in dogs of xenobiotics that are metabolized by the cytochrome P450 2C subfamily of enzymes.


Therapeutic drug monitoring of ceftazidime/avibactam: why one leg is not enough to run.
Therapeutic drug monitoring (TDM) is becoming an increasingly recommended approach for assessing optimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime/avibactam. Some authors hypothesized that the PK/PD target attainment of ceftazidime/avibactam could be assessed by means of the TDM of solely ceftazidime, since avibactam concentrations might be extrapolated based on the fixed 4:1 ceftazidime-to-avibactam ratio present in the vial. The reliability of this hypothesis could be called into question if a wide interindividual variability in the ceftazidime-to-avibactam ratio would exist among patients. This study aimed to assess the distribution of the individual ceftazidime-to-avibactam ratios in relation to renal function in a cohort of adult patients who were treated with continuous infusion ceftazidime/avibactam and underwent TDM of both ceftazidime and avibactam. Individual ceftazidime-to-avibactam ratio was calculated at each TDM assessment. Receiving operating characteristics (ROC) curve analysis was performed for testing the potential impact of renal function on ceftazidime-to-avibactam ratio variability. A total of 188 TDM assessments were collected from 107 patients. The ceftazidime-to-avibactam ratios ranged from 1.29:1 to 13.46:1. Seventy-seven out of 188 ceftazidime-to-avibactam ratios (41.0%) were >5:1, and 36 (19.1%) were >6:1. Patients without renal dysfunction had significantly higher proportions of ceftazidime-to-avibactam ratio >5:1 (59.3% versus 23.8%; P < 0.001) and >6:1 (32.1% versus 6.3%; P < 0.001) compared with those with mild-to-severe renal dysfunction. The findings may strengthen the contention that for properly assessing the PK/PD target attainment of ceftazidime/avibactam, both ceftazidime and avibactam concentrations should be measured, given the unpredictability of the ceftazidime-to-avibactam ratio occurring among patients.


Immunotoxicological profile of chloroform in female B6C3F1 mice when administered in drinking water.
Chloroform can be formed as a disinfection by-product during water chlorination, one of the primary modalities for purifying municipal water supplies for human consumption. The aim of this study was to characterize the immunotoxic effects of chloroform in female B6C3F1 mice when exposure occurred via the drinking water. Consistent with human exposure, female B6C3F1 mice were exposed to chloroform-containing drinking water at 2.5, 10, 25, 100, and 250 ppm for 28 days. The examined endpoints included the effects of chloroform on body and organ weights, water consumption, hematology, innate immunity, humoral immunity, and cell-mediated immunity. The functions of natural killer, B-, and T-cells were not altered by chloroform in drinking water at the concentrations tested, except that an increase in splenocyte basal proliferation was observed at chloroform levels of 100 and 250 ppm. Following chloroform administration, there was a decreased number of circulating neutrophils in the blood in all treatment groups, but neutrophil function in lung homogenates, as evaluated using an assay for myeloperoxidase activity following lipopolysaccharide and N-Formyl-Met-Leu-Phe stimulation, was not compromised. Further, the results of host resistance to Listeria monocytogenes infection also suggested that neutrophil function was normal. At the highest treatment level of chloroform (250 ppm), erythrocyte number and hemoglobin levels were significantly decreased. Some significant changes were also observed for body weights, water consumption, and organ weights; however, most of these effects were only observed at the highest treatment level of chloroform (250 ppm). Taken together, the results demonstrate that while chloroform administered via the drinking water affects body weight and selected hematological parameters at high dose levels, overall immune responses, as measured in several tests for immune function, are not compromised.


Tackling important issues in Europe.
Forthcoming animal health legislation, antimicrobial resistance and corporate practice were all discussed at the recent general assembly of the Federation of Veterinarians of Europe. Karin de Lange reports.


[Changes in serum vitamin D assay usage and the need for evidence-based recommendations].
Result of renewed interest due to the large amount of literature that reported numerous epidemiological data demonstrating the high prevalence of vitamin D deficiency, the number of prescriptions of serum vitamin D assays has grown exponentially in recent years with a cost for health insurance that increased almost fivefold in four years. The quantitative and qualitative analysis of assays carried out from 2007 to 2011 in a French university adult short-stay hospital shows changes in practices not only quantitatively but also qualitatively resulting in an overtime increase in the frequency of prescriptions in patients younger, less vitamin D deficient and more frequently male. In the absence of French guidelines, this development cannot be qualified as deviant but justifies the urgent need to establish evidence-based recommendations for good prescriptions and adequate assays of blood vitamin D.


Towards single-cell LC-MS phosphoproteomics.
Protein phosphorylation is a ubiquitous posttranslational modification, which is heavily involved in signal transduction. Misregulation of protein phosphorylation is often associated with a decrease in cell viability and complex diseases such as cancer. The dynamic and low abundant nature of phosphorylated proteins makes studying phosphoproteome a challenging task. In this review, we summarize state of the art proteomic techniques to study and quantify peptide phosphorylation in biological systems and discuss their limitations. Due to its short-lived nature, the phosphorylation event cannot be precisely traced in a heterogonous cell population, which highlights the importance of analyzing phosphorylation events at the single cell level. Mainly, we focus on the methodical and instrumental developments in proteomics and nanotechnology, which will help to build more accurate and robust systems for the feasibility of phosphorylation analysis at the single cell level. We propose that an automated and miniaturized construction of analytical systems holds the key to the future of phosphoproteomics; therefore, we highlight the benchmark studies in this direction. Having advanced and automated microfluidic chip LC systems will allow us to analyze single-cell phosphoproteomics and quantitatively compare it with others. The progress in the microfluidic chip LC systems and feasibility of the single-cell phosphoproteomics will be beneficial for early diagnosis and detection of the treatment response of many crucial diseases.


[Methods of treatment of external fistula of gastrointestinal tract].
Experience in the treatment of external gastrointestinal fistulas in 1970-1988 consisted of 127 patients with 158 fistulas; 11 patients had a gastric fistula; 14, a duodenal fistula, 42, a fistula of the small intestine; 38, a fistula of the large intestine, and 22 patients had mixed fistulas. Operation for acute appendicitis was the main cause of fistula formation (20.3%). In undeveloped fistulas with considerable and uncontrolled loss of the intestinal contents, treatment consisted in early operation for vital indications for disconnection of the fistula, with preference given to complete bilateral disconnection. In developed fistulas most operations for their closure were carried out through an intraabdominal approach. Total mortality was 25.2%; in most of the fatal cases (90.6%) the fistulas were undeveloped.


Aging is associated with increased brain iron through cortex-derived hepcidin expression.
Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.


The Potential Role of Combination Pharmacotherapy to Improve Outcomes of Pediatric Obesity: A Case Report and Discussion.
There is a gap in treatment modalities for pediatric patients with obesity for whom lifestyle modification therapy, on the one hand, may be insufficient to meaningfully reduce BMI, and bariatric surgery, which on the other hand, may not be indicated, available or desired. Although pharmacotherapy may help fill this treatment void, there is a paucity of FDA-approved medications indicated for pediatric obesity and further, most are single agents with only modest mean treatment effects. In contrast, combination pharmacotherapy, such as phentermine/topiramate, appears to offer greater weight loss efficacy in adults and may prove to be superior to monotherapy for pediatric patients as well. This case report describes the clinical management of severe obesity in a 10 year old girl with lifestyle modification therapy and subsequent addition of first topiramate and later phentermine. Using the case as a platform, the current state of pharmacotherapy for pediatric obesity will be described thereby highlighting the limited efficacy of single agents. Additionally, the biological rationale for combination pharmacotherapy, including potential mechanisms which may account for the poor response to single agents, will be discussed.


Bullous pemphigoid and associated malignant neoplasms.
To evaluate the significance of the association of systemic malignant disease with bullous pemphigoid, we reviewed the records of patients with bullous pemphigold seen at the Mayo Clinic between 1960 and 1972. Data from 73 patients with bullous pemphigoid were compared with data from 146 controls (73 with contact dermatitis and 73 with psoriasis) matched for age, sex, and calendar year of diagnosis. In the three groups, eight patients with bullous pemphigoid, 11 with contact dermatitis, and ten with psoriasis were found to have malignant disease within the period covering the five years before and five years after the diagnosis of the skin disease. These data indicate that pemphigoid does not seem to be significantly associated with malignant disease.


Acute effects of smoking on QT dispersion in healthy males.
Cigarette smoking increases the risk of ventricular fibrillation and sudden cardiac death (SCD). QT dispersion (QTD) is an important predictor of cardiac arrhythmia. The aim of this study was to assess the acute effect of smoking a single standard cigarette containing 1.7 mg nicotine on QT interval and QTD in healthy smokers and nonsmokers. The study sample population consisted of 40 healthy male hospital staff, including 20 smokers and 20 nonsmokers. They were asked to refrain from smoking at least 6 h before attending the study. A 12-lead surface electrocardiogram (ECG), recorded at paper speed of 50 mm/s, was obtained from all participants before and 10 min after smoking of a single complete cigarette. QT interval, corrected QT interval, QTD, and corrected QT dispersion (QTcD) were measured before and after smoking. Smokers and nonsmokers did not have any significant differences in heart rate (HR) (before smoking = 67.35 ± 5.14 vs. 67.70 ± 5.07, after smoking = 76.70 ± 6.50 vs. 76.85 ± 6.50, respectively), QTD (before smoking = 37.75 ± 7.16 vs. 39.15 ± 6.55, after smoking = 44.75 ± 11.97 vs. 45.50 ± 9.58, respectively), and QTcD (before smoking = 39.85 ± 7.40 vs. 41.55 ± 6.57, after smoking = 50.70 ± 14.31 vs. 51.50 ± 11.71, respectively). However, after smoking a single cigarette, HR, mean QTD, and QTcD significantly increased (all had P value <0.001) in comparison to the measures before smoking. Smoking of a single complete cigarette in both smokers and nonsmokers results in significant QTD increase, which can cause arrhythmia and SCD.