The effect of ethanol feeding on zinc balance and tissue zinc levels in rats maintained on zinc-deficient diets.
We have studied tissue zinc levels and zinc balance in isocalorically pair-fed weanling rats on ZD liquid diets (0.9 microgram of zinc per milliliter of diet). Tissues were analyzed for zinc levels at weekly intervals while the animals were on the diets. The experimental animals were fed a ZDE diet, whereas sucrose was isocalorically substituted for alcohol in the pair-fed controls. After 1 week on ethanol feeding, the zinc content (microgram/gm wet weight) of the testes of the ethanol-fed rats was significantly lower than of the controls (p less than 0.001). After 2 weeks of ethanol, ethanol-fed animals also showed significantly lower zinc content in liver, hair, spleen, and kidneys (p less than 0.02) than their pair-fed controls. The zinc levels of the experimental animals in all tissues after 3 and 4 weeks of ethanol feeding were significantly lower (p less than 0.001) than that of the pair-fed controls with the exception of bone. Urinary and fecal zinc excretions of the ethanol-fed rats were significantly higher than that of the controls. Cumulative mean +/- S.D. fecal zinc excretions (microgram/28 days) were 1557 +/- 160 among the ethanol-fed animals vs. 730 +/- 150 among controls, p less than 0.01. Ethanol resulted in a mean negative zinc balance of 520 micrograms over 28 days, whereas controls showed a positive cumulative zinc balance of 300 micrograms. Thus ethanol ingestion resulted in negative zinc balance and decreased zinc concentrations of most tissues as compared to pair-fed controls.


A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo.
The genetic mechanisms that regulate CFTR, the gene responsible for cystic fibrosis, have been widely investigated in cultured cells. However, mechanisms responsible for tissue-specific and time-specific expression are not completely elucidated in vivo. Through the survey of public databases, we found that the promoter of CFTR was associated with bivalent chromatin in human embryonic stem (ES) cells. In this work, we analyzed fetal (at different stages of pregnancy) and adult tissues and showed that, in digestive and lung tissues, which expressed CFTR, H3K4me3 was maintained in the promoter. Histone acetylation was high in the promoter and in two intronic enhancers, especially in fetal tissues. In contrast, in blood cells, which did not express CFTR, the bivalent chromatin was resolved (the promoter was labeled by the silencing mark H3K27me3). Cis-regulatory sequences were associated with lowly acetylated histones. We also provide evidence that the tissue-specific expression of CFTR is not regulated by dynamic changes of DNA methylation in the promoter. Overall, this work shows that a balance between activating and repressive histone modifications in the promoter and intronic enhancers results in the fine regulation of CFTR expression during development, thereby ensuring tissue specificity.


The extracranial bypass: neurologic aspects.
The extracranial intracranial bypass operation is a relatively new procedure in the treatment of cerebrovascular disease. The clinical indications for the surgery are not yet well delineated. It is concluded that a careful prospective randomized study evaluating the clinical indications for surgery and the comparison to available medical management needs to be completed before the true value of this operation is known.


A [Na+]o-independent, pHo-dependent mechanism for reduction of intracellular [Ca2+] after influx through Ca2+ channels in mouse pituitary cells.
The effect of extracellular pH (pHo) on the duration of calcium-dependent chloride currents (ICl(Ca] was studied in voltage clamped AtT-20 pituitary cells. ICl(Ca) was activated by Ca2+ influx through plasma membrane Ca2+ channels, which were opened by step depolarization to voltages between -20 and +60 mV. Increasing pHo from 7.3 to 8.0 reversibly prolonged ICl(Ca) tail currents in perforated patch recordings from cells bathed in both Na(+)-containing and Na(+)-free solutions. This prolongation was prevented in standard whole cell recordings when the pipette solution contained 0.5 mM EGTA. The effects of raised pHo were not due to alteration of intracellular pH, since tail current prolongation still occurred when intracellular pH was buffered at 7.3 with 80 mM HEPES. The prolongation of ICl(Ca) at pHo 8 could not be accounted for by a direct action on Ca2+ channels, since tail currents were prolonged when pHo was changed rapidly during the tail current, after all Ca2+ channels were closed. The effects of increasing pHo on ICl(Ca) also could not be explained by a direct action on Cl- channels, since changing to pHo 8 did not prolong Cl- tail currents when intracellular Ca2+ concentration [( Ca2+]i) was fixed by EGTA in whole cell recordings. Raising pHo did, however, prolong depolarization-evoked [Ca2+]i transients, measured directly with the Ca2+ indicator dye, fura-2. Taken together, these data demonstrate the presence of a Na(+)-independent, pHo-sensitive mechanism for reduction of [Ca2+]i after influx through Ca2+ channels. This mechanism is associated with the plasma membrane, and is active on a time scale that is relevant to the duration of single action potentials in these cells. We suggest that this mechanism is the plasma membrane Ca2+ ATPase.


Novel Mode of Molybdate Inhibition of Desulfovibrio vulgaris Hildenborough.
Sulfate-reducing microorganisms (SRM) are found in multiple environments and play a major role in global carbon and sulfur cycling. Because of their growth capabilities and association with metal corrosion, controlling the growth of SRM has become of increased interest. One such mechanism of control has been the use of molybdate (MoO4 2-), which is thought to be a specific inhibitor of SRM. The way in which molybdate inhibits the growth of SRM has been enigmatic. It has been reported that molybdate is involved in a futile energy cycle with the sulfate-activating enzyme, sulfate adenylyl transferase (Sat), which results in loss of cellular ATP. However, we show here that a deletion of this enzyme in the model SRM, Desulfovibrio vulgaris Hildenborough, remained sensitive to molybdate. We performed several subcultures of the ∆sat strain in the presence of increasing concentrations of molybdate and obtained a culture with increased resistance to the inhibitor (up to 3 mM). The culture was re-sequenced and three single nucleotide polymorphisms (SNPs) were identified that were not present in the parental strain. Two of the SNPs seemed unlikely candidates for molybdate resistance due to a lack of conservation of the mutated residues in homologous genes of closely related strains. The remaining SNP was located in DVU2210, a protein containing two domains: a YcaO-like domain and a tetratricopeptide-repeat domain. The SNP resulted in a change of a serine residue to arginine in the ATP-hydrolyzing motif of the YcaO-like domain. Deletion mutants of each of the three genes apparently enriched with SNPs in the presence of inhibitory molybdate and combinations of these genes were generated in the Δsat and wild-type strains. Strains lacking both sat and DVU2210 became more resistant to molybdate. Deletions of the other two genes in which SNPs were observed did not result in increased resistance to molybdate. YcaO-like proteins are distributed across the bacterial and archaeal domains, though the function of these proteins is largely unknown. The role of this protein in D. vulgaris is unknown. Due to the distribution of YcaO-like proteins in prokaryotes, the veracity of molybdate as a specific SRM inhibitor should be reconsidered.


[Effect of endogenous factors on the chemical perception of Grapholita molesta (Busck) (Lepidoptera: Tortricidae) to sex pheromone].
The oriental fruit moth, Grapholita molesta (Busck), stands out as one of the most important pest in Rosaceae orchards in Brazil. During feeding, caterpillars bore into shoots, branches and fruits, impairing the commercial production. This work aimed to study the effect of endogenous factors in the chemical perception and in the species chemotactic behavior, seeking to optimize monitoring and the behavioral control of this pest. We evaluated male electroantennographical (EAG) and chemotactical (olfactometry) responses to the synthetic sex pheromone in different ages, virgins or mated and fed or unfed. The EAG responses of males did not differ for all evaluated factors. Nevertheless, the chemotactical behavior of males seems to decrease with age, not varying as a function of mating or feeding conditions. The knowledge about the interference of these factors in G. molesta may help with the interpretation of field results, allowing the development of suitable and reliable control measures based on infochemicals for behavioral control.


Revised NESARC personality disorder diagnoses: gender, prevalence, and comorbidity with substance dependence disorders.
We applied different diagnostic rules for diagnosing personality disorders to the NESARC epidemiological study of over 40,000 individuals. Specifically, unlike previous NESARC publications, we required that each personality disorder criterion be associated with significant distress or impairment in order to be counted toward a personality disorder (PD) diagnosis. Results demonstrated significant reductions in prevalence rates for PDs (9.1% versus 21.5% using original NESARC algorithms), and these revised prevalence rates were much more consistent with recent epidemiological studies in the U.S. and Great Britain. We also found gender differences in the prevalence rate for most PDs. Comorbidity analyses revealed strong associations between PDs and alcohol dependence, drug dependence, and tobacco dependence. PD diagnoses were also associated with scores on dysfunction and impairment, perceived stress and less social support, lifetime history of suicide attempts, interpersonal difficulties, and problems with legal authorities.


Maternal vitamin B12 and the risk of fetal neural tube defects in Egyptian patients.
Folic acid insufficiency is a known risk factor for neural tube defects (NTDs), while the role of vitamin B12 is questionable. Thus, our purpose was to investigate whether low maternal serum vitamin B12 is associated with an increased risk of NTDs. Prenatal Diagnosis and Clinical Genetics Clinics, National Research Centre, in collaboration with the Radioisotope Department, Nuclear Research Centre, Cairo. The study groups included 36 women who were, or had been, pregnant with a NTD-affected fetus. The control groups comprised 35 healthy women with normal prior or current pregnancy and uncomplicated obstetric histories. Fasting plasma homocysteine, serum folate and cobalamin (vitamin B12) were determined. Odds ratio (OR) and 95% confidence intervals were calculated. The fasting homocysteine was significantly higher in the study groups as compared to the controls. The median serum folate concentrations were similar in cases and controls, while the median vitamin B12 concentrations were significantly lower in the study groups compared to the controls. Low vitamin B12 concentration was associated with an approximately 2- to 3-fold increased risk for NTDs. Low maternal serum values of vitamin B12 can be considered an important etiologic factor for the development of neural tube defects in our population. This may help in both genetic counseling for families with a history of NTD malformation, and as a pre-conceptional prophylactic measure by maternal supplementation of vitamin B12 and folic acid.


Effect of maternal mental health during pregnancy on infant growth at six months of age in Suburban communities in South of Iran.
Background: Due to the controversial effects of mental health disorders during pregnancy on infant health, the present study aimed to evaluate the effect of gestational depression, stress, and anxiety on the growth of offspring at six months of age in disadvantaged communities in South of Iran. Methods: The sample comprised of 470 pregnant women (response rate=98%) who are participated in the Bandar Abbas Pregnancy Cohort study. Maternal mental health was measured by the DASS-21 questionnaire during pregnancy. Data on infant growth was collected based on infant`s growth chart at six months of age. The relative risk of suboptimal infant growth was calculated by Modified Poisson regression models at 5% significant level. Results: The prevalence of depression, anxiety, and stress was 19.0%, 26.1% and 6.5%, respectively. At six months of age, the mean (SD) of infant`s weight (gram), height (cm) and head circumference (cm) were 7287.30 (1019.85), 63.23 (5.62) and 41.39 (2.70), respectively. Compared to normal mothers, the risk of suboptimal weight at six months of age significantly increased by 71% in mothers who were classified as having depression (Adjusted RR: 1.71, 95% CI: 1.07, 2.09). The presence of anxiety significantly increased the risk of suboptimal height at six months of age by 43% (ARR: 1.43, 95% CI: 1.07, 1.92). There were no statistically significant effects of either depression anxiety or stress on the suboptimal head circumference at six months of age. Conclusion: Our results showed that mental health disorders of pregnant women might adversely influence the weight and height growth of offspring within the first six months of age. Screening protocols to early diagnose of mental health disorders during pregnancy, and to strict follow up of diagnosed cases postpartum are proposed.


Pelczaria aurantia ATCC 49321T (=DSM 12801T) is a strain of Kocuria rosea (Flügge 1886) Stackebrandt et al. 1995.
Phylogenetic and chemotaxonomic analyses of Pelczaria aurantia ATCC 49321T (= DSM 12801T) indicate that this species is very closely related to Kocuria rosea. The DNA-DNA reassociation value of 87.1% determined for the type strains of the two species supports this finding. The results of phylogenetic analysis of the 16S rDNA of a subculture of the original strain of Pelczaria aurantia, deposited at the National Institutes of Health, Bethesda, MD, USA, as 'Neisseria aurantia', are identical to those for strain ATCC 49321T and indicate that Pelczaria aurantia ATCC 49321T is an authentic subculture of the original culture described by Poston (1993). On the basis of these findings it is concluded that P. aurantia ATCC 49321T and K. rosea DSM 20447T are members of the same taxon. The taxonomic consequences of this union are discussed.


fMRI reveals greater within- than between-hemifield integration in the human lateral occipital cortex.
Early visual areas within each hemisphere (V1, V2, V3/VP, V4v) contain distinct representations of the upper and lower quadrants of the contralateral hemifield. As receptive field size increases, the retinotopy in higher-tier visual areas becomes progressively less distinct. Using functional magnetic resonance imaging (fMRI) to map the visual fields, we found that an intermediate level visual area, the lateral occipital region (LO), contains retinotopic maps with a contralateral bias, but with a combined representation of the upper and lower visual field. Moreover, we used the technique of fMRI adaptation to determine whether neurons in LO code for both the upper and lower contralateral quadrants. We found that even when visual stimulus locations are equivalent across comparisons, the LO was more sensitive to location changes that crossed hemifields than location changes within a hemifield. These results suggested that within high-tier visual areas the increasing integration of visual field information is a two-stage process. The upper and lower visual representations are combined first, in LO, then the left and right representations. Furthermore, these results provided evidence for a neural mechanism to explain behavioral findings of greater integration within than between hemifields.


[The application of endoscopy in aesthetic breast surgery].
During the last decades, numerous surgical techniques have been described for breast augmentation. In addition to the very popular inframammary and the periareolar approaches, the transaxillary technique provides an elegant means of conducting a safe and accurate implant placement without producing visible scars on the breast mound. Due to a questionable lack of intraoperative visualisation with resultant higher complication rates,we conducted a retrospective analysis comparing the endoscopy-assisted transaxillary approach with the inframammary technique. A retrospective analysis was conducted comparing the endoscopy-assisted transaxillary approach with the more commonly chosen inframammary aditus. Patients undergoing breast augmentation from 1997 to 2005 were analysed retrospectively. The analysis was conducted in patients undergoing this procedure for aesthetic reasons only. Underlying breast pathology as well as previously performed breast surgery were among the exclusion criteria. The Client Satisfaction Questionnaire (CSQ-8) was applied for assessment of patient satisfaction. From 1997 to 2005, 96 patients underwent breast augmentation at our institution. Implant volumes ranged from 150 to 400 ml.62.5% preferred the transaxillary technique vs. 37.5% who chose the inframammary route. Complication rates were low in both patient subsets, the statistics revealing no differences. Assessment of patient satisfaction displayed high levels of satisfaction in both groups without any significant differences. The endoscopy-assisted transaxillary breast augmentation is a safe technique which generates high levels of patient satisfaction. Predictable results can be achieved by this approach which is preferred by the majority of patients when offered.


[The application of laser rays in gastroenterology].
After reminding the difference between the surface electro-coagulation-section and the photo-coagulation "at distance" by Laser-ray, the author underlines that the most interesting indications of the Laser-ray introduced into the digestive endoscopes are the destruction of esophageal and colonic tumors for inoperable patients or patients with operative risks. The palliative destructions avoid mutilating operations which won't increase the survival time of the patients.


Novel preoperative predictive score to evaluate lymphovascular space involvement in endometrial cancer: an aid to the sentinel lymph node algorithm.
Sentinel lymph node (SLN) dissection has been recognized as a valid tool for staging in patients with endometrial cancer. Several factors are predictors of recurrence and survival in endometrial cancer, including positive lymphovascular space invasion. The aim of this study is to formulate a pre-operative score that, in the event of no-SLN identification, may give an estimate of the true probability of lymphovascular space invasion and guide management. This was a multi-institutional retrospective study conducted from January 2007 to December 2017. We included all patients with any grade endometrial tumor with a complete pathological description of the surgical specimen and with a minimum follow-up of 12 months. All patients underwent a class A hysterectomy according to Querleu and Morrow and bilateral salpingo-oophorectomy. Lymphadenectomy was performed based on patient risk of node metastases. In order to verify the predictive capacity of the parameters associated with lymphovascular space invasion status, grading, abnormal CA125 (>35 units/ml), myometrial invasion, and tumor size, a synthetic score was calculated. The score was introduced in the receiver operating characteristic curve model in which the binary classifier was represented by the lymphovascular space invasion status. The ideal cut-off was calculated with the determination of the Youden index. Sensitivity and negative predictive value of lymphovascular space invasion score was calculated in patients with lymph node metastasis. Six hundred and fourteen patients were included in the study. The average age and BMI of patients were 64.8 (range 33-88) years and 30.1 (range 17-64) respectively. Of the 284 patients who underwent lymphadenectomy, 231 (81.3%) patients had no lymph node metastases, 33 (11.6%) patients had metastatic pelvic lymph nodes, 12 (4.2%) patients had metastatic aortic lymph nodes, and eight (2.8%) patients had both pelvic and aortic metastatic lymph nodes. Lymphovascular space invasion was associated with deep myometrial infiltration (P<0.001), G3 grading (P<0.001), tumor size ≥25 mm (P=0.012), abnormal CA125 (P<0.001), recurrence (P<0.001), overall survival (P<0.001), and disease-free survival (P<0.01). Of all patients with lymphovascular space invasion, 79% had an lymphovascular space invasion score ≥5. The score ranged from a minimum score of 1 to a maximum of 7. The score shows 78.9% sensitivity (95% CI 0.6971 to 0.8594), 65.3% specificity (95% CI 0.611 to 0.693), 29.4% positive predictive value (95% CI 0.241 to 0.353), and 94.4% negative predictive value (95% CI 0.916 to 0.964). We found that when lymphovascular space invasion score ≤4, there is a very low possibility of finding lymph nodal involvement. The preoperative lymphovascular space invasion score could complement the SLN algorithm to avoid unnecessary lymphadenectomies.


A New Tool to Tackle the Opioid Epidemic: Description, Utility, and Results from the Maine Diversion Alert Program.
The opioid epidemic continues to impact the United States, and new strategies are needed to combat this epidemic. The objective of this study was to analyze 2015 drug arrest data from Maine's Diversion Alert (DA) program (diversionalert.org), compare arrest data between the first quarters of 2015 and 2016, and provide an analysis of the sex differences in the arrests as well as information about DA use. This was a population-based descriptive study using data from the Maine DA program. The study population consisted of persons arrested for prescription, nonprescription, or illicit drugs. DA database. The DA program addresses Maine's prescription drug abuse epidemic with innovative resources that provide access to drug arrest data for health care providers to identify and respond to patients at risk for overdose, those engaged in illegal prescription drug distribution, and those who need treatment. Drug arrest data from 2015 (2723 arrests) and the first quarter of 2016 (788 arrests) were compared and analyzed. The drugs implicated in the arrests were organized by Drug Enforcement Agency (DEA) schedule category and whether they were pharmaceuticals (synthesized and distributed by a pharmaceutical company) or nonpharmaceuticals (grown or synthesized in clandestine laboratories). Most arrests were for possession (64.5%) followed by trafficking (23.8%). Heroin was listed in more than three-quarters (76.4%) of the Schedule I arrests, followed by marijuana (11.7%) and "bath salts" (6.3%). Cocaine and crack cocaine were implicated in almost half (46.7%) of the Schedule II arrests, followed by oxycodone (21.0%) and methamphetamine/amphetamine (15.8%). Buprenorphine was responsible for almost all (96.7%) of the Schedule III arrests. The benzodiazepines alprazolam (34.3%), clonazepam (33.8%), diazepam (11.9%), and lorazepam (8.5%) were listed in the preponderance of the Schedule IV arrests. Arrests increased in 2016 by 49.2% for heroin (p<0.01) and 170.0% for methamphetamine (p≤0.0005) relative to 2015. Arrests for trafficking increased by 42.9% (p<0.05). Males outnumbered females 2:1 in DA. Schedule IV agents accounted for only 6.8% of arrests for males versus 11.5% for females (p≤0.0001). Conversely, Schedule I agents were implicated in 33.0% of arrests for males versus only 27.3% for females (p<0.005). DA is an important tool for providing timely information for health care providers regarding individuals with a history of past misuse of psychotherapeutic agents, particularly opioids and stimulants.


New approaches to blockade of the renin-angiotensin-aldosterone system: characteristics and usefulness of the direct renin inhibitor aliskiren.
Since renin inhibition interferes with the first and rate-limiting steps in the renin-angiotensin system, the renin step is a very attractive target for lowering blood pressure and minimizing target-organ damage. The newly developed direct renin inhibitor aliskiren has several attractive characteristics: it definitively reduces plasma renin activity among inhibitors of the renin-angiotensin system, is remarkably specific for human renin, exhibits a long half-life in plasma comparable to that of amlodipine, and has a high affinity for renal glomeruli and vasculature. Although these characteristics suggest the clinical usefulness and safety of aliskiren, several problems remain unsolved. Why does aliskiren have beneficial effects on the heart and kidneys of patients treated with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1-receptor blockers (ARBs)? Is the blood-pressure-lowering effect of aliskiren dependent on the plasma renin activity? Does aliskiren exert a possible adverse effect via (pro)renin receptor-dependent intracellular signals? Here, we review the characteristics and usefulness of aliskiren and discuss the current issues associated with this direct renin inhibitor.


Chitosan supports the expression of extracellular matrix proteins in human osteoblasts and chondrocytes.
The search for biocompatible materials that can support the growth and phenotypic expression of osteoblasts and chondrocytes is a major challenge in the application of tissue engineering techniques for the repair of bone and cartilage defects. Chitosan, a copolymer of glucosamine and N-acetylglucosamine, may provide an answer to this search. Chitosan is the deacetylated product of chitin, a ubiquitous biopolymer found in the exoskeleton of insects and marine invertebrates. Little is known about the utility of chitosan in propagating human osteoblasts and chondrocytes. In this study, we test the hypothesis that chitosan promotes the survival and function of osteoblasts and chondrocytes. Chitosan (4%, w/v in 2% HAc) was coated onto plastic coverslips that had been fitted into 24-well plates. Human osteoblasts and articular chondrocytes were seeded on either uncoated or chitosan-coated coverslips at 1 x 10(5)/cells per well. Cultures were incubated at 37 degrees C, 5% CO(2) for a period of 7 days. Cell viability was assessed at that time using a fluorescent molecular probe. The phenotypic expression of osteoblasts and chondrocytes was analyzed by reverse transcriptase-polymerase chain reaction and immunocytochemistry. Osteoblasts and chondrocytes appeared spherical and refractile on chitosan-coated coverslips. In contrast, greater than 90% of cells on plastic coverslips were elongated and spindle shaped after 7 days of culture. Similar to cells propagated on uncoated control wells, greater than 90% of human osteoblasts and chondrocytes propagated on chitosan remained viable. Human osteoblasts propagated on chitosan films continued to express collagen type I whereas chondrocytes expressed collagen type II and aggrecan, as shown by reverse transcriptase-polymerase chain reaction analysis and immunostaining. The present in vitro work demonstrates the biocompatibility of chitosan as a substrate for the growth and continued function of human osteoblasts and chondrocytes. Chitosan may have potential use as a tissue engineering tool for the repair of osseous and chondral defects.


Ascorbic acid: a nonradioactive extracellular space marker in canine heart.
The distribution pattern of ascorbic acid and L-[14C]ascorbic acid in myocardial tissue was compared with those of the classical radioactive extracellular space markers [3H]-inulin, [3H]sucrose, and Na82Br. A new polarographic technique was developed for analogue registration of ascorbic acid concentration in coronary venous blood. The kinetic data of the markers were studied in an open-chest canine heart preparation (n = 17 dogs) during a constant tracer infusion of up to 9 min. Distribution volumes were calculated based on the mean transit time method of Zierler (K. L. Zierler, Circ. Res. 10:393-407, 1962). The distribution volume of ascorbic acid (23.6 ml/100 g wet wt) as well as of L-[14C]ascorbic acid (24.5 ml/100 g wet wt) in myocardial tissue agreed closely with those of [3H]inulin (18.6 ml/100 g wet wt) and [3H]sucrose (22.0 ml/100 g wet wt), as well as 82Br- (27.3 ml/100 g wet wt). The obtained kinetic data confirmed that ascorbic acid exhibits the physicochemical properties of an extracellular space marker, though this compound was shown to leak slowly into myocardial cells. Favorable attributes of this indicator are its low molecular weight, high diffusibility in interstitial fluid, low binding affinity to macromolecules, and high transcapillary (1.8 X 10(-5) cm/s) as well as low transplasmalemmal penetration rate (3.7 X 10(-8) cm/s). Therefore, this nonradioactive marker can be applied in a safe and simple fashion, and without untoward side effects in experimental animals as well as in patients.


Yeast mitochondrial initiator tRNA is methylated at guanosine 37 by the Trm5-encoded tRNA (guanine-N1-)-methyltransferase.
The TRM5 gene encodes a tRNA (guanine-N1-)-methyltransferase (Trm5p) that methylates guanosine at position 37 (m(1)G37) in cytoplasmic tRNAs in Saccharomyces cerevisiae. Here we show that Trm5p is also responsible for m(1)G37 methylation of mitochondrial tRNAs. The TRM5 open reading frame encodes 499 amino acids containing four potential initiator codons within the first 48 codons. Full-length Trm5p, purified as a fusion protein with maltose-binding protein, exhibited robust methyltransferase activity with tRNA isolated from a Delta trm5 mutant strain, as well as with a synthetic mitochondrial initiator tRNA (tRNA(Met)(f)). Primer extension demonstrated that the site of methylation was guanosine 37 in both mitochondrial tRNA(Met)(f) and tRNA(Phe). High pressure liquid chromatography analysis showed the methylated product to be m(1)G. Subcellular fractionation and immunoblotting of a strain expressing a green fluorescent protein-tagged version of the TRM5 gene revealed that the enzyme was localized to both cytoplasm and mitochondria. The slightly larger mitochondrial form was protected from protease digestion, indicating a matrix localization. Analysis of N-terminal truncation mutants revealed that a Trm5p active in the cytoplasm could be obtained with a construct lacking amino acids 1-33 (Delta1-33), whereas production of a Trm5p active in the mitochondria required these first 33 amino acids. Yeast expressing the Delta1-33 construct exhibited a significantly lower rate of oxygen consumption, indicating that efficiency or accuracy of mitochondrial protein synthesis is decreased in cells lacking m(1)G37 methylation of mitochondrial tRNAs. These data suggest that this tRNA modification plays an important role in reading frame maintenance in mitochondrial protein synthesis.


Skin cancer in organ transplant recipients--where do we stand today?
Skin cancers are the most frequent malignancies in organ transplant recipients (OTR), with 95% being nonmelanoma skin cancers (NMSC), especially squamous (SCC) and basal cell carcinomas. Most OTR with a first SCC subsequently develop multiple NMSC within 5 years, highlighting the concept of 'field cancerization', and are also at high risk for noncutaneous cancers. In order to reduce the tumor burden in these patients, their management requires an interdisciplinary approach including revision of immunosuppression, new dermatological treatments and adequate education about photoprotection in specialized dermatology clinics for OTR. Whereas surgery remains the gold-standard therapy for NMSC, noninvasive methods have shown promising results to treat superficial keratoses and subclinical lesions on large body areas. Although the threshold of skin cancer necessitating revision of immunosuppression is debated, this measure should be envisaged at the occurrence of the first SCC, or in case of multiple non-SCC NMSC. While the role of immunosuppressants in the occurrence of NMSC is widely recognized, the best immunosuppressive strategies remain to be defined. Presently, randomized prospective studies assess the burden of new skin tumors, as well as graft and patient survival, in patients with one or several NMSC after the introduction of mTOR (mammalian target of rapamycin) inhibitors.


Gene coexpression patterns during early development of the native Arabidopsis reproductive meristem: novel candidate developmental regulators and patterns of functional redundancy.
During very early stages of flower development in Arabidopsis thaliana, a series of key decisions are taken. Indeed, the position and the basic patterning of new flowers are determined in less than 4 days. Given that the scientific literature provides hard evidence for the function of only 10% of A. thaliana genes, we hypothesized that although many essential genes have already been identified, many poorly characterized genes are likely to be involved in floral patterning. In the current study, we use high-throughput sequencing to describe the transcriptome of the native inflorescence meristem, the floral meristem and the new flower immediately after the start of organ differentiation. We provide evidence that our experimental system is reliable and less affected by experimental artefacts than a widely used floral induction system. Furthermore, we show how these data can be used to identify candidate genes for functional studies, and to generate hypotheses of functional redundancies and regulatory interactions.


Refinements in abdominoplasty: a critical outcomes analysis over a 20-year period.
The use of liposuction combined with abdominoplasty has been controversial. The combination of techniques has been associated with an increased rate of venous thromboembolism and wound-healing complications. Through improvements in venous thromboembolism prophylaxis, refinements in liposuction techniques, and an understanding of anatomy, this cumulative risk has decreased, although the negative stigmata persist. This study describes the evolution of abdominal body contouring through a critical review of a single surgeon's 20-year experience with abdominoplasty. This clinical outcome analysis will highlight the significant contributions that have led to the improvement in the safety and efficacy of this technique. A retrospective review of patients undergoing abdominoplasty procedures was performed. Patient demographics and procedural information, including postoperative course and complications, were recorded. Preoperative and postoperative photographs were scored by blinded evaluators for aesthetic result and scar quality. Two hundred fifty patients undergoing abdominoplasty from 1987 to 2007 were included in the study. The use of a "superwet" liposuction technique in combination with abdominoplasty significantly decreased intraoperative blood loss (p < 0.04) and length of hospital stay (p < 0.05). Liposuction volume and region had no significant effect on abdominoplasty outcome, although refinements in operative technique, including abdominal and flank ultrasound-assisted liposuction, high superior tension, and limited abdominal undermining, did improve the postoperative aesthetic score. Venous thromboembolic events significantly decreased with aggressive venous thromboembolism prophylaxis (p < 0.001). The technical evolution of a single surgeon's 20-year experience demonstrates that liposuction can be safely and effectively combined with abdominoplasty. Preoperative trunk analysis, intraoperative surgical refinements including superwet technique and ultrasound-assisted liposuction, and perioperative venous thromboembolism prophylaxis significantly improve the outcome of abdominoplasty.


Usefulness of direct-conversion flat-panel detector system as a quality assurance tool for high-dose-rate 192Ir source.
The routine quality assurance (QA) procedure for a high-dose-rate (HDR) 192Ir radioactive source is an important task to provide appropriate brachytherapy. Traditionally, it has been difficult to obtain good quality images using the 192Ir source due to irradiation from the high-energy gamma rays. However, a direct-conversion flat-panel detector (d-FPD) has made it possible to confirm the localization and configuration of the 192Ir source. The purpose of the present study was to evaluate positional and temporal accuracy of the 192Ir source using a d-FPD system, and the usefulness of d-FPD as a QA tool. As a weekly verification of source positional accuracy test, we obtained 192Ir core imaging by single-shot radiography for three different positions (1300/1400/1500 mm) of a check ruler. To acquire images for measurement of the 192Ir source movement distance with varying interval steps (2.5/5.0/10.0 mm) and temporal accuracy, we used the high-speed image acquisition technique and digital subtraction. For accuracy of the 192Ir source dwell time, sequential images were obtained using various dwell times ranging from 0.5 to 30.0 sec, and the acquired number of image frames was assessed. Analysis of the data was performed using the measurement analysis function of the d-FPD system. Although there were slight weekly variations in source positional accuracy, the measured positional errors were less than 1.0 mm. For source temporal accuracy, the temporal errors were less than 1.0%, and the correlation between acquired frames and programmed time showed excellent linearity (R2 = 1). All 192Ir core images were acquired clearly without image halation, and the data were obtained quantitatively. All data were successfully stored in the picture archiving and communication system (PACS) for time-series analysis. The d-FPD is considered useful as the QA tool for the 192Ir source.


Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome.
Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events. A randomized, double-blind, placebo-controlled trial of prednisone (1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded. The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day. One hundred and ten participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm {median hospital days 3 [interquartile range (IQR) 0-9] and 0 (IQR 0-3), respectively; P = 0.04}. There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone vs. the placebo arm at 2 and 4 weeks, but not at later time points. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (P = 0.002) and 4 (P = 0.02). Infections on study medication occurred in more participants in prednisone than in placebo arm (27 vs. 17, respectively; P = 0.05), but there was no difference in severe infections (2 vs. 4, respectively; P = 0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrolment. Prednisone reduced the need for hospitalization and therapeutic procedures and hastened improvements in symptoms, performance, and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.


[Frequency of intestinal parasites in samples of lettuce (Lactuca sativa) commercialized in Lavras, Minas Gerais State].
The aim of this study was to evaluate the parasitological contamination in samples of lettuce (Lactuca sativa) commercialized in Lavras city, Minas Gerais. The samples of lettuce showed low hygienic conditions, indicated by the presence of parasites of animal or human origin and high concentration of fecal coliforms.


Both gastrocnemius aponeurosis flaps and semitendinosus tendon grafts are effective in the treatment of chronic Achilles tendon ruptures - a systematic review.
A chronic Achilles tendon rupture (ATR) is defined as an ATR that has been left untreated for more than four weeks following rupture. This systematic review aims to summarize the outcomes of chronic ATR treated using either a gastrocnemius aponeurosis flap or semitendinosus tendon graft. A systematic search was conducted in three databases (PubMed, Scopus and Cochrane), for studies describing outcomes after surgical treatment of chronic ATR using gastrocnemius aponeurosis flaps or semitendinosus tendon grafts with more than 10 patients included. The studies were assessed for quality and risk of bias using the Methodological Items used to assess risk of bias in Non-Randomized Studies (MINORS). Out of the 818 studies identified with the initial search, a total of 36 studies with 763 individual patients were included in this systematic review. Gastrocnemius aponeurosis flap was used in 21 and semitendinosus tendon graft was used in 13 of the studies. The mean (SD) postoperative Achilles tendon Total Rupture Score (ATRS) for patients treated with a gastrocnemius aponeurosis flap was 83 (14) points and the mean (SD) American Orthopaedic Foot and Ankle Score (AOFAS) was 96 (1.7) points compared with ATRS 88 (6.9) points and AOFAS 92 (5.6) points for patients treated with a semitendinosus tendon graft. The included studies generally had low-quality according to MINORS, with a median of 8 (range 2-13) for all studies. Both gastrocnemius aponeurosis flaps and semitendinosus tendon grafts give acceptable results with minimal complications and are valid methods for treating chronic ATR. The main difference is more wound healing complications in patients treated with a gastrocnemius aponeurosis flap and more sural nerve injuries in patients treated with a semitendinosus grafts. The current literature on the subject is of mainly low quality and the absence of a patient-related outcome measure validated for chronic ATR makes comparisons between studies difficult. Level IV.


The clinical course of immediate breast implant reconstruction after breast cancer.
The number of women suitable for breast conserving treatment as well as immediate reconstruction after breast cancer has been increasing, and studies of complications hereafter are needed. The cohort was identified in the prospective database of the Danish Registry for Plastic Surgery of the Breast during the period 1999 to 2006; 167 women with 189 immediate breast reconstructions (40 one-stage and 149 two-stage procedures) after breast cancer without a history of radiation therapy. The women were followed for complications until November 2009. Cumulative incidence risks were computed for infection, hematoma, seroma, severe capsular contracture (modified Baker III and IV), extrusion of the implant, implant rupture, asymmetry/displacement of the implant, any complication, and reoperation. In addition, we compared the postoperative course of immediate two-stage procedures with delayed two-stage procedures. The overall eight-year risk estimates for the immediate procedures were 76.4% for any complication, 5.3% for severe capsular contracture, 29.5% for displacement/asymmetry of the implant and 40.6% for reoperation. Significantly higher risk for reoperation was observed after immediate one-stage than after two-stage procedures. For immediate two-stage procedures acute complications such as infection, seroma and hematoma were higher in the expansion period than after the second planned surgery. Higher risks for acute complications were observed after immediate than after delayed two-stage procedures. Immediate breast implant reconstruction was found to have substantial risks of complications in non-radiated women, which should be considered in the guidance of breast cancer patients before choosing reconstructive procedure.


Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer.
Gastric cancer is a fatal malignancy with a rising incidence rate. Effective methods for early diagnosis, monitoring metastasis, and prognosis are currently unavailable for gastric cancer. In this study, we examined the association of programmed death ligand-1 (PD-L1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with the prognosis of gastric cancer. The expressions of PD-L1 and APE1 were detected by immunohistochemistry in 107 cases of human gastric carcinoma. The correlation of PD-L1 and APE1 expression with the clinicopathologic features of gastric carcinoma was analyzed by SPSS version 19.0. The positive expression rates of PD-L1 and APE1 in gastric cancer tissues were 50.5% (54/107) and 86.9% (93/107), respectively. PD-L1 and APE1 positive expressions were significantly associated with depth of invasion, lymph node metastasis, pathological type, overall survival, and higher T stage. Furthermore, the expression of PD-L1 in highly differentiated gastric cancers was higher than that in poorly differentiated cancers (P=0.008). Moreover, the expression of APE1 and PD-L1 in gastric cancers was positively correlated (r=0.336, P<0.01). Multivariate analysis showed that the depth of invasion was a significant prognostic factor (risk ratio 19.91; P=0.000), but there was no significant relationship with PD-L1, APE1, prognosis, and other characteristics. The deregulation of PD-L1 and APE1 might contribute to the development and the poor prognosis of gastric cancer. Our findings suggest that high expression of PD-L1 and APE1 is a risk factor of gastric cancer and a new biomarker to predict the prognosis of gastric cancer. Furthermore, our findings suggest that targeting the PD-L1 and APE1 signaling pathways may be a new strategy for cancer immune therapy and targeted therapy for gastric cancer, especially in patients with deep invasion and lymph node metastasis.


Prevalence of and risk factors associated with Cryptosporidium infection in an underdeveloped rural community of southwest China.
Cryptosporidium spp. is an important intestinal protozoan causing diarrhea in humans, livestock, and wild animals. Cryptosporidium infection remains a major public health issue, but its epidemiology in humans is still unclear, particularly in rural China. This study was designed to determine the prevalence of and risk factors associated with Cryptosporidium infection in a rural southwestern Chinese community. A community-based cross-sectional survey was conducted among 687 residents of a small town in a Yi autonomous prefecture of southwest China in 2014. Blood samples were examined using a broad set of quality-controlled diagnostic methods for hepatitis B virus (HBV) and human immunodeficiency virus (HIV). Stool specimens were processed using the modified acid-fast staining method, and microscopically examined for Cryptosporidium infection. Univariable and multivariable analyses were performed to determine the risk factors associated with Cryptosporidium infection. The majority of the participants were Yi people with poor living conditions and unsatisfactory hygiene habits, and the study area was of very low socioeconomic status. Of the 615 individuals included in the analysis, 14 (2.3%) were HIV positive, 51 (8.3%) were infected with HBV, and 74 (12.0%) had Cryptosporidium infection. The prevalences of HIV/HBV, HIV/Cryptosporidium, and HBV/Cryptosporidium co-infections were 0.3%, 0.3%, and 1.8%, respectively. The prevalence of HBV infection was higher in individuals with Cryptosporidium infection (χ 2 = 5.00, P = 0.03). Owning livestock or poultry was an important risk factor for Cryptosporidium infection (aOR = 2.27, 95% CI: 1.01-5.08, P < 0.05). Cryptosporidium infection was significantly associated with HBV infection (aOR = 3.42, 95% CI: 1.47-7.92, P < 0.01), but not with HIV infection (aOR = 0.57, 95% CI: 0.07-4.39, P = 0.59). The prevalence of Cryptosporidium infection was high in the rural area of southwestern China that was investigated, and there was a significant association between HBV infection and Cryptosporidium infection. Further investigations are needed to determine the significance of Cryptosporidium infection in patients infected with HBV.


Primary care in Canada: coming or going?
Despite an early start in the transformation of its health system toward a primary care infrastructure, Canada has not kept pace in the production of knowledge that is needed to support forward momentum. Having achieved the three key system features needed for primary care practice (attempted distribution of resources equitably; government control or heavy regulation of insurance; and low or no copayments), Canada now needs to take bold steps to address at least two interrelated challenges: (1) to shift from a disease orientation to a population orientation toward multi-morbidity and (2) to better understand the delineation of the relative roles of primary care physicians and specialists. The Canadian commitment to primary care research has been very weak. Its strengthening would help Canada to move ahead and could contribute greatly to the advancement of primary care as a worldwide imperative of the 21st century.


Liver Pathologic Changes After Direct-Acting Antiviral Agent Therapy and Sustained Virologic Response in the Setting of Chronic Hepatitis C Virus Infection.
Treatment of chronic viral hepatitis C (HCV) infection with direct-acting antiviral agents (DAAs) results in cure, or sustained viral response (SVR), in more than 90% of patients. However, there are subsets of patients who have persistent liver inflammation and fibrosis and develop hepatocellular carcinoma (HCC) despite achieving SVR. A possible reason for these phenomena may be the presence of virus particles in liver tissue but not blood, otherwise defined as occult infection. To describe liver histologic findings following successful DAA therapy, test HCV RNA by (liver) tissue polymerase chain reaction in treated cases, and identify predictive markers for HCC development in treated cases. A total of 96 identified patients were divided into 4 groups, each differentiated by the presence or absence of SVR and HCC. Groups were compared for several clinicopathologic variables, including degree of inflammation and fibrosis, and the 'directionality' of fibrosis in cirrhotic livers using the novel progressive-indeterminate-regressive scoring system. Overall, we found a significant decrease in inflammation in SVR patients. None of the patients showed regression of their cirrhosis following treatment. No evidence of occult HCV infection was seen in 40 livers tested, including 21 with HCC. The number of patients who developed HCC was similar in the SVR and non-SVR groups, and increased inflammation and fibrosis were associated with HCC development. Following DAA-SVR there appears to be an overall decrease in inflammation, but the fibrosis tends to persist, at least in the short term (median follow-up of 20.2 months).


Low serum levels of dehydroepiandrosterone sulfate predict all-cause and cardiovascular mortality in elderly Swedish men.
The age-related decline in dehydroepiandrosterone (DHEA) levels is thought to be of importance for general and vascular aging. However, data on the association between DHEA and mortality are conflicting. We tested the hypothesis that low serum DHEA and DHEA sulfate (DHEA-S) levels predict all-cause and cardiovascular disease (CVD) death in elderly men. We used gas/liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based MrOS Sweden study (2644 men, aged 69-81 yr). Mortality data were obtained from central registers and analyzed using Cox proportional hazards regressions. All-cause and CVD mortality by serum DHEA(-S) levels. During a mean 4.5-yr follow-up, 328 deaths occurred. Low levels of DHEA-S (quartile 1 vs. quartiles 2-4), predicted death from all causes [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.21-1.96; adjusted for traditional cardiovascular risk factors], from CVD (n = 123 deaths; HR 1.61, 95% CI 1.10-2.37) and ischemic heart disease (n = 73; HR 1.67, 95% CI 1.02-2.74) but not cancer. Analyses with DHEA gave similar results. The association between low DHEA-S and CVD death remained after adjustment for C-reactive protein and circulating estradiol and testosterone levels. When stratified by the median age of 75.4 yr, the mortality prediction by low DHEA-S was more pronounced among younger (age adjusted HR for CVD death 2.64, 95% CI 1.37-5.09) than older men (HR 1.30, 95% CI 0.83-2.04). Low serum levels of DHEA(-S) predict death from all causes, CVD, and ischemic heart disease in older men.


Cardiopulmonary magnetic resonance imaging in children after lung transplantation: preliminary observations.
Lung transplantation carries a guarded prognosis and is burdened by short-term and long-term complications that affect the airway, lungs, and vasculature. In this pilot study we aimed to assess the feasibility of magnetic resonance imaging (MRI) in 8 pediatric patients after lung transplantation. The 8 patients in the study were aged between 9 and 17 years and were clinically stable. The scan protocol included MR angiography, phase contrast imaging of the pulmonary arteries and veins, ventricular volumetry, lung parenchyma imaging, and lung volumetry. This protocol was successfully done in all patients. Lung volumes measured by MRI correlated well with those by body plethysmography (r = 0.83, p = 0.01). Angiography detected caliber differences between the donor and recipient pulmonary arteries in 5 patients. One patient had hemodynamically relevant pulmonary vein stenosis, as evidenced by MR angiography, a reduction in ipsilateral flow, and an abnormal pulmonary venous flow profile. Three patients had mild left (2 patients) or right (1 patient) ventricular systolic dysfunction. One patient had left main bronchus compression, and 3 patients showed varying degrees of pleural thickening. Our preliminary experience suggests that cardiopulmonary MRI is feasible in pediatric lung transplant recipients and that it provides clinically useful information, especially on the vascular and bronchial anastomoses. However, the value of MRI for routine follow-up in pediatric lung transplant patients needs to be determined in a larger cohort.


The feasibility of nurse practitioner-performed, telementored lung telesonography with remote physician guidance - 'a remote virtual mentor'.
Point-of-care ultrasound (POC-US) use is increasingly common as equipment costs decrease and availability increases. Despite the utility of POC-US in trained hands, there are many situations wherein patients could benefit from the added safety of POC-US guidance, yet trained users are unavailable. We therefore hypothesized that currently available and economic 'off-the-shelf' technologies could facilitate remote mentoring of a nurse practitioner (NP) to assess for recurrent pneumothoraces (PTXs) after chest tube removal. The simple remote telementored ultrasound system consisted of a handheld ultrasound machine, head-mounted video camera, microphone, and software on a laptop computer. The video output of the handheld ultrasound machine and a macroscopic view of the NP's hands were displayed to a remote trauma surgeon mentor. The mentor instructed the NP on probe position and US machine settings and provided real-time guidance and image interpretation via encrypted video conferencing software using an Internet service provider. Thirteen pleural exams after chest tube removal were conducted. Thirteen patients (26 lung fields) were examined. The remote exam was possible in all cases with good connectivity including one trans-Atlantic interpretation. Compared to the subsequent upright chest radiograph, there were 4 true-positive remotely diagnosed PTXs, 2 false-negative diagnoses, and 20 true-negative diagnoses for 66% sensitivity, 100% specificity, and 92% accuracy for remotely guided chest examination. Remotely guiding a NP to perform thoracic ultrasound examinations after tube thoracostomy removal can be simply and effectively performed over encrypted commercial software using low-cost hardware. As informatics constantly improves, mentored remote examinations may further empower clinical care providers in austere settings.


On natural attunement: Shared rhythms between the brain and the environment.
Rhythms exist both in the embodied brain and the built environment. Becoming attuned to the rhythms of the environment, such as repetitive columns, can greatly affect perception. Here, we explore how the built environment affects human cognition and behavior through the concept of natural attunement, often resulting from the coordination of a person's sensory and motor systems with the rhythmic elements of the environment. We argue that the built environment should not be reduced to mere states, representations, and single variables but instead be considered a bundle of highly related continuous signals with which we can resonate. Resonance and entrainment are dynamic processes observed when intrinsic frequencies of the oscillatory brain are influenced by the oscillations of an external signal. This allows visual rhythmic stimulations of the environment to affect the brain and body through neural entrainment, cross-frequency coupling, and phase resetting. We review how real-world architectural settings can affect neural dynamics, cognitive processes, and behavior in people, suggesting the crucial role of everyday rhythms in the brain-body-environment relationship.


Ethical and legal issues on HIV testing, policy and the practice of dentistry.
This paper is structured around the following: autonomy and consent, confidentiality, disclosure, knowledge of patient and provider HIV status, the right to choose whom to treat, testing for HIV and the importance of HIV policies in the workplace to guard against discrimination. The emergence of the HIV/AIDS pandemic has challenged traditional ethical values of the health care profession. These include the infectious nature of HIV, the social stigma of the disease and its ethical and legal dilemmas. This paper addresses some of the pertinent questions related to HIV infection and AIDS. The three broad principles of ethics, namely, autonomy, beneficence and justice, provide the basic framework on which this paper is based. Advances in the biotechnology of rapid oral fluid testing particularly in the detection of HIV antibodies from patients in the dental setting have raised additional ethical and legal considerations in the subsequent management of HIV infected patients to include disclosure of test results to the patient and proper referral to physicians or nurse practitioners. The oral health care worker must thus have a solid foundation in the application of bioethical principles. A clinical case scenario related to HIV testing in the dental setting is presented to illustrate how a lack of understanding and the wrongful application of ethical principles may lead to patient harm and legal liability. Given the increasing infection rate of HIV worldwide, polices must be upheld and revised as needed to protect healthcare providers, patients, and society generally against discrimination.


Trust versus concerns-how parents reason when they accept HPV vaccination for their young daughter.
From spring of 2012, human papillomavirus (HPV) vaccine against cervical cancer is offered free of charge to all girls aged 10-12 years through a school-based vaccination programme in Sweden. The aim of this study was to explore how parents reason when they accept HPV vaccination for their young daughter and also their views on HPV-related information. Individual interviews with parents (n = 27) of 11-12-year-old girls. The interviews were recorded, transcribed verbatim, and analysed using thematic content analysis. Three themes emerged through the analysis: Trust versus concern, Responsibility to protect against severe disease, and Information about HPV and HPV vaccination is important. The parents expressed trust in recommendations from authorities and thought it was convenient with school-based vaccination. They believed that cervical cancer was a severe disease and felt a responsibility to protect their daughter from it. Some had certain concerns regarding side effects and vaccine safety, and wished for a dialogue with the school nurse to bridge the information gaps. Trust in the recommendations from authorities and a wish to protect their daughter from a severe disease outweighed concerns about side effects. A school-based vaccination programme is convenient for parents, and the school nurse has an important role in bridging information gaps. The findings from this qualitative study cannot be generalized; however, it can provide a better understanding of how parents might reason when they accept the HPV vaccination for their daughter.


Lipid/polydiacetylene films for colorimetric protein surface-charge analysis.
The distribution and organization of charges on a protein surface are fundamental properties which affect protein functions and interactions. We demonstrate a new approach for protein surface-charge analysis through modulating protein interactions with chromatic lipid/polydiacetylene (PDA) films. We show that visible and easily quantifiable blue-red transitions, induced on the film surface through electrostatic interactions between the negatively charged PDA and positive soluble species, constitute an effective means for characterizing protein surface charge. Specifically, protein-film interactions can be significantly modulated by complexation between the tested macromolecules and lipid-embedded multivalent calixarene ligands displaying charged residues, making possible protein discrimination based upon the abundance and organization of surface charge. The lipid/PDA film system, in conjunction with the calixarene-derived ligands, facilitates characterization of protein surface charges and identification of anomalous protein electrostatic properties.


Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity.
The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B*1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B*5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B*5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.


Measuring positive mental health in Canada: construct validation of the Mental Health Continuum-Short Form.
Positive mental health is increasingly recognized as an important focus for public health policies and programs. In Canada, the Mental Health Continuum-Short Form (MHC-SF) was identified as a promising measure to include on population surveys to measure positive mental health. It proposes to measure a three-factor model of positive mental health including emotional, social and psychological well-being. The purpose of this study was to examine whether the MHC-SF is an adequate measure of positive mental health for Canadian adults. We conducted confirmatory factor analysis (CFA) using data from the 2012 Canadian Community Health Survey (CCHS)-Mental Health Component (CCHS-MH), and cross-validated the model using data from the CCHS 2011-2012 annual cycle. We examined criterion-related validity through correlations of MHC-SF subscale scores with positively and negatively associated concepts (e.g. life satisfaction and psychological distress, respectively). We confirmed the validity of the three-factor model of emotional, social and psychological well-being through CFA on two independent samples, once four correlated errors between items on the social well-being scale were added. We observed significant correlations in the anticipated direction between emotional, psychological and social well-being scores and related concepts. Cronbach's alpha for both emotional and psychological well-being subscales was 0.82; for social well-being it was 0.77. Our study suggests that the MHC-SF measures a three-factor model of positive mental health in the Canadian population. However, caution is warranted when using the social well-being scale, which did not function as well as the other factors, as evidenced by the need to add several correlated error terms to obtain adequate model fit, a higher level of missing data on these questions and weaker correlations with related constructs. Social well-being is important in a comprehensive measure of positive mental health, and further research is recommended.


Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae.
Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. Since repurposing drugs is an ideal strategy for orphan diseases, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 μM) against N. fowleri (n = 19), A. castellanii (n = 12), and B. mandrillaris (n = 27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design.


Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling.
The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.


Acquired and Persistent Eldercare Demands: Impact on Worker Well-Being.
Eldercare demands (ECD) may result in stress when finite resources needed to fulfill life roles (i.e., family, work) become scarce. ECD may be acquired, continue over time, or be relinquished. They thus may represent acute stress (immediate, severe) or chronic stress (persistent, milder). Workers at six U.S. manufacturing companies completed surveys (N = 520). ECD were operationalized as providing assistance to an adult aged 65+ years due to disability or illness. Workers were categorized into four ECD groups (persistent, relinquished, acquired, and none), and we examined the ECD groups' association with person-centric and work-centric outcomes. Respondents with acquired ECD had worse mental health and greater depressive symptoms than those with none, and those with persistent ECD had greater work stress and family-work conflict than those with none. Findings suggesting that acute stress is more related to person-centric outcomes and chronic stress is more related to work-centric outcomes could inform development of tailored interventions.


Performance improvements of a tunable bandpass microwave photonic filter based on a notch ring resonator using phase modulation with dual optical carriers.
A tunable bandpass microwave photonic filter can be achieved by using a notch ring resonator with optical phase modulation. However, the filter's out of band rejection ratio and shape factor are limited due to the ring resonator's residual phase, which can seriously degrade the filter's performance. By using dual optical carriers and setting their wavelengths oppositely detuned from two resonant frequencies of a notch ring resonator, the residual phase induced by the ring resonator at radio frequencies falling outside the region of the notch stopband is reduced, thus the out-of-band rejection ratio and shape factor of the microwave photonic filter are greatly improved. The proposed microwave photonic filter was both verified theoretically and experimentally. Compared with single optical carrier method, the out-of-band rejection ratio of the filter can be enhanced from 17.7dB to 31.5dB, and the filter's shape factor is improved from 3.05 to 1.78. Besides, the filter's frequency and bandwidth can be tuned by varying the wavelengths of the two optical carriers and the ring resonator's coupling coefficients. Finally, a tunable bandpass microwave photonic filter with frequency tuning range of 2~14GHz, 3dB bandwidth tuning range of 0.673~2.798GHz is demonstrated.


[Activity index in Crohn's disease].
The gold standard to quantify Crohn's disease activity is still not defined and a world consensus to unify criteria is necessary. Criticism has been directed towards every existing indexes. We summarize some of the currently used criteria for the assessment of disease activity, point out the controversies and issues that will need further investigations, and discuss their usefulness based on our experience.


The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases.
Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites or [reactive oxygen species (ROS)] and their elimination by through protective mechanisms, including (antioxidants). This Such imbalance leads to damage of cells and important biomolecules and cells, with hence posing a potential adverse impact on the whole organism. At the center of the day-to-day biological response to oxidative stress is the Kelch-like ECH-associated protein 1 (Keap1) - nuclear factor erythroid 2-related factor 2 (Nrf2)- antioxidant response elements (ARE) pathway, which regulates the transcription of many several antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in the maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and pro-apoptotic conditions, which allows us to consider it as a pharmacological target. Herein, we review and discuss the recent advancements in the regulation of the Keap1/Nrf2/ARE system, and its role under physiological and pathophysiological conditions, e.g. such as in exercise, diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, stroke, liver and kidney system, etc. and such.


Comparison of the predictive value of four different risk scores for outcomes of patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention.
Accurate risk stratification has an important role in the management of patients with acute coronary syndromes. Even in patients with ST-elevation acute myocardial infarction (STEMI), for whom early therapeutic options are well defined, risk stratification has an impact on early and late therapeutic decision making. We aimed to compare the prognostic value of 4 risk scores used to evaluate patients with STEMI. We conducted a prospective registry of all patients treated with primary percutaneous coronary intervention for STEMI from January 2001 to June 2006. Excluded were patients with cardiogenic shock. A total of 855 consecutive patients were included in the analysis (age 60.5 +/- 13 years, 19% women, 28% with diabetes, and 48% with anterior wall myocardial infarction). For each patient, the Thrombolysis In Myocardial Infarction (TIMI), Controlled Abciximab and Device Investigation to Lower Late Angioplasty complications (CADILLAC), Primary Angioplasty in Myocardial Infarction (PAMI), and Global Registry for Acute Coronary Events (GRACE) risk scores were calculated using specific clinical variables and angiographic characteristics. Thirty-day and 1-year clinical outcomes were assessed. The predictive accuracy of the 4 risk scores was evaluated using the area under the curve or C statistic method. The CADILLAC, TIMI, and PAMI risk scores all had relatively high predictive accuracy for 30-day and 1-year mortality (C statistic range 0.72 to 0.82), with slight superiority of the CADILLAC score. These 3 risk scores also performed well for prediction of reinfarction at 30 days (C statistic range 0.6 to 0.7). The GRACE score did not perform as well and had low predictive accuracy for mortality (C statistic 0.47). In conclusion, risk stratification of patients with STEMI undergoing primary percutaneous coronary intervention using the CADILLAC, TIMI, or PAMI risk scores provide important prognostic information and enables accurate identification of high-risk patients.


3D organic bioelectronics for electrical monitoring of human adult stem cells.
Three-dimensional in vitro stem cell models have enabled a fundamental understanding of cues that direct stem cell fate. While sophisticated 3D tissues can be generated, technology that can accurately monitor these complex models in a high-throughput and non-invasive manner is not well adapted. Here we show the development of 3D bioelectronic devices based on the electroactive polymer poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate)-(PEDOT:PSS) and their use for non-invasive, electrical monitoring of stem cell growth. We show that the electrical, mechanical and wetting properties as well as the pore size/architecture of 3D PEDOT:PSS scaffolds can be fine-tuned simply by changing the processing crosslinker additive. We present a comprehensive characterization of both 2D PEDOT:PSS thin films of controlled thicknesses, and 3D porous PEDOT:PSS structures made by the freeze-drying technique. By slicing the bulky scaffolds we generate homogeneous, porous 250 μm thick PEDOT:PSS slices, constituting biocompatible 3D constructs able to support stem cell cultures. These multifunctional slices are attached on indium-tin oxide substrates (ITO) with the help of an electrically active adhesion layer, enabling 3D bioelectronic devices with a characteristic and reproducible, frequency dependent impedance response. This response changes drastically when human adipose derived stem cells (hADSCs) grow within the porous PEDOT:PSS network as revealed by fluorescence microscopy. The increase of cell population within the PEDOT:PSS porous network impedes the charge flow at the interface between PEDOT:PSS and ITO, enabling the interface resistance (R1) to be used as a figure of merit to monitor the proliferation of stem cells. The non-invasive monitoring of stem cell growth allows for the subsequent differentiation 3D stem cell cultures into neuron like cells, as verified by immunofluorescence and RT-qPCR measurements. The strategy of controlling important properties of 3D PEDOT:PSS structures simply by altering processing parameters can be applied for development of a number of stem cell in vitro models as well as stem cell differentiation pathways. We believe the results presented here will advance 3D bioelectronic technology for both fundamental understanding of in vitro stem cell cultures as well as the development of personalized therapies.


Antioxidant, Cytotoxic, and Toxic Activities of Propolis from Two Native Bees in Brazil: Scaptotrigona depilis and Melipona quadrifasciata anthidioides.
Propolis is a natural mixture of compounds produced by various bee species, including stingless bees. This compound has been shown to exhibit antioxidant, antiproliferative, and antitumor activities. The present study aimed to determine the chemical constituents as well as the antioxidant, cytotoxic, and toxic activities of ethanol extracts of propolis obtained from the stingless bees Scaptotrigona depilis and Melipona quadrifasciata anthidioides, which are found in Brazil. Phytosterols, terpenes, phenolic compounds, and tocopherol were identified in the ethanol extracts of propolis (EEPs) in different concentrations. The compounds stigmasterol, taraxasterol, vanilic acid, caffeic acid, quercetin, luteolin, and apigenin were found only in EEP-M. The EEPs were able to scavenge the free radicals 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and protected human erythrocytes against lipid peroxidation, with the latter effect being demonstrated by their antihemolytic activity and inhibition of malondialdehyde formation. The EEPs showed cytotoxic activity against erythroleukemic cells and necrosis was the main mechanism of death observed. In addition, the concentrations at which the EEPs were cytotoxic were not toxic against Caenorhabditis elegans. In this context, it is concluded that EEP-S and EEP-M show antioxidant and cytotoxic activities and are promising bioactive mixtures for the control of diseases associated with oxidative stress and tumor cell proliferation.


Evaluation of Digital Breast Tomosynthesis as Replacement of Full-Field Digital Mammography Using an In Silico Imaging Trial.
Expensive and lengthy clinical trials can delay regulatory evaluation of innovative technologies, affecting patient access to high-quality medical products. Simulation is increasingly being used in product development but rarely in regulatory applications. To conduct a computer-simulated imaging trial evaluating digital breast tomosynthesis (DBT) as a replacement for digital mammography (DM) and to compare the results with a comparative clinical trial. The simulated Virtual Imaging Clinical Trial for Regulatory Evaluation (VICTRE) trial was designed to replicate a clinical trial that used human patients and radiologists. Images obtained with in silico versions of DM and DBT systems via fast Monte Carlo x-ray transport were interpreted by a computational reader detecting the presence of lesions. A total of 2986 synthetic image-based virtual patients with breast sizes and radiographic densities representative of a screening population and compressed thicknesses from 3.5 to 6 cm were generated using an analytic approach in which anatomical structures are randomly created within a predefined breast volume and compressed in the craniocaudal orientation. A positive cohort contained a digitally inserted microcalcification cluster or spiculated mass. The trial end point was the difference in area under the receiver operating characteristic curve between modalities for lesion detection. The trial was sized for an SE of 0.01 in the change in area under the curve (AUC), half the uncertainty in the comparative clinical trial. In this trial, computational readers analyzed 31 055 DM and 27 960 DBT cases from 2986 virtual patients with the following Breast Imaging Reporting and Data System densities: 286 (9.6%) extremely dense, 1200 (40.2%) heterogeneously dense, 1200 (40.2%) scattered fibroglandular densities, and 300 (10.0%) almost entirely fat. The mean (SE) change in AUC was 0.0587 (0.0062) (P < .001) in favor of DBT. The change in AUC was larger for masses (mean [SE], 0.0903 [0.008]) than for calcifications (mean [SE], 0.0268 [0.004]), which was consistent with the findings of the comparative trial (mean [SE], 0.065 [0.017] for masses and -0.047 [0.032] for calcifications). The results of the simulated VICTRE trial are consistent with the performance seen in the comparative trial. While further research is needed to assess the generalizability of these findings, in silico imaging trials represent a viable source of regulatory evidence for imaging devices.


Monte Carlo study of fluence perturbation effects on cavity dose response in clinical proton beams.
Current protocols for clinical proton beam dosimetry have not implemented any chamber-dependent correction factors for absorbed dose determination. The present work initiates a Monte Carlo study of these factors with emphasis on proton fluence perturbation effects and preliminary calculations of perturbation effects from secondary electrons. The proton Monte Carlo code PTRAN was modified to allow simulation of proton transport in non-homogeneous geometries of both unmodulated and modulated beams. The dose to water derived from the dose calculated in an air cavity agrees well with results from analytical calculations assuming a displacement of the point of measurement. For unmodulated beams small differences, limited to 0.8%, could be partially attributed to proton multiple scattering. Effects of replacing water around the cavity with wall material are explained by the introduction of a water-equivalent wall thickness. For modulated beams no significant perturbation effects arise. Secondary electron spectra are calculated analytically. Preliminary electron transport calculations with EGS4 show that wall perturbations of the order of 1% could result. Perturbation effects caused by the energy transport of secondary particles from inelastic nuclear interactions have not been studied here. Inclusion of inelastic nuclear energy transfers in the cavity dose, assuming total local absorption, indicate that separate scaling of this contribution with the ratio of total inelastic nuclear cross sections could be important.


Relationship of alcohol drinking pattern to risk of hypertension: a population-based study.
Epidemiological studies have demonstrated a positive relationship between heavy alcohol use and hypertension, but few studies have directly addressed the role of drinking pattern. This study was designed to investigate the association of current alcohol consumption and aspects of drinking pattern with hypertension risk in a sample of 2609 white men and women from western New York, aged 35 to 80 years, and free from other cardiovascular diseases. Hypertension was defined by systolic blood pressure > or =140 mm Hg or diastolic blood pressure > or =90 mm Hg or use of antihypertensive medication. Odds ratios (95% confidence intervals) were computed after adjustment for several covariates. Compared with lifetime abstainers, participants reporting drinking on a daily basis (1.75 [1.13 to 2.72]) or mostly without food (1.64 [1.08 to 2.51]) exhibited significantly higher risk of hypertension. When analyses were restricted to current drinkers, daily drinkers and participants consuming alcohol without food exhibited a significantly higher risk of hypertension compared with those drinking less than weekly (1.65 [1.18 to 2.30]) and those drinking mostly with food (1.49 [1.10 to 2.00]), respectively. After additional adjustment for the amount of alcohol consumed in the past 30 days, the results were follows: 0.90 (0.58 to 1.41) for daily drinkers and 1.41 (1.04 to 1.91) for drinkers without food. For predominant beverage preference, no consistent association with hypertension risk was found across the various types of beverages considered (beer, wine, and liquor). In conclusion, drinking outside meals appears to have a significant effect on hypertension risk independent of the amount of alcohol consumed.


Outcomes of intracranial germinoma-A retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies.
This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes. A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken. From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had β-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%). Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease.


Changes in Vedolizumab Utilization Across US Academic Centers and Community Practice Are Associated With Improved Effectiveness and Disease Outcomes.
Vedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn's disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval. We used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014-June 2015 (Era 1) and July 2015-June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses. A total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P < 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease-related hospitalization (22.4% vs 9.6%, P < 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD. Since FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later.


Mice lacking β-carotene-15,15'-dioxygenase exhibit reduced serum testosterone, prostatic androgen receptor signaling, and prostatic cellular proliferation.
β-Carotene-15,15'-dioxygenase (BCO1) cleaves dietary carotenoids at the central 15,15' double bond, most notably acting on β-carotene to yield retinal. However, Bco1 disruption also impacts diverse physiological end points independent of dietary carotenoid feeding, including expression of genes controlling androgen metabolism. Using the Bco1-/- mouse model, we sought to probe the effects of Bco1 disruption on testicular steroidogenesis, prostatic androgen signaling, and prostatic proliferation. Male wild-type (WT) and Bco1-/- mice were raised on carotenoid-free AIN-93G diets before euthanasia between 10 and 14 wk of age. Weights of the prostate and seminal vesicles were significantly lower in Bco1-/- than in WT mice (-18% and -29%, respectively). Serum testosterone levels in Bco1-/- mice were significantly reduced by 73%. Bco1 disruption significantly reduced Leydig cell number and decreased testicular mRNA expression of Hsd17b3, suggesting inhibition of testicular testosterone synthesis. Immunofluorescent staining of the androgen receptor (AR) in the dorsolateral prostate lobes of Bco1-/- mice revealed a decrease in AR nuclear localization. Analysis of prostatic morphology suggested decreases in gland size and secretion. These findings were supported by reduced expression of the proliferation marker Ki-67 in Bco1-/- prostates. Expression analysis of 200 prostate cancer- and androgen-related genes suggested that Bco1 loss significantly disrupted prostatic androgen receptor signaling, cell cycle progression, and proliferation. This is the first demonstration that Bco1 disruption lowers murine circulating testosterone levels and thereby reduces prostatic androgen receptor signaling and prostatic cellular proliferation, further supporting the role of this protein in processes more diverse than carotenoid cleavage.


Tunable thermal conductivity of thin films of polycrystalline AlN by structural inhomogeneity and interfacial oxidation.
The effect of the structural inhomogeneity and oxygen defects on the thermal conductivity of polycrystalline aluminum nitride (AlN) thin films deposited on single-crystal silicon substrates is experimentally and theoretically investigated. The influence of the evolution of crystal structure, grain size, and out-of plane disorientation along the cross plane of the films on their thermal conductivity is analyzed. The impact of oxygen-related defects on thermal conduction is studied in AlN/AlN multilayered samples. Microstructure, texture, and grain size of the films were characterized by X-ray diffraction and scanning and transmission electron microscopy. The measured thermal conductivity obtained with the 3-omega technique for a single and multiple layers of AlN is in fairly good agreement with the theoretical predictions of our model, which is developed by considering a serial assembly of grain distributions. An effective thermal conductivity of 5.92 W m(-1) K(-1) is measured for a 1107.5 nm-thick multilayer structure, which represents a reduction of 20% of the thermal conductivity of an AlN monolayer with approximately the same thickness, due to oxygen impurities at the interface of AlN layers. Our results show that the reduction of the thermal conductivity as the film thickness is scaled down, is strongly determined by the structural inhomogeneities inside the sputtered films. The origin of this non-homogeneity and the effect on phonon scattering are also discussed.


The outcome competency framework for practitioners in infection prevention and control: use of the outcome logic model for evaluation.
Healthcare is delivered in a dynamic environment with frequent changes in populations, methods, equipment and settings. Infection prevention and control practitioners (IPCPs) must ensure that they are competent in addressing the challenges they face and are equipped to develop infection prevention and control (IPC) services in line with a changing world of healthcare provision. A multifaceted Framework was developed to assist IPCPs to enhance competence at an individual, team and organisational level to enable quality performance and improved quality of care. However, if these aspirations are to be met, it is vital that competency frameworks are fit for purpose or they risk being ignored. The aim of this unique study was to evaluate short and medium term outcomes as set out in the Outcome Logic Model to assist with the evaluation of the impact and success of the Framework. This study found that while the Framework is being used effectively in some areas, it is not being used as much or in the ways that were anticipated. The findings will enable future work on revision, communication and dissemination, and will provide intelligence to those initiating education and training in the utilisation of the competences.


[Modeling changes in the muscle fiber T-system during direct current flow].
Quantitative calculations of the dynamics of changes in K+, Na+, and Cl- concentrations in the T-system (TS) with changeable volume have been made using the computer "Dniepr-24". It was assumed that the current is transferred throught the TS membrane by K+ and in the lumen of the TS by K+, Na+ and Cl- ions in accordance with their mobilities and concentrations. The model predicts the accumulation of salt and water in the TS at the site of outgoing current. The swelling of TS due to DC effect according to the model was found to be about 9 and 18% for the current densities of 0.39 X 10(-8) a- cm-2 and 2.34 X 10(-8) a-cm-2, resp. The model shows that changes in the ion concentration and in the TS volume with current densities used experimentally reach a steady-state level. The increase of the current by almost 4 times, according to the model, suggests some disturbance in the steady-state and in the TS swelling comparable with experimental observations of vacuole formation.


Central mechanisms of real and sham electroacupuncture in the treatment of chronic low back pain: study protocol for a randomized, placebo-controlled clinical trial.
Chronic low back pain (CLBP) is the most common chronic pain condition and is often resistant to conventional treatments. Acupuncture is a popular alternative for treating CLBP but its mechanisms of action remain poorly understood. Evidence suggests that pain regulatory mechanisms (particularly the ascending and secondarily the descending pain modulatory pathways) and psychological mechanisms (e.g., expectations, pain catastrophizing and self-efficacy) may be involved in the pathogenesis of CLBP and its response to treatments. We will examine these mechanisms in the treatment of CLBP by electroacupuncture (EA). We present the aims and methods of a placebo-controlled, participant-blinded and assessor-blinded mechanistic study. Adult patients with CLBP will be randomized to receiving 16 sessions of real (active) or sham (placebo) EA over the course of 8 weeks. The primary pain regulatory measure for which the study was powered is temporal summation (TS), which approximates ascending pain facilitation. Conditioned pain modulation (CPM), representing a descending pain modulatory pathway, will be our secondary pain regulatory measure. The primary psychological measure is expectations of benefit, and the secondary psychological measures are pain catastrophizing and self-efficacy in managing pain. Main clinical outcomes are back pain bothersomeness on a 0-100 visual analog scale (primary), Roland Morris Disability Questionnaire (secondary), and relevant items from the National Institutes of Health (NIH) Patient-Reported Outcome Measures Information System (secondary). We hypothesize that compared to sham, real EA will lead to greater reduction in TS after 8 treatment sessions (4 weeks); and that reduction in TS (and secondarily, increase in CPM) after 8 treatment sessions will mediate reduction in back pain bothersomeness from baseline to week 10 (clinical response) to EA. We also hypothesize that the three psychological factors are moderators of clinical response. With 100 treatment completers, the study is designed to have 80% power to detect a medium-sized between-group effect (d = 0.5) on temporal summation. To the best of our knowledge, this is the first appropriately powered, placebo-controlled clinical trial evaluating mechanisms of EA in the treatment of CLBP. ClinicalTrials.gov, NCT02503475 . Registered on 15 July 15 2015. Retrospectively registered.