Human autoreactive CD4+ T cells from naive CD45RA+ and memory CD45RO+ subsets differ with respect to epitope specificity and functional antigen avidity.
T cells with specificity for self-Ags are normally present in the peripheral blood, and, upon activation, may target tissue Ags and become involved in the pathogenesis of autoimmune processes. In multiple sclerosis, a demyelinating disease of the CNS, it is postulated that inflammatory damage is initiated by CD4+ T cells reactive to myelin Ags. To investigate the potential naive vs memory origin of circulating myelin-reactive cells, we have generated myelin basic protein (MBP)- and tetanus toxoid-specific T cell clones from CD45RA+/RO- and CD45RO+/RA- CD4+ T cell subsets from the peripheral blood of multiple sclerosis patients and controls. Our results show that 1) the response to MBP, different from that to TT, predominantly emerges from the CD45RA+ subset; 2) the reactivity to immunodominant MBP epitopes mostly resides in the CD45RA+ subset; 3) in each individual, the recognition of single MBP epitopes is skewed to either subset, with no overlap in the Ag fine specificity; and 4) in spite of a lower expression of costimulatory and adhesion molecules, CD45RA+ subset-derived clones recognize epitopes with higher functional Ag avidity. These findings point to a central role of the naive CD45RA+ T cell subset as the source for immunodominant, potentially pathogenic effector CD4+ T cell responses in humans.


COX-2 inhibitory NSAID-induced multiple stenosis in the small intestine diagnosed by double-balloon endoscopy.
The patient was a 72 year old man who had been given non-steroidal anti-inflammatory drug (NSAID) for two years. He repeatedly developed small intestinal ileus; therefore, he underwent several imaging examinations, but the cause was not identified. He subsequently underwent a double-balloon endoscopy (DBE). The membranous stenoses were detected in the jejunum, and the biopsy specimens were taken during the DBE. The membranous stenoses in the gastrointestinal tract were characteristic of NSAID-induced enteropathy, and he was endoscopically and histopathologically diagnosed with NSAID-induced small intestinal disorder. NSAID administration was withdrawn, and the balloon dilation was conducted for small intestinal stenosis. After that, no small intestinal ileus developed again. Some studies were conducted on the mechanism of NSAID-induced small intestinal dysfunction, but the drug that was administered to the patient was a highly selective NSAID for cyclooxygenase (COX)-2, and there are few studies that reported a dysfunctional mechanism induced by this drug. In the tissue sampled by DBE, apoptotic bodies were found; therefore, it was suggested that the stenoses in this case were caused by the COX-2 inhibitor from the relationship between COX-2 inhibition and apoptosis. Further studies are necessary to investigate the mechanism of NSAID enteropathy.


Biocompatibility of nitinol stapes prosthesis.
Use of the SMart piston, a nitinol-based, self-crimping prosthesis in stapes surgery may allow improved functional results because of better sound transmission properties at the incus-prosthesis interface because of the elimination of manual crimping. Possible disadvantages include thermal damage or strangulation of the incus and its mucoperiosteum or nickel intolerance. The goal of this study was to morphologically assess the fixation of this prosthesis to the incus, investigate the reaction of the middle ear mucosa to the prosthesis, identify alterations to the incudal bone, and detect deposits of nickel in the tissue around the prosthesis. Prospective consecutive case analysis. Tertiary referral center. Four patients with an unfavorable functional result after primary SMart-piston stapedotomy. Revision malleostapedotomy with explantation of the incus and prosthesis for further analysis. Analysis of intraoperative findings and postoperative examination of the explants using light- and scanning-electron microscopy, energy dispersive x-ray analysis, and atom absorption spectrometry. The intraoperative, macroscopic, and scanning electron microscopic investigation showed tight circular fixation of the prostheses, whereas a gap between the prosthesis and the lateral incus was found in 1 case. All prostheses were overgrown by mucosa. Superficial localized erosion of the incudal bone was found in 2 cases. There was no elevation in nickel content in the removed tissue samples. The lateral gap between prosthesis and incus did not affect fixation of the prosthesis, neither did covering by a mucosal layer. Bone erosion was most likely caused by laser in one and by the prosthesis in another explant. No signs of increased nickel deposits could be found on energy dispersive x-ray analysis or atom absorption spectrometry. We conclude that a nitinol stapes prosthesis is safe for treatment of stapedial fixation.


[Upper gastrointestinal tract lesions in patients with nonspecific ulcerative colitis].
Endoscopic and morphological examinations of the upper gastrointestinal tract (GIT) were made in 80 patients with nonspecific ulcerative colitis (NUC). Tests for Helicobacter pylori infection and gastric juice acidity were also conducted. It was found that in many patients NUC was associated with development of nonspecific esophagitis, gastritis and duodenitis. The endoscopic examination revealed erosions of the abdominal esophagus in 13.8% cases, erosive-ulcerative alterations in the stomach and duodenum in 27.5% of NUC patients. The most marked changes occurred in patients with severe NUC. Alterations in the upper GIT were not related with either Hp or the acidity. Morphological examinations of the biopsies from the esophagus, stomach and duodenum demonstrated changes similar to those in biopsy material from the colon. The same type of morphological changes in mucosa from the upper GIT and the colon in NUC indicates that their pathogenesis is also the same.


Ouabain binding, Na+-K+-ATPase activity, and 86Rb uptake of canine arteries.
In a previous report [Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H598-H603, 1983] we measured potassium-induced relaxation of canine femoral and renal arteries as an index of sodium pump function and concluded that it may not be an accurate measure. In this report, the sodium pumps of femoral and renal arteries were examined using three separate approaches to compare sodium pump function more directly. The number of pump sites in subcellular fractions was measured using [3H]ouabain binding. No differences were observed (femoral artery 14.5 +/- 4.8 pmol/g wet wt; renal artery 17.4 +/- 6.5). Similarly, there was no difference in ouabain-inhibitable Na+-K+-ATPase activity in NaI-treated microsomal fractions of these arteries (femoral artery 3.10 +/- 0.65 mumol Pi X mg-1 X h-1; renal artery 3.42 +/- 0.23). Finally, sodium pump function was measured using the ouabain-inhibitable 86Rb uptake method. The rate of ouabain-inhibitable 86Rb uptake was found to be identical for the two arteries, as were the dissociation constants of the two arteries for rubidium. However, in the presence of 3.5 microM norepinephrine, the rate of 86Rb uptake in the renal artery was greater than that of the femoral artery. We conclude that, under resting conditions, the sodium pumps of femoral and renal arteries are identical, whereas in the presence of norepinephrine, the renal artery sodium pump is not rate limiting with respect to contractility. These data have significant implications with regard to the use of potassium-induced relaxation as an index of sodium pump activity.


Resource variability, aggregation and direct density dependence in an open context: the local regulation of an African elephant population.
1. An emerging perspective in the study of density dependence is the importance of the spatial and temporal heterogeneity of resources. Although this is well understood in temperate ungulates, few studies have been conducted in tropical environments where both food and water are limiting resources. 2. We studied the regulation of one of the world's largest elephant populations in Hwange National Park, Zimbabwe. The study period started in 1986 when the population was released from culling. Using census data we investigated changes in elephant abundance with respect to rainfall and density across the entire park and across waterholes. 3. The population more than doubled since culling stopped. The population increased continuously during the first 6 years, and then fluctuated widely at about 30,000 individuals. Immigration processes must have been involved in the increase of the population size. 4. Population growth rates were negatively related to previous population density by a convex relationship, and negatively related to the ratio of previous population density on annual rainfall by a linear relationship. However, only this latter model (i.e. assuming a fluctuating carrying capacity related to annual rainfall) produced realistic dynamics. Overall, population decreased during dry years when the elephant density was high. 5. During dry years there were fewer waterholes retaining water during the dry season and consequently elephant numbers at waterholes increased, while their aggregation level across waterholes decreased. On the long-run elephant numbers increased only at the less crowded waterholes. 6. We suggest that the interaction between population size and the available foraging range determined by the number of active waterholes during the dry season controls the park population. 7. Our results emphasize the need to understand how key-resource areas cause resource-based aggregation, which ultimately influences the strength of density dependence. More specifically, this study suggests that climate variability strongly affects local elephant population dynamics through changes in surface-water availability. Finally, as dispersal is likely to be an important driver of the dynamics of this population, our results support views that a metapopulation framework should be endorsed for elephant management in open contexts.


Second-to-Fourth Digit Ratio (2D:4D) in Psychiatric Disorders: A Systematic Review of Case-control Studies.
The second-to-fourth digit ratio (2D:4D) is an indirect, retrospective, non-invasive measure that correlates negatively with intrauterine exposure to testosterone. The present meta-analysis aimed to evaluate if 2D:4D differs between patients with psychiatric disorders and controls. In September 2019, we searched in Web of Knowledge, PsycINFO, Embase, and CINHAL, and retrieved 619 papers. We finally included 43 case-control studies which compared the 2D:4D ratio of patients with autism spectrum disorder (ASD) (n = 16), schizophrenia (n = 8), gender non-conformity (n = 7), addictions (n = 5), attention deficit-hyperactivity disorder (ADHD) (n = 4), mood disorders (n = 2), and intellectual disability (n = 1) to non-clinical controls. Meta-analyses showed that, overall, psychiatric patients had lower 2D:4D than healthy controls (n = 43, overall sample = 9,484, mean difference = -0.0056, 95% confidence interval from -0.0093 to -0.002, I2 = 74%), with more pronounced differences in the right hand, males, and children. Considering psychiatric disorders individually, significant differences were found in the ASD, ADHD, and addictions groups, in which 2D:4D was significantly lower than healthy controls. Conversely, the right hand of males with schizophrenia showed higher 2D:4D than healthy controls. No other significant differences were detected. Although our results need to be cautiously interpreted and find limited applications in clinical practice, they may suggest that 2D:4D is altered in some psychopathological conditions, underlining the role of prenatal exposure to sex steroids in the etiology of psychiatric disorders.


Quantitative synthesis of protein-DNA conjugates with 1 : 1 stoichiometry.
We describe here a binding-facilitated reaction strategy, enabling quantitative conjugation of DNA to native proteins with a desirable 1 : 1 stoichiometry. The technique takes advantage of the iterative affinity interaction and covalent binding processes to achieve complete conjugation. The complete conjugation obviates the need for separation of the protein-DNA conjugates as required by other DNA-protein conjugation methods.


[Neopterin variations during the menstrual cycle].
During a complete estrous cycle Neopterin levels were followed up daily in sera of six healthy female volunteers below 30 years of age. Average values found in these individuals were within the normal range. Only two single data--measured on the 29th and the 30th day of one test person's estrous cycle--out of 145 were elevated (between 10 and 15 nmol/l). Therefore elevated Neopterin values of clinically healthy persons should only be taken as an indicator for pathological activation of the cellular immune system if the elevation continues after repeated confirmation in a possibly different estrous phase.


Clinical and patient-reported outcome of implant restorations with internal conical connection in daily dental practices: prospective observational multicenter trial with up to 7-year follow-up.
The interpretation of the results of randomized clinical trials is often questioned in relation with daily circumstances in practices. This prospective observational multicenter study was instigated to reflect the need for information in real-life situations with dental implants with internal conical implant-abutment connection (Conelog implant system). The implants were followed up at least 5-year post-loading; survival analysis (Kaplan-Meier), changes of soft tissue, and bone level over time, as well as patient satisfaction were evaluated. In total, 130 dental implants were placed in 94 patients (64 female, 30 male). Mean age of patients was 50.4 ± 13.7. At 5-year post-loading, 104 implants in 76 patients were available for evaluation. The cumulative implant survival rate was 96.6%. After an initial bone remodeling process post-surgery (bone loss of - 0.52 ± 0.55 mm), the bone level change remained clinically stable from loading to 5-year post-loading (- 0.09 ± 0.43 mm). Patient satisfaction surveyed by questionnaire (comfort, ability to chew and taste, esthetics, general satisfaction) steadily increased towards the end. At the last study follow-up, all the patients rated their general satisfaction as either very satisfied (87.5%) or satisfied (12.5%). The study implants have shown to be highly effective with reliable peri-implant tissue stability over the 5 to 7 years of observation for both single tooth restorations and fixed partial dentures while used in standard conditions in daily dental practice. The results obtained are comparable with those obtained in controlled clinical trials.


Novel insights into the origin and diversification of photosynthesis based on analyses of conserved indels in the core reaction center proteins.
The evolution and diversification of different types of photosynthetic reaction centers (RCs) remains an important unresolved problem. We report here novel sequence features of the core proteins from Type I RCs (RC-I) and Type II RCs (RC-II) whose analyses provide important insights into the evolution of the RCs. The sequence alignments of the RC-I core proteins contain two conserved inserts or deletions (indels), a 3 amino acid (aa) indel that is uniquely found in all RC-I homologs from Cyanobacteria (both PsaA and PsaB) and a 1 aa indel that is specifically shared by the Chlorobi and Acidobacteria homologs. Ancestral sequence reconstruction provides evidence that the RC-I core protein from Heliobacteriaceae (PshA), lacking these indels, is most closely related to the ancestral RC-I protein. Thus, the identified 3 aa and 1 aa indels in the RC-I protein sequences must have been deletions, which occurred, respectively, in an ancestor of the modern Cyanobacteria containing a homodimeric form of RC-I and in a common ancestor of the RC-I core protein from Chlorobi and Acidobacteria. We also report a conserved 1 aa indel in the RC-II protein sequences that is commonly shared by all homologs from Cyanobacteria but not found in the homologs from Chloroflexi, Proteobacteria and Gemmatimonadetes. Ancestral sequence reconstruction provides evidence that the RC-II subunits lacking this indel are more similar to the ancestral RC-II protein. The results of flexible structural alignments of the indel-containing region of the RC-II protein with the homologous region in the RC-I core protein, which shares structural similarity with the RC-II homologs, support the view that the 1 aa indel present in the RC-II homologs from Cyanobacteria is a deletion, which was not present in the ancestral form of the RC-II protein. Our analyses of the conserved indels found in the RC-I and RC-II proteins, thus, support the view that the earliest photosynthetic lineages with living descendants likely contained only a single RC (RC-I or RC-II), and the presence of both RC-I and RC-II in a linked state, as found in the modern Cyanobacteria, is a derivation from these earlier phototrophs.


Analysis of human papillomavirus types in exophytic condylomata acuminata by hybrid capture and Southern blot techniques.
Exophytic condylomata acuminata of the external genitalia of 40 patients were analyzed for human papillomavirus (HPV) DNA by the Southern blot and hybrid capture methods. All lesions were initially analyzed by the Southern blot method by using a mixture of HPV type 6, 11, 16, and 18 whole genomic probes. Southern blots demonstrated characteristic PstI restriction patterns of HPV type 6, 11, or 16 in all but one lesion. HPV 6 subtypes accounted for 28 of 39 HPV-positive lesions. Twenty-seven of these 28 lesions contained HPV type 6a, and 1 lesion contained HPV type 6c. Eight lesions contained HPV type 11 and three contained HPV type 16. Two of the three condylomata acuminata containing HPV type 16 were obtained from solid-organ transplant recipients receiving immunosuppressive medications. The third lesion containing HPV type 16 was a typical exophytic condyloma acuminatum from a woman with previously resected vulvar carcinoma. The hybrid capture assay detected HPV DNAs in all lesions except the Southern blot-negative lesion. Twenty-five lesions were positive for the A probe only (HPV types 6 and 11 and related types). All of these lesions were found to contain HPV type 6 or 11 sequences in the Southern blot assay. The remaining 14 lesions were positive for both the A probe and the B probe (HPV types 16 and 18 and related types). The strongest signal in these 14 lesions by the hybrid capture assay was consistent with the result of the Southern blot assay in all but one case. We conclude that (i) HPV type 6a is the most common type found in these lesions, (ii) HPV type 16 may be present more often in exophytic condylomata acuminata from immunosuppressed individuals, (iii) hybrid capture is a useful tool for documenting the presence of HPV sequences in DNAs from exophytic condylomata acuminata, and (iv) in samples containing multiple HPV types, hybrid capture allows detection of minority HPV types.


Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce.
DYT1 early-onset generalized torsion dystonia is an inherited movement disorder caused by mutations in DYT1 coding for torsinA with ∼30% penetrance. Most of the DYT1 dystonia patients exhibit symptoms during childhood and adolescence. On the other hand, DYT1 mutation carriers without symptoms during these periods mostly do not exhibit symptoms later in their life. Little is known about what controls the timing of the onset, a critical issue for DYT1 mutation carriers. DYT11 myoclonus-dystonia is caused by mutations in SGCE coding for ε-sarcoglycan. Two dystonia patients from a single family with double mutations in DYT1 and SGCE exhibited more severe symptoms. A recent study suggested that torsinA contributes to the quality control of ε-sarcoglycan. Here, we derived mice carrying mutations in both Dyt1 and Sgce and found that these double mutant mice showed earlier onset of motor deficits in beam-walking test. A novel monoclonal antibody against mouse ε-sarcoglycan was developed by using Sgce knock-out mice to avoid the immune tolerance. Western blot analysis suggested that functional deficits of torsinA and ε-sarcoglycan may independently cause motor deficits. Examining additional mutations in other dystonia genes may be beneficial to predict the onset in DYT1 mutation carriers.


Special issue on the teenage brain: Sensitivity to social evaluation.
Relative to childhood, peer relationships take on a heightened importance during adolescence. Might adolescents be highly attuned to information that concerns when and how they are being evaluated, and what their peers think of them? This review evaluates how continuing brain development - which influences brain function - partially explains or reflects adolescents' attunement to social evaluation. Though preliminary, evidence is mounting to suggest that while processing information relevant to social evaluation and the internal states of other people, adolescents respond with greater emotional intensity and corresponding nonlinear recruitment of socioaffective brain circuitry. This review highlights research findings that relate trajectories of brain development and social behavior, and discusses promising avenues of future research that will inform how brain development might lead adolescents sensitized to social evaluation.


High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations.
This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.


Short-term efficacy of nasal immunotherapy.
The purpose of this study was to evaluate the efficacy of nasal immunotherapy in the management of allergic rhinitis. Sixteen patients (10 Female; 6 Male) aged 15-60 years (mean age--31.9) were selected on the bases of clinical history, skin prick tests and RAST positivity. Allergen extract is a "macronized" powder form (Allerkin), it was supplied by Laboratorio Farmaceutico Lofarma (Milano Italy) and administered for 12 months to 8 patients with perennial rhinitis (Dermatophagoides extract) and for 6 months to 8 patients with seasonal rhinitis (grass or Parietaria pollens extract). This treatment was carried out by self administration in two phases: the first one (3 months) consisted of administration of increasing doses; the second phase (maintenance period) was carried out 3 months in seasonal rhinitis and 9 months in perennial rhinitis. All the patients were evaluated before and after immunotherapy and scores from 0 to 3 were attributed according to the symptoms presented and need of drugs for symptomatic relief. Scores before and after immunotherapy were compared using the Wilcoxon Matched-Pairs Signed-Ranks Test and a significant decrease was observed for every symptom in seasonal and perennial rhinitis (p < 0.05). In conclusion, this trial shows that nasal immunotherapy in powder form can be a valuable short-term option in patients with allergic rhinitis.


Exploring the complexity of compliance in schizophrenia.
A large body of literature indicates that people diagnosed with schizophrenia are highly likely to not comply with their prescribed treatment regime at some stage during the illness process. Factors that indicate the risk of noncompliance have been the subject of considerable research over a number of years. This paper presents an extensive review of the research literature on the subject of compliance in schizophrenia. A number of factors have constituted the focus of research into this area. These include: socio-demographic characteristics, including age, gender and socioeconomic status; illness factors including insight, psychiatric symptomatology, duration of illness, substance abuse, and adverse side-effects of medication; psychosocial factors such as health beliefs and social supports; and treatment factors including the nature of the therapeutic relationship between patients and health care professionals. While the results of relevant research do not provide a clear and conclusive picture of compliance, they provide important information to guide the pivotal role of the mental health nurse in facilitating patient compliance.


Scoring Depression on a Common Metric: A Comparison of EAP Estimation, Plausible Value Imputation, and Full Bayesian IRT Modeling.
There are a growing number of item response theory (IRT) studies that calibrate different patient-reported outcome (PRO) measures, such as anxiety, depression, physical function, and pain, on common, instrument-independent metrics. In the case of depression, it has been reported that there are considerable mean score differences when scoring on a common metric from different, previously linked instruments. Ideally, those estimates should be the same. We investigated to what extent those differences are influenced by different scoring methods that take into account several levels of uncertainty, such as measurement error (through plausible value imputation) and item parameter uncertainty (through full Bayesian IRT modeling). Depression estimates from different instruments were more similar, and their corresponding confidence/credible intervals were larger when plausible value imputation or Bayesian modeling was used, compared to the direct use of expected a posteriori (EAP) estimates. Furthermore, we explored the use of Bayesian IRT models to update item parameters based on newly collected data.


Growth stimulatory effect and metabolism of testosterone in MCF-7 human breast cancer cells.
The purpose of our study was to evaluate the effect of testosterone and its metabolic pathway in MCF-7 cells in culture. Testosterone exhibited a dose-dependent (from 0.1 to 10 nM) and time-dependent (from 3 to 9 days) growth stimulation. The metabolic pathway was investigated following treatment with two testosterone concentrations: one stimulating (10 nM) and one not affecting (0.1 nM) cell growth. Celite column chromatography was used to separate H-3-testosterone metabolites, whose identity was confirmed by gas chromatography-mass spectrometry analysis. The main findings of the metabolic study were: i) recovery of a large amount of untransformed testosterone; ii) a high conversion of testosterone to conjugated, biologically inactive metabolites; iii) the highest level of Sa-diol among the metabolites of testosterone; iv) a conversion (2%) of testosterone into oestradiol, which resulted in a growth stimulatory concentration when testosterone was used at 10 nM. We conclude that in our experimental conditions androgens and oestrogens can concur to stimulate MCF-7 cell growth through androgen receptor-mediated and oestrogen receptor-mediated mechanisms.


The role of factor V Leiden in maternal health and the outcome of pregnancy.
There is growing evidence that women with thrombophilia are at increased risk of pregnancy related venous thromboembolism and of adverse pregnancy outcome including pregnancy loss, pre-eclampsia, intrauterine growth retardation and placental abruption. The factor V Leiden mutation is a heritable thrombophilia present in 5-8% of Caucasian populations. In its heterozygous form it is associated with a 4-to 8-fold increase in thrombotic risk. Homozygous inheritance, however, confers around an 80-fold increase in relative risk of thrombosis. The relationship between factor V Leiden and adverse pregnancy outcome has been studied in the recent literature, however the size of the estimated risks varies between individual studies due to heterogeneity of study design and small sample size in many cases. The management of women with factor V Leiden in pregnancy with low molecular weight heparin has been shown to be both safe and effective in preventing venous thromboembolism and improving pregnancy loss. Large scale, randomised controlled studies are required to confirm these findings. Selective screening for factor V Leiden based on prior venous thromboembolism has been shown to be marginally more cost-effective than universal screening in pregnancy and a recent consensus statement has recommended screening for thrombophilia based on a strong personal or family history of venous thromboembolism. There is now some evidence that placental problems may be associated with factor V Leiden in the fetus. There has also been an observed association between maternal factor V Leiden and fetal or neonatal stroke. These areas require further study and at present there is no evidence-based approach to investigation, prevention or management.


Mepacrine accumulation during treatment of chloroquine-resistant falciparum malaria.
Oral mepacrine dihydrochloride, 200 mg (158 mg of the base) six-hourly for five doses followed by 100 mg (79 mg of the base) eight-hourly for six days (half dosage for those less than or equal to 50 kg) was given to 21 patients with high-grade chloroquine-resistant falciparum malaria in eastern Thailand. Fifteen patients (71%) had a clinical response [fever clearance time of 81 +/- 35 hours (mean +/- S.D.)] and 13 (62%) had complete clearance of parasitaemia (clearance time 92 +/- 42 hours). Two patients were cured, but 11 patients returned with recurrent parasitaemia between 11 and 40 days after starting treatment. Five patients had an R2 response and three had an R3 response. Mepacrine retains some activity against chloroquine-resistant falciparum malaria but it cannot be recommended for use in Thailand. The doses used, which are those also recommended for giardiasis, led to progressive and potentially toxic mepacrine accumulation. Further evaluation of regimens which produce safer plasma concentration profiles is needed.


Regulation of monocyte subset proinflammatory responses within the lung microvasculature by the p38 MAPK/MK2 pathway.
Margination and activation of monocytes within the pulmonary microcirculation contribute substantially to the development of acute lung injury in mice. The enhanced LPS-induced TNF expression exhibited by Gr-1(high) compared with Gr-1(low) monocytes within the lung microvasculature suggests differential roles for these subsets. We investigated the mechanisms responsible for such heterogeneity of lung-marginated monocyte proinflammatory response using a combined in vitro and in vivo approach. The monocyte subset inflammatory response was studied in vitro in mouse peripheral blood mononuclear cell-lung endothelial cell coculture and in vivo in a two-hit model of intravenous LPS-induced monocyte margination and lung inflammation in mice, by flow cytometry-based quantification of proinflammatory genes and intracellular phospho-kinases. With LPS stimulation in vitro, TNF expression was consistently higher in Gr-1(high) than Gr-1(low) monocytes, markedly enhanced by coculture with endothelial cells, and abrogated by p38 MAPK inhibitors. Expression of IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) was only detectable under coculture conditions, was substantially higher in Gr-1(high) monocytes, and was attenuated by p38 inhibition. Consistent with these differential responses, phosphorylation of p38 and its substrate MAPK-activated protein kinase 2 (MK2) was significantly higher in the Gr-1(high) subset. In vivo, p38 inhibitor treatment significantly attenuated LPS-induced TNF expression in "lung-marginated" Gr-1(high) monocytes. LPS-induced p38/MK2 phosphorylation was higher in lung-marginated Gr-1(high) than Gr-1(low) monocytes and neutrophils, mirroring TNF expression. These results indicate that the p38/MK2 pathway is a critical determinant of elevated Gr-1(high) subset responsiveness within the lung microvasculature, producing a coordinated proinflammatory response that places Gr-1(high) monocytes as key orchestrators of pulmonary microvascular inflammation and injury.


The molecular mechanisms and gene expression profiling for shikonin-induced apoptotic and necroptotic cell death in U937 cells.
Shikonin (SHK), a natural naphthoquinone derived from the Chinese medical herb Lithospermum erythrorhizon, induces both apoptosis and necroptosis in several cancer cell lines. However, the detailed molecular mechanisms involved in the initiation of cell death are still unclear. In the present study, caspase-dependent apoptosis was induced by SHK treatment at 1μM after 6h in U937 cells, with increase in DNA fragmentation, generation of intracellular reactive oxygen species (ROS), fraction of cells with low mitochondrial membrane potential (MMP), and in the expression of BH3 only proteins Noxa and tBid. Interestingly, caspase-independent cell death was also detected with SHK treatment at 10μM, observed as increase in SYTOX® Green staining and release of lactate dehydrogenase (LDH). Necrostatin-1 (Nec-1) completely inhibited the SHK-induced leakage of LDH and SYTOX® Green staining. Cell permeable exogenous glutathione (GSH) completely inhibited 1μM SHK-induced apoptosis and converted 10μM SHK-induced necroptosis to apoptosis. Gene expression profiling revealed that 353 genes were found to be significantly regulated by 1μM and 85 genes by 10μM of SHK treatment, respectively. Among these genes, the transcription factor 3 (ATF3) and DNA-damage-inducible transcript 3 (DDIT3) were highly expressed at 1μM of SHK treatment, while tumor necrosis factor (TNF) expression mainly increased at 10μM treatment. These findings provide novel information for the molecular mechanism of SHK-induced apoptosis and necroptosis.


HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection.
Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.


Do work and family care histories predict health in older women?
Social and policy changes in the last several decades have increased women's options for combining paid work with family care. We explored whether specific combinations of work and family care over the lifecourse are associated with variations in women's later life health. We used sequence analysis to group women in the English Longitudinal Study of Ageing according to their work histories and fertility. Using logistic regression, we tested for group differences in later life disability, depressive symptomology and mortality, while controlling for childhood health and socioeconomic position and a range of adult socio-economic circumstances and health behaviours. Women who transitioned from family care to either part-time work after a short break from the labour force, or to full-time work, reported lower odds of having a disability compared with the reference group of women with children who were mostly employed full-time throughout. Women who shifted from family care to part-time work after a long career break had lower odds of mortality than the reference group. Depressive symptoms were not associated with women's work and family care histories. Women's work histories are predictive of their later life disability and mortality. This relationship may be useful in targeting interventions aimed at improving later life health. Further research is necessary to explore the mechanisms linking certain work histories to poorer later life health and to design interventions for those affected.


Echinococcosis in immunocompromised patients: A systematic review.
Human echinococcoses are the infection caused by the larval stages of different species of the genus Echinococcus, mostly E. granulosus and E. multilocularis. There is no aggregated information on the nature and characteristics echinococcosis in patients with immunodeficiency. This study presents a systematic review of the current literature published on the status of echinococcosis in immunocompromised individuals. An electronic search of related articles in four major databases (PubMed, Scopus, Web of Science and Google Scholar) was performed up to November 2021. All related studies meeting the inclusion criteria were assessed for qualitative analysis. Data available on different characteristics of the diseases were extracted. The data were subsequently categorized into two subgroups: Cystic Echinococcosis (CE) and Alveolar Echinococcosis (AE). Twenty-eight articles related to the existence of echinococcosis in immunocompromised hosts were included. HIV/AIDS was found as the most frequent condition in immunocompromised CE patients. Most of the CE cases with immunodeficiency were female (66.4%). The dominant stages of the cysts were CE2 and CE3. Surgery was performed for 76.2% of the patients. A high mortality rate of 23.8% was recorded in CE patients. Malignancies was the dominant condition in AE patients. Findings of the present study can potentially improve our understanding of the impact of immunodeficiency syndromes on echinococcoses and contribute to an improved diagnosis, treatment and quality of care in immunocompromised patients suffering from cystic and alveolar echinococcosis.


Mutations in the NH2-terminal domain of the signal peptide of preproparathyroid hormone inhibit translocation without affecting interaction with signal recognition particle.
The amino-terminal domain of a eukaryotic signal peptide, from bovine parathyroid hormone, was altered by in vitro mutagenesis of the cDNA. The function of "internalized" signal sequence mutants and of deletion mutants was assayed using an in vitro translation-translocation system. The addition of 11 amino acids to the NH2 terminus of the signal peptide did not prevent normal processing of the precursor protein, whereas a 23-amino acid extension blocked processing. These data suggest that the NH2-terminal sequences of internal signal peptides must be permissive of the signal function. Deletion of 6 NH2-terminal amino acids from the signal peptide had no effect on its cleavage by microsomal membranes, but removal of 10 or 13 amino acids, including all charged residues prior to the hydrophobic core, prevented processing. For both the extension and deletion mutations, processed proteins were protected from proteolytic digestion, whereas unprocessed forms were not, which indicated that the unprocessed mutant proteins were not translocated across the microsomal membrane. Translation of both the extension and deletion translocation-deficient mutants was arrested by signal recognition particle, and salt-washed microsomal membranes reversed the translational arrest. These data demonstrate that the NH2-terminal domain is not required for the interaction of signal recognition particle with the signal peptide or with signal recognition particle receptor, but is required for formation of a maximally translocation-competent complex with the microsomal membrane.


Effectiveness of speech intervention for phonological disorders: a randomized controlled trial.
Thirty children of preschool age with severe phonological disorders were randomly assigned to two treatment groups. Group 1 received treatment for 4 months followed by 4 months without treatment while group 2 underwent 4 months without treatment followed by 4 months of treatment. The outcome measures used were the Assessment of Phonological Processes-Revised (APP-R), the Goldman-Fristoe Test of Articulation (GFTA), the Percentage Consonants Correct (PCC), and Mean Length of Utterance (MLU). Group 1 showed significant differences on scores of phonological measures (APP-R, GFTA, and PCC) after the first 4 months of the study. At the 8-month assessment point the measures for conversational speech intelligibility continued to be significantly different, with group 1 scores higher than those of group 2. The expressive language measure did not detect a difference between groups at any time; however group 1 scores were consistently higher than group 2 scores.


A cohort study of morbidity, mortality and health seeking behavior following rural health center visits by children under 12 in southwestern Uganda.
Children discharged from hospitals in developing countries are at high risk of morbidity and mortality. However, few data describe these outcomes among children seen and discharged from rural outpatient centers. The objective of this exploratory study was to identify predictors of immediate and follow-up morbidity and mortality among children visiting a rural health center in Uganda. Subjects 0-12 years of age seeking care with a caregiver were consecutively enrolled from a single rural health center in Southwestern Uganda. Baseline variables were collected by research nurses and outcomes of referral, admission or death were recorded (immediate events). Death, hospital admission and health seeking occurring during the 30 days following the clinic visit were also determined (follow-up events). Univariate logistic regression was performed to identify baseline variables associated with immediate outcome and follow-up outcomes. Over the four-month recruitment period 717 subjects were enrolled. There were 85 (11.9%) immediate events (10.1% were admitted, 2.2% were referred, none died). Forty-seven (7.8%) events occurred within 30 days after the visit (7.3% sought care from a health provider, 1.5% were admitted and 0.5% died). Variables associated with immediate events included living more than 30 minutes from the health center, age older than 5 years, having received an antimalarial prior to the visit, having seen a community health worker prior to the visit, elevated respiratory rate or temperature, and depressed weight-for-age z score or decreased oxygen saturation. These variables were not associated with follow-up events. Sick-child visits at a rural health center in South Western Uganda were associated with rates of mortality and subsequent admission of less than 2% in the period following the sick child visits. Other types of health seeking behavior occurred in approximately 7% of subjects during this same period. Several variables were associated with immediate events but there were no reliable predictors of follow-up events, possibly due to low statistical power.


Discrimination of globally unpolarized fields through Stokes vector element correlations.
In a previous publication [J. Opt. Soc. Am. A 21, 988 (2004)], we examined theoretically joint probability distributions of Stokes vector elements and suggested the existence of various types of globally unpolarized light that could be discriminated through measurement of the Stokes vector element correlations. We now study the joint distribution of the degree of polarization and the three Stokes parameters as it relates to material properties in highly scattering, depolarizing random media. We describe numerical and experimental results of second-order Stokes vector element correlations, demonstrating the existence of various types of nonclassical, globally unpolarized light, and we suggest experimental means for discriminating between such field distributions. We also discuss the usefulness of the Stokes vector element correlations as an experimental tool for discriminating between different globally unpolarized fields and for verifying the assumption of Gaussian statistics usually invoked in the context of multiple light scattering.


The CHROMEVALOA database: a resource for the evaluation of Okadaic Acid contamination in the marine environment based on the chromatin-associated transcriptome of the mussel Mytilus galloprovincialis.
Okadaic Acid (OA) constitutes the main active principle in Diarrhetic Shellfish Poisoning (DSP) toxins produced during Harmful Algal Blooms (HABs), representing a serious threat for human consumers of edible shellfish. Furthermore, OA conveys critical deleterious effects for marine organisms due to its genotoxic potential. Many efforts have been dedicated to OA biomonitoring during the last three decades. However, it is only now with the current availability of detailed molecular information on DNA organization and the mechanisms involved in the maintenance of genome integrity, that a new arena starts opening up for the study of OA contamination. In the present work we address the links between OA genotoxicity and chromatin by combining Next Generation Sequencing (NGS) technologies and bioinformatics. To this end, we introduce CHROMEVALOAdb, a public database containing the chromatin-associated transcriptome of the mussel Mytilus galloprovincialis (a sentinel model organism) in response to OA exposure. This resource constitutes a leap forward for the development of chromatin-based biomarkers, paving the road towards the generation of powerful and sensitive tests for the detection and evaluation of the genotoxic effects of OA in coastal areas.


Epstein-Barr virus-encoded LMP-1 protein upregulates the pNDCF group of nucleoskeleton-cytoskeleton-associated proteins.
In a recent study, we described a group of monoclonal antibodies that identify five high molecular mass proteins which associate with intermediate filaments in the cytoplasm and accumulate in nuclear foci as well. The proteins have been designated pNDCFs, proteins associated with nuclear dots and cytoplasmic filaments. Their expression in human B cells was upregulated by Epstein-Barr virus (EBV) infection or by exposure to anti-CD40 antibodies and IL4. Phenotypically representative (type I) Burkitt's lymphoma (BL) cell lines do not express pNDCFs or, if they do, the proteins accumulate preferentially in nuclear dots. Type III BL cell lines that have drifted to a more immunoblastic phenotype during in vitro passage and EBV-transformed lymphoblastoid cell lines (LCLs) of non-neoplastic origin express these proteins regularly at high levels. They are preferentially but not exclusively associated with vimentin filaments in the cytoplasm. Here we show that all five pNDCFs can be upregulated by expressing the EBV-encoded membrane protein LMP1 in type I BLs. Three of them could also be upregulated in the human keratinocyte cell line RHEK-1 by LMP1 transfection. This upregulation was paralleled by the LMP1-induced increase in vimentin expression in both cell types. One of the pNDCFs, detected by the MAb DM_4A6, accumulated in cap-like structures under the cell membrane that colocalized with membrane patches of LMP1, in addition to its localization in nuclear dots and in association with cytoplasmic vimentin filaments.


Immunoelectron microscopical localization of phospholamban in adult canine ventricular muscle.
The subcellular distribution of phospholamban in adult canine ventricular myocardial cells was determined by the indirect immunogold-labeling technique. The results presented suggest that phospholamban, like the Ca2+-ATPase, is uniformly distributed in the network sarcoplasmic reticulum but absent from the junctional portion of the junctional sarcoplasmic reticulum. Unlike the Ca2+-ATPase, but like cardiac calsequestrin, phospholamban also appears to be present in the corbular sarcoplasmic reticulum. Comparison of the relative distribution of phospholamban immunolabeling in the sarcoplasmic reticulum with that of the sarcolemma showed that the density of phospholamban in the network sarcoplasmic reticulum was approximately 35-fold higher than that of the cytoplasmic side of the sarcolemma, which in turn was found to be three- to fourfold higher than the density of the background labeling. However, a majority of the specific phospholamban labeling within 30 nm of the cytoplasmic side of the sarcolemma was clustered and present over the sarcoplasmic reticulum in the subsarcolemmal region of the myocardial cells, suggesting that phospholamban is confined to the junctional regions between the sarcolemma and the sarcoplasmic reticulum, but absent from the nonjunctional portion of the sarcolemma. Although the resolution of the immunogold-labeling technique used (60 nm) does not permit one to determine whether the specific labeling within 30 nm of the cytoplasmic side of the sarcolemma is associated with the sarcolemma and/or the junctional sarcoplasmic reticulum, it is likely that the low amount of labeling in this region represents phospholamban associated with sarcoplasmic reticulum. These results suggest that phospholamban is absent from the sarcolemma and confined to the sarcoplasmic reticulum in cardiac muscle.


Use of OMIC technologies to study arsenic exposure in human populations.
Exposure to arsenic (As) in drinking water is a major health concern. More than 100 million individuals are exposed to levels over the current World Health Organization standard of 10 µg/L worldwide. Arsenic is one of the few agents established as a human carcinogen prior to understanding its mechanism of carcinogenicity. OMIC technologies have enabled researchers to utilize agnostic approaches to explore new, unknown mechanisms through which As causes disease in exposed human populations. In this article, we present recent studies in which OMIC technologies have been used to explore differences in human biological samples to identify markers of exposure, disease susceptibility, and effect in As-exposed and/or diseased tissues.


Gastric cancer surgery for patients with liver cirrhosis.
To elucidate the influence of liver cirrhosis (LC) on the prognosis of patients with gastric cancer (GC). Of the 1347 GC patients who underwent curative gastrectomy for GC between January 1984 and June 2007, 25 patients (21 men and 4 women with a median age of 67 years; range 54-77 years) with LC were enrolled in this study. Using the Child-Pugh classification, 15 patients were evaluated as grade A and 10 patients as grade B. No grade C patient underwent gastrectomy in this series. Clinical outcomes, including postoperative morbidity and survival, were retrospectively analyzed based on medical records and surgical files. There was no significant difference in operative blood loss and perioperative blood transfusion between the two groups. The most common postoperative complication was intractable ascites, which was the single postoperative morbidity noted more frequently in grade B patients (40.0%) than in grade A patients (6.7%) with statistical significance (P = 0.041). Operative mortality due to hepatic failure was seen in one grade A patient. Three patients had hepatocellular carcinoma (HCC) at presentation and two patients developed HCC after surgery. Overall 5-year survival rate was 58.9% in patients with early GC and 33.3% in patients with advanced GC (P = 0.230). GC-specific 5-year survival rate of early GC patients was 90.0% while that of advanced GC patients was 58.3% (P = 0.010). Four patients with early GC died of uncontrolled HCC, of which two were synchronous and two metachronous. The risk of postoperative intractable ascites is high, particularly in grade B patients. Early detection and complete control of HCC is vital to improve a patient's prognosis.


Ready-to-use parenteral amiodarone: a feasibility study towards a long-term stable product formulation.
To determine the feasibility of preparing a long-term stable ready-to-use parenteral amiodarone formulation using cyclodextrins as dissolution enhancer. A preformulation study was performed with different molar ratios of hydroxypropyl-beta-cyclodextrin (HP-BCD) or sulfobutylether-beta-cyclodextrin (SBE-BCD) to amiodarone in order to investigate enhancement of amiodarone's water solubility. Further, effects of pH and temperature on the dissolution rate during production were investigated. Shelf-life was determined for a ready-to-use iso-osmotic preparation of 1.8 mg/mL amiodarone with SBE-BCD in a molar ratio of 1:3. Amiodarone content was assessed using a validated high-pressure liquid chromatography ultraviolet method. Amiodarone-SBE-BCD in a molar ratio of 1:3 at pH 4.0-5.0 yielded the best results in terms of increased solubility and dissolution time (90 min). With SBE-BCD, a smaller molar ratio to amiodarone was needed than with HP-BCD. The amiodarone content of the final formulation stored 12 months at 21°C in daylight remained unchanged. A ready-to-use or ready-to-administer amiodarone product, prepared in a hospital pharmacy, for intravenous application in an acute clinical setting is a feasible option from a chemical, physical and microbiological point of view. The availability of such a product will have a significant impact on medication safety, and production should therefore be considered.


Assessment of the U3O7 Crystal Structure by X-ray and Electron Diffraction.
Polycrystalline U3O7 powder was synthesized by oxidation of UO2 powder under controlled conditions using in situ thermal analysis, and by heat treatment in a tubular furnace. The O/U ratio of the U3O7 phase was measured as 2.34 ± 0.01. The crystal structure was assessed from X-ray diffraction (XRD) and selected-area electron diffraction (SAED) data. Similar to U4O9-ε (more precisely U64O143), U3O7 exhibits a long-range ordered structure, which is closely related to the fluorite-type arrangement of UO2. Cations remain arranged identical to that in the fluorite structure, and excess anions form distorted cuboctahedral oxygen clusters, which periodically replace the fluorite anion arrangement. The structure can be described in an expanded unit cell containing 15 fluorite-like subcells (U15O35), and spanned by basis vectors A = ap - 2bp, B = -2ap + bp, and C = 3cp (lattice parameters of the subcell are ap = bp = 538.00 ± 0.02 pm and cp = 554.90 ± 0.02 pm; cp/ap = 1.031). The arrangement of cuboctahedra in U3O7 results in a layered structure, which is different from the well-known U4O9-ε crystal structure.


Single-incision midurethral sling shows less pain and similar success rate in a short-term follow-up compared to the transobturator tape method in the treatment of stress urinary incontinence.
To compare the efficacy, complications, quality of life, and patient satisfaction rates in women treated for stress urinary incontinence (SUI) using the adjustable anchored single-incision midurethral sling (SIMS) and standard midurethral sling (MUS) procedures. A total of 113 women between October 2012 and October 2016 underwent either the adjustable SIMS (n=54) or MUS (n=57) procedure. The postoperative pain profile was assessed using a 10-point visual analog scale at the fixed time-point quality of life and an additional postoperative 3rd week appointment. We asked our patients the following two questions to evaluate their satisfaction with surgery and their preference: "Would you have this kind of surgery again?" (Q1), and "Would you recommend this type of surgery to another patient with same symptoms?" (Q2). For the evaluation of patient complaints, the Incontinence Impact Questionnaire (IIQ-7) and Urinary Distress Inventory (UDI-6) were used before and after the procedure. Women in the SIMS group had a significantly lower postoperative pain profile for up to 3 weeks (p<0.001). There was no significant difference in perioperative complications and postoperative continence rates between the groups. With regard to Q1 and Q2, a significant difference was found between the groups (p=0.003 and p=0.002, respectively). While the questionnaire scores of the IIQ-7 and UDI-6 were also significantly improved at postoperative evaluations (p<0.001), there was no significant difference between the two groups. SIMS is associated with a significantly improved postoperative pain profile and earlier return to work when compared to MUS.


Trajectory of Improvement in Children and Adolescents With Chronic Migraine: Results From the Cognitive-Behavioral Therapy and Amitriptyline Trial.
We compared headache frequency trajectories between clinical trial participants who received cognitive-behavioral therapy (CBT) and amitriptyline (CBT+A) or headache education (HE) and amitriptyline (HE+A) to determine if there was a differential time course of treatment response between the groups. One hundred thirty-five patients (age 10-17 years) diagnosed with chronic migraine participated, attending 8 one-hour one-on-one CBT or HE sessions with a trained psychologist for 8 weekly sessions, 2 sessions at weeks 12 and 16, and a post-treatment visit at week 20. Participants kept daily headache diaries and completed take-home assignments between visits. Data from daily headache diaries are presented for each day and according to 28-day periods. Trajectories of improvement indicate initial decrease in headache days began during the first month of treatment, for both groups, and continued to decrease throughout treatment. The CBT+A group had greater daily improvement than the HE+A group. A significantly greater proportion of the CBT+A group had a ≥50% reduction in headache days each month, and a significantly greater proportion of the CBT+A group had ≤4 headache days per month in months 3 through 5. Results indicate the trajectory of decrease in headache days is significantly better for patients receiving CBT+A versus HE+A. This article presents daily information about headache frequency over a 20-week clinical trial. Youth with chronic migraine who received CBT+A improved faster than those in the control group. Findings provide clinicians with evidence-based expectations for treatment response over time and ways of monitoring treatment success. clinicaltrials.gov identifier NCT00389038.


Urinary excretion of brush border antigens and other proteins in children with vesico-ureteric reflux.
This study was designed to evaluate the occurrence and the type of proteinuria in 82 children with vesico-ureteric reflux (VUR) with or without renal scars. The urinary excretion of the high molecular weight protein albumin was taken as an index of glomerular alterations and the excretion of retinol-binding protein (RBP), beta 2-microglobulin and brush border antigens (BBA) (measured by monoclonal antibody-based enzyme-linked immunosorbent assay) was taken as an index of tubular alterations. All such markers were increased in children with VUR and were related to the degree of renal function. Patients showing reduced creatinine clearance had very high levels of albuminuria, microproteinuria and BBA, with all these variables reciprocally correlated. In children with normal renal function however, only microproteins (not albumin or BBA) were slightly increased, thus indicating an isolated tubular defect without involvement of the proximal segment of the tubule. However, microprotein excretion did not correlate with the grade of scarring (99mtechnetium-dimercaptosuccinic acid scan), both RBP and beta 2-microglobulin excretion being normal in 75% of children with radioisotopic signs of renal lesions but increased in 17% of children without scars. Therefore, tubular proteinuria identifies different groups of children with VUR but is not related to renal scarring. Prospective studies will define the usefulness of proteinuria as a reliable indicator of renal outcome.


Leucine signaling in the pathogenesis of type 2 diabetes and obesity.
Epidemiological evidence points to increased dairy and meat consumption, staples of the Western diet, as major risk factors for the development of type 2 diabetes (T2D). This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). mTORC1, a pivotal nutrient-sensitive kinase, promotes growth and cell proliferation in response to glucose, energy, growth factors and amino acids. Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine, a primary and independent stimulator for mTORC1 activation. The downstream target of mTORC1, the kinase S6K1, induces insulin resistance by phosphorylation of insulin receptor substrate-1, thereby increasing the metabolic burden of β-cells. Moreover, leucine-mediated mTORC1-S6K1-signaling plays an important role in adipogenesis, thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased β-cell growth and β-cell proliferation promoting an early onset of replicative β-cell senescence with subsequent β-cell apoptosis. Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D, which are all associated with hyperactivation of mTORC1. In contrast, the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling. Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects. Furthermore, bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids. Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine-rich animal and dairy proteins may offer a great chance for the prevention of T2D and obesity, as well as other epidemic diseases of civilization with increased mTORC1 signaling, especially cancer and neurodegenerative diseases, which are frequently associated with T2D.


Controlling fluid adhesion force with electric fields.
Developing adhesives whose bond strength can be externally manipulated is a topic of considerable interest for practical and scientific purposes. In this work, we propose a method of controlling the adhesion force of a regular fluid, such as water and/or glycerol, confined between two parallel plates by applying an external electric field. Our results show the possibility of enhancing or diminishing the bond strength of the liquid sample by appropriately tuning the intensity and direction of the electric current generated by the applied electric field. Furthermore, we verify that, for a given direction of the electric current, the adhesion force can be reduced enough for the fluid to lose its adhesive properties and begin exerting a force to move apart the confining plates. In these circumstances, we obtain an analytical expression for the minimum electric current required to detach the plates without requiring the action of an external force.


Molecularly imprinted polymers for selective extraction of synephrine from Aurantii Fructus Immaturus.
In this work, molecularly imprinted solid-phase extraction (MISPE) has been used to selectively enrich, purify, or remove synephrine from Aurantii Fructus Immaturus. To this end, a molecularly imprinted polymer (MIP) was prepared by self-assembly from the template synephrine, the functional monomer methacrylic acid, and the crosslinker ethylene glycol dimethacrylate in 1:4:20 molar ratio. Subsequent molecular interrogation of the MIP binding sites revealed preferential structural selectivity for synephrine relative to other structurally related naturally occurring compounds (i.e. octopamine and tyramine ). This selectivity was subsequently exploited to achieve substantial sample clean-up of extracts of crude Aurantii Fructus Immaturus and Aurantii Fructus Immaturus stir-baked with bran. The purity of synephrine in the extracts after MISPE represented approximately 24.21-fold enrichment of the synephrine in the untreated extracts of Aurantii Fructus Immaturus stir-baked with bran. High recoveries (85-90%) from the samples proved that the method was valid for selective enrichment, purification, or removal of synephrine from Aurantii Fructus Immaturus.


Phospholipase Cdelta4 is required for Ca2+ mobilization essential for acrosome reaction in sperm.
Zona pellucida (ZP)-induced acrosome reaction in sperm is a required step for mammalian fertilization. However, the precise mechanism of the acrosome reaction remains unclear. We previously reported that PLCdelta4 is involved in the ZP-induced acrosome reaction in mouse sperm. Here we have monitored Ca2+ responses in single sperm, and we report that the [Ca2+]i increase in response to ZP, which is essential for driving the acrosome reaction in vivo, is absent in PLCdelta4-/- sperm. Progesterone, another physiological inducer of the acrosome reaction, failed to induce sustained [Ca2+]i increases in PLCdelta4-/- sperm, and consequently the acrosome reaction was partially inhibited. In addition, we observed oscillatory [Ca2+]i increases in wild-type sperm in response to these acrosome inducers. Calcium imaging studies revealed that the [Ca2+]i increases induced by exposure to ZP and progesterone started at different sites within the sperm head, indicating that these agonists induce the acrosome reaction via different Ca2+ mechanisms. Furthermore, store-operated channel (SOC) activity was severely impaired in PLCdelta4-/- sperm. These results indicate that PLCdelta4 is an important enzyme for intracellular [Ca2+]i mobilization in the ZP-induced acrosome reaction and for sustained [Ca2+]i increases through SOC induced by ZP and progesterone in sperm.


Prevalence of angle closure in siblings of patients with primary angle-closure glaucoma.
To determine the frequency of angle closure in siblings of patients with primary angle-closure glaucoma (PACG). In this cross-sectional observational study, siblings of consecutive patients with PACG underwent a comprehensive ophthalmologic examination, including slit-lamp biomicroscopy, measurement of intraocular pressure, stereoscopic optic nerve head examination, and dynamic gonioscopy. Ultrasonic pachymetry was obtained in all subjects; peripapillary retinal nerve fiber layer thickness measurement by optical coherence tomography and standard achromatic perimetry were performed in subjects with angle closure, categorized as primary angle-closure suspect (PACS), primary angle closure (PAC), and PACG, or any suspicion of glaucoma in the presence of open angles. Overall, 95 siblings from 47 families with at least 1 subject affected with PACG participated in the evaluations; 55 (57.9%) individuals were categorized within the spectrum of angle closure, including 34 (35.8%) subjects with PACS, 7 (7.4%)individuals with PAC, and 14 (14.7%) cases of PACG. Nine (9.5%) individuals with open angles demonstrated other abnormal features, these included 3 (3.2%) subjects with suspicious discs, 5 (5.3%) cases of primary open-angle glaucoma, and 1 patient (1.1%) with normal-tension glaucoma. The remaining 31 individuals (32.6%) had no evidence of glaucoma. Our findings indicate familial segregation of angle closure. Siblings of PACG patients are at high risk for the condition, such that two thirds of them demonstrate clinical findings related to glaucoma. These observations suggest a hereditary basis for angle closure; therefore, siblings of patients affected with angle closure should undergo targeted screening for glaucoma.


Influenza-associated mortality in Hong Kong.
The impact of influenza on mortality in countries in subtropical and tropical regions is poorly quantified. Estimation of influenza-related illness in warm-climate regions is more difficult, because the seasonality of virus circulation is less well-defined. Partly as a result of these factors, influenza vaccine is grossly underutilized in the tropics, even for individuals >or=65 years of age. Weekly numbers of deaths were modeled by Poisson regression, and excess deaths attributable to influenza in Hong Kong were estimated for 1996-1999. Comparison of weekly mortality during periods of influenza predominance and periods of low influenza activity was used to derive an alternative estimate of influenza-associated mortality. Estimates derived from the Poisson model indicated that influenza resulted in 7.3 deaths per 100,000 population per year (95% confidence interval [CI], 3.1-11.4) from cardiorespiratory disease among individuals aged 40-65 years and 102.0 deaths per 100,000 per population per year (95% CI, 61.2-142.7) among individuals aged >or=65 years. Although respiratory diseases accounted for the majority of influenza-related deaths, influenza also contributed to 13.8% (95% CI, 4.8%- 22.7%) and 5.3% (95% CI, 1.2%-9.3%) of deaths related to ischemic heart disease. Influenza is associated with deaths due to ischemic heart disease as well from respiratory diseases. Overall influenza-associated mortality in a region with a warm climate, such as Hong Kong, is comparable with that documented in temperate regions. The need for influenza vaccination in tropical regions needs to be reassessed.


Sex-specific difference in outcome after cardiac resynchronization therapy.
Observation of better outcome in women after cardiac resynchronization therapy (CRT) has led to controversies about a potential sex-specific response. In this study, we investigated to which extent this sex-specific difference in CRT outcome could be explained by differences in baseline characteristics between both sexes. We retrospectively analysed data from a multicentre registry of 1058 patients who received CRT. Patients were examined by echocardiography before and 12 ± 6 months after implantation. Response was defined as ≥15% reduction of left ventricular end-systolic volume at follow-up. Patient's characteristics at baseline, including New York Heart Association class, ejection fraction, QRS width and morphology, ischaemic aetiology of cardiomyopathy (ICM), number of scarred segments, age at implantation, atrial fibrillation, and mechanical dyssynchrony (Dyss) were analysed. Patients were followed for a median duration of 59 months. Primary end point was all-cause mortality. Women (24% of the population) had less ICM (23% vs. 49%, P < 0.0001), less scarred segments (0.4 ± 1.3 vs. 1.0 ± 2.1, P < 0.0001), more left bundle branch block (LBBB; 87% vs. 80%, P = 0.01), and more Dyss at baseline (78% vs. 57%, P < 0.0001). Without matching baseline differences, women showed better survival (log rank P < 0.0001). After matching, survival was similar (log rank P = 0.58). In multivariable analysis, female sex was no independent predictor of neither volumetric response (P = 0.06) nor survival (P = 0.31). Our data suggest that the repeatedly observed better outcome in women after CRT is mainly due to the lower rate ICM and smaller scars. When comparing patients with similar baseline characteristics, the response of both sexes to CRT is similar.


Parameters of Aggressive Behavior in a Treatment-Seeking Sample of Military Personnel: A Secondary Analysis of Three Randomized Controlled Trials of Evidence-Based PTSD Treatments.
Aggressive behavior is prevalent among veterans of post-9/11 conflicts who have posttraumatic stress disorder (PTSD). However, little is known about whether PTSD treatments reduce aggression or the direction of the association between changes in PTSD symptoms and aggression in the context of PTSD treatment. We combined data from three clinical trials of evidence-based PTSD treatment in service members (N = 592) to: (1) examine whether PTSD treatment reduces psychological (e.g., verbal behavior) and physical aggression, and; (2) explore temporal associations between aggressive behavior and PTSD. Both psychological (Estimate = -2.20, SE = 0.07) and physical aggression (Estimate = -0.36, SE = 0.05) were significantly reduced from baseline to posttreatment follow-up. Lagged PTSD symptom reduction was not associated with reduced reports of aggression; however, higher baseline PTSD scores were significantly associated with greater reductions in psychological aggression (exclusively; ß = -0.67, 95% CI = -1.05, -0.30, SE = -3.49). Findings reveal that service members receiving PTSD treatment report substantial collateral changes in psychological aggression over time, particularly for participants with greater PTSD symptom severity. Clinicians should consider cotherapies or alternative ways of targeting physical aggression among service members with PTSD and alternative approaches to reduce psychological aggression among service members with relatively low PTSD symptom severity when considering evidence-based PTSD treatments.


Impact of long-term exposure to sodium arsenite on cytogenetic radiation damage.
The aim of this work was to investigate the impact of long-term exposure to low concentrations of sodium arsenite on the cellular response to ionising radiation. Human lymphoblastoid GM1899a cells were cultured in the presence of sodium arsenite for up to six months. Following chemical exposure, acute challenge doses of X-rays were given and chromosome damage (dicentrics, acentric fragments, translocations, micronuclei) as well as cell growth and changes in cell cycle kinetics were determined. Initial short-term chemical exposures determined 8 ng/ml (60 nM) sodium arsenite as a suitable concentration for chronic exposures, which is below the current World Health Organization limit for arsenic in drinking water. At this concentration, cell growth was slightly, but consistently, slower than in untreated cultures throughout the six-month exposure period. Long-term exposure to the chemical induced no dicentrics and did not significantly alter the yield of dicentrics induced by 1 Gy acute X-irradiation. Similar results were obtained for chromosome translocations. In contrast, exposure to 8 ng/ml sodium arsenite induced significant levels of acentric fragments and micronuclei. Fragment/micronuclei data in combined treatment samples compared with single treatments were consistent with an additive effect of chemical and radiation exposure. As for X-rays, micronuclei induced by sodium arsenite tended to show no centromere in situ hybridisation signal, indicating that they represent structural aberrations rather than mis-segregated chromosomes. Similar results were obtained in human peripheral lymphocytes following short-term exposure to sodium arsenite or X-rays. Overall, an additive effect was observed for all combined exposures. Cellular radiation responses therefore seem to operate without any modulatory effects from chronic low level exposure to sodium arsenite in the systems analysed here.


Genetic interaction between Pax6 and β-catenin in the developing retinal pigment epithelium.
Wnt/β-catenin signaling plays an essential role in the retinal pigment epithelium (RPE) determination. Since activity of Pax6 (together with Pax2) is also required for the RPE determination, we investigated a possible genetic interaction between Pax6 and Wnt/β-catenin signaling pathway by analyzing Pax6, β-catenin, and Pax6/β-catenin conditional knockout mice. Although Pax6 inactivation alone had no impact on initial specification determined by the expression of Mitf and Otx2, melanin pigmentation was reduced in the RPE. This suggests that along with Mitf and Otx2, Pax6 is required for the full differentiation of RPE. Reporter gene assays in vitro suggest that hypopigmentation is at least in part due to the direct regulation of genes encoding enzymes involved in melanin synthesis by Pax6, Mitf, and β-catenin. The RPE of a β-catenin/Pax6 double mutant was differentiated into the neural retina; however, the tissue was thinner than that of the conditional β-catenin mutant due to reduced proliferation. Together, our data demonstrate that Pax6 is required for the RPE differentiation by regulating pigmentation and accountable for hyperproliferation in the transdifferentiated RPE. In this context, Pax6 appears to function as a pleiotropic regulator, directing development of ocular tissues in concert with the signaling pathway and, at the same time, regulating expression of structural component of the eye, such as shielding pigment.


The vlhA loci of Mycoplasma synoviae are confined to a restricted region of the genome.
Mycoplasma synoviae, a major pathogen of poultry, contains a single expressed, full-length vlhA gene encoding its haemagglutinin, and a large number of vlhA pseudogenes that can be recruited by multiple site-specific recombination events to generate chimaeric variants of the expressed gene. The position and distribution of the vlhA pseudogene regions, and their relationship with the expressed gene, have not been investigated. To determine the relationship between these regions, a physical map of the M. synoviae genome was constructed using the restriction endonucleases SmaI, I-CeuI, BsiWI, ApaI and XhoI and radiolabelled probes for rrnA, recA and tufA. A cloned fragment encoding the unique portion of the expressed vlhA gene and two PCR products containing conserved regions of the ORF 3 and ORF 6 vlhA pseudogenes were used to locate the regions containing these genes on the map. The chromosome of M. synoviae was found to be 890.4 kb and the two rRNA operons were in the same orientation. Both the expressed vlhA gene and the vlhA pseudogenes were confined to the same 114 kb region of the chromosome. These findings indicate that, unlike Mycoplasma gallisepticum, in which the vlhA genes are located in several loci around the chromosome and in which antigenic variation is generated by alternating transcription of over 40 translationally competent genes, M. synoviae has all of the vlhA sequences clustered together, suggesting that close proximity is needed to facilitate the site-specific recombinations used to generate diversity in the expressed vlhA gene.


Initiation of Low-threshold Buprenorphine in Nontreatment Seeking Patients With Opioid Use Disorder Engaged in Hepatitis C Treatment.
The ANCHOR program offered buprenorphine treatment to people who inject drugs engaged in hepatitis C (HCV) treatment at a Washington, DC harm reduction organization. This analysis describes the program model and outcomes of the opioid care continuum at 1 year. Primary outcomes were initiation of buprenorphine and retention in care, defined by an active buprenorphine prescription at given time points. Secondary outcomes included treatment interruptions, reasons for treatment noninitiation and termination, buprenorphine and opiate use, and HIV risk behaviors. Buprenorphine and opiate use were measured by urine toxicology screens and HIV risk behavior was quantified using a validated survey. Of 67 patients receiving HCV treatment not on opioid agonist therapy at baseline, 96% (n = 64) were interested and 73% (n = 49) initiated buprenorphine. Retention was 82% (n = 40), 65% (n = 32), and 59% (n = 29) at months 1, 6, and 12, respectively. Retention at 12 months was associated with self-reported engagement in routine medical care (P < 0.01), but was not associated with gender, stable housing, past opioid agonist therapy, or past overdose. Among retained patients, urine screens positive for opioids were 73% (n = 29), 56% (n = 18), and 79% (n = 23) at months 1, 6, and 12. There was a significant mean decrease in HIV risk-taking behavior scores over the treatment period, primarily driven by reduced injection frequency. Patients engaged in HCV treatment at a harm reduction organization showed a high rate of initiation of buprenorphine treatment, with retention comparable to other treatment settings. Although most patients continued using opioids on treatment, there was a reduced frequency of injection drug use, a significant driver of OUD-related risk. These data support the use of low-threshold buprenorphine access alongside HCV treatment to reduce morbidity and mortality in people with OUD.


Insights on the Excitation Spectrum of Graphene Contacted with a Pt Skin.
The excitation spectrum in the region of the intraband (Dirac plasmon) and interband ( π plasmon) plasmons in graphene/Pt-skin terminated Pt 3 Ni(111) is reproduced by using an ab-initio method and an empirical model. The results of both methods are compared with experimental data. We discover that metallic screening by the Pt layer converts the square-root dispersion of the Dirac plasmon into a linear acoustic-like plasmon dispersion. In the long-wavelength limit, the Pt d electron excitations completely quench the π plasmon in graphene at about 4.1 eV, that is replaced by a broad peak at about 6 eV. Owing to a rather large graphene/Pt-skin separation (≈3.3 Å), the graphene/Pt-skin hybridization becomes weak at larger wave vectors, so that the π plasmon is recovered with a dispersion as in a free-standing graphene.


Detection of Candida species resistant to azoles in the microbiota of rheas (Rhea americana): possible implications for human and animal health.
There is growing interest in breeding rheas (Rhea americana) in Brazil. However, there are no data on the yeast microbiota of the gastrointestinal tract of this avian species, and the phenotypic characteristics of these yeasts are not known. Therefore, the aim of this work was to isolate Candida species from the digestive tract of rheas and to evaluate the in vitro antifungal susceptibility and secretion of phospholipases of the recovered isolates. For this purpose, 58 rheas from breeding operations in the cities of Fortaleza and Mossoró, north-eastern Brazil, were used. Samples were gathered from the oropharynx and cloaca of the animals using sterile swabs. Stool samples were collected from their pens by scraping with a scalpel blade. For the primary isolation, the material was seeded onto 2 % Sabouraud dextrose agar supplemented with chloramphenicol (0.5 g l(-1)). The isolates were identified based on morphological and biochemical features. After identification, all the strains were submitted to antifungal susceptibility testing for amphotericin B, itraconazole and fluconazole. The phospholipase activity of the Candida species isolates was also tested by culturing on egg yolk agar. Candida species were isolated from at least one anatomical site in 36/58 birds (14/17 juveniles and 22/41 adults) and in 6/10 faecal samples. Mostly, only a single species was isolated from each collection site (36/56 positive sites), with up to three species being observed only in four cases (4/56). A total of 77 isolates were obtained, belonging to the species Candida parapsilosis sensu lato (19), Candida albicans (18), Candida tropicalis (13), Candida guilliermondii (12), Candida krusei (10) and Candida famata (5). C. albicans was more prevalent in the oropharynx of the juvenile rheas when compared with adult ones (P<0.001). All tested isolates were susceptible to amphotericin B, but 16 isolates were simultaneously resistant to the two azole derivatives (11/18 C. albicans, 1/10 C. krusei, 2/19 C. parapsilosis sensu lato and 2/13 C. tropicalis). C. albicans presented a particularly high resistance rate to fluconazole (15/18) and itraconazole (13/18). Finally, 23/77 strains secreted phospholipases. In summary, healthy rheas carry potentially pathogenic Candida species in their gastrointestinal tract, including azole-resistant strains that secrete phospholipases, and are prone to disseminating them in the environment. Thus, breeding and handling these animals may have some implications for human and animal health.


The Chinese translations of Alcohol Use Disorders Identification Test (AUDIT) in China: a systematic review.
To systematically review the literature on the Chinese translations of the Alcohol Use Disorders Identification Test (AUDIT) and their cross-cultural applicability in Chinese language populations. We identified peer-reviewed articles published in English (n = 10) and in Chinese (n = 11) from 1980 to September 2009, with key words China, Chinese and AUDIT among PubMed, EBSCO, PsycInfo, FirstSearch electronic databases and two Chinese databases. Five teams from Beijing, Tibet, Taiwan and Hong Kong reported their region-specific translation procedures, cultural adaptations, validity (0.93-0.95 in two versions) and reliability (0.63-0.99). These Chinese translations and short versions demonstrated relatively high sensitivity (0.880-0.997) and moderate specificity (0.709-0.934) for hazardous/harmful drinking and alcohol dependence, but low specificity for alcohol dependence among Min-Nan Taiwanese (0.58). The AUDIT and its adaptations were most utilized in workplace- and hospital-settings for screening and brief intervention. However, they were under-utilized in population-based surveys, primary care settings, and among women, adolescents, rural-to-urban migrants, the elderly and minorities. Among 12 studies from mainland China, four included both women and men, and only one in Tibet was published in English. There is a growing amount of psychometric, epidemiologic and treatment research using Chinese translations of the AUDIT, much of it still unavailable in the English-language literature. Given the increase in burden of disease and injury attributable to alcohol use in the Western Pacific region, the use of an internationally comparable instrument (such as the AUDIT) in research with Chinese populations presents a unique opportunity to expand clinical and epidemiologic knowledge about alcohol problem epidemics.


Genetic and epigenetic divergence between disturbed and undisturbed subpopulations of a Mediterranean shrub: a 20-year field experiment.
Little is known on the potential of ecological disturbance to cause genetic and epigenetic changes in plant populations. We take advantage of a long-term field experiment initiated in 1986 to study the demography of the shrub Lavandula latifolia, and compare genetic and epigenetic characteristics of plants in two adjacent subplots, one experimentally disturbed and one left undisturbed, 20 years after disturbance. Experimental setup was comparable to an unreplicated 'Before-After-Control-Impact' (BACI) design where a single pair of perturbed and control areas were compared. When sampled in 2005, plants in the two subplots had roughly similar ages, but they had established in contrasting environments: dense conspecific population ('Undisturbed' subpopulation) versus open area with all conspecifics removed ('Disturbed' subpopulation). Plants were characterized genetically and epigenetically using amplified fragment length polymorphism (AFLP) and two classes of methylation-sensitive AFLP (MSAP) markers. Subpopulations were similar in genetic diversity but differed in epigenetic diversity and multilocus genetic and epigenetic characteristics. Epigenetic divergence between subpopulations was statistically unrelated to genetic divergence. Bayesian clustering revealed an abrupt linear boundary between subpopulations closely coincident with the arbitrary demarcation line between subplots drawn 20 years back, which supports that genetic and epigenetic divergence between subpopulations was caused by artificial disturbance. There was significant fine-scale spatial structuring of MSAP markers in both subpopulations, which in the Undisturbed one was indistinguishable from that of AFLP markers. Genetic differences between subpopulations could be explained by divergent selection alone, while the concerted action of divergent selection and disturbance-driven appearance of new methylation variants in the Disturbed subpopulation is proposed to explain epigenetic differences. This study provides the first empirical evidence to date suggesting that relatively mild disturbances could leave genetic and epigenetic signatures on the next adult generation of long-lived plants.


An inexpensive family index of risk for mood issues improves identification of pediatric bipolar disorder.
Family history of mental illness provides important information when evaluating pediatric bipolar disorder (PBD). However, such information is often challenging to gather within clinical settings. This study investigates the feasibility and utility of gathering family history information using an inexpensive method practical for outpatient settings. Families (N=273) completed family history, rating scales, and the Mini-International Neuropsychiatric Interview (Sheehan et al., 1998) and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kaufman et al., 1997) about youths 5-18 (median=11) years of age presenting to an outpatient clinic. Primary caregivers completed a half-page Family Index of Risk for Mood issues (FIRM). All families completed the FIRM quickly and easily. Most (78%) reported 1+ relatives having a history of mood or substance issues (M=3.7, SD=3.3). A simple sum of familial mood issues discriminated cases with PBD from all other cases (area under receiver operating characteristic [AUROC]=.63, p=.006). FIRM scores were specific to youth mood disorder and not attention-deficit/hyperactivity disorder or disruptive behavior disorder. FIRM scores significantly improved the detection of PBD even controlling for rating scales. No subset of family risk items performed better than the total. Family history information showed clinically meaningful discrimination of PBD. Two different approaches to clinical interpretation showed validity in these clinically realistic data. Inexpensive and clinically practical methods of gathering family history can help to improve the detection of PBD.


Alcohol use among NTNU students 2007-19.
Alcohol consumption is widespread in student environments. The objective of the study was to examine alcohol use among students at the Norwegian University of Science and Technology (NTNU) in a twelve-year perspective. The study is cross-sectional, based on two questionnaire surveys conducted in lecture breaks at NTNU in 2007 and 2019. Participation was voluntary and anonymous. The questionnaire surveyed background variables and alcohol use, and included questions from the Alcohol Use Disorders Identification Test (AUDIT). The respondents were categorised into risk profiles based on their results. An AUDIT score of ≥ 8 was used as the threshold value for risky/potentially harmful alcohol use. The study included 2,247 students: 857 from 2007 and 1,390 from 2019. The proportion of women was 42.3 % in 2007 and 54.9 % in 2019. The average age was 21.5 years (2007) and 22.5 years (2019). The average AUDIT score was 10.7 in 2007 and 8.5 in 2019. A total of 937 students (67.6 %) consumed alcohol two to four times per month or more in 2019, a reduction of 9.8 % from 2007. Altogether 885 students (67.8 %) consumed five or more alcohol units on a typical drinking day in 2019, a reduction of 12.8 % from 2007. A considerable one-fifth reduction in the proportion of students with risky alcohol use occurred from 2007 to 2019. However, the alcohol use of more than half of the students may still pose a long-term risk.


Joint Image Encryption and Screen-Cam Robust Two Watermarking Scheme.
This paper proposes a joint encryption and screen-cam robust watermarking scheme. This method combines the advantages of smartphone, encryption and watermarking technologies, thereby achieving watermark extraction with a smartphone, partial decryption and tracking leakage from sneak shots. We design a dual watermarking algorithm to achieve watermark detection from both encrypted and decrypted images. First, a watermark is embedded in the discrete Fourier transform (DFT) domain to enable leakage tracking. Then, a second watermark is generated based on QR (Quick response) code encoding and inverse DFT to achieve high watermark capacity and error correction ability, where the secret key for decryption is included in the watermark message. By hiding this message carrying the watermark for the encrypted image in the changes caused by embedding the first watermark, we can improve imperceptibility and will not affect the effectiveness of the proposed scheme. Finally, to enhance the robustness of watermark after encryption, a chaotic mapping-based segment encryption algorithm is proposed. In the process of watermark detection, to cope with perspective correction, a frame locating based algorithm is employed to achieve watermark synchronization from a recaptured picture of the encrypted image. Considering the severe quality degradation, we use a noise component and local statistic feature-based method to extract the message bits. The experimental results show that the proposed scheme is secure, and highly robust, to screen-cam the process for both before and after decryption. Additionally, after decryption, the proposed scheme also has high robustness against common image processing attacks.


What Happens After the Demonstration Phase? The Sustainability of Canada's At Home/Chez Soi Housing First Programs for Homeless Persons with Mental Illness.
This research examined the sustainability of Canada's At Home/Chez Soi Housing First (HF) programs for homeless persons with mental illness 2 years after the end of the demonstration phase of a large (more than 2000 participants enrolled), five-site, randomized controlled trial. Qualitative interviews were conducted with 142 participants (key informants, HF staff, and persons with lived experience) to understand sustainability outcomes and factors that influenced those outcomes. Also, a self-report HF fidelity measure was completed for nine HF programs that continued after the demonstration project. A cross-site analysis was performed, using the five sites as case studies. The findings revealed that nine of the 12 HF programs (75%) were sustained, and that seven of the nine programs reported a high level of fidelity (achieving an overall score of 3.5 or higher on a 4-point scale). The sites varied in terms of the level of systems integration and expansion of HF that were achieved. Factors that promoted or impeded sustainability were observed at multiple ecological levels: broad contextual (i.e., dissemination of research evidence, the policy context), community (i.e., partnerships, the presence of HF champions), organizational (i.e., leadership, ongoing training, and technical assistance), and individual (i.e., staff turnover, changes, and capacity). The findings are discussed in terms of the implementation science literature and their implications for how evidence-based programs like HF can be sustained.


The course of post-traumatic amnesia: three little words.
To provide a simple means of "real time" recognition of emergence from post-traumatic amnesia (PTA). Ninety-one patients with traumatic brain injury (PBI); 53 minor (GCS 13-15), 19 moderate (GCS 9-12), 18 severe (GCS 3-8). Twenty-seven control subjects treated at two regional trauma units for their acute phase and followed in a hospital-based research institute were studied prospectively. Subjects were examined repeatedly following injury with the Galveston Orientation and Amnesia Test (GOAT) and tests of their ability to learn and retain new information. Word triplets balanced for concreteness and frequency were presented. Immediate and 24-hour recall were tested. If 24-hour recall was imperfect, recognition was tested by presenting the 3 target words and 6 distracters. The target words were then re-presented and recall was tested the next day. The time intervals to first perfect recognition and first free perfect recall were compared with the patients' first GOAT score of 75 or greater on 2 successive days. Simple line drawings of common objects were also presented to the subjects using an identical paradigm. The outcome measures were GOAT, 3-word recognition and recall, 3 picture recognition and recall. For all categories of head injury severity, the median interval to perfect free recall of words followed the achievement GOAT criterion by a significant interval. The mean GOAT scores for perfect 3-word recall and recognition corresponding to minor, moderate and severe injuries were 97, 90 and 88, and 97, 76 and 68 respectively. The recognition and recall of pictures preceded the recognition and recall of words by approximately 1 day. The orientation measures of the GOAT that contain material that the patient knew prior to injury obscure the determination of recovery of continuous memory and should be tested separately. Three-word recall which is simpler to administer than the GOAT is a more reliable measure of emergence from PTA. For patients who are dysphasic or who do not share a common language with the examiner, 3-picture recognition and recall may substitute for word recognition and recall.