Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas.
An increased occurrence of colorectal cancer and its adenoma precursor is observed among individuals with low intakes or circulating levels of folate, especially if alcohol intake is high, although results have not been statistically significant in all studies. We examined folate and alcohol intake and genetic polymorphisms in methylenetetrahydrofolate reductase [MTHFR 667-->T (ala-->val) and MTHFR 1298A-->C (gln-->ala)] (associated with reduced MTHFR activity) and in alcohol dehydrogenase 3 [ADH3 (2-2) associated with decreased alcohol catabolism] in relation to risk of colorectal adenoma in the Health Professionals Follow-Up Study. Among 379 cases and 726 controls, MTHFR genotypes were not appreciably related to risk of adenoma, but a suggestive interaction (P = 0.09) was observed between MTHFR 677C-->T and alcohol intake; men with TT homozygotes who consumed 30+ g/day of alcohol had an odds ratio (OR) of 3.52 [95% confidence interval (CI), 1.41-8.78] relative to drinkers of < or =5 g/day with the CC/CT genotypes. ADH3 genotype alone was not appreciably related to risk, but its influence was modified by alcohol intake. Compared with fast alcohol catabolizers [ADH3(1-1)] with low intakes of alcohol (< or =5 g/day), high consumers of alcohol (30+ g/day) had a marked increase in risk if they had the genotype associated with slow catabolism [ADH3(2-2); OR, 2.94; 95% CI, 1.24-6.92] or intermediate catabolism [ADH3(1-2)] of alcohol (OR, 1.83; 95% CI, 1.03-3.26) but not if they were fast catabolizers [ADH3(1-1); OR = 1.27; 95% CI = 0.63-2.53). In addition, an increased risk of colorectal adenoma (OR, 17.1; 95% CI, 2.1-137) was observed for those with the ADH3(2-2) genotype and high alcohol-low folate intake compared with those with low alcohol-high folate intake and the ADH3(1-1) genotype (P for interaction = 0.006). Our results indicate that high intake of alcohol is associated with an increased risk of colorectal adenoma, particularly among MTHFR 677TT and ADH3(2-2) homozygotes. The findings that alcohol interacts with a folate-related gene (MTHFR) and that the interaction between alcohol and ADH3 is stronger among those with low folate intake support the hypothesis that the carcinogenic influence of alcohol in the large bowel is mediated through folate status.


Managing human-mediated range shifts: understanding spatial, temporal and genetic variation in marine non-native species.
The use of molecular tools to manage natural resources is increasingly common. However, DNA-based methods are seldom used to understand the spatial and temporal dynamics of species' range shifts. This is important when managing range shifting species such as non-native species (NNS), which can have negative impacts on biotic communities. Here, we investigated the ascidian NNS Ciona robusta, Clavelina lepadiformis, Microcosmus squamiger and Styela plicata using a combined methodological approach. We first conducted non-molecular biodiversity surveys for these NNS along the South African coastline, and compared the results with historical surveys. We detected no consistent change in range size across species, with some displaying range stability and others showing range shifts. We then sequenced a section of cytochrome c oxidase subunit I (COI) from tissue samples and found genetic differences along the coastline but no change over recent times. Finally, we found that environmental DNA metabarcoding data showed broad congruence with both the biodiversity survey and the COI datasets, but failed to capture the complete incidence of all NNS. Overall, we demonstrated how a combined methodological approach can effectively detect spatial and temporal variation in genetic composition and range size, which is key for managing both thriving NNS and threatened species. This article is part of the theme issue 'Species' ranges in the face of changing environments (part I)'.


Personality disorder traits and self-reported target problems in a treatment-seeking sample.
Assessments of personality disorder (PD) by clinicians or researchers are not always congruent with the problems that clients view as most salient. This can result in disagreement over areas for change, leading to dissatisfaction and the risk of treatment attrition. The sample comprised 141 treatment-seeking adults with PD. Each described the five things they most wanted to change about themselves. These target problems were compared with PD diagnoses obtained from the International Personality Disorder Examination. The congruence between the clients' target problems and PD traits identified by the professionals was generally weak. Disagreement arose where a client's target problem was not a PD trait and, less frequently, where the client and the professional agreed on the presence of a trait but not on its importance. Surprisingly, doubting the trustworthiness of others was the most commonly reported target problem in this treatment-seeking sample even though many such participants did not qualify for that particular paranoid trait. Personality disorder diagnoses were generally poor indicators of the problems these clients cited as most important. This lack of correspondence may explain some of the lack of effectiveness of interventions for PD. The problem that a client with personality disorder (PD) views as most important may only be weakly identified in a formal diagnostic assessment. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, PD traits are insufficient to describe fully the things clients most want to change about themselves. Many clients with PD consider difficulty trusting others to be their most important problem, despite not qualifying for that particular paranoid trait. Risk of disagreement between the clinician and the client might be reduced if both parties can engage in a discussion about the results of any formal diagnostic assessment.


Reporting of ethical approval and informed consent in clinical research published in leading anesthesia journals.
Ethical conduct in human research in anesthesia includes approval by an institutional review board (IRB) or ethics committee and informed consent. Evidence of these is sometimes lacking in journal publications. The authors reviewed all publications involving human subjects in six leading anesthesia journals for the year 2001 (n = 1189). Rates of IRB approval and informed consent were examined and compared with potential predictors that included journal, type of publication, and patient demographics (age, sex, elective or emergency status). Rates were compared by use of chi-square and logistic regression. The authors found that IRB approval was documented in 71% of publications and consent was obtained in 66% of publications. Significant variation in IRB approval and consent was found among journals (P < 0.0005) and according to type of publication (P < 0.0005). Because publication type affected rates of IRB approval and consent (trials > mechanistic studies > observational studies > case reports), an analysis restricted to prospective studies also found a significant difference in IRB approval and consent among journals (P < 0.0005). This study suggests that rates of IRB approval and informed consent vary among publications in anesthesia journals. Clearer guidelines (and author adherence) for all types of publication are needed, both as a protection for research subjects and to maintain public trust in the process.


Coupling specificity of NOP opioid receptors to pertussis-toxin-sensitive Galpha proteins in adult rat stellate ganglion neurons using small interference RNA.
The opioid receptor-like 1 (NOP or ORL1) receptor is a G-protein-coupled receptor the endogenous ligand of which is the heptadecapeptide, nociceptin (Noc). NOP receptors are known to modulate pain processing at spinal, supraspinal, and peripheral levels. Previous work has demonstrated that NOP receptors inhibit N-type Ca2+ channel currents in rat sympathetic stellate ganglion (SG) neurons via pertussis toxin (PTX)-sensitive Galphai/o subunits. However, the identification of the specific Galpha subunit that mediates the Ca2+ current modulation is unknown. The purpose of the present study was to examine coupling specificity of Noc-activated NOP receptors to N-type Ca2+ channels in SG neurons. Small interference RNA (siRNA) transfection was employed to block the expression of PTX-sensitive Galpha subunits. RT-PCR results showed that siRNA specifically decreased the expression of the intended Galpha subunit. Evaluation of cell surface protein expression and Ca2+ channel modulation were assessed by immunofluorescence staining and electrophysiological recordings, respectively. Furthermore, the presence of mRNA of the intended siRNA target Galpha protein was examined by RT-PCR experiments. Fluorescence imaging showed that Galphai1, Galphai3, and Galphao were expressed in SG neurons. The transfection of Galphai1-specific siRNA resulted in a significant decrease in Noc-mediated Ca2+ current inhibition, while silencing of either Galphai3 or Galphao was without effect. Taken together, these results suggest that in SG neurons Galphai1 subunits selectively couple NOP receptors to N-type Ca2+ channels.


One-Year Follow-Up Diagnostic Stability of Autism Spectrum Disorder Diagnosis in a Clinical Sample of Children and Toddlers.
Some studies show that the diagnosis of Autism Spectrum Disorder could be considered reliable and stable in children aged 18 to 24 months. Nevertheless, the diagnostic stability of early ASD diagnosis has not yet been fully demonstrated. This observational study examines the one-year diagnostic stability of autism spectrum disorder diagnosis in a clinical sample of 147 children diagnosed between 18 and 48 months of age. The ADOS-2 scores were used in order to stratify children in three levels of symptom severity: Autism (AD; comparison score 5-7), Autism Spectrum Disorder (ASD; comparison score 3-4), and Sub-Threshold Symptoms; (STS; comparison score 1-2). Results: Overall, the largest part of children and toddlers diagnosed with autism spectrum disorder between 18 and 48 months continued to show autistic symptoms at one-year follow-up evaluation. Nevertheless, a significant percentage of children with higher ADOS severity scores exhibited a reduction of symptom severity and, therefore, moved towards a milder severity class one year later. Conversely, the number of subjects of the STS group meaningfully increased. Therefore, at one-year follow-up a statistically significant (χ2(2) = 181.46, p < 0.0001) percentage of subjects (25.2% of the total) who had received a categorical diagnosis of Autistic Disorder or Autism Spectrum Disorder in baseline no longer met the criteria for a categorical diagnosis. Furthermore, children who no longer met the criteria for autism spectrum disorder continue to show delays in one or more neurodevelopmental areas, possibly related to the emergence of other neurodevelopmental/neuropsychiatric disorders. Overall, the comprehensive results of the study account for a high sensibility but a moderate stability of ASD early diagnosis.


Time interval to conversion of interferon-gamma release assay after exposure to tuberculosis.
The proper interval for repeating an interferon-γ release assay (IGRA) among tuberculosis contacts with initially negative results is unknown. The interval for IGRA conversion after exposure to patients with active pulmonary tuberculosis in an outbreak setting was evaluated. In a platoon of 32 soldiers, four active pulmonary tuberculosis patients, in addition to one index patient, were diagnosed during a contact investigation. For the other 27 contacts, a tuberculin skin test (TST) and QuantiFERON® TB-Gold In-Tube (QFT-GIT) assay were performed. For soldiers with a negative result on the initial QFT-GIT assay, the test was repeated at 2, 4, 8, 14, 18 and 30 weeks until positive conversion occurred. When conversion was identified, the subject was treated for latent tuberculosis infection. Initially, 17 (63.0%) soldiers gave positive QFT-GIT results, whereas 21 (77.8%) showed positive TST results. Among 10 participants with initially negative QFT-GIT results, three showed conversion at 2 weeks, three at 4 weeks and three at 14 weeks. Conversion did not occur during the 30-week observation period in one contact. Based on the tuberculosis exposure time-points among the contacts, IGRA conversion generally occurred 4-7 weeks after exposure, although it could occur as late as 14-22 weeks after exposure.


Metschnikowia bicuspidata dominates in Taiwanese cold-weather yeast infections of Macrobrachium rosenbergii.
At water temperatures below 17 degrees C, yeast infections often occurred in 6 to 11 mo old giant freshwater prawn Macrobrachium rosenbergii (8 to 12 cm) in Taiwan from May 2001 to December 2003, with a cumulative mortality of 20 to 95%. Gross signs of disease included milky hemolymph, a yellow exoskeleton, opaque muscles, and a swollen hepatopancreas (HP). Histopathology included marked edema and extensive necrotic lesions associated with large numbers of yeast aggregates and inflammation within the muscles, HP, and other internal organs such as the heart, ovary, and intestine. Yeast cell numbers isolated from various tissues ranged from 4.5 x 10(8) to 9.0 x 10(9) colony forming units (CFU) per 100 mg. From diseased prawns from 12 affected farms, the presence of Metschnikowia bicuspidata (98.4% prevalence), Saccharomyces cerevisiae (0.8% prevalence), and Candida albicans (0.8% prevalence) was confirmed by biochemical tests and sequencing of PCR products from the D1/D2 domain of 26S rDNA. Experimental infection with these isolates caused gross signs and histopathological changes similar to those observed in naturally infected prawns, and lethal doses (LD50) were 3.8 x 10(3), 2.0 x 10(3), and 4.3 x 10(3) CFU prawn-1, respectively. Although the results of this study revealed that M. bicuspidata may be the major cause of yeast infections in the giant freshwater prawns in Taiwan, this is the first time that S. cerevisiae and C. albicans are also reported as pathogens.


Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS.
We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer acetate (GA) therapies, using propensity score-matched cohorts from observational multiple sclerosis registries. The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity. First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) (p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28-0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58-0.93; p = 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale-time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-β/GA.


Expression of HLA-A,B,C antigens on primary and metastatic tumor cell populations of human carcinomas.
The expression of monomorphic determinants of the histocompatibility leukocyte antigens (HLA) class I antigens by human malignant tumor cells was studied in tissue specimens of 70 primary tumor lesions obtained from patients with carcinoma of the breast (41 patients), colon (8 patients), urinary bladder (8 patients), and kidney (13 patients), and in samples of either synchronous or metachronous lymph node, lung, or liver metastases available in 44 of the patients. The frequencies of HLA class I expressor and nonexpressor tumor cells were determined by immunohistochemical staining of histological sections of fresh frozen tissue samples with the W6/32 monoclonal antibody. The tumor cell populations in the majority of the primary lesions consisted predominantly of HLA-immunoreactive cells (observed in 38 of 70 patients; 54%), especially in those patients who did not have clinical evidence of metastatic disease (8 of 11 patients; 73%). Various degrees of loss of reactivity were observed in other primary lesions, although in only 8 (12%) tumors (7 of which were obtained from patients with metastatic disease), the neoplastic cells were nearly exclusively HLA-nonreactive. In contrast, the majority of metastatic lesions consisted of either predominantly HLA-negative cells (33 of 44 specimens; 75%) or mixed populations (10 of 44 specimens; 23%), whereas only one metastatic lesion manifested HLA class I antigen staining in more than 70% of its tumor cells (P = 0.0005). Intravascular clusters of tumor cells consisted predominantly of HLA class I nonexpressors. The observed patterns of distribution of HLA expressors and nonexpressor tumor cells are compatible with the notion that HLA-negative cells in human carcinomas manifest a selective advantage with regard to metastatic progression and growth. The suppressed expression of major histocompatibility complex class I antigens on metastatic cells may lead to failure of presentation of cell surface tumor specific epitopes to host cytotoxic T-lymphocytes. Such a process would enable tumor cells to evade host immune responses and would promote and enhance cell dissemination and metastatic growth.


Safety of once- or twice-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with nonvalvular atrial fibrillation: A NOAC-TR study.
Once-daily dosing of non-vitamin K antagonist oral anticoagulants (NOACs) may increase patient adherence to treatment but may also be associated with a higher risk of bleeding. In this study, we investigated the adherence to once- or twice-daily dosing of NOACs and the risk of bleeding in nonvalvular atrial fibrillation (NVAF) patients. This multicenter cross-sectional study, conducted between 1 September 2015 and 28 February 2016, included 2214 patients receiving NOACs for at least 3 months, due to NVAF. Patients receiving once-daily or twice-daily NOAC doses were 1:1 propensity score matched for baseline demographic characteristics and the presence of other diseases. The medication adherence was assessed by the 8-item Morisky Medication Adherence Scale. Risk factors were investigated in relation to minor and major bleeding. The mean age of patients was 71 ± 10 years, and 53% of the patients were women. The medication adherence was lower in patients receiving twice-daily NOAC doses compared to once-daily-dose group (47% versus 53%, p = 0.001), and there was no difference between the groups in terms of minor (15% versus 16%, p = 0.292) and major bleeding (3% versus 3%, p = 0.796). Independent risk factors for bleeding were non-adherence to medication (OR: 1.62, 95% CI: 1.23-2.14, p = 0.001), presence of 3 or more other diseases (OR: 10.3, 95% CI: 5.3-20.3, p < 0.001), and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol) score (OR: 4.84, 95% CI: 4.04-5.8, p < 0.001). In summary, the once-daily dose of NOACs was associated with increased patient adherence to medication, while it was not associated with bleeding complications.


Parkinsonism; early results of occlusion of the anterior choroidal artery.
Occlusion of the anterior choroidal artery was carried out in four cases for relief of Parkinsonism. Results were disappointing but there was temporary cessation of tremor in three cases and sustained alleviation of rigidity in two cases. The causes of these changes following operation are unknown.


Differential patterns of insulin-like growth factor-I and -II mRNA expression in medulloblastoma.
Insulin-like growth factors (IGFs) play an important role in tumour growth and development. We hypothesized that this is also the case for medulloblastomas, which are highly malignant cerebellar brain tumours usually occurring in children. In these tumours the expression patterns of IGF-I and -II mRNA were studied. Tumour specimens obtained from 12 children and two adults at diagnosis were hybridized in situ with digoxigenin-labelled cRNA probes for hIGF-I and hIGF-II mRNAs. In all cases, tumour cells showed abundant expression of IGF-I mRNA. Nine of the 14 tumours showed variable but significant IGF-II expression. In these tumours, the hybridization signal almost exclusively colocalized with a subpopulation of Ki-M1P positive cells that were identified as ramified microglia (RM) cells. In the five tumours without IGF-II expression, microglia/brain macrophages with a more rounded amoeboid-like morphology predominated. RM cells in normal cerebellar tissues, residing abundantly in areas of the white and, to a less extent, in the grey matter, were IGF-II mRNA-negative. These RM cells showed a thinner and more extensively branched appearance and were more evenly distributed than those encountered in medulloblastoma. Probably, during the transformation from the resting ramified towards the amoeboid morphology (or vice versa) IGF-II mRNA expression is only temporarily induced. The physiological meaning of the induction of IGF-II mRNA expression by these cells in medulloblastoma remains unclear but any IGF-II peptide synthesized could exert unfavourable mitogenic and antiapoptotic effects on adjacent tumour cells. However, in this relatively small number of cases we could not find any indications for a relationship between clinical characteristics of the various cases and the extent of IGF-II mRNA expression.


Cladistic analysis of extant and fossil African papionins using craniodental data.
This study examines African papionin phylogenetic history through a comprehensive cladistic analysis of extant and fossil craniodental morphology using both quantitative and qualitative characters. To account for the well-documented influence of allometry on the papionin skull, the general allometric coding method was applied to characters determined to be significantly affected by allometry. Results of the analyses suggest that Parapapio, Pliopapio, and Papio izodi are stem African papionin taxa. Crown Plio-Pleistocene African papionin taxa include Gorgopithecus, Lophocebus cf. albigena, Procercocebus, Soromandrillus (new genus defined herein) quadratirostris, and, most likely, Dinopithecus. Furthermore, S. quadratirostris is a member of a clade also containing Mandrillus, Cercocebus, and Procercocebus; ?Theropithecus baringensis is strongly supported as a primitive member of the genus Theropithecus; Gorgopithecus is closely related to Papio and Lophocebus; and Theropithecus is possibly the most primitive crown African papionin taxon. Finally, character transformation analyses identify a series of morphological transformations during the course of papionin evolution. The origin of crown African papionins is diagnosed, at least in part, by the appearance of definitive and well-developed male maxillary ridges and maxillary fossae. Among crown African papionins, Papio, Lophocebus, and Gorgopithecus are further united by the most extensive development of the maxillary fossae. The Soromandrillus/Mandrillus/Cercocebus/Procercocebus clade is diagnosed by upturned nuchal crests (especially in males), widely divergent temporal lines (especially in males), medially oriented maxillary ridges in males, medially oriented inferior petrous processes, and a tendency to enlarge the premolars as an adaptation for hard-object food processing. The adaptive origins of the genus Theropithecus appear associated with a diet requiring an increase in size of the temporalis, the optimal placement of occlusal forces onto the molar battery, and an increase in the life of the posterior dentition. This shift is associated with the evolution of distinctive morphological features such as the anterior union of the temporal lines, increased enamel infoldings on the premolars and molars, a reversed curve of Spee, and delayed molar eruption.


Glucocorticoid-Induced Leucine Zipper Suppresses ICAM-1 and MCP-1 Expression by Dephosphorylation of NF-κB p65 in Retinal Endothelial Cells.
Glucocorticoid-induced leucine zipper (GILZ) is involved in anti-inflammatory activities in several animal models and in various cell types. In this study, we explored the role of GILZ in rat retinal vascular endothelial cells. Glucocorticoid-induced leucine zipper overexpression or silencing was established using GILZ overexpressing recombinant lentivirus (OE-GILZ-rLV) or short-hairpin RNA targeting GILZ recombinant lentivirus (shRNA-GILZ-rLV), respectively, in rat primary retinal microvascular endothelial cells (RMECs) and intact retina. Seventy-two hours after transfection, RMECs were stimulated with 1000 ng/mL lipopolysaccharide (LPS), 20 μM isoliensinine (an alkaloid derived from the embryos of Nelumbo nucifera, could enhance the dephosphorylation of p65 at Ser536), or PBS for another 24 hours. Western blotting and immunofluorescence were performed to measure protein expression. The concentrations of intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP)-1 in the RMEC culture media were measured by ELISA. Lipopolysaccharide downregulated GILZ expression in RMECs in a time- and dose-dependent manner, and the decrease in GILZ expression was accompanied by increased ICAM-1 and MCP-1 expression. Glucocorticoid-induced leucine zipper overexpression decreased LPS-induced ICAM-1 and MCP-1 expression, whereas GILZ silencing significantly attenuated the production of both cytokines. Glucocorticoid-induced leucine zipper overexpression also inhibited LPS-induced nuclear factor-κB p65 nuclear translocation in RMECs that was mediated by enhanced p65 dephosphorylation. The dephosphorylation of NF-κB p65 further downregulated ICAM-1 and MCP-1 expression in RMECs. Glucocorticoid-induced leucine zipper overexpression inhibited NF-κB p65 nuclear translocation by enhancing p65 dephosphorylation. Exogenous GILZ regulated ICAM-1 and MCP-1 expression, which was probably mediated by enhanced p65 dephosphorylation.


Effects of 5-HT1A receptor agonists, partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat.
In the present study, the effects of 5-HT1A receptor ligands with varying degrees of intrinsic activity at the 5-HT1A receptor were examined in the conditioned emotional response (CER) test and their effects compared to those of the benzodiazepine receptor agonists, diazepam and chlordiazepoxide. Diazepam (3.0 mg/kg) and chlordiazepoxide (3.0 mg/kg), and the 5-HT1A receptor partial agonists, ipsapirone (10.0 mg/kg) and gepirone (3.0 mg/kg), alleviated conditioned suppression of lever pressing. The 5-HT1A receptor partial agonist, buspirone (0.1-1.0 mg/kg), the 5-HT1A receptor agonist, 8-OH-DPAT (0.01-0.10 mg/kg), and the 5-HT1A receptor antagonist, WAY-100635 (0.03-3.0 mg/kg), had no effects on conditioned fear. Neither enhancing the level of food deprivation nor pretreatment with the amnesic agent scopolamine induced anxiolytic-like effects in the present CER test. The anxiolytic-like effects of ipsapirone in this test were completely reversed by WAY-100635. These results indicate that 5-HT1A agonist, but not antagonist actions, induce an anxiolytic effect in the CER test in rats.


Serum amyloid A levels in kidney-transplanted patients with familial Mediterranean fever-amyloidosis.
Amyloidosis of familial Mediterranean fever (FMF) may lead to end-stage renal failure, culminating in kidney transplantation. Since amyloidosis is prompted by high serum amyloid A (SAA) levels, increased SAA is expected to persist after transplantation. However, no data are available to confirm such an assumption. To determine SAA levels in kidney-transplanted FMF-amyloidosis patients and evaluate risk factors for the expected high SAA levels in this patient group. SAA, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values were obtained from 16 kidney-transplanted FMF-amyloidosis patients, 18 FMF patients without amyloidosis and 20 kidney-transplanted patients with non-inflammatory underlying disease. Demographic, clinical and genetic risk factors evaluation was based on data extracted from files, interviews and examination of the patients. SAA level in FMF patients who underwent kidney transplantation due to amyloidosis was elevated with a mean of 21.1 +/- 11.8 mg/L (normal < or = 10 mg/L). It was comparable to that of transplanted patients with non-inflammatory disorders, but tended to be higher than in FMF patients without amyloidosis (7.38 +/- 6.36, P = 0.08). Possible risk factors for the elevated SAA levels in kidney transplant patients that were excluded were ethnic origin, MEFV mutations, gender, age and disease duration. Kidney-transplanted patients with FMF-amyloidosis and with other non-FMF causes displayed mildly elevated SAA levels, possibly resulting from exposure to foreign tissue rather than from various FMF-related factors.


Diameter-selective growth of single-walled carbon nanotubes with high quality by floating catalyst method.
High-quality single-walled carbon nanotubes (SWNTs) with tunable diameters were synthesized by an improved H(2)/CH(4)-based floating catalyst method. Transmission electron microscopy observations and Raman results demonstrated the overall quality of the as-synthesized samples with finely tailored large diameters at 1.28, 1.62, 1.72, 1.91, and 2.13 nm, depending on the experimental conditions. In addition, Raman analysis revealed that the abundance of specific (n, m) SWNTs could be selectively enriched simultaneously along with the diameter modulation. It was found that the selective etching effects of high hydrogen flow stabilized the decomposition of ultralow CH(4) flow and considerably suppressed the deposition of amorphous carbon and small nanotubes, leading to very pure samples with high structural homogeneity suitable for further applications in practical electronic systems.


Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception.
The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.


Racial and Socioeconomic Differences and Surgical Outcomes in Pancreaticoduodenectomy Patients: A Systematic Review of High- Versus Low-Volume Hospitals in the United States.
Pancreaticoduodenectomy (PD) is associated with better outcomes in high-volume hospitals. However, it is unknown whether and to what extent the improved performance of high-volume hospitals may be associated with racial and socioeconomic factors, which have been shown to impact operative and postoperative outcomes in major surgeries. This review aims to identify the differences in racial and socioeconomic characteristics of patients who underwent PD surgery in high- and low-volume hospitals. PubMed, Cochrane, and Web of Science were systematically searched between May 1, 2023 and May 7, 2023 without any time restriction on publication date. Studies that were conducted in the United States and had a direct comparison between high- and low-volume hospitals were included. A total of 30 observational studies were included. When racial proportions were compared by hospital volume, thirteen studies reported that compared to high-volume hospitals, a higher percentage of racial minorities underwent PD in low-volume hospitals. Disparities in traveling distance, education levels, and median income at baseline between high- and low-volume hospitals were reported by four, three, and two studies, respectively. A racial difference at baseline between high- and low-volume hospitals was observed. Socioeconomic factors were less frequently included in existing literature. Future studies are needed to understand the socioeconomic differences between patients receiving PD surgery in high- and low-volume hospitals.


RelB/p50 complexes regulate cytokine-induced YKL-40 expression.
The secreted protein, YKL-40, has been proposed as a biomarker of a variety of human diseases characterized by ongoing inflammation, including chronic neurologic pathologies such as multiple sclerosis and Alzheimer's disease. However, inflammatory mediators and the molecular mechanism responsible for enhanced expression of YKL-40 remained elusive. Using several mouse models of inflammation, we now show that YKL-40 expression correlated with increased expression of both IL-1 and IL-6. Furthermore, IL-1 together with IL-6 or the IL-6 family cytokine, oncostatin M, synergistically upregulated YKL-40 expression in both primary human and mouse astrocytes in vitro. The robust cytokine-driven expression of YKL-40 in astrocytes required both STAT3 and NF-κB binding elements of the YKL-40 promoter. In addition, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IκBα. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-κB and instead required subunits RelB and p50. Mechanistically, we show that IL-1-induced RelB/p50 complex formation was further promoted by oncostatin M and that these complexes directly bound to the YKL-40 promoter. Moreover, we found that expression of RelB was strongly upregulated during inflammation in vivo and by IL-1 in astrocytes in vitro. We propose that IL-1 and the IL-6 family of cytokines regulate YKL-40 expression during sterile inflammation via both STAT3 and RelB/p50 complexes. These results suggest that IL-1 may regulate the expression of specific anti-inflammatory genes in nonlymphoid tissues via the canonical activation of the RelB/p50 complexes.


A molecular perspective of water at metal interfaces.
Water/solid interfaces are relevant to a broad range of physicochemical phenomena and technological processes such as corrosion, lubrication, heterogeneous catalysis and electrochemistry. Although many fields have contributed to rapid progress in the fundamental knowledge of water at interfaces, detailed molecular-level understanding of water/solid interfaces comes mainly from studies on flat metal substrates. These studies have recently shown that a remarkably rich variety of structures form at the interface between water and even seemingly simple flat surfaces. In this Review we discuss the most exciting work in this area, in particular the emerging physical insight and general concepts about how water binds to metal surfaces. We also provide a perspective on outstanding problems, challenges and open questions.


Characterizing microbial community and geochemical dynamics at hydrothermal vents using osmotically driven continuous fluid samplers.
Microbes play a key role in mediating aquatic biogeochemical cycles. However, our understanding of the relationships between microbial phylogenetic/physiological diversity and habitat physicochemical characteristics is restrained by our limited capacity to concurrently collect microbial and geochemical samples at appropriate spatial and temporal scales. Accordingly, we have developed a low-cost, continuous fluid sampling system (the Biological OsmoSampling System, or BOSS) to address this limitation. The BOSS does not use electricity, can be deployed in harsh/remote environments, and collects/preserves samples with daily resolution for >1 year. Here, we present data on the efficacy of DNA and protein preservation during a 1.5 year laboratory study as well as the results of two field deployments at deep-sea hydrothermal vents, wherein we examined changes in microbial diversity, protein expression, and geochemistry over time. Our data reveal marked changes in microbial composition co-occurring with changes in hydrothermal fluid composition as well as the temporal dynamics of an enigmatic sulfide-oxidizing symbiont in its free-living state. We also present the first data on in situ protein preservation and expression dynamics highlighting the BOSS's potential utility in meta-proteomic studies. These data illustrate the value of using BOSS to study relationships among microbial and geochemical phenomena and environmental conditions.


The site-specific ribosomal insertion element type II of Bombyx mori (R2Bm) contains the coding sequence for a reverse transcriptase-like enzyme.
Two classes of DNA elements interrupt a fraction of the rRNA repeats of Bombyx mori. We have analyzed by genomic blotting and sequence analysis one class of these elements which we have named R2. These elements occupy approximately 9% of the rDNA units of B. mori and appear to be homologous to the type II rDNA insertions detected in Drosophila melanogaster. Approximately 25 copies of R2 exist within the B. mori genome, of which at least 20 are located at a precise location within otherwise typical rDNA units. Nucleotide sequence analysis has revealed that the 4.2-kilobase-pair R2 element has a single large open reading frame, occupying over 82% of the total length of the element. The central region of this 1,151-amino-acid open reading frame shows homology to the reverse transcriptase enzymes found in retroviruses and certain transposable elements. Amino acid homology of this region is highest to the mobile line 1 elements of mammals, followed by the mitochondrial type II introns of fungi, and the pol gene of retroviruses. Less homology exists with transposable elements of D. melanogaster and Saccharomyces cerevisiae. Two additional regions of sequence homology between L1 and R2 elements were also found outside the reverse transcriptase region. We suggest that the R2 elements are retrotransposons that are site specific in their insertion into the genome. Such mobility would enable these elements to occupy a small fraction of the rDNA units of B. mori despite their continual elimination from the rDNA locus by sequence turnover.


Interactive focused stimulation for toddlers with expressive vocabulary delays.
This study explores the effects of training parents to administer focused stimulation intervention to teach specific target words to their toddlers with expressive vocabulary delays. Twenty-five mothers and their late-talking toddlers were randomly assigned to treatment and delayed-treatment (control) groups. Vocabulary targets were individually selected for each toddler based on the child's phonetic repertoire and parent report of vocabulary development. Following treatment, mothers' language input was slower, less complex, and more focused than mothers in the control group. Concomitantly, their children used more target words in naturalistic probes, used more words in free-play interaction, and were reported to have larger vocabularies overall as measured by parent report. In addition, the treatment had an effect on language development-children in the experimental group used more multiword combinations and early morphemes than children in the control group. The implications of these results are discussed with regard to the role of focused stimulation intervention for children with expressive vocabulary delays.


Considerations in minimally invasive adrenal surgery: the frontdoor or the backdoor?
Over the last few decades, in the field of minimally invasive adrenal surgery, retroperitoneoscopic adrenalectomy (PRA) has shown favorable results when compared to laparoscopic transperitoneal adrenalectomy (LTA). However, for many endocrine surgeons it is unclear if, when, and how to transition from LTA to PRA. Although the length of the learning curve for both approaches is comparable, the LTA is a technically more challenging procedure whilst PRA demands an orientation in a new environment in a patient that is positioned upside down. Visiting a proctor is crucial for successfully adopting the PRA procedure, and continued mentorship in a surgeon's own hospital during the first procedures is preferable. There are several other aspects related to the decision to transition to PRA; the caseload of adrenal patients, learning aspects of other members of the team, technical considerations, case selection, and a well-developed emergency plan in case of complications during surgery. In a dedicated endocrine center with a considerable annual case load of approximately 30 procedures, we recommend to transition to PRA in order to provide the highest quality of care to adrenal patients.


Attenuated activation of the unfolded protein response following exercise in skeletal muscle of older adults.
Sarcopenia is linked with impaired adaptive responses to exercise in aging skeletal muscle. The unfolded protein response (UPR) is an important intramyocellular molecular response pathway that is activated by exercise. The influence of age on skeletal muscle adaptive UPR in response to exercise, and the relationship to other key exercise-responsive regulatory pathways is not well-understood. We evaluated age-related changes in transcriptional markers of UPR activation following a single bout of resistance exercise in 12 young (27 ± 5yrs) and 12 older (75 ± 5yrs) healthy men and women. At baseline, there were modest differences in expression of UPR-related genes in young and older adults. Following exercise, transcriptional markers of UPR pathway activation were attenuated in older adults compared to young based on specific salient UPR-related genes and gene set enrichment analysis. The coordination of post-exercise transcriptional patterns between the UPR pathway, p53/p21 axis of autophagy, and satellite cell differentiation were less evident in older compared to young adults. In conclusion, transcriptomic analysis revealed an age-related decline in the adaptive UPR transcriptional response following a single bout of exercise that could contribute to impaired exercise responsiveness with age.


Complement factor I deficiency: A potentially treatable cause of fulminant cerebral inflammation.
To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation. Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature. We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function. Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role.


DNA ploidy status, S-phase fraction, and p53 are not independent prognostic factors for survival in endometrioid endometrial carcinoma FIGO stage I-III.
To assess the effects on relative survival of established and new prognostic factors in stage I-III grade 1-3 endometrioid endometrial carcinoma and in the subgroup of stage I grade 1-2. This was a population-based, retrospective study including all women (n=1113) in the western Swedish healthcare region diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I-III grade 1-3 endometrioid endometrial carcinoma in 2006-2011. Histology, grade, stage, and age were prospectively reported to the regional clinical and national cancer registers. DNA ploidy and S-phase fraction were analyzed by flow cytometer. S-phase fraction cut-off was set at ≥8%. Tumor biopsies were classified as diploid if there was one G0/G1 peak or the DNA index was 1.0±0.04. Overexpression of p53 as determined by immunohistochemistry was positive if strong nuclear staining was found in >30% of the neoplastic cells. Based on univariable statistical analyses we found that 5-year relative survival was significantly associated with S-phase fraction, DNA ploidy, p53, stage, grade, and age. Excess mortality for S-phase fraction ≥8%, aneuploidy, and p53 overexpression was 8, 14, and 8 and times higher, respectively. However, in a multivariable regression model, adjusted for stage, grade, and age, S-phase fraction, DNA ploidy, and p53 were not statistically independent prognostic factors (p=0.413, p=0.107, p=0.208, respectively) for 5-year relative survival in stage I-III grade 1-3 endometrioid endometrial carcinoma. In a subgroup analysis of stage I grade 1-2, aneuploidy identified a subgroup with impaired 5-year relative survival. We can conclude that S-phase fraction, DNA ploidy, and p53 overexpression did not improve identification of high-risk patients by stage, grade, and age in stage I-III endometrioid endometrial carcinoma. In stage I, aneuploidy and grade 2 predicted lower relative survival rates than other variables.


Hybrid cellulose nanocrystal/magnetite glucose biosensors.
There exists a high demand for simple and affordable blood glucose monitoring methods. For this purpose, new generations of biosensors are being developed for possible in vivo or dermal use. We present (non)sulphated cellulose nanocrystal/magnetite thin films to act as dermal and oral glucose biosensors. The biocompatible (N-CNC)-Fe3O4 and (S-CNC)-Fe3O4 hybrid systems exhibit peroxidase-like activity, indicated by an almost instant color change when in the presence of glucose and ABTS. Both types of biosensors detect glucose concentrations as low as 5 mM (which corresponds to the level of glucose in biological fluids), with (S-CNC)-Fe3O4 being 1.5 - 2 times as sensitive as (N-CNC)-Fe3O4. Hybrid catalytic activity is more pronounced at room temperature and in acidic environments. The hybrids can therefore be used to determine glucose levels by using sweat and saliva - non-blood bodily secretions which tend to be slightly to moderately acidic and have relatively low glucose levels.


High levels of C-reactive protein are associated with reduced vagal modulation and low physical activity in young adults.
The purpose of this study was to examine the relationship between cardiac autonomic control derived from heart rate variability (HRV), high-sensitivity C-reactive protein (hs-CRP) and physical activity (PA) levels measured using accelerometers. A total of 80 healthy university students volunteered to participate in this study (20.56 ± 0.82 years, 1.36 ± 1.5 mg/L of hs-CRP). The participants were divided into groups based on tertiles of hs-CRP. Analysis of covariance adjusted to PA was used to assess group differences in HRV. Associations between hs-CRP, HRV indices and PA were analyzed using Pearson's correlation. The participants at the highest tertile of hs-CRP (tertile 3) had lower cardiac vagal modulation (SDNN, tertile 1=78.05 ± 5.9,tertile 2=82.43 ± 5.9,tertile 3=56.03 ± 6.1; SD1, tertile 1=61.27 ± 5.3, tertile 2=62.93 ± 5.4, tertile 3=40.03 ± 5.5). In addition, vagal indices were inversely correlated with hs-CRP but positively correlated with PA (SDNN r=-0.320, SD1 r=-0.377; SDNN r=0.304, SD1 r=0.299; P<0.05). Furthermore, the most physically active subjects had lower levels of hs-CRP and the highest levels of vagal modulation.


Quantitative comparison of alternative methods for coarse-graining biological networks.
Markov models and master equations are a powerful means of modeling dynamic processes like protein conformational changes. However, these models are often difficult to understand because of the enormous number of components and connections between them. Therefore, a variety of methods have been developed to facilitate understanding by coarse-graining these complex models. Here, we employ Bayesian model comparison to determine which of these coarse-graining methods provides the models that are most faithful to the original set of states. We find that the Bayesian agglomerative clustering engine and the hierarchical Nyström expansion graph (HNEG) typically provide the best performance. Surprisingly, the original Perron cluster cluster analysis (PCCA) method often provides the next best results, outperforming the newer PCCA+ method and the most probable paths algorithm. We also show that the differences between the models are qualitatively significant, rather than being minor shifts in the boundaries between states. The performance of the methods correlates well with the entropy of the resulting coarse-grainings, suggesting that finding states with more similar populations (i.e., avoiding low population states that may just be noise) gives better results.


Associations of Arterial Thickness, Stiffness, and Blood Pressure With Brain Morphology in Early Adolescence: A Prospective Population-Based Study.
Arterial wall thickness and stiffness, and high blood pressure have been repeatedly associated with poorer brain health. However, previous studies largely focused on mid- or late-life stages. It is unknown whether any arterial health-related brain changes may be observable already in adolescence. We examined whether (1) carotid intima-media thickness, (2) carotid distensibility, and (3) systolic blood pressure and diastolic blood pressure, measured at the age of 10 years, were associated with brain volumes and white matter microstructure (ie, fractional anisotropy and mean diffusivity) at the age of 14 years. In addition to cross-sectional analyses, we explored associations with longitudinal change in each brain outcome from 10 to 14 years. Analyses were based on 5341 children from the Generation R Study. Higher diastolic blood pressure was associated with lower total brain volume (β, -0.04 [95% CI, -0.07 to -0.01]) and gray matter volume (β, -0.04 [95% CI, -0.07 to -0.01]) at the age of 14 years, with stronger associations in higher diastolic blood pressure ranges. Similar associations emerged between systolic blood pressure and brain volumes, but these were no longer significant after adjusting for birth weight. No associations were observed between blood pressure and white matter microstructure or between carotid intima-media thickness or distensibility and brain morphology. Arterial blood pressure, but not intima-media thickness and distensibility, is associated with structural neuroimaging markers in early adolescence. Volumetric measures may be more sensitive to these early arterial health differences compared with microstructural properties of the white matter, but further studies are needed to confirm these results and assess potential causal mechanisms.


Macronuclear division and cytokinesis in Tetrahymena.
Tetrahymena contains a micronucleus and a macronucleus. The micronucleus divides with typical mitosis, while the macronucleus divides amitotically. Although the mechanism responsible for macronuclear division was previously unknown, we clarified the organization of microtubules during macronuclear division. The macronuclear microtubules dynamically changed their distribution in an organized way throughout the macronuclear division. The macronuclear microtubules and the cytoplasmic microtubules cooperatively carried out the macronuclear division. When the micronuclear division was finished, p85 appeared at the presumptive division plane prior to the cytokinesis. The p85 directly interacted with calmodulin in a Ca(2+)-dependent manner, and p85 and CaM colocalized to the division furrow during cytokinesis. Moreover, the Ca(2+)/CaM inhibitor, W7, inhibited the direct interaction between p85 and CaM, the localization of both proteins to the division plane, and the formation of the division furrow. Thus, Ca(2+)/CaM and p85 have important roles in initiation and progression of cytokinesis in Tetrahymena.


Survival rate of eukaryotic cells following electrophoretic nanoinjection.
Insertion of foreign molecules such as functionalized fluorescent probes, antibodies, or plasmid DNA to living cells requires overcoming the plasma membrane barrier without harming the cell during the staining process. Many techniques such as electroporation, lipofection or microinjection have been developed to overcome the cellular plasma membrane, but they all result in reduced cell viability. A novel approach is the injection of cells with a nanopipette and using electrophoretic forces for the delivery of molecules. The tip size of these pipettes is approximately ten times smaller than typical microinjection pipettes and rather than pressure pulses as delivery method, moderate DC electric fields are used to drive charged molecules out of the tip. Here, we show that this approach leads to a significantly higher survival rate of nanoinjected cells and that injection with nanopipettes has a significantly lower impact on the proliferation behavior of injected cells. Thus, we propose that injection with nanopipettes using electrophoretic delivery is an excellent alternative when working with valuable and rare living cells, such as primary cells or stem cells.


Comparison of olive oil and dry-clean keeping methods in umbilical cord care as microbiological.
The application of olive oil is one of the traditional practices used in umbilical cord care in Turkey. The study was conducted experimentally, so as to compare microbiologically the efficacy of olive oil use and keeping the stump dry. Data were obtained using a personal information form and an omphalitis follow-up form, as well as from cultures taken from the infants' umbilical cords. Cultures were taken from the neonates' umbilical cords at three different times. The Pearson chi-square test, student t test, percentages, and averages were used for statistical data analysis. The average time for separation is 9.46 days. For the control group, this period is 9.8 days, while for the study group, it is 9.1, lacking a statistically significant difference between the two groups (P > 0.05). However, when the cut-off point for umbilical cord detachment is set at 10 days, the cords of 71.6% of the neonates in the study group, compared with 55.6% of the control group, are observed to have separated before 10 days, representing a significant difference between the groups (P < 0.05). In all of the cultures collected, growth was noted in 35.9% of the study group and 33.3% of the control group. The correlation between the method used for the care of the cord and the total culture results was not statistically significant (P > 0.05). Olive oil can be used in the umbilical cord care of neonates under appropriate conditions; we recommended that this investigation be repeated on expanded sample groups.


Initiatives to reduce the waiting time to initiate oncological treatment: a scoping literature review.
To identify the managerial actions proposed and employed to reduce the waiting time to initiate oncological treatments in the public health system and its application in Latin America. We searched seven databases in December 2020. Search terms were conceptualized into three groups: waiting time, cancer, and terms related to public sector. The eligibility criteria included theoretical or empirical academic articles written in English, Spanish, or Portuguese, that focused on managerial solutions to face oncological healthcare queues' dilemma. The search returned 1 255 articles, and 20 were selected and analysed in this review. Results show that most of the proposals are related to the process and people dimensions. The actions related to the process dimension were mainly associated with programming new treatment pathways and integrating cancer systems. People's dimension initiatives referred mostly to task forces and groups of specialists. Some initiatives were related to implementing technological solutions and the technology dimension, mainly concerning radiotherapy devices' acquisition. Few studies focus on analysing actions to minimize waiting time to initiate oncological treatments. The prevalence of conceptual and illustrative case studies indicates the lack of research maturity on this theme. Future studies should focus on setting the field's theoretical foundations, considering the existing paradigms, or developing new ones. There is a need for empirical studies applying a multidisciplinary approach to face the oncological treatment waiting time challenge and proposing new and innovative initiatives.


Nicolle finger joint prosthesis: a preliminary study of total joint replacement for lesser metatarsophalangeal joints.
Although designed for finger joint replacement, the Calnan-Nicolle prosthesis and the Swanson prosthesis have been successfully adapted for use in the foot. The author discusses the advantages and disadvantages of a new joint prosthesis developed by Nicolle which, with slight modification, is also being used in the lesser metatarsophalangeal joints.


Central immune tolerance depends on crosstalk between the classical and alternative NF-κB pathways in medullary thymic epithelial cells.
Medullary thymic epithelial cells (mTECs) contribute to self-tolerance by expressing and presenting peripheral tissue antigens for negative selection of autoreactive T cells and differentiation of natural regulatory T cells. The molecular control of mTEC development remains incompletely understood. We here demonstrate by TEC-specific gene manipulation in mice that the NF-κB transcription factor subunit RelB, which is activated by the alternative NF-κB pathway, regulates development of mature mTECs in a dose-dependent manner. Mice with conditional deletion of Relb lacked mature mTECs and developed spontaneous autoimmunity. In addition, the NF-κB subunits RelA and c-Rel, which are both activated by classical NF-κB signaling, were jointly required for mTEC differentiation by directly regulating the transcription of Relb. Our data reveal a crosstalk mechanism between classical and alternative NF-κB pathways that tightly controls the development of mature mTECs to ensure self-tolerance.


Balancing population size and genetic information in parentage analysis studies.
In parentage analysis studies, the parameters of interest typically are not the parent assignments themselves, but population parameters such as variance in fertility, self-pollination rate, or average dispersal distances. The precision of parameter estimates is affected by two factors: the number of offspring under consideration, and the precision with which the offspring can be assigned to parents. When assignment of parents is based on genetic information, the confidence in assignments is affected by the number and polymorphism of the loci considered, and by the number of potential parents in the population. Studying larger populations may yield higher numbers of offspring, but since larger populations contain more potential parents, more (or more highly polymorphic) loci are necessary to attain a given level of confidence in the parent assignments. This article addresses how to relate the size of the population and the number of loci when designing a study. It is shown that the number of loci needed to assign all offspring unambiguously is proportional to the logarithm of the population size. In some cases, the constant of proportionality can be determined, eliminating the need for simulation-based projections. Population-wide measures of uncertainty in parent assignments are also introduced, and it is shown that holding uncertainty "steady" as the population size increases also requires increasing the number of loci proportional to the logarithm of the population size. Data from a study of self-pollination are used to illustrate the techniques suggested.


Tuberculosis patients' knowledge and beliefs about tuberculosis: a mixed methods study from the Pacific Island nation of Vanuatu.
The setting for this study was the Pacific island nation of Vanuatu, an archipelago of 82 islands, located in the South Pacific Ocean. Our objective was to assess the knowledge, attitudes and practices of tuberculosis (TB) patients towards TB. This was a descriptive study using qualitative and quantitative methods. Quantitative analysis was based on the responses provided to closed questions, and we present frequencies to describe the TB patients' knowledge, attitudes and practice relating to TB. Qualitative analysis was based on open questions permitting fuller explanations. We used thematic analysis and developed a posteriori inductive categories to draw conclusions. Thirty five TB patients were interviewed; 22 (63%) were male. They attributed TB to cigarettes, kava, alcohol, contaminated food, sharing eating utensils and "kastom" (the local term for the traditional way of life, but also for sorcery). Most (94%) did not attribute TB to a bacterial cause. However, almost all TB patients (89%) thought that TB was best treated at a hospital with antibiotics. Three quarters (74%) experienced stigma after their TB diagnosis. Seeking health care from a traditional healer was common; 54% of TB patients stated that they would first consult a traditional healer for any illness. When seeking a diagnosis for signs and symptoms of TB, 34% first consulted a traditional healer. Patients cited cost, distance and beliefs about TB causation as reasons for first consulting a traditional healer or going to the hospital. Of the TB patients who consulted a traditional healer first, there was an average of two weeks delay before they consulted the health service. In some cases, however, the delay was up to six years. The majority of the TB patients interviewed did not attribute TB to a bacterial cause. Consulting a traditional healer for health care, including while seeking a diagnosis for TB symptoms, was common and may have delayed diagnosis. People require better information about TB to correct commonly held misperceptions about the disease. Traditional healers could also be engaged with the national TB programme, in order to refer people with signs and symptoms of TB to the nearest health service.


Blockade of transforming growth factor-{beta} signaling in tumor-reactive CD8(+) T cells activates the antitumor immune response cycle.
Transforming growth factor-beta (TGF-beta) is a potent immunosuppressant. Overproduction of TGF-beta by tumor cells leads to evasion of host immune surveillance and tumor progression. Results of our early studies showed that adoptive transfer of tumor-reactive, TGF-beta-insensitive CD8(+) T cells into immunocompetent mice was able to eradicate lung metastasis of mouse prostate cancer. The present study was conducted with three objectives. (a) We tested if this technology could be applied to the treatment of solid xenograft tumors in allogeneic immunodeficient hosts. (b) We determined relevant variables in the tumor microenvironment with the treatment. (c) We tested if immune cells other than CD8(+) T cells were required for the antitumor effect. Mouse prostate cancer cells, TRAMP-C2 of the C57BL/6 strain, grown in immunodeficient allogeneic hosts of BALB/c strain, were used as a xenograft model. Tumor-reactive CD8(+) T cells from C57BL/6 mice were isolated, expanded ex vivo, and rendered insensitive to TGF-beta by introducing a dominant-negative TGF-beta type II receptor vector. Seven days following s.c. injection of TRAMP-C2 cells (5 x 10(5)) into the flank of male BALB/c-Rag1(-/-) mice, tumor-reactive, TGF-beta-insensitive CD8(+) T cells (1.5 x 10(7)) were transferred with and without the cotransfer of an equal number of CD8-depleted splenocytes from C57BL/6 donors. Naive CD8(+) T cells or green fluorescent protein-empty vector-transfected tumor-reactive CD8(+) T cells were transferred as controls. Forty days following the transfer, the average tumor weight in animals that received cotransfer of tumor-reactive, TGF-beta-insensitive CD8(+) T cells and CD8-depleted splenocytes was at least 50% less than that in animals of all other groups (P < 0.05). Tumors in animals of the former group showed a massive infiltration of CD8(+) T cells. This was associated with secretion of relevant cytokines, decreased tumor proliferation, reduced angiogenesis, and increased tumor apoptosis. Based on these results, we postulated a concept of antitumor immune response cycle in tumor immunology.


Prospective analysis of patient-reported outcomes and physician-reported outcomes with gynecologic cancer chemotherapy.
Gynecologic cancer chemotherapy impacts the quality of life (QOL) of patients, with lasting adverse events that may require treatment adjustments or discontinuation. Consequently, real-time symptom monitoring before outpatient visits has resulted in improved QOL for patients and extended survival times. This study investigated whether there are differences between electronic patient-reported outcomes (e-PRO-CTCAE) and physician-assessed outcomes (NCI-CTCAE) evaluated in an outpatient setting in gynecologic cancer chemotherapy. The study was conducted on 50 patients who received their first chemotherapy treatment at St. Marianna University Hospital Obstetrics and Gynecology from July 1, 2021 to December 31, 2022. PRO-CTCAE and NCI-CTCAE were evaluated at each instance of chemotherapy and 2 weeks after. The PRO-CTCAE was additionally collected weekly using e-PRO. The values for "Joint Pain," "Nausea," "Taste Disturbance," "Constipation," "Insomnia," "Fatigue," "Limb Edema," and "Concentration Impairment" were consistently higher in PRO-CTCAE than in NCI-CTCAE, indicating that physicians underestimated the severity of adverse events. In contrast, there was no significant difference in "Peripheral Neuropathy," demonstrating that physicians had a good understanding of this condition in patients. The weekly responses obtained from e-PRO revealed that symptom exacerbations peaked outside of clinic visits. This study demonstrated physicians tend to underestimate most adverse events. Moreover, the responses using e-PRO revealed peak symptom deterioration occurred outside of outpatient visits. This suggested that e-PRO and actions taken in response to them can improve patients' QOL.


Human papillomavirus type 6a DNA in the lung carcinoma of a patient with recurrent laryngeal papillomatosis is characterized by a partial duplication.
Transcriptionally active human papillomavirus type 6a (HPV-6a) DNA was detected in a lung carcinoma of a patient with recurrent laryngeal papillomatosis. The carcinoma contained episomal HPV-6a genomes that had a duplication of the upstream regulatory region, the late region and a portion of the early region. HPV-6a genomes found in benign laryngeal papillomas from the same patient did not contain this duplication. A role for the mutant molecules in the pathogenesis of the malignancy is suggested.


Tissue factor and thrombosis models.
Mouse models of thrombosis have extended our understanding of the role of tissue factor (TF) in thrombogenesis. Because tissue factor deficiency is embryonic lethal in mice, inventive genetic models are required to probe the role of TF in thrombosis. TF is expressed by different cell types, including vascular smooth muscle cells, cardiomyocytes, fibroblasts, and monocytes. Platelets and endothelial cells also express TF under certain conditions, but the importance of this TF remains controversial. Animal models are commonly used to evaluate the contribution of TF from each cell type to thrombogenesis. Although a variety of well-established injury techniques are used to induce thrombosis, it is likely that the sources of TF that drive thrombosis are model dependent. Therefore, rigorous controls are needed before thrombogenesis can be attributed to TF from a particular cell type. This review summarizes data from mouse models that have attempted to delineate the role of TF in thrombus formation in response to various types of vascular injury. We have consolidated this information to generate unifying concepts that require testing in future studies.


Individualized treatment of chronic hepatitis C with pegylated interferon and ribavirin.
Chronic infection with hepatitis C virus (HCV) is a major public health problem, with perhaps 180 million people infected worldwide. A significant proportion of these will eventually develop clinical complications, such as cirrhosis, liver decompensation and hepatocellular carcinoma. Sustained virological response (SVR) to antiviral therapy is associated with improvement in liver histology and survival free of liver-related complications. Great effort has been made to improve SVR rate by adapting the duration of therapy according to HCV genotype and to on-treatment response. Rapid virological response (RVR, undetectable HCV RNA at week 4) usually has a high positive predictive value for achieving SVR and early virological response (EVR, ≥ 2 log reduction or undetectable HCV RNA at week 12) exhibits a high negative predictive value for non-response. Individualized approach can improve cost-effectiveness of HCV antiviral therapy by reducing side effects and the costs of therapy associated with unnecessary exposure to treatment and through extending therapy for those with unfavorable features. This article summarizes recent data on strategies of individualized treatment in naïve patients with mono-infection by the different HCV genotypes. The management of common side effects, the impact of HCV infection on health-related quality of life and the potential applications of host genomics in HCV therapy are also briefly discussed.


Ventricular arrhythmia and torsade de pointe: dose limiting toxicities of the MDR-modulator S9788 in a phase I trial.
S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788.


Cytoscape: the network visualization tool for GenomeSpace workflows.
Modern genomic analysis often requires workflows incorporating multiple best-ofbreed tools. GenomeSpace is a web-based visual workbench that combines a selection of these tools with mechanisms that create data flows between them. One such tool is Cytoscape 3, a popular application that enables analysis and visualization of graph-oriented genomic networks. As Cytoscape runs on the desktop, and not in a web browser, integrating it into GenomeSpace required special care in creating a seamless user experience and enabling appropriate data flows. In this paper, we present the design and operation of the Cytoscape GenomeSpace app, which accomplishes this integration, thereby providing critical analysis and visualization functionality for GenomeSpace users. It has been downloaded it over 850 times since the release of its first version in September, 2013.


Microelectrode arrays: a physiologically based neurotoxicity testing platform for the 21st century.
Microelectrode arrays (MEAs) have been in use over the past decade and a half to study multiple aspects of electrically excitable cells. In particular, MEAs have been applied to explore the pharmacological and toxicological effects of numerous compounds on spontaneous activity of neuronal and cardiac cell networks. The MEA system enables simultaneous extracellular recordings from multiple sites in the network in real time, increasing spatial resolution and thereby providing a robust measure of network activity. The simultaneous gathering of action potential and field potential data over long periods of time allows the monitoring of network functions that arise from the interaction of all cellular mechanisms responsible for spatio-temporal pattern generation. In these functional, dynamic systems, physical, chemical, and pharmacological perturbations are holistically reflected by the tissue responses. Such features make MEA technology well suited for the screening of compounds of interest, and also allow scaling to high throughput systems that can record from multiple, separate cell networks simultaneously in multi-well chips or plates. This article is designed to be useful to newcomers to this technology as well as those who are currently using MEAs in their research. It explains how MEA systems operate, summarizes what systems are available, and provides a discussion of emerging mathematical schemes that can be used for a rapid classification of drug or chemical effects. Current efforts that will expand this technology to an influential, high throughput, electrophysiological approach for reliable determinations of compound toxicity are also described and a comprehensive review of toxicological publications using MEAs is provided as an appendix to this publication. Overall, this article highlights the benefits and promise of MEA technology as a high throughput, rapid screening method for toxicity testing.


Spatial sensitivity in the dorsal zone (area DZ) of cat auditory cortex.
We compared the spatial sensitivity of neural responses in three areas of cat auditory cortex: primary auditory cortex (A1), the posterior auditory field (PAF), and the dorsal zone (DZ). Stimuli were 80-ms pure tones or broadband noise bursts varying in free-field azimuth (in the horizontal plane) or elevation (in the vertical median plane), presented at levels 20-40 dB above units' thresholds. We recorded extracellular spike activity simultaneously from 16 to 32 sites in one or two areas of alpha-chloralose-anesthetized cats. We examined the dependence of spike counts and response latencies on stimulus location as well as the information transmission by neural spike patterns. Compared with units in A1, DZ units exhibited more complex frequency tuning, longer-latency responses, increased prevalence and degree of nonmonotonic rate-level functions, and weaker responses to noise than to tonal stimulation. DZ responses also showed sharper tuning for stimulus azimuth, stronger azimuthal modulation of first-spike latency, and enhanced spatial information transmission by spike patterns, compared with A1. Each of these findings was similar to differences observed between PAF and A1. Compared with PAF, DZ responses were of shorter overall latency, and more DZ units preferred stimulation from ipsilateral azimuths, but the majority of analyses suggest strong similarity between PAF and DZ responses. These results suggest that DZ and A1 are physiologically distinct cortical fields and that fields like PAF and DZ might constitute a "belt" region of auditory cortex exhibiting enhanced spatial sensitivity and temporal coding of stimulus features.


The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice.
Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110δ subunit of PI3K (PI3K p110δ) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110δ inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and α4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110δ significantly attenuated eotaxin-1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110δ with siRNA in BM-Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110δ inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110δ in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation.


Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study.
Since the beginning of the coronavirus disease 2019 (COVID-19) outbreak initiated on the Diamond Princess Cruise Ship at Yokohama harbor in February 2020, we have been doing our best to treat COVID-19 patients. In animal experiments, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are reported to suppress the downregulation of angiotensin converting enzyme 2 (ACE2), and they may inhibit the worsening of pathological conditions. We aimed to examine whether preceding use of ACEIs and ARBs affected the clinical manifestations and prognosis of COVID-19 patients. One hundred fifty-one consecutive patients (mean age 60 ± 19 years) with polymerase-chain-reaction proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were admitted to six hospitals in Kanagawa Prefecture, Japan, were analyzed in this multicenter retrospective observational study. Among all COVID-19 patients, in the multiple regression analysis, older age (age ≥ 65 years) was significantly associated with the primary composite outcome (odds ratio (OR) 6.63, 95% confidence interval (CI) 2.28-22.78, P < 0.001), which consisted of (i) in-hospital death, (ii) extracorporeal membrane oxygenation, (iii) mechanical ventilation, including invasive and noninvasive methods, and (iv) admission to the intensive care unit. In COVID-19 patients with hypertension, preceding ACEI/ARB use was significantly associated with a lower occurrence of new-onset or worsening mental confusion (OR 0.06, 95% CI 0.002-0.69, P = 0.02), which was defined by the confusion criterion, which included mild disorientation or hallucination with an estimation of medical history of mental status, after adjustment for age, sex, and diabetes. In conclusion, older age was a significant contributor to a worse prognosis in COVID-19 patients, and ACEIs/ARBs could be beneficial for the prevention of confusion in COVID-19 patients with hypertension.


Gender differences in alpha-[(11)C]MTrp brain trapping, an index of serotonin synthesis, in medication-free individuals with major depressive disorder: a positron emission tomography study.
Women are at higher risk than men for developing major depressive disorder (MDD), but the mechanisms underlying this higher risk are unknown. Here, we report proportionally normalized alpha-[(11)C]methyl-L-tryptophan brain trapping constant (alpha-[(11)C]MTrp K*(N)), an index of serotonin synthesis, in 25 medication-free individuals with MDD and in 25 gender- and age-matched healthy subjects who were studied using positron emission tomography (PET). Comparisons of alpha-[(11)C]MTrp K*(N) values between the men and women were conducted at the voxel and cluster levels using Statistical Parametric Mapping 2 (SPM2) analysis. In addition, the alpha-[(11)C]MTrp K*(N) values on both sides of the brain were extracted and compared to identify the left to right differences, as well as the gender differences. Women with MDD displayed higher alpha-[(11)C]MTrp K*(N) than men in the inferior frontal gyrus, anterior cingulate cortex (ACC), parahippocampal gyrus, precuneus, superior parietal lobule, and occipital lingual gyrus. In a matched group of normal subjects the gender differences were opposite from those found in MDD patients. Significant hemispheric differences in fronto-limbic structures between men and women with MDD were also observed. The K*(N) extracted from the volumes identified in MDD patients and in male and female normal subjects suggested no significant differences between males and females. In conclusion, depressed women have higher serotonin synthesis in multiple regions of the prefrontal cortex and limbic system involved with mood regulation, as compared with depressed men. Gender differences in brain serotonin synthesis may be related to higher risk for MDD in women.


Castration-resistant prostate cancer: latest evidence and therapeutic implications.
Medical oncologists who treat men with castration-resistant prostate cancer (CRPC) have seen an abundance of new agents approved by the United States Food and Drug Administration in the last decade for a disease that was previously difficult to treat after becoming resistant to androgen-deprivation therapy. Advances in understanding of the mechanisms of castration-resistance and prostate cancer progression have highlighted several pathways and targets that appear promising to better treat CRPC. As the majority of CRPC appears to continue to rely on the androgen receptor for growth and progression, several of these agents directly or indirectly target the androgen receptor. A novel microtubule-targeted agent, cabazitaxel, has demonstrated an overall survival benefit following progression on docetaxel. Other agents target tumor immunogenicity and immune checkpoint pathways to attempt to harness the host immune system. The recently approved radiopharmaceutical, radium-223 dichloride, has demonstrated impressive results in patients with extensive bony metastases with minimal toxicity. Lastly, further understanding of the pathways underlying CRPC progression has led to late-phase clinical trials with the novel agents: custirsen, tasquinimod and cabozantinib. This article reviews the approved therapies for CRPC, the agents currently in late-phase clinical trials, and notable early-phase trials of novel therapies and their combinations, with particular attention to trials incorporating novel biomarkers and intermediate endpoints to better identify those men who may or may not benefit from specific therapies.


Biomedical and Behavioral Outcomes of Keep It Up!: An eHealth HIV Prevention Program RCT.
HIV diagnoses among young men who have sex with men are increasing, but few effective HIV prevention interventions exist for this population. An RCT was conducted of the online Keep It Up! intervention to determine if it significantly reduced condomless anal sex and sexually transmitted infections compared with an HIV knowledge condition. From May 2013 to March 2017, a total of 901 participants were enrolled in a double-blinded RCT of Keep It Up! with 1-year follow-up. After completing baseline surveys and sexually transmitted infection testing, participants were randomized by an eHealth platform to the intervention or control condition. HIV-negative men who have sex with men reporting condomless anal sex, aged 18-29 years, were recruited through advertising and from HIV testing sites and outreach in Atlanta, Georgia; Chicago, Illinois; and New York, New York. Multimedia was used to address HIV knowledge and motivate safer behaviors. The control condition reflected existing online HIV information. Primary outcomes were incident gonorrhea or chlamydia at 12-month follow-up and self-reported condomless anal sex with casual partners at 3-, 6-, and 12-month follow-up. In 2017, data were analyzed from 445 (49%) participants randomized to the intervention and 456 (51%) to the control. Participants were primarily racial/ethnic minorities (63%). Sexually transmitted infections at Month 12 was 40% lower for intervention participants (risk ratio=0.60, 95% CI=0.38, 0.95, p=0.01). For the primary behavioral outcome, both arms showed reductions over time with 44% of control and 37% of intervention participants reporting condomless anal sex at Month 12 (prevalence ratio=0.83, 95% CI=0.70, 0.99, p=0.04). The Keep It Up! intervention resulted in significantly lower sexually transmitted infection incidence and a small but significant decrease in condomless anal sex 12 months post-intervention relative to an online HIV knowledge condition. In addition, this study demonstrated the feasibility and acceptability of at-home sexually transmitted infection testing as part of an eHealth intervention. This study is registered at www.clinicaltrials.gov NCT01836445.


Aspirin resistance: Fact or fiction? A point of view.
Aspirin is a wonder drug that has been used for well over 100 years for its analgesic and antipyretic effects. For the past three decades, it has increasingly been used for the prevention of primary and secondary cardiovascular events. Lately, it has been suggested that a significant number of individuals taking aspirin have become resistant to this drug. The phenomenon of "aspirin resistance" is based on the observation of clinical events in some patients taking aspirin, and/or a diminished platelet aggregation inhibitory response to aspirin therapy. Unfortunately, laboratory assays used to monitor the efficacy of aspirin are far from accurate and the results are not reproducible. Furthermore, results of different platelet function tests are often not congruent. In addition, platelet aggregation studies show marked inter-individual and intra-individual variability. Patients with coronary heart disease take many drugs that interfere with the effect of aspirin on platelet aggregation. Besides inhibiting formation of thromboxane A(2) from arachidonic acid, aspirin has a host of platelet-independent effects that complement its platelet inhibitory effects. Laboratory assays designed to measure platelet function do not take into account these pleiotropic effects of aspirin. In our view, use of the term "aspirin resistance" based on inadequate knowledge of imperfect laboratory tests does a disservice to physicians and patients.


[Characteristics of skeletal muscle tissue ribosomes].
Electron-microscopic and chemical analysis of the fraction of RNP-particles, samples of the muscle tissue of the posterior limb of rat and of the human musculus rectus abdominis was carried out for the purpose of characterizing ribosomes of the skeletomuscular tissue. RNP-particle fraction proved to contain functionally-active mono- and poly ribosomes. Two RNA fractions-- RNA1 and RAN11 were isolated. RNA1 proved to represent a set of ribosomic RNA with sedimentation coefficients 26-28S, 16-18S and 4-5S. RNA11 contained no ribosomal RNA, and by its nucleotide composition was affiliated to the nucleotide compostion of rat DNA. The structural organization of ribosomes in the cytoplasm of the muscular fibers corresponded to the pictures observed in the RNP-particle fraction. Polyribosomes are determined in the regions of physiological regeneration of myofibrillae and represent complexes consisting of 5 and more monoribosomes arranged in the form of beads. Ribosomes-like particles proved to escape through the nuclear menbrane; this fact, along with the data of chemical analysis pointed to the periodic passage of RNA from the nucleus into the cytoplasm of hte muscle fiber.


Higher risk of incident hepatitis C virus coinfection among men who have sex with men, in whom the HIV genetic bottleneck at transmission was wide.
High-risk sexual behaviors have been suggested as drivers of the recent dramatic increase of sexually transmitted hepatitis C virus (HCV) among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). We assessed the association between the genetic bottleneck of HIV at transmission and the prevalence and incidence of HCV coinfection in HIV-infected MSM from the Swiss HIV Cohort Study (SHCS). As a proxy for the width of the transmission bottleneck, we used the fraction of ambiguous nucleotides detected by genotypic resistance tests sampled during early HIV infection. We defined a broad bottleneck as a fraction of ambiguous nucleotides exceeding a previously established threshold (0.5%). From the SHCS, we identified 671 MSM with available results of HCV serologic tests and with an HIV genotypic resistance test performed during early HIV infection. Of those, 161 (24.0%) exhibited a broad HIV transmission bottleneck, 38 (5.7%) had at least 1 positive HCV test result, and 26 (3.9%) had an incident HCV infection. Individuals with broad HIV transmission bottlenecks exhibited a 2-fold higher odds of having ever experienced an HCV coinfection (odds ratio, 2.2 [95% confidence interval {CI}, 1.1-4.3]) and a 3-fold higher hazard of having an incident HCV infection (hazard ratio, 3.0 [95% CI, 1.4-6.6]) than individuals with narrow HIV transmission bottlenecks. Our results indicate that the currently occurring sexual spread of HCV is focused on MSM who are prone to exhibit broad HIV transmission bottlenecks. This is consistent with an important role of high-risk behavior and mucosal barrier impairment in the transmission of HCV among MSM.


Major depression and anxiety disorders associated with Norplant.
Norplant is a relatively new long-acting subdermal implant system that is used widely for contraception. In a recent report, Wagner and Berenson described two cases of Norplant-associated major depression and panic disorder. These were the first reports of severe psychiatric disorders linked to the use of Norplant. Five cases are described of women who developed major depression, two of whom also developed obsessive-compulsive disorder and one of whom also developed agoraphobia, while using the Norplant system. These women who had no prior psychiatric history developed major depression within 1 to 3 months after Norplant insertion. The depression worsened over time and in all cases resolved within 1 to 2 months after Norplant removal. There was no recurrence of depression after 7 to 8 months in four cases available for follow-up. In addition to major depression, obsessive-compulsive disorder developed in two women and symptoms of agoraphobia developed in one woman during Norplant treatment, which resolved after Norplant removal. These cases provide further support for the association between Norplant and major depression, as well as a broad spectrum of anxiety disorders. It is important to design prospective studies to carefully examine the incidence of major depression and anxiety disorders in women who use Norplant. Risk factors for these disorders require further clarification.


[Cardiac minute volume and its pattern in Rana ridibunda frogs].
In frogs with an average body mass 56 g, the minute volume of the heart is equal to 4.5 ml/min X 100 g, which is approximately an order lower than in mammals with the same body mass. Pulmonary fraction constitutes 52% of the minute volume of the heart. The main bulk of systemic fraction of the minute volume of the heart (78%) passes to locomotor system and skin, whereas 19% of this volume are adressed to vegetative organs. This pattern of distribution significantly differs from that in mammals with a similar body mass, in which the vegetative and locomotor fractions are approximately equal. Differentiation in muscular blood supply was noted--there is a threefold difference in the volume of blood flow between gastrocnemius and submandibular muscles.


Technology progress on quantum dot light-emitting diodes for next-generation displays.
Quantum dot light-emitting diodes (QD-LEDs) are widely recognised as great alternatives to organic light-emitting diodes (OLEDs) due to their enhanced performances. This focus article surveys the current progress on the state-of-the-art QD-LED technology including material synthesis, device optimization and innovative fabrication processes. A discussion on the material synthesis of core nanocrystals, shell layers and surface-binding ligands is presented for high photoluminescence quantum yield (PLQY) quantum dots (QDs) using heavy-metal free materials. The operational principles of several types of QD-LED device architectures are also covered, and the recent evolution of device engineering technologies is investigated. By exploring the fabrication process for pixel-patterning of QD-LEDs on an active-matrix backplane for full-colour display applications, we anticipate further improvement in device performance for the commercialisation of next-generation displays.


A method for the early health technology assessment of novel biomarker measurement in primary prevention programs.
Many promising biomarkers for stratifying individuals at risk of developing a chronic disease or subsequent complications have been identified. Research into the potential cost-effectiveness of applying these biomarkers in actual clinical settings has however been lacking. Investors and analysts may improve their venture decision making should they have indicative estimates of the potential costs and effects associated with a new biomarker technology already at the early stages of its development. To assist in obtaining such estimates, this paper presents a general method for the early health technology assessment of a novel biomarker technology. The setting considered is that of primary prevention programs where initial screening to select high-risk individuals eligible for a subsequent intervention occurs, for example, prevention of type 2 diabetes. The method is based on quantifying the health outcomes and downstream healthcare consumption of all individuals who get reclassified as a result of moving from a screening variant based on traditional risk factors to a screening variant based on traditional risk factors plus a novel biomarker. As these individuals form well-defined subpopulations, a combination of disease progression modeling and sensitivity analysis can be used to perform an initial assessment of the maximum increase in screening cost for which the use of the new biomarker technology is still likely to be cost effective.