Copy number alterations are associated with metastatic-lethal progression in prostate cancer.
Aside from Gleason score few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that copy number alterations (CNAs), assessed using CpG methylation probes on Illumina Infinium® Human Methylation450 (HM450K) BeadChip arrays, could identify primary prostate tumors with potential to develop metastatic progression. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from two cohorts of PCa patients with clinically localized disease who underwent radical prostatectomy (RP) as primary therapy and were followed prospectively for at least 5 years: (1) a Fred Hutchinson (FH) Cancer Research Center-based cohort (n = 323 patients); and (2) an Eastern Virginia (EV) Medical School-based cohort (n = 78 patients). CNAs were identified using the R package ChAMP. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death. We detected 15 recurrent CNAs were associated with metastasis in the FH cohort and replicated in the EV cohort (p < 0.05) without adjusting for Gleason score in the model. Eleven of the recurrent CNAs were associated with metastatic progression in the FH cohort and validated in the EV cohort (p < 0.05) when adjusting for Gleason score. This study shows that CNAs can be reliably detected from HM450K-based DNA methylation data. There are 11 recurrent CNAs showing association with metastatic-lethal events following RP and improving prediction over Gleason score. Genes affected by these CNAs may functionally relate to tumor aggressiveness and metastatic progression.


Hsp90 inhibitor, BIIB021, induces apoptosis and autophagy by regulating mTOR-Ulk1 pathway in imatinib-sensitive and -resistant chronic myeloid leukemia cells.
Development of drug resistance due to BCR-ABL point mutations and the persistence of leukemia initiating cells has become a major obstacle for tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The BCR-ABL protein is an important client protein of heat shock protein 90 (Hsp90). BIIB021, an orally available Hsp90 inhibitor, has activity against various cancer cells. However, little is known about the inhibitory effect of BIIB021 on CML cells. We evaluated the inhibitory effects of BIIB021 on K562, K562/G (an imatinib-resistant cell lines), as well as 32D mouse leukemic cells expressing wild-type BCR-ABL (b3a2, 32Dp210) and T315I mutant BCR-ABL (32Dp210-T315I) cells. Our data showed that BIIB021 induced significant growth inhibition and apoptosis that was predominantly mediated by the mitochondrial pathway. BIIB021 also resulted in proteasomal degradation of BCR-ABL proteins. In addition to induction of apoptosis, we report for the first time that BIIB021 induced autophagic response as evidenced by the formation of autophagosome, increased conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, decreased p62 (SQSTM1) protein levels. Further study suggested that Akt-mTOR-Ulk1 signaling pathway was involved in BIIB021-triggered autophagy. Moreover, blocking autophagy using pharmacological inhibitor 3-methyladenine and bafilomycin A1 significantly enhanced cell death and apoptosis induced by BIIB021, indicating the cytoprotective role of autophagy in BIIB021-treated CML cells. Collectively, these data provide possible molecular mechanisms for the antileukemic effect of BIIB021 on imatinib-sensitive and -resistant CML cells and provide new insights into the future application of BIIB021 in the clinical treatment of CML.


Preclinical testing of neuroprotective neurotrophic factors in a model of chronic motor neuron degeneration.
Many neurotrophic factors have been shown to enhance survival of embryonic motor neurons or affect their response to injury. Few studies have investigated the potential effects of neurotrophic factors on more mature motor neurons that might be relevant for neurodegenerative diseases. Using organotypic spinal cord cultures from postnatal rats, we have demonstrated that insulin-like growth factor-I (IGF-I) and glial-derived neurotrophic factor (GDNF) significantly increase choline acetyltransferase (ChAT) activity, but brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4/5), and neurotrophin-3 (NT-3) do not. Surprisingly, ciliary neurotrophic factor (CNTF) actually reduces ChAT activity compared to age-matched control cultures. Neurotrophic factors have also been shown to alter the sensitivity of some neurons to glutamate neurotoxicity, a postulated mechanism of injury in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Incubation of organotypic spinal cord cultures in the presence of the glutamate transport inhibitor threo-hydroxyaspartate (THA) reproducibly causes death of motor neurons which is glutamate-mediated. In this model of motor neuron degeneration, IGF-I, GDNF, and NT-4/5 are potently neuroprotective, but BDNF, CNTF, and NT-3 are not. The organotypic glutamate toxicity model appears to be the best preclinical predictor to date of success in human clinical trials in ALS.


Psychosocial risk factors for HIV sexual risk among Indian men who have sex with men.
Indian men who have sex with men (MSM) are at increased risk for HIV compared to the general Indian population. Psychosocial factors may be uniquely associated with HIV risk among Indian MSM and may moderate the beneficial impact of standard HIV prevention approaches. Psychiatric diagnostic interviews and psychosocial and sexual risk assessments were conducted among 150 MSM in Mumbai, India. Logistic regression was employed to examine the association of psychiatric disorders and psychosocial problems to recent sexual risk behavior. Twenty-five percent of participants reported engaging in unprotected anal sex (UAS) during their last sexual contact with a man. Men who were married to a woman were more likely to have engaged in UAS during their last sexual contact with a man (35% vs. 17%, p=0.018). In multivariable models, significant predictors of engaging in UAS were current major depression (adjusted odds ratio [AOR]=2.61; 95% confidence interval [CI] 1.07, 6.39) and number of stressful life events (AOR=0.91; 95% CI 0.83, 0.99). Alcohol dependence, anxiety, and self-esteem were not associated with engaging in UAS. Indian MSM with depression are at higher odds of engaging in UAS compared to MSM without depression. HIV prevention programs for Indian MSM may benefit from incorporating treatment or triage for mental health problems.


Genotyping of Mycobacterium tuberculosis with additional markers enhances accuracy in epidemiological studies.
Two highly polymorphic Mycobacterium tuberculosis genomic domains, characterized by hybridization to the oligonucleotide (GTG)5, were identified as potential DNA fingerprinting probes. These domains were cloned [pMTB484(1) and pMTB484(2K4), respectively] and shown to be useful for genotype analysis by Southern blotting. These probes were used to genotype geographically linked strains of M. tuberculosis previously shown to have identical IS6110 fingerprints. Subsequent DNA fingerprints generated with MTB484(1) and MTB484(2K4) showed a high degree of polymorphism, allowing subclassification of IS6110-defined clusters into composites of smaller clusters and unique strains. Correlation of the molecular data with patient interviews and clinical records confirmed the sensitivity of these probes, as contacts were established only within subclusters. These findings demonstrate the requirement for multiple probes to accurately classify M. tuberculosis strains, even those with high copy numbers of IS6110. The enhanced accuracy of strain typing should, in turn, further our understanding of the epidemiology of tuberculosis.


An itinerant model for delivery of clinical low vision services in a rural community.
In 1976, a premise was developed that resulted in the inception of a mobile low vision service in the State of New Hampshire. Today, the New Hampshire Association for the Blind continues to provide low vision service throughout the state using a mobile clinical van and a training staff who provide training in aid use within the home. The model has proved effective in dealing with the special needs of the low vision population in a rural area.


Correlative fluorescence microscopy and scanning transmission electron microscopy of quantum-dot-labeled proteins in whole cells in liquid.
Correlative fluorescence microscopy and transmission electron microscopy (TEM) is a state-of-the-art microscopy methodology to study cellular function, combining the functionality of light microscopy with the high resolution of electron microscopy. However, this technique involves complex sample preparation procedures due to its need for either thin sections or frozen samples for TEM imaging. Here, we introduce a novel correlative approach capable of imaging whole eukaryotic cells in liquid with fluorescence microscopy and with scanning transmission electron microscopy (STEM); there is no additional sample preparation necessary for the electron microscopy. Quantum dots (QDs) were bound to epidermal growth factor (EGF) receptors of COS7 fibroblast cells. Fixed whole cells in saline water were imaged with fluorescence microscopy and subsequently with STEM. The STEM images were correlated with fluorescence images of the same cellular regions. QDs of dimensions 7x12 nm were visible in a 5 microm thick layer of saline water, consistent with calculations. A spatial resolution of 3 nm was achieved on the QDs.


Cholesterol and triglyceride levels in first-episode psychosis: systematic review and meta-analysis.
BackgroundThe extent of metabolic and lipid changes in first-episode psychosis (FEP) is unclear.AimsTo investigate whether individuals with FEP and no or minimal antipsychotic exposure show lipid and adipocytokine abnormalities compared with healthy controls.MethodWe conducted a meta-analysis of studies examining lipid and adipocytokine parameters in individuals with FEP and no or minimal antipsychotic exposure v. a healthy control group. Studies reported fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and leptin levels.ResultsOf 2070 citations retrieved, 20 case-control studies met inclusion criteria including 1167 patients and 1184 controls. Total cholesterol and LDL cholesterol levels were significantly decreased in patients v. controls, corresponding to an absolute reduction of 0.26 mmol/L and 0.15 mmol/L respectively. Triglyceride levels were significantly increased in the patient group, corresponding to an absolute increase of 0.08 mmol/L. However, HDL cholesterol and leptin levels were not altered in patients v. controls.ConclusionsTotal and LDL cholesterol levels are reduced in FEP, indicating that hypercholesterolaemia in patients with chronic disorder is secondary and potentially modifiable. In contrast, triglycerides are elevated in FEP. Hypertriglyceridaemia is a feature of type 2 diabetes mellitus, therefore this finding adds to the evidence for glucose dysregulation in this cohort. These findings support early intervention targeting nutrition, physical activity and appropriate antipsychotic prescription.


The effect of static stretching of the calf muscle-tendon unit on active ankle dorsiflexion range of motion.
Masked randomized trial. To examine the effects of a 6-week program of static stretching of the calf muscle-tendon unit (MTU) on active ankle dorsiflexion range of motion (ADFROM) in healthy subjects. Static stretching of the calf MTU is often prescribed to increase flexibility in patients with shortened connective tissues or to maintain ADFROM in healthy individuals. Presently, physical therapists lack specific information on the optimal dosage of calf MTU stretching necessary to produce improvement in ADFROM. One hundred one adults (63 women, 38 men; mean age +/- SD, 40.0 +/- 10.9 years; range, 21-59) with no visual evidence of gait impairment due to lower-extremity dysfunction participated in the study. Active ADFROM was measured with a universal goniometer. Participants were randomly assigned to group 1, no stretch controls (n = 24), or to 1 of 3 experimental groups carrying out a 6-week program of standing wall stretches once per day: individuals in group 2 stretched for 30 seconds (n = 26); individuals in group 3 stretched for 1 minute (n = 24); individuals in group 4 stretched for 2 minutes (n = 27). After 6 weeks, the results of an analysis of variance found no effect of treatment on active ADFROM. The results of this study show that a 6-week program of once-per-day static stretching for up to 2 minutes is not sufficient to increase active ADFROM in healthy subjects.


Pilot study to develop telehealth tinnitus management for persons with and without traumatic brain injury.
Tinnitus, or "ringing in the ears," affects 10%-15% of adults; cases can be problematic and require lifelong management. Many people who have experienced traumatic brain injury (TBI) also experience tinnitus. We developed Progressive Tinnitus Management (PTM), which uses education and counseling to help patients learn how to self-manage their reactions to tinnitus. We adapted PTM by delivering the intervention via telephone and by adding cognitive-behavioral therapy. A pilot study was conducted to evaluate the feasibility and potential efficacy of this approach for individuals with and without TBI. Participants with clinically significant tinnitus were recruited into three groups: probable symptomatic mild TBI (n = 15), moderate to severe TBI (n = 9), and no symptomatic TBI (n = 12). Participants received telephone counseling (six sessions over 6 months) by an audiologist and a psychologist. Questionnaires were completed at baseline, 12 weeks, and 24 weeks. All groups showed trends reflecting improvement in self-perceived functional limitations due to tinnitus. A follow-up randomized clinical study is underway.


Pharmacokinetics of beta2-sympathomimetics at the example of fenoterol and conclusion for the administration.
The pharmacokinetics of fenoterol (salbutamol, terbutaline) after systemic administration (i.v., infusion, nasal administration) can be best described by a three-compartmental model. Nasal administration causes an effect-time profile between that of infusion and inhalation. The effects of nasal administration on the lung function and the heart rate depend on the plasma levels of the beta2-agonist. The absorption rate after inhalation differs individually in a large variability (1-27% of the dosage). After inhalation the effect on the lung function does not depend on the absorption rate nor on the plasma levels of the beta2-agonist. After inhalation the effect on the lung function is three- to fivefold more expressed than predictable from the plasma level. From the pk/pd data it can be assumed, that there are 10-20 fold higher concentrations in the airways than in the plasma. It is assumed that there are structures nearby the beta2-receptor responsible for the long-lasting effect observed after inhalation. These depot structures cannot be reached from the plasma in concentrations needed for bronchodilation under in vivo conditions. In respect to the effect/side effect relations, there is no doubt that inhalation is the optimal solution for administering beta2-agonists. In respect to the effect/side effect relations more frequent administration of small doses seems to be more favourable than high doses inhaled in long periods.


Does the Patent Linkage System Prolong Effective Market Exclusivity? Recent Evidence From the Korea-U.S. Free Trade Agreement in Korea.
This study evaluated the effect of the patent linkage system, fully introduced by the Korea-U.S. Free Trade Agreement in 2015, on patent challenges and the effective market exclusivity of new medicines in Korea. We used pharmaceutical approval data and pharmaceutical litigation data to detect new medicines and their counterparts, to collect patent challenges against new medicines, and to calculate effective market exclusivity for new medicines. Then, a nonparametric event history model was applied to statistically explain the duration of the market exclusivity of new medicines. Between 2007 and 2011, a total of 94 new medicines, consisting of 82 new chemical entities and 12 new biologics, were approved. The patent linkage system encouraged patent litigations to occur sooner, with a race to challenge the patents by various generic applicants. However, it was difficult to conclude that patent challenges had a significant impact on the prolongation of effective market exclusivity. The patent linkage system had a neutral effect on the effective market exclusivity of new medicines and encouraged patent challenges without abbreviating effective market exclusivity. In addition, this study highlights an important issue regarding biologics that has not been the subject of market competition, even for patent challenges.


Micronucleus frequency in lymphocytes and 8-hydroxydeoxyguanosine level in plasma of women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) has recently been linked with genomic instability and DNA damage. The aim of this study was to test genomic damage in women PCOS, using two different methods for assessing damage in both chromosome and base level. The study was performed on 36 newly diagnosed women with PCOS and 29 healthy women as controls. The micronucleus (MN) analysis used as a biomarker of chromosomal/DNA damage was performed in peripheral lymphocytes by cytokinesis-block method. 8-hydroxydeoxyguanosine (8-OHdG) levels used as a reliable marker of oxidative DNA damage were measured in plasma using an ELISA kit. We found that MN frequencies obtained from lymphocytes of the women with PCOS were significantly higher than those of controls (4.1 +/- 1.0 vs. 2.1 +/- 0.6, P = 0.001), whereas, no differences in 8-OHdG level were found between the patients with PCOS and controls (0.5 +/- 0.3 vs. 0.5 +/- 0.2, P = 0.858). These findings indicate that women with PCOS seem to have increased genomic instability, but do not appear to have oxidative DNA damage despite the increased oxidative stress associated with PCOS.


Kinetic signature of fractal-like filament networks formed by orientational linear epitaxy.
We study a broad class of epitaxial assembly of filament networks on lattice surfaces. Over time, a scale-free behavior emerges with a 2.5-3 power-law exponent in filament length distribution. Partitioning between the power-law and exponential behaviors in a network can be used to find the stage and kinetic parameters of the assembly process. To analyze real-world networks, we develop a computer program that measures the network architecture in experimental images. Application to triaxial networks of collagen fibrils shows quantitative agreement with our model. Our unifying approach can be used for characterizing and controlling the network formation that is observed across biological and nonbiological systems.


Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity: central role of N-methyl-D-aspartate receptors in the sensitivity mechanism.
The elevated nitric oxide/peroxynitrite and the neural sensitization theories of multiple chemical sensitivity (MCS) are extended here to propose a central mechanism for the exquisite sensitivity to organic solvents apparently induced by previous chemical exposure in MCS. This mechanism is centered on the activation of N-methyl-D-aspartate (NMDA) receptors by organic solvents producing elevated nitric oxide and peroxynitrite, leading in turn to increased stimulating of and hypersensitivity of NMDA receptors. In this way, organic solvent exposure may produce progressive sensitivity to organic solvents. Pesticides such as organophosphates and carbamates may act via muscarinic stimulation to produce a similar biochemical and sensitivity response. Accessory mechanisms of sensitivity may involve both increased blood-brain barrier permeability, induced by peroxynitrite, and cytochrome P450 inhibition by nitric oxide. The NMDA hyperactivity/hypersensitivity and excessive nitric oxide/peroxynitrite view of MCS provides answers to many of the most puzzling aspects of MCS while building on previous studies and views of this condition.


Central and midperipheral corneal thickness measured with Scheimpflug imaging and optical coherence tomography.
To compare corneal thickness measurements using Pentacam (Oculus, Germany), Sirius (CSO, Italy), Galilei (Ziemer, Switzerland), and RTVue-100 OCT (Optovue Inc., USA). Sixty-six eyes of 66 healthy volunteers were enrolled. Three consecutive measurements were performed with each device. The mean value of the three measurements was used for subsequent analysis. Central corneal thickness (CCT), thinnest corneal thickness (TCT), and midperipheral corneal thickness (MPCT; measured at superior, inferior, nasal, and temporal locations with a distance of 1 mm (CT2mm) or 2.5 mm (CT5mm) from the corneal apex) were analyzed. Differences and agreement between measurements were assessed using the repeated-measures analysis of variance (ANOVA) and Bland-Altman analyses, respectively. Statistically significant differences (p<0.001) among the four devices were revealed in CCT, TCT and CT2mm measurements. The CCT, TCT, and CT2mm values were ranked from the thickest to the thinnest as follows: Galilei>Sirius>Pentacam>RTVue OCT. For these measurements, agreement between measurements by Sirius and Pentacam was good, whereas Galilei overestimated and RTVue underestimated corneal thickness compared to Sirius and Pentacam. As regards CT5mm measurements, Pentacam provided the largest values, whereas RTVue OCT yielded the smallest values. Agreement of the CT5mm measurements was good between the Pentacam, Sirius, moderate between Galilei and the other two Scheimpflug systems, and poor between the RTVue OCT and the remaining devices. The Pentacam and Sirius can be used interchangeably for CCT measurements, while the Galilei and RTVue systematically over- and underestimate CCT, respectively. The three Scheimpflug cameras, but not the RTVue, may be used interchangeably for MPCT measurements.


Disease Status-Dependent Drug-Herb Interactions: NASH Lowered the Risk of Hepatotoxicity in Rats Coadministered With Simvastatin and Gardenia jasminoides J. Ellis.
Concurrent use of simvastatin (SV) and Gardenia jasminoides J. Ellis (GJ) was adopted in patients with multi-morbidity, such as stroke rehabilitation patients with NASH. Although hepatotoxicity has been reported in both of them and NASH could alter the pharmacokinetics of drugs/herbs, the interaction between SV and GJ and the related hepatotoxicity remained uninvestigated under neither healthy nor NASH condition. The current study aimed to evaluate the potential hepatotoxicity resulted from the interactions between SV and GJ in both healthy and NASH rats. Both healthy and NASH rats received two-week SV (p. o., 8.66 mg/kg, once daily) and/or GJ (p.o., 325 mg/kg, twice daily). Pharmacokinetic profiles of SV, simvastatin acid (SVA, active metabolite of SV), and geniposide (major component in GJ); hepatic Cyp2c11/Oatp1b2/P-gp expression; and biomarker levels of liver function, lipid levels, and liver histology were compared to demonstrate the interactions in rats. To explore the mechanism of the interaction-mediated hepatotoxicity, hepatic genipin-protein adduct content and iNOS/COX-1/COX-2 expressions from related groups were compared. Moreover, liver histology of healthy/NASH rats at 90 days after discontinuation of two-week GJ in the absence and presence of SV was evaluated to estimate the long-term impact of the interactions. GJ reduced the systemic exposures of SV and SVA by up-regulating the hepatic P-gp expression in healthy but not NASH rats. Meanwhile, SV increased the systemic exposure of geniposide via inhibiting the activity of P-gp in both healthy and NASH rats. Although neither SV nor GJ induced hepatotoxicity in healthy rats, their co-treatment elevated serum ALT and AST levels, which may attribute to the aggravated genipin-protein adduct formation, inflammation infiltration, and iNOS/COX-1 expressions in the liver. In NASH rats, SV and/or GJ reduced serum ALT, AST, LDL/vLDL, and TC levels via alleviating hepatic inflammation infiltration and iNOS/COX-1 expressions. Moreover, in comparison to NASH rats, more severe fibrosis was observed in the livers of healthy rats at 90 days after discontinuation of two-week SV and GJ coadministration. Although interactions between SV and GJ induced short-term and long-term liver injuries in healthy rats, NASH condition in rats could lower such risk.


Enhanced Attentional Bias Variability in Post-Traumatic Stress Disorder and its Relationship to More General Impairments in Cognitive Control.
Hypervigilance towards threat is one of the defining features of post-traumatic stress disorder (PTSD). This symptom predicts that individuals with PTSD will be biased to attend to potential dangers in the environment. However, cognitive tasks designed to assess visual-spatial attentional biases have shown mixed results. A newer proposal suggests that attentional bias is not a static phenomenon, but rather is characterized by fluctuations towards and away from threat. Here, we tested 28 combat Veterans with PTSD and 28 control Veterans on a dot probe task with negative-neutral word pairs. Combat-related words and generically negative words were presented in separate blocks. Replicating previous results, neither group showed a bias to attend towards or away from threat, but PTSD patients showed greater attentional bias variability (ABV), which correlated with symptom severity. However, the cognitive processes indexed by ABV are unclear. The present results indicated that ABV was strongly correlated with standard deviation at the reaction time (RT) level and with excessively long RTs (ex-Gaussian tau) related to cognitive failures. These findings suggest an overall increase in response variability unrelated to threat-related biases in spatial attention, and support a disruption in more general cognitive control processes in PTSD.


Ciona intestinalis: chordate development made simple.
Thanks to their transparent and rapidly developing mosaic embryos, ascidians (or sea squirts) have been a model system for embryological studies for over a century. Recently, ascidians have entered the postgenomic era, with the sequencing of the Ciona intestinalis genome and the accumulation of molecular resources that rival those available for fruit flies and mice. One strength of ascidians as a model system is their close similarity to vertebrates. Literature reporting molecular homologies between vertebrate and ascidian tissues has flourished over the past 15 years, since the first ascidian genes were cloned. However, it should not be forgotten that ascidians diverged from the lineage leading to vertebrates over 500 million years ago. Here, we review the main similarities and differences so far identified, at the molecular level, between ascidian and vertebrate tissues and discuss the evolution of the compact ascidian genome.


[Retinal toxicity following chloroquine therapy].
Two cases of bilateral ocular toxicity following chloroquine therapy in two women with systemic lupus erythematosus are presented. Retinal toxicity due to chloroquine is an uncommon iatrogenic disease. It is dose-dependent. New cases are still being described despite the application of ophthalmic screening techniques.


The Life of Meaning: A Model of the Positive Contributions to Well-Being from Veterinary Work.
We present a veterinary model of work-derived well-being, and argue that educators should not only present a (potentially self-fulfilling) stress management model of future wellness, but also balance this with a positive psychology-based approach depicting a veterinary career as a richly generative source of satisfaction and fulfillment. A review of known sources of satisfaction for veterinarians finds them to be based mostly in meaningful purpose, relationships, and personal growth. This positions veterinary well-being within the tradition of eudaimonia, an ancient concept of achieving one's best possible self, and a term increasingly employed to describe well-being derived from living a life that is engaging, meaningful, and deeply fulfilling. The theory of eudaimonia for workplace well-being should inform development of personal resources that foster resilience in undergraduate and graduate veterinarians.


Motivating inpatients to engage with treatment: the role of depression and ward atmosphere.
Although a number of effective treatments are available for patients on inpatient psychiatric units, the motivation of patients to engage with these treatments is frequently poor. Unmotivated patients may be more likely to drop out of treatment, or discontinue treatment after discharge. The present study examined the relationship of depression and ward atmosphere in influencing motivation. Using a cross-sectional design, 60 patients at a South London Medium Secure Unit completed the Centre for Epidemiological Studies Depression Scale, the Ward Atmosphere Scales and the Patient Motivation Inventory. Regression analyses demonstrated that depression predicts motivation in a relationship that is mediated by ward atmosphere. In addition, ward atmosphere predicts motivation in a relationship that is mediated by depression. The findings suggest a reciprocal relationship between depression and ward atmosphere, and both factors are important in influencing a patient's motivation to engage with treatment. Improving motivation of psychiatric inpatients seems to require both factors to be addressed.


An exponential build-up in seismic energy suggests a months-long nucleation of slow slip in Cascadia.
Slow slip events result from the spontaneous weakening of the subduction megathrust and bear strong resemblance to earthquakes, only slower. This resemblance allows us to study fundamental aspects of nucleation that remain elusive for classic, fast earthquakes. We rely on machine learning algorithms to infer slow slip timing from statistics of seismic waveforms. We find that patterns in seismic power follow the 14-month slow slip cycle in Cascadia, arguing in favor of the predictability of slow slip rupture. Here, we show that seismic power exponentially increases as the slowly slipping portion of the subduction zone approaches failure, a behavior that shares a striking similarity with the increase in acoustic power observed prior to laboratory slow slip events. Our results suggest that the nucleation phase of Cascadia slow slip events may last from several weeks up to several months.


An opposition procedure for detecting age-related deficits in recollection: telling effects of repetition.
In 2 experiments, the advantages of placing automatic and consciously controlled memory processes in opposition to study age-related declines in memory performance were examined. Drawing on the common memory failure of mistakenly repeating oneself, a task was designed in which participants had to rely on conscious memory (recollection) to avoid repetition errors. Recollection proved to be severely affected by aging; older adults showed significantly more repetition errors than did younger adults, even at very short retention intervals. These results contrast sharply with the small age differences found with a standard recognition test. Moreover, L. L. Jacoby's (1991) process-dissociation procedure (Experiment 2) showed that automatic memory processes were unaffected with age and could support recognition performance in older adults. The advantages of the opposition procedure for studying memory in older adults relative to other measures are discussed.


Changing paradigms in the surgical management of hyperparathyroidism at a tertiary care hospital in a developing country.
We report the presentation, management and outcomes of patients operated for hyperparathyroidism at our hospital. Patient sunder going surgery for hyper parathyroidism from 20 05 to 2 015 were retrospectively reviewed. Preoperative biochemistry, diagnostic scans and surgical procedures were studied. Follow up for cure rates, complications and histology were recorded. Out of 72 patients reviewed 54 (75%) were females and the rest males. The mean age was 48.04±15.5 years. Musculoskeletal complains were the most common (76.4%) among the cases reviewed. Asymptomatic hypercalcemia was seen in 13 (18.1%). The mean preoperative PTH level was 658.95 pg/ml and the mean preoperative calcium was 11.9 mg/dl. Bilateral neck exploration was done in 42 (58.3%) while focused unilateral approach was done in 27 (37.5%) cases. Solitary adenoma was the most frequent pathology in 58 (80.5%) patients. Asymptomatic hyperparathyroidism was less frequently detected in our population owing to lack of screening programme. Our patients are younger with a greater severity of the disease both symptomatically and biochemically compared to the West. In almost two decades, preoperative symptoms, calcium and PTH levels have changed marginally. Bilateral explorations are now giving way to focused less invasive procedures.


Exploring lexical gaps in Australian Sign Language for the purposes of health communication.
Until recently no linguistic research had been carried out on Australian Sign Language (Auslan) with regard to its use in healthcare settings, although anecdotal information suggests that the health lexicon of Auslan is strikingly under-developed. This paper describes a study that examined health terminology from the perspective of deaf people. Based on a thematic analysis of focus group data, the paper outlines strategies that deaf Australians report using when communicating about health concepts that do not have established signs in Auslan. Participants described a variety of communicative strategies--including the use of fingerspelling, depiction and explanations--that they employ in order to circumnavigate lexical gaps when talking about health. The study provides a crucial starting point for a discussion of the implications of lexical gaps in Auslan and highlights issues of particular relevance for interpreters who take responsibility for brokering health terms and mediating health communication.


Near-infrared luminescent metallacrowns for combined in vitro cell fixation and counter staining.
Cell fixation is an essential approach for preserving cell morphology, allowing the targeting and labelling of biomolecules with fluorescent probes. One of the key requirements for more efficient fluorescent labelling is the preservation of cell morphology, which usually requires a combination of several fixation techniques. In addition, the use of a counter stain is often essential to improve the contrast of the fluorescent probes. Current agents possess significant limitations, such as low resistance toward photobleaching and sensitivity to changes in the microenvironment. Luminescent Ln3+ 'encapsulated sandwich' metallacrowns (MCs) overcome these drawbacks and offer complementary advantages. In particular, they emit sharp emission bands, possess a large difference between excitation and emission wavelengths and do not photobleach. Herein, MCs formed with pyrazinehydroxamic acid (Ln3+[Zn(ii)MCpyzHA], Ln3+ = Yb, Nd) were used, combined with near-infrared (NIR) counter staining and fixation agents for HeLa cells upon an initial five minute exposure to UV-A light. The validity and quality of the cell fixation were assessed with Raman spectroscopy. Analysis of the NIR luminescence properties of these MCs was performed under different experimental conditions, including in a suspension of stained cells. Moreover, the high emission intensity of Ln3+[Zn(ii)MCpyzHA] in the NIR region allows these MCs to be used for imaging with standard CCD cameras installed on routine fluorescence microscopes. Finally, the NIR-emitting Ln3+[Zn(ii)MCpyzHA] compounds combine, within a single molecule, features such as cell fixation and staining abilities, good photostability and minimal sensitivity of the emission bands to the local microenvironment, and they are highly promising for establishing the next generation of imaging agents with a single biodistribution.


Neonatal septicaemia in the tropics.
This review has shown a high incidence of neonatal septicaemia in a tropical environment. The predisposing factors leading to increased incidence of primary septicaemia include low maternal socioeconomic status, lack of adequate prenatal care, unsterile delivery practices in those born at home and increased incidence of susceptible hosts. Apart from gram-negative organisms, Staphylococcus aureus was the next common agent responsible for neonatal septicaemia. A combination of penicillinase-resistant penicillin and an eminoglycoside in particular gentamycin, should be the initial antibiotic of choice in suspected cases of neonatal septicaemia. Suggestions for reduction in the incidence of neonatal septicaemia were discussed.


Isolation and characterizations of oxalate-binding proteins in the kidney.
Oxalate-binding proteins are thought to serve as potential modulators of kidney stone formation. However, only few oxalate-binding proteins have been identified from previous studies. Our present study, therefore, aimed for large-scale identification of oxalate-binding proteins in porcine kidney using an oxalate-affinity column containing oxalate-conjugated EAH Sepharose 4B beads for purification followed by two-dimensional gel electrophoresis (2-DE) to resolve the recovered proteins. Comparing with those obtained from the controlled column containing uncoupled EAH-Sepharose 4B (to subtract the background of non-specific bindings), a total of 38 protein spots were defined as oxalate-binding proteins. These protein spots were successfully identified by quadrupole time-of-flight mass spectrometry (MS) and/or tandem MS (MS/MS) as 26 unique proteins, including several nuclear proteins, mitochondrial proteins, oxidative stress regulatory proteins, metabolic enzymes and others. Identification of oxalate-binding domain using the PRATT tool revealed "L-x(3,5)-R-x(2)-[AGILPV]" as a functional domain responsible for oxalate-binding in 25 of 26 (96%) unique identified proteins. We report herein, for the first time, large-scale identification and characterizations of oxalate-binding proteins in the kidney. The presence of positively charged arginine residue in the middle of this functional domain suggested its significance for binding to the negatively charged oxalate. These data will enhance future stone research, particularly on stone modulators.


Calculation of the effective index for nonguiding regions.
When the effective-index method is used to reduce a three-dimensional refractive-index distribution to two dimensions, e.g., for use with the two-dimensional beam propagation method, strictly speaking, the effective index n(eff) cannot be calculated for nonguiding regions. Here a technique for obtaining values of n(eff) in such regions is described. The method begins with the index distributions in regions for which values of n(eff) are calculable and then perturbs them for those regions of interest. Using an electro-optic Y-branch optical modulator and a voltage-induced optical waveguide modulator as examples, we demonstrate this method and compare predicted results with measured results.


Human EFO1p exhibits acetyltransferase activity and is a unique combination of linker histone and Ctf7p/Eco1p chromatid cohesion establishment domains.
Proper segregation of chromosomes during mitosis requires that the products of chromosome replication are paired together-termed sister chromatid cohesion. In budding yeast, Ctf7p/Eco1p is an essential protein that establishes cohesion between sister chromatids during S phase. In fission yeast, Eso1p also functions in cohesion establishment, but is comprised of a Ctf7p/Eco1p domain fused to a Rad30p domain (a DNA polymerase) both of which are independently expressed in budding yeast. In this report, we identify and characterize the first candidate human ortholog of Ctf7p/Eco1p, which we term hEFO1p (human Establishment Factor Ortholog). As in fission yeast Eso1p, the hEFO1p open reading frame extends well upstream of the C-terminal Ctf7p/Eco1p domain. However, this N-terminal extension in hEFO1p is unlike Rad30p, but instead exhibits significant homology to linker histone proteins. Thus, hEFO1p is a unique fusion of linker histone and cohesion establishment domains. hEFO1p is widely expressed among the tissues tested. Consistent with a role in chromosome segregation, hEFO1p localizes exclusively to the nucleus when expressed in HeLa tissue culture cells. Moreover, biochemical analyses reveal that hEFO1p exhibits acetyltransferase activity. These findings document the first characterization of a novel human acetyltransferase, hEFO1p, that is comprised of both linker histone and Ctf7p/Eco1p domains.


Hyperthyroidism in Patients with Graves' Ophthalmopathy, and Thyroidal, Skeletal and Eye Muscle Specific Type 2 Deiodinase Enzyme Activities.
Graves' ophthalmopathy is characterized by hyperthyroidism, which is associated with higher serum T3 levels than T4 due to deiodinase enzymes.The effect of Graves' patient's sera (n=52) with elevated thyroid hormone and TSH receptor or thyroid peroxidase antibody (anti-TPO) levels was investigated on thyroidal, skeletal and eye muscle type 2 deiodinase enzyme (DII) activities. DII activities were measured with 125I-T4 substrate, while thyroid hormone and antibody levels with immunoassays.In Graves' ophthalmopathy, sera with elevated FT4 or FT3 levels reduced DII activites remarkably in all tissue fractions. Thyroidal DII activities were lower than those using eye muscle fraction (0.6±0.22 vs 1.14±0.43 pmol/mg/min, P<0.006). Effect of sera with increased FT3 levels demonstrated also reduced DII activities in patients with Graves' ophthalmopathy after methimazole therapy compared to those who had no ophthalmopathy (2.88±2 vs 20.42±11.82 pmol/mg/min, P<0.006 for thyroidal fraction, 4.07±2.72 vs 29.22±15.46 pmol/mg/min, P<0.004 for skeletal muscle, 5.3±3.47 vs 37.87±18.82 pmol/mg/min, P<0.003 for eye muscle). Hyperthyroid sera with TSH receptor antibodies resulted in increased DII activities, while sera with anti-TPO antibodies were connected to lower DII activities in Graves' ophthalmopathy.In summary, the actions of hyperthyroid sera derived from patients with Graves' disease were tested on tissue-specific DII activities. Elevated FT4 level-induced DII inactivation is present in Graves' ophthalmopathy, which seems to be also present at the beginning of methimazole therapy. Stimulating TSH receptor antibiodies increased DII activities via their nongenomic effects using sera of hyperthyroid Graves' ophthalmopathy, but anti-TPO antibodies could influence DII activities via altering FT4 levels.


Organochlorine compound levels in fertile and infertile women from Rio de Janeiro, Brazil.
The aim of the study was quantify organochlorine compounds in women seeking for infertility treatment (n = 15) and in spontaneously pregnant ones (n = 21). A questionnaire was applied regarding lifestyle, occupational and reproductive history. Blood samples were collected from both groups. From the pesticides studied, pp'DDE was detected in 100% of infertile women, at higher mean levels than in pregnant women (3.02 mcg/L vs. 0.88 mcg/L; p = 0.001; power of 69%), without correlation with the etiology of infertility. Levels of the polychlorinated biphenyls (PCBs) were low, with positive samples in 100% in the infertile women for PCBs 138, 153, 180, while in pregnant women, they were 85.7% for congeners 138 and 153. Only PCB180 showed significance, with frequency of 71.4% (p = 0.019). The risk factors for female infertility were: age, consumption of untreated water and of canned foods. Exposure to the most prevalent organochlorine compounds described in literature was confirmed in the study, indicating that pp'DDE may adversely influence female fertility.


"One pill, once daily": what clinicians need to know about Atriplatrade mark.
As the number of persons chronically prescribed antiretrovirals has grown and the realization that antiretrovirals are required to be continued for life, pharmaceutical manufacturers have developed new classes of agents, improved the pharmacokinetics of marketed products through dosing reformulations, and in an effort to maximize success with respect to adherence, compiled into a single dosing unit all necessary elements for an antiretroviral regimen. Atriplatrade mark represents the first ever fixed-dose combination antiretroviral available. This article reviews currently available data on this agent, the impact of resistance on clinical use and implementation, as well as extensive descriptions of the pharmacokinetics, adverse effects and drug-interactions warranting consideration. Whether beginning in a naïve patient or switching from other regimens for tolerability issues, Atriplatrade mark represents a viable option. Its demonstrated advantages with respect to lipid and hematologic parameters and equivalent incidence of renal toxicity are tempered by the findings of bone mineral density decreases, however. Combining multiple mechanisms of action in a single dosing unit appears to improve efficacy, increase the likelihood for adherence and maintain viral suppression compared to administering these agents independently. It is suggested other pharmaceutical companies assess the potential to replicate this for the remaining antiretrovirals.


Involvement of p27KIP1 in the proliferation of the developing corneal endothelium.
To examine the involvement of p27(KIP1) in the regulation of the proliferation of the developing corneal endothelium. Central and peripheral corneas in C57Bl6 mice at postnatal day (P)1, P11, and 12 weeks after birth were analyzed by immunocytochemistry with anti-p27(KIP1), -p57(KIP2), and -proliferating cell nuclear antigen (PCNA) antibodies. Nuclear staining was performed with 4',6'-diamino-2-phenylindole (DAPI) in wholemounts of corneal endothelium of the center and peripheral cornea in wild-type and p27(KIP1) knockout (-/-) mice at 12 weeks of age. p27(KIP1-/-) and control mice were injected with bromodeoxyuridine (BrdU) once on P7, twice per day on P8 and P9, and once on P10 and then were analyzed by a BrdU cell-proliferation assay on P11. On P1, p27(KIP1) immunoreactivity was detected in a small number of corneal endothelial cells, and many endothelial cells expressed PCNA. At P11 and 12 weeks after birth, p27(KIP1) immunoreactivity was detected in many corneal endothelial cells. PCNA-positive cells in the endothelium were rare on P11 and completely absent at 12 weeks after birth. p57(KIP2) was not detected in either corneal epithelium or endothelium at P1, P11, or 12 weeks after birth. In wholemounts of corneal endothelium at 12 weeks of age, the number of endothelial nuclei in the p27(KIP1-/-) mice was significantly higher than that in wild-type mice in both the center and peripheral regions of the cornea. In the BrdU assay, positive cells were abundant in the corneal endothelium of p27(KIP1-/-) mice, whereas there were few positive cells in control mice. PCNA immunoreactivity in the endothelium of the p27(KIP1-/-) mice was completely absent at 12 weeks after birth. These results suggest that p27(KIP1) is involved in the regulation of proliferation in the endothelium of the developing cornea.


Real-life anti-vascular endothelial growth factor treatment for age-related macular degeneration and diabetic macular edema in an Italian tertiary referral hospital.
To study the real-life outcomes of intravitreal anti-vascular endothelial growth factor treatment in patients affected by age-related macular degeneration and diabetic macular edema in an Italian tertiary referral hospital over a 2-year follow-up. Patients with confirmed diagnosis of age-related macular degeneration or diabetic macular edema and 2 years of follow-up were retrospectively analyzed. They underwent a loading dose of three monthly anti-vascular endothelial growth factor injections, with re-treatment performed following a "pro-re-nata" regimen. Best-corrected visual acuity and central retinal thickness were collected and statistically analyzed. In total, 167 diabetic macular edema eyes and 108 age-related macular degeneration eyes were included. Mean age was 63.4 ± 11.8 years for diabetic macular edema and 75.6 ± 8.4 years for age-related macular degeneration. For diabetic macular edema patients, mean number of injections was 5.0 ± 1.7 at 1 year and 2.8 ± 1.8 at 2 years. Mean best-corrected visual acuity improved from 60 Early Treatment for Diabetic Retinopathy Study letters to 66.7 letters at 1 year, and to 70 letters at 2 years (p < 0.001). Mean central retinal thickness decreased from 459 ± 148 µm to 327 ± 163 µm and 261 ± 89 µm, respectively, at the first and the second year (p < 0.001).With respect to age-related macular degeneration patients, mean number of injections was 5.3 ± 2.2 at 1 year and 3.3 ± 1.5 at 2 years. Mean best-corrected visual acuity improved from 63 Early Treatment for Diabetic Retinopathy Study letters to 68 letters at 1 year and to 70 letters at 2 years (p < 0.001). Mean central retinal thickness was 411 ± 146 µm, decreasing to 271 ± 93 µm at 1 year and 260 ± 68 µm at 2 years (p < 0.001). Our study described the 2-year real-life outcome of anti-vascular endothelial growth factor treatment of diabetic macular edema and age-related macular degeneration.


Preparation of uniform-sized colloidosomes based on chitosan-coated alginate particles and its application for oral insulin delivery.
Colloidosomes are microcapsules that consist of a hollow core coated by a shell composed of self-assembled colloidal particles. In recent years, they have attracted significant attention as potential vehicles for the controlled delivery of active ingredients. A key challenge in such applications is the production of uniform-sized colloidosomes for the encapsulation of active ingredients such that the actual delivery amount can be well controlled. Based on our previous study on an ethyl acetate-in-water emulsion stabilized by chitosan-coated alginate particles, we further prepared monodisperse colloidosomes with a high yield and low permeability by combining the premix membrane emulsification technique and polymer deposition method. The potential application of the formed colloidosomes as oral insulin delivery vehicles was investigated. Our results revealed that in comparison to conventional PLGA microspheres, the formulated colloidosomes showed high drug encapsulation efficiency (up to 96.7%) and an obvious pH sensitive release profile. Moreover, in animal testing, the colloidosomes formulation achieved a long-term hypoglycemic effect up to 6 h, which confirmed its application as an oral drug delivery system.


Hairy cell leukemia-new genes, new targets.
Hairy cell leukemia (HCL), a B cell malignancy comprising 2 % of all leukemias, has become quite exciting recently with regard to the development of new targets for therapy. This review will focus on advancements made within the past 1-2 years in targeted therapy for this disease. These advances may be grouped into two very difference categories, namely targeting of CD22 with the recombinant immunotoxin moxetumomab pasudotox, and targeting of the mutated BRAF component of the MAP kinase pathway. Moxetumomab pasudotox in phase I testing was recently reported to be associated with an overall response rate of 86 % and a complete remission (CR) rate of 46 % in 28 patients with relapsed and refractory HCL. Many of the CRs are without minimal residual disease (MRD). Severe or dose limiting toxicity was not observed on this trial, but a completely reversible and largely asymptomatic form of grade 2 hemolytic uremic syndrome occurred in two patients during retreatment. This agent has commenced phase III multicenter testing to validate its phase I results. An extensive number of studies have documented the V600E mutation in nearly all HCL patients, but not in similar hematologic malignancies. The thymidine kinase inhibitor vemurafenib, which inhibits the V600E mutant of BRAF, was reported to induce a CR in multiply relapsed and refractory HCL, with nearly complete clearing of MRD. One additional partial and one additional complete remission were subsequently reported.


[Epicondylitis: etiology, pathogenesis and therapy].
Epicondilites are pathologies poorly understood from the aetiopathogenetic point of view. In this regard, many hypotheses have been considered and numerous anatomical structures are involved. Current therapeutic options are either conservative or surgical. Conservative treatments are: immobilization of the elbow flexed at 90-degrees, stretching the forearm muscles, manipulating the wrist, the application of low-energy extracorporeal shock waves, acupuncture, autologous blood injection under the extensor carpi radialis brevis, laser therapy and pulsed electromagnetic field therapy. Surgical treatments are: fasciotomy, excision of angiofibroblastic hyperplasias located at the origin of extensor carpi radialis brevis, partial release of the orbicular ligament, release of the extensor muscles, elongation of the tendon of extensor carpi radialis brevis and arthroscopic treatment. Advantages and disadvantages are described for each treatment according to the international literature.


Second lytic target of beta-lactam compounds that have a terminal D-amino acid residue.
A new biochemical mechanism of lysing bacterial cells by treatment with certain beta-lactam compounds that possess a terminal D-amino acid moiety in their side chain was demonstrated. The two functions of the molecule, the beta-lactam and terminal D-amino acid moiety, are both involved in the activity of lysing gram-negative bacteria, which is characterized by very rapid lysis of the cells in the first few hours after their contact with the compound. This mechanism was proved by studies on one such compound, named MT-141, which contains a terminal D-cysteine moiety with free amino and carboxyl groups in the 7 beta-side chain of the 7 alpha-methoxy-cephalosporin skeleton. This compound bound to the cell-wall peptidoglycan of Escherichia coli through the D-amino group of its terminal D-amino acid moiety and this seemed to cause rapid cell lysis. Both activities, of binding to peptidoglycan and of causing rapid cell lysis, were inhibited by certain D-amino acids, but not by L-amino acids. Mutants were isolated that had simultaneously gained decreased sensitivity to this kind of beta-lactam compound and supersensitivity to globomycin, an inhibitor of formation of lipoproteins which function in linking the peptidoglycan to the outer membrane. These results suggest that binding of the terminal D-amino acid moiety of the beta-lactam compound to peptidoglycan somehow influences formation of the linkage between the outer membrane and the peptidoglycan and consequently enhances the cell lytic activity of the beta-lactam portion of the molecule.


Diabetes in urban Guinea-Bissau; patient characteristics, mortality and prevalence of undiagnosed dysglycemia.
The burden of diabetes mellitus in Sub-Saharan Africa is growing rapidly, and yet the prevalence and patient characteristics are still largely unknown. We analyzed clinical and demographic characteristics of Type 2 diabetes (T2DM) patients attending a diabetes clinic in Guinea-Bissau from February 2008 to April 2014, and estimated the prevalence and risk factors of unknown-impaired fasting plasma glucose (FPG) and diabetes, as well as excess mortality associated with T2DM. We characterized T2DM patients attending the national diabetes clinic in Bissau. Diabetes was diagnosed based on FPG. We matched T2DM patients 1:1 with non-diabetes community controls on age and sex to determine relevant risk factors for T2DM using logistic regression. Furthermore, we matched patients 1:6 with community controls to assess long-term survival (until February 2019) in a Cox regression using calendar time as the underlying timescale. Verbal autopsies determined the cause of death among T2DM patients and controls. The mean age among T2DM was 50.6 (SD 11.1), and the mean FPG at first consultation was high (13.2 mmol/L (SD 5.1)). Ethnicity, family history of diabetes, hypertension, and anthropometrics differed among T2DM patients, community controls with impaired FPG, and healthy controls. Family history of diabetes (OR = 5.65, 95% CI: 3.10-10.3) and elevated waist circumference (2.33, 1.26-4.29) were significant risk factors for T2DM. 20.4% (59/289) of community controls had abnormal FPG. T2DM patients had an excess mortality hazard ratio of 3.53 (95%CI: 1.92-6.52). Deaths caused by bacterial infections, including foot ulcers, were more common among T2DM patients, compared with community controls (54% (7/13) vs. 19% (5/27) (P = 0.02)). Several risk factors including were associated with T2DM in Guinea-Bissau. We found a high prevalence of elevated FPG among randomly selected community controls. In combination with higher mortality among T2DM patients, an urgent need for better treatment options and increased awareness.


Cancer trends and incidence and mortality patterns in Turkey.
Cancer incidence and mortality rates have been increasing in Turkey as most of the developing countries. Besides socioeconomic factors, one of the most prominent attributes of developing countries is the dissimilarity of their age-dependent demographic structure. In Turkey, cancer incidence rates rise due to individual and environmental risk factors as well as due to the improvement in the registry system and to increase in access to health services. According to the data retrieved from the Ministry of Health Department of Cancer Control database cancer incidence rates increased between 2002 and 2005. Incidence rates rose from 133.78 per 100 thousand in 2002 to 173.85 per 100 thousand in 2005. Between 2002 and 2005 the average growth rate of increase for men comes about 9.7%, which is higher than 8.6% for women leading to the widening of incidence gap between man and women. First five frequent cancer types in Turkey are lung (30.13), prostate (24.33), skin (18.91), breast (17.96), stomach (9.92) cancer with an incidence of per 100 thousand. Cancer incidence growth rates for men exceed the cancer incidence growth rate for women. This gap is resulting mainly from lung cancer incidence which is much higher for men. Further extension of the nationwide cancer screening and prevention programs will result in improvement of cancer control.


Risk of COVID-19 in Rheumatoid Arthritis: A National Veterans Affairs Matched Cohort Study in At-Risk Individuals.
Rheumatoid arthritis (RA) and its treatments are associated with an increased risk of infection, but it remains unclear whether these factors have an impact on the risk or severity of COVID-19. The present study was undertaken to assess the risk and severity of COVID-19 in a US Department of Veterans Affairs (VA) cohort of patients with RA and those without RA. A matched cohort study using national VA data was conducted. Patients diagnosed as having RA were identified among nondeceased individuals who were active in the VA health care system as of January 1, 2020 and who had received care in a VA medical center in 2019; patients for whom no RA diagnostic code was indicated were matched to the RA patients (1:1) by age, sex, and VA site (non-RA controls). Patients diagnosed as having COVID-19 and those with severe COVID-19 (defined as requiring hospitalization or leading to death) were ascertained from a national VA COVID-19 surveillance database through December 10, 2020. Multivariable Cox models were used to compare the risk of COVID-19 and COVID-19 hospitalization or death between RA patients and non-RA controls, after adjusting for demographic characteristics, comorbidities, health care utilization and access, and county-level COVID-19 incidence rates. This VA cohort of RA patients and non-RA controls (n = 33,886 subjects per group) predominantly comprised male patients (84.5%), and the mean age was 67.8 years. During follow-up, 1,503 patients in the cohort were diagnosed as having COVID-19; among them, 388 patients had severe COVID-19 (hospitalization or death), while in 228 patients, the deaths were not related to COVID-19. In the multivariable model, RA was associated with a higher risk of COVID-19 (adjusted hazard ratio [HR] 1.25 [95% confidence interval (95% CI) 1.13-1.39]) and a higher risk of COVID-19 hospitalization or death (adjusted HR 1.35 [95% CI 1.10-1.66]) as compared to non-RA controls. Use of disease-modifying antirheumatic drugs and prednisone, as well as self-reported Black race, self-reported Hispanic ethnicity, and presence of several chronic conditions, but not seropositivity for RA autoantibodies, were each associated with risk of COVID-19 and severe COVID-19 (hospitalization or death). Patients with RA are at higher risk of developing COVID-19 and severe COVID-19 (leading to hospitalization or death) compared to those without RA. With a risk of COVID-19 that approaches that of other recognized chronic conditions, these findings suggest that RA patients should be prioritized for COVID-19 prevention and management strategies.


Proprioceptive and Visual Feedback Responses in Macaques Exploit Goal Redundancy.
A common problem in motor control concerns how to generate patterns of muscle activity when there are redundant solutions to attain a behavioral goal. Optimal feedback control is a theory that has guided many behavioral studies exploring how the motor system incorporates task redundancy. This theory predicts that kinematic errors that deviate the limb should not be corrected if one can still attain the behavioral goal. Studies in humans demonstrate that the motor system can flexibly integrate visual and proprioceptive feedback of the limb with goal redundancy within 90 ms and 70 ms, respectively. Here, we show monkeys (Macaca mulatta) demonstrate similar abilities to exploit goal redundancy. We trained four male monkeys to reach for a goal that was either a narrow square or a wide, spatially redundant rectangle. Monkeys exhibited greater trial-by-trial variability when reaching to the wide goal consistent with exploiting goal redundancy. On random trials we jumped the visual feedback of the hand and found monkeys corrected for the jump when reaching to the narrow goal and largely ignored the jump when reaching for the wide goal. In a separate set of experiments, we applied mechanical loads to the arm of the monkey and found similar corrective responses based on goal shape. Muscle activity reflecting these different corrective responses were detected for the visual and mechanical perturbations starting at ∼90 and ∼70 ms, respectively. Thus, rapid motor responses in macaques can exploit goal redundancy similar to humans, creating a paradigm to study the neural basis of goal-directed motor action and motor redundancy.SIGNIFICANCE STATEMENT Moving in the world requires selecting from an infinite set of possible motor commands. Theories predict that motor commands are selected that exploit redundancies. Corrective responses in humans to either visual or proprioceptive disturbances of the limb can rapidly exploit redundant trajectories to a goal in <100 ms after a disturbance. However, uncovering the neural correlates generating these rapid motor corrections has been hampered by the absence of an animal model. We developed a behavioral paradigm in monkeys that incorporates redundancy in the form of the shape of the goal. Critically, monkeys exhibit corrective responses and timings similar to humans performing the same task. Our paradigm provides a model for investigating the neural correlates of sophisticated rapid motor corrections.


Suppression subtractive hybridization as a basis to assess Mycoplasma agalactiae and Mycoplasma bovis genomic diversity and species-specific sequences.
The phylogenically related Mycoplasma agalactiae and Mycoplasma bovis species are two ruminant pathogens difficult to differentiate and for which a limited amount of sequence data are available. To assess the degree of genomic diversity existing between and within these mycoplasma species, sets of DNA fragments specific for M. bovis type-strain PG45 or for M. agalactiae type-strain PG2 were isolated by suppression subtractive hybridization and used as probes on a panel of M. agalactiae and M. bovis field isolates. Results indicated that approximately 70 % of the DNA fragments specific to one or the other type strain are represented in all field isolates of the corresponding species. Only one M. bovis isolate, which was first classified as M. agalactiae, reacted with 15 % of the PG2-specific probes, while several M. agalactiae isolates reacted with 15 % of the PG45-specific probes. Sequence analyses indicated that most of the genomic diversity observed within one species is related to ORFs with (i) no homologies to proteins recorded in the databases or (ii) homologies to proteins encoded by restriction modification systems. Reminiscent of gene transfer as a means for genomic diversity, a PG45-specific DNA fragment with significant homologies to a central protein of an integrative conjugative element of Mycoplasma fermentans (ICEF) was found in most M. bovis field isolates and in a few M. agalactiae isolates. Finally, sequences encoding part of DNA polymerase III were found in both sets of M. agalactiae- and M. bovis-specific DNA fragments and were used to design a species-specific PCR assay for the identification and differentiation of M. agalactiae and M. bovis.


Cellular events during ovine implantation and impact for gestation.
The establishment of pregnancy in sheep includes elongation of the blastocyst into a filamentous conceptus, pregnancy recognition, production of histotroph, attachment of the conceptus to the endometrium for implantation, and development of synepitheliochorial placentation. These processes are complex, and this review describes some of the molecular events that underlie and support successful pregnancy. The free-floating sheep blastocyst elongates into a filamentous conceptus and metabolizes, or is responsive to, molecules supplied by the endometrium as histotroph. Amongst these molecules are SPP1, glucose and fructose, and arginine that stimulate the MTOR nutrient sensing system. The placental trophectoderm of elongating conceptuses initiate pregnancy recognition and implantation. The mononucleate cells of the trophectoderm secrete IFNT, which acts on the endometrial LE to block increases in estrogen receptor α to preclude oxytocin receptor expression, thereby preventing oxytocin from inducing luteolytic pulses of PGF2α. In addition, IFNT increases expression of IFN stimulated genes in the endometrial stroma, including ISG15, a functional ubiquitin homologue. Implantation is the initial step in placentation, and includes sequential pre-contact, apposition, and adhesion phases. Implantation in sheep includes downregulation of Muc1 and interaction of GLYCAM1, galectin 15 (LGALS15) and SPP1 with lectins and integrins (αvβ3). Sheep have synepitheliochorial placentation in which mononucleate trophectoderm cells fuse to form binucleate cells (BNCs). BNCs migrate and fuse with endometrial LE cells to form trinucleate syncytial cells, and these syncytia enlarge through continued BNC fusion to form syncytial plaques that form the interface between endometrial and placental tissues within the placentome. The placentae of sheep organize into placentomal and interplacentomal regions. In placentomes there is extensive interdigitation of endometrial and placental tissues to provide hemotrophic nutrition to the fetus. In interplacentomal regions there is epitheliochorial attachment of endometrial LE to trophectoderm, mediated through focal adhesion assembly, and areolae that take up histotroph secreted by endometrial GE.


pH, healing rate, and symptom relief in patients with GERD.
Gastroesophageal reflux symptoms are common and occur in all of us from time to time. In others, reflux may be associated with ulcerative esophagitis. The symptoms may be aggravated by large meals, coffee, smoking and position. Physiological and pathological reflux can be separated by the frequency and duration of the exposure of the lower esophagus to acid. Pathological reflux results in symptoms and also esophagitis and ulceration in some patients. Although gastroesophageal reflux disease (GERD) is considered to result from a disorder of motility in the esophagus, gastric acid and peptic activity are deemed pivotal to the initiation and continuation of the esophageal damage and the development of symptoms. Acid exposure in the esophagus is normally less than 4 percent of the 24 hours with a pH below 4. An increase over 4 percent of the time with a pH less than 4 is considered pathological. Hence, antisecretory drugs have become the principle approach to the treatment of reflux symptoms and esophagitis since they reduce the acidity, of gastric juice and the activity of pepsin. Importantly, they also reduce the volume of gastric juice available for reflux into the esophagus. There is a clear relationship between the degree and duration of acid suppression and the relief of heartburn and healing of esophagitis. Pharmacodynamic studies with different dose regimens of the H2-receptor antagonists and the proton pump inhibitors show a difference in the degree and duration of the antisecretory effect, and this correlates closely with the results of clinical trials with respect to the healing of esophagitis and the relief of symptoms. Proton pump inhibitors achieve healing rates by week four, which are not achieved by H2-receptor antagonists even after 12 weeks of treatment. The advantage of proton pump inhibitors over H2-receptor antagonists is due to the greater degree, longer duration of effect and more complete inhibition of acid secretion that maintains intragastric pH above 4 for a maximal duration. Although there is no significant difference between proton pump inhibitors with respect to healing of esophagitis, symptom relief occurs earlier with lansoprazole than omeprazole, and this is probably due to the greater oral bioavailability and faster onset of action of lansoprazole when compared to omeprazole.


Rates and risk factors for suicidal ideation, suicide attempts and suicide deaths in persons with HIV: a protocol for a systematic review and meta-analysis.
The prevalence of HIV/AIDS is high and is associated with psychiatric morbidity and suicide risk. The objective of this study will be to assess the rates of suicidal ideation, suicide attempts and suicide deaths in people living with HIV/AIDS (PLWHA). We present a study protocol for a systematic review and meta-analysis of studies reporting the suicidality outcomes (suicidal ideation, suicide attempts and suicide deaths) in PLWHA. PubMed (MEDLINE), Scopus, EMBASE, Cochrane Library, OVID (HEALTH STAR), OVID (MEDLINE), Joanna Briggs Institute EBP Database, Web of Science and PsychINFO databases will be searched from their inception until 1 January 2020. The primary outcome of interest will be the incidence of suicidality in PLWHA. In addition, we will delineate risk factors associated with suicidality in PLWHA. Citations, full-text articles and abstracts will be screened by four reviewers independently. Disagreements will be resolved through discussion. The study methodological quality (or bias) will be appraised using an appropriate tool. Random-effects meta-analysis will be conducted if we find that the studies are very heterogenous. For the suicidality outcome, probability of suicide risk will be reported. Relative risk ratios (with 95% CIs) will be reported for the effects of the risk factors. Potential publication bias will be assessed by conducting Egger's test and creating funnel plots. We will conduct additional analyses to explore the potential sources of heterogeneity (eg, age, sex and geographical location). No ethics clearance is required as no primary data will be collected. The results of this systematic review and meta-analysis will be presented at scientific conferences and published in a peer-reviewed journal. The results may inform clinical management of PLWHA and may guide future population-specific interventions.We will search PubMed (MEDLINE), Scopus, EMBASE, Cochrane Library, OVID (HEALTH STAR), OVID (MEDLINE), Joanna Briggs Institute EBP Database, Web of Science and PsychINFO from their inception until 1 January 2020. CRD42020161501.


Developmental changes in Cl(-)-ATPase activity in rat brains.
Developmental changes in brain Cl(-)-ATPase activity were examined using fetal, neonatal and adult rats. The Cl(-)-ATPase activity rapidly increased over 20 postnatal days to a level four-fold higher than that in an 18-day-old fetus. On Western blot analysis using an anti-Cl(-)-ATPase/pump 51 kDa subunit (ClP51) antibody, the amount of ClP51 protein increased in parallel with Cl(-)-ATPase activity. Immunohistochemistry using the same antibody showed Cl(-)-ATPase-like immunoreactivity on the cell membranes of neurons such as cerebral and hippocampal pyramidal cells and cerebellar Purkinje cells, where the immunoreactivity increased with developmental changes in the size and shape of the neurons. These findings suggest that neuronal Cl(-)-ATPase activity markedly increases during early postnatal development with an increase in the amount of Cl(-)-ATPase protein, which may support the formation of inwardly directed neuronal Cl(-) gradients.


Reversal of glaucomatous cupping in adults.
Six cases of reversal of cupping have been collected in 28- to 62-year-old patients with open angle glaucoma. Reversal of cupping occurred after filtration surgery in five of the cases and after resolution of a glaucomatocyclitic crisis in one. The average intraocular pressure reduction was 27.5 mm Hg (a 68% fall). Reversal of cupping preponderantly consisted of a reduction in saucerization and undermining of the cup wall. An omnidirectional decrease in cup size resulted. A slight improvement in the visual field occurred in one eye after reversal of cupping. The most likely mechanism to explain reversal of cupping is a reduction in the posterior bowing of the lamina cribrosa and a reduction of scleral canal diameter after normalization of IOP. A distinction between true reversal of cupping and pseudoreversal (caused by disc edema from hypotony) could be made from studying the caliber of the large retinal veins. Treatment of early glaucoma, at which stage reversal of cupping is possible, is suggested.


Muscarinic cholinergic receptors on cultured thyroid cells. I. Biological effect of carbachol and characterization of the receptors.
A muscarinic cholinergic effect on thyrotropin-stimulated cyclic AMP accumulation in cultured porcine thyroid cells is characterized. The muscarinic agonists carbachol, acetylcholine, oxotremorine, and pilocarpine decreased the acute cyclic AMP response to stimulation with thyrotropin (20 mU/ml). A 50% decrease was obtained in the presence of 0.1 mM carbachol. Maximal effects were observed when cells were cultured in the presence of thyrotropin (100 microU/ml) or prostaglandin E2 (1 microM), whereas cells cultured in basal medium or in the presence of dibutyryl cyclic AMP showed a low response to carbachol. Evidence is reported suggesting that carbachol acutely decreases cyclic AMP synthesis. The properties of the muscarinic receptors present in thyroid cells were defined by using the binding of the muscarinic antagonist [3H]quinuclidinyl benzilate to cell homogenates. Scatchard plots revealed a single population of binding sites with a KD of 0.3 nM. The numbers of binding sites per cell after 4 days in culture were 880 in control cells, 4335 in thyrotropin (100 microU/ml)-treated cells, 5600 in prostaglandin (1 microM)-treated cells, and 1420 in dibutyryl cyclic AMP-treated cells. Therefore the sensitivity to carbachol appeared to be related to the number of antagonist binding sites and to be independent of the sensitivity of the cells to acute thyrotropin stimulation.


Ral activation promotes melanomagenesis.
Up to one-third of human melanomas are characterized by an oncogenic mutation in the gene encoding the small guanosine triphosphatase (GTPase) NRAS. Ras proteins activate three primary classes of effectors, namely, Rafs, phosphatidyl-inositol-3-kinases (PI3Ks) and Ral guanine exchange factors (RalGEFs). In melanomas lacking NRAS mutations, the first two effectors can still be activated through an oncogenic BRAF mutation coupled with a loss of the PI3K negative regulator PTEN. This suggests that Ras effectors promote melanoma, regardless of whether they are activated by oncogenic NRas. The only major Ras effector pathway not explored for its role in melanoma is the RalGEF-Ral pathway, in which Ras activation of RalGEFs converts the small GTPases RalA and RalB to an active guanosine triphosphate-bound state. We report that RalA is activated in several human melanoma cancer cell lines harboring an oncogenic NRAS allele, an oncogenic BRAF allele or wild-type NRAS and BRAF alleles. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of RalA, and to a lesser extent of RalB, variably inhibited the tumorigenic growth of melanoma cell lines having these three genotypes. Thus, as is the case for Raf and PI3 K signaling, Rals also contribute to melanoma tumorigenesis.


Early management of myocardial infraction: a report from the Waikato Hospital, New Zealand.
A retrospective review was made of the early management of 50 consecutive patients admitted with an acute myocardial infarction to assess the potential suitability and actual application of thrombolysis, intravenous beta-blockade and aspirin therapy. Thrombolysis was indicated for 15 patients (30%), of whom 14 actually did receive intravenous streptokinase. Thus, 93.3% of all eligible patients received thrombolysis. The main contraindication to thrombolysis was a presentation more than six hours from onset of symptoms in 26 patients (52%). Intravenous beta-blockade was indicated for 17 patients (34%), six patients were actually treated resulting in a therapeutic coverage of 35.3%. Heart failure in 21 patients (42%) was the main contraindication. Aspirin was indicated for 48 patients (96%). However, only 14 were treated giving a therapeutic coverage of 29.2%. A large majority of our patients with an acute myocardial infarction were eligible to receive aspirin which has been a neglected therapeutic modality.


Widespread pain as a risk factor for dysfunctional temporomandibular disorder pain.
Widespread pain has been found to be a risk factor for onset and persistence of temporomandibular disorder (TMD) pain. The aim of this cohort study was to determine if widespread pain is associated with interference and disability related to TMD pain. Three hundred and ninety-seven TMD patients were interviewed at 1 and 2 years following enrollment. Dysfunctional TMD pain was defined as grades IV, III and II with any disability points on the graded chronic pain scale (GCPS). Widespread pain was defined by the number of pain sites (0-4: head, back, stomach, chest) outside the masticatory system. Multivariable logistic regression analysis, controlling for the effects of age, education, depression, baseline GCPS, and time since study enrollment, was used to examine the relationship between widespread pain and risk of onset or maintenance of dysfunctional TMD pain during follow-up. Among women without dysfunctional TMD pain at baseline, widespread pain was a risk factor for development of dysfunctional TMD pain (odds ratio (OR): 1.9, 95% confidence interval (CI): 1.2-2.8, P=0.003). However, there was no association between widespread pain and onset of dysfunctional TMD pain among men (OR: 1.0, 95% CI: 0.4-2.8, P=0.95) or maintenance of dysfunctional TMD among either women (OR: 1.0, 95% CI: 0.8-1.4, P=0.85) or men (OR: 0.4, 95% CI: 0.1-3.2, P=0.40). Widespread pain was independently and highly associated with risk of developing pain-related disability among women who did not have pain dysfunction at baseline, but was not predictive of risk of onset of dysfunctional TMD pain among men or maintenance of dysfunctional pain among either women or men.


Is Empirical Research on Periodization Trustworthy? A Comprehensive Review of Conceptual and Methodological Issues.
Periodization is a core concept in training. Recently, systematic reviews and meta-analyses have attempted to provide a comprehensive overview of the topic, but theoretical criticisms have arisen with regard to how such research has been conducted. The purpose of the study was to review comprehensively the conceptual and methodological issues surrounding empirical research on periodization in training with human subjects. A search was conducted late in February 2016 on Academic Search Complete, CINAHL Plus, MedicLatina, MEDLINE, PsycINFO, PubMed, Scielo, Scopus, SPORTDiscus and Web of Science. Forty-two randomized or randomized controlled trials were retrieved. Problems emerged in three domains: (a) Conceptually, periodization and variation were applied differently in research, while no empirical research tested predictions concerning direction, timing or magnitude of the adaptations; (b) Study design: More than 95% of papers investigated the 'physical' factor (mainly strength). Research on long-term effects was absent (no study lasted more than nine months). Controlling for confounding factors such as nutrition, supplementation and medication was largely ignored; (c) Data analysis was biased as dispersion in responsiveness was ignored when discussing the findings. Overall, research on periodization fails to analyze the conceptual premises proposed by these approaches.


11β-Hydroxylase (CYP11B1) gene variants and new-onset depression in later life.
Cumulative exposure to high glucocorticoid levels is detrimental for the brain and may have particular implications in later life. A feature of late-life depression is increased cortisol secretion. Variants in the CYP11B1 gene, which codes for the enzyme responsible for cortisol synthesis, could influence risk of late-life depression, but this hypothesis has not been examined. We investigated the associations between variants in the CYP11B1 gene and late-life depression, taking into account history of depression and potential sex-specific effects. We assessed depression in 1007 community-dwellers aged 65 years or older (60% women) at baseline and over a 14-year follow-up. A clinical level of depression was defined as a score of ≥ 16 on the Centre for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). We examined incident and recurrent depression in participants without or with a history of major depression, respectively. We genotyped 5 single-nucleotide polymorphisms (SNPs) spanning CYP11B1. We used multivariable analyses to adjust for age, body mass index, cardiovascular ischemic pathologies, hypertension, cognitive impairment and anxiety. In women, rs6471580 and rs7016924 were associated with a 50% lower rate of incident (new-onset) late-life depression, and rs11783855 was associated with a 2.4-fold higher rate of late-life depression. These associations remained after correction for multiple testing, but we found no associations for recurrent depression in women or men. This study focused on the major gene involved in corticosteroid biosynthesis, but other genes may also be implicated in this pathway. Variants of the CYP11B1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner.


Macronuclear genetics of Tetrahymena. I. Random distribution of macronuclear genecopies in T. pyriformis, syngen 1.
The objective of this study was to test the idea that the macronuclear (somatic) genetic information is randomly distributed at each cell division in Tetrahymena pyriformis, syngen 1. We took advantage of a quick and reliable test for the detection of stable vegetative segregants in clones heterozygous for ts2, a heat-sensitive mutation. Clonesthat originated from cells inferred to contain very few (1-3) copies of the ts2-+ allelein their macronuclei were selected for pedigree analysis. Experimental results were compared with the results of a computer simulation of the experiment. Our results are fully consistent with the predictions of the ALLEN-NANNEY-SCHENISTED model concerning the replication and distribution of functional gene copies. This model proposes that themacronucleus contains many functional copies of a given gene that are duplicated once during the cell cycle and are randomly distributed to the two-daughter nuclei. Our work has provided a more sensitive test of the assumption of randomness than was previously available. Our evidence for complete randomness suggests that 45, the effective number ofmacronuclear gene copies previously inferred from the segregation rate, indeed representsthe actual number of copies. This conclusion, coupled with previously available evidence that the macronucleus is approximately 45-ploid, suggest that the segregating genetic units in the macronucleus are in effect haploid. This appears to remove the need to postulate inter-allelic repression to account for the phenomenon of phenotypic assortment. Our results, as well as those of others, also are inconsistent with any simple formof the masterslave hypothesis of ALLEN and GIBSON.


Understanding pediatric bacterial preseptal and orbital cellulitis.
Pediatric preseptal and orbital cellulitis are infectious disorders that result in periorbital inflammation. Preseptal cellulitis is often associated with breaches in the skin barrier whereas orbital cellulitis is commonly associated with paranasal sinusitis. Orbital cellulitis may be associated with subperiosteal abscess. It is important to distinguish between preseptal from orbital cellulitis. Clinical examination and diagnostic imaging are useful in determining appropriate management. Patients are usually treated with broad spectrum antibiotics and surgery when indicated.


A picture-based carbohydrate-counting resource for Somalis.
Objective Carbohydrate counting is essential for effective management of type 1 diabetes (T1D). Somali diet-specific carbohydrate-counting references are lacking, creating an additional barrier to effective diabetes control. We developed a picture-based carbohydrate-counting resource for Somalis with T1D. Methods Traditional Somali foods were selected using a variety of methods. Serving sizes and carbohydrate calculations were tabulated using the United States Department of Agriculture National Nutrient Database for Standard Reference. Carbohydrate contents of home-prepared foods were calculated by measuring the total yield and total carbohydrates of ingredients in the recipe divided by the number of servings to be consumed. When available, recipes were used for food preparation and analysis for more accurate carbohydrate estimation. Results Photographs of prepared Somali foods were compiled into a PDF file. While introductions are written in text, the resource is primarily picture-based to bypass limited literacy. The resource is shared free of charge via the following link: http://journals.sagepub.com/doi/suppl/10.1177/0300060517718732 . The link will be updated annually with new information. Conclusion There is a necessity to tailor educational materials to address the needs of Somalis with diabetes. We have created a picture-based nutrition resource for carbohydrate counting of traditional Somali foods and have made this freely available to individuals worldwide.


Latent Network Features and Overlapping Community Discovery via Boolean Intersection Representations.
We propose a new latent Boolean feature model for complex networks that captures different types of node interactions and network communities. The model is based on a new concept in graph theory, termed the Boolean intersection representation of a graph, which generalizes the notion of an intersection representation. We mostly focus on one form of Boolean intersection, termed cointersection, and describe how to use this representation to deduce node feature sets and their communities. We derive several general bounds on the minimum number of features used in cointersection representations and discuss graph families for which exact cointersection characterizations are possible. Our results also include algorithms for finding optimal and approximate cointersection representations of a graph.


Cell-Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation.
Cell aggregation is frequently impaired during the growth of primary tumors and the formation of metastatic lesions. Cell aggregation depends on cell-cell adhesion; however, no rigorous approach exists to monitor and quantify it accurately in the absence of the confounding factors of cell-substrate adhesion and the resulting cell motility on the substrate. We report here a highly reproducible, automated, microscopy-based quantification of tumor-cell spheroid formation in the absence of cell-substrate adhesion and use it to characterize cell aggregation dynamics in the early steps of this process. This method is based on fluorescence and bright-field microscopy and on a custom MATLAB program to quantify automatically the cells' aggregation kinetics. We demonstrate that the cell-cell adhesion protein E-cadherin and the desmosome proteins DSG2 and DSC2 are important for aggregation. Furthermore, we show that inhibition or silencing of myosin IIa enhances aggregation, suggesting that cytoskeleton tension inhibits tumor cell aggregation. This work opens new avenues to study the principles that govern multicellular aggregation, to characterize the aggregation properties of various tumor cell types, as well as to screen for drugs that inhibit or promote aggregation.


Ayurvedic therapy (shirodhara) for insomnia: a case series.
Insomnia is one of the most common complaints faced by primary care practitioners after pain. Non-pharmacological management of Insomnia that is noninvasive is gaining interest among patients with insomnia. To determine the feasibility of recruiting and retaining participants in a clinical trial on shirodhara, Ayurvedic oil dripping therapy, for insomnia in the United States and also to investigate the therapeutic usefulness of Shirodhara for insomnia using standardized outcome measures. Case series. Shirodhara with Brahmi oil was done for 45 minutes on each participant for 5 consecutive days. Insomnia Severity Index (ISI) was used to evaluate the severity of insomnia as well as to determine the response to Shirodhara therapy. Data were collected at baseline, end of the treatment (day 5) and 1 week after the treatment ended (follow-up). Two males and eight females with a mean age of 40 years (range 23 to 72), SD ± 14.2, were enrolled in the study. One dropped out of the study, but all remaining nine participants experienced improvement at the end of treatment. The percentage of improvement range varied from 3.85% to 69.57%. At follow-up, most participants continued to improve. Comparison of means between baseline and day 5 indicated an overall significant improvement (P < .005), but in a comparison of baseline vs 1 week posttreatment the improvement was not significant (P < .089). No adverse events were reported during the study. Shirodhara with Brahmi oil may be beneficial for moderate to severe insomnia. It is feasible to recruit and retain participants for such therapies in the United States. It is important to validate these findings and investigate the mechanism of action using a larger sample and rigorous research design.


Suppression effect of N-acetylcysteine on bone loss in ovariectomized mice.
Oxidative stress can trigger DNA damage response and activation of cellular senescence. Accumulating studies have demonstrated that senescent cells can produce senescence-associated secretory phenotype that leads to increased bone resorption and decreased bone formation. And elimination of senescent cells or inhibition of SASP secretion has been shown to prevent bone loss in mice. N-acetylcysteine (NAC) is a strong antioxidant. However, it is unclear whether reversed estrogen deficiency-induced bone loss by antioxidant NAC was associated with the inhibition of oxidative stress, DNA damage, osteocyte senescence and SASP. In this study, OVX mice were supplemented with/without E2 or NAC, and were compared with each other. Our results showed that oxidative stress, DNA damage, osteocyte senescence and the secretion of senescence-associated inflammatory cytokines were increased in OVX mice compared with sham-operated mice. However, these parameters were obviously rescued in OVX mice supplemented with E2 or NAC. Data from this study suggest that NAC can prevent OVX-induced bone loss by inhibiting oxidative stress, DNA damage, cell senescence and the secretion of the senescence-associated secretory phenotype.


Two cases of autoimmune hemolytic anemia secondary to brucellosis: a review of hemolytic disorders in patients with brucellosis.
Brucellosis is a worldwide zoonotic disease associated with hemolytic complications, including thrombotic microangiopathy (TMA) and hemolytic anemia. Autoimmune hemolytic anemia (AIHA) is a rare clinical presentation of this disease. In this report, we describe the cases of two patients with brucellosis who presented with Coombs-positive AIHA. We also include a review of the literature on the hemolytic complications of brucellosis. Both patients were successfully treated with a combination of doxycycline and rifampicin in addition to steroids. In the medical literature, there are several cases of TMA associated with brucellosis, although only a few cases of Coombs test-positive AIHA have been reported. Antibiotic therapy is the mainstay of treatment, and the selection of antibiotics and duration of treatment do not differ between brucellosis patients with and without hemolysis. Although rare, the potential for brucellosis should always be kept in mind in patients who present with hemolysis, especially those living in areas where brucellosis is endemic.


An evaluation of acute hydrogen sulfide poisoning in rats through serum metabolomics based on gas chromatography-mass spectrometry.
Hydrogen sulfide (H2S) is the second leading cause of toxin-related deaths in the operational site. Its main target organs of toxic effects are the central nervous system and respiratory system. In this study, we developed a serum metabonomic method, based on gas chromatography-mass spectrometry (GC/MS), to evaluate the effect of acute poisoning by hydrogen sulfide on rats. Pattern recognition analysis, including both principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA), revealed that acute hydrogen sulfide poisoning induced metabolic perturbations. Compared to the control group, the level of urea, glucose, glyceryl stearate in rat serum of the poisoning group increased after two hours, and the level of glucose, docosahexaenoic acid, glyceryl stearate and arachidonic acid in rat serum of the poisoning group increased after 48 h, while the L-valine, galactose, L-tyrosine levels decreased. Our results indicate that metabonomic methods based on GC/MS may be useful to elucidate acute hydrogen sulfide poisoning through the exploration of biomarkers.


Magnetism in AV_{3}Sb_{5} (A=Cs, Rb, and K): Origin and Consequences for the Strongly Correlated Phases.
The V-based kagome systems AV_{3}Sb_{5} (A=Cs, Rb, and K) are unique by virtue of the intricate interplay of nontrivial electronic structure, topology, and intriguing fermiology, rendering them to be a playground of many mutually dependent exotic phases like charge-order and superconductivity. Despite numerous recent studies, the interconnection of magnetism and other complex collective phenomena in these systems has yet not arrived at any conclusion. Using first-principles tools, we demonstrate that their electronic structures, complex fermiologies and phonon dispersions are strongly influenced by the interplay of dynamic electron correlations, nontrivial spin-polarization and spin-orbit coupling. An investigation of the first-principles-derived intersite magnetic exchanges with the complementary analysis of q dependence of the electronic response functions and the electron-phonon coupling indicate that the system conforms as a frustrated spin cluster, where the occurrence of the charge-order phase is intimately related to the mechanism of electron-phonon coupling, rather than the Fermi-surface nesting.


[Asymmetrical otocraniofacial syndrome (hemifacial microsomy) in discordant monozygotic twins. Otologic aspects].
The authors present a case of otocraniofacial syndrome with asymmetric involvement (hemifacial microsomia) in monozygotic twins discordant for the syndrome. Only a few cases of discordance in monozygotic twins have been previously describe in world literature. The occurrence of discordance in identical twins indicates the significance of exogenous factors. The patient had bilateral involvement right side being more severely involved than left side. Conductive hearing loss due to middle ear abnormalities was also present. Usefulness of tomographic examination to study structural ear abnormalities is emphasized, and some comments on the otologic involvement in this syndrome are made.


Bioactive triterpenoids from Salvia species.
Salvia species are important medicinal and culinary plants, and they have been the subject of numerous chemical and biological studies. The bioactive triterpenoids of Salvia species, reported in the literature to date, are reviewed. About 200 triterpenoids, almost 80 of which are new, isolated, and characterized from about 100 Salvia species, are presented herein. In addition to the diverse biological activities of the pure triterpenoids, studies on biological activity of extracts of Salvia species are also described.