Mindfulness Training Changes Brain Dynamics During Depressive Rumination: A Randomized Controlled Trial.
Depression is a leading cause of disability worldwide and its prevalence is on the rise. One of the most debilitating aspects of depression is the dominance and persistence of depressive rumination, a state of mind that is linked to onset and recurrence of depression. Mindfulness meditation trains adaptive attention regulation and present-moment embodied awareness, skills that may be particularly useful during depressive mind states characterized by negative ruminative thoughts. In a randomized controlled functional magnetic resonance imaging study (N = 80), we looked at the neurocognitive mechanisms behind mindfulness-based cognitive therapy (n = 50) for recurrent depression compared with treatment as usual (n = 30) across experimentally induced states of rest, mindfulness practice and rumination, and the relationship with dispositional psychological processes. Mindfulness-based cognitive therapy compared with treatment as usual led to decreased salience network connectivity to the lingual gyrus during a ruminative state, and this change in salience network connectivity mediated improvements in the ability to sustain and control attention to body sensations. These findings showed that a clinically effective mindfulness intervention modulates neurocognitive functioning during depressive rumination and the ability to sustain attention to the body.


Sex-Based Differences in Presentation, Treatment, and Complications Among Older Adults Hospitalized for Acute Myocardial Infarction: The SILVER-AMI Study.
Studies of sex-based differences in older adults with acute myocardial infarction (AMI) have yielded mixed results. We, therefore, sought to evaluate sex-based differences in presentation characteristics, treatments, functional impairments, and in-hospital complications in a large, well-characterized population of older adults (≥75 years) hospitalized with AMI. We analyzed data from participants enrolled in SILVER-AMI (Comprehensive Evaluation of Risk Factors in Older Patients With Acute Myocardial Infarction)-a prospective observational study consisting of 3041 older patients (44% women) hospitalized for AMI. Participants were stratified by AMI subtype (ST-segment-elevation myocardial infarction [STEMI] and non-STEMI [NSTEMI]) and subsequently evaluated for sex-based differences in clinical presentation, functional impairments, management, and in-hospital complications. Among the study sample, women were slightly older than men (NSTEMI: 82.1 versus 81.3, P<0.001; STEMI: 82.2 versus 80.6, P<0.001) and had lower rates of prior coronary disease. Women in the NSTEMI subgroup presented less frequently with chest pain as their primary symptom. Age-associated functional impairments at baseline were more common in women in both AMI subgroups (cognitive impairment, NSTEMI: 20.6% versus 14.3%, P<0.001; STEMI: 20.6% versus 12.4%, P=0.001; activities of daily living disability, NSTEMI: 19.7% versus 11.4%, P<0.001; STEMI: 14.8% versus 6.4%, P<0.001; impaired functional mobility, NSTEMI: 44.5% versus 30.7%, P<0.001; STEMI: 39.4% versus 22.0%, P<0.001). Women with AMI had lower rates of obstructive coronary disease (NSTEMI: P<0.001; STEMI: P=0.02), driven by lower rates of 3-vessel or left main disease than men (STEMI: 38.8% versus 58.7%; STEMI: 24.3% versus 32.1%), and underwent revascularization less commonly (NSTEMI: 55.6% versus 63.6%, P<0.001; STEMI: 87.3% versus 93.3%, P=0.01). Rates of bleeding were higher among women with STEMI (26.2% versus 15.6%, P<0.001) but not NSTEMI (17.8% versus 15.7%, P=0.21). Women had a higher frequency of bleeding following percutaneous coronary intervention with both NSTEMI (11.0% versus 7.8%, P=0.04) and STEMI (22.6% versus 14.8%, P=0.02). Among older adults hospitalized with AMI, women had a higher prevalence of age-related functional impairments and, among the STEMI subgroup, a higher incidence of overall bleeding events, which was driven by higher rates of nonmajor bleeding events and bleeding following percutaneous coronary intervention. These differences may have important implications for in-hospital and posthospitalization needs.


Molecular signaling mechanisms underlying epileptogenesis.
Epilepsy, a disorder of recurrent seizures, is a common and frequently devastating neurological condition. Available therapy is only symptomatic and often ineffective. Understanding epileptogenesis, the process by which a normal brain becomes epileptic, may help identify molecular targets for drugs that could prevent epilepsy. A number of acquired and genetic causes of this disorder have been identified, and various in vivo and in vitro models of epileptogenesis have been established. Here, we review current insights into the molecular signaling mechanisms underlying epileptogenesis, focusing on limbic epileptogenesis. Study of different models reveals that activation of various receptors on the surface of neurons can promote epileptogenesis; these receptors include ionotropic and metabotropic glutamate receptors as well as the TrkB neurotrophin receptor. These receptors are all found in the membrane of a discrete signaling domain within a particular type of cortical neuron--the dendritic spine of principal neurons. Activation of any of these receptors results in an increase Ca2+ concentration within the spine. Various Ca2+-regulated enzymes found in spines have been implicated in epileptogenesis; these include the nonreceptor protein tyrosine kinases Src and Fyn and a serine-threonine kinase [Ca2+-calmodulin-dependent protein kinase II (CaMKII)] and phosphatase (calcineurin). Cross-talk between astrocytes and neurons promotes increased dendritic Ca2+ and synchronous firing of neurons, a hallmark of epileptiform activity. The hypothesis is proposed that limbic epilepsy is a maladaptive consequence of homeostatic responses to increases of Ca2+ concentration within dendritic spines induced by abnormal neuronal activity.


Fear of falling: association between the Modified Falls Efficacy Scale, in-hospital falls and hospital length of stay.
Falls in hospital are costly and may impact psychologically on fallers causing them to avoid mobilization, thereby affecting recovery rate and hospital length of stay. The study aim was to investigate the relationships between fear of falling, falls risk, in-hospital falls and hospital length of stay. A convenience sample (n=141) of patients from a large tertiary hospital was recruited. Data were collected over 6 months using the Modified Falls Efficacy Scale (MFES) on ward admission, prior to discharge, and in the event of a fall. A third of the sample (n=44) was admitted to hospital following a fall. The majority (65%) was categorized as medium falls risk. Twenty-five participants sustained a total of 30 falls during their hospital admission of which 13 sustained a total of 15 falls on the study wards. The mean admission MFES score was 5.5, which increased to 6.1 on hospital discharge. Fallers scored significantly lower admission MFES scores than non-fallers (P=0.003). Receiver-operating curve analysis indicated that admission MFES score was a 'fair' predictor of sustaining a fall (area under curve=0.71, P=0.013). With a cut-off score of 5, admission MFES sensitivity was 77% and specificity was 55%. Study ward fallers had significantly longer hospital length of stay (49 days) than non-fallers (27 days; P=0.037). Furthermore, regardless of whether the participant was a faller or not, significantly longer hospital stay was associated with an admission MFES score of less than 5. An admission MFES score of less than 5 is an effective predictor of patient falls and is associated with a significantly longer hospital length of stay.


HPV types, HIV and invasive cervical carcinoma risk in Kampala, Uganda: a case-control study.
While the association of human papillomavirus (HPV) with cervical cancer is well established, the influence of HIV on the risk of this disease in sub-Saharan Africa remains unclear. To assess the risk of invasive cervical carcinoma (ICC) associated with HIV and HPV types, a hospital-based case-control study was performed between September 2004 and December 2006 in Kampala, Uganda. Incident cases of histologically-confirmed ICC (N=316) and control women (N=314), who were visitors or care-takers of ICC cases in the hospital, were recruited. Blood samples were obtained for HIV serology and CD4 count, as well as cervical samples for HPV testing. HPV DNA detection and genotyping was performed using the SPF10/DEIA/LiPA25 technique which detects all mucosal HPV types by DEIA and identifies 25 HPV genotypes by LiPA version 1. Samples that tested positive but could not be genotyped were designated HPVX. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression, adjusting for possible confounding factors. For both squamous cell carcinoma (SCC) and adenocarcinoma of the cervix, statistically significantly increased ORs were found among women infected with HPV, in particular single HPV infections, infections with HPV16-related types and high-risk HPV types, in particular HPV16, 18 and 45. For other HPV types the ORs for both SCC and adenocarcinoma were not statistically significantly elevated. HIV infection and CD4 count were not associated with SCC or adenocarcinoma risk in our study population. Among women infected with high-risk HPV types, no association between HIV and SCC emerged. However, an inverse association with adenocarcinoma was observed, while decrease in CD4 count was not associated with ICC risk. The ORs for SCC and adenocarcinoma were increased in women infected with HPV, in particular single HPV infections, infections with HPV16- and 18-related types, and high-risk HPV types, specifically HPV16, 18 and 45. HIV infection and CD4 count were not associated with SCC or adenocarcinoma risk, but among women infected with high-risk HPV types there was an inverse association between HIV infection and adenocarcinoma risk. These results suggest that HIV and CD4 count may have no role in the progression of cervical cancer.


Pre-exposure prophylaxis for conception (PrEP-C) as a risk reduction strategy in HIV-positive men and HIV-negative women in the UK.
Couples wishing to have biological children when one partner is HIV positive and the other is HIV negative present clinicians with complex clinical, social and ethical considerations. We established two multidisciplinary pre-conception services for HIV-positive individuals and their partners. We report the first UK use of pre-exposure prophylaxis for conception (PrEP-C) as part of an overall risk reduction strategy. Couples were counselled and written informed consent for PrEP-C was obtained. Patient demographics, HIV and medical histories were recorded. Males underwent baseline semen analysis and seminal HIV viral load testing. Females had full fertility screens. Both partners were screened for sexually transmitted infections. All couples used timed ovulatory intercourse (TOI). Tenofovir±emtricitabine was taken by the female at protocol designated times before±after TOI. Thirty-two male positive/female negative couples used the services. Thirteen couples have used PrEP-C (median age of male 41 years (range 32-56), female 31 (28-43); median CD4 533 (236-1194); all male plasma and seminal HIV viral loads were undetectable). Eleven pregnancies in 10 couples have resulted in 7 live births, 1 ongoing pregnancy and 4 miscarriages (5/40, 6/40, 10/40 and 1 twin 17/40) after a median of 2.5 attempts (range 1-5). PrEP-C was well tolerated with no discontinuations and no HIV transmissions. These data suggest that PrEP-C is a safe and effective option for serodiscordant couples wishing to conceive; a standardised protocol has been developed; data collection via a central database is under way.


Active Learning of Regular Expressions for Entity Extraction.
We consider the automatic synthesis of an entity extractor, in the form of a regular expression, from examples of the desired extractions in an unstructured text stream. This is a long-standing problem for which many different approaches have been proposed, which all require the preliminary construction of a large dataset fully annotated by the user. In this paper, we propose an active learning approach aimed at minimizing the user annotation effort: the user annotates only one desired extraction and then merely answers extraction queries generated by the system. During the learning process, the system digs into the input text for selecting the most appropriate extraction query to be submitted to the user in order to improve the current extractor. We construct candidate solutions with genetic programming (GP) and select queries with a form of querying-by-committee, i.e., based on a measure of disagreement within the best candidate solutions. All the components of our system are carefully tailored to the peculiarities of active learning with GP and of entity extraction from unstructured text. We evaluate our proposal in depth, on a number of challenging datasets and based on a realistic estimate of the user effort involved in answering each single query. The results demonstrate high accuracy with significant savings in terms of computational effort, annotated characters, and execution time over a state-of-the-art baseline.


Glycaemia (haemoglobin A1c) and incident ischaemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study.
Individuals with diabetes have a raised risk of stroke, but it is unclear whether sustained hyperglycaemia contributes to the development of cerebrovascular disease. Haemoglobin A1c (HbA(1c)), a measure of long-term glycaemia, is strongly related to retinopathy, nephropathy, and neuropathy in diabetes. We sought to assess the association between HbA(1c) and stroke in people with and without diabetes. 10,886 participants without diabetes and 1635 participants with diabetes in the ARIC study, who did not have cardiovascular disease, were followed up for incident ischaemic stroke over 8-10 years. We assayed HbA(1c) for all 167 stroke cases and a sample of 680 non-cases in the adults without diabetes and for the full cohort of 1635 adults with diabetes (including 89 stroke cases). We assessed the relation between HbA(1c) concentrations (in tertiles specific for individuals with and without diabetes) and incident ischaemic stroke during follow-up using Cox proportional hazards models, controlling for risk factors for stroke. The adjusted relative risks of stroke increased with increasing tertile of HbA1c in both adults without diabetes (p=0.02) and with diabetes (p<0.0001). Compared with adults without diabetes in the lowest tertile of HbA1c, the adjusted relative risks of stroke by HbA(1c) tertile were 1.18 (0.70-2.00) and 1.58 (0.94-2.66) in adults without diabetes and 1.75 (0.90-3.42), 2.29 (1.24-4.21), and 4.71 (2.69-8.25) in adults with diabetes. Raised HbA(1c) could be an independent risk factor for stroke in people with and without diabetes, with relative risks similar to those previously reported for coronary heart disease.


Curcumin suppresses stem-like traits of lung cancer cells via inhibiting the JAK2/STAT3 signaling pathway.
Tumor recurrence and drug resistance are the main obstacles blocking effective treatment of cancer patients. Cancer stem cells (CSCs) have been demonstrated to be highly related to tumor recurrence and drug resistance. Thus, eliminating CSCs may be an alternative for cancer therapy. Tumor sphere formation is a functional assay to enrich the CSC-like cells. In the present study, we tested the effects of curcumin on lung cancer stem-like cells and report that in addition to inhibition on the proliferation and colony formation of lung cancer cells, curcumin reduces tumor spheres of H460 cells. Moreover, by molecular docking analysis and tumor sphere assay we discover that curcumin was able to inhibit JAK2 activity and reduce tumor spheres via inhibiting the JAK2/STAT3 signaling pathway. In a lung cancer xenograft nude mouse model, curcumin strongly repressed tumor growth. These results imply curcumin may be a potential drug in lung CSC elimination and cancer therapy.


Severe Staphylococcus aureus infections caused by clonally related community-acquired methicillin-susceptible and methicillin-resistant isolates.
We investigated the genetic relatedness of 5 community-acquired (CA) Staphylococcus aureus isolates obtained from 4 consecutive pediatric patients presenting with sepsis syndrome and severe pneumonia during a 3-week period in 2000. Two patients were infected with methicillin-susceptible S. aureus (MSSA), and 2 were infected with methicillin-resistant S. aureus (MRSA). The pulsed-field gel electrophoresis patterns for the 2 CA-MRSA isolates were identical to each other, as were the patterns for the 3 CA-MSSA isolates. A 2-band difference reflecting the presence of a staphylococcal cassette chromosome mec (SCCmec) element distinguished the CA-MRSA isolates from the CA-MSSA isolates. The small, mobile type IV SCCmec element was present in the CA-MRSA isolates. These data suggest that an insertion or, less likely, a deletion of the SCCmec type IV element occurred in a highly virulent S. aureus background. Staphylococcal toxin genes sea, seh, lukS-PV, and lukF-PV were detected in all isolates. Also, in all isolates, was a partial homolog of seo (seo'). The relationship among these patient isolates strengthens the assumption that CA-MRSA infections may be caused by isolates closely related to MSSA isolates.


Inferring progression models for CGH data.
One of the mutational processes that has been monitored genome-wide is the occurrence of regional DNA copy number alterations (CNAs), which may lead to deletion or over-expression of tumor suppressors or oncogenes, respectively. Understanding the relationship between CNAs and different cancer types is a fundamental problem in cancer studies. This article develops an efficient method that can accurately model the progression of the cancer markers and reconstruct evolutionary relationship between multiple types of cancers using comparative genomic hybridization (CGH) data. Such modeling can lead to better understanding of the commonalities and differences between multiple cancer types and potential therapies. We have developed an automatic method to infer a graph model for the markers of multiple cancers from a large population of CGH data. Our method identifies highly related markers across different cancer types. It then builds a directed acyclic graph that shows the evolutionary history of these markers based on how common each marker is in different cancer types. We demonstrated the use of this model in determining the importance of markers in cancer evolution. We have also developed a new method to measure the evolutionary distance between different cancers based on their markers. This method employs the graph model we developed for the individual markers to measure the distance between pairs of cancers. We used this measure to create an evolutionary tree for multiple cancers. Our experiments on Progenetix database show that our markers are largely consistent to the reported hot-spot imbalances and most frequent imbalances. The results show that our distance measure can accurately reconstruct the evolutionary relationship between multiple cancer types.


Noninvasive Transorbital Assessment of the Optic Nerve Sheath in Children: Relationship Between Optic Nerve Sheath Diameter, Deformability Index, and Intracranial Pressure.
Measurement of optic nerve sheath diameter (ONSD) is a promising technique for noninvasive assessment of intracranial pressure (ICP), but has certain limitations. A recent study showed that the deformability index (DI), a dynamic parameter quantifying the pulsatile nature of the optic nerve sheath, could differentiate between patients with high vs normal ICP. To further evaluate the diagnostic accuracy of the DI, when interpreted together with ONSD. This prospective study included children undergoing invasive ICP measurement as part of their clinical management. Ultrasound images of the optic nerve sheath were acquired prior to measuring ICP, the images were further processed to obtain the DI. Patients were dichotomized into high (≥20 mm Hg) or normal ICP groups and compared using the Mann-Whitney U-test. Diagnostic accuracy was described using area under the receiver operating characteristic curve (AUC), sensitivity and specificity, correlation between DI, ONSD, and ICP was investigated using linear regression. A total of 28 patients were included (19 high ICP). The DI was lower in the high ICP group (0.105 vs 0.28, P = .001). AUC was 0.87, and a cut-off value of DI ≤ 0.185 demonstrated sensitivity of 89.5% and specificity of 88.9%. Diagnostic accuracy improved when combining DI with ONSD (AUC 0.98, sensitivity 94.7%, specificity 88.9%) and correlation with ICP improved when combined analysis of DI and ONSD was performed (Pearson correlation coefficient: 0.82 vs 0.42, respectively, P = .012). The DI was significantly lower for patients with high vs normal ICP. This relationship improved further when the DI and ONSD were interpreted together.


Moral injury and psychological wellbeing in UK healthcare staff.
Potentially morally injurious events (PMIEs) can negatively impact mental health. The COVID-19 pandemic may have placed healthcare staff at risk of moral injury. To examine the impact of PMIE on healthcare staff wellbeing. Twelve thousand nine hundred and sixty-five healthcare staff (clinical and non-clinical) were recruited from 18 NHS-England trusts into a survey of PMIE exposure and wellbeing. PMIEs were significantly associated with adverse mental health symptoms across healthcare staff. Specific work factors were significantly associated with experiences of moral injury, including being redeployed, lack of PPE, and having a colleague die of COVID-19. Nurses who reported symptoms of mental disorders were more likely to report all forms of PMIEs than those without symptoms (AOR 2.7; 95% CI 2.2, 3.3). Doctors who reported symptoms were only more likely to report betrayal events, such as breach of trust by colleagues (AOR 2.7, 95% CI 1.5, 4.9). A considerable proportion of NHS healthcare staff in both clinical and non-clinical roles report exposure to PMIEs during the COVID-19 pandemic. Prospective research is needed to identify the direction of causation between moral injury and mental disorder as well as continuing to monitor the longer term outcomes of exposure to PMIEs.


The road to gold: training and peaking characteristics in the year prior to a gold medal endurance performance.
To describe training variations across the annual cycle in Olympic and World Champion endurance athletes, and determine whether these athletes used tapering strategies in line with recommendations in the literature. Eleven elite XC skiers and biathletes (4 male; 28±1 yr, 85±5 mL x min(-1) x kg(-1) VO2max, 7 female, 25±4 yr, 73±3 mL x min(-1) x kg(-1) VO2max) reported one year of day-to-day training leading up to the most successful competition of their career. Training data were divided into periodization and peaking phases and distributed into training forms, intensity zones and endurance activity forms. Athletes trained ∼800 h/500 sessions x year(-1), including ∼500 h x year(-1) of sport-specific training. Ninety-four percent of all training was executed as aerobic endurance training. Of this, ∼90% was low intensity training (LIT, below the first lactate threshold) and 10% high intensity training (HIT, above the first lactate threshold) by time. Categorically, 23% of training sessions were characterized as HIT with primary portions executed at or above the first lactate turn point. Training volume and specificity distribution conformed to a traditional periodization model, but absolute volume of HIT remained stable across phases. However, HIT training patterns tended to become more polarized in the competition phase. Training volume, frequency and intensity remained unchanged from pre-peaking to peaking period, but there was a 32±15% (P<.01) volume reduction from the preparation period to peaking phase. The annual training data for these Olympic and World champion XC skiers and biathletes conforms to previously reported training patterns of elite endurance athletes. During the competition phase, training became more sport-specific, with 92% performed as XC skiing. However, they did not follow suggested tapering practice derived from short-term experimental studies. Only three out of 11 athletes took a rest day during the final 5 days prior to their most successful competition.


Why herd size matters - mitigating the effects of livestock crashes.
Analysing the effect of pastoral risk management strategies provides insights into a system of subsistence that have persevered in marginal areas for hundreds to thousands of years and may shed light into the future of around 200 million households in the face of climate change. This study investigated the efficiency of herd accumulation as a buffer strategy by analysing changes in livestock holdings during an environmental crisis in the Saami reindeer husbandry in Norway. We found a positive relationship between: (1) pre- and post-collapse herd size; and (2) pre-collapse herd size and the number of animals lost during the collapse, indicating that herd accumulation is an effective but costly strategy. Policies that fail to incorporate the risk-beneficial aspect of herd accumulation will have a limited effect and may indeed fail entirely. In the context of climate change, official policies that incorporate pastoral risk management strategies may be the only solution for ensuring their continued existence.


Magnetic resonance imaging and T2 relaxometry of human median nerve at 7 Tesla.
Measurements of T2 relaxation times in tissues have provided a unique, noninvasive method to investigate the microenvironment of water molecules in vivo. As more clinical imaging is performed at higher field strengths, tissue relaxation times need to be reassessed in order to optimize tissue contrast. The purpose of this study was to investigate the water proton T2 relaxation time in human median nerve at 7 T. High-resolution images of the wrist were obtained using a home-built dedicated microstrip coil. Gradient echo images provided a good anatomical delineation of the wrist structure, with a clear definition of the median nerve, tendons, bone, and connective tissue within the wrist in an acquisition time of 2 min. Measurements of the T2 relaxation time were performed with a spin echo imaging sequence. The T2 relaxation time of the median nerve was 18.3 +/- 1.9 ms, which is significantly shorter than the T2 measured in previous studies performed at 1.5 T and 3 T. Further, the T2 relaxation time of the median nerve is shorter than the T2 relaxation time of other tissues, such as brain tissue, at the same field strength. Since the T2 relaxation time of water protons is sensitive to the water microenvironment, relaxation measurements and, in general, a more quantitative magnetic resonance imaging approach might help in detecting and investigating diseases of peripheral nervous system, such as compressive and inflammatory neuropathies, in humans.


Significance of positive and negative syndromes in chronic schizophrenia.
Positive and negative syndromes were studied in relation to demographic, historical, genealogical, clinical, psychometric, extrapyramidal, and follow-up measures of 101 chronic schizophrenic patients. The criterion scales proved to be reliable, normally distributed, and strongly correlated with general psychopathology, but otherwise inversely related to one another. Multiple regression analysis identified sets of 4-6 independent variables that explained 74%-81% of the scales' variance. A positive syndrome was associated chiefly with productive features, family history of sociopathy, more previous hospital admissions, and longer in-patient stay during the 30-month follow-up period. A negative syndrome correlated with deficits in cognitive, affective, social, and motor spheres, higher incidence of major psychiatric illness but less affective disorder among relatives, lower education, and greater cognitive developmental impairment. The results underscore the importance of genetic and biodevelopmental variables for understanding schizophrenic syndromes.


Addressing the shortage of kidneys for transplantation: purchase and allocation through chain auctions.
Transplantation is generally the treatment of choice for those suffering from kidney failure. Not only does transplantation offer improved quality of life and increased longevity relative to dialysis, it also reduces end-stage renal disease program expenditures, providing savings to Medicare. Unfortunately, the waiting list for kidney transplants is long, growing, and unlikely to be substantially reduced by increases in the recovery of cadaveric kidneys. Another approach is to obtain more kidneys through payment to living "donors," or vendors. Such direct commodification, in which a price is placed on kidneys, has generally been opposed by medical ethicists. Much of the ethical debate, however, has been in terms of commodification through market exchange. Recognizing that there are different ethical concerns associated with the purchase of kidneys and their allocation, it is possible to design a variety of institutional arrangements for the commodification of kidneys that pose different sets of ethical concerns. We specify three such alternatives in detail sufficient to allow an assessment of their likely consequences and we compare these alternatives to current policy in terms of the desirable goals of promoting human dignity, equity, efficiency, and fiscal advantage. This policy analysis leads us to recommend that kidneys be purchased at administered prices by a nonprofit organization and allocated to the transplant centers that can organize the longest chains of transplants involving willing-but-incompatible donor-patient dyads.


Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls.
The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls. Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone. Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively. Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.


Structural determinants in human DNA polymerase gamma account for mitochondrial toxicity from nucleoside analogs.
Although antiviral nucleoside analog therapy successfully delays progression of HIV infection to AIDS, these drugs cause unwelcome side-effects by inducing mitochondrial toxicity. We and others have demonstrated that the mitochondrial polymerase, DNA polymerase gamma (pol gamma), participates in mitochondrial toxicity by incorporating these chain-terminating antiviral nucleotide analogs into DNA. Here, we explore the role of three highly conserved amino acid residues in the active site of human pol gamma that modulate selection of nucleotide analogs as substrates for incorporation. Sequence alignments, crystal structures and mutagenesis studies of family A DNA polymerases led us to change Tyr951 and Tyr955 in polymerase motif B to Phe and Ala, and Glu895 in polymerase motif A was changed to Ala. The mutant polymerases were tested for their ability to incorporate natural nucleotides and the five antiviral nucleoside analogs currently approved for antiviral therapy: AZT, ddC, D4T, 3TC and carbovir. Steady-state kinetic analysis of the pol gamma derivatives with the normal and antiviral nucleotides demonstrated that Tyr951 is largely responsible for the ability of pol gamma to incorporate dideoxynucleotides and D4T-MP. Mutation of Tyr951 to Phe renders the enzyme resistant to dideoxynucleotides and D4T-TP without compromising the activity of the polymerase. Alteration of Glu895 and Tyr955 to Ala had the largest effect on overall polymerase activity with normal nucleotides, producing dramatic increases in K(m(dNTP)) and large decreases in k(cat). Mutation of Tyr955 in pol gamma causes the degenerative disease progressive external ophthalmoplegia in humans, and we show that this residue partially accounts for the ability of pol gamma to incorporate D4T-MP and carbovir. Alteration of Glu895 to Ala slightly increased discrimination against dideoxynucleotides and D4T-TP. The mechanisms by which pol gamma selects certain nucleotide analogs are discussed.


R-(+) and S-(-) isomers of cotinine augment cholinergic responses in vitro and in vivo.
The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in some model systems; however, the mechanism of these effects is unknown. In this study, both the R-(+) and S-(-) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at α4β2 or α7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at α7 nAChRs exposed to 1.0 μM R-(+)- or S-(-)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(+)- or S-(-)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer's disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-β-erythroidine, indicating that both α7 and α4β2 nAChRs contribute to the response. These results indicate that cotinine may sensitize α7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders.


In vitro sensitivity and cross-resistance to deoxynucleoside analogs in childhood acute leukemia.
Cytarabine (ara-C) is a key drug in the treatment of acute leukemia. Resistance to ara-C might be circumvented by the use of other deoxynucleoside analogs. Using the MTT assay, we determined in vitro sensitivity and cross-resistance to deoxynucleoside analogs in 362 acute leukemia samples from untreated children and 32 normal bone marrow mononuclear cell samples. Normal bone marrow samples were significantly more resistant to ara-C, cladribine and fludarabine than were acute myeloid leukemia (AML) samples and significantly more resistant to ara-C and fludarabine than were acute lymphoblastic leukemia (ALL) samples. The only drug to which AML samples were more sensitive in vitro than ALL was cladribine. AML FAB M5 was significantly more sensitive in vitro to ara-C and cladribine than FAB M1/2 or FAB M4. T-ALL was significantly more resistant to cladribine than B-cell precursor ALL. A paired analysis of 60 AML and 99 ALL samples demonstrated significant cross-resistance between all four deoxynucleoside analogs. Cross-resistance was also observed between ara-C and etoposide (Rp=0.54, p<0.0001), and ara-C and daunorubicin (Rp=0.48, p<0.0001) in AML. In ALL blasts, cross-resistance was observed between ara-C and vincristine (Rp=0.50; p<0.0001), and between ara-C and daunorubicin and L-asparaginase (Rp=0.25; p=0.01; Rp=0.28; p=0.005). Cladribine appears to be a useful drug in AML, particularly in FAB M5. We observed cross-resistance between ara-C and other deoxynucleoside analogs, as well as between ara-C and drugs with different modes of action in childhood acute leukemia.


A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration.
Ras was found to regulate Dictyostelium chemotaxis, but the mechanisms that spatially and temporally control Ras activity during chemotaxis remain largely unknown. We report the discovery of a Ras signaling complex that includes the Ras guanine exchange factor (RasGEF) Aimless, RasGEFH, protein phosphatase 2A (PP2A), and a scaffold designated Sca1. The Sca1/RasGEF/PP2A complex is recruited to the plasma membrane in a chemoattractant- and F-actin-dependent manner and is enriched at the leading edge of chemotaxing cells where it regulates F-actin dynamics and signal relay by controlling the activation of RasC and the downstream target of rapamycin complex 2 (TORC2)-Akt/protein kinase B (PKB) pathway. In addition, PKB and PKB-related PKBR1 phosphorylate Sca1 and regulate the membrane localization of the Sca1/RasGEF/PP2A complex, and thereby RasC activity, in a negative feedback fashion. Thus, our study uncovered a molecular mechanism whereby RasC activity and the spatiotemporal activation of TORC2 are tightly controlled at the leading edge of chemotaxing cells.


B chromosome in the beetle Coprophanaeus cyanescens (Scarabaeidae): emphasis in the organization of repetitive DNA sequences.
To contribute to the knowledge of coleopteran cytogenetics, especially with respect to the genomic content of B chromosomes, we analyzed the composition and organization of repetitive DNA sequences in the Coprophanaeus cyanescens karyotype. We used conventional staining and the application of fluorescence in situ hybridization (FISH) mapping using as probes C0t-1 DNA fraction, the 18S and 5S rRNA genes, and the LOA-like non-LTR transposable element (TE). The conventional analysis detected 3 individuals (among 50 analyzed) carrying one small metacentric and mitotically unstable B chromosome. The FISH analysis revealed a pericentromeric block of C0t-1 DNA in the B chromosome but no 18S or 5S rDNA clusters in this extra element. Using the LOA-like TE probe, the FISH analysis revealed large pericentromeric blocks in eight autosomal bivalents and in the B chromosome, and a pericentromeric block extending to the short arm in one autosomal pair. No positive hybridization signal was observed for the LOA-like element in the sex chromosomes. The results indicate that the origin of the B chromosome is associated with the autosomal elements, as demonstrated by the hybridization with C0t-1 DNA and the LOA-like TE. The present study is the first report on the cytogenetic mapping of a TE in coleopteran chromosomes. These TEs could have been involved in the origin and evolution of the B chromosome in C. cyanescens.


Dopamine D2-receptor blockade enhances decoding of prefrontal signals in humans.
The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2-receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors, post hoc analyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs.


Words and Patterns That Comprise Resistance Training Exercise Names.
Nuzzo, JL. Words and patterns that comprise resistance training exercise names. J Strength Cond Res 31(3): 826-830, 2017-Limited research exists on the language associated with resistance training. The purpose of this study was to identify the ways in which resistance training exercises are named. Names of 57 exercises were obtained from the National Strength and Conditioning Association's Exercise Technique Manual for Resistance Training. The analysis consisted of categorizing into themes all the words of the exercise names and then identifying naming patterns. Names of the 57 exercises were comprised 188 total words. Seven percent of the words described body position (e.g., "seated"), 1.1% described body position direction (e.g., "over"), 19.1% described a body part (e.g., "shoulder"), 1.1% were body part adjectives ("stiff"), 30.3% described action (e.g., "row"), 5.9% described action direction (e.g., "lateral"), 23.4% described equipment (e.g., "barbell"), 8% described equipment position (e.g., "incline"), and 4.3% were considered miscellaneous (e.g., "power"). Of the 57 exercise names, 22.8% contained a body position word, 3.5% contained a body position direction word, 54.4% contained a body part word, 3.5% contained a body part adjective word, 94.7% contained an action word, 19.3% contained an action direction word, 61.4% contained an equipment word, 26.3% contained an equipment position word, and 12.3% contained a miscellaneous word. These types of words were used inconsistently. Additionally, 35 different naming patterns were discovered among the 57 exercise names. Overall, the findings reveal that current strategies for naming exercises are inconsistent. The strength and conditioning field can use this information to move toward standardizing the way in which resistance training exercises are named.


International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. To establish a common international consensus addressing practical, clinically relevant questions in this setting. An international consensus working group of experts was set up to develop guidelines according to an evidence-based medicine approach, using the GRADE system. For the initial treatment of established VTE: low-molecular-weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case-by-case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long-term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3-6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit-risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12-2 h preoperatively and continued for at least 7-10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l-asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low-dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl<30 mL min(-1) ), thrombocytopenia and pregnancy. Guidances are provided in these contexts. Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.


Bispectral index to monitor propofol sedation in trauma patients.
This study tested the hypothesis that the bispectral index (BIS) is reliable relative to clinical judgment for estimating sedation level during daily propofol spontaneous awakening trials (SATs) in trauma patients. This was a prospective observational trial with waiver of consent conducted in the intensive care unit of Level I trauma center in 94 mechanically ventilated trauma patients sedated with propofol alone or in combination with midazolam. BIS, Richmond Agitation Sedation Scale (RASS), electromyography, and heart rate variability, as a test of autonomic function, were measured for 45 minutes during daily SATs. Data were evaluated with analysis of variance, linear regression, and nonparametric tests. The BIS wave form coincided almost exactly with propofol on/off. Steady-state BIS correlated with RASS (p < 0.0001) and with propofol dose (p < 0.0001), but the strengths of association were relatively low (all r(2) < 0.5). BIS wave form was not altered by age, heart rate, or heart rate variability and was similar with propofol alone or propofol plus midazolam, but the presence of brain injury or the use of paralytics shifted the curve downward (both p < 0.001). The overall test characteristics for BIS versus RASS without neuromuscular blockade were sensitivity: 90% versus 77% (p = 0.034); specificity: 90% versus 75% (p = 0.021); positive predictive value: 90% versus 76% (p = 0.021), and negative predictive value: 90% versus 76% (p = 0.021). In the first trial in trauma patients and largest trial in any surgical population, the (1) BIS was reliable and has advantages over RASS of being continuous and objective, at least during a propofol SAT; (2) BIS interpretation remains somewhat subjective in patients receiving paralytic agents or with traumatic brain injury.


A generic strategy to analyze the spatial organization of multi-protein complexes by cross-linking and mass spectrometry.
Most cellular functions are performed by multi-protein complexes. The identity of the members of such complexes can now be determined by mass spectrometry. Here we show that mass spectrometry can also be used in order to define the spatial organization of these complexes. In this approach, components of a protein complex are purified via molecular interactions using an affinity tagged member and the purified complex is then partially cross-linked. The products are separated by gel electrophoresis and their constituent components identified by mass spectrometry yielding nearest-neighbor relationships. In this study, a member of the yeast nuclear pore complex (Nup85p) was tagged and a six-member sub-complex of the pore was cross-linked and analyzed by 1D SDS-PAGE. Cross-linking reactions were optimized for yield and number of products. Analysis by MALDI mass spectrometry resulted in the identification of protein constituents in the cross-linked bands even at a level of a few hundred femtomoles. Based on these results, a model of the spatial organization of the complex was derived that was later supported by biological experiments. This work demonstrates, that the use of mass spectrometry is the method of choice for analyzing cross-linking experiments aiming on nearest neighbor relationships.


Exposure to metals and semivolatile organic compounds in Australian fire stations.
Firefighting is an occupation with exposure to a wide range of chemicals by means of inhalation, ingestion or dermal contact. Although advancements in personal protective clothing and equipment have reduced the risks for acute exposure during fire suppression operations, chronic exposure may still be present at elevated levels in fire stations. The aim of this study was to assess chemicals in air and on surfaces in fire stations, compare this with other indoor environments, and use this data to estimate firefighter exposure within the fire station. Fifteen Australian fire stations were selected for chemical exposure assessment by means of 135 active air monitors, 60 passive air monitors, and 918 wipe samples. These samples were collected from the interior and exterior of fire stations, from personal protective clothing and equipment, and from within the cabins of vehicles. Chemicals analysed included polycyclic aromatic hydrocarbons, volatile organic compounds, metals, and diesel particulate matter. Specific chemicals were detected from within each class of chemicals, with metals being most frequently detected. Statistical analysis by means of Pearson's Correlations and threshold tests were used to consider the source of exposure, and a collective addition risk quotient calculation was used to determine firefighter exposure. The presence of metals in fire stations was compared with findings from global indoor dust measurements. Concentrations across firefighter ensemble, inside vehicle cabins, and within fire stations for chromium (39.5-493 μg/m2), lead (46.7-619 μg/m2), copper (594-3440 μg/m2), zinc (11100-20900 μg/m2), nickel (28.6-2469 μg/m2) and manganese (73.0-997 μg/m2) were in most instances orders of magnitude higher when compared with concentrations measured in homes and offices. Our study suggests that the elevated concentrations are associated with the transfer of chemicals from fire suppression operations. Due to this elevated concentration of chemicals, firefighters may face increased exposure, and in turn increased risk of adverse health effects. Data suggest that exposure may be mitigated by means of increased laundering frequency and increased decontamination at the scene of the fire.


A novel in ovo model to study cancer metastasis using chicken embryos and GFP expressing cancer cells.
Cancer metastasis is the leading cause of cancer-related mortality worldwide. To date, several in vitro methodologies have been developed to understand the mechanisms of cancer metastasis and to screen various therapeutic agents against it. Nevertheless, mimicking an in vivo microenvironment in vitro is not possible; while in vivo experiments are complex, expensive and bound with several regulatory requirements. Herein, we report a novel in ovo model that relies on chicken embryo to investigate cancer cell invasion and metastasis to various organs of the body. In this model, we directly injected green fluorescent protein (GFP) expressing cancer cells to the heart of chicken embryo at 3 days of incubation, then monitored cell migration to various organs. To this end, we used a simple tissue processing technique to achieve rapid imaging and quantification of invasive cells. We were able to clearly observe the migration of GFP expressing cancer cells into various organs of chicken embryo. Organ specific variation in cell migration was also observed. Our new slide pressing based tissue processing technique improved the detectability of migrated cells. We herein demonstrate that the use of GFP expressing cancer cells allows easy detection and quantification of migrated cancer cells in the chicken embryo model, which minimizes the time and effort required in this types of studies compared to conventional histopathological analysis. In conclusion, our investigation provides a new cancer metastasis model that can be further improved to include more complex aspects, such as the use of multiple cell lines and anti-metastatic agents, thus opening new horizons in cancer biology and pharmaceutical research.


Desipramine treatment of cocaine dependence in methadone-maintained patients.
We performed a double-blind, placebo-controlled, randomized 12-week trial of desipramine hydrochloride treatment of cocaine dependence among methadone-maintained patients. Fifty-nine patients completed the 12-week medication trial (36 received desipramine and 23 received placebo), and 94% were recontacted 1, 3, and 6 months after treatment. There were significantly more dropouts in the desipramine than in the placebo group. Baseline to 12-week comparisons of Addiction Severity Index interview data indicated that both groups showed improvements. At 12 weeks, the desipramine group showed significantly better psychiatric status than the placebo group but did not differ from the placebo group on any of 21 other outcome measures, including cocaine use. During the 12-week medication phase and at the 1-month follow-up evaluation, urine toxicology screenings showed no significant difference between groups, but the placebo group had significantly less cocaine use at both the 3- and 6-month follow-up points. We conclude that desipramine has few benefits with regard to control of cocaine use in this population.


Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen.
Inactivation of the retinoblastoma tumor suppressor protein (pRB) contributes to tumorigenesis in a wide variety of cancers. In contrast, the role of the two pRB-related proteins, p130 and p107, in oncogenic transformation is unclear. The LXCXE domain of simian virus 40 large T antigen (TAg) specifically binds to pRB, p107, and p130. We have previously shown that the N terminus and the LXCXE domain of TAg cooperate to alter the phosphorylation state of p130 and p107. Here, we demonstrate that TAg promotes the degradation of p130 and that the N terminus of TAg is required for this activity. The N terminus of TAg has homology to the J domain of the DnaJ family of molecular chaperone proteins. Mutants with mutations in the J-domain homology region of TAg are defective for altering p130 and p107 phosphorylation and for p130 degradation. A heterologous J-domain from a human DnaJ protein can functionally substitute for the N terminus of TAg in the effect on p107 and p130 phosphorylation and p130 stability. We further demonstrate that the J-domain homology region of TAg confers a growth advantage to wild-type mouse embryo fibroblasts (MEFs) but is dispensable in the case of MEFs lacking both p130 and p107. This indicates that p107 and p130 have overlapping growth-suppressing activities whose inactivation is mediated by the J domain of TAg.


Correlating the crystal structure of a thiol-protected Au25 cluster and optical properties.
The total structure determination of thiol-protected Au clusters has long been a major issue in cluster research. Herein, we report an unusual single crystal structure of a 25-gold-atom cluster (1.27 nm diameter, surface-to-surface distance) protected by eighteen phenylethanethiol ligands. The Au25 cluster features a centered icosahedral Au13 core capped by twelve gold atoms that are situated in six pairs around the three mutually perpendicular 2-fold axes of the icosahedron. The thiolate ligands bind to the Au25 core in an exclusive bridging mode. This highly symmetric structure is distinctly different from recent predictions of density functional theory, and it also violates the empirical golden rule "cluster of clusters", which would predict a biicosahedral structure via vertex sharing of two icosahedral M13 building blocks as previously established in various 25-atom metal clusters protected by phosphine ligands. These results point to the importance of the ligand-gold core interactions. The Au25(SR)18 clusters exhibit multiple molecular-like absorption bands, and we find the results are in good correspondence with time-dependent density functional theory calculations for the observed structure.


A clinical and radiographical comparison of buccolingual crestal bone changes after immediate and delayed implant placement.
The study aims to clinically and radiographically compare the bucco-lingual crestal bone changes after immediate and delayed placement of implants. Two groups that consisted of fifty implants were considered for this study. In group A the implants were placed immediately post extraction, whereas, in group B implants placement were delayed by four to six weeks. All the implants were submerged within the alveoli confines. Bone grafts were only placed if the jumping distance was more than 1.5 mm. Barrier membrane was not placed in any of the cases. Bucco-lingual width was measured at the time of implant placement and during abutment placement after four to six weeks. Primary flap closure was ensured in all the cases. Thirty-one implants were placed in the mandible and nineteen were placed in the maxilla. All the implants achieved osseointegration. Immediate implant group showed a mean width of 8.80 mm (SD2.280) at the time of implant placement whereas, 7.60 mm (SD 1.871) after six months. Delayed implant group showed a mean width of 8.40 mm (SD1.673) at the time of implant placement, and 7.40 mm (SD 1.658) after six months. Intragroup showed statistically significant data (P<0.05). When the intergroup comparison of group 1 and group 2 was made at implant placement day and abutment placement day, it was found to be statistically non-significant. This study suggests that circumferential defect heals on itself without any guided bone regeneration in both the groups. The data suggests that the healing in both the group were equally good. The equally good results suggest placing the implant immediately post extraction. This saves the cost, time and most importantly the need for an extra surgery.


Effects of active/passive interventions on pain, anxiety, and quality of life in women with fibromyalgia: Randomized controlled pilot trial.
The authors of this study compared the effects of pilates exercises and connective tissue massage (CTM) on pain intensity; pain-pressure threshold; and tolerance, anxiety, progress, and health-related quality of life in females with fibromyalgia. It was a pilot, assessor masked, randomized controlled trial conducted between January and August of 2013. Twenty-one women with fibromyalgia were randomly assigned to the pilates exercise program (six of whom did not complete the program), and 22 were randomly assigned to CTM (one of whom did not complete this program). Each group received the assigned intervention three times per week during a 4-week period. The Visual Analogue Scale, algometry, State-Trait Anxiety Inventory, Fibromyalgia Impact Questionnaire, and Nottingham Health Profile were used at baseline and at the end of treatments. Significant improvements were found in both groups for all parameters. However, the scores for pain-pressure threshold were significantly elevated and the symptoms of anxiety were significantly diminished in the exercise group compared to the massage group. Thus, exercise and massage might be used to provide improvements in women with fibromyalgia. The exercise group showed more advantages than the massage group and thus might be preferred for patients with fibromyalgia. However, an adequately powered trial is required to determine this with certainty.


Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes.
Clinical studies in diabetic patients have demonstrated that there is a high incidence of complications in distal tibia and ankle fracture treatments. One strategy to mitigate issues with wound healing and infection in diabetic patients is to use a percutaneous technique in which autologous, bone marrow-derived, concentrated cells are injected at the site of non-unions. Eighty-six ankle non-union in diabetic patients were treated with bone marrow mesenchymal stem cells (BM-MSCs) delivered in an autologous bone marrow concentrate (BMC). Clinical outcomes of the 86 diabetic non-union patients treated with BMC were compared with 86 diabetic matched non-unions treated with a standard bone iliac crest autograft. Treatment with BMC promoted non-union healing in 70 among 86 diabetic patients (82.1 %) with a low number of complications. Of the 86 diabetic patients treated with iliac bone graft, 53 (62.3 %) had healing; major complications were observed: 5 amputations, 11 osteonecroses of the fracture wound edge and 17 infections. In diabetic patients with ankle non-unions, treatment with BM-MSCs from bone marrow concentrate may be preferable in view of the high risks of major complications after open surgery and iliac bone grafting, and improved healing rates compared with standard iliac bone autograft treatment.


Different incidences of knee arthroplasty in the Nordic countries.
Background and purpose - The annual number of total knee arthroplasties (TKAs) has increased worldwide in recent years. To make projections regarding future needs for primaries and revisions, additional knowledge is important. We analyzed and compared the incidences among 4 Nordic countries Patients and methods - Using Nordic Arthroplasty Register Association (NARA) data from 4 countries, we analyzed differences between age and sex groups. We included patients over 30 years of age who were operated with TKA or unicompartmental knee arthroplasty (UKA) during the period 1997-2012. The negative binomial regression model was used to analyze changes in general trends and in sex and age groups. Results - The average annual increase in the incidence of TKA was statistically significant in all countries. The incidence of TKA was higher in women than in men in all 4 countries. It was highest in Finland in patients aged 65 years or more. At the end of the study period in 2012, Finland's total incidence was double that of Norway, 1.3 times that of Sweden and 1.4 times that of Denmark. The incidence was lowest in the youngest age groups (< 65 years) in all 4 countries. The proportional increase in incidence was highest in patients who were younger than 65 years. Interpretation - The incidence of knee arthroplasty steadily increased in the 4 countries over the study period. The differences between the countries were considerable, with the highest incidence in Finland. Patients aged 65 years or more contributed to most of the total incidence of knee arthroplasty.


Plasmodium falciparum merozoite surface protein 3 is a target of allele-specific immunity and alleles are maintained by natural selection.
Plasmodium falciparum merozoite surface protein (MSP) 3 is an asexual blood-stage malaria vaccine candidate antigen. Sequence polymorphisms divide alleles into 2 major types, but the adaptive and immunological significance of the types has not been defined. One hundred one msp3 allele sequences were sampled from 2 populations living in areas where malaria is endemic and were analyzed for evidence of natural selection. Recombinant antigens representing full-length sequences of different allelic types and a relatively conserved C-terminal region were produced, to evaluate immunization-induced antibody responses in mice and protective associations for naturally acquired antibodies in a cohort of 319 Gambian children under surveillance for malaria. Frequency-based statistical analyses indicated that polymorphisms are maintained by balancing selection in each of the 2 populations studied. Immunization of mice with full-length MSP3 antigens induced predominantly type-specific antibodies, and a large proportion of naturally acquired antibodies to MSP3 in humans also discriminated between the alleles. Among Gambian children, antibodies to allele-specific and conserved epitopes in MSP3 were associated prospectively with protection from clinical malaria, even after adjustment for age and for the presence of antibodies to other merozoite antigens. A vaccine incorporating both major allelic types of this promising candidate antigen could be particularly useful for induction of protective immunity in infants and young children.


MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition.
The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is acetylated in epithelial but not mesenchymal cells. Acetylation of LSD1 reduces its association with nucleosomes, thus increasing histone H3K4 methylation at its target genes and activating transcription. The MOF acetyltransferase interacts with LSD1 and is responsible for its acetylation. MOF is preferentially expressed in epithelial cells and is downregulated by EMT-inducing signals. Expression of exogenous MOF impedes LSD1 binding to epithelial gene promoters and histone demethylation, thereby suppressing EMT and tumor invasion. Conversely, MOF depletion enhances EMT and tumor metastasis. In human cancer, high MOF expression correlates with epithelial markers and a favorable prognosis. These findings provide insight into the regulation of LSD1 and EMT and identify MOF as a critical suppressor of EMT and tumor progression.


Antieosinophil serum and the kinetics of eosinophilia in Schistosomiasis mansoni.
Mice were exposed to different intensities of infection with Schistosoma mansoni (10, 50, or 200 cercariae) and the kinetics of peripheral and bone marrow eosinophilia was followed for as long as 20 wk. When the schistosomula (immature worms) were migrating from the lungs to the liver there was a mild, transient eosinophilia, but soon after the onset of egg laying by the schistosomes, a major and prolonged increase in eosinophils occurred. This was terminated in the heavier infections by the death of the animals, but showed a spontaneous decline beginning at 18 wk in the lightly infected mice. The effect of S. mansoni eggs on eosinophilia in the blood, bone marrow, and granulomatous lesions was then examined by injecting schistosome eggs into mice intraperitoneally, subcutaneously, and intravenously. While the host response was dependent on the route by which eggs were administered, primary peripheral and bone marrow responses were seen on intravenous injection, and secondary responses occurred on intravenous and subcutaneous injection. In unsensitized and egg-sensitized mice, eosinophils were first seen around eggs injected into the pulmonary microvasculature at 96 and 24 h respectively. When the granulomas were maximal in size eosinophils made up at least 50% of the lesions. Administration of antieosinophil serum profoundly suppressed eosinophils in the peripheral blood, eliminated mature eosinophils and markedly increased eosinophil precursors in the bone marrow, and ablated eosinophils from the tissue lesions, considerably reducing their area.


Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas.
The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of the characteristics of β-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function.


Sequential effects of phonological priming in visual word recognition.
Two masked priming experiments were conducted to examine phonological priming of bisyllabic words in French, and in particular, whether it operates sequentially or in parallel. Bisyllabic target words were primed by pseudowords that shared either the first or the second phonological syllable of the target. Overlap of the first syllable only-not the second-produced facilitation in both the lexical decision and the naming tasks. These findings suggest that, for polysyllabic words, phonological codes are computed sequentially during silent reading and reading aloud.


Medicaid coverage of maternity care for aliens in California.
The quantity and cost-effectiveness of prenatal care is a critical reproductive health issue as federal and state legislators consider reducing publicly funded services to aliens. An analysis of data from medi-Cal, California's Medicaid program, shows that undocumented and legalized aliens who qualified for coverage under the provisions of federal legislation or the state's expansion of eligibility criteria accounted for 45% of deliveries financed by Medi-Cal in 1991; outlays for these deliveries are estimated at less than 2% of all Medi-Cal payments for that year. Most of these women also received prenatal care covered by Medi-Cal, but more than half were not enrolled in the program until after the first trimester of pregnancy (and thus may not have received adequate prenatal care). Alien women were enrolled for an average of 5-6 months of their pregnancy, whereas nonalien women who qualified for coverage were enrolled for about seven months. California's Proposition 187 would eliminate funding for prenatal care for undocumented aliens, but public outlays for labor and delivery could grow as a result of an increase in poor birth outcomes.


Beyond core object recognition: Recurrent processes account for object recognition under occlusion.
Core object recognition, the ability to rapidly recognize objects despite variations in their appearance, is largely solved through the feedforward processing of visual information. Deep neural networks are shown to achieve human-level performance in these tasks, and explain the primate brain representation. On the other hand, object recognition under more challenging conditions (i.e. beyond the core recognition problem) is less characterized. One such example is object recognition under occlusion. It is unclear to what extent feedforward and recurrent processes contribute in object recognition under occlusion. Furthermore, we do not know whether the conventional deep neural networks, such as AlexNet, which were shown to be successful in solving core object recognition, can perform similarly well in problems that go beyond the core recognition. Here, we characterize neural dynamics of object recognition under occlusion, using magnetoencephalography (MEG), while participants were presented with images of objects with various levels of occlusion. We provide evidence from multivariate analysis of MEG data, behavioral data, and computational modelling, demonstrating an essential role for recurrent processes in object recognition under occlusion. Furthermore, the computational model with local recurrent connections, used here, suggests a mechanistic explanation of how the human brain might be solving this problem.


[Effects of lead exposure on the human body and health implications].
To review the literature concerning the risks associated with exposure to lead and lead compounds, especially in children and in populations that are occupationally exposed. Using "chumbo" [lead] and "efeitos" [effects] as search terms, two large databases, namely PubMed (United States National Library of Medicine) and LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde [Latin American and Caribbean Literature in the Health Sciences]), were searched for studies on lead toxicity from 1988 to 2002. Other sources used to conduct the search include the web page of the United States Agency for Toxic Substances and Disease Registry, in Atlanta, Georgia, and the library of the Toxicology Laboratory of the Center for Workers' Health and Human Ecology at the National School of Public Health [Centro de Estudos da Saúde de Trabalhador e Ecologia Humana, Escola Nacional de Saúde Pública], Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. The toxic effects of lead and lead compounds have been extensively studied for over a century. In recent years, epidemiologic studies have focused primarily on the neurotoxic effects of lead on children, particularly in terms of impaired intellectual ability and behavioral problems. However, there is still insufficient information on the mechanisms of action that account for such toxicity. More in-depth studies are also needed on the effects of lead exposure on bone, the central nervous system, the cardiovascular system, the kidneys, the liver, the male and female reproductive systems, and the endocrine system. The potential teratogenicity and carcinogenicity of lead, as well as its effect on pregnancy outcomes and neonatal growth and development, also require further study.


A Kuramoto model of self-other integration across interpersonal synchronization strategies.
Human social behaviour is complex, and the biological and neural mechanisms underpinning it remain debated. A particularly interesting social phenomenon is our ability and tendency to fall into synchronization with other humans. Our ability to coordinate actions and goals relies on the ability to distinguish between and integrate self and other, which when impaired can lead to devastating consequences. Interpersonal synchronization has been a widely used framework for studying action coordination and self-other integration, showing that even in simple interactions, such as joint finger tapping, complex interpersonal dynamics emerge. Here we propose a computational model of self-other integration via within- and between-person action-perception links, implemented as a simple Kuramoto model with four oscillators. The model abstracts each member of a dyad as a unit consisting of two connected oscillators, representing intrinsic processes of perception and action. By fitting this model to data from two separate experiments we show that interpersonal synchronization strategies rely on the relationship between within- and between-unit coupling. Specifically, mutual adaptation exhibits a higher between-unit coupling than within-unit coupling; leading-following requires that the follower unit has a low within-unit coupling; and leading-leading occurs when two units jointly exhibit a low between-unit coupling. These findings are consistent with the theory of interpersonal synchronization emerging through self-other integration mediated by processes of action-perception coupling. Hence, our results show that chaotic human behaviour occurring on a millisecond scale may be modelled using coupled oscillators.


A fraction of neurofibromin interacts with PML bodies in the nucleus of the CCF astrocytoma cell line.
Neurofibromatosis type 1 is a common genetic disease that causes nervous system tumors, and cognitive deficits. It is due to mutations within the NF1 gene, which encodes the Nf1 protein. Nf1 has been shown to be involved in the regulation of Ras, cAMP and actin cytoskeleton dynamics. In this study, using immunofluorescence experiments, we have shown a partial nuclear localization of Nf1 in the astrocytoma cell line: CCF and we have demonstrated that Nf1 partially colocalizes with PML (promyelocytic leukemia) nuclear bodies. A direct interaction between Nf1 and the multiprotein complex has further been demonstrated using "in situ" proximity ligation assay (PLA).


The Saccharomyces cerevisiae U2 snRNA:pseudouridine-synthase Pus7p is a novel multisite-multisubstrate RNA:Psi-synthase also acting on tRNAs.
The Saccharomyces cerevisiae Pus7 protein was recently characterized as a novel RNA:pseudouridine (Psi)-synthase acting at position 35 in U2 snRNA. However, U2 snRNA was the only potential substrate tested for this enzyme. In this work, we demonstrated that although Pus7p is responsible for the formation of only one of the six Psi residues present in yeast UsnRNAs, it catalyzes U to Psi conversion at position 13 in cytoplasmic tRNAs and at position 35 in pre-tRNA(Tyr). Sites of RNA modification by Pus7p were identified by analysis of the in vivo RNA modification defects resulting from the absence of active Pus7p production and by in vitro tests using extracts from WT and genetically modified yeast cells. For demonstration of the direct implication of Pus7p in RNA modification, the activity of the WT and mutated Pus7p recombinant proteins was tested on in vitro produced tRNA and pre-tRNA transcripts. Mutation of an aspartic acid residue (D256) that is conserved in all Pus7 homologs abolishes the enzymatic activity both in vivo and in vitro. This suggests the direct involvement of D256 in catalysis. Target sites of Pus7p in RNAs share a common sequence Pu(G/C)UNPsiAPu (Pu = purine, N = any nucleotide), which is expected to be important for substrate recognition. Modification of tRNAs by Pus7p explains the presence of Pus7p homologs in archaea and some bacteria species, which do not have U2 snRNA, and in vertebrates, where Psi34 (equivalent to Psi35 in yeast) formation in U2 snRNA is an H/ACA snoRNA guided process. Our results increase the number of known RNA modification enzymes acting on different types of cellular RNAs.


Water soluble two-photon fluorescent organic probes for long-term imaging of lysosomes in live cells and tumor spheroids.
The morphological alteration of lysosomes is a powerful indicator of various pathological disorders. In this regard, we have designed and synthesized a new water soluble fluorescent Schiff-base ligand (L-lyso) containing two hydroxyl groups. L-lyso exhibits excellent two-photon properties with tracking of lysosomes in live cells as well as in 3D tumor spheroids. Furthermore, it can label lysosomes for more than 3 days. Thus, L-lyso has an edge over the commercially available expensive LysoTracker probes and also over other reported probes in terms of its long-term imaging, water solubility and facile synthesis.


Fibroblast growth factor (FGF) induces different responses in lens epithelial cells depending on its concentration.
We reported previously that epithelial cells in explants from neonatal rat lenses, when cultured in the presence of fibroblast growth factor (FGF), showed increased proliferation, cell migration and fibre differentiation; moreover, fibre differentiation in response to the basic form of FGF (bFGF) was virtually completely blocked by an anti-bFGF antibody. In the present study, we report a detailed analysis of the effects of bFGF on cells in the central region of lens epithelial explants. Proliferation in explants was assessed by measuring [3H]thymidine incorporation. Cell migration was measured by labelling cells in explants with fluorescein isothiocyanate (FITC)-dextran and monitoring them by UV fluorescence microscopy. Fibre differentiation in explants was assessed on the basis of beta-crystallin accumulation. This study showed that half maximal activities for the three responses, proliferation, migration and fibre differentiation, were achieved at different concentrations of bFGF, namely, 0.15, 3 and 40 ng ml-1, respectively. Thus, the response of lens epithelial cells to bFGF varied qualitatively, as well as quantitatively, as the concentration increased. Monitoring FITC-dextran injection cells for up to 5 days after exposure to bFGF allowed analysis of the interrelation between various responses to bFGF in individual cells. As expected some cells divided in response to FGF, mainly within the first three days. However, whether or not they divided, all labelled cells responded to FGF by migrating and elongating. Maximal migration occurred during the first day of culture and maximal elongation was achieved by day 4.(ABSTRACT TRUNCATED AT 250 WORDS)


Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.
Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5-7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4 × 10(-5), allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8 × 10(-10)) and intron 8 polymorphism rs9930761-T>C (5.6 × 10(-8)) (in high linkage disequilibrium with allele frequencies 6-7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6 × 10(-28) and rs5883 p = 8.6 × 10(-10), adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29-4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulating HDL-C levels.


Impacts of Degradation on Water, Energy, and Carbon Cycling of the Amazon Tropical Forests.
Selective logging, fragmentation, and understory fires directly degrade forest structure and composition. However, studies addressing the effects of forest degradation on carbon, water, and energy cycles are scarce. Here, we integrate field observations and high-resolution remote sensing from airborne lidar to provide realistic initial conditions to the Ecosystem Demography Model (ED-2.2) and investigate how disturbances from forest degradation affect gross primary production (GPP), evapotranspiration (ET), and sensible heat flux (H). We used forest structural information retrieved from airborne lidar samples (13,500 ha) and calibrated with 817 inventory plots (0.25 ha) across precipitation and degradation gradients in the eastern Amazon as initial conditions to ED-2.2 model. Our results show that the magnitude and seasonality of fluxes were modulated by changes in forest structure caused by degradation. During the dry season and under typical conditions, severely degraded forests (biomass loss ≥66%) experienced water stress with declines in ET (up to 34%) and GPP (up to 35%) and increases of H (up to 43%) and daily mean ground temperatures (up to 6.5°C) relative to intact forests. In contrast, the relative impact of forest degradation on energy, water, and carbon cycles markedly diminishes under extreme, multiyear droughts, as a consequence of severe stress experienced by intact forests. Our results highlight that the water and energy cycles in the Amazon are driven by not only climate and deforestation but also the past disturbance and changes of forest structure from degradation, suggesting a much broader influence of human land use activities on the tropical ecosystems.


Induction of IP-10/CXCL10 secretion as an immunomodulatory effect of low-dose adjuvant interferon-alpha during treatment of melanoma.
This study investigated the immunomodulatory effects of low-dose interferon-alpha (IFN-alpha) in a cohort of 21 stage II or III melanoma patients treated in an adjuvant setting. Serial assessments in peripheral blood were performed at baseline and at regular intervals. Depletion of CD3+CD4+ T cells was predominant within the "central memory" and "memory" subsets. The impact of IFN-alpha was more marked at the level of all CD3+CD8+ T-cell subsets that showed a sustained and significant decrease. Both myeloid and plasmacytoid dendritic cell (DC) subsets were depleted, but the MDC/PDC ratio tended to increase 12 months after treatment. Also, CD14+CD16+ monocytes showed a significant increase of both MHC class I and the CD86 costimulatory molecule. IP-10/CXCL10 plasma levels significantly increased already at 3 months of therapy and remained at significantly high levels during the study period. The dramatic increase of IP-10/CXCL10 inversely correlated with a significant decrease of the CXCR3+CD8+ T lymphocytes. Low-dose IFN-alpha therapy can significantly affect phenotypic and functional properties of blood circulating lymphocytes and antigen-presenting cells, and production of IP-10/CXCL10, that appear to be important for the orchestration of an effective immune response during adjuvant IFN-alpha therapy for melanoma.


Evaluation of the antisense effect of PEGylated oligodeoxynucleotides containing intelligent nucleoside analogues.
We have previously reported that the 2-amino-6-vinylpurine (AVP) in oligonucleotide (ODN) showed the highly selective and effective cross-linking reaction toward cytosine within target complementary sequences. Recently, we revealed that the PEGylated ODN containing AVP analogues exhibited the effective antisense effect in the cultured cell. However, subsequent studies showed that the cross-linking ability of AVP for cytosine was affected by the target RNA sequences. We therefore developed new intelligent nucleoside analogues connected AVP to sugar through the ethylene linker (et-AVP), that exhibited highly effective cross-linking ability to rC in the target RNA. In this paper, we described the synthesis of the PEGylated ODN containing cross-linking nucleoside analogues and properties of it about RNase H activity and antisense effect in cell lysate. As a result, the PEGylated ODN containing et-AVP showed the effective antisense effect in the non-cell system for targeting the luciferase mRNA by non-RNase-H mechanism.


Transitions to asexuality result in excess amino acid substitutions.
Theory predicts that linkage between genetic loci reduces the efficiency of purifying selection. Because of the permanent linkage of all heritable genetic material, asexual lineages may be exceptionally prone to deleterious-mutation accumulation in both nuclear and organelle genes. Here, we show that the ratio of the rate of amino acid to silent substitution (Ka/Ks) in mitochondrial protein-coding genes is higher in obligately asexual lineages than in sexual lineages of the microcrustacean Daphnia pulex. Using a phylogeny-based approach to quantify the frequency of mutational-effect classes, we estimate that mitochondrial protein-coding genes in asexual lineages accumulate deleterious amino acid substitutions at four times the rate in sexual lineages. These results support the hypothesis that sexual reproduction plays a prominent role in reducing the mutational burden in populations.


Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets.
Thrombospondin-1 (TSP-1) is released by platelets upon activation and can increase platelet activation, but its role in hemostasis in vivo is unclear. We show that TSP-1 is a critical mediator of hemostasis that promotes platelet activation by modulating inhibitory cyclic adenosine monophosphate (cAMP) signaling. Genetic deletion of TSP-1 did not affect platelet activation in vitro, but in vivo models of hemostasis and thrombosis showed that TSP-1-deficient mice had prolonged bleeding, defective thrombosis, and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild-type (WT) but not TSP-1-/- platelets ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1-deficient platelets showed an increased sensitivity to cAMP signaling, inhibition of platelet aggregation, and arrest under flow by prostacyclin (PGI2). Plasma swap experiments showed that plasma TSP-1 did not correct PGI2 hypersensitivity in TSP-1-/- platelets. By contrast, incubation of TSP-1-/- platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1-/- platelets, reduced the inhibitory effects of PGI2. Activation of WT platelets resulted in diminished cAMP accumulation and downstream signaling, which was associated with increased activity of the cAMP hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A activity and cAMP accumulation were unaffected in platelets from TSP-1-/- mice. Platelets deficient in CD36, a TSP-1 receptor, showed increased sensitivity to PGI2/cAMP signaling and diminished PDE3A activity, which was unaffected by platelet-derived or purified TSP-1. This scenario suggests that the release of TSP-1 regulates hemostasis in vivo through modulation of platelet cAMP signaling at sites of vascular injury.


The Salt Swap intervention to reduce salt intake in people with high blood pressure: protocol for a feasibility randomised controlled trial.
High salt intake is a risk factor for hypertension and cardiovascular disease. Reducing salt intake has been shown to reduce blood pressure. Despite population-level interventions, including product reformulation and public awareness campaigns, adult salt consumption in the UK still exceeds recommendations; this is primarily due to salt consumed in processed and pre-packaged foods. Moderate or high-intensity dietary advice to encourage individuals to reduce their salt intake has been shown to be effective at reducing blood pressure, but evidence of the effectiveness of interventions that are suitable for delivery at scale in routine primary care is scarce. This feasibility trial investigates a complex behavioural change intervention to reduce dietary salt intake and blood pressure by encouraging individuals to purchase lower-salt foods when grocery shopping. This randomised controlled trial will test the feasibility of a novel intervention to reduce salt intake, and the trial procedures to assess its effectiveness. We will recruit participants through UK general practices and randomise 40 participants with high blood pressure, in a 2:1 allocation to receive either the Salt Swap intervention or a control information leaflet. The primary outcomes relate to the criteria for progression to a large-scale trial. These include follow-up rates at 6 weeks, fidelity of intervention delivery and use of the intervention mobile app. Secondary outcomes include the effect of the intervention on the salt content of purchased foods (grams per 100 g), urinary sodium excretion assessed through 24-hour urine samples and blood pressure. Trial process measures will be collected and qualitative assessment will provide insights into participant engagement with the intervention content and perceived barriers to and facilitators of salt reduction dietary behavioural change. If the outcomes indicate the trial is feasible and there is evidence that behavioural change may result in salt reduction, we will proceed to a definitive trial to test the effectiveness of the intervention to lower blood pressure. If successful, this intervention approach could be applied not only to people with high blood pressure, but also to the wider population with normal blood pressure in whom dietary salt intake exceeds recommendations. ISRCTN, 20910962 . Registered on 5 April 2017.


Single-incision laparoscopic surgery: feasibility for pediatric appendectomies.
Single-incision laparoscopic surgery (SILS) is a novel area of minimally invasive surgery using a single incision. The end result is a lone incision at the umbilicus for a perceived scarless abdomen. We report our early experience using the SILS technique for appendectomies in the pediatric population. A retrospective chart review was performed on our first patients to undergo SILS appendectomy (SILS-A) or laparoscopic appendectomy (LAP-A) during the same period at a freestanding children's hospital. Thirty-nine patients were reviewed. Nineteen patients underwent SILS-A (8.7 +/- 0.76 [SEM] years old), and 20 patients underwent LAP-A (10.5 +/- 0.87 years old, 2-17). Ages were 19 months to 14 years in the SILS-A group, with 21% (4 patients) not older than 6 years. Median weight for SILS-A was 32 kg (14.5-80.3). Twelve patients had acute nonperforated appendicitis (62%). Mean duration of operation was 58 +/- 5.6 (30-135) minutes vs 43 +/- 3.6 (30-85) minutes for standard LAP-A. Two patients were converted to a transumbilical appendectomy, one for inability to maintain a pneumoperitoneum and one for extensive adhesions. Postoperative complications consisted of one wound seroma. No wound infections, hernias, readmissions, or difference in length of stay were noted. The SILS approach for acute appendicitis is feasible in the pediatric population even in patients as young as 19 months. Operating room times are somewhat longer than with LAP-A, but should decrease with improved instrumentation and experience. Larger studies and further technical refinements are needed before its widespread implementation.


Epidemiological, clinical, and echocardiographic features and survival times of dogs and cats with tetralogy of Fallot: 31 cases (2003-2014).
OBJECTIVE To characterize the epidemiological, clinical, and echocardiographic features of dogs and cats with tetralogy of Fallot (TOF) and determine their survival times. DESIGN Retrospective case series. ANIMALS 15 dogs and 16 cats with a diagnosis of TOF as determined via echocardiography. PROCEDURES Medical records of dogs and cats were reviewed to extract information on signalment, clinical status at the time of TOF diagnosis, echocardiographic findings, and any outcome data. RESULTS The most common canine breeds were terrier types (n = 7). Most animals (28/31 [90%]) had clinical signs of TOF at the time of diagnosis, including cyanosis (16/31 [52%]). Pulmonic stenosis was characterized by a variable systolic Doppler-derived pressure gradient (median [range], 108 mm Hg [26 to 255 mm Hg]). Most ventricular septal defects were large, with a median (range) ratio of the diameter of the ventricular septal defect to that of the aorta of 0.60 (0.18 to 1.15). Median age at cardiac-related death was 23.4 months, with no significant difference between dogs and cats. Median survival time from TOF diagnosis to cardiac-related death was briefer for animals with no or low-grade heart murmur (3.4 months) than for those with higher-grade heart murmur (16.4 months). After adjustment for age and sex, having a lack of or a low- to mild-grade systolic heart murmur was significantly associated with a briefer survival time. CONCLUSIONS AND CLINICAL RELEVANCE With a few exceptions, cardiac-related death occurred predominantly in young adult dogs and cats with TOF, and most animals had severe clinical signs at the time of TOF diagnosis.