Annuity and lump-sum decisions in defined benefit plans: the role of plan rules.
Amidst growing concerns about workers outliving their retirement savings, a key question-both as a matter of national retirement policy and understanding the potential role of plan design and education in influencing individual decision-making-is how many retiring workers actually choose to annuitize (to take a stream of lifetime income) vs. opting for a lump-sum payment. The key finding of this study is that differences in defined benefit (DB) plan rules or features result in very different annuitization rates in DB plans. In fact, the results show that the rate of annuitization varies directly with the degree to which plan rules restrict the ability to choose a partial or lump-sum distribution. This study shows that annuitization rates vary significantly across these different plan types, which makes any attempt to combine the annuitization rates across these different plan types uninformative. Combining all the plans across the years 2005-2010, workers who made their payout decision between ages 50 and 75 had a minimum job tenure of five years, a minimum account balance of $5,000, and had an annuitization rate of 65.8 percent. But within this group of workers, those who had no plan restrictions on a lump-sum distribution had an annuitization rate of only 27.3 percent. In all the years studied, plans with no lump-sum distribution (LSD) options have the highest annuitization rates, very close to 100 percent. Traditional defined benefit and cash balance plans with no restrictionson LSDs had the lowest annuitization rates. In 2010, the annuitization rate for all plans combined was 65.5 percent, while for plans with no LSD option it was 98.8 percent, but the annuitization rate for defined benefit plans with no restrictions on LSDs was 44.3 percent, while for cash balance plans with no restrictions on LSDs it was 22.3 percent. For older workers across most plan types, annuitization rates increase steadily with account balance, but this is not the case for younger workers. Annuitization rates also increase with tenure, but for younger workers (20-50) with low tenure (less than 10 years), annuitization rates are very low. For older workers (50-75), annuitization rates are higher even in cases of low tenure. Annuitization rates are very low for those below age 40, but from that point onwards, annuitization rates increase for all types of plans. Annuitization rates appear to peak between 65 and 69, but then fall sharply.


[Anti-anginal action of antihypoxants].
It was shown in experiments on anesthetized cats with modelled acute coronary insufficiency that sodium hydroxybutyrate (200 mg/kg) and in a lesser degree piracetam (400 mg/kg) improve the functional state of the acute myocardial ischemic focus, reduce the rate of growth of creatinephosphokinase activity in coronary sinus blood, increase the retrograde bloodflow to the ischemized zone. Glyo-6 (100 mg/kg) has practically no effect on the investigated indicators.


The adsorption of sympathomimetic agents by activated carbon hemoperfusion.
Sympathomimetic agents with mixed and pure alpha and beta adrenergic activity are adsorbed by coconut shell activated carbon from blood, sufficiently rapidly to markedly reduce the activity of these agents. The results of this study suggest that the site of injection of sympathomimetic agents being considered for correcting hypotension during activated carbon hemoperfusion be selected to permit systemic mixing before circulation into the adsorption device.


Irreproducibility in searches of scientific literature: A comparative analysis.
Repeatability is the cornerstone of science, and it is particularly important for systematic reviews. However, little is known on how researchers' choice of database, and search platform influence the repeatability of systematic reviews. Here, we aim to unveil how the computer environment and the location where the search was initiated from influence hit results.We present a comparative analysis of time-synchronized searches at different institutional locations in the world and evaluate the consistency of hits obtained within each of the search terms using different search platforms.We revealed a large variation among search platforms and showed that PubMed and Scopus returned consistent results to identical search strings from different locations. Google Scholar and Web of Science's Core Collection varied substantially both in the number of returned hits and in the list of individual articles depending on the search location and computing environment. Inconsistency in Web of Science results has most likely emerged from the different licensing packages at different institutions.To maintain scientific integrity and consistency, especially in systematic reviews, action is needed from both the scientific community and scientific search platforms to increase search consistency. Researchers are encouraged to report the search location and the databases used for systematic reviews, and database providers should make search algorithms transparent and revise access rules to titles behind paywalls. Additional options for increasing the repeatability and transparency of systematic reviews are storing both search metadata and hit results in open repositories and using Application Programming Interfaces (APIs) to retrieve standardized, machine-readable search metadata.


Nucleus A10 dopaminergic neurons in inbred mouse strains: firing rate and autoreceptor sensitivity are independent of the number of cells in the nucleus.
Inbred mouse strains have different numbers of midbrain dopaminergic neurons; for example, BALB/cJ mice have 20-25% more neurons than CBA/J mice. As the number of cells decrease, for example in Parkinson's disease and in animals with midbrain dopaminergic cell lesions, the activity of their remaining cells increases. The purpose of the present experiment was to determine whether the functional properties of dopaminergic neurons in the ventral tegmental area (nucleus A10) differ in inbred mouse strains which possess different numbers of cells. The firing rate and autoreceptor sensitivity of A10 dopaminergic cells were examined in the in vitro slice preparation in BALB/cJ, C3H/HeJ, CBA/J, and DBA/2J mouse strains. It was observed that the autoreceptors on mouse dopaminergic neurons exhibit pharmacological properties of dopamine autoreceptors; activation of the autoreceptor produced a marked inhibition (50-70%) in cell firing rate by quinpirole (10(-8) M), LY-141865 (10(-7) M), (+)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine (10(-6) M), propyl-norapomorphine (10(-5) M) and dopamine (10(-4) M), and this inhibition was blocked or reversed by specific dopamine D2 receptor antagonists [(-) sulpiride and spiroperidol, 10(-6) M]. The baseline firing rates of the A10 cells did not differ among the four inbred strains [range 2.5 +/- 0.2 (C3H/HeJ)-3.4 +/- 0.3 (CBA/J) spikes/s +/- SEM], and there was no significant difference in autoreceptor sensitivity among the mouse strains as assessed either by superfused dopamine (inhibitory dose 50% approximately 150 microM), or by superfused quinpirole (inhibitory dose 50% approximately 10 nM).(ABSTRACT TRUNCATED AT 250 WORDS)


General and abdominal adiposity and risk of stroke in Chinese women.
Although both general and abdominal adiposity are well-established risk factors for coronary heart disease, their associations with stroke are less well characterized, particularly in generally lean Asian populations. We evaluated associations of body mass index (BMI), waist-hip ratio (WHR), waist circumference (WC), and waist-height ratio (WHtR) with stroke risk in the Shanghai Women's Health Study, a population-based prospective cohort study of 74 942 Chinese women aged 40 to 70 years with anthropometric measurement taken at recruitment in 1996 to 2000. For this analysis, we included 67 083 women with no prior history of stroke, coronary heart disease, rheumatic heart disease, cardiac surgery, or cancer at recruitment. Incident stroke was ascertained by biennial home visits and linkage with vital statistics registries. Cut points for the highest quintiles of BMI, WHR, WC, and WHtR among this cohort were 26.6 (kg/m(2)), 0.85 (cm/cm), 84.1 (cm), and 0.54 (cm/cm), respectively. During a mean follow-up of 7.3 years, 2403 incident stroke cases were identified. All selected anthropometric measurements were positively and significantly associated with risk of total, ischemic, and hemorrhagic stroke in a dose-response manner (all probability values for trend <0.01). The multivariable-adjusted hazard ratios (95% confidence intervals) for total stroke comparing the highest versus lowest quintiles of these measurements were 1.71 (1.49 to 1.97), 1.59 (1.37 to 1.85), 1.77 (1.53 to 2.05), and 1.91 (1.61 to 2.27) for BMI, WHR, WC, and WHtR, respectively. Increasing levels of general or abdominal adiposity consistently predict increased risk of stroke in predominantly nonobese Chinese women.


Design, synthesis and in vitro evaluation of 4-androstene-3,17-dione/adenosine hybrid compounds as bisubstrate inhibitors of type 3 17beta-hydroxysteroid dehydrogenase.
Steroidogenic enzyme type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is an important therapeutic target for androgen-sensitive diseases. This enzyme selectively reduces the C17 ketone of 4-androstene-3,17-dione (Delta4-dione), thus producing testosterone (T) using NADPH as cofactor. Our group previously synthesized hybrid (estradiol/adenosine) inhibitors that successfully inhibit the biosynthesis of the potent estrogen estradiol by type 1 17beta-HSD. To similarly lower the level of the potent androgen testosterone, inhibitors of type 3 17beta-HSD were designed and synthesized applying the same hybrid (substrate/cofactor) strategy. Two chemical approaches were developed to join the three components of the bisubstrate inhibitor (the substrate Delta4-dione, an alkyl spacer and the cofactor moiety adenosine). An alkylation in the alpha position of steroidal 17-ketone or a cross-metathesis was used as a key step to efficiently join the substrate and the alkyl spacer, whereas an esterification was employed to link the spacer to adenosine. An enzymatic assay in homogenated HEK-293 cells overexpressing type 3 17beta-HSD revealed that the best inhibitors of that series are those bearing an alkyl side-chain spacer of 11 or 12 methylenes: inhibition of 69 and 78% at 1 microM were respectively observed. As expected, these bisubstrate inhibitors were less potent in intact cells than in homogenated cells. However, both enzymatic assays revealed that the strategy of substrate/cofactor dual inhibitors seems to work for type 3 17beta-HSD, although the inhibitors designed have not been optimized yet.


Integration of low-frequency sleep oscillations in corticothalamic networks.
The corticothalamic system acts as a complex network in promoting the various oscillatory patterns (slow oscillation, spindles, delta) that characterize the state of quiet sleep. Local synchronizing mechanisms of any of the above-mentioned oscillations occur at the site of their genesis, thalamic or cortical. These mechanisms are assisted by the wide-range, synchronized occurrence of the cortical slow oscillation, which finally produces the coalesced picture of slow-wave sleep EEG. Multisite, simultaneous intracellular and field potential recordings in cat, as well as EEG recordings in human were performed in order to assess the state of synchrony and the propagation of various sleep rhythms in the corticothalamic network.


The clinical value of sperm nuclear DNA assessment.
Traditional semen analysis is essential for the diagnosis of male infertility. A number of studies over the past decade have reported that a significant contributing factor to male fertility that is not revealed as part of semen analysis is sperm DNA, specifically its composition and organization. Exogenous and endogenous factors can cause damage to sperm DNA. For example, topoisomerase II activity, which is necessary for sperm DNA packaging, can adversely influence the competence of sperm DNA if the activity of the enzyme is abnormal. Germ cell apoptosis can be induced by oxygen radicals produced from environmental (for example cigarette smoke) or testicular (for example localized ischaemia) sources. Several assays have been developed that are useful for assessing sperm DNA composition and organization. To date, each of these assays has revealed that when sperm DNA has been damaged or packaged improperly there is a concomitant and often significant decline in male fertility.


Integrin beta 1 regulates phagosome maturation in macrophages through Rac expression.
Phagocytosis and subsequent phagosome maturation by professional phagocytes are essential in the clearance of infectious microbial pathogens. The molecular regulation of phagosome maturation is largely unknown. We show that integrin beta(1) plays critical roles in the phagocytosis of microbial pathogens and phagosome maturation. Macrophages lacking integrin beta(1) expression exhibit reduced phagocytosis of bacteria, including group B streptococcus and Staphylococcus aureus. Furthermore, phagosomes from macrophages lacking integrin beta(1) show lowered maturation rate, defective acquisition of lysosome membrane markers, and reduced F-actin accumulation in the periphagosomal region. Integrin beta(1)-deficient macrophages exhibit impaired bactericidal activity. We found that the expression of the Rho family GTPases Rac1, Rac2, and Cdc42 was reduced in integrin beta(1)-deficient macrophages. Ectopic expression of Rac1, but not Cdc42, in integrin beta(1)-deficient macrophages restored defective phagosome maturation and F-actin accumulation in the periphagosomal region. Importantly, macrophages lacking Rac1/2 also exhibit defective maturation of phagosomes derived from opsonized Escherichia coli or IgG beads. Taken together, these results suggest that integrin beta(1) regulates phagosome maturation in macrophages through Rac expression.


HEREDITARY PITUITARY TUMOR SYNDROMES: GENETIC AND CLINICAL ASPECTS.
The pituitary gland is responsible for the synthesis and secretion of various hormones that play a key role in regulating endocrine function and homeostasis. Pituitary adenomas (PA) are benign epithelial tumors arising from the endocrine cells of the anterior pituitary gland. Clinically relevant PA are relatively common and they occur in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior pituitary gland. PA are categorized as either functioning or non-functioning, depending on whether or not they produce a hormonal hypersecretion syndrome. Both functioning and non-functioning adenomas can produce symptoms or signs resulting from compression of the optic chiasm or invasion of cavernous sinuses. Only 5% of PA occur within the context of hereditary syndromes with reasonably well-defined oncogenic mechanisms. The vast majority of PA are sporadic, and their etiopathogenesis remains largely unknown. Pituitary tumor oncogenesis involves several mechanisms that eventually lead to abnormal cell proliferation and dysregulated hormone production. Among these factors, we found inactivating mutations of tumor suppressor genes, activating mutation of oncogenes and the participation of hormonal signals coming from the hypothalamus, all resulting in cell-cycle regulation abnormalities. In this review, we summarize the clinical and pathophysiological aspects of the different hereditary pituitary tumor syndromes.


Adrenocortical suppression in the dog after a single dose of methylprednisolone acetate.
Adrenal function was assessed in dogs after intramuscular administration of a single dose of methylprednisolone acetate (MPA). Twelve dogs were test challenged with adrenocorticotropic hormone (ACTH) and then assigned randomly to 1 of 3 groups and given MPA. Individual groups were test challenged with ACTH 2, 3, or 4 weeks later. All dogs were rechallenged 5 weeks after MPA administration. Plasma cortisol concentration was determined by radioimmunoassay. Basal plasma cortisol (time 0) was depressed on weeks 2 and 3, but not on weeks 4 and 5. Adrenal response to ACTH (increment of cortisol change) was suppressed on weeks 2, 4, and 5, but not on week 3. It was concluded that a single dose of MPA is capable of altering adrenal cortical function in dogs for at least 5 weeks.


The University of California Los Angeles Dizziness Questionnaire: advantages and disadvantages.
Dizziness is one of the most troublesome symptoms of vestibular disorders, although its description remains somewhat imprecise, encompassing vertigo, lightheadedness, disequilibrium and giddiness. Symptoms include sensitivity to motion stimuli and discomfort with open spaces, such as empty streets and bridges. It is accompanied by varying degrees of anxiety and phobic behaviors. Several tools have been developed in an attempt to quantify the degree of disability, self-perceived health status and quality of life in patients with dizziness. This review focuses on the University of California, Los Angeles Dizziness Questionnaire (UCLA-DQ), which is used to assess the effect of dizziness on quality of life. This paper also includes a summary of the advantages and disadvantages of the UCLA-DQ and compares it to other instruments used to assess dizziness. In spite of a few disadvantages, we believe that this multidimensional questionnaire is an appropriate tool for evaluating patients with vestibular impairment. It should be used during the acute phase of symptoms, as well as during and after rehabilitative therapy, to assess patient improvement.


Participation restriction, not fear of falling, predicts actual balance and mobility abilities in rural community-dwelling older adults.
Fear of falling (FOF) has been correlated with an increased risk for falls, self-restriction of physical activity, and subsequent decrease in quality of life in older adults. The relationship between perceived FOF, participation restriction, and balance and mobility abilities is unclear, as results from prior studies are inconsistent. Few studies have used the Survey of Activities and Fear of Falling in the Elderly (SAFE) as a standard measure of FOF, although this survey provides both a measure of FOF and participation restriction. Only one study has explored the relationship of individual items from the SAFE with balance and mobility tests that predict fall risk. The primary purpose of this study was to investigate the relationships between FOF and participation restriction as measured by the SAFE and actual balance and mobility abilities in a diverse group of older adults. Eighty-two community-dwelling older adults (17 men) with a mean age of 74 (SD = 8.8; range = 55-91) participated in this study. The sample comprised 45% African Americans and 54% whites. Fear of falling and participation restriction were assessed using the SAFE, a self-assessment survey. The SAFE assesses information about participation in 11 functional activities as well as the extent to which fear is a source of participation restriction. Balance and functional mobility were measured using the Berg Balance Scale (BBS) and Timed Get Up & Go Test (TUG), respectively. Participants were categorized as low (N = 36), mixed (N = 19), or high (N = 24) risk for future falls based on their past fall history and results on the BBS and the TUG. Data analysis included χ(2) and Spearman correlation and 2 regression analyses. Both SAFE FOF and participation restriction scores were significantly correlated with BBS and TUG scores. However, SAFE participation restriction scores, but not SAFE FOF scores, predicted BBS and TUG scores. SAFE FOF scores could discriminate older adults at high risk for falls from those at mixed and low risk but could not discriminate between the mixed- and low-risk groups. The relationship between self-reported participation restriction and objectively measured balance and mobility abilities is stronger than the relationship between self-reported FOF and objectively measured balance and mobility abilities. These findings lend support to the argument that participation restriction may be the critical mediating factor between FOF, balance and mobility limitations, and fall risk. Evaluation of and intervention for FOF and fall risk without direct and specific attention to participation restriction may not yield optimal results. Older adults whose goals include both reduction in fall risk and increase in participation level may need combined treatment approaches.


Widespread introgression across a phylogeny of 155 Drosophila genomes.
Genome-scale sequence data have invigorated the study of hybridization and introgression, particularly in animals. However, outside of a few notable cases, we lack systematic tests for introgression at a larger phylogenetic scale across entire clades. Here, we leverage 155 genome assemblies from 149 species to generate a fossil-calibrated phylogeny and conduct multilocus tests for introgression across 9 monophyletic radiations within the genus Drosophila. Using complementary phylogenomic approaches, we identify widespread introgression across the evolutionary history of Drosophila. Mapping gene-tree discordance onto the phylogeny revealed that both ancient and recent introgression has occurred across most of the 9 clades that we examined. Our results provide the first evidence of introgression occurring across the evolutionary history of Drosophila and highlight the need to continue to study the evolutionary consequences of hybridization and introgression in this genus and across the tree of life.


A conserved amphipathic helix in WASP/Scar proteins is essential for activation of Arp2/3 complex.
Members of the Wiskott-Aldrich syndrome protein (WASP) family link Rho GTPase signaling pathways to the cytoskeleton through a multiprotein assembly called Arp2/3 complex. The C-terminal VCA regions (verprolin-homology, central hydrophobic, and acidic regions) of WASP and its relatives stimulate Arp2/3 complex to nucleate actin filament branches. Here we show by differential line broadening in NMR spectra that the C (central) and A (acidic) segments of VCA domains from WASP, N-WASP and Scar bind Arp2/3 complex. The C regions of these proteins have a conserved sequence motif consisting of hydrophobic residues and an arginine residue. Point mutations in this conserved sequence motif suggest that it forms an amphipathic helix that is required in biochemical assays for activation of Arp2/3 complex. Key residues in this motif are buried through contacts with the GTPase binding domain in the autoinhibited structure of WASP and N-WASP, indicating that sequestration of these residues is an important aspect of autoinhibition.


Developmental or degenerative--NR2E3 gene mutations in two patients with enhanced S cone syndrome.
Enhanced S Cone Syndrome is a rare autosomal recessive disorder characterized clinically by an absence of rod function, a replacement of most L and M cone function by S cone activity (Goldmann-Favre Syndrome) and by variable degrees of retinal degeneration in different families. The causative gene, nuclear receptor subfamily 2, group E, member 3 (NR2E3), controls the developmental sequence for rods and cones. The purpose of this study was to compare the nature and implications of mutations in two subjects with Enhanced S Cone Syndrome who have significantly different degrees of degenerative damage. A direct sequencing approach was used to identify the mutations. Genomic DNA was amplified from all the exons of NR2E3 and used as a template for sequencing. Of the two families studied, Case 1 is of Persian ethnicity while Case 2 is Brazilian. A total of six individuals within the two families were studied. Case 1 (original propositus of the syndrome) has the characteristic developmental rod/cone abnormality with large amplitude electroretinogram responses and no retinal degeneration. She was homozygous for a novel mutation, c.[del196-201del6] (p.G66-C67del), which lies entirely within the P-box for this gene. By comparison, Case 2 had Goldmann-Favre Syndrome with retinal degeneration and low electroretinogram signals. She was a compound heterozygote for c.[119-2A>C]+[del194-202del9] (p.N65-C67del), mutations that have been reported previously. Her second mutation overlaps that of Case 1 within the P-box. The novel in-frame homozygous deletion of Case 1, within the P-box motif of the DNA binding domain, caused a developmental abnormality without retinal degeneration. Case 2, with more traditional Goldmann-Favre Syndrome with retinal degeneration, was a compound heterozygote where one allele had a similar P-box deletion but the other was a splicing defect. Case 1 is the first reported homozygous deletion within the P-box. This is the first report of NR2E3 mutations in a Persian and a Brazilian family.


Recurrent carpal tunnel syndrome, epineural fibrous fixation, and traction neuropathy.
This article has reviewed recurrent carpal tunnel syndrome, epineural fibrous fixation, and traction neuropathy of the median nerve. The problems surrounding the diagnosis and treatment of recurrent CTS have been discussed at length. The percent of failures from traditional open ligament surgery is observed to be high, and will become more prevalent as more casual treatments are carried out. This article makes a positive statement with reference to mobilization of the median nerve and anatomic restoration of the transverse carpal ligament. Fibrous fixation of the median nerve is a product of life and function. All cases are different, reflecting the strength, abilities, and personalities of the patients. A bottom line is drawn on these patients, where the summation of the problems of life become symptomatic and disabling. Epineural fibrous fixations induce median nerve traction, governed by hand, wrist, and forearm movements. Traction and tension suggest the intermittent disturbance of nerve nutrition and nerve conduction as the elastic limits of the nerve are approached. These factors accumulate and, in time, cause traction neuropathies with pain. This is followed by a reduced work capability. This impairment can be reversed by surgical nerve mobilization followed by functional nerve gliding therapy. A background history injury to the hand and wrist may be significant, as well as factors such as overuse and misuse of the hand and extremity. Prior to surgery, the careful application of diagnostic stress tests are essential, for the differential diagnosis of fixation traction and positional peripheral neuropathies. Nerve mobilization supported by magnification and the techniques of hand surgery has been successful by the methods discussed and has permitted, importantly, the restoration of the anatomic retinaculum for the flexor tendon system. This can be restored in carpal tunnel surgery and reconstructed with basic ligament material in recurrent carpal tunnel surgery.


Comparison of phosphorylation of ribosomal proteins from HeLa and Krebs II ascites-tumour cells by cyclic AMP-dependent and cyclic GMP-dependent protein kinases.
Phosphorylation of eukaryotic ribosomal proteins in vitro by essentially homogeneous preparations of cyclic AMP-dependent protein kinase catalytic subunit and cyclic GMP-dependent protein kinase was compared. Each protein kinase was added at a concentration of 30nM. Ribosomal proteins were identified by two-dimensional gel electrophoresis. Almost identical results were obtained when ribosomal subunits from HeLa or ascites-tumour cells were used. About 50-60% of the total radioactive phosphate incorporated into small-subunit ribosomal proteins by either kinase was associated with protein S6. In 90 min between 0.7 and 1.0 mol of phosphate/mol of protein S6 was incorporated by the catalytic subunit of cyclic AMP-dependent protein kinase. Of the other proteins, S3 and S7 from the small subunit and proteins L6, L18, L19 and L35 from the large subunit were predominantly phosphorylated by the cyclic AMP-dependent enzyme. Between 0.1 and 0.2 mol of phosphate was incorporated/mol of these phosphorylated proteins. With the exception of protein S7, the same proteins were also major substrates for the cyclic GMP-dependent protein kinase. Time courses of the phosphorylation of individual proteins from the small and large ribosomal subunits in the presence of either protein kinase suggested four types of phosphorylation reactions: (1) proteins S2, S10 and L5 were preferably phosphorylated by the cyclic GMP-dependent protein kinase; (2) proteins S3 and L6 were phosphorylated at very similar rates by either kinase; (3) proteins S7 and L29 were almost exclusively phosphorylated by the cyclic AMP-dependent protein kinase; (4) protein S6 and most of the other proteins were phosphorylated about two or three times faster by the cyclic AMP-dependent than by the cyclic GMP-dependent enzyme.


MRI in multiple sclerosis: current status and future prospects.
Many promising MRI approaches for research or clinical management of multiple sclerosis (MS) have recently emerged, or are under development or refinement. Advanced MRI methods need to be assessed to determine whether they allow earlier diagnosis or better identification of phenotypes. Improved post-processing should allow more efficient and complete extraction of information from images. Magnetic resonance spectroscopy should improve in sensitivity and specificity with higher field strengths and should enable the detection of a wider array of metabolites. Diffusion imaging is moving closer to the goal of defining structural connectivity and, thereby, determining the functional significance of lesions at specific locations. Cell-specific imaging now seems feasible with new magnetic resonance contrast agents. The imaging of myelin water fraction brings the hope of providing a specific measure of myelin content. Ultra-high-field MRI increases sensitivity, but also presents new technical challenges. Here, we review these recent developments in MRI for MS, and also look forward to refinements in spinal-cord imaging, optic-nerve imaging, perfusion MRI, and functional MRI. Advances in MRI should improve our ability to diagnose, monitor, and understand the pathophysiology of MS.


MUC1 carrying core 2 O-glycans functions as a molecular shield against NK cell attack, promoting bladder tumor metastasis.
Core 2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in O-glycans (core 2 O-glycans) of cell surface glycoproteins. C2GnT-expressing bladder tumors acquire highly metastatic phenotypes by surviving longer in host blood circulation. However, the detailed mechanisms underlying this increased survival remain unclear. In this study, we report that the expression of C2GnT in bladder tumors positively correlates with tumor progression and that bladder tumor cell-surface mucin 1 (MUC1) carrying core 2 O-glycans plays an important role in the evasion from natural killer (NK) cell attack. In C2GnT-expressing bladder tumor cells, heavily core 2 O-glycosylated MUC1 carries poly-N-acetyllactosamine in its O-glycans and galectin-3 binds to MUC1 through this poly-N-acetyllactosamine. The binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans attenuates the interaction of the tumor cells with NK cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to the tumor cell surface. These effects of MUC1 carrying core 2 O-glycans on NK cell attack facilitate C2GnT-expressing tumor cells to evade NK cell immunity and survive longer in host blood circulation. We reveal that MUC1 carrying core 2 O-glycans thus functions as a molecular shield against NK cell attack, thereby promoting bladder tumor metastasis.


Risk factors for suicide and medically serious suicide attempts among alcoholics: analyses of Canterbury Suicide Project data.
Alcohol dependence is a potent risk factor for completed suicide and medically serious attempts, but data are limited on factors that distinguish risk within this high-risk population. The purpose of this study is to identify risk factors for serious suicidal behavior among individuals with alcohol dependence. Data on completed suicides and medically serious suicide attempters and controls were gathered in the Canterbury region of New Zealand, using psychological autopsy methodology. A subsample of adult alcoholic subjects was selected for analyses yielding 38 completed suicides, 62 medically serious suicide attempters and 46 community controls, all with alcohol dependence (past month). Multinomial logistic analyses were used to compare the two case groups to controls on demographic and diagnostic variables. Mood disorders and financial difficulties were more frequent among medically serious attempters than controls. Completed suicides were older and were more likely to be male, to have mood disorders, partner-relationship difficulties and other interpersonal life events than were controls. Completed suicides were older and more likely to be male than were medically serious attempters. Risk factors in alcoholics are generally consistent with reports based on general samples of suicide and medically serious suicide attempts. Suicide prevention efforts in alcoholics, if they are to be successful, must include a focus on depression as well as interpersonal factors, including partner-relationship difficulties.


Case Report: Multi-Modality Imaging of a Right Atrial Pseudoaneurysm in a Patient With Breast Cancer.
Cardiac pseudoaneurysms occur when a blood vessel wall is injured and the leaking blood is collected in the surrounding tissue. They are very rare events and have a high risk of rupture and poor prognosis. We report a case of right atrial pseudoaneurysm in a 54-year-old female patient diagnosed with breast cancer and lung metastasis. The patient underwent five intrapericardial infusions of cisplatin and nine cycles of systemic chemotherapy. Non-contrast-enhanced computed tomography (CT) was performed at follow-up evaluation during the chemotherapeutic process as this patient was contraindicated to iodine. CT without contrast and ultrasonography showed a crescent-shaped lesion near the right atrium but its nature could not be determined. Cardiac magnetic resonance (CMR) imaging with gadolinium contrast provided important information as an alternative enhanced imaging modality. By combining CT, ultrasonography and CMR images with the medical history of the patient, we inferred that the lesion was a pseudoaneurysm in the right atrium. This condition was related to the erosion of metastasized tumor cells or the accumulated cardiac toxicity of multiple cycles of chemotherapy or pericardiocentesis. This single case report suggests that cardiac rupture should be considered as a potential complication in patients with suspected pericardial metastasis. CMR imaging is an excellent tool for the detection of right atrial rupture.


1,N6-ethenoadenosine formation, mutagenicity and murine tumor induction as indicators of the generation of an electrophilic epoxide metabolite of the closely related carcinogens ethyl carbamate (urethane) and vinyl carbamate.
Previous studies from this laboratory showed that (i) vinyl carbamate (VC) was much more carcinogenic than ethyl carbamate (EC) and that both carbamates induced the same spectrum of tumors in mice and rats, (ii) adducts of [14C]- or [3H]1,N6-ethenoadenosine and [14C]- or [3H]3,N4-ethenocytidine e were formed in the hepatic RNA of infant male B6C3F1 mice administered [1-14C]ethyl or [1,2-3H]ethyl EC and (iii) VC formed much more of the 1,N6-ethenoadenosine (epsilon Ado) adduct in the hepatic RNA and the 7-(2-oxoethyl)-guanine adduct in the hepatic DNA of mice than did EC. By analogy to the similar results of earlier studies by other investigators on the related carcinogen vinyl chloride, the above data suggested that VC epoxide was a reactive electrophilic metabolite of these carbamates. In the present studies, VC, but not EC, was found to be oxidized by 3-chloroperbenzoic acid to a derivative that reacted with adenosine to form epsilon Ado. Far more of this etheno nucleoside was formed from VC than from EC when these carbamates were metabolized by cofactor-fortified mouse liver microsomes in the presence of adenosine. Sodium diethyldithiocarbamate strongly inhibited these microsomal reactions and the formation of epsilon Ado in the hepatic RNA of mice administered either carbamate. Likewise, the i.p. preadministration of deithyldithiocarbamate markedly inhibited the induction of tumors by single i.p. doses of EC or VC in the livers of infant male B6C3F1 mice and in the livers, lungs and Harderian glands of infant female B6C3F1 mice. This inhibitor also considerably reduced lung tumor induction by VC in adult female A/Jax mice. 2-(2,4-Dichloro-6-phenyl) phenoxyethyl amine, a cytochrome P450 inhibitor, reduced the carcinogenicity of low doses of EC but appeared to increase the carcinogenicity of low doses of VC. The mutagenicity of VC for Salmonella typhimurium TA1535 in the presence of a hepatic activating system was greatly reduced by these inhibitors. The data from all these studies are consistent with the proposal that VC epoxide is an ultimate electrophilic and carcinogenic metabolite of EC and VC in the mouse.


The Association Between State-Level Racial Attitudes Assessed From Twitter Data and Adverse Birth Outcomes: Observational Study.
In the United States, racial disparities in birth outcomes persist and have been widening. Interpersonal and structural racism are leading explanations for the continuing racial disparities in birth outcomes, but research to confirm the role of racism and evaluate trends in the impact of racism on health outcomes has been hampered by the challenge of measuring racism. Most research on discrimination relies on self-reported experiences of discrimination, and few studies have examined racial attitudes and bias at the US national level. This study aimed to investigate the associations between state-level Twitter-derived sentiments related to racial or ethnic minorities and birth outcomes. We utilized Twitter's Streaming application programming interface to collect 26,027,740 tweets from June 2015 to December 2017, containing at least one race-related term. Sentiment analysis was performed using support vector machine, a supervised machine learning model. We constructed overall indicators of sentiment toward minorities and sentiment toward race-specific groups. For each year, state-level Twitter-derived sentiment data were merged with birth data for that year. The study participants were women who had singleton births with no congenital abnormalities from 2015 to 2017 and for whom data were available on gestational age (n=9,988,030) or birth weight (n=9,985,402). The main outcomes were low birth weight (birth weight ≤2499 g) and preterm birth (gestational age <37 weeks). We estimated the incidence ratios controlling for individual-level maternal characteristics (sociodemographics, prenatal care, and health behaviors) and state-level demographics, using log binomial regression models. The accuracy for identifying negative sentiments on comparing the machine learning model to manually labeled tweets was 91%. Mothers living in states in the highest tertile for negative sentiment tweets referencing racial or ethnic minorities had greater incidences of low birth weight (8% greater, 95% CI 4%-13%) and preterm birth (8% greater, 95% CI 0%-14%) compared with mothers living in states in the lowest tertile. More negative tweets referencing minorities were associated with adverse birth outcomes in the total population, including non-Hispanic white people and racial or ethnic minorities. In stratified subgroup analyses, more negative tweets referencing specific racial or ethnic minority groups (black people, Middle Eastern people, and Muslims) were associated with poor birth outcomes for black people and minorities. A negative social context related to race was associated with poor birth outcomes for racial or ethnic minorities, as well as non-Hispanic white people.


Endoscopic intragastric balloon: a gimmick or a viable option for obesity?
Worldwide, the prevalence of obesity has doubled since 1980 in 70 countries. More than one in three adults now suffer from overweight or obesity. Health problems related to obesity include orthopedic problems, psychiatric conditions, metabolic and cardiovascular diseases, and of increasing concern, cancer. Thus, obesity has an enormous impact on the individual's wellbeing as well as on society's workforce and health care expenses. Medical efforts are ongoing to find safe and effective treatment options for obesity and its metabolic implications. At present, available treatment options include lifestyle interventions, pharmacotherapy, endoscopic applications, and bariatric surgery. Within the range of endoscopic treatment options, the intragastric balloon is the most widely used device. The idea is simple: the gastric volume is reduced by a balloon that is in most cases implanted by an endoscopic procedure similar to a gastroscopy. During the past decades, different models have been developed, which we will briefly introduce in this review. We aim at reviewing the pathophysiology underlying the effect of endoscopic intragastric balloon on weight loss and metabolic changes. We will assess expected short-term and long-term benefits for the patient, and we will discuss common side effects as well as rare complications. We will compare endoscopic intragastric balloon to conservative treatment options with or without pharmacological support on the one hand and to the spectrum of bariatric surgery on the other hand. In most patients, obesity must be considered a chronic disease that requires a lifelong treatment concept. In view of current treatment options for obesity, we will discuss whether endoscopic intragastric balloon is a viable treatment option, and who may be the right patient to benefit from it.


Experimental Campylobacter jejuni infection of adult mice.
HA-ICR adult mice were studied to develop an animal model for Campylobacter jejuni enteritis in humans. Fecal and ileal cultures made by selective and nonselective methods showed that C. jejuni and related organisms are not bowel commensals. Intragastric feeding of 10(8) CFU of three different strains of C. jejuni produced infection in 100% of the animals, and infection rates were dose dependent. Pretreatment with antibiotics or opiates was not necessary to induce infection. Fresh isolates and strains passed on artificial media yielded similar infection rates. Infected mice did not show signs of illness, but transient bacteremia within 10 min of oral infection was observed in nearly 100%. The small intestine was the principal target organ, with epithelial inflammation seen 48 h after infection. Control mice of four species had undetectable serum immunoglobulin G antibody specific for the infecting strain, but infected mice showed peak titers at 1 week with rapid decline. Immunoglobulin M titers rose minimally, and immunoglobulin A titers did not rise. Infected mice uniformly became chronic asymptomatic excretors, shedding 10(4) to 10(6) CFU/g of feces; a minority were biliary carriers. Intestine carriage was most pronounced in the stomach and proximal small intestine. Because this experimental infection led to bacteremia, transient pathological changes, and immunoglobulin G titer rises, this model may be useful for evaluating the effects of prophylactic and therapeutic interventions.


Power of tests for a dichotomous independent variable measured with error.
To examine the implications for statistical power of using predicted probabilities for a dichotomous independent variable, rather than the actual variable. An application uses 271,479 observations from the 2000 to 2002 CAHPS Medicare Fee-for-Service surveys. STUDY DESIGN AND DATA: A methodological study with simulation results and a substantive application to previously collected data. Researchers often must employ key dichotomous predictors that are unobserved but for which predictions exist. We consider three approaches to such data: the classification estimator (1); the direct substitution estimator (2); the partial information maximum likelihood estimator (3, PIMLE). The efficiency of (1) (its power relative to testing with the true variable) roughly scales with the square of one less the classification error. The efficiency of (2) roughly scales with the R(2) for predicting the unobserved dichotomous variable, and is usually more powerful than (1). Approach (3) is most powerful, but for testing differences in means of 0.2-0.5 standard deviations, (2) is typically more than 95 percent as efficient as (3). The information loss from not observing actual values of dichotomous predictors can be quite large. Direct substitution is easy to implement and interpret and nearly as efficient as the PIMLE.


Methodology for image-based reconstruction of ventricular geometry for patient-specific modeling of cardiac electrophysiology.
Patient-specific modeling of ventricular electrophysiology requires an interpolated reconstruction of the 3-dimensional (3D) geometry of the patient ventricles from the low-resolution (Lo-res) clinical images. The goal of this study was to implement a processing pipeline for obtaining the interpolated reconstruction, and thoroughly evaluate the efficacy of this pipeline in comparison with alternative methods. The pipeline implemented here involves contouring the epi- and endocardial boundaries in Lo-res images, interpolating the contours using the variational implicit functions method, and merging the interpolation results to obtain the ventricular reconstruction. Five alternative interpolation methods, namely linear, cubic spline, spherical harmonics, cylindrical harmonics, and shape-based interpolation were implemented for comparison. In the thorough evaluation of the processing pipeline, Hi-res magnetic resonance (MR), computed tomography (CT), and diffusion tensor (DT) MR images from numerous hearts were used. Reconstructions obtained from the Hi-res images were compared with the reconstructions computed by each of the interpolation methods from a sparse sample of the Hi-res contours, which mimicked Lo-res clinical images. Qualitative and quantitative comparison of these ventricular geometry reconstructions showed that the variational implicit functions approach performed better than others. Additionally, the outcomes of electrophysiological simulations (sinus rhythm activation maps and pseudo-ECGs) conducted using models based on the various reconstructions were compared. These electrophysiological simulations demonstrated that our implementation of the variational implicit functions-based method had the best accuracy.


Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes.
Bardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alström syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes (BBS1-BBS16) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly. We tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as proof-of-principle and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene ALMS1 and the proposed modifier CCDC28B. This strategy allowed the reliable detection of causative mutations (including homozygous/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all proof-of-principle samples. Three probands carried homozygous truncating mutations in ALMS1 confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of 'classical' BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants. This strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes.


On the similarity of functional connectivity between neurons estimated across timescales.
A central objective in neuroscience is to understand how neurons interact. Such functional interactions have been estimated using signals recorded with different techniques and, consequently, different temporal resolutions. For example, spike data often have sub-millisecond resolution while some imaging techniques may have a resolution of many seconds. Here we use multi-electrode spike recordings to ask how similar functional connectivity inferred from slower timescale signals is to the one inferred from fast timescale signals. We find that functional connectivity is relatively robust to low-pass filtering--dropping by about 10% when low pass filtering at 10 hz and about 50% when low pass filtering down to about 1 Hz--and that estimates are robust to high levels of additive noise. Moreover, there is a weak correlation for physiological filters such as hemodynamic or Ca2+ impulse responses and filters based on local field potentials. We address the origin of these correlations using simulation techniques and find evidence that the similarity between functional connectivity estimated across timescales is due to processes that do not depend on fast pair-wise interactions alone. Rather, it appears that connectivity on multiple timescales or common-input related to stimuli or movement drives the observed correlations. Despite this qualification, our results suggest that techniques with intermediate temporal resolution may yield good estimates of the functional connections between individual neurons.


An Ambulatory System for Gait Monitoring Based on Wireless Sensorized Insoles.
A new gait phase detection system for continuous monitoring based on wireless sensorized insoles is presented. The system can be used in gait analysis mobile applications, and it is designed for real-time demarcation of gait phases. The system employs pressure sensors to assess the force exerted by each foot during walking. A fuzzy rule-based inference algorithm is implemented on a smartphone and used to detect each of the gait phases based on the sensor signals. Additionally, to provide a solution that is insensitive to perturbations caused by non-walking activities, a probabilistic classifier is employed to discriminate walking forward from other low-level activities, such as turning, walking backwards, lateral walking, etc. The combination of these two algorithms constitutes the first approach towards a continuous gait assessment system, by means of the avoidance of non-walking influences.


The use of cellular and molecular biomarkers to manage COPD exacerbations.
Chronic obstructive pulmonary disease (COPD) exacerbations are a common cause of respiratory morbidity and mortality, and have various etiologies. Multiple cellular and molecular biomarkers have been associated with exacerbations. Quantitative sputum cell counts are able to identify the presence and type of bronchitis, which is an important contributor to exacerbations. Their utility to monitor bronchitis and to help treat exacerbations has been evaluated, yet they are not used in routine clinical practice. Areas covered: This review will provide a brief summary of biomarkers utilized in COPD, with a focus on the application of cellular markers for the management of exacerbations. A case study will demonstrate the application of these methods. With quantitative sputum cell counts, the presence of eosinophilic bronchitis predicts corticosteroid-responsiveness, while neutrophilic bronchitis identifies infection and suggests the need for antibiotics. Gastroesophageal reflux-related aspiration and heart failure can also be identified by examining sputum. Expert commentary: Quantitative sputum cytometry is an essential tool in the management of exacerbations of COPD, particularly those prone to frequent exacerbations. Treatment based on sputum cell counts is superior to current guideline-based recommendations to prevent future exacerbations and hospitalizations in observational and single-centre controlled trials. Large multicentre clinical trials are necessary to confirm this.


Hypergastrinaemia in chronic renal failure.
Fasting serum gastrin was measured by radioimmunoassay in 89 patients with chronic renal failure. When the serum creatinine level was used as an index of the degree of renal impairment serum gastrin rose proportionately with the degree of renal failure. Haemodialysis did not significantly alter serum gastrin levels but renal transplantation tended to return them towards normal. This study indicates that the kidney has a role in the degradation of gastrin.


Incidence of fecal indicator and pathogenic bacteria in reclaimed and return flow waters in Arizona, USA.
The quality of irrigation water used to cultivate produce that is consumed raw is an important issue with regard to food safety. In this study, the microbiological quality of potential irrigation water sources in Arizona was evaluated by testing for the presence of indicator and pathogenic bacteria. Reclaimed water samples were collected from two wastewater treatment plants and return flow samples were collected from two drainage canals and one return flow pond. Standard membrane filtration methods were used for detection of indicator bacteria. Water samples (n = 28) were filtered through cellulose ester membrane filters and bacterial populations were enumerated by placing the filters on selective agar. For detection of pathogens (Salmonella enterica, Listeria monocytogenes and Shiga toxin-producing E. coli (STEC)), water samples were filtered through Modified Moore swabs and enriched in Universal Pre-enrichment Broth, followed by selective enrichment broth for each pathogen. The enriched broth was streaked onto agar media selective for each pathogen. Presumptive colonies were confirmed by PCR/real-time PCR. Among the 14 reclaimed water samples from two sites, the ranges of recovered populations of E. coli, total coliforms, and enterococci were 0-1.3, 0.5-8.3 × 103, and 0-5.5 CFU/100 mL, respectively. No L. monocytogenes, Salmonella or STEC were found. In the 13 return flow water samples from 3 sites, the ranges of recovered populations of E. coli, total coliforms and enterococci were 1.9-5.3 × 102, 6.5 × 102-9.1 × 104, and 2.9-3.7× 103 CFU/100 mL, respectively. All samples were negative for L. monocytogenes. One (7.1%) of the return flow samples was positive for E. coli O145. Nine (64.3%) of the samples were positive for Salmonella. Both real-time PCR and culture-based methods were used for the detection of Salmonella and L. monocytogenes, and the results from the two methods were comparable. The findings of this study provide evidence that irrigation waters in Arizona, including reclaimed water and return flows, could be potential sources of bacterial contamination of produce. Additional work is needed to evaluate whether bacteria present in irrigation water sources transfer to the edible portion of irrigated plants and are capable of persisting through post-harvest activities.


Low back pain: a radiographic enigma.
Ninety-nine anteroposterior and lateral lumbar radiographs taken of males ages 18-55 were independently analyzed by three chiropractors who assessed 56 variables, including determinations of disc space height, vertebral malalignments and subluxations, spondylosis, postural disturbances, relationships between pelvis and spine, and other congenital or acquired abnormalities. The distribution of low back complaints in this study included 31% with no low back pain, 44% with previous or present mild low back pain and 24% with previous or current severe, and often disabling, low back pain. Determinations were made of interobserver reliability between the three chiropractors and a medical radiologist. Of the 56 radiographic variables assessed by the chiropractors, six demonstrated a high interobserver reliability. In general, the best reliability was for variables that were actual measurements, rather than subjective observations. Sixteen additional variables demonstrated a fair interobserver reliability. Comparison of the observations between a radiologist and the chiropractors showed correlations in their assessments of disc space height at L3-4 and L4-5; otherwise, there was poor interobserver reliability. Few of the radiographic variables were found to be reliable predictors of present or prior history of low back and leg complaints. A few variables (most notably disc space narrowing) were statistically associated with back or leg complaints (P = 0.025). We conclude that spinal radiographs, whether analyzed by measurements, by a radiologist or by chiropractors, have minimal value in predicting the presence or absence of low back complaints and, in particular, have no value in epidemiological studies.


Validation of the Slovenian version of patient assessment of chronic illness care (PACIC) in patients with coronary heart disease.
The Chronic Care Model (CCM) is a conceptual framework that supports the evidence-based proactive and planned care of chronic diseases. Our aim was to validate a Slovenian translation of Patient Assessment of Chronic Illness Care (PACIC)--a self-reported instrument designed to measure the extent to which patients with chronic illnesses receive care congruent with CCM--on a sample of patients with coronary heart disease. Secondary analysis of patients' evaluation of general practice care (EPA Cardio study) was done in patients with coronary heart disease in Slovenia. Patients completed a written questionnaire, which included the instrument for assessing chronic illness care (PACIC), the EUROPEP questionnaire and demographical data. Internal consistency was expressed in terms of Cronbach's alpha. Reliability was expressed as the intra class correlation coefficient (ICC). Correlation between PACIC and EUROPEP was considered as a measure of construct validity. Factor analysis was done to identify number and types of domains in the instrument. Questionnaires of 843 patients were analysed. The mean age was 68.2 (SD 11.1) years, 34.6% of participants were female. 32.7% of PACIC questionnaires were not completely fulfilled. The internal consistency of the entire questionnaire assessed by Cronbach's alpha was 0.953 and reliability was 0.937. Construct validity was confirmed with important and significant correlation between PACIC and EUROPEP questionnaire (Spearman's correlation coefficient = 0.60, p < 0.001). Principal component factor analysis identifies two major factors which we labeled according to the PACIC domains as "Patient activation, decision support and problem solving" and "Goal settings and coordination". A translated and validated Slovenian version of PACIC questionnaire is now available. Further research on its validity in other groups of chronically ill patients and the use of instrument for monitoring changes of chronic care over time is recommended.


Transient GFER knockdown in vivo impairs liver regeneration after partial hepatectomy.
Augmenter of Liver Regeneration is a protein encoded by the Growth Factor Erv1-Like gene. Its biological properties are crucial for cell survival since knock-out mice for Growth Factor Erv1-Like gene do not survive. In this study, we injected hepatotropic adenoviral particles harboring oligonucleotide sequences against Growth Factor Erv1-Like gene into 70% partially hepatectomized rats and studied the effect of gene silencing on the progression liver regeneration. Partially hepatectomized rats were divided into three groups of animals and, before surgery, received either phosphate buffer saline, or adenoviral particles alone or adenoviral particles harboring the oligonucleotide silencing sequence. In each group, rats were sacrificed at 12, 24 and 48 h after surgery. Liver tissues were collected to analyze the expression of Augmenter of Liver Regeneration, Bax, Bcl-2 and activated Caspase-9 and -3, as well as hepatocyte proliferation and apoptosis, polyamines levels and histological and ultrastructural features. Growth Factor Erv1-Like gene silencing reduced the compensatory hepatocellular proliferation triggered by surgery through (i) the reduction of polyamines synthesis, hepatocyte proliferation and anti-apoptotic gene expression and (ii) the increase of pro-apoptotic gene expression and caspase activation. For the first time, using a technique of gene silencing in vivo, our results demonstrate that Growth Factor Erv1-Like gene knock-down, i.e., the lack of Augmenter of Liver Regeneration, modifies the expression of genes involved in cell apoptosis and inhibits early phase of DNA synthesis. As a consequence, a promotion of cell death and a reduction of cell proliferation occurs.


Localization of ανβ6 integrin-TGF-β1/Smad3, mTOR and PPARγ in experimental colorectal fibrosis.
A simultaneous action of several pro-fibrotic mediators appears relevant in the development of fibrosis. There are evidences that transforming growth factor-β (TGF-β)/Smad3 pathway forms with αvβ6 integrin, mammalian target of Rapamycin (mTOR) and peroxisome proliferator-activated receptor-γ (PPARγ) a complex signalling network with extensive crosstalk and strong effects on fibrosis development. The present study evaluated the expression of TGFβ, Smad3, αvβ6 integrin, mTOR and PPARγ in 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colorectal fibrosis in Smad3 wild-type (WT) and null mice. Smad3 WT mice treated with TNBS developed a marked colorectal fibrosis and showed a concomitant up-regulation of TGFβ, Smad3, αvβ6 and mTOR and a reduction of PPARγ expression. On the other hand, Smad3 Null mice similarly treated with TNBS did not develop fibrosis and showed a very low or even absent expression of TGFβ, Smad3, αvβ6 and mTOR and a marked over-expression of PPARγ. At the same time the expression of α-smooth muscle actin (a marker of activated myofibroblasts), collagen I-III and connective tissue growth factor (a downstream effector of TGFβ/Smad3-induced extracellular matrix proteins) were up-regulated in Smad3 WT mice treated with TNBS compared to Null TNBS-treated mice. These preliminary results suggest a possible interaction between these pro-fibrotic molecules in the development of intestinal fibrosis.


Protective effect of gabexate mesilate against experimental disseminated intravascular coagulation in rats.
Experimental disseminated intravascular coagulation (DIC) can be induced by 4 h sustained infusion of endotoxin at a dose of 100 mg/kg in rats. The experimental model of DIC in rats was used to study the preventive effect of gabexate mesilate (GM) against DIC. Before the infusion of endotoxin, 10(-6), 10(-3), 1, 10, 50 or 100 mg/kg of GM was injected intraperitoneally. The preventive effects against DIC were noted in all the parameters, such as fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count, and the number of renal glomeruli with fibrin thrombi, in rats treated with 1, 10 or 50 mg/kg of GM. From these results it was shown that GM inhibited the aggravation of endotoxin-induced experimental DIC in rats.


Estrogen receptor-related receptor alpha (ERRalpha) regulates osteopontin expression through a non-canonical ERRalpha response element in a cell context-dependent manner.
We previously demonstrated that the orphan nuclear receptor, estrogen receptor-related receptor alpha (ERRalpha) is highly expressed in osteoblasts and osteoclasts, regulates osteogenesis and expression of osteoblast-associated markers in the rat calvaria cell differentiation system, and is dysregulated in the rat ovariectomy model of postmenopausal osteoporosis. There are conflicting published data on the transcriptional regulation by ERRalpha of the gene for osteopontin (OPN), an extracellular matrix protein required in bone remodeling, and a potential direct target mediating ERRalpha effects in bone. We therefore readdressed OPN gene regulation by ERRalpha in both osteoblastic (rat osteosarcoma ROS17/2.8 cells) and non-osteoblastic (HeLa) cell lines using a mouse proximal 2 kb OPN promoter fragment. A minimal OPN promoter fragment spanning from -56 to +9 bp is activated in HeLa cells but repressed it in ROS17/2.8 cells. Adenine scanning mutagenesis revealed the presence of a non-canonical ERRalpha response element in this minimal promoter. Surprisingly, prototypical inactivating mutations in the activation function 2 (AF2) domain or a naturally occurring allelic variant of ERRalpha (ERRalphaH408) were all better activators than wild-type ERRalpha in HeLa cells, activities that were generally paralleled by repression in ROS17/2.8 cells. Finally, we found that the N-terminus of ERRalpha harbors a repressor domain that acts in a cell context-dependent manner. We conclude that OPN is an ERRalpha target gene whose promoter is regulated by ERRalpha in a cell context-dependent manner and that a predicted silencing mutation in AF2 or a more flexible helix 12 increases ERRalpha transcriptional activity, effects with implications for ERRalpha as a therapeutic target in bone.


Swine antibody-dependent cellular cytotoxicity against pseudorabies virus-infected cells.
In pseudorabies virus (PRV) infection of pigs, antibody-dependent cellular cytotoxicity (ADCC) may be an early defense mechanism. Peripheral blood leukocytes (PBL) and pulmonary macrophages mediate ADCC activity. Antibody-dependent cellular cytotoxicity against PRV-infected target cells was assessed, and the effect of infection of cells having an ADCC-effector function was determined. Although pulmonary lavage cells (PLC) had ADCC activity, in vitro infection of PLC led to PRV replication, loss of cell viability, and loss of ADCC activity. In contrast, infection of PBL did not lead to replication, decreased cell viability, or reduced ADCC activity, compared with those in non-infected controls. Measuring ADCC activity in a longitudinal study revealed that PBL from neonates had lower ADCC activity than did PBL from pigs greater than 3.5 months old. Peripheral blood leukocytes and not PLC may have a greater role in control of PRV dissemination in the pig. The difference in activity between cells from neonates and older pigs might explain, in part, the age dependency in the severity of the disease.


A novel dimeric zinc(II) complex: bis[mu-1,2-bis(1H-1,2,4-triazol-1-yl)ethane-kappa(2)N(4):N(4')]bis[diisothiocyanatozinc(II)].
The coordination geometry of the Zn(II) atom in the title complex, [Zn(2)(NCS)(4)(C(6)H(8)N(6))(2)], is that of a distorted tetrahedron, in which the Zn(II) atom is coordinated by four N atoms from the triazole rings of two symmetry-related 1,2-bis(1,2,4-triazol-1-yl)ethane ligands and two thiocyanate ligands. Two Zn(II) atoms are bridged by two organic ligands to form a dimer. The dimer lies about an inversion center.


Class I HDAC modulates angiotensin II-induced fibroblast migration and mitochondrial overactivity.
Inhibition of histone deacetylases (HDACs) attenuates cardiac fibrosis. In this study, we evaluated whether the inhibition of class I HDACs can attenuate angiotensin II (ANG II)-induced fibrogenesis and mitochondrial malfunction through its effects on reactive oxygen species (ROS) and calcium dysregulation in human cardiac fibroblasts (CFs). Seahorse XF24 extracellular flux analyser, fluorescence staining, Western blotting, HDAC activity assays and Transwell migration assay were used to study mitochondrial respiration, adenosine triphosphate (ATP) production, mitochondrial calcium uptake and ROS, HDAC expression and activity and fibroblast activity in CFs without (control) or with ANG II (100 nM) and/or MS-275 (HDAC class 1 inhibitor, 10 μM) for 24 h. ANG II increased HDAC activity without changing protein expression in CFs. Compared with controls, ANG II-treated CFs had greater migration activity, higher ATP production, maximal respiration and spare capacity with higher mitochondrial Ca2+ uptake and ROS generation, which was attenuated by the administration of MS-275. ANG II activated CFs by increasing mitochondrial calcium content and ATP production, which may be caused by increased HDAC activity. Inhibition of HDAC1 attenuated the effects of ANG II by reducing mitochondrial ROS generation and calcium overload. Modulating mitochondrial function by regulation of HDAC may be a novel strategy for controlling CF activity.


Oxidative stress in early diabetic nephropathy: fueling the fire.
Diabetic nephropathy is a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease worldwide. The treatment costs of diabetes mellitus and its complications represent a huge burden on health-care expenditures, creating a major need to identify modifiable factors concerned in the pathogenesis and progression of diabetic nephropathy. Chronic hyperglycemia remains the primary cause of the metabolic, biochemical and vascular abnormalities in diabetic nephropathy. Promotion of excessive oxidative stress in the vascular and cellular milieu results in endothelial cell dysfunction, which is one of the earliest and most pivotal metabolic consequences of chronic hyperglycemia. These derangements are caused by excessive production of advanced glycation end products and free radicals and by the subjugation of antioxidants and antioxidant mechanisms. An increased understanding of the role of oxidative stress in diabetic nephropathy has lead to the exploration of a number of therapeutic strategies, the success of which has so far been limited. However, judicious and timely use of current therapies to maintain good glycemic control, adequate blood pressure and lipid levels, along with lifestyle measures such as regular exercise, optimization of diet and smoking cessation, may help to reduce oxidative stress and endothelial cell dysfunction and retard the progression of diabetic nephropathy until more definitive therapies become available.


Crohn disease arthropathy: antigens in synovial fluid share epitopes with strains of two species of viridans streptococci.
There is evidence to suggest that Crohn disease is caused by an immunologic response to an unknown intestinal luminal antigen, probably of bacterial origin. The reported demonstration of yersinia antigen in the synovial fluid of patients with yersinosis therefore prompted a search for bacterial antigens in the synovial fluid of patients with Crohn arthropathy. Antisera were raised in rabbits to synovial fluids obtained from seven patients with Crohn arthropathy and from seven 'control' subjects with other forms of arthropathy. These antisera were used to probe sonicates of the bacteria cultured from the gastric juice of patients with gastric Crohn disease. The antisera made from the Crohn synovial fluids, but none of those made from the controls, reacted uniquely with antigens in sonicates of strains of two species of viridans streptococci (Streptococcus parasanguis and an atypical S. oralis) isolated from four of the five patients with gastric Crohn disease. These findings suggest that the arthropathy of Crohn disease and, possibly, the intestinal disease itself may involve an immunologically mediated inflammatory response to these antigens.


High-Risk Factors for Suppurative Mastitis in Lactating Women.
BACKGROUND Acute mastitis is a common disease occurring in postpartum lactating women. This study aimed to identify the high-risk factors for suppurative mastitis (SM) in women who were breastfeeding. MATERIAL AND METHODS A total of 262 non-SM patients and 63 SM patients admitted to the Department of Breast and Thyroid Surgery of Liaocheng People's Hospital were retrospectively enrolled in this study. The high-risk factors for SM during lactation were determined by assessing admission time after acute mastitis, galactostasis, primipara or pluripara, nipple injuries, antibiotic treatment course, and diabetes. RESULTS The incidence of SM in patients with admission time greater than 72 h after occurrence of acute mastitis was significantly higher than that in patients whose admission time was less than 72 h (p<0.0001). Patients with galactostasis were more prone to develop SM compared to patients without galactostasis (p<0.0001), and the incidence of SM in primiparous patients was significantly higher than that in pluriparous patients (p=0.003). The incidence rate of SM was significantly higher in patients with diabetes than in patients without diabetes (p=0.002). Patients with nipple injuries were more prone to suffer from SM relative to the patients without nipple injuries (p<0.0001). However, there was no significant difference in the incidence of SM according to the antibiotic treatment course (p=0.134). CONCLUSIONS SM during lactation was closely associated with admission time after the occurrence of acute mastitis, galactostasis, primipara, diabetes, and nipple injuries.


Acclimation to short-term low temperatures in two Eucalyptus globulus clones with contrasting drought resistance.
We tested the hypothesis that Eucalyptus globulus Labill. genotypes that are more resistant to dry environments might also exhibit higher cold tolerances than drought-sensitive plants. The effect of low temperatures was evaluated in acclimated and unacclimated ramets of a drought-resistant clone (CN5) and a drought-sensitive clone (ST51) of E. globulus. We studied the plants' response via leaf gas exchanges, leaf water and osmotic potentials, concentrations of soluble sugars, several antioxidant enzymes and leaf electrolyte leakage. Progressively lowering air temperatures (from 24/16 to 10/-2 degrees C, day/night) led to acclimation of both clones. Acclimated ramets exhibited higher photosynthetic rates, stomatal conductances and lower membrane relative injuries when compared to unacclimated ramets. Moreover, low temperatures led to significant increases of soluble sugars and antioxidant enzymes activity (glutathione reductase, ascorbate peroxidase and superoxide dismutases) of both clones in comparison to plants grown at control temperature (24/16 degrees C). On the other hand, none of the clones, either acclimated or not, exhibited signs of photoinhibition under low temperatures and moderate light. The main differences in the responses to low temperatures between the two clones resulted mainly from differences in carbon metabolism, including a higher accumulation of soluble sugars in the drought-resistant clone CN5 as well as a higher capacity for osmotic regulation, as compared to the drought-sensitive clone ST51. Although membrane injury data suggested that both clones had the same inherent freezing tolerance before and after cold acclimation, the results also support the hypothesis that the drought-resistant clone had a greater cold tolerance at intermediate levels of acclimation than the drought-sensitive clone. A higher capacity to acclimate in a short period can allow a clone to maintain an undamaged leaf surface area along sudden frost events, increasing growth capacity. Moreover, it can enhance survival chances in frost-prone sites expanding the plantation range with more adaptive clones.


Plastic debris in the coastal environment: The invincible threat? Abundance of buried plastic debris on Malaysian beaches.
Studies on marine debris have gained worldwide attention since many types of debris have found their way into the food chain of higher organisms. Thus, it is crucial that more focus is given to this area in order to curb contaminations in sea food. This study was conducted to quantify plastic debris buried in sand at selected beaches in Malaysia. Marine debris was identified according to size range and distribution, and this information was related to preventive actions to improve marine waste issues. For the purpose of this study, comparison of plastic waste abundance between a recreational beach and fish-landing beaches was also carried out, since the different beach types represent different activities that produce debris. Six beaches along the Malaysian coastline were selected for this study. The plastic types in this study were related to the functions of the beach. While recreational beaches have abundant quantities of plastic film, foamed plastic including polystyrene, and plastic fragment, fish-landing beaches accumulated line and foamed plastic. A total of 2542 pieces (265.30 g m(-2)) of small plastic debris were collected from all six beaches, with the highest number from Kuala Terengganu, at 879 items m(-2) on Seberang Takir Beach, followed by Batu Burok Beach with 780 items m(-2). Findings from studies of Malaysian beaches have provided a clearer understanding of the distribution of plastic debris. This demonstrates that commitments and actions, such as practices of the 'reduce, reuse, recycle' (3R) approach, supporting public awareness programmes and beach clean-up activities, are essential in order to reduce and prevent plastic debris pollution.


Impact of Crosslinking on the Characteristics of Pectin Monolith Cryogels.
In this research, the pectin monoliths were prepared via the sol-gel process through different routes of crosslinking and additional freeze-drying. The crosslinking reaction was induced by the use of calcium ions in aqueous solutions and in alcohol/water solutions. The resulting pectin monoliths obtained by freeze-drying were macroporous with open cells, limited specific surface area, moderate mechanical stability and moderate biodegradation rate. The presence of alcohol in crosslinking solution significantly changed the morphology of final pectin monoliths, which was evidenced by the reduction of their pore size for one order. The specific surface area of pectin monoliths obtained through the calcium-water-alcohol route was 25.7 m2/g, the Young compressive modulus was 0.52 MPa, and the biodegradation rate was 45% after 30 days of immersion in compost media. Considering that pectin can be obtained from food waste, and its physical properties could be tailored by different crosslinking routes, the pectin monoliths could find wide application in the pharmaceutical, agricultural, medical and food industries, providing sustainable development concepts.


All-Polymer Solar Cell Performance Optimized via Systematic Molecular Weight Tuning of Both Donor and Acceptor Polymers.
The influence of the number-average molecular weight (Mn) on the blend film morphology and photovoltaic performance of all-polymer solar cells (APSCs) fabricated with the donor polymer poly[5-(2-hexyldodecyl)-1,3-thieno[3,4-c]pyrrole-4,6-dione-alt-5,5-(2,5-bis(3-dodecylthiophen-2-yl)thiophene)] (PTPD3T) and acceptor polymer poly{[N,N'-bis(2-octyldodecyl)naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} (P(NDI2OD-T2); N2200) is systematically investigated. The Mn effect analysis of both PTPD3T and N2200 is enabled by implementing a polymerization strategy which produces conjugated polymers with tunable Mns. Experimental and coarse-grain modeling results reveal that systematic Mn variation greatly influences both intrachain and interchain interactions and ultimately the degree of phase separation and morphology evolution. Specifically, increasing Mn for both polymers shrinks blend film domain sizes and enhances donor-acceptor polymer-polymer interfacial areas, affording increased short-circuit current densities (Jsc). However, the greater disorder and intermixed feature proliferation accompanying increasing Mn promotes charge carrier recombination, reducing cell fill factors (FF). The optimized photoactive layers exhibit well-balanced exciton dissociation and charge transport characteristics, ultimately providing solar cells with a 2-fold PCE enhancement versus devices with nonoptimal Mns. Overall, it is shown that proper and precise tuning of both donor and acceptor polymer Mns is critical for optimizing APSC performance. In contrast to reports where maximum power conversion efficiencies (PCEs) are achieved for the highest Mns, the present two-dimensional Mn optimization matrix strategy locates a PCE "sweet spot" at intermediate Mns of both donor and acceptor polymers. This study provides synthetic methodologies to predictably access conjugated polymers with desired Mn and highlights the importance of optimizing Mn for both polymer components to realize the full potential of APSC performance.


Adenoid cystic carcinoma of the subglottic larynx: a case report and review of the literature.
Laryngeal adenoid cystic carcinoma (ACC) is a rare clinical entity that poses a number of diagnostic and therapeutic challenges. We present a case of ACC of the subglottic larynx, and we review its diagnosis and management. We also discuss the workup of submucosal masses of the subglottic larynx, with an emphasis on clinical and radiologic diagnosis, surgical treatment, radiotherapy, and emerging therapies. The presence of a submucosal mass in the subglottic larynx should raise suspicion for the presence of ACC.


Re-engaging students in medical school accreditation: the independent student analysis action (ISA2) approach.
This article was migrated. The article was marked as recommended. Background: Student satisfaction with key aspects of a medical school program plays a major role in an institution's accreditation in the United States (US). There is limited evidence regarding how to best engage students in responding to areas of lower student satisfaction that are identified through the national Liaison Committee on Medication Education (LCME) accreditation self-study process. Methods:We present a student-led innovation to promote greater levels of student engagement throughout Harvard Medical School's re-accreditation experience, which we refer to as the Independent Student Analysis Action (ISA 2) process. This innovation built directly upon the Independent Student Analysis (ISA) survey, which is expected by the LCME for accreditation. The ISA 2 process allowed medical student leaders to leverage ISA results to identify 11 priority areas that had relatively lower levels of satisfaction and subsequently coordinate focused, time-limited ISA 2 working groups to address these problematic areas. These working groups then presented their solutions to the student body, and a follow-up survey gauged satisfaction with these areas in light of the changes made. Results: The ISA 2 process engaged over 110 students, faculty, and staff. The majority of the student body completed the follow-up survey, which demonstrated higher levels of satisfaction with these previously problematic areas as identified in the original ISA survey. Further, 96% of students reported being satisfied with the ISA 2 process as a mechanism for utilizing student feedback in the ISA to create meaningful institutional changes. Conclusions: The ISA 2 served as a powerful convening mechanism for engaging a large number of students in our institution's re-accreditation efforts. Other medical schools looking to involve students in their continuous quality improvement systems and accreditation experience may benefit from reviewing and customizing this model to their institution's needs.


Development and Validation of a Genomic Knowledge Scale to Advance Informed Decision Making Research in Genomic Sequencing.
This study evaluated the psychometric properties of a new, comprehensive measure of knowledge about genomic sequencing, the University of North Carolina Genomic Knowledge Scale (UNC-GKS). The UNC-GKS assesses knowledge in four domains thought to be critical for informed decision making about genomic sequencing. The scale was validated using classical test theory and item response theory in 286 adult patients and 132 parents of pediatric patients undergoing diagnostic whole exome sequencing (WES) in the NCGENES study. The UNC-GKS assessed a single underlying construct (genomic knowledge) with good internal reliability (Cronbach's alpha = 0.90). Scores were most informative (able to discriminate between individuals with different levels of genomic knowledge) at one standard deviation above the scale mean or lower, a range that included most participants. Convergent validity was supported by associations with health literacy and numeracy (rs=0.41-0.46). The scale functioned well across subgroups differing in sex, race/ethnicity, education, and English proficiency. Findings supported the promise of the UNC-GKS as a valid and reliable measure of genomic knowledge among people facing complex decisions about WES and comparable sequencing methods. It is neither disease- nor population-specific, and it functioned well across important subgroups, making it usable in diverse populations.


The Evolution of Fangs, Venom, and Mimicry Systems in Blenny Fishes.
Venom systems have evolved on multiple occasions across the animal kingdom, and they can act as key adaptations to protect animals from predators [1]. Consequently, venomous animals serve as models for a rich source of mimicry types, as non-venomous species benefit from reductions in predation risk by mimicking the coloration, body shape, and/or movement of toxic counterparts [2-5]. The frequent evolution of such deceitful imitations provides notable examples of phenotypic convergence and are often invoked as classic exemplars of evolution by natural selection. Here, we investigate the evolution of fangs, venom, and mimetic relationships in reef fishes from the tribe Nemophini (fangblennies). Comparative morphological analyses reveal that enlarged canine teeth (fangs) originated at the base of the Nemophini radiation and have enabled a micropredatory feeding strategy in non-venomous Plagiotremus spp. Subsequently, the evolution of deep anterior grooves and their coupling to venom secretory tissue provide Meiacanthus spp. with toxic venom that they effectively employ for defense. We find that fangblenny venom contains a number of toxic components that have been independently recruited into other animal venoms, some of which cause toxicity via interactions with opioid receptors, and result in a multifunctional biochemical phenotype that exerts potent hypotensive effects. The evolution of fangblenny venom has seemingly led to phenotypic convergence via the formation of a diverse array of mimetic relationships that provide protective (Batesian mimicry) and predatory (aggressive mimicry) benefits to other fishes [2, 6]. Our results further our understanding of how novel morphological and biochemical adaptations stimulate ecological interactions in the natural world.


Insight into wild-type and T1372E TET2-mediated 5hmC oxidation using ab initio QM/MM calculations.
Ten-eleven translocation 2 (TET2) is an Fe/α-ketoglutarate (α-KG) dependent enzyme that dealkylates 5-methylcytosine (5mC). The reaction mechanism involves a series of three sequential oxidations that convert 5mC to 5-hydroxy-methylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Our previous biochemical and computational studies uncovered an active site scaffold that is required for wild-type (WT) stepwise oxidation (Nat. Chem. Bio., 13, 181). We showed that the mutation of a single residue, T1372 to some amino acids, such as Glu, can impact the iterative oxidation steps and stop the oxidation of 5hmC to 5fC/caC. However, the source of the stalling at the first oxidation step by some mutant TET proteins still remains unclear. Here, we studied the catalytic mechanism of oxidation of 5hmC to 5fC by WT and T1372E TET2 using an ab initio quantum mechanical/molecular mechanical (QM/MM) approach. Our results suggest that the rate limiting step for WT TET2 involves a hydrogen atom abstraction from the hydroxyl group of 5hmC by the ferryl moiety in the WT. By contrast, our calculations for the T1372E mutant indicate that the rate limiting step for this variant corresponds to a second proton abstraction and the calculated barrier is almost twice as large as for WT TET2. Our results suggest that the large barrier for the 5hmC to 5fC oxidation in this mutant is due (at least in part) to the unfavorable orientation of the substrate in the active site. Combined electron localization function (ELF) and non-covalent interaction (NCI) analyses provide a qualitative description of the evolution of the electronic structure of the active site along the reaction path. Energy decomposition analysis (EDA) has been performed on the WT to investigate the impact of each MM residue on catalytic activity.


Mindset-Oriented Negotiation Training (MONT): Teaching More Than Skills and Knowledge.
In this conceptual paper, we propose that both skill set development and mindset development would be desirable dimensions of negotiation training. The second dimension has received little attention thus far, but negotiation mindsets, i.e., the psychological orientations by which people approach negotiations, are likely to have a considerable influence on the outcome of negotiations. Referring to empirical and conceptual mindset studies from outside the negotiation field, we argue that developing mindsets can leverage the effectiveness of skills and knowledge, increase learning transfer, and lead to long-term behavioral changes. We introduce an integrative negotiation mindset that comprises three inclinations which complement each other: a collaborative, a curious, and a creative one. We also discuss activities that help people to develop and enhance this mindset both in and out of the classroom. Our general claim is that by moving beyond the activities of conventional negotiation training, which focuses on skills and knowledge, mindset-oriented negotiation training can increase training effectiveness and enable participants to more often reach what we define as sustainable integrative agreements.


Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion.
T-cell depletion facilitates reduced immunosuppression following organ transplantation and has been suggested to be pro-tolerant. However, the characteristics of post-depletional T cells have not been evaluated as they relate to tolerance induction. We therefore studied patients undergoing profound T-cell depletion with alemtuzumab or rabbit anti-thymocyte globulin following renal transplantation, evaluating the phenotype and functional characteristics of their residual cells. Naive T cells and T cells with potential regulatory function (CD4+CD25+) were not prevalent following aggressive depletion. Rather, post-depletion T cells were of a single phenotype (CD3+CD4+CD45RA-CD62L-CCR7-) consistent with depletion-resistant effector memory T cells that expanded in the first month and were uniquely prevalent at the time of rejection. These cells were resistant to steroids, deoxyspergualin or sirolimus in vitro, but were calcineurin-inhibitor sensitive. These data demonstrate that therapeutic depletion begets a limited population of functional memory-like T cells that are easily suppressed with certain immunosuppressants, but cannot be considered uniquely pro-tolerant.


The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition.
Several IAP (inhibitor of apoptosis) proteins regulate cell fate decisions, and the X-linked IAP (XIAP) does so in part by inhibiting caspases, proteases that execute the apoptotic pathway. A tissue-specific homologue of XIAP, known as ILP2 (IAP-like protein 2), has previously been implicated in the control of apoptosis in the testis by direct inhibition of caspase 9. In examining this protein we found that the putative caspase 9 interaction domain is a surprisingly weak inhibitor and is also conformationally unstable. Comparison with the equivalent domain in XIAP demonstrated that the instability is due to the lack of a linker segment N-terminal to the inhibitory BIR (baculovirus IAP repeat) domain. Fusion of a 9-residue linker from XIAP to the N-terminus of ILP2 restored tight caspase 9 inhibition, dramatically increased conformational stability and allowed crystallization of the ILP2 BIR domain in a form strikingly similar to the XIAP third BIR domain. We conclude that ILP2 is an unstable protein, and cannot inhibit caspase 9 in a physiological way on its own. We speculate that ILP2 requires assistance from unidentified cellular factors to be an effective inhibitor of apoptosis in vivo.


Randomized Clinical Trial of Brief Primary Care-Based Mindfulness Training Versus a Psychoeducational Group for Veterans With Posttraumatic Stress Disorder.
Objective: Individuals with posttraumatic stress disorder (PTSD) symptoms are often reluctant to engage in traditional mental health care but do seek primary care services. Alternative strategies are needed to develop emotional regulation skills among individuals with PTSD symptoms. This study examined the feasibility and effectiveness of Primary Care Brief Mindfulness Training (PCBMT) compared to a psychoeducational group for reducing PTSD symptoms. Methods: Primary care patients (n = 55) with DSM-5 PTSD symptoms but not engaged in PTSD psychotherapies were randomized to 4-week PCBMT or a PTSD psychoeducation group (EDU). Both groups were cofacilitated by mental health providers and veteran peer specialists. Between January 2019 and March 2020, assessments were completed at baseline, post-treatment, and 16- and 24-week follow-up. Results: PCBMT participants had significantly larger decreases in PTSD symptoms from pre- to post-treatment (d = 0.57) and depression from pre-treatment to 16- and 24-week follow-ups (d = 0.67, 0.60) compared to EDU. PCBMT participants also reported significantly greater improvements in health responsibility (d = 0.79), stress management (d = 0.99), and not feeling dominated by symptoms (d = 0.71). Both interventions resulted in the majority of participants "stepping up" to a higher level of PTSD care. Conclusions: Brief mindfulness training is effective for reducing psychiatric symptoms and improving broader recovery outcomes and health promoting behaviors. For individuals who are not yet willing to engage in trauma-focused PTSD treatment, PCBMT may be preferable and more effective than psychoeducational classes as preliminary treatments. Further research is needed to confirm the effectiveness of PCBMT in a larger sample and investigate factors that will support wider implementation in primary care settings. Clinical Trials Registration: ClinicalTrials.gov identifier: NCT03352011.


[Concentration of 25-hydroxyvitamin D in postmenopausal women with low bone mineral density].
This study was designed to determine mean serum concentrations of 25-hydroxyvitamin D (25OHD) in postmenopausal women with low bone mineral density (BMD), to find the cutoff of parathormone (PTH) elevation, and to evaluate the correlation 25OHD with BMD, biochemical parameters and vertebral fracture presence. Transversal study, with collection of 25OHD and PTH, and determination of DMO and column radiograph. A high incidence of inadequate serum concentrations of 25OHD (68.3%) was found and 8% of secondary hyperparathyreoidism. No significant differences were found between 25OHD serum concentrations and the evaluated parameters, except for PTH, which showed a negative association. The established cutoff was 61.5 nmol/L. The elevated incidence of hipovitaminosis D in elderly women with low BMD suggests that a systematic evaluation of 25OHD serum concentrations must be done for this population.The use of 61.5 nmol/L as a cutoff is recommended until the realization of an epidemiologic study that represents all Rio de Janeiro city (RJ, Brazil).


Combined effect of prefrontal transcranial direct current stimulation and a working memory task on heart rate variability.
Prefrontal cortex activity has been associated with changes to heart rate variability (HRV) via mediation of the cortico-subcortical pathways that regulate the parasympathetic and sympathetic branches of the autonomic nervous system. Changes in HRV due to altered prefrontal cortex functioning can be predicted using the neurovisceral integration model, which suggests that prefrontal hyperactivity increases parasympathetic tone and decreases contributions from the sympathetic nervous system. Working memory (WM) tasks and transcranial direct current stimulation (tDCS) have been used independently to modulate brain activity demonstrating changes to HRV in agreement with the model. We investigated the combined effects of prefrontal tDCS and a WM task on HRV. Bifrontal tDCS was administered for 15 minutes at 2mA to 20 participants in a sham controlled, single-blind study using parallel groups. A WM task was completed by participants at three time points; pre-, during-, and post-tDCS, with resting state data collected at similar times. Frequency-domain HRV was computed for high frequency (HF; 0.15-0.4Hz) and low frequency (LF; 0.04-0.15Hz) power reflecting parasympathetic and sympathetic branch activity, respectively. Response time on the WM task, but not accuracy, improved from baseline to during-tDCS and post-tDCS with sham, but not active, stimulation. HF-HRV was significantly increased in the active tDCS group compared to sham, lasting beyond cessation of stimulation. Additionally, HF-HRV showed a task-related reduction in power during performance on the WM task. Changes in LF-HRV were moderately inversely correlated (r > 0.4) with changes in WM accuracy during and following tDCS compared to baseline levels. Stimulation of the prefrontal cortex resulted in changes to the parasympathetic branch of the nervous system in agreement with a linearly additive interpretation of effects. Sympathetic activity was not directly altered by tDCS, but was correlated with changes in WM performance. This suggests that the parasympathetic and sympathetic branches respond differentially due to similar, but distinct neural pathways. Given the ease of HRV data collection, studies of prefrontal tDCS would benefit from collection of this data as it provides unique insight into tDCS effects resulting from propagation through brain networks.