Lesion evidence for a human mirror neuron system.
More than two decades ago, the mirror neuron system (MNS) was discovered in non-human primates: Single-cell recordings detected visuo-motor neurons that discharged not only when the monkey performed an action, but also when it observed conspecifics performing the same action. It has been proposed that a fronto-parietal circuitry constitutes the human homolog of the MNS. However, the functional role of a human MNS (i.e., whether it is functionally necessary for imitation or action understanding) to date remains controversial. We here examined how patients with left hemisphere (LH) stroke imitate, recognize, and comprehend intransitive meaningful limb actions. In particular, we investigated whether apraxic patients with lesions affecting key nodes of the putative human MNS show deficits in action imitation, action recognition, and action comprehension to a similar degree - as predicted by the MNS hypothesis. Behavioral results showed that patients with apraxia (n = 18) indeed performed significantly worse in all three motor cognitive tasks compared to non-apraxic patients (n = 26) and healthy controls (n = 19), whose performance did not differ significantly. Lesions of the apraxic (compared to non-apraxic) patients with LH stroke affected more frequently key regions of the putative human MNS, i.e., the left inferior frontal, superior temporal, and supramarginal gyri as well as the inferior parietal lobe (p < .01, false discovery rate - FDR-corrected). Albeit largely overlapping, voxel-based lesion-symptom mapping (VLSM) revealed that deficits in gesture comprehension were mainly associated with lesions of more anterior parts of the MNS, whereas lesions located more posteriorly mainly resulted in gesture imitation deficits (p < .05, FDR-corrected). Our clinical data support key hypotheses derived from the notion of a human MNS: LH lesions to the MNS core regions affected - critically and to a similar extent - the imitation, recognition, and comprehension of meaningful actions.


Structure and evolution of Cyclops: a novel giant retrotransposon of the Ty3/Gypsy family highly amplified in pea and other legume species.
We characterized a novel giant Gypsy-like retrotransposon, Cyclops, present in about 5000 copies in the genome of Pisum sativum. The individual element Cyclops-2 measures 12 314 bp including long terminal repeats (LTRs) of 1504 bp and 1594 bp, respectively, showing 4.1% sequence divergence between one another. Cyclops-2 carries a polypurine tract (PPT) and an unusual primer binding site (PBS) complementary to tRNA-Glu. The element is bounded by 5 bp target site duplications and harbors three successive internal regions with homology to retroviral genes gag (424 codons) and pol (1382 codons) and an additional open reading frame (423 codons) of unknown function indicating the element's potential capacity for gene transduction. The pol region contains sequence motifs related to the enzymes protease, reverse transcriptase, RNAse H and integrase in the same typical order (5'-PR-RT-RH-IN-3') known for retroviruses and Gypsy-like retrotransposons. The reading frame of the pol region is disrupted by several mutations suggesting that Cyclops-2 does not encode functional enzymes. A phylogenetic analysis of the reverse transcriptase domain confirms our differential genetic assessment that Cyclops from pea is a novel element with no specific relationship to the previously described Gypsy-like elements from plants. Genomic Southern hybridizations show that Cyclops is abundant not only in pea but also in common bean, mung bean, broad bean, soybean and the pea nut suggesting that Cyclops may be an useful genetic tool for analyzing the genomes of agronomically important legumes.


A test of the measurement invariance of a brief version of the Penn State Worry Questionnaire between American and Spanish older adults.
Both anxiety disorders and subclinical anxiety symptoms are related to poorer health and functioning in later life. Because worry is an important component of anxiety, the accurate measurement of worry is crucial to studying the etiology, prevention and treatment of anxiety disorders. Assessment of the trait worry has emerged as the most widely used strategy to establish the presence and extent of pathological worry. However, the Penn State Worry Questionnaire (PSWQ), the most widely used measure of the trait worry, has not been validated cross-culturally in groups outside of the U.S.A. We tested the psychometric properties and measurement invariance of an 8 item abbreviated version of the PSWQ (PSWQ-A) in American (N = 206) and Spanish (N = 137) older adult samples. Internal consistency was high and analyses supported a unidimensional solution in both samples. Measurement invariance was tested using confirmatory factor analysis (CFA) and Rasch models. Results of the CFA suggest that measurement invariance between the samples can be assumed for women but not for men. Rasch modeling results by gender suggested that three items have different endorsability levels in the two samples, suggesting that certain items may more closely represent the construct of the trait worry in American and Spanish older adults. Overall, the PSWQ-A appears appropriate for cross-cultural use, although deletion of one item (item 6) may improve the psychometric properties of the scale across different populations.


Nursing home care: part I. Principles and pitfalls of practice.
Approximately 1.5 million Americans reside in nursing homes. A family physician often leads the interdisciplinary team that provides for the medical, functional, emotional, nutritional, social, and environmental needs of these patients. The treatment of nursing home residents is a dynamic process of ongoing assessment, transitions, and shifting care plans. The clinical assessment of nursing home residents focuses on cognition, mood, disability, skin integrity, and medication management. Advance care planning includes the development of realistic goals of care with the patient and family that go beyond living wills and do-not-resuscitate orders. The nursing home medical record and Minimum Data Set document the interdisciplinary findings and care plan. Transitions between different health care environments are facilitated by communication among health care professionals and detailed transfer documentation. Palliative care encompasses continuing reassessment of the goals of care; general supportive care (e.g., family, cultural, spiritual); and legal planning. Identifying and reporting resident abuse and neglect, and infection control practices are also essential in nursing home care.


An S-alkyl thiocarbamate-based biosensor for highly sensitive and selective detection of hypochlorous acid.
We reported a near-infrared biosensor that features a dihydromethylene blue and an S-alkyl thiocarbamate linker to detect hypochlorous acid in a drastic fluorescence turn-on response. We achieved high sensitivity at the nanomolar level and high selectivity that resolves the interference issue with mercury ions and other transition metal ions. We demonstrated the response mechanism by analysing the released segments, and investigated the imaging capability to detect both exogenous and endogenous hypochlorous acid in living cells.


[Clinical application of flat-panel CT in the angio suite].
The introduction of flat-panel detectors in modern angiographic C-arm systems makes it possible to acquire CT-like images in the angiographic suite (flat-panel CT; FD-CT). In this review, after a short technical introduction of FD-CT including the discussion of the advantages and disadvantages of this new imaging modality, the most commonly and best evaluated indications for FD-CT will be described. FD-CT has become an important adjunctive imaging modality in neurointerventional procedures and embolizations, especially during liver embolization. Another attractive indication for FD-CT is musculoskeletal interventions. FD-CT may provide important additional information in complicated peripheral vascular interventions and stent-graft procedures. FD-CT has a broad spectrum of possible applications, which finally depends on the experience and innovative thinking of the operator. However, it has to be kept in mind that FD-CT causes additional radiation exposure. Roughly, it can be assumed that currently one FD-CT sequence causes at least the same radiation exposure as one spiral CT sequence of the corresponding body region.


Self-Management of Cardiac Pain in Women: A Meta-Summary of the Qualitative Literature.
Symptom recognition and self-management is instrumental in reducing the number of deaths related to coronary artery disease (CAD) in women. The purpose of this study was to synthesize qualitative research evidence on the self-management of cardiac pain and associated symptoms in women. Seven databases were systematically searched, and the concepts of the Individual and Family Self-Management Theory were used as the framework for data extraction and analysis. Search strategies yielded 22,402 citations, from which 35 qualitative studies were included in a final meta-summary, comprising data from 769 participants, including 437 (57%) women. The available literature focused cardiac pain self-management from a binary sex and gender perspective. Ethnicity was indicated in 19 (54%) studies. Results support individualized intervention strategies that promote goal setting and action planning, management of physical and emotional responses, and social facilitation provided through social support.


Non-triggered quantification of central and peripheral pulse-wave velocity.
Stiffening of the arteries results in increased pulse-wave velocity (PWV), the propagation velocity of the blood. Elevated aortic PWV has been shown to correlate with aging and atherosclerotic alterations. We extended a previous non-triggered projection-based cardiovascular MR method and demonstrate its feasibility by mapping the PWV of the aortic arch, thoraco-abdominal aorta and iliofemoral arteries in a cohort of healthy adults. The proposed method "simultaneously" excites and collects a series of velocity-encoded projections at two arterial segments to estimate the wave-front velocity, which inherently probes the high-frequency component of the dynamic vessel wall modulus in response to oscillatory pressure waves. The regional PWVs were quantified in a small pilot study in healthy subjects (N = 10, age range 23 to 68 yrs) at 3T. The projection-based method successfully time-resolved regional PWVs for 8-10 cardiac cycles without gating and demonstrated the feasibility of monitoring beat-to-beat changes in PWV resulting from heart rate irregularities. For dual-slice excitation the aliasing was negligible and did not interfere with PWV quantification. The aortic arch and thoracoabdominal aorta PWV were positively correlated with age (p < 0.05), consistent with previous reports. On the other hand, the PWV of the iliofemoral arteries showed decreasing trend with age, which has been associated with the weakening of muscular arteries, a natural aging process. The PWV map of the arterial tree from ascending aorta to femoral arteries may provide additional insight into pathophysiology of vascular aging and atherosclerosis.


Antlerogenic stem cells: molecular features and potential in rabbit bone regeneration.
(i) To assess the expression profiles of stem cell-associated markers including Oct4, Sox2, Klf4, Nanog, C-myc, Stat3 and Cd9, (ii) analyze the nanotopography of the MIC-1 stem cells and (iii) evaluate the efficiency of live stem cell implants and stem cell culture derivatives on the regeneration of bone deficiencies in rabbit mandibles. The expression profiles of stem cell-associated genes, including Oct4, Sox2, Klf4, Nanog, C-myc, Stat3 and CD9 were assessed using reverse transcription polymerase chain reaction and flow cytometry. Nanotopography of the antlerogenic MIC-1 cell lineage was analyzed using atomic force microscopy. The effect of MIC-1 stem cells, their homogenate and supernatant on the regeneration of bone deficiencies in rabbit mandibles was evaluated using histological analysis. The effect of MIC-1 stem cells and stem cell-based derivatives on the immune responses of the animals was assessed by analyses of acute phase protein levels (haptoglobin and fibrinogen). We found that the MIC-1 cells isolated from the apical regions of growing antlers exhibited molecular features that were characteristics of pluripotent stem cells. Using atomic force microscopy, we determined the details of the cell surface morphologies with a particular emphasis on the patterns of formation of plasma extensions for interlinking adjacent cells. We also demonstrated that not only implanted stem cells but also cell homogenates and cell post-culture supernatants have potential in the regeneration of bone deficiencies in the rabbit mandible. Our findings indicate that the use of both antlerogenic stem cell implants and the preparations derived from the cells offer alternative approaches to those based on autologous stem cells in the biological stimulation of osteogenesis and in bone regeneration.


Cinnamaldehyde induces fat cell-autonomous thermogenesis and metabolic reprogramming.
Cinnamaldehyde (CA) is a food compound that has previously been observed to be protective against obesity and hyperglycemia in mouse models. In this study, we aimed to elucidate the mechanisms behind this protective effect by assessing the cell-autonomous response of primary adipocytes to CA treatment. Primary murine adipocytes were treated with CA and thermogenic and metabolic responses were assessed after both acute and chronic treatments. Human adipose stem cells were differentiated and treated with CA to assess whether the CA-mediated signaling is conserved in humans. CA significantly activated PKA signaling, increased expression levels of thermogenic genes and induced phosphorylation of HSL and PLIN1 in murine primary adipocytes. Inhibition of PKA or p38 MAPK enzymatic activity markedly inhibited the CA-induced thermogenic response. In addition, chronic CA treatment regulates metabolic reprogramming, which was partially diminished in FGF21KO adipocytes. Importantly, both acute and chronic effects of CA were observed in human adipose stem cells isolated from multiple donors of different ethnicities and ages and with a variety of body mass indexes (BMI). CA activates thermogenic and metabolic responses in mouse and human primary subcutaneous adipocytes in a cell-autonomous manner, giving a mechanistic explanation for the anti-obesity effects of CA observed previously and further supporting its potential metabolic benefits on humans. Given the wide usage of cinnamon in the food industry, the notion that this popular food additive, instead of a drug, may activate thermogenesis, could ultimately lead to therapeutic strategies against obesity that are much better adhered to by participants.


Trajectories of Externalizing and Internalizing Behaviors in Preterm Children Admitted to a Neonatal Intensive Care Unit.
To examine the trajectories of internalizing and externalizing behavior problems of preterm children between 16 months and 6 years of age and predictors of trajectories, including gestational age, child dysregulation, maternal depression, socioeconomic status, and parenting. This longitudinal study followed 148 children and their mothers from neonatal intensive care unit discharge until 6 years of age. Gestational ages ranged from 23 to 36 weeks. The study included assessment of maternal-reported behavior problems, maternal depression, neonatal and socioeconomic characteristics, and observations of dysregulated behavior and parenting. Trajectories were identified with a semiparametric group-based analytic method, and multinomial logistic regression was used to identify significant risk factors. Three distinct trajectories for preterm children were found for both internalizing and externalizing behavior problems. For the 2 groups with greater behavior problems (groups 1 and 2), trajectories reached their peak between 24 and 36 months of age, then leveled off or decreased. Group 3 showed a stable low level of externalizing behaviors, and a low, but slightly increasing level of internalizing behaviors. Maternal depression, child dysregulation, gestational age, and socioeconomic challenges were identified as risk factors that predicted less optimal behavior problem trajectories. Children born prematurely followed 1 of 3 distinct developmental trajectories for both internalizing and externalizing behavior problems. The most severe behavior problems started early in development and were associated with increased child dysregulation, maternal depression, and lower socioeconomic status. These findings have implications for screening and monitoring preterm children.


Blood Pressure Control and Adherence to Drug Treatment in Patients with Hypertension Treated at a Specialized Outpatient Clinic: A Cross-Sectional Study.
To evaluate and identify variables associated with the control of hypertension and adherence to antihypertensive drug treatment in a group of patients with hypertension monitored in a specialized, highly complex outpatient service. A prospective, cross-sectional study was carried out in the hypertension unit of a tertiary teaching hospital. Patients diagnosed with hypertensive aged 18 years and over and accompanied for at least six months were included in the study. Patients with secondary hypertension and pregnant women were excluded. The sample consisted of 253 patients. Adherence/concordance to antihypertensive treatment was assessed using the Morisky Green Levine Scale. Blood pressure control was set for values less than 140/90 mmHg. Variables with p≤0.20 in univariate analysis were included in multiple logistic regression. The level of significance adopted was p ≤0.05. Most of patients were white, married and women, with a mean age of 65 (13.3) years old, low income, and education levels. Blood pressure control and adherence were observed in 69.2% and 90.1% of the patients, respectively. Variables that were independently associated with blood pressure control were (OR, odds ratio; CI, 95% confidence interval): married marital status (OR 2.3; CI 1.34-4.28), use of calcium channel blockers (OR 0.4; CI 0.19-0.92) and number of prescribed antihypertensive drugs (OR 0.78; CI 0.66-0.92). Adherence was not associated with any of the variables studied. There was a high frequency of patients with satisfactory adherence to antihypertensive drug treatment. Blood pressure control was less frequent and was associated with social and treatment-related factors.


Hexokinase isoenzymes of RIN-m5F insulinoma cells. Expression of glucokinase gene in insulin-producing cells.
We have analysed the pattern of expression of the hexokinase isoenzyme group in RIN-m5F insulinoma cells. Three hexokinase forms were resolved by DEAE-cellulose chromatography. The most abundant isoenzyme co-eluted with hexokinase type II from rat adipose tissue and displayed a Km for glucose of 0.15 mM, similar to the adipose-tissue enzyme. Hexokinase type II was in large part associated with a particulate subcellular fraction in RIN-m5F cells. The two other hexokinases separated by ion-exchange chromatography were an enzyme similar to hexokinase type I from brain and glucokinase (or hexokinase type IV). The latter isoenzyme was identified as the liver-type glucokinase by the following properties: co-elution with hepatic glucokinase from DEAE-cellulose and DEAE-Sephadex; sigmoid saturation kinetics with glucose with half-maximal velocity at 5.6 mM and Hill coefficient (h) of 1.54; suppression of enzyme activity by antibodies raised against rat liver glucokinase; apparent Mr of 56,500 and pI of 5.6, as shown by immunoblotting after one- and two-dimensional gel electrophoresis; peptide map identical with that of hepatic glucokinase after proteolysis with chymotrypsin and papain. These data indicate that the gene coding for hepatic glucokinase is expressed in RIN-m5F cells, a finding consistent with indirect evidence for the presence of glucokinase in the beta-cell of the islet of Langerhans. On the other hand, the overall pattern of hexokinases is distinctly different in RIN-m5F cells and islets of Langerhans, since hexokinase type II appears to be lacking in islets. Alteration in hexokinase expression after tumoral transformation has been reported in other systems.


Increased prevalence of obesity, diabetes mellitus and hypertension with associated risk factors in a mine-based workforce, Democratic Republic of Congo.
The burden of non-communicable diseases (NCDs) is increasing rapidly in low- and middle-income countries, with the largest portion occurring in Africa. Results from earlier baseline measures on obesity, diabetes and hypertension (ODH) in the Tenke Fungurume Mining (TFM) workforce in 2010 showed high proportions of overweight, pre-diabetic and pre-hypertensive individuals, predicting an upward trend in the burden of ODH over time. The 2010-2015 longitudinal trends on ODH and related risk factors among the TFM workforce is presented herein, and projects the consequent burden of these diseases on the workforce by 2025 if an effective prevention program is not implemented. A longitudinal, retrospective cohort study with 3-time intervals was conducted using occupational health records collected on all employees and contractors who had a pre-employment or follow up medical checkups covering the period between January 2010 and December 2015. Repeated paired t tests measured changes in mean values of quantitative risk factors, while a chi-square test assessed changes in prevalence and categorical risk factors over time. A linear projection model was used to predict the consequent morbidity of ODH for the subsequent 10 years up to 2025. Between 2010 and 2015, prevalence increased from 4.5% to 11.1% for obesity, 11.9% to 15.6% for diabetes, and 18.2% to 26.5% for hypertension. By 2025, provided no prevention program is implemented, prevalence is predicted to reach 25%, 24% and 42% respectively for obesity, diabetes and hypertension. Without implementation of a comprehensive NCD prevention plan, the burden of ODH and other NCDs is predicted to increase dramatically in the TFM workforce. Alone or combined, NCDs have the potential to dramatically increase operational costs while decreasing productivity over time.


Ferredoxin containing bacteriocins suggest a novel mechanism of iron uptake in Pectobacterium spp.
In order to kill competing strains of the same or closely related bacterial species, many bacteria produce potent narrow-spectrum protein antibiotics known as bacteriocins. Two sequenced strains of the phytopathogenic bacterium Pectobacterium carotovorum carry genes encoding putative bacteriocins which have seemingly evolved through a recombination event to encode proteins containing an N-terminal domain with extensive similarity to a [2Fe-2S] plant ferredoxin and a C-terminal colicin M-like catalytic domain. In this work, we show that these genes encode active bacteriocins, pectocin M1 and M2, which target strains of Pectobacterium carotovorum and Pectobacterium atrosepticum with increased potency under iron limiting conditions. The activity of pectocin M1 and M2 can be inhibited by the addition of spinach ferredoxin, indicating that the ferredoxin domain of these proteins acts as a receptor binding domain. This effect is not observed with the mammalian ferredoxin protein adrenodoxin, indicating that Pectobacterium spp. carries a specific receptor for plant ferredoxins and that these plant pathogens may acquire iron from the host through the uptake of ferredoxin. In further support of this hypothesis we show that the growth of strains of Pectobacterium carotovorum and atrosepticum that are not sensitive to the cytotoxic effects of pectocin M1 is enhanced in the presence of pectocin M1 and M2 under iron limiting conditions. A similar growth enhancement under iron limiting conditions is observed with spinach ferrodoxin, but not with adrenodoxin. Our data indicate that pectocin M1 and M2 have evolved to parasitise an existing iron uptake pathway by using a ferredoxin-containing receptor binding domain as a Trojan horse to gain entry into susceptible cells.


tRNA cleavage: a new insight.
Over the past decades, tRNA was found to be a rich hub of RNA modifications such as 1-methyladenosine and 5-methycytosine modifications and others, holding more than half of all modifications occurring in RNA molecules. Moreover, tRNA was discovered to be a source of various small noncoding RNA species, such as the stress induced angiogenin cleaved tRNA halves (tiRNA) or the miRNA like tRNA derived fragments. tRNA cleavage under stress was fist discovered in bacteria and later was found to be conserved across different species, including mammals. Under cellular stress conditions, tRNA undergoes conformational changes and angiogenin cleaves it into 3' and 5' halves. 5'tiRNA halves were shown to repress protein translations. tRNA cleavage is thought of to be a cytoprotective mechanism by which cells evade apoptosis, however some data hints to the opposite; that tiRNA are cytotoxic or at least related to apoptosis initiation. tRNA cleavage also was shown to be affected by tRNA modifications via different enzymes in the cytosol and mitochondria. In this review, we will highlight the biology of tRNA cleavage, show the evidence of it being cytoprotective or a marker of cell death and shed a light on its role in disease models and human diseases as well as possible future directions in this field of RNA research.


Functional lateralization of the anterior insula during feedback processing.
Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self-attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self- and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence × attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self-attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self-attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello-thalamic-cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations.


Intestinal tuberculosis: return of an old disease.
Tuberculosis (TB) can no longer be considered a rare disease in the United States due, in part, to the AIDS epidemic. Because the signs and symptoms of intestinal TB are nonspecific, a high index of suspicion must be maintained to ensure a timely diagnosis. The aim of this article is to review the history, epidemiology, pathophysiology, and treatment of TB. This review is based on an examination of the world literature. In only 20% of TB patients is there associated active pulmonary TB. Areas most commonly affected are the jejunoileum and ileocecum, which comprise >75% of gastrointestinal TB sites. Diagnosis requires colonoscopy with multiple biopsies at the ulcer margins and tissue sent for routine histology, smear, and culture. If intestinal TB is suspected, empiric treatment is warranted despite negative histology, smear, and culture results. Treatment is medical, and all patients should receive a full course of antituberculous chemotherapy. Exploratory laparotomy is necessary if the diagnosis is in doubt, in cases in which there is concern about a neoplasm, or for complications that include perforation, obstruction, hemorrhage, or fistulization. This review draws attention to the resurgence of tuberculosis in the United States. An increased awareness of intestinal tuberculosis, coupled with knowledge of the pathophysiology, diagnostic methods, and treatment should increase the number of cases diagnosed, thus improving the outcome for patients with this disease.


Class I histone deacetylase-mediated repression of the proximal promoter of the activity-regulated cytoskeleton-associated protein gene regulates its response to brain-derived neurotrophic factor.
We examined the transcriptional regulation of the activity-regulated cytoskeleton-associated protein gene (Arc), focusing on BDNF-induced Arc expression in cultured rat cortical cells. Although the synaptic activity-responsive element (SARE), located -7 kbp upstream of the Arc transcription start site, responded to NMDA, BDNF, or FGF2, the proximal region of the promoter (Arc/-1679) was activated by BDNF or FGF2, but not by NMDA, suggesting the presence of at least two distinct Arc promoter regions, distal and proximal, that respond to extracellular stimuli. Specificity protein 4 (SP4) and early growth response 1 (EGR1) controlled Arc/-1679 transcriptional activity via the region encompassing -169 to -37 of the Arc promoter. We found that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, significantly enhanced the inductive effects of BDNF or FGF2, but not those of NMDA on Arc expression. Inhibitors of class I/IIb HDACs, SAHA, and class I HDACs, MS-275, but not of class II HDACs, MC1568, enhanced BDNF-induced Arc expression. The enhancing effect of TSA was mediated by the region from -1027 to -1000 bp, to which serum response factor (SRF) and HDAC1 bound. The binding of HDAC1 to this region was reduced by TSA. Thus, Arc expression was suppressed by class I HDAC-mediated mechanisms via chromatin modification of the proximal promoter whereas the inhibition of HDAC allowed Arc expression to be markedly enhanced in response to BDNF or FGF2. These results contribute to our understanding of the physiological role of Arc expression in neuronal functions such as memory consolidation.


High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients.
L-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and L-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] µM vs. 2.78 [2.89-3.35] µM (P < 0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA.


Serum pepsinogens I and II and gastric mucosal histology after partial gastrectomy.
We determined the effect of postgastrectomy gastritis on serum pepsinogen I and pepsinogen II concentrations in 108 subjects with subtotal gastric resection. Eleven had normal remnant mucosa, 22 had superficial gastritis, and 75 had atrophic gastritis. In the subjects with superficial gastritis, serum pepsinogen I and II concentrations were significantly higher than in those with normal remnant mucosa, but the ratio of pepsinogen I to II did not differ from normal. In atrophic gastritis, serum pepsinogen I concentrations fell with increasing severity of mucosal damage, but pepsinogen II was persistently raised. Consequently, the ratio of pepsinogen I to II in subjects with atrophic gastritis was significantly lower than in those with superficial gastritis or normal remnant mucosa. Discriminant function analysis revealed that the ratio of pepsinogen I to II, in combination with the absolute level of pepsinogen II, had a sensitivity of 80%, a specificity of 73%, and a positive predictive value of 87% for atrophic gastritis in this population. We propose that the parallel increase in serum pepsinogen I and II concentrations in postgastrectomy superficial gastritis is because of an increased rate of endocrine release of both zymogens from the fundic glands, and that the dichotomy in pepsinogen I and II concentrations in postgastrectomy atrophic gastritis results from the loss of fundic glands, which produce both zymogens, and the appearance of metaplastic pyloric glands, which produce only pepsinogen II.


The effects of mild hypoxia on a logical reasoning task.
In an attempt to replicate the findings of Crow and Kelman (1969) and Denison et al. (1966), which suggest that the performance of novel tasks can be impaired at altitudes below 3,050 m, 150 subjects were divided into five independent groups and their performance tested on a logical reasoning task. One group was tested at ground level in a lecture room; the remaining groups were tested in a decompression chamber, one at 305 m, one at 2,440 m, one at 3,050 m and one at 3,660 m. Significant differences were identified between the 'lecture room' and 'chamber' groups in both speed of work and error rate (p less than 0.05); this finding is interpreted as the effect of apprehension on the naive subjects. A significant difference was found between the group tested at 3660 m and the remaining groups for error rate (p less than 0.05); this finding is interpreted as the effect of apprehension on the naive subjects. A significant difference was found between the group tested at 3660 m and the remaining groups for error rate (p less than 0.05) but not for speed of work. However, no effect of altitude on the way in which the task was learned could be demonstrated.


Minimizing inbreeding by managing genetic contributions across generations.
Here we present the strategy that achieves the lowest possible rate of inbreeding (DeltaF) for a population with unequal numbers of sires and dams with random mating. This new strategy results in a DeltaF as much as 10% lower than previously achieved. A simple and efficient approach to reducing inbreeding in small populations with sexes of unequal census number is to impose a breeding structure where parental success is controlled in each generation. This approach led to the development of strategies for selecting replacements each generation that were based upon parentage, e.g., a son replacing its sire. This study extends these strategies to a multigeneration round robin scheme where genetic contributions of ancestors to descendants are managed to remove all uncertainties about breeding roles over generations; i.e., male descendants are distributed as equally as possible among dams. In doing so, the sampling variance of genetic contributions within each breeding category is eliminated and consequently DeltaF is minimized. Using the concept of long-term genetic contributions, the asymptotic DeltaF of the new strategy for random mating, M sires and d dams per sire, is phi/(12M), where phi = [1 + 2((1)/(4))(d)]. Predictions were validated using Monte Carlo simulations. The scheme was shown to achieve the lowest possible DeltaF using pedigree alone and showed that further reductions in DeltaF below that obtained from random mating arise from preferential mating of relatives and not from their avoidance.


The interaction between concrete pavement and corrosion-induced copper runoff from buildings.
Changes in chemical speciation of copper and the capacity of concrete pavement to retain copper in runoff water from external buildings have been investigated at urban field conditions, and in parallel laboratory experiments simulating outdoor scenarios. The research study showed the concrete surface to form a copper rich surface layer ( approximately 50 microm thick) upon exposure, and a high capacity to significantly reduce the bioavailable fraction of released copper (20-95%). The retention capacity of copper varied between 5 and 20% during single runoff events in the laboratory, and between 10 and 40% of the total copper release during single natural runoff events. The capacity to retain and reduce the bioavailable fraction of non-retained copper increased with increasing wetness of the concrete surfaces, increasing pH of the runoff water and decreasing flow rates. Bioassay testing with bacterial and yeast bioreporters showed the bioavailable fraction of non-retained copper to be significantly lower than the total copper concentration in the runoff water, between 22 and 40% for bacteria and between 8 and 31% for yeast. The application of generated data to simulate a fictive outdoor scenario, suggests a significant reduction of bioavailable and total copper to background values during environmental entry as a result of dilution, and the interaction with solid surfaces, organic matter and complexing agents already in the drainage system.


Dual delivery of rhPDGF-BB and bone marrow mesenchymal stromal cells expressing the BMP2 gene enhance bone formation in a critical-sized defect model.
Bone tissue healing is a dynamic, orchestrated process that relies on multiple growth factors and cell types. Platelet-derived growth factor-BB (PDGF-BB) is released from platelets at wound sites and induces cellular migration and proliferation necessary for bone regeneration in the early healing process. Bone morphogenetic protein-2 (BMP-2), the most potent osteogenic differentiation inducer, directs new bone formation at the sites of bone defects. This study evaluated a combinatorial treatment protocol of PDGF-BB and BMP-2 on bone healing in a critical-sized defect model. To mimic the bone tissue healing process, a dual delivery approach was designed to deliver the rhPDGF-BB protein transiently during the early healing phase, whereas BMP-2 was supplied by rat bone marrow stromal cells (BMSCs) transfected with an adenoviral vector containing the BMP2 gene (AdBMP2) for prolonged release throughout the healing process. In in vitro experiments, the dual delivery of rhPDGF-BB and BMP2 significantly enhanced cell proliferation. However, the osteogenic differentiation of BMSCs was significantly suppressed even though the amount of BMP-2 secreted by the AdBMP2-transfected BMSCs was not significantly affected by the rhPDGF-BB treatment. In addition, dual delivery inhibited the mRNA expression of BMP receptor type II and Noggin in BMSCs. In in vivo experiments, critical-sized calvarial defects in rats showed enhanced bone regeneration by dual delivery of autologous AdBMP2-transfected BMSCs and rhPDGF-BB in both the amount of new bone formed and the bone mineral density. These enhancements in bone regeneration were greater than those observed in the group treated with AdBMP2-transfected BMSCs alone. In conclusion, the dual delivery of rhPDGF-BB and AdBMP2-transfected BMSCs improved the quality of the regenerated bone, possibly due to the modulation of PDGF-BB on BMP-2-induced osteogenesis.


Vitamin D Daily short-term Supplementation does not Affect Glycemic Outcomes of Patients with Type 2 Diabetes.
There is currently insufficient evidence of a beneficial effect to recommend vitamin D supplementation for optimizing glycemic status in patients with type 2 diabetes mellitus (T2DM). Taking into consideration the significant extra-skeletal effect of vitamin D on pancreatic β-cell function and insulin secretion and the large number of scientific evidence supporting the inverse association between vitamin D status and hyperglycemia, this review article aims to examine whether vitamin D supplementation therapies are beneficial to patients with T2DM considering specific factors through randomized controlled trials (RCTs). EBSCOhost and Medline databases were searched from the beginning of 2009 until the end of 2014 for RCTs in patients with T2DM. Parameters, such as baseline vitamin D levels, frequency/dosage of supplementation, length of the study and type of supplementation, were independently assessed, based on their effect on glycemic status. Although all different types of supplementation were safe and effective in the achievement of vitamin D sufficiency in a dose-dependent way, the impact on glycemic status was different. 14 RCTs were included with daily supplementations ranging from 400-11.200 IU/daily, 40.000-50.000 IU/weekly and 100.000-300.000 IU/intramuscularly or once given, for a period from 8 to 24 weeks. Daily supplementation of vitamin D (up to 11.200 IU) showed no effect, whereas combined supplementation, with calcium (≥300 mg), and with vitamin D doses similar to the RDA, showed positive effects. Additionally, high weekly doses of vitamin D (40.000-50.000 IU) were effective on glycemic outcomes but available data are limited.


Per-oral endoscopic myotomy for achalasia. Are results comparable to laparoscopic Heller myotomy?
Per-oral endoscopic myotomy (POEM) has recently been introduced as a minimal invasive alternative to conventional treatment for achalasia. This study aimed to clarify the feasibility and the short-term clinical efficacy of POEM as compared to laparoscopic Heller myotomy (LHM). Treatment outcomes were prospectively recorded and compared between the procedures in a nonrandomized fashion. Reduction rate (RR) in timed barium esophagogram (TBE) was calculated at 1, 2 and 5 min after barium ingestion as: RR = 1- postoperative barium height/preoperative barium height. Risk factors for treatment failure defined as the proportion of patients with RR <0.5 (1 min) and gastroesophageal reflux (GER) after POEM were analyzed. Forty-two consecutive patients who underwent POEM were compared to 41 patients who had a LHM during the immediate time period prior to the introduction of POEM. Ninety percent of the cases reported complete symptom relief after POEM. The percentage of esophageal emptying and RR in TBE improved dramatically by both procedures without significant difference. A longer operation time (odds ratio [OR] 32.80, 95%CI 2.99-359.82, p = 0.004) and younger age (OR 26.81, 95%CI 2.09-344.03, p = 0.012) were the independent predictors of treatment failure after POEM. GER was observed in seven patients where previous dilatation (OR 8.59, 95%CI 1.16-63.45, p = 0.035) and higher body mass index (OR 8.69, 95%CI 1.13-66.63, p = 0.037) were the independent predictors for symptomatic GER after POEM. POEM seems to be a safe and effective treatment option for achalasia in the short-term perspective; an effect well comparable to LHM.


Carvacrol Prodrugs with Antimicrobial Activity Loaded on Clay Nanocomposites.
Carvacrol, an essential oil with antimicrobial activity against a wide range of pathogens, and its water soluble carvacrol prodrugs (WSCP1-3) were intercalated into montmorillonite (VHS) interlayers to improve their stability in physiological media and promote their absorption in the intestine. Intercalation of prodrugs by cation exchange with montmorillonite interlayer counterions was verified by X-ray powder diffraction and confirmed by Fourier transform infrared spectroscopy and thermal analysis. In vitro release studies demonstrated that montmorillonite successfully controlled the release of the adsorbed prodrugs and promoted their bioactivation only in the intestinal tract where carvacrol could develop its maximum antimicrobial activity. The amount of WSCP1, WSCP2, and WSCP3 released from VHS were 38%, 54%, and 45% at acid pH in 120 min, and 65%, 78%, and 44% at pH 6.8 in 240 min, respectively. The resultant hybrids successfully controlled conversion of the prodrugs to carvacrol, avoiding premature degradation of the drug.


Outer-context determinants in the sustainment phase of a reimbursement-driven implementation of evidence-based practices in children's mental health services.
Although there is increasing investment to implement evidence-based practices (EBPs) in public systems across the USA, continued or sustained use of EBPs after initial implementation remains a challenge. The low integration of EBPs in routine practice severely limits their public health impact, highlighting the need to understand factors that affect the return on costly investments in EBP implementation. This study aims to (1) characterize trajectories of EBP delivery volume through a reimbursement-driven implementation and (2) examine impacts of system-level policy regulatory activity and state-level mental health services funding on the implementation reimbursement strategy. This study involved secondary data analyses. Psychotherapy administrative claims and regulatory site visit data from the Los Angeles County Department of Mental Health and California state mental health expenditures were extracted from 2010 to 2017. Multilevel regression examined EBP claims volume over time with state expenditures and regulatory compliance as predictors. EBP claims volume trajectories demonstrated a rapid initial increase, followed by a period of decrease, and a small increase in the final year. State mental health expenditures increased across time reflecting increased funding availability. State mental health expenditures and system regulatory compliance were inversely related to EBP claims volume. The impact of reimbursement-driven EBP implementation strategy is sensitive to multiple outer-context determinants. At the system level, commitment to fidelity of implementation regulations resulted in reduced use of the reimbursement strategy. Alternative reimbursement streams not tied to EBPs coupled with an expanded array of reimbursable services also impacted the use of the reimbursement strategy to implement EBPs.


Identifying quality improvement targets to facilitate colorectal cancer screening completion.
The colorectal cancer (CRC) screening process involves multiple interfaces (communication exchanges and transfers of responsibility for specific actions) among primary care and gastroenterology providers, laboratory, and administrative staff. After a retrospective electronic health record (EHR) analysis discovered substantial clinic variation and low CRC screening prevalence overall in an urban, integrated safety-net system, we launched a qualitative analysis to identify potential quality improvement targets to enhance fecal immunochemical test (FIT) completion, the system's preferred screening modality. Here, we report examination of organization-, clinic-, and provider-level interfaces over a three-year period (December 2011-October 2014). We deployed in parallel 3 qualitative data collection methods: (1) structured observation (90+ hours, 10 sites); (2) document analysis (n > 100); and (3) semi-structured interviews (n = 41) and conducted iterative thematic analysis in which findings from each method cross-informed subsequent data collection. Thematic analysis was guided by a conceptual model and applied deductive and inductive codes. There was substantial variation in protocols for distributing and returning FIT kits both within and across clinics. Providers, clinic and laboratory staff had differing access to important data about FIT results based on clinical information system used and this affected results reporting. Communication and coordination during electronic referrals for diagnostic colonoscopy was suboptimal particularly for co-morbid patients needing anesthesia clearance. Our multi-level approach elucidated organizational deficiencies not evident by quantitative analysis alone. Findings indicate potential quality improvement intervention targets including: (1) best-practices implementation across clinics; (2) detailed communication to providers about FIT results; and (3) creation of EHR alerts to resolve pending colonoscopy referrals before they expire.


Awareness of Self and Disease Assessment: Development and Validation of a Subjective Measure in People with Alzheimer's Disease.
People with Alzheimer's disease (PwAD) remain able to speak coherently about their daily life for a long time, and their level of awareness could be determined through their discourse. In a grounded-theory approach, awareness of self and awareness of disease are intertwined and can be observed through three domains: mechanisms, objects and modes of expression. Based on preliminary results, in this article, we present the ASDA (Awareness of Self and Disease Assessment), a new subjective measurement tool for awareness in PwAD. To consider its use in research and practice, we initially performed validation analyses, including internal consistency, test-retest reliability and interrater reliability analyses. The new assessment tool consists of a semi-structured interview and ratings of 22 items divided into three categories. As part of our observational study, we assessed a sample of 28 PwAD who participated in four interviews (one every two weeks). The ASDA shows good homogeneity within the domains of awareness and a certain degree of stability between two measurement times and between investigators. Missing values in the results provided information regarding awareness levels within and across the subjects. The results suggest that awareness could be assessed through subjective experience without reference to a comparison.


Multiplexed Electrochemical Immunosensors for Clinical Biomarkers.
Management and prognosis of disease requires the accurate determination of specific biomarkers indicative of normal or disease-related biological processes or responses to therapy. Moreover since multiple determinations of biomarkers have demonstrated to provide more accurate information than individual determinations to assist the clinician in prognosis and diagnosis, the detection of several clinical biomarkers by using the same analytical device hold enormous potential for early detection and personalized therapy and will simplify the diagnosis providing more information in less time. In this field, electrochemical immunosensors have demonstrated to offer interesting alternatives against conventional strategies due to their simplicity, fast response, low cost, high sensitivity and compatibility with multiplexed determination, microfabrication technology and decentralized determinations, features which made them very attractive for integration in point-of-care (POC) devices. Therefore, in this review, the relevance and current challenges of multiplexed determination of clinical biomarkers are briefly introduced, and an overview of the electrochemical immunosensing platforms developed so far for this purpose is given in order to demonstrate the great potential of these methodologies. After highlighting the main features of the selected examples, the unsolved challenges and future directions in this field are also briefly discussed.


General anesthesia: as a challenge and treatment need option in pediatric dentistry.
The purpose of this study was to determine the type and characteristics of the interventions, indications of dental treatment and procedures performed to patients treated under general anesthesia (GA) by pediatric dentistry residents, during the 1997-1999 period. A sample of 57 hospital records of patients treated as part of the Special Pediatric Course at the Puerto Rico Pediatric Hospital were reviewed. Statistical analysis was done using the chi-square test for inferences on proportions. MR patients made up 59.7% and NMR patients made up 40.3% of the sample studied. Ages ranged from 2 to 35 years with a mean age of 11 years (SD=8.54). MR patients were classified into 7 categories: mental retardation (38.2%), cerebral palsy (14.7%), epileptic (5.9%), mental syndromes (26.9%), hydrocephalic (5.9%), autism (5.9%) and others (2.9%). The NMR were classified into 5 categories: early childhood caries (65.2%), cardiac patients (8.7%), maxillofacial anomalies (4.3%), organic syndromes (13.1%) and others (8.7%). The dental procedures performed were: dental extractions 84%(MR) and 68% (NMR), restorative procedures 87.3%(MR) and 12.7%(NMR). Oral prophylaxis was performed in 76.8%, fissure sealants in 10.7% and topical fluoride applications in 21.8%. Dental extraction was a frequently performed procedure in both groups. The prevalence of exodontia and restorative procedures indicates the need to design and implement prevention programs for special pediatric patients.


Retrospective study of morbidity and mortality of captive Iberian lynx (Lynx pardinus) in the ex situ conservation programme (2004-June 2010).
Medical records of 120 Iberian lynx (Lynx pardinus) from the captive breeding population (CBP), 96 of which were older than 1 wk old, were studied from January 2004 to June 2010. From a total of 413 clinical signs recorded, it was possible to obtain a diagnosis in 258 (62.5%). Inappetence, skin wound, and vomiting had the highest incidence. Adult (2 to 6 yr old) and juvenile (1 wk to 1 yr old) animals accounted for most of the clinical signs. Vitamin D toxicosis and intraspecific trauma accounted for 55.4% and 15.1% of the clinical signs, respectively. Renal toxicosis due to the administration of supplements with an excess of vitamin D occurred in 2009 and affected a total of 39 individuals. Intraspecific trauma cases were predominantly observed from sibling aggression. Diet-related conditions consisted of sporadic cases of fatal salmonellosis, dermatophytosis, and gastrointestinal episodes. Suspected idiopathic epilepsy and femoral neck metaphyseal osteopathy were also observed. A total of 15 animals older than 1 wk old died including five vitamin D toxicosis cases and three juveniles due to intraspecific trauma. Mycobacterium bovis was found as a secondary infection in two animals that died from vitamin D toxicosis. Abortions, premature births, and stillbirths accounted for 12 mortalities, and 13 neonatal deaths due to maternal neglect or bacterial sepsis were observed. Data show that improvement of diet-related conditions is a key factor in preserving the health of animals in the CBP. Thus, the control of food and supplement composition, rabbit farm suppliers, and hygiene should be standardized and improved. Furthermore, data recording and diagnostic protocols should be standardized.


Therapeutic Vaccines for Genitourinary Malignancies.
The field of genitourinary malignancies has been a showcase for therapeutic cancer vaccine success since the application of intravesicular Bacillus Calmette-Guerin (BCG) for bladder cancer in the 1970s and enjoyed a renaissance in 2010 with the US Food and Drug Administration (FDA) approval of sipuleucel-T for prostate cancer. Several vaccine strategies have emerged, such as autologous or allogeneic whole-tumor vaccines, DNA vaccines, use of viral vectors, and peptides as immunostimulatory adjuvants. Despite impressive early trials, vaccine monotherapy has achieved limited success in the clinical world; however, combinations of vaccine and immune checkpoint inhibition or vaccine and cytokine stimulation are expected to move the field forward. This article reviews pivotal trials of cancer vaccines in prostate, renal, and bladder cancer and ongoing trials combining vaccines with other immune therapy agents.


Effects of Air Pollution and Other Environmental Exposures on Estimates of Severe Influenza Illness, Washington, USA.
Ecologic models of influenza burden may be confounded by other exposures that share winter seasonality. We evaluated the effects of air pollution and other environmental exposures in ecologic models estimating influenza-associated hospitalizations. We linked hospitalization data, viral surveillance, and environmental data, including temperature, relative humidity, dew point, and fine particulate matter for 3 counties in Washington, USA, for 2001-2012. We used negative binomial regression models to estimate the incidence of influenza-associated respiratory and circulatory (RC) hospitalizations and to assess the effect of adjusting for environmental exposures on RC hospitalization estimates. The modeled overall incidence rate of influenza-associated RC hospitalizations was 31/100,000 person-years. The environmental parameters were statistically associated with RC hospitalizations but did not appreciably affect the event rate estimates. Modeled influenza-associated RC hospitalization rates were similar to published estimates, and inclusion of environmental covariates in the model did not have a clinically important effect on severe influenza estimates.


Papillary thyroid carcinoma with BRAFV600E mutation: sonographic prediction.
The purpose of this article is to assess the clinical and sonographic findings that can predict the presence of the BRAF(V600E) mutation of a papillary thyroid carcinoma. The study included 135 consecutive patients with surgically confirmed papillary thyroid carcinoma. All patients underwent ultrasound and ultrasound-guided fine-needle aspiration. The BRAF(V600E) mutation was determined using allelespecific polymerase chain reaction and direct DNA sequencing from fine-needle aspiration samples. We retrospectively compared the clinical and ultrasound findings of nodules with and without the mutation, including size, margin, shape, calcifications, echogenicity, and ultrasound diagnosis. Of 135 patients, results were positive for the mutation for 106 patients (79%) and negative for 29 (21%). Among the patients with the BRAF(V600E) mutation, the ratio of men to women was 1:5.2 (p = 0.156), and the mean age was 47 years (range, 26-73 years; p = 0.326). The mean tumor size was 0.9 cm (range, 0.3-4.0 cm; p = 0.099). On ultrasound, papillary thyroid carcinomas with the BRAF(V600E) mutation tended to show a taller-than-wide shape, but this finding was not statistically significant (p = 0.055). The BRAF(V600E) mutation was not associated with the presence of calcifications (54% vs 71%; p = 0.032), although it was not an independent predictor. There were no significant differences in tumor echogenicity, tumor margin, and ultrasound diagnosis between the two groups. Papillary thyroid carcinoma with the BRAF(V600E) mutation tends to be taller than wide and is not associated with the presence of calcifications on ultrasound. However, these findings are not specific enough to predict the presence or absence of the BRAF(V600E) mutation of a papillary thyroid carcinoma.


Haemoglobin Levels in Acute Coronary Syndrome Patients Admitted in Cardiology Intensive Care Units in a Tertiary Care Hospital.
Epidemiology of abnormal haemoglobin levels and its association with severity of coronary artery disease in Indian patients is uncertain. This prospective observational study was conducted to determine the haemoglobin levels in acute coronary syndrome (ACS) patients and the association of anaemia with the severity of coronary artery disease (CAD) on coronary angiography (CAG). The patients diagnosed with ACS (ST-elevated and non-elevated MI, unstable angina) based on ECG and cardiac enzymes and admitted in cardiology ICU were enrolled in the study after fulfilling study criteria and the baseline haemoglobin level was recorded. The severity of coronary disease of patients who underwent coronary angiography was recorded. A total of 162 patients were enrolled for the study. The overall haemoglobin of patients was 11.99 ± 2.24 g/dl with 12.46 ± 2.33 g/dl in males and 11.17 ± 1.82 g/dl in females (p < 0.05). Anaemia was found in 62.96% patients with no significant gender difference (p > 0.05), however abnormal haemoglobin level (Hb > 16g/dl) was found exclusively in 7.7% males. One hundred one patients underwent coronary angiography and anaemia was present in 60 patients (58.82%) and absent in 41 (40.59%). The difference in mean haemoglobin levels in anaemic patients with single, double, and triple vessel disease was significant (p < 0.05) and corresponding levels in non-anaemic patients were insignificant (p > 0.05). A weak correlation was observed between the haemoglobin level of patients and the percentage of obstruction in CAG (r = 0.26). The odds of having triple vessel disease in anaemic patient are 1.77 (95% CI 0.71 to 4.43). However, the association between anaemia and the severity of coronary artery disease was statistically found to be non-significant. The mean haemoglobin levels decreased as the severity of CAD increased in CAG, however the association was not established between anaemia and the severity of coronary artery disease statistically.


Monitoring malaria using health facility based surveys: challenges and limitations.
Health facility data are more readily accessible for operational planning and evaluation of disease control programmes. The importance, potential challenges and limitations of using facility based survey as an alternative tool for monitoring changes in local malaria epidemiology were examined. The study involved six areas within the administrative divisions of The Gambia. The areas were selected to reflect socioeconomic and malaria transmission intensities across the country. The study design involved an age stratified cross sectional surveys that were conducted during the wet season in 2008 and in the 2009 during the dry season. Participants were patients attending clinics in six health centres and the representative populations from the catchment communities of the health centres. Overall participants' characteristics were mostly not comparable in the two methodological approaches in the different seasons and settings. More females than males were enrolled (55.8 vs. 44.2 %) in all the surveys. Malaria infection was higher in the surveys in health centres than in the communities (p < 0.0001) and also in males than in females (OR = 1.3; p < 0.001). Males were less likely than females to sleep under an insecticide treated net in the communities (OR = 1.6; 95 % CI 1.3, 1.9) and in the health centres (OR = 1.3; 95 % CI 1.1, 1.5). Representativeness of the ethnic groups was better in the health centre surveys than in the community surveys when compared to the 2003 national population census in The Gambia. Health facility based survey though a potential tool for monitoring changes in the local epidemiology of malaria will require continuous validation of the facility and participants sociodemograhic characteristics as these may change over time. The effects of health seeking practices on service utilization and health facility surveys as an approach will also need continuous review.


Design of a Configurable 16-Electrode Sense and Stimulation Neuromodulation System.
Electrical sensing and stimulation of nervous system activity is a valuable tool to investigate neural activity both in vivo and in vitro. A general system capable of supporting users across a variety of use cases would be valuable for the field of neuroscience. We propose a new system capable of supporting a variety of experimental cases including low and high impedance electrodes with stimulation amplitudes up to multiple mA. The system is designed to support sampling frequencies up to 26 kHz and to maximize stimulation flexibility with an electrically isolated system.


Periodontitis patient and the spouse: periodontal bacteria before and after treatment.
Suspected periodontal pathogens can be transmitted between spouses. The treatment response may be unsuccessful in periodontitis patients, if the spouse harbors these bacteria. The aim of the present 6-month follow-up study was to clarify whether the microbiological treatment outcome of periodontitis patients is related to the detection of suspected periodontal pathogens in the saliva of the spouse. 10 patients with advanced periodontitis and their spouses were included in the study. The patients received mechanical periodontal treatment and 500 mg metronidazole systemically 2x a day for 7 days. The presence of visible plaque, gingival bleeding after probing, suppuration, supragingival and subgingival calculus and pocket depths were assessed at baseline and 1 and 6 months after treatment. Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia/Prevotella nigrescens, Campylobacter rectus and Peptostreptococcus micros were cultured from pooled subgingival samples from the patients and from salivary samples from the spouses at corresponding occasions. Periodontal conditions in the patients improved after treatment as determined by the significantly lower values of clinical variables 1 and 6 months after treatment compared to those at baseline. However, the re-emergence of periodontal bacteria after treatment of the patients was not related to the concurrent detection of the respective bacteria in the saliva of the spouses. In this study design, it seemed that the salivary bacterial load in the spouse was of minor importance for the microbiological treatment outcome of the patient.


The anti-glycolytic action of (S)-alpha-chlorohydrin on epididymal bovine spermatozoa in vitro.
(S)-alpha-Chlorohydrin interferes with glycolysis in bovine spermatozoa whereas the (R)-isomer is ineffective. The action of the (S)-isomer, which involves inhibition of the reaction catalysed by glyceraldehyde 3-phosphate dehydrogenase, is not immediate but is evident only after a brief period of incubation with the spermatozoa. This inhibitory action is prevented when glycerol is present suggesting that the mechanism of action of (S)-alpha-chlorohydrin requires its oxidation to (S)-3-chlorolactaldehyde which is the active metabolite. Addition of racemic 3-chlorolactaldehyde to bovine spermatozoa caused immediate inhibition of glycolysis. It is proposed that the action of (S)-alpha-chlorohydrin in bovine spermatozoa is similar to that observed in the spermatozoa of other species in being a two-stage process; first, its oxidation to (S)-3-chlorolactaldehyde, and then inhibition of the glycolytic enzyme by this metabolite.


Interactive effects of Zn, Pb and Cd in barley.
The effects of different concentrations of Zn, Pb and Cd singly as well as in the combination of zinc-lead, zinc-cadmium and lead-cadmium on the shoot root length and dry mass as well as chlorophyll contents of barley plants during early seedling growth were studied. The effects of different concentrations of Zn x Pb and Pb x Cd in combinations showed a synergistic relationship, while at higher concentrations the relationship was antagonistic. Lower as well as higher Zn x Cd concentrations showed antagonistic effects.


Gene expression-based chemical genomics identifies potential therapeutic drugs in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Currently, only sorafenib is approved by the FDA for advanced HCC treatment; therefore, there is an urgent need to discover candidate therapeutic drugs for HCC. We hypothesized that if a drug signature could reverse, at least in part, the gene expression signature of HCC, it might have the potential to inhibit HCC-related pathways and thereby treat HCC. To test this hypothesis, we first built an integrative platform, the "Encyclopedia of Hepatocellular Carcinoma genes Online 2", dubbed EHCO2, to systematically collect, organize and compare the publicly available data from HCC studies. The resulting collection includes a total of 4,020 genes. To systematically query the Connectivity Map (CMap), which includes 6,100 drug-mediated expression profiles, we further designed various gene signature selection and enrichment methods, including a randomization technique, majority vote, and clique analysis. Subsequently, 28 out of 50 prioritized drugs, including tanespimycin, trichostatin A, thioguanosine, and several anti-psychotic drugs with anti-tumor activities, were validated via MTT cell viability assays and clonogenic assays in HCC cell lines. To accelerate their future clinical use, possibly through drug-repurposing, we selected two well-established drugs to test in mice, chlorpromazine and trifluoperazine. Both drugs inhibited orthotopic liver tumor growth. In conclusion, we successfully discovered and validated existing drugs for potential HCC therapeutic use with the pipeline of Connectivity Map analysis and lab verification, thereby suggesting the usefulness of this procedure to accelerate drug repurposing for HCC treatment.


Dietary walnut reduces hepatic triglyceride content in high-fat-fed mice via modulation of hepatic fatty acid metabolism and adipose tissue inflammation.
In this study, we evaluated the protective effects of dietary walnuts on high-fat diet (HFD)-induced fatty liver and studied the underlying mechanisms. Male C57BL/6J mice were fed either a regular rodent chow or HFD (45% energy-derived) with or without walnuts (21.5% energy-derived) for 20weeks. Walnut supplementation did not change HFD-induced increase in body weight or visceral fat mass. However, dietary walnuts significantly decreased the amounts of hepatic triglyceride (TG) observed in HFD-fed mice. The addition of walnuts significantly altered the levels of proteins, involved in the hepatic lipid homeostasis, including AMP-activated protein kinase, fatty acid synthase and peroxisome proliferator-activated receptor-α. Since adipocyte inflammation and apoptosis are reportedly important in regulating hepatic fat accumulation, we also evaluated the protective effects of walnuts on adipose tissue injury. Real-time polymerase chain reaction results revealed that adipose tissues isolated from mice fed the HFD+walnut diets showed significantly decreased levels of macrophage infiltration with suppressed expression of proinflammatory genes compared to those significantly elevated in mice fed HFD alone. These improvements also coincided with reduction of HFD-induced apoptosis of adipocytes by dietary walnuts. However, the supplemented walnuts did not significantly alter HFD-induced peripheral glucose intolerance or insulin resistance despite a trend of improvement. Collectively, these results demonstrate that the protective effects of walnuts against HFD-induced hepatic TG accumulation in mice are mediated, at least partially, by modulating the key proteins in hepatic lipid homeostasis and suppression of the genes related to adipose tissue inflammation and macrophage infiltration as well as prevention of adipocyte apoptosis.


Cell therapy for immunosuppression after kidney transplantation.
To give an overview over cell therapeutic approaches to immunosuppression in clinical kidney transplantation. A focus is on myeloid suppressor cell therapy by mitomycin C-induced cells (MICs). Literature review with an emphasis on already existing therapies. Several cell therapeutic approaches to immunosuppression and donor-specific unresponsiveness are now being tested in early phase I and phase II trials in clinical kidney transplantation. Cell products such as regulatory T cells or regulatory macrophages, or other myeloid suppressor cell therapies, may either consist of donor-specific, third-party, or autologous cell preparations. Major problems are the identification of the suppressive cell populations and their expansion to have sufficient amount of cells to achieve donor unresponsiveness (e.g., with regulatory T cells). We show a simple and safe way to establish donor unresponsiveness in living-donor kidney transplantation by MIC therapy. A phase I clinical trial is now under way to test the safety and efficacy of this cell therapeutic approach. Cell therapeutic approaches to immunosuppression after kidney transplantation may revolutionize clinical transplantation in the future.


A prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients with stringent cessation criteria for adefovir.
Adefovir is usually applied for therapy of chronic hepatitis B (CHB), but its effectiveness after cessation is still unknown. This study was to evaluate the effectiveness of adefovir treatment with strict cessation criteria in hepatitis B e antigen (HBeAg)-negative patients and to identify potentially important factors. One hundred forty-five HBeAg-negative CHB patients who had received adefovir treatment for at least 24 months and for whom serum hepatitis B virus (HBV) DNA had remained undetectable for at least 18 months before cessation were included. They were followed up monthly during the first four months and at 3-month or 6-month intervals thereafter. Patients with ≥10(4) copies of HBV DNA per mL were defined as relapsed. In total, 95 patients relapsed within the follow-up time, and more than 93% relapsed within 12 months after adefovir cessation. Cumulative relapse rates at months 6, 12, 24, 36, 48 and 60 were 53.8%, 61.4%, 65.5%, 65.5%, 65.5% and 65.5%, respectively. Age was the only factor associated with relapse, with lower relapse rates in younger patients shown by Cox regression analysis. HBsAg seroconversion occurred in 12 patients, and none of them relapsed during follow-up. The effectiveness of adefovir therapy does not persist in HBeAg-negative CHB patients, even when strict cessation criteria are applied, except for patients aged ≤ 25 years. HBsAg seroconversion is the ideal endpoint of adefovir treatment.


Accurate Prediction of Stress in Fibers with Distributed Orientations Using Generalized High-Order Structure Tensors.
The orientation of collagen fibers plays an important role on the mechanics of connective tissues. Connective tissues have fibers with different orientation distributions. The angular integration formulation used to model the mechanics of fibers with distributed orientation is accurate, but computationally expensive for numerical methods such as finite elements. This study presents a formulation based on pre-integrated Generalized High-Order Structure Tensors (GHOST) which greatly improves the accuracy of the predicted stress. Simplifications of the GHOST formulation for transversely-isotropic and planar fiber distributions are also presented. Additionally, the GHOST and the angular integration formulations are compared for different loading conditions, fiber orientation functions, strain energy functions and degrees of fiber non-linearity. It was found that the GHOST formulation predicted the stress of the fibers with an error lower than 10% for uniaxial and biaxial tension. Fiber non-linearity increased the error of the GHOST formulation; however, the error was reduced to negligible values by considering higher order structure tensors. The GHOST formulation produced lower errors when used with an elliptical fiber density function and a binomial strain energy function. In conclusion, the GHOST formulation is able to accurately predict the stress of fibers with distributed orientation without requiring numerous integral calculations. Consequently, the GHOST formulation may reduce the computational effort needed to analyze the mechanics of fibrous tissues with distributed orientations.


Influence of perceived emotion and gender on social motor coordination.
Theorists have long postulated that facial properties such as emotion and sex are potent social stimuli that influence how individuals act. Yet extant scientific findings were mainly derived from investigations on the prompt motor response upon the presentation of affective stimuli, which were mostly delivered by means of pictures, videos, or text. A theoretical question remains unaddressed concerning how the perception of emotion and sex would modulate the dynamics of a continuous coordinated behaviour. Conceived in the framework of dynamical approach to interpersonal motor coordination, the present study aimed to address this question by adopting the coupled-oscillators paradigm. Twenty-one participants performed in-phase and anti-phase coordination with two avatars (male and female) displaying three emotional expressions (neutral, happy, and angry) at different frequencies (100% and 150% of the participant's preferred frequency) by executing horizontal rhythmic left-right oscillatory movements. Time to initiate movement (TIM), mean relative phase error (MnRP), and standard deviation of relative phase (SDRP) were calculated as indices of reaction time, deviation from the intended pattern of coordination, and coordination stability, respectively. Results showed that in anti-phase condition at 150% frequency, MnRP was lower with the angry and the female avatar. In addition, coordination was found to be more stable with the male avatar than the female one when both displaying neutral emotion. But the happy female avatar was found to elicit more stable coordination than the neutral female avatar. These results implied that individuals are more relaxed to coordinate with the female than the male, and the sensorimotor system becomes more flexible to coordinate with an angry person. It is also suggested social roles influence how people coordinate, and individuals attend more to interact with a happy female. In sum, the present study evidenced that social perception is embodied in the interactive behaviour during social interaction.


Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells.
Pituitary adenomas, accounting for 15% of diagnosed intracranial neoplasms, are usually benign and pharmacologically and surgically treatable; however, the critical location, mass effects and hormone hypersecretion sustain their significant morbidity. Approximately 35% of pituitary tumors show a less benign course since they are highly proliferative and invasive, poorly resectable, and likely recurring. The latest WHO classification of pituitary tumors includes pituitary transcription factor assessment to determine adenohypophysis cell lineages and accurate designation of adenomas, nevertheless little is known about molecular and cellular pathways which contribute to pituitary tumorigenesis. In malignant tumors the identification of cancer stem cells radically changed the concepts of both tumorigenesis and pharmacological approaches. Cancer stem cells are defined as a subset of undifferentiated transformed cells from which the bulk of cancer cells populating a tumor mass is generated. These cells are able to self-renew, promoting tumor progression and recurrence of malignant tumors, also conferring cytotoxic drug resistance. On the other hand, the existence of stem cells within benign tumors is still debated. The presence of adult stem cells in human and murine pituitaries where they sustain the high plasticity of hormone-producing cells, allowed the hypothesis that putative tumor stem cells might exist in pituitary adenomas, reinforcing the concept that the cancer stem cell model could also be applied to pituitary tumorigenesis. In the last few years, the isolation and phenotypic characterization of putative pituitary adenoma stem-like cells was performed using a wide and heterogeneous variety of experimental models and techniques, although the role of these cells in adenoma initiation and progression is still not completely definite. The assessment of possible pituitary adenoma-initiating cell population would be of extreme relevance to better understand pituitary tumor biology and to identify novel potential diagnostic markers and pharmacological targets. In this review, we summarize the most updated studies focused on the definition of pituitary adenoma stem cell phenotype and functional features, highlighting the biological processes and intracellular pathways potentially involved in driving tumor growth, relapse, and therapy resistance.


Interaction of the 268-282 region of glycoprotein Ibalpha with the heparin-binding site of thrombin inhibits the enzyme activation of factor VIII.
Activation of factor VIII (FVIII) by thrombin plays a fundamental role in the amplification of the coagulation cascade and takes place through specific proteolytic cleavages at Arg(372), Arg(740) and Arg(1689). Full FVIII activation requires cleavage at Arg(372), a process involving the alpha-thrombin exosite-II; referred to as heparin-binding site (HBS). The present study was aimed at investigating the effect of glycoprotein Ibalpha (GpIbalpha; 1-282 fragment) binding to thrombin HBS on FVIII activation. Similar experiments were also performed using a synthetic peptide modelled on the 268-282 sequence of GpIbalpha, and sulphated successfully at all tyrosine residues present along its sequence, at positions 276, 278 and 279. Both GpIbalpha 1-282 and the sulphated GpIb 268-282 peptides induced a progressive decrease (up to 70%) in activated FVIII generation, assessed by coagulation and FXa-generation assays. Furthermore, SDS/PAGE and Western-blot experiments showed that the specific appearance of the 44 kDa A2 domain on cleavage of the FVIII Arg(372)-Ser(373) peptide bond was delayed significantly in the presence of either GpIbalpha 1-282 or GpIb 268-282 peptide. Moreover, the effect of the latter on thrombin-mediated hydrolysis of a peptide having the sequence 341-376 of FVIII was investigated using reverse-phase HPLC. The k (cat)/ K (m) values of the FVIII 341-376 peptide hydrolysis by thrombin decreased linearly as a function of the GpIbalpha 268-282 peptide concentration, according to a competitive inhibition effect. Taken together, these experiments suggest that the sulphated 268-282 region of GpIbalpha binds to thrombin HBS, and is responsible for the inhibition of the Arg(372)-Ser(373) bond cleavage and activation of FVIII.


Long non‑coding RNA associated‑competing endogenous RNAs are induced by clusterin in retinal pigment epithelial cells.
Age related macular degeneration is one of the most common causes of vision loss in the elderly. Long noncoding RNAs (lncRNAs) serve important roles in regulating gene expression by acting as competing endogenous RNAs (ceRNAs). However, the roles of specific lncRNAs and their associated ceRNA function induced by clusterin in cultured retinal pigment epithelial (RPE) cells remain to be fully elucidated. Based on high throughput sequencing data from RPE cells treated with or without clusterin, the present study identified differentially expressed mRNAs, lncRNAs and microRNAs (miRNAs). A lncRNA‑mRNA‑microRNA (miRNA) network (ceRNA network) was subsequently constructed based on the bioinformatic database miRanda and miRNA targets database miRTarBase. These results demonstrated the expression pattern of several lncRNAs, and a clear clusterin‑associated ceRNA network in RPE cells, which included 75 lncRNAs and 32 miRNAs in RPE cells induced by clusterin. Collectively, the present study uncovered and characterized via bioinformatics the global properties of the ceRNA network in human RPE cells in response to clusterin. These results may aid in the elucidation of the molecular mechanisms of clusterin in age‑related macular degeneration.


Platelet-Rich Plasma Gel Combined with Bovine-Derived Xenograft for the Treatment of Dehiscence Around Immediately Placed Conventionally Loaded Dental Implants in Humans: Cone Beam Computed Tomography and Three-Dimensional Image Evaluation.
This study clinically and radiographically investigated the potential of platelet-rich plasma (PRP) gel combined with bovine-derived xenograft to treat dehiscence defects around immediate dental implants. This study was performed on 32 sites from 16 patients who each received an immediate implant for a single tooth replacement at a maxillary anterior or premolar site. Patients were divided into two groups according to the augmented materials used. One group received an immediate implant and filling of defects using a PRP gel plus bovine-derived xenograft. The other group received an immediate implant and filling of defects with a bovine-derived xenograft without PRP gel. Cone beam computed tomography (CBCT) was taken before placement, and at 6 and 12 months postsurgery. Both treatment procedures resulted in significant improvements for the primary outcome regarding bone fill, as well as the marginal bone level. In addition, statistically significant differences were found in the bone density for the combined therapy compared with sites treated with bovine-derived xenografts alone (P ≤ .01). Autogenous PRP gel combined with bovine-derived xenograft demonstrated superiority to the bovine-derived xenograft alone, which suggested that it could be successfully applicable for the treatment of dehiscence around an immediate dental implant. Moreover, CBCT can be used to measure dehiscence and to assess bone thickness along the implant.


Extensively drug-resistant tuberculosis, Burkina Faso.
Because data from countries in Africa are limited, we measured the proportion of extensively drug-resistant (XDR) tuberculosis (TB) cases among TB patients in Burkina Faso for whom retreatment was failing. Of 34 patients with multidrug-resistant TB, 2 had an XDR TB strain. Second-line TB drugs should be strictly controlled to prevent further XDR TB increase.


Effect of lifestyle and dietary factors in the development of brain tumors.
A brain tumor occurs when neurons are mutated and thus abnormal cells are formed. Glioma and meningioma are the two most common types, comprising approximately 75% of all brain tumors. The incidence rate of all primary brain tumors was 15.80/100,000 person-years in females and 14.33/100,000 person-years in males. An association of higher risk of brain tumors in adults with cured meat and fruit/vegetable consumption, the primary source of dietary N-nitroso compounds, is seen. Cigarette smoking is a major source of chemical carcinogens. The present study aimed at determining the effects of lifestyle and dietary habits in the development of brain tumor. The study aimed at the assessment of various dietary factors, lifestyle, and occupational and personal habits in patients diagnosed with brain tumor in a rural tertiary health-care hospital, using a structured questionnaire and statistical analysis. It was observed that - (1) people with stressful, sedentary lifestyle and wrong diet and those addicted to alcohol consumption and the habit of cigarette smoking have higher risk of brain tumors; (2) males are more prone to brain tumors; and (3) among subtypes, majority had glioblastoma and the least had meningioma and opdivoglioblastoma and according to location, majority had cerebellopontine angle tumor and the least had left thalamic glioma and multicentric glioma. Primary care to preoperative brain tumor patients should be given in terms of preventing exposure to radiations, avoiding cigarette smoking, providing healthy diet, and avoiding chronic stress and environmental pollution and postoperative patients should be taken care including avoiding infections by maintaining proper hygiene and providing healthy diet for their speedy recovery. People with stressful life condition, wrong diet, and sedentary lifestyle and those addicted to alcohol, with the habit of cigarette smoking, have higher risk of brain tumors. Males are more prone to brain tumors.


Comparative evaluation of the efficacy of light amplification by the stimulated emission of radiation, desensitizing agents, and their combined effect on dentinal hypersensitivity in cuspids and bicuspids - In Vivo Study.
Dentinal Hypersensitivity is the most common dental problem, in order to find a suitable treatment plan this study was conducted incorporating LASER and desensitizing agents on the patients complaining of dentinal hypersensitivity in cuspids and bicuspids. Most of the desensitizing agents provided incomplete relief hence the combination of LASER and Desensitizing agents proved to be successful. The aim of this study is to evaluate and compare the efficacy of individual desensitizing agents and c (LASER) and also to know their potential in reducing dentinal hypersensitivity when both desensitizing agents and LASER are combined together and applied on cuspids and bicuspids. Sixty patients with sensitivity only in cuspids and bicuspids and not having caries, restoration, or undergoing any desensitizing therapy were selected. Patients were divided into 5 groups with 12 patients in each group. Air blast stimulus was given for 10 s from 1 cm distance on the affected group. Verbal analog score was recorded. Treatment was carried on according to the groups mentioned: Group I - nanohydroxyapatite was applied for 15 min; Group II - biosilicate was applied for 15 min; Group III - LASER application was done twice for 60 s in noncontact mode; Group IV - Nanohydroxyapatite plus LASER application; and Group V - biosilicate plus LASER application. Desensitizing agent was applied with the applicator tip and was left for 15 min. It was then rinsed and again the stimulus was given, and the score was recorded. The same treatment procedure was repeated on 1st, 7th, and 14th day and the score was recorded and analyzed using ANOVA. The maximum reduction in sensitivity score was observed in patients where nanohydroxyapatite and LASER application was done. All the investigated treatments have promising desensitizing potential, but maximum was found in Group IV > Group V > Group III > Group I > Group II.


Partial characterization and "quantitation" of a human prostatic estramustine-binding protein.
The [3H]estramustine-binding macromolecule in human prostate was partially characterized using a number of chromatographic procedures. Although human estramustine-binding protein (HEMBP) had a marked tendency to aggregate in several systems, a molecular weight of about 54,000 was determined by gel filtration on Sephacryl S-200 Superfine and high-performance liquid chromatography. A sedimentation-coefficient of about 3.6S was obtained for HEMBP when analyzed by sucrose density gradient centrifugation. Isoelectric focusing in polyacrylamide gels indicated an isoelectric point of 4.7 to 4.8, which was in agreement with the elution position of HEMBP following chromatofocusing on Polybuffer Exchanger 94. Furthermore, HEMBP was eluted from diethylaminoethyl-Sepharose with 0.23 M KCl, was retained by concanavalin A-Sepharose (indicating that HEMBP is a glycoprotein), but did not interact with Affi-Gel Blue. Special efforts were concentrated on establishing that HEMBP was a species distinct from human serum albumin. Separation between the [3H]estramustine-labeled HEMBP and the [3H]estramustine-human serum albumin complex was obtained both on sucrose density gradients by chromatography on Affi-Gel Blue, by chromatofocusing, by gel filtration, by isoelectric focusing, and on concanavalin A-Sepharose by affinity chromatography. Twenty-two of 27 human benign hyperplastic prostate cytosol samples were found to contain protein immunochemically similar to estramustine-binding protein (EMBP) purified from rat ventral prostate as determined by the EMBP radioimmunoassay method. Concentrations from 0.2 to 139.6 ng EMBP per mg of total cytosolic protein (mean, 19.3) were determined. Furthermore, four of seven prostatic cancer specimens as well as two of two normal prostatic specimens were also found to contain rat EMBP-immunoreactive material. The unequivocal demonstration of the presence of a HEMBP is of great potential interest in consideration of estramustine phosphate (Estracyt) therapy against prostatic carcinoma. It is not inconceivable that the concentration of HEMBP in the carcinomatous tissue will be of significance in determining the drug uptake in the malignant tissue.


Identity and divergence of protein domain architectures after the yeast whole-genome duplication event.
Gene duplication is a key mechanism in evolution for generating new functionality, and it is known to have produced a large proportion of genes. Duplication mechanisms include small-scale, or "local", events such as unequal crossing over and retroposition, together with global events, such as chromosomal or whole genome duplication (WGD). In particular, different studies confirmed that the yeast S. cerevisiae arose from a 100-150 million-year old whole-genome duplication. Detection and study of duplications are usually based on sequence alignment, synteny and phylogenetic techniques, but protein domains are also useful in assessing protein homology. We develop a simple and computationally efficient protein domain architecture comparison method based on the domain assignments available from public databases. We test the accuracy and the reliability of this method in detecting instances of gene duplication in the yeast S. cerevisiae. In particular, we analyze the evolution of WGD and non-WGD paralogs from the domain viewpoint, in comparison with a more standard functional analysis of the genes. A large number of domains is shared by genes that underwent local and global duplications, indicating the existence of a common set of "duplicable" domains. On the other hand, WGD and non-WGD paralogs tend to have different functions. We find evidence that this comes from functional migration within similar domain superfamilies, but also from the existence of small sets of WGD and non-WGD specific domain superfamilies with largely different functions. This observation gives a novel perspective on the finding that WGD paralogs tend to be functionally different from small-scale paralogs. WGD and non-WGD superfamilies carry distinct functions. Finally, the Gene Ontology similarity of paralogs tends to decrease with duplication age, while this tendency is weaker or not observable by the comparison of the domain architectures of paralogs. This suggests that the set of domains composing a protein tends to be maintained, while its function, cellular process or localization diversifies. Overall, the gathered evidence gives a different viewpoint on the biological specificity of the WGD and at the same time points out the validity of domain architecture comparison as a tool for detecting homology.


Immune Activation Mediates the Association of Advanced Hepatic Fibrosis With Adverse Outcomes in Patients With Coronary Artery Disease.
Literature suggests a bidirectional association between advanced hepatic fibrosis (AHF) and coronary artery disease (CAD). We evaluated the association of AHF with immune activation, systemic inflammation, and adverse outcomes in patients with CAD. A fibrosis-4 index cutoff value ≥2.67 was used to define AHF. Circulating levels of soluble urokinase plasminogen activator receptor and hsCRP (high-sensitivity C-reactive protein) were measured as markers for immune activation and systemic inflammation, respectively. The relationship of AHF with soluble urokinase plasminogen activator receptor, hsCRP, and adverse cardiovascular outcomes was evaluated. Among 3406 participants with CAD, 479 had AHF. Participants with AHF were older; were less likely to be Black individuals; and had a lower body mass index, worse renal function, and a prior history of heart failure. In multivariable linear regression models adjusted for clinical and demographic confounders, participants with AHF had 15.6% higher soluble urokinase plasminogen activator receptor and 24.0% higher hsCRP levels. They were more likely to experience the following adverse outcomes: all-cause death (adjusted hazard ratio [HR], 1.57 ([95% CI, 1.29-1.92]; P<0.001) and cardiovascular death: (subdistribution HR, 1.50 [95% CI, 1.14-1.95]; P=0.003). Mediation analysis showed that 47.0% (95% CI, 13.6%-81.2%]; P=0.006) of the indirect effect of AHF on cardiovascular death was mediated by circulating soluble urokinase plasminogen activator receptor levels. AHF is independently associated with immune activation, systemic inflammation, and adverse cardiovascular outcomes in patients with CAD. The association of AHF with adverse outcomes is partly mediated by immune activation, and targeting this pathway may help reduce the residual risk in patients with CAD.