Sexual dimorphism of somatostatin and growth hormone-releasing factor signaling in the control of pulsatile growth hormone secretion in the rat.
A striking sexual dimorphism exists in the pattern of GH secretion and rate of somatic growth; however, the mechanism(s) mediating this sex difference is unknown. To elucidate the physiological roles of the hypothalamic neuropeptides, somatostatin (SRIF) and GRF, and their interrelation, in generating the sexually dimorphic GH secretory pattern we examined: 1) GH responsiveness to exogenous GRF and 2) the effects of immunoneutralization of endogenous SRIF and GRF on GH secretory dynamics, in free-moving male and female rats. In males, the GH response to 1 microgram rat(r)GRF(1-29)NH2 iv was significantly greater at peak compared to trough times of GH secretion (925.2 +/- 250.8 vs. 95.6 +/- 27.8 ng/ml; P less than 0.02), the latter known to be due to antagonization by the cyclic increased release of endogenous SRIF. In contrast, females failed to exhibit a time-dependent difference in GH responsiveness to GRF. Passive immunization with a specific antiserum to SRIF in males resulted in significant elevation of GH nadir levels but had no effect on GH peak amplitude. In contrast, immunoneutralization of endogenous SRIF in females caused a marked augmentation of plasma GH levels at all time points; there was a significant increase in GH peak amplitude (171.3 +/- 39.9 vs. 67.5 +/- 11.3 ng/ml; P less than 0.05), GH nadir (18.3 +/- 2.7 vs. 5.8 +/- 1.1 ng/ml; P less than 0.01) and mean 6-h plasma GH level (78.7 +/- 4.1 vs. 33.1 +/- 5.8 ng/ml; P less than 0.001), compared to normal sheep serum-treated controls. These results indicate that the pattern of hypothalamic SRIF secretion in females does not follow the male-like ultradian rhythm. Passive immunization with a specific antiserum to GRF obliterated spontaneous GH pulses in both sexes. Moreover, in females, anti-GRF serum attenuated GH nadir levels (4.3 +/- 1.7 vs. 21.4 +/- 3.5 ng/ml; P less than 0.01) indicating a physiological role for GRF in maintaining the elevated basal GH level of females, in addition to its important role in generating the episodic GH pulses. Taken together, these findings provide support for the hypothesis that, in female rats, the pattern of hypothalamic SRIF secretion into hypophyseal portal blood is continuous, rather than cyclical, as in the male; whereas in the case of GRF secretion, in addition to steady-state release which occurs at a higher level in females than males, there is also episodic GRF bursting which does not follow a specific rhythm, as in the male.(ABSTRACT TRUNCATED AT 400 WORDS)


Enzyme immunoassay of human placental and germ-cell alkaline phosphatase in serum.
Placental alkaline phosphatase (placental ALP, PLAP) and germ-cell ALP (GCAP, also known as placental-like ALP), expressed in gonadal cancer tissues, are potential tumor markers. Four monoclonal antibodies, raised against PLAP and recognizing different epitopes, were selected to study the influence of the following variables on the accuracy of PLAP and GCAP measurement: phenotype, molecular form, and glycation pattern of PLAP and GCAP; incubation temperature; and interferences by serum during immunobinding. Nine GCAP phenotypes were identified, interacting with each antibody at a lower affinity than was seen for the more common PLAP phenotypes. Antibody affinity is higher for the free hydrophilic dimeric forms of PLAP and GCAP, and is not influenced by the degree of glycation. In serum or tissue extracts, measurement of PLAP or GCAP is most nearly accurate when immunoincubations are performed at 37 degrees C, with use of antibodies 327 and 7E8, respectively. In addition, correct measurements are achieved only when, during immunobinding, serum is incubated with an equal volume of deoxycholate (9 g/L final concentration).


Kluyveromyces osmophilus is not a synonym of Zygosaccharomyces mellis; reinstatement as Zygosaccharomyces osmophilus comb. nov.
Kluyveromyces osmophilus, a single-strain species isolated from Mozambique sugar, has been treated a synonym of Zygosaccharomyces mellis. Analyses of D1/D2 LSU rRNA gene sequences confirmed that the species belongs to the genus Zygosaccharomyces but showed it to be distinct from strains of Z. mellis. During studies of yeasts associated with stingless bees in Brazil, nine additional isolates of the species were obtained from unripe and ripe honey and pollen of Scaptotrigona cfr. bipunctata, as well as ripe honey of Tetragonisca angustula. The D1/D2 sequences of the Brazilian isolates were identical to those of the type strain of K. osmophilus CBS 5499 (=ATCC 22027), indicating that they represent the same species. Phylogenomic analyses using 4038 orthologous genes support the reinstatement of K. osmophilus as a member of the genus Zygosaccharomyces. We, therefore, propose the name Zygosaccharomyces osmophilus comb. nov. (lectotype ATCC 22027; MycoBank no. MB 833739).


Cecal mucosal response to coccidiosis in growing chickens.
The cecal mucosal changes of a subclinical coccidial (E. tenella) in chickens was studied by scanning electron microscopy. Oral inoculation was used and the mucosal surface of the ceca was studied. A control group from the same hatch of chickens was sampled simultaneously. The ceca from the infected birds was markedly smaller and contained some hemorrhagic areas. The control birds maintained a relatively smooth continuous epithelium throughout the study. During the infection, early fenestration was seen in the epithelium followed by its disruption. The crypts were easily seen as the disease progressed and in some cases the epithelium became denuded. The infective organism may inhibit replacement of degenerating epithelium.


Q fever in members of the United States armed forces returning from Iraq.
Large numbers of armed forces personnel returning from southwest Asia may present with infections that are not endemic to the United States or that occur rarely and are underdiagnosed in the United States. We report 2 cases of acute Q fever in members of the US Military recently returned from Iraq. Because a number of recent reports suggest that the risk of Q fever may be higher than initially thought among US forces deployed to this region, clinicians need to have a high index of clinical suspicion, an understanding of the available diagnostic tests, and knowledge regarding the methodology and capabilities of the laboratory to which specimens are submitted.


Antimicrobial effects of Boesenbergia pandurata and Piper sarmentosum leaf extracts on planktonic cells and biofilm of oral pathogens.
Increasing awareness of hazards associated with the use of antibiotic and chemical agents has accelerated investigations into plants and their extracts as new sources of antimicrobial agents. Therefore, this study aimed at determining the effects of oil and 95% ethanol extracts of Boesenbergia pandurata rhizomes and Piper sarmentosum leaf against four oral pathogens which were Streptococcus mutans, Lactobacillus sp., Aggregatibacter actinomycetemcomitans and Candida albicans. Employing the disc diffusion and broth microdilution methods, the results showed that B. pandurata oil (BPO) was the most effective extract against C. albicans. Time-kill assay with the BPO demonstrated killing of C. albicans at concentrations equal to 2 and 2.5 times the MIC. The times required to reach the fungicidal endpoint at 2 and 2.5 times the MIC were 60 and 44 min, respectively. In addition, our results also demonstrated that the BPO possesses potent anti-Candida biofilm activity in vitro. Therefore, the BPO could be considered as a natural antifungal agent against Candida infections and has significant potential for further investigation.


Immunomodulations of thymocytes and splenocytes in trained rats.
The aim of this study was to describe the effects of training (running) on thymus and spleen cells in the rat. Young Wistar control rats (n = 6), rats trained for 4 wk (n = 5), and rats trained for 4 wk followed by 1 wk of intensive training (3 h/day, n = 6) were studied. Various lymphocyte surface and nuclear markers were determined by immunocytochemistry. The results show that 4 wk of training 1) decreased the percentage of bromodeoxyuridine (BrdU+) thymocytes (cell in phase S of the cycle, immature thymocytes; P less than 0.05) and the viability of thymocytes stimulated with concanavalin A (Con A; P less than 0.05) and 2) increased the absolute number of CD8+ (suppressor/cytotoxic T cells; 29%) and the percentage of CD8+ splenocytes (P less than 0.01). An additional week of intensive training in the 4-wk trained rats induced 1) a decrease in the absolute number of thymocytes (25%, P less than 0.05), TCR+ thymocytes, splenocytes (28%, P less than 0.01), T, CD4+ (helper T cells; 34%), and CD8+ (31%) splenocytes (P less than 0.01) and 2) an increase in the viability of splenocytes after stimulation with Con A for 72 h (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Rape Culture, Revictimization, and Social Representations: Images and Discourses on Sexual and Violent Crimes in the Digital Sphere in Mexico.
The digital sphere has become a space in which misogyny-laden discourses are constantly presented. In fact, in Mexico persists a rape culture that justifies violent acts against women and blames the victims of the crimes through social opinions. The present study proposed an approach based on the Theory of Social Representations. In this sense, this study aimed to analyze the discourses that emerge in the digital sphere when users give their opinion on five types of crimes against women: femicide, rape, enforced disappearance, abuse, and sexual harassment. The results revealed that there are four types of discourse (representations) framed within rape culture: disbelief of rape, blaming the victim, revictimization, and disempowering women. It is concluded that Mexican society maintains a representation that stereotypes and devalues the image of women, which allows us to understand the aggressions that women suffer in their daily lives.


Impact of aerobic exercise training during chemotherapy on cancer related cognitive impairments in patients suffering from acute myeloid leukemia or myelodysplastic syndrome - Study protocol of a randomized placebo-controlled trial.
Cancer related cognitive impairments (CRCI) are frequently reported by patients prior to, during and after medical treatment. Although this cognitive decline severely affects patients' quality of life, little is known about effective treatments. Exercise programs represent a promising supportive strategy in this field. However, evidence is sparse and existing studies display methodological limitations. In the planned study, 83 men and women newly diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) will be randomized into one of three treatment groups. During 4weeks of induction chemotherapy with Anthracycline and Cytarabin patients allocated to exercise group will cycle 3×/week for 30min at moderate to vigorous intensity on an ergometer. Patients allocated to placebo group will receive a supervised myofascial release training (3×/week, approx. 30min) and patients at control group will get usual care. As primary endpoints a cognitive test battery will be conducted measuring performances depending on verbal/spatial memory and executive functioning. Secondary endpoints will be self-perceived cognitive functioning, as well as neurotrophic and inflammatory serum markers. All assessments will be conducted immediately after hospitalization and before chemotherapy is commenced, immediately before discharge of hospital after 4-5weeks as well as before continuing medical treatment 3-4weeks after discharge. This will be the first study investigating the impact of an aerobic exercise training on CRCI in AML/MDS patients. We hope that the study design and the state-of-the-art assessments will help to increase knowledge about CRCI in general and exercise as potential treatment option in this under investigated population.


Using Eye Tracking to Explore Consumers' Visual Behavior According to Their Shopping Motivation in Mobile Environments.
Despite a strong shift to mobile shopping trends, many in-depth questions about mobile shoppers' visual behaviors in mobile shopping environments remain unaddressed. This study aims to answer two challenging research questions (RQs): (a) how much does shopping motivation like goal orientation and recreation influence mobile shoppers' visual behavior toward displays of shopping information on a mobile shopping screen and (b) how much of mobile shoppers' visual behavior influences their purchase intention for the products displayed on a mobile shopping screen? An eye-tracking approach is adopted to answer the RQs empirically. The experimental results showed that goal-oriented shoppers paid closer attention to products' information areas to meet their shopping goals. Their purchase intention was positively influenced by their visual attention to the two areas of interest such as product information and consumer opinions. In contrast, recreational shoppers tended to visually fixate on the promotion area, which positively influences their purchase intention. The results contribute to understanding mobile shoppers' visual behaviors and shopping intentions from the perspective of mindset theory.


Vacuolar H(+)-ATPase in the kidney.
Proton-translocating vacuolar ATPases (H+V-ATPase) are increasingly recognized as essential components of most eukaryotic cells. This electrogenic transporter is present in the cell membranes of many differentiated cell types and in the membranes of many subcellular organelles. The primary active pump is a multi-subunit enzyme with a membrane-bound component (V0 domain) and an intracellular catalytic component (V1 domain). The V0 domain is responsible for proton translocation and the V1 domain is responsible for ATP hydrolysis. All the subunits of the H+V-ATPase are now identified and many of their structural and molecular properties are characterized. The H+V-ATPase plays an important role in many physiological processes such as receptor-mediated transport, endocytosis, protein degradation and processing, and intracellular trafficking. In the cell membranes, it contributes to regulation of intracellular pH, secretion of acid, and generation of transmembrane electrical gradients that serve as a driving force for transport across the membrane of these cells. The role of this transporter is perhaps most significant in the kidney where it has been demonstrated in almost all segments of the nephron. H+V-ATPase in the apical membranes contributes significantly to proximal tubule bicarbonate reabsorption and is chiefly responsible for H+ secretion in the distal portions of the nephron. Basolateral H+V-ATPase in other cell types drives luminal HCO3- secretion. Regulation of distal nephron H+V-ATPase is predominantly via shuttling of transporters into and out of the surface membrane.


Synthesis and some pharmacological properties of deamino(4-threonine,8-D-arginine)vasopressin and deamino(8-D-arginine)vasopressin, highly potent and specific antidiuretic peptides, and (8-D-arginine)vasopressin and deamino-arginine-vasopressin.
Deamino[4-threonine,8-D-arginine]vasopressin (dTDAVP), deamino[8-D-arginine]vasopressin (dDAVP), [8-D-arginine[vasopressin (DAVP), and deamino-arginine-vasopressin (dAVP) were synthesized by the solid-phase method and tested for their biological activities. dTDAVP has an antidiuretic potency of 793+/-95 units/mg and undetectable vasporessor activity, less than 0.02unit/mg. The antidiuretic-pressor (A/P) ratio of dTDAVP is greater than 39 000. dDAVP has an antidiuretic potency of 1200+/-126 units/mg and a vasopressor potency of 0.39+/-0.02; its A/P ratio is thus 3000. DAVP has an antidiuretic potency of 253+/-44 units/mg, a vasopressor potency of 1.1+/-0.04 units/mg, and an A/P ratio of 240. The A/P ratios of dDAVP and DAVP are much higher than those originally reported. dAVP has an antidiuretic potency of 1745+/-385 units/mg, a vasopressor potency of 346+/-13, and an A/P ratio of 5; values are in general agreement with those in the literature. Threonine subsitution has thus brought about a significant enhancement in antidiuretic specificity, a finding entirely consistent with earlier observations that enhancement of lipophilicity at position 4 alone or in combination in arginine-vasopressin can lead to enhanced antidiuretic specificity.


Rho kinase cascade activation in circulating leukocytes in patients with diabetes mellitus type 2.
The intracellular ROCK signaling pathway is an important modulator of blood pressure and of cardiovascular and renal remodeling when Rho-kinase activity is increased. Besides, in preclinical models of diabetes, ROCK activation has also a role in abnormal glucose metabolism as well as in subsequent vascular and myocardial dysfunction. In humans, there are a few data assessing ROCK activation in patients with type 2 diabetes mellitus (T2D) and no studies assessing upstream/downstream components of the ROCK pathway. We assessed here levels of ROCK activation and some of the RhoA/ROCK cascade molecules in peripheral blood mononuclear cells (PBMCs) in T2D patients under current treatment. Cross-sectional observational study comparing 28 T2D patients under current antidiabetic treatment with 31 consecutive healthy subjects, matched by age and gender. Circulating levels of malondialdehyde, angiotensin II and inflammatory cytokines IL-6 and IL-8 were determined in all subjects. ROCK activation in PMBCs, upstream and downstream cascade proteins, and levels of the proinflammatory molecules VCAM, ICAM-1 and IL-8 were determined in their PMBCs by Western blot. Compared to healthy controls, ROCK activation in T2D patients measured by 2 direct ROCK targets in PBMCs was increased by 420 and 570% (p < 0001) and it correlated significantly with serum glucose levels. p38 MAPK phosphorylation (downstream from ROCK) and JAK-2 (upstream from ROCK) were significantly higher in the T2D patients by 580% and 220%, respectively. In T2D patients, significantly increased PBMC levels of the proinflammatory molecules VCAM-1, ICAM-1 and IL-8 were observed compared to control subjects (by 180%, 360% and 260%, respectively). Circulating levels of Ang II and MDA were significantly higher in T2D patients by 29 and 63%, respectively. T2D patients under treatment with glucose-lowering drugs, antihypertensive treatment as well as with statins have significantly increased ROCK activation in their circulating leukocytes along with higher phosphorylation of downstream cascade proteins despite pharmacologic treatment, along with increased plasma angiotensin II and MDA levels. ROCK inhibition might have an additional role in the prevention and treatment of T2D.


Elevated systolic blood pressure after trauma: tolerated in the elderly.
We undertook the current study to determine the impact of elevated admission systolic blood pressure (SBP) on trauma patients without severe brain injury. We conducted a retrospective review of the Los Angeles County Trauma System database to identify all patients with moderate to severe injuries (injury severity score >9) admitted between 2003 and 2008. Patients with head abbreviated injury score >3 were excluded. We divided the remaining patients into three age cohorts and conducted multivariate regression modeling at increasing SBP thresholds to identify independent predictors of mortality. A total of 23,931 patients met inclusion criteria. Overall mortality was 8.6% and it increased with age across the three groups. The admission SBP thresholds associated with significantly increased mortality in the young and middle-aged were >190 mm Hg (AOR 1.5, P = 0.04) and >180 mm Hg (AOR 1.5, P = 0.01), respectively. In the elderly, no admission SBP threshold was associated with significantly increased mortality. Interestingly, several elevated admission SBP thresholds were associated with significantly reduced mortality in the elderly (>150 mm Hg AOR 0.6, P < 0.01; >160 mm Hg AOR 0.6, P < 0.01; and >170 mm Hg AOR 0.7, P = 0.02). The admission SBP thresholds that predicted higher mortality for the young and middle-aged were >190 mm Hg and >180 mm Hg, respectively. Elderly trauma patients tolerated higher admission SBP than their younger counterparts and multiple elevated SBP thresholds were associated with significantly reduced mortality in the elderly.


Assay Stability, the missing component of the Error Budget.
Gaining a better understanding of Quality Control (QC) processes is a key requirement to improving performance and reducing patient risk. Detecting analytical error is dependent on a QC strategy that reliably detects a critical shift in a result away from the true value. Recently the concept of Six Sigma has been used by diagnostic laboratories to assess the performance of assays and to assist in the selection of QC rules. The sigma metric is one measure of an assay's ability to perform within specification. However an additional dimension to managing an assay is its stability in bias over time. The concept of long term stability is the same as measured QC drift (SEdrift) which is the effect of numerous calibrations, changes in reagent lots and other conditions i.e. a long term effect. This implies that the standard error budget is wrong because it is modelled on short term QC and misses this SEdrift stability component. We show that SEdrift provides a measure of Assay Stability that should be included in Quality Planning and that by including an allowance for this drift, determining target imprecision appropriate for matched QC algorithms that provide high error detection is as simple as dividing the Allowable Performance Specification by 4, 5 or 6.


Phosphoproteomic analysis of platelets activated by pro-thrombotic oxidized phospholipids and thrombin.
Specific oxidized phospholipids (oxPCCD36) promote platelet hyper-reactivity and thrombosis in hyperlipidemia via the scavenger receptor CD36, however the signaling pathway(s) induced in platelets by oxPCCD36 are not well defined. We have employed mass spectrometry-based tyrosine, serine, and threonine phosphoproteomics for the unbiased analysis of platelet signaling pathways induced by oxPCCD36 as well as by the strong physiological agonist thrombin. oxPCCD36 and thrombin induced differential phosphorylation of 115 proteins (162 phosphorylation sites) and 181 proteins (334 phosphorylation sites) respectively. Most of the phosphoproteome changes induced by either agonist have never been reported in platelets; thus they provide candidates in the study of platelet signaling. Bioinformatic analyses of protein phosphorylation dependent responses were used to categorize preferential motifs for (de)phosphorylation, predict pathways and kinase activity, and construct a phosphoproteome network regulating integrin activation. A putative signaling pathway involving Src-family kinases, SYK, and PLCγ2 was identified in platelets activated by oxPCCD36. Subsequent ex vivo studies in human platelets demonstrated that this pathway is downstream of the scavenger receptor CD36 and is critical for platelet activation by oxPCCD36. Our results provide multiple insights into the mechanism of platelet activation and specifically in platelet regulation by oxPCCD36.


Nanoindentation-enhanced tip-enhanced Raman spectroscopy.
We combine nanoindentation, herein achieved using atomic force microscopy-based pulsed-force lithography, with tip-enhanced Raman spectroscopy (TERS) and imaging. Our approach entails indentation and multimodal characterization of otherwise flat Au substrates, followed by chemical functionalization and TERS spectral imaging of the indented nanostructures. We find that the resulting structures, which vary in shape and size depending on the tip used to produce them, may sustain nano-confined and significantly enhanced local fields. We take advantage of the latter and illustrate TERS-based ultrasensitive detection/chemical fingerprinting as well as chemical reaction imaging-all using a single platform for nano-lithography, topographic imaging, hyperspectral dark field optical microscopy, and TERS.


Protein expression of p53, p21WAF1, and Rb as prognostic indicators in patients with surgically treated hepatocellular carcinoma.
Many genes participate in the regulation of cell cycle progression from G1 to S phase. Functional loss of one or more of these genes has been reported to be associated with carcinogenesis and/or tumor progression and poor prognosis in many cancers. In a series of 126 patients with hepatocellular carcinoma (HCC), we immunohistochemically evaluated tumor expression of the cell cycle-related gene protein products of Rb, p21 (WAF1), and p53. Positive immunostaining for Rb, p21, and mutant p53 protein was detected in 58%, 33%, and 37% of the tumors, respectively. The proportion of HCCs exhibiting aberrant p53 protein expression increased significantly with advancing stage of disease (p < 0.001), poorer histological classification of differentiation (p < 0.01), and increasing tumor size (p < 0.01). A decrease in the proportion of HCCs expressing p21 protein was also associated with advancing clinical stage of disease (p < 0.01), and larger tumor size (p < 0.05). The only clinicopathological feature found to be associated with Rb status, was intrahepatic metastasis, which occurred with a higher frequency in HCCs exhibiting positive immunoreactivity for Rb protein expression (p < 0.05). Multivariate survival analysis revealed that, amongst the protein products of the different genes evaluated, only positive immunostaining for aberrant p53 protein expression served as an independent prognostic indicator, being significantly associated with worse survival in patients with HCC (p = 0.023). Analysis for relationships between gene products showed an inverse correlation between expression of aberrant p53 protein and p21 protein (p < 0.01), and also an inverse correlation between p21 protein and Rb protein expression (p < 0.05) in these cases of HCC. These findings demonstrate that positive immunostaining for mutant p53 protein expression is a significant indicator of tumor progression and poor prognosis, confirm that p21 protein expression is induced in a p53-dependent manner, and suggest that Rb protein expression may be regulated to some extent by p21 in HCC.


Nelfinavir and Ritonavir Kill Bladder Cancer Cells Synergistically by Inducing Endoplasmic Reticulum Stress.
The human immunodeficiency virus (HIV) protease inhibitor nelfinavir acts against malignancies by inducing endoplasmic reticulum (ER) stress. The HIV protease inhibitor ritonavir, on the other hand, not only induces ER stress but also inhibits P-glycoprotein's pump activity and thereby enhances the effects of its substrate drugs. We therefore postulated that ritonavir in combination with nelfinavir would kill bladder cancer cells effectively by inducing ER stress cooperatively and also enhancing nelfinavir's effect. Nelfinavir was shown to be a P-glycoprotein substrate, and the combination of nelfinavir and ritonavir inhibited bladder cancer cell growth synergistically. It also suppressed colony formation significantly. The combination significantly increased the number of cells in the sub-G1 fraction and also the number of annexin V+ cells, confirming robust apoptosis induction. The combination induced ER stress synergistically, as evidenced by the increased expression of glucose-regulated protein 78, ER-resident protein 44, and endoplasmic oxidoreductin-1-like protein. It also increased the expression of the mammalian target of rapamycin (mTOR) inhibitor AMP-activated protein kinase and caused dephosphorylation of S6 ribosomal protein, demonstrating that the combination also inhibited the mTOR pathway. We also found that the combination enhanced histone acetylation synergistically by decreasing the expression of HDACs 1, 3, and 6.


Ubiquitin ligases in cancer: ushers for degradation.
The regulated degradation of cellular proteins by the ubiquitin-proteasome system impacts a range of vital cellular processes in both normal and cancerous cells. An ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) catalyzes the conjugation of the protein ubiquitin to a target protein and, thereby, tags that protein for recognition and destruction by the proteasome. Ubiquitin ligases are particularly interesting because they determine substrate selection. This review examines the role of dysregulated ubiquitin ligase activity in the development and progression of various cancers, and highlights why ubiquitin ligases have emerged as extremely attractive targets for therapeutic intervention in a number of human malignancies.


Prevalence, comorbidity and factors associated with sleeping, crying and feeding problems at 1 month of age: A community-based survey.
To examine, in a community cohort of healthy one-month-old infants, (i) the prevalence of early infant sleeping, crying and feeding problems; (ii) the extent to which they co-exist; and (iii) infant and mother characteristics associated with each problem alone and with comorbid problems. A survey at 4 weeks of infant age examined the presence of infant sleeping, crying and feeding problems (yes/no); parenting self-efficacy; rating of self as a tense person; and doubts about parenting at bedtime. A total of 770 mothers (39% of those approached) with a total of 781 infants (11 twins) took part. Infant sleeping, crying and feeding problems were reported by 38.5, 27.4 and 25.2% of mothers, respectively. On comorbidity, 25.5% reported one problem, 20.5% reported two and 7.3% reported all three problems. Mothers of first-born infants reported more crying problems and comorbid problems. Mothers who described themselves as a 'tense person' reported more infant feeding problems. Maternal doubt and low self-efficacy were consistently associated with each type of infant problem and comorbid problems (adjusting for other factors). Mothers expressing doubt and low parenting self-efficacy may benefit from additional support and guidance on normal infant behaviour.


[Comparative blood coagulation studies in PGF2a- and 15-methyl-PGF2a-induced therapeutic abortion].
In 15 pregnant women of the first trimenon of gravidity an interruption was performed by means of extra-amnial application of PGF2a and in 10 pregnant women by means of i. m. application of 15-methyl-PGF2a. Bleeding time, recalcification time, number of thrombocytes, heat fibrin, and thrombocyte adhesiveness were determined before, during and after treatment. Statistically significant changes could be observed during bleeding time, heat fibrin, and thrombocyte number. The investigations of coagulation, however, did not reveal any considerable impairment of the coagulation system, thus confirming the positive evaluation of prostaglandines used for therapeutic induction of abortion.


Cardiovascular and hormonal responses to DDAVP before and after beta-blockade in patients with mild essential hypertension.
The aim of this study was to assess the cardiovascular and hormonal responses to 1-desamino-8,D-arginine vasopressin (DDAVP) in hypertensive patients before and after non-selective beta-blockade. We infused DDAVP at 400 ng/kg body weight for 10 min in nine subjects with mild essential hypertension before and 14 days after administration of nadolol at 80 mg/day. Blood pressure and heart rate were recorded, and blood was drawn at 0, 30 and 60 min for measurement of plasma renin activity, aldosterone, cortisol, noradrenaline, adrenaline and dopamine. Before the administration of nadolol, DDAVP induced a significant decrease in blood pressure, and significant increases in the heart rate, plasma renin activity, cortisol and noradrenaline; there were no changes in adrenaline or dopamine. After the administration of nadolol, baseline noradrenaline was significantly increased, while cortisol, adrenaline and dopamine remained unchanged. A second infusion of DDAVP did not significantly alter blood pressure, [corrected] heart rate, noradrenaline, adrenaline or dopamine, but plasma renin activity, aldosterone and cortisol still showed a significant increase. The blunted hypotensive effect of DDAVP after the administration of nadolol may be aspecific, due to lower basal blood pressure levels, or may indicate a mechanism of action common to both drugs. A similar post-DDAVP increase before and after beta-blockade suggests that the drug has a direct effect on the renin-secretory apparatus. An indirect effect, mediated by changes in intrarenal haemodynamics or by other factors with renin-stimulating activity, e.g. tissue plasminogen activator, can also be hypothesized.


Effect of ruminal acidosis and short-term low feed intake on indicators of gastrointestinal barrier function in Holstein steers.
The objective of this study was to determine effect of ruminal acidosis (RA) and low feed intake [LFI] on the regional barrier function of the gastrointestinal tract. Twenty-one Holstein steers were fed for ad libitum intake for 5 d (control [CON]), fed at 25% of ad libitum intake for 5 d (LFI), or provided 2 d of ad libitum intake followed by 1-d of feed restriction (25% of ad libitum intake), 1 d where 30% of ad libitum dry matter intake (DMI) was provided as pelleted barley followed by the full allocation (RA) and fed for ad libitum intake the following day. Tissues and digesta from the rumen, omasum, duodenum, jejunum, ileum, cecum, proximal, and distal colon were collected. Permeability was assessed using the mucosal-to-serosal flux of inulin (JMS-inulin) and mannitol (JMS-mannitol). Digesta pH was 0.81, 0.63, and 0.42 pH units less for RA than CON in the rumen, cecum, and proximal colon; while, LFI had pH that was 0.47 and 0.36 pH units greater in the rumen and proximal colon compared to CON. Total ruminal short-chain fatty acid (SCFA) concentration were less for LFI (92 mM; P = 0.010) and RA (87 mM; P = 0.007) than CON (172 mM) steers. In the proximal colon, the proportion of butyrate (P = 0.025 and P = 0.022) and isobutyrate (P = 0.019 and P = 0.019) were greater, and acetate (P = 0.028 and P = 0.028) was less for LFI and RA, respectively, when compared to CON steers. Ruminal papillae length, width, perimeter, and surface area were 1.21 mm, 0.78 mm, 3.84 mm, and 11.15 mm2 less for LFI than CON; while, RA decreased papillae width by 0.52 mm relative to CON. The JMS-mannitol was less for LFI steers than CON in the proximal colon (P = 0.041) and in the distal colon (P = 0.015). Increased gene expression for claudin 1, occludin, tight-cell junction protein 1 and 2, and toll-like receptor 4 were detected for LFI relative to CON in the rumen, jejunum, and proximal colon. For RA steers, expression of toll-like receptor 4 in the rumen, and occludin and tight-cell junction protein 1 were greater in the jejunum than CON. An acute RA challenge decreased pH in the rumen and large intestine but did not increase tissue permeability due to increases in the expression of genes related to barrier function within 1 d of the challenge. Steers exposed to LFI for 5 d had reduced ruminal SCFA concentrations, smaller ruminal papillae dimensions, and increased tissue permeability in the proximal and distal colon despite increases for genes related to barrier function and immune function.


Microwave ablation induces a lower systemic stress response in patients than open surgery for treatment of benign thyroid nodules.
In this study, we compared the systemic stress response induced by microwave ablation with that induced by conventional open surgery for treatment of benign thyroid nodules. A total of 108 patients with benign thyroid nodules were randomly assigned to receive ultrasound-guided thyroid microwave ablation (microwave group, n = 57) and conventional open thyroid surgery (open group, n = 51). Body temperature, white blood cell (WBC) counts, visual analogue scale (VAS) scores for pain, and serum levels of high sensitive C-reactive protein (hs-CRP), interleukin 6 (IL-6) and cortisol were measured at 24 h before operation and at 8 h, 24 h and 48 h after operation. No significant between-group differences were observed with respect to preoperative body temperature, VAS scores, WBC counts, serum hs-CRP, IL-6 and cortisol levels. Patients in the open group exhibited higher body temperature at 24 h after operation and higher WBC counts at both 24 h and 48 h after operation, as compared to those in the microwave group. As compared with microwave ablation, open surgery was associated with significantly higher VAS scores, and significantly higher serum levels of hs-CRP, IL-6 and cortisol at all postoperative time-points (8 h, 24 h and 48 h). Microwave ablation induces a lower systemic stress response than open surgery for treatment of benign thyroid nodules.


Initial In Vitro Development of a Potassium-Based Intra-Articular Injection for Osteoarthritis.
The long-term goal of this work is to develop a potassium (K+)-based intra-articular (IA) injection for osteoarthritis treatment. Within this context, the objectives of this study were to (1) demonstrate that hyperosmolar K+ solutions can suppress proinflammatory macrophage activation and (2) evaluate the therapeutic potential of a hyperosmolar K+ solution relative to a clinically utilized drug-based (methylprednisolone acetate [MPA]-a corticosteroid) or cell-based (human mesenchymal stem cell [hMSC]) IA injectable. A 3D in vitro model with poly(ethylene glycol) diacrylate hydrogels encapsulated with proinflammatory interferon-gamma (IFN)-stimulated macrophages (M(IFN)s) was utilized. Long-term changes in cell phenotype in response to short-term stimulation (i.e., mimicking an IA injection) were assessed following treatment with 80 mM K+ gluconate, hMSCs, or MPA. Addition of 80 mM K+ gluconate to culture media significantly reduced iNOS and TNF protein levels in M(IFN)s. Furthermore, short-term stimulation with K+ gluconate elicited a significant increase in the anti/proinflammatory cytokine profile in M(IFN)s, a response that is not noticed with either clinically utilized MPA or an hMSC injectable. Hyperosmolar K+ solutions are capable of attenuating proinflammatory macrophage activation. Moreover, when evaluated in an in vitro setting mimicking an IA injection, K+ performed significantly better than hMSCs or the corticosteroid MPA. Cumulatively, these results support further development and application of a K+-based IA injection toward osteoarthritis research.


Metabolic syndrome and nonalcoholic fatty liver disease in a Spanish population: influence of the diagnostic criteria used.
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and it is considered the hepatic component of the metabolic syndrome (MetS). The WHO, the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF) have different criteria to define MetS. The aim of this study was to analyze the association between NAFLD and MetS using the three existing criteria. Cross-sectional, descriptive population-based study derived from a previous study on the prevalence and factors associated with NAFLD in Spain. A total of 696 individuals [mean age 53 ± 14 years (range 17-83 years)] were included, 59% of whom were women. The prevalence of MetS was 34.2% according to the IDF, 17.7% according to the NCEP and 15.5% according to the WHO. Concordance among the different criteria was between 76 and 87%, with kappa indexes between 0.39 and 0.54. NAFLD was present in 184 individuals according to echographic criteria (prevalence 26.4%). The prevalence of NAFLD among patients with MetS was 43% (IDF), 53% (NCEP) and 64% (WHO). The odds ratio (95% confidence interval) for a logistic regression using NAFLD as a dependent variable varied from 3.44 (2.42-4.88) for IDF to 7.28 (4.68-11.3) for WHO, being 4.28 (2.84-6.43) for NCEP. The MetS is quite frequent in the general population, although its prevalence varies considerably according to the criteria used for its definition. The MetS is associated with NAFLD, with the WHO definition being the best to determine its presence, probably because of the inclusion of insulin resistance as a main component. Unification of criteria is needed to adequately compare the prevalence of MetS and its relationship with NAFLD in different population groups.


Three-Dimensional Holographic Refractive-Index Measurement of Continuously Flowing Cells in a Microfluidic Channel.
Refractive index of biological specimens is a source of intrinsic contrast that can be explored without any concerns of photobleaching or harmful effects caused by extra contrast agents. In addition, RI contains rich information related to the metabolism of cells at the cellular and subcellular levels. Here, we report a no-moving parts approach that provides three-dimensional refractive index maps of biological samples continuously flowing in a microfluidic channel. Specifically, we use line illumination and off-axis digital holography to record the angular spectra of light scattered from flowing samples at high speed. Applying the scalar diffraction theory, we obtain accurate RI maps of the samples from the measured spectra. Using this method, we demonstrate label-free 3-D imaging of live RKO human colon cancer cells and RPMI8226 multiple myeloma cells, and obtain the volume, dry mass and density of these cells from the measured 3-D refractive index maps. Our results show that the reported method, alone or in combination with the existing flow cytometry techniques, promises as a quantitative tool for stain-free characterization of large number of cells.


Bile acid analysis in biliary tract cancer.
The etiology of biliary tract cancer is obscure, but there are evidences that bile acid plays a role in carcinogenesis. To find the association between biliary tract cancer and bile acid, this study compared the bile acid concentration and composition among patients with biliary cancer, biliary tract stones, and no biliary disease. Bile was compared among patients with biliary tract cancer (n = 26), biliary tract stones (n = 29), and disease free controls (n = 9). Samples were obtained by percutaneous transhepatic biliary drainage, endoscopic nasobiliary drainage, or gallbladder puncture, and analyzed for cholic, deoxycholic, chenodeoxycholic, lithocholic, and ursodeoxycholic acid composition. Total bile acid concentration was lower in the cancer group than the biliary stone and control groups; the proportions of deoxycholic (2.2% vs. 10.2% and 23.6%, p < 0.001 and p < 0.001, respectively) and lithocholic acid (0.3% vs. 0.6% and 1.0%, p = 0.065 and p < 0.001, respectively) were also lower. This result was similar when disease site was limited to bile duct or gallbladder. Analysis of cases with bilirubin <or= 2.0 mg/dL also showed lower total bile acid concentration and deoxycholic acid composition in the cancer group compared to controls (5.7% vs. 23.6%, p = 0.003). Although the presence of bile duct obstruction explains some of the difference in total concentration and composition of bile acid, there are other contributing mechanisms. We suspect the alteration of bile acid transport might decrease bile acid excretion and cause the accumulation of carcinogenic bile acid in bile duct epithelium.


[Ultrasonic diagnosis of the salivary glands].
Sonography of the salivary glands is a valuable diagnostic tool in acute and chronic sialadenitis, sialadenoses, lymphadenopathies and tumours lesions. A new examination technique is presented: ultrasound-guided fine needle biopsy. We report on our experience in 308 patients with parotid and in 47 patients with submaxillary gland diseases examined between 1982 and 1987. The diagnostic accuracy and limitations of sonography are discussed compared with sialography, computed tomography and magnetic resonance imaging.


[A retrospective survey of diagnostic techniques of pulmonary embolism in 13 general hospitals in Guangxi area].
To survey different diagnostic techniques in diagnosing pulmonary embolism (PE). Hospital records of PE cases in 13 AAA general hospitals in Guangxi area from 1995 to 2007 were studied retrospectively. Probable PE was defined as the diagnosis based on the clinical data and non-specific imaging, while the definite PE was defined as those with the diagnosis confirmed by specific imaging or autopsy. The percentage of various diagnostic methods of PE was analyzed. From 1995 to 2007, 237 definite PE and 223 probable PE were found in 13 hospitals, and they accounted for 51.52% and 48.48%, respectively, for all patients diagnosed as having PE. The percentage of definite PE cases during 1995-2001 and 2002-2007 were 14.63% and 55.13%, respectively (chi (2)=24.522, P<0.01). Among 237 definite PE, 2 positive diagnostic techniques were employed in 17 patients. Twenty-seven (11.39%), 214 (90.30%), 6 (2.53%), 5 (2.11%) and 2 (0.84%) patients were diagnosed by pulmonary angiography, CT pulmonary angiography (CTPA), ultrasonography, magnetic resonance imaging (MRI) and autopsy, respectively. No ventilation-perfusion lung scanning was performed in these patients. Compared with other diagnostic imaging, the percentage of CTPA in diagnosis of PE increased slightly since 2003. CTPA is the first choice in the diagnosis of PE in Guangxi area, and more attention should be paid to other diagnostic imaging techniques.


Cloning of a rice cDNA encoding a transcription factor homologous to barley GAMyb.
A cDNA clone, OsGAmyb, which encodes a homologue to the barley Myb-like transcription factor, HvGAMyb, was isolated from a rice endosperm cDNA library. The clone was used to show that expression of the OsGAmyb gene in aleurone cells was stimulated by gibberellic acid and the gene product was shown to transactivate an alpha-amylase gene promoter in transient expression analyses.


Nurses performing embryo transfer: the development and results of the Birmingham experience.
Although in-vitro fertilization treatment is doctor-led, many of its steps are performed by nurses. The embryo transfer step, however, is performed exclusively by doctors in the majority of units. In our unit, doctors performed embryo transfers from June 1994 until December 1995 (period I). From January 1996 until May 1997 (period II) the nurses, after appropriate training, performed the procedure. When they experienced difficulties during the mock transfer performed immediately before the real transfer, or if they were not available to do the procedure, a doctor performed it. In period I, 488 embryo transfers were performed (all by doctors), with a pregnancy rate per transfer of 35% and an implantation rate of 16%. In period II, 522 embryo transfers were performed. Nurses performed 371 (71%) and doctors 151 (29%) of the procedures. The pregnancy rate per nurse-transfer was 40.2% and per doctor-transfer 41%. The corresponding implantation rates were 16.9% and 17%. None of these differences were statistically significant (P > 0.05). These data indicate that, with appropriate training and medical back-up, nurses can perform the majority of embryo transfers with ease and outcome comparable to that of doctor embryo transfer.


[Pathophysiology of chronic obstructive lung diseases].
Chronic obstructive lung disease (COLD) includes chronic bronchitis, chronic obstructive bronchitis and pulmonary emphysema. Bronchial obstruction can be caused by intraluminal processes (mucous secretion) as well as alterations of the bronchial wall (i.e. spasm of bronchial smooth muscle, hypertrophy of mucous glands, cellular infiltrates) or of the lung parenchyma (destruction of pulmonary structures). The development of pulmonary emphysema may be related to an imbalance of oxidants and antioxidants as well as that of elastases and anti-elastases. Smoking appears to play the most important role in this process.


Arterial Load and Norepinephrine Are Associated With the Response of the Cardiovascular System to Fluid Expansion.
Fluid responsiveness has been extensively studied by using the preload prism. The arterial load might be a factor modulating the fluid responsiveness. The norepinephrine (NE) administration increases the arterial load and modifies the vascular properties. The objective of the present study was to determine the relationship between fluid responsiveness, preload, arterial load, and NE use. We hypothesized that as a preload/arterial load, NE use may affect fluid responsiveness. The retrospective multicentered analysis of the pooled data from 446 patients monitored using the transpulmonary thermodilution before and after fluid expansion (FE) was performed. FE was standardized between intensive care units (ICUs). The comparison of patients with and without NE at the time of fluid infusion was performed. Stroke volume (SV) responsiveness was defined as an increase of more than 15% of SV following the FE. Pressure responsiveness was defined as an increase of more than 15% of mean arterial pressure (MAP) following the FE. Arterial elastance was used as a surrogate for the arterial load. A total of 244 patients were treated with NE and 202 were not treated with NE. By using the univariate analysis, arterial elastance was correlated to SV variations with FE. However, the SV variations were not associated with NE administration (26 [15; 46]% vs. 23 [10; 37]%, p = 0.12). By using the multivariate analysis, high arterial load and NE administration were associated with fluid responsiveness. The association between arterial elastance and fluid responsiveness was less important in patients treated with NE. Arterial compliance increased in the absence of NE, but it did not change in patients treated with NE (6 [-8; 19]% vs. 0 [-13; 15]%, p = 0.03). The changes in total peripheral and arterial elastance were less important in patients treated with NE (-8 [-17; 1]% vs. -11 [-20; 0]%, p < 0.05 and -10 [-19; 0]% vs. -16 [-24; 0]%, p = 0.01). The arterial load and NE administration were associated with fluid responsiveness. A high arterial load was associated with fluid responsiveness. In patients treated with NE, this association was lower, and the changes of arterial load following FE seemed to be driven mainly by its resistive component.


Determination of the diffuser reference plane for accurate illuminance responsivity calibrations.
It is difficult to predict where the effective measurement plane is situated with dome-shaped diffusers often used in commercial photometers and radiometers. Insufficient knowledge of this plane could lead to large systematic errors in calibration of the illuminance responsivity of photometers. We propose a method that can be used to determine this reference plane accurately, based on the inverse-square law between the measured signal and the distance from the source. The method is demonstrated with three commercial photometers with dome-shaped diffusers of different geometries. By taking into account the measured shifts of the reference planes (5.0 +/- 0.5 mm, 7.8 +/- 0.3 mm, and 8.5 +/- 0.7 mm), we reduced the systematic measurement errors up to 2% to statistical uncertainty components at the level of 0.2%.


Gd13Fe10C13: indications of Fe-Fe multiple bonding emerging from chemical frustration.
We report the synthesis and crystal structure of the carbide Gd(13)Fe(10)C(13). This compound adopts a new structure type that is remarkable for its "H"-shaped C(2)FeFeC(2) units, which have some of the shortest Fe-Fe contacts known. A bonding analysis using DFT-calibrated Hückel calculations hints that Fe-Fe multiple bonding underlies these short distances. Gd(13)Fe(10)C(13) undergoes ferromagnetic ordering at ∼55 K.


Chemiluminescence Resulting from Electrochemically Generated Species.
Chemiluminescence is reported from chemical species produced during electrolysis of aromatic hydrocarbons in deoxygenated nonaqueous solvents. Emission occurs in the solution near the cathode, and the emitting species is the excited singlet state of the hydrocarbon. Oxygen exerts a severe quenching effect on the chemiluminescence. Possible mechanisms are discussed.


Collection of NO and NO2 for isotopic analysis of NO(x) emissions.
There have been several measurements made of the nitrogen isotopic composition of gaseous NOx (NOx = NO + NO2) from various emission sources, utilizing a wide variety of methods to collect the NOx in solution as nitrate or nitrite. However, previous collection techniques have not been verified for complete or efficient capture of NOx such that the isotopic composition of NOx remains unaltered during collection. Here, we present a method of collecting NOx (NO + NO2) in solution as nitrate to evaluate the nitrogen isotopic composition of the NOx (δ(15)N-NOx). Using a 0.25 M KMnO4 and 0.5 M NaOH solution, quantitative NOx collection was achieved under a variety of conditions in laboratory and field settings, allowing for isotopic analysis without correcting for fractionations. The uncertainty across the entire analytic procedure is ±1.5‰ (1σ). With this method, a more robust inventory of NOx source isotopic composition is possible, which has implications for studies of air quality and acid deposition.


Assessment of Two Years' Sputum Smear Results among Tuberculosis Suspected Patients in Gambella Regional Hospital, Western Ethiopia.
Determining burden of pulmonary tuberculosis (PTb) may be associated with success of directly observed theraphy (DOT) services in high PTb areas, such as Gambella, Ethiopia. To assess burden of sputum smear positive SSP-PTb reports in Gambella Regional Hospital, in two consecutive years: mid 2013 to 2015. From March 2013 to February 2015, PTb suspected patients' sputum Acid Fast Bacilli test results were collected from laboratory registration book of Gambella Regional Hospital, western Ethiopia. Of the total 3064 results, the proportions of males and individuals whose age is between 16 and 25 years were 1823 (59.5%) and 1046 (34.1%), respectively. Majority of samples were coming from newly PTb suspected patients (2587, or 84.4%); and of them, SSP-PTb cases were 9.9%. The overall SSP-PTb cases decreased by 2.1% in March 2014 to February 2015 as compared to March 2013 to Feburary 2014. Meanwhile, AFB smear negative cases were significantly associated with being male [1.384 (1.064-1.801)] and being of age group 16-25 years [1.517 (1.007-2.287)]. In Gambella region, although the distribution of AFB smear results had no significant yearly variations and the overall burden of SSP cases was decreased, still a lot of work needs to be undertaken on the PTb prevention and control program.


The future of e-learning in healthcare professional education: some possible directions. Commentary.
E-learning in healthcare professional education still seems like it is a new innovation but the reality is that e-learning has been around for as long as the internet has been around. This is approximately twenty years and so it is probably appropriate to now take stock and consider what the future of e-learning in healthcare professional education might be. One likely occurrence is that there will be more formats, more interactive technology, and sometimes game-based learning. Another future of healthcare professional education will likely be in simulation. Like other forms of technology outside of medicine, the cost of e-learning in healthcare professional education will fall rapidly. E-learning will also become more adaptive in the future and so will deliver educational content based on learners' exact needs. The future of e-learning will also be mobile. Increasingly in the future e-learning will be blended with face to face education.


Involvement of CaMKIV in neurogenic effect with chronic fluoxetine treatment.
Calcium-calmodulin dependent protein kinase IV (CaMKIV) is a protein kinase that has been suggested to participate in fluoxetine (FLX)-induced phosphorylation of cyclic AMP-response element binding protein (CREB). CREB is a key transcription factor in adult neurogenesis. The present study aimed at evaluating whether CaMKIV is involved in adult hippocampal neurogenesis with FLX treatment. Effects of chronic FLX on hippocampal cell proliferation, survival and phenotypes were assessed using bromodeoxyuridine (BrdU) immunohistochemistry or BrdU/neuronal nuclei (NeuN)/S100β immunofluorescence staining in wild-type (WT) and CaMKIV knockout (KO) mice. Expression and phosphorylation of CaMKIV and CREB were assessed using RT-PCR and Western blotting. The behavioural action with FLX was assessed in the novelty suppressed feeding test (NSF), which is considered neurogenesis-dependent. CaMKIV KO mice have reduced cell proliferation, but not survival in the dentate gyrus of hippocampus with chronic treatment of FLX when compared to wild littermates. Phenotype analysis showed that most newborn cells matured into neurons. Phosphorylation of CaMKIV was up-regulated in WT mice and phosphorylation of CREB was impaired in CaMKIV KO mice after FLX treatment. The behavioural effects of FLX in NSF were similar in both types. These data suggest that CaMKIV is involved in some aspects of FLX-promoting hippocampal neurogenesis.


Use of Immunomodulators and Biologics Before, During, and After Pregnancy.
Immunomodulators and biologic medications, alone or in combination, form the core therapeutic strategy for managing moderate-to-severe inflammatory bowel disease (IBD). IBD incidence peaks during the prime reproductive years, raising concerns about the impact of disease and its treatment on fertility, maternal and fetal health during pregnancy, breastfeeding safety, and childhood development. Although IBD increases risk of pregnancy complications independent of disease activity, adverse pregnancy outcomes are more common when disease is active. To mitigate fetal risk, women should conceive while disease is quiescent. Aside from methotrexate, immunomodulators and biologics may be used during pregnancy to achieve and maintain disease control. Based on available safety data, there is no increased risk of congenital anomalies among infants exposed to these medications. Active thiopurine metabolites and most monoclonal antibodies cross the placenta and are detectable in neonates. They are detectable in breast milk in minute levels as well. The impact of this exposure on neonatal outcomes is discussed. Adjusted dosing schedules during gestation may reduce fetal drug exposure, though the maternal risks of such manipulation require careful consideration. Ongoing prospective studies will further inform risk assessment, including for newer medications such as the anti-integrin agents.


Conjugated Molecules Based Multi-Component Artificial Photosynthesis System for Producing Multi-Objective Products.
The development of artificial photosynthesis systems that mimics natural photosynthesis can help address the issue of energy scarcity by efficiently utilizing solar energy. Here, it presents liposomes-based artificial photosynthetic nanocapsules (PSNC) integrating photocatalytic, chemical catalytic, and biocatalytic systems through one-pot method. The PSNC contains 5,10,15,20-tetra(4-pyridyl) cobalt-porphyrin, tridipyridyl-ruthenium nitrate, oligo-pphenyl-ethylene-rhodium complex, and creatine kinase, efficiently generating oxygen, nicotinamide adenine dinucleotide (NADH), and adenosine triphosphate with remarkable enhancements of 231%, 30%, and 86%, compared with that of molecules mixing in aqueous solution. Additionally, the versatile PSNC enables simulation of light-independent reactions, achieving a controllable output of various target products. The regenerated NADH within PSNC further facilitates alcohol dehydrogenase, yielding methanol with a notable efficiency improvement of 37%. This work introduces a promising platform for sustainable solar energy conversion and the simultaneous synthesis of multiple valuable products in an ingenious and straightforward way.


Urea-Assisted Room Temperature Stabilized Metastable β-NiMoO4: Experimental and Theoretical Insights into its Unique Bifunctional Activity toward Oxygen Evolution and Supercapacitor.
Room-temperature stabilization of metastable β-NiMoO4 is achieved through urea-assisted hydrothermal synthesis technique. Structural and morphological studies provided significant insights for the metastable phase. Furthermore, detailed electrochemical investigations showcased its activity toward energy storage and conversion, yielding intriguing results. Comparison with the stable polymorph, α-NiMoO4, has also been borne out to support the enhanced electrochemical activities of the as-obtained β-NiMoO4. A specific capacitance of ∼4188 F g-1 (at a current density of 5 A g-1) has been observed showing its exceptional faradic capacitance. We qualitatively and extensively demonstrate through the analysis of density of states (DOS) obtained from first-principles calculations that, enhanced DOS near top of the valence band and empty 4d orbital of Mo near Fermi level make β-NiMoO4 better energy storage and conversion material compared to α-NiMoO4. Likewise, from the oxygen evolution reaction experiment, it is found that the state of art current density of 10 mA cm-2 is achieved at overpotential of 300 mV, which is much lower than that of IrO2/C. First-principles calculations also confirm a lower overpotential of 350 mV for β-NiMoO4.


From the ganglioside GQ1balpha to glycomimetic antagonists of the myelin-associated glycoprotein (MAG).
The tetrasaccharide 4, a substructure of ganglioside GQ1balpha, shows a remarkable affinity for the myelin-associated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 4, antagonists with modifications of the core disaccharide Galbeta(1-3)GalNAc, as well as the terminal alpha(2-3)- and the internal alpha(2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17.


Unprecedented Activity of Bifunctional Electrocatalyst for High Power Density Aqueous Zinc-Air Batteries.
The development of nonprecious metal catalysts with desirable bifunctional activities to supersede noble metal catalysts is of vital importance for high performance aqueous zinc-air batteries. Here, an unprecedented activity of bifunctional electrocatalyst is reported by in situ growth of nitrogen-enriched carbon nanotubes with transition metal composite. The resultant catalyst delivers surprisingly high OER (potential@10 mA cm-2 of 1.58 V) and ORR (onset potential of 0.97 V, half-wave potential of 0.86 V) performance. The overall oxygen electrode activity (overvoltage between ORR and OER) of the catalyst is as low as 0.72 V. In aqueous Zn-air battery tests, primary batteries demonstrate high maximum power density and two-electrode rechargeable batteries also exhibit good cycle performance. The unprecedented electrocatalyst opens up new avenues for developing highly active nitrogen-doped carbon nanotube-supported electrocatalysts and offers prospects for the next generation of fuel cells, metal-air batteries, and photocatalysis applications.


Naringenin ameliorates progression of endometriosis by modulating Nrf2/Keap1/HO1 axis and inducing apoptosis in rats.
Endometriosis is mainly characterized by the presence of endometrial tissue exterior to the uterus, however, the exact pathophysiology of this disease still remains uncertain. Moreover, the incidence significantly contributes to infertility among women and hence, a novel treatment for endometriosis is widely investigated. Naringenin is a plant-derived flavonoid having anti-proliferative, anti-inflammatory, and anti-angiogenic properties in chronic and metabolic diseases. The current study was planned with an objective to demonstrate the anti-endometriotic therapeutic potential of naringenin in rats and to examine its impact on various cellular aspects with a view to define the mechanism involved. The endometrial lesion volumes, weight, serum TNF-α level and the histopathologic scores were significantly reduced in the naringenin- treated group as compared to the endometriotic control group. Naringenin ameliorated the expression of prognostic markers (TAK1, PAK1, VEGF and PCNA) involved in development and progression of endometriotic cells. Naringenin caused dose-dependent loss of mitochondrial membrane potential, induced apoptosis and inhibited proliferation in these cells. Further, a significant increase in level of Nrf2 and its downstream molecules (NQO1, HO-1) was found in endometriotic lesion, with a subsequent decrease in its repressor molecule Keap-1. Naringenin significantly modulated the expression of Nrf2 and its effector molecules downstream. It also inhibited the invasion of endometrial cells by reducing the expression of MMP-2 and MMP-9 in in-vitro primary culture. We conclude that naringenin may have a therapeutic potential in the treatment of endometriosis via induction of ROS-mediated apoptosis and its anti-invasive effects.


In Situ Cs and H Exchange into Gaidonnayite and Proposed Mechanisms of Ion Diffusion.
The microporous mineral gaidonnayite Na2ZrSi3O9·2H2O was studied to better understand its ion-exchange mechanisms, specifically for Cs+ and H+ ions. In situ Raman spectroscopy, in situ X-ray diffraction (XRD), simultaneous thermogravimetric analysis and differential scanning calorimetry (TGA/DSC), and in situ X-ray fluorescence were used to determine the exchange processes involved. The Raman spectra contain strong peaks that can be attributed to the vibrational modes for the 3MR symmetric stretch at 500 cm-1, Si-O-Zr-O chain stretches at 938 cm-1, and Si-O stretching in the 1000-1100 cm-1 range. The most prominent Raman shift during ion exchange is found near the 520 cm-1 peak, which corresponds to distortions of the 3MR substructure of gaidonnayite. In all instances of this study, the 3MR exhibited the highest amount of distortion during ion exchange, and the evolution of this distortion is compared to unit-cell changes as measured from XRD data and elemental changes via XRF. The correlations between the Raman, XRD, and XRF data show rapid deformation of the 3MR during the onset of H+ ion exchange in the Na form of gaidonnayite. Even when unit-cell volume changes were small (<3 Å3) as in the cases for Cs+ into Na-gaidonnayite and Cs+ into H-gaidonnayite, significant changes in the ≈520 cm-1 peak were measured. By comparing XRD data and Raman data, and verifying the cation uptake by XRF, we were able to identify and confirm conformational changes and distortions in the crystal structure before, during, and after Cs+ and H+ exchange. Cs exchange occurred the fastest and with the greatest capacity when starting in the H-form at room temperature, and at elevated temperatures when starting in the Na-form.


Integrative Oncology Physician Consultations at a Comprehensive Cancer Center: Analysis of Demographic, Clinical and Patient Reported Outcomes.
Background: Integrative oncology (IO) is a relatively new field that seeks to bring evidence-based, non-conventional approaches into conventional oncology care in a coordinated and safe manner. Though complementary and alternative medicine (CAM) are highly utilized by cancer patients, little is known about the characteristics of patients seeking IO consultation. Methods: Patients presenting for an outpatient IO consultation completed a CAM use questionnaire, Measure Yourself Concerns and Wellbeing (MYCaW), Edmonton Symptom Assessment Scale (ESAS), Quality of Life Short Form 12 (SF-12), and post-consultation satisfaction item. Results: 2,474 new patient IO consultations were conducted from 9/2009 to 12/2013 and 2367 (96%) completed at least one measure. Most were female (69%); the most frequent cancer type was breast (29%); 38% had distant/advanced disease; 75% had used a CAM approach in prior 12 months. The most common concerns were seeking an integrative/holistic approach (34%), herbs/supplements (34%), and diet/nutrition (21%). Overall symptom burden was low, with baseline symptom scores (ESAS) highest (worst) for sleep (4.2; SD 2.8), fatigue (4.0; SD 2.8), and well-being (3.8; SD 2.6). On the SF-12, the physical health scores (35.3; SD 7.5) were significantly lower than that of a healthy population (50), but mental health scores were not (46.8; SD 10.2). Satisfaction was high (9.4; SD 1.3) with the consultation. Conclusions: Patients presenting for IO consultation tended to have early stage disease, had previously used a CAM approach, had a relatively low symptom burden, and were most interested in developing an integrative approach to their care or discussing herbs/supplement use.


MicroRNAs -the next generation therapeutic targets in human diseases.
MicroRNAs (miRNAs), an abundant class of ~22-nucleotide non-coding RNAs, regulate the expression of genes at post transcriptional level. MiRNAs are important regulators of eukaryotic gene expression and therefore implicated in a wide range of biological processes. The miRNA-related genetic alterations are possibly more implicated human diseases than currently appreciated. Genetic variants in miRNA target sites, called miRNA genes are identified to be associated with human diseases. This review discusses about the role of micro-RNA genes in various human diseases such as neurodegenerative disorders, cardio-vascular diseases, and metabolic disorders, and how they can be targeted as a new therapeutic tool in future with reference to drug discoveries/ development.


Serotonergic activity in man as a function of pain, pain mechanisms, and depression.
Lumbar cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, which are used as indicators of central nervous system serotonergic neuronal activity, were significantly higher in 67 patients with chronic pain and in 32 patients with acute pain (23.6 +/- 3.3 and 23.1 +/- 3.8, respectively) than in 30 patients (8.8 +/- 1.7) who had no pain. However, there was no correlation between levels of 5-hydroxyindoleacetic acid in patients with chronic or acute pain, nor between groups of patients with chronic pain whose pain mechanisms were of psychogenic, sympathetic, somatic, or central origin, based on their responses to differential spinal block; there was also no correlation between levels of depression, as evaluated by the Zung scale, in patients with different types of chronic pain, even though all of these patients were depressed. The elevated levels of 5-hydroxyindoleacetic acid in the depressed patients with chronic pain are not consistent with previous studies on the etiology and types of chronic pain. As recent research indicates that the perception of pain may be modulated by endogenous analgesic systems involving enkephalin and serotonin (5-HT), this study was undertaken to clarify the association between 5-HT activity and nociception. Our findings did show a link between acute noxious stimulation and central increases in serotonergic activity. However, we could not differentiate between pain mechanisms and degree of depression. Our studies did indicate that, because of both the persistence of pain complaints and the increased levels of brain 5-HT activity, the endogenous analgesic systems are not totally effective as natural inhibitors of pain. Furthermore, the increased depression and continued pain in the presence of elevated 5-HT activity in patients with chronic pain may represent a tolerance or decreased responsiveness to 5-HT.


Female sex organs malignancies incidence in Plovdiv district for the period 1986-1996.
The aim of the recent survey is to investigate the dynamics of female sex organs malignancies (carcinoma of the uterine corpus, cervical carcinoma and ovarial carcinoma) incidence and to make a structural analysis. The incidence of female sex organs malignancies increases every other year from 37.7 cases in 1986 to 58.64 cases per 100,000 women in 1996. The cervical carcinoma incidence for that period increases from 8.1 cases in 1986 to 14.65 cases per 100,000 women in 1996. For the same period endometrial carcinoma incidence increases from 16.2 cases to 24.74 cases per 100,000 and ovarial carcinoma incidence--from 13.0 cases to 19.64 cases per 100,000. Malignancy staging is an important part of the study. Clinical stage I is diagnosed only in 25.28% of the new cases, stage II--in 46.02%, stage III--in 17.75% and, stage IV--in 10.95% of the cases. The incidence of female sex organs malignancies in the examined, regions and locations shows that there are some differences between the three regions of Plovdiv district (Plovdiv, Pazardjik and Smolyan). The region of Plovdiv has a highest incidence. There are also a differences in the incidence between the citizens of the town and the villages.


Adaptive Motion Artifact Reduction Based on Empirical Wavelet Transform and Wavelet Thresholding for the Non-Contact ECG Monitoring Systems.
Electrocardiogram (ECG) signals are crucial for determining the health status of the human heart. A clean ECG signal is critical in analysis and diagnosis of heart diseases. However, ECG signals are often contaminated by motion artifact noise in the non-contact ECG monitoring systems. In this paper, an ECG motion artifact removal approach based on empirical wavelet transform (EWT) and wavelet thresholding (WT) is proposed. This method consists of five steps, namely, spectrum preprocessing, spectrum segmentation, EWT decomposition, wavelet threshold denoising, and EWT reconstruction. The proposed approach was used to process real ECG signals collected by the non-contact ECG monitoring equipment. The results of quantitative study and analysis indicate that this approach produces a better performance in terms of restorage of QRS complexes of the original ECG with reduced distortion, retaining useful information in ECG signals, and improvement of the signal to noise ratio (SNR) value of the signal. The output results of the practical ECG signal test show that motion artifact in the real recorded ECG is effectively filtered out. The proposed method is feasible for reducing motion artifacts from ECG signals, whether from simulation ECG signals or practical non-contact ECG monitoring systems.


Genetics of vascular dementia - review from the ICVD working group.
Vascular dementia is a common disorder resulting in considerable morbidity and mortality. Determining the extent to which genes play a role in disease susceptibility and their pathophysiological mechanisms could improve our understanding of vascular dementia, leading to a potential translation of this knowledge to clinical practice. In this review, we discuss what is currently known about the genetics of vascular dementia. The identification of causal genes remains limited to monogenic forms of the disease, with findings for sporadic vascular dementia being less robust. However, progress in genetic research on associated phenotypes, such as cerebral small vessel disease, Alzheimer's disease, and stroke, have the potential to inform on the genetics of vascular dementia. We conclude by providing an overview of future developments in the field and how such work could impact patients and clinicians. The genetic background of vascular dementia is well established for monogenic disorders, but remains relatively obscure for the sporadic form. More work is needed for providing robust findings that might eventually lead to clinical translation.


[Leptin and leptin receptor evaluation in atherosclerotic plaques in patients with type 2 diabetes mellitus].
Diabetes mellitus (DM) is a significant predictor of atherosclerosis, cardiovascular disease, and cardiovascular mortality. It is known that atherosclerosis occurs earlier in patients with diabetes, reducing the duration of their life. Leptin as well as other inflammatory markers can contribute to the progression of atherosclerosis in patients with DM, participate in the development of a local inflammatory reaction. Determine the cells immunophenotype of atherosclerotic plaques in patients with diabetes. We analyzed 24 patients (20 men and 4 women), who underwent aortofemoral bypass, femoral-tibial bypass or carotid endarterectomy. During the operation, a fragment of the arterial wall with an atherosclerotic plaque was obtained for further immunohistochemical studies. Five histologic plaque characteristics (CD68+, -SMA, CD34, leptin and leptin receptor) were compared. No difference in the expression of CD68 (p=0.922), -SMA (p=0.192), CD34 (p=0.858), leptin receptor (p=0.741) and leptin (p=0.610) in atherosclerotic plaques were observed between patients with and without DM. The lack of significant differences between the two groups was possibly due to the small number of observations with DM. In particular, when assessing the expression of selected markers in atherosclerotic plaques, patients with DM showed significantly more leptin receptors than patients without DM (2160.716 and 1205.88 respectively); and also significantly less CD68+ (0.39 and 0.98 respectively) and -SMA+ (6.5 and 13.5 respectively). Based on the expression of CD68, -SMA, CD34, leptin receptor and leptin, no significant differences were observed in atherosclerotic plaque between patients with and without DM. At the same time, despite the limitations of the study (a small number of patients, moderate severity of DM, elderly patients in the DM group), we found a tendency in the increased number of leptin receptors and a decreased number of -SMA+, CD68+ in DM atherosclerotic plaques. Further study needed, taking into account the limitations of this work.


Percutaneous internal ring suturing: a simple minimally invasive technique for inguinal hernia repair in children.
Laparoscopic herniorrhaphy in pediatric surgery is usually performed through three ports in the abdominal wall with intraperitoneal suturing. Our technique of percutaneous internal ring suturing (PIRS) requires only one umbilical port and needle puncture point. We describe the technique and evaluate the efficacy of percutaneous internal ring suturing for inguinal hernia repair in children. We performed percutaneous internal ring suturing on 106 children (ages 28 days-14.5 years) with 140 hernias. The procedures were performed under general endotracheal anesthesia. Pneumoperitoneum was established with an open technique. Under laparoscopic-guided vision an 18-gauge injection needle with a nonabsorbable thread inside the barrel of the needle was placed through the abdominal wall into the peritoneal cavity. By moving the injection needle, the thread passed under the peritoneum around the entrance into the hernia sac. The knot was tightened from outside and placed in the subcutaneous space. The contralateral open inguinal ring was closed in the same procedure. The average operative time was 19 minutes for unilateral and 24 minutes for bilateral hernias. Follow-up ranged between 18 and 29 months. Cosmetic results are excellent with almost invisible scars. There were 3 cases of intraoperative complication: incidental puncture of the iliac vein that required no treatment. There were 4 cases of postoperative complications: one case of ileus adhesion with bowel strangulation, and hernia recurrence in 3 boys, one of whom was reoperated with percutaneous internal ring suturing. In 5 boys, transient hydroceles were observed that disappeared spontaneously after 3 to 5 months. The percutaneous internal ring suturing method seems to be a simple and effective minimally invasive procedure with excellent cosmetic results. The rate of complications is comparable to other laparoscopic techniques of inguinal hernia repair in children. According to our experience, percutaneous internal ring suturing should be considered as a treatment alternative.


Implicit ligand theory for relative binding free energies.
Implicit ligand theory enables noncovalent binding free energies to be calculated based on an exponential average of the binding potential of mean force (BPMF)-the binding free energy between a flexible ligand and rigid receptor-over a precomputed ensemble of receptor configurations. In the original formalism, receptor configurations were drawn from or reweighted to the apo ensemble. Here we show that BPMFs averaged over a holo ensemble yield binding free energies relative to the reference ligand that specifies the ensemble. When using receptor snapshots from an alchemical simulation with a single ligand, the new statistical estimator outperforms the original.


Effect of magnesium lithospermate B on the renal and urinary kallikrein activities in rats with adenine-induced renal failure.
A study was conducted to examine the effect of magnesium lithospermate B on both the urinary and renal total and active kallikrein and prokallikrein in rats with adenine-induced renal failure. In rats given magnesium lithospermate B at a dose of 10 mg/kg body weight/day for 12 days, significant increases of urinary total and active kallikrein were associated with significant increases of urine volume and urinary total and active kallikrein were associated with significant increases of urine volume and urinary creatinine excretion. The renal total and active kallikrein levels were also significantly elevated by the treatment with magnesium lithospermate B. On day 24, the urinary excretion of total and active kallikrein and prokallikrein was significantly increased. Concomitantly, a significant increase in renal kallikrein (total, active and pro-) was found in the rats given magnesium lithospermate B. A significant relationship existed between the urinary creatinine and active kallikrein excretion. These results suggest that magnesium lithospermate B may stimulate the synthesis of kallikrein and/or conversion to active kallikrein, thus improving renal function.


Evaluation of Different N-Glycopeptide Enrichment Methods for N-Glycosylation Sites Mapping in Mouse Brain.
N-Glycosylation of proteins plays a critical role in many biological pathways. Because highly heterogeneous N-glycopeptides are present in biological sources, the enrichment procedure is a crucial step for mass spectrometry analysis. Five enrichment methods, including IP-ZIC-HILIC, hydrazide chemistry, lectin affinity, ZIC-HILIC-FA, and TiO2 affinity were evaluated and compared in the study of mapping N-glycosylation sites in mouse brain. On the basis of our results, the identified N-glycosylation sites were 1891, 1241, 891, 869, and 710 and the FDR values were 3.29, 5.62, 9.54, 9.54, and 20.02%, respectively. Therefore, IP-ZIC-HILIC enrichment method displayed the highest sensitivity and specificity. In this work, we identified a total of 3446 unique glycosylation sites conforming to the N-glycosylation consensus motif (N-X-T/S/C; X ≠ P) with (18)O labeling in 1597 N-glycoproteins. N-glycosylation site information was used to confirm or correct the transmembrane topology of the 57 novel transmembrane N-glycoproteins.


Pool and synthesis of phosphoribosylpyrophosphate in rat embryo cells infected with X14 or H-1 parvovirus.
In rat embryo cell cultures infected with X14 or H-1 parvovirus the PRPP pool and the PRPP synthetase activity have been assayed. A radiometric method, prepared by Authors, based on the conversion of [6-14C) orotate to [6-14C) UMP by the mixed enzyme orotate phosphoribosyltransferase and orotidylate decarboxylase and on the separation of UMP by ascending chromatography, has been utilized. The PRPP pool and te PRPP synthetase activity appeared nearly unmodified in the cells infected with X14 or H-1 parvovirus compared to the mock-infected cells. Therefore, the lowered pyrimidine nucleotide synthesis in infected cells, shown in previous studies, may depend, rather than on the diminished PRPP pool, on the lower PRPP utilization; in fact, some inhibition by metabolites, that may be removed by added PRPP, might occur in the infected cells.


Pathophysiology of telangiectasias of the lower legs and its therapeutic implication: A systematic review.
Objective Telangiectasias of the lower legs are intradermal dilatations of the subpapillary venous plexus, but their pathophysiology and risk factors are still largely unknown. The purpose of this review is to summarize the current knowledge on the pathophysiology and risk factors for telangiectasias. Methods A systematic review of the literature indexed in Medline completed with textbooks and European phlebology journals from the French, Swiss, and German phlebology societies was performed. Results A multitude of risk factors and several pathophysiological hypotheses, such as reflux, arterio-venous micro-shunts, parietal, and connective tissue abnormalities, are described in the literature. The different hypotheses are discussed and put in a clinical perspective, in particular their therapeutic implications for phlebologists. Conclusion In conclusion, pathophysiology and risk factors of telangiectasias are still largely unknown, and a better understanding could improve treatment results and reduce recurrence.


Incidence and Patient Outcomes in Renal Replacement Therapy After Orthotopic Liver Transplant.
Our objective was to evaluate the incidence of renal replacement therapy after orthotopic liver transplant and to evaluate and analyze patient outcomes. We performed a retrospective analysis of 177 consecutive patients at a tertiary care unit who underwent orthotopic liver transplant between January 2010 and June 2016. Patients who were admitted to the intensive care unit after orthotopic liver transplant and who required renal replacement therapy were included. A total of 177 (79 adult, 98 pediatric) orthotopic liver transplants were performed during the study period. Of these, 35 patients (19%) required renal replacement therapy during the early posttransplantation period. After excluding 5 patients with previous chronic renal failure, 30 patients (17%; 20 adult [25% ], 10 pediatric [10% ]) with acute kidney injury required renal replacement therapy. The mean patient age was 31.1 ± 20.0 years, with a mean Model for End-stage Liver Disease score of 16.7 ± 12.3. Of the patients with acute kidney injury who underwent renal replacement therapy, in-hospital mortality was 23.3% (7 of 30 patients), and 40% remained on dialysis. No significant difference was seen in mortality between early versus delayed initiation of renal replacement therapy in patients with stage 3 acute kidney injury (P = .17). Of liver transplant recipients who present with acute kidney injury, 19% require renal replacement therapy, and in-hospital mortality is 20% in the early postoperative period.


The association between experiences of religious discrimination, social-emotional and sleep outcomes among youth in Australia.
Religious-based hate crimes are on the rise worldwide. However, the relationship of religious discrimination on health and well-being, especially earlier on the lifecourse, is largely understudied. This study examines the prevalence of religious discrimination and the relationship it has on social-emotional adjustment and sleep outcomes among a diverse sample of students in Australia. Data came from Speak Out Against Racism, a population-representative cross-sectional study of 4664 public school students in grades 5-9 in Australia in 2017. An adaption of the Adolescent Discrimination Distress Index (ADDI), was used to derive four measures of religious discrimination (peer, school, societal and the sum of those as a "total" score). The Strengths and Difficulties Questionnaire measured the total difficulties, conduct, emotional, and prosocial behavior subscales. Measures of sleep outcomes included duration, latency, and disruption. 27 % (95 % CI 22.82, 31.12) of students reported experiences of direct total religious discrimination with higher levels being reported by students identifying as a religious minority. There was strong evidence that experiences of religious discrimination (across all four sources) was related to all measures of socioemotional adjustment and sleep outcomes. Religious discrimination is an understudied form of social disadvantage that has implications for adolescents' development, health and well-being. Conclusion: More programs, particularly in the school-context, address religious-based discrimination may reduce inequities in health.


Update of Sepsis in the Intensive Care Unit.
Sepsis, the most common cause of admission to an intensive care unit (ICU), has had an increased incidence and prevalence over the last years with a simultaneous decrease in its short-term mortality. Sepsis survivors are more frequently discharged from hospital and often experience long-term outcomes such as late mortality, immune dysfunction, secondary infections, impaired quality of life, and unplanned readmissions. Early recognition and management of sepsis have challenged emergency care and critical care physicians and nurses. New sepsis definitions were produced and the Surviving Sepsis Campaign (SSC) 2016 was updated recently. Although hospital readmissions after sepsis are common, associated risk factors and how to manage patients who survive an episode of sepsis still need clarification. The immune dysfunction caused by sepsis/septic shock is complex, persistent, affects inflammatory and anti-inflammatory systems, and might be associated with long-term outcomes of sepsis. Several randomized controlled trials (RCT) that analyzed new (and old) interventions in sepsis/septic shock are discussed in this review in parallel with the SSC 2016 recommendations and other guidelines when relevant. RCTs addressing incidence, treatment, and prevention of important sepsis-associated organ dysfunction such as the acute respiratory distress syndrome, acute kidney injury, and brain dysfunction are highlighted. Finally, we briefly discuss the need for novel targets, predictive biomarkers, and new designs of RCTs in sepsis.


Use of monoclonal antibodies in cancer immunotherapy: types and mechanisms of action.
Immunotherapy is one of the most innovative treatments in the current field of oncology and consists of stimulating the immune system to eliminate tumoral cells. Monoclonal antibodies (mAbs) are glycoproteins secreted by B-cells capable of recognizing and neutralizing foreign organisms or antigens. Structurally, they are composed of two heavy and two light chains. The generation of therapeutic mAbs is one of the most developed and fastest-growing areas of the biotechnological and pharmaceutical industries and is an important adjunct to cancer therapy. Several antibodies have been approved for human administration and can be mouse-derived, chimeric, humanized, or fully human. mAbs main mechanism of action includes the lysis of the tumoral cells through inducing apoptosis, phagocytosis, complement activation, or signaling inhibition.


A Novel Colorimetric PCR-Based Biosensor for Detection and Quantification of Hepatitis B Virus.
Hepatitis B virus (HBV) can cause viral infection that attacks the liver and it is a major global health problem that puts people at a high risk of death from cirrhosis of the liver and liver cancer. HBV has infected one-third of the worldwide population, and 350 million people suffer from chronic HBV infection. For these reasons, development of an accurate, sensitive, and expedient detection method for diagnosing, monitoring, and assessing therapeutic response of HBV is very necessary and urgent for public health and disease control. Here we report a new strategy for detection of viral load quantitation of HBV based on colorimetric polymerase chain reaction (PCR) with DNAzyme-containing probe. The special DNAzyme adopting a G-quadruplex structure exhibited peroxidase-like activity in the presence of hemin to report colorimetric signal. This method has shown a broad range of linearity and high sensitivity. This study builds an important foundation to achieve the specific and accurate detection level of HBV DNA with a low-cost and effective method in helping diagnosing, preventing and protecting human health form HBV all over the world, and especially in developing countries.


Valsartan and the renin-angiotensin-aldosterone system: blood pressure control and beyond.
Patients treated for hypertension are still at significantly elevated risk for cardiovascular complications when compared with normotensive patients, even when on antihypertensive therapy. In all fairness though, a majority of these patients have uncontrolled blood pressure. Blocking the renin-angiotensin-aldosterone system (RAAS) prevents or reverses cardiac remodelling and improves prognosis in cardiovascular disease beyond the effects on blood pressure (BP). Valsartan acts by selectively blocking the AT1-receptor and shows similar efficacy and improved tolerability compared with ACE inhibitors. This drug may provide additional benefits in controlling the cardiovascular complications of hypertension. Results of large clinical trials with valsartan, such as VALUE, Val-HEFT, VALIANT and ABCD-2V, are eagerly awaited.


Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment.
Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the cellular antioxidant response, allowing adaptation and survival under conditions of oxidative, electrophilic and inflammatory stress, and has a role in metabolism, inflammation and immunity. Activation of Nrf2 provides broad and long-lasting cytoprotection, and is often hijacked by cancer cells, allowing their survival under unfavorable conditions. Moreover, Nrf2 activation in established human tumors is associated with resistance to chemo-, radio-, and immunotherapies. In addition to cancer cells, Nrf2 activation can also occur in tumor-associated macrophages (TAMs) and facilitate an anti-inflammatory, immunosuppressive tumor immune microenvironment (TIME). Several cancer cell-derived metabolites, such as itaconate, L-kynurenine, lactic acid and hyaluronic acid, play an important role in modulating the TIME and tumor-TAMs crosstalk, and have been shown to activate Nrf2. The effects of Nrf2 in TIME are context-depended, and involve multiple mechanisms, including suppression of pro-inflammatory cytokines, increased expression of programmed cell death ligand 1 (PD-L1), macrophage colony-stimulating factor (M-CSF) and kynureninase, accelerated catabolism of cytotoxic labile heme, and facilitating the metabolic adaptation of TAMs. This understanding presents both challenges and opportunities for strategic targeting of Nrf2 in cancer.


Reproductive ability of a cloned male detector dog and behavioral traits of its offspring.
In 2007, seven detector dogs were produced by somatic cell nuclear transfer using one nuclear donor dog, then trained and certified as excellent detector dogs, similar to their donor. In 2011, we crossed a cloned male and normal female by natural breeding and produced ten offspring. In this study, we investigated the puppies' temperaments, which we later compared with those of the cloned parent male. The results show that the cloned male had normal reproductive abilities and produced healthy offspring. All puppies completed narcotic detector dog training with a success rate for selection of 60%. Although the litter of cloned males was small in this study, a cloned male dog bred by natural mating produced puppies that later successfully completed the training course for drug detection. In conclusion, cloning an elite dog with superior genetic factors and breeding of the cloned dog was found to be a useful method to efficiently procure detector dogs.


A comparison of the treatment results of dpen reduction internal fixation and intramedullary nailing in adult forearm diaphyseal fractures.
We compared the union and functional results of intramedullary nailing and open reduction internal fixation treatment applied to adults with a forearm diaphysis fracture (fracture of the radius and/or ulna). We retrospectively examined 90 patients with completed skeletal maturation who were surgically treated for a forearm diaphyseal fracture. Patients with a Monteggia Galeazzi and ipsilateral upper extremity fracture and those with an open epiphyseal line, Type 3 open fracture, pathological fracture, or brain trauma were excluded from the study. Open reduction and internal fixation (ORIF) was applied to 42 patients (plate group), and intramedullary nailing was performed in 48 patients (intramedullary nailing group). Both treatment groups were compared with respect to time to union, joint range of motion, operating time, grip strength, Grace-Eversman criteria, and complications. The mean operating time was 63.29 (range, 40-100) min in the plate group and 46.02 (range, 17-85) min in the intramedullary nailing group. The mean time to union was 13.19 (range, 10-20) and 10.85 (range, 8-20) weeks, respectively. While a statistically significant difference was determined between groups with respect to operating time and time to union, no difference was determined in the Grace-Eversman evaluation criteria, forearm supination, pronation degrees, and grip strength. The results of this study showed a significant difference in the intramedullary nailing treatment with respect to time to union, operating time, and amount of bleeding compared with the ORIF treatment. However, no difference was determined in the functional evaluation criteria. Thus, both treatment methods are acceptable in the treatment of forearm diaphyseal fractures in adults with skeletal maturation.


Effects of antiretroviral drugs on human immunodeficiency virus type 1-induced CD4(+) T-cell death.
Apoptosis of peripheral blood T cells plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 (HIV-1) primes CD4(+) T cells from healthy donors for apoptosis, which occurs after CD95 ligation or CD3-T-cell receptor (TCR) stimulation. CD95-mediated death did not depend on CD4 T-cell infection, since it occurred in the presence of the reverse transcriptase inhibitor didanosine (ddI). In contrast, apoptosis induced by productive infection (CD3-TCR stimulation) is prevented by both CD95 decoy receptor and ddI. Our data suggest that HIV-1 triggers at least two distinct death pathways: a CD95-dependent pathway that does not require viral replication and a viral replication-mediated cell death independent of the CD95 pathway. Further experiments indicated that saquinavir, a protease inhibitor, at a 0.2 microM concentration, decreased HIV-mediated CD95 expression and thus cell death, which is independent of its role in inhibiting viral replication. However, treatment of peripheral blood mononuclear cells from healthy donors with a higher concentration (10 microM) of an HIV protease inhibitor, saquinavir or indinavir, induced both a loss in mitochondrial membrane potential (DeltaPsim) and cell death. Thus, protease inhibitors have the potential for both beneficial and detrimental effects on CD4(+) T cells independent of their antiretroviral effects.