Visual salience improves spatial working memory via enhanced parieto-temporal functional connectivity.
In everyday life, the brain is bombarded with a multitude of concurrent and competing stimuli. Only some of these enter consciousness and memory. Attention selects relevant signals for in-depth processing depending on current goals, but also on the intrinsic properties of stimuli. We combined behavior, computational modeling, and functional imaging to investigate mechanisms supporting access to memory based on intrinsic sensory properties. During fMRI scanning, human subjects were presented with pictures of naturalistic scenes that entailed high levels of competition between possible target objects. Following a retention interval of 8 s, participants judged the location (same/different) of a target object extracted from the initial scene. We found that memory performance at retrieval increased with increasing object salience at encoding, indicating a "prior entry" for salient information. fMRI analyses revealed encoding-related activation in the posterior parietal cortex, selectively for salient objects that were later remembered. Moreover, parietal cortex showed increased functional coupling with the medial-temporal lobe, for remembered objects only. These findings reveal a parietotemporal circuit that integrates available sensory cues (based on attention-grabbing saliency signals) and current memory requirements (storing objects' locations) to encode object-related spatial information in working memory.


Comparison of vision through surface modulated and spatial light modulated multifocal optics.
Spatial-light-modulators (SLM) are increasingly used as active elements in adaptive optics (AO) systems to simulate optical corrections, in particular multifocal presbyopic corrections. In this study, we compared vision with lathe-manufactured multi-zone (2-4) multifocal, angularly and radially, segmented surfaces and through the same corrections simulated with a SLM in a custom-developed two-active-element AO visual simulator. We found that perceived visual quality measured through real manufactured surfaces and SLM-simulated phase maps corresponded highly. Optical simulations predicted differences in perceived visual quality across different designs at Far distance, but showed some discrepancies at intermediate and near.


Postjunctional selectivity of alpha-blockade with prazosin, trimazosin, and UK-33,274 in man.
The effects of 3 quinazoline alpha-adrenoreceptor antagonists, prazosin, trimazosin, and UK-33,274, on lying blood pressure (BP), BP response to 60 degrees tilt, pressor response to noradrenaline, phenylephrine, and exercise (isometric and dynamic) were measured in a double-blind study in 6 volunteers. There was no difference between the effects of prazosin 2 mg, trimazosin 200 mg, and UK-33,274 4 mg on lying and tilted BP or on BP response to exercise. All three drugs competitively antagonised the systolic and diastolic pressor effect of phenylephrine and the systolic pressor effect of noradrenaline. Prazosin and UK 33,274 completely suppressed the diastolic pressor effect of noradrenaline and produced an increase rather than a decrease in heart rate (HR). Trimazosin produced a parallel shift in noradrenaline dose response curves for diastolic pressure ahd HR. Prazosin and UK-33,274, but not trimazosin, therefore, produced effects unlike those previously described with alpha-blockers, e.g., phentolamine. The difference between antagonism of the systolic and diastolic effects suggests that the resistance component of the noradrenaline pressor effect, mediated principally via alpha 1-stimulation, is more effectively blocked than the cardiac component, which depends on venous return and alpha 2-mediated venoconstriction. Prazosin and UK-33,274 are clearly alpha 1-selective. Trimazosin is less selective.


Resistin polymorphisms are associated with rheumatoid arthritis susceptibility in Chinese Han subjects.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. To date, the specific mechanisms that drive RA disease remain unknown and provide the impetus for genetic investigations into the development of RA. Researchers hope to identify gene polymorphisms that could serve as treatment targets in patients with RA. We have previously suggested that the gene encoding the pro-inflammatory adipokine resistin (RETN) may correlate with RA development. In this report, we sought to determine whether selected RETN single nucleotide polymorphisms (SNPs) are associated with RA susceptibility and clinicopathological characteristics. Four RETN SNPs (rs3745367, rs7408174, rs1862513, and rs3219175) were assessed using TaqMan genotyping in Chinese Han patients with RA and healthy controls. We found that carriers with the C allele of the RETN SNP rs7408174 as well as those with the AG allele or who had at least one A allele of the SNP rs3219175 are at greater risk of developing RA disease compared with wild-type carriers. Moreover, RA patients with the AG allele of the RETN SNP rs3219175 had higher serum C-reactive protein expression compared with controls, and these patients had a high likelihood of being on tumor necrosis factor (TNF) inhibitor therapy. This study is the first to discuss risk factors associated with RETN SNPs in RA progression in a Chinese Han population.


Organochlorine pesticides in the Hawaii Kai Marina, 1970-74.
Sediments, water, and oysters from the receiving waters of the Hahaione Valley, a suburban development in south-easter Oahu, Hawaii, were analyzed for organochlorine pesticidal compounds. The insecticides dieldrin, alpha- and gamma- chlordane, and p,p'-DDT were found in the study site environment. Levels were in the low parts per billion range for oysters and sediments and in the low parts per trillion range for water. During the past several years dieldrin residues in the marina study site have increased, even though the only activity known to influence pesticide levels in the valley is the chronic treatment for subterranean and dry wood termites. If present trends continue, dieldrin may pose a threat to biota of the aquatic environment. Findings have shown that residue levels of dieldrin and p,p'-DDT in the sediments are within the LD50 (median lethal dose) range for estuarine fish and thus may have a deleterious effect on bottom-feeding organisms. According to present standards of the Food and Agriculture Organization/World Health Organization, pesticide residue levels within the study site do not appear to constitute a health hazard to humans.


Aldehyde Dehydrogenase-2 Attenuates Myocardial Remodeling and Contractile Dysfunction Induced by a High-Fat Diet.
Consumption of a high-fat (HF) diet exacerbates metabolic cardiomyopathy through lipotoxic mechanisms. In this study, we explored the role of aldehyde dehydrogenase-2 (ALDH2) in myocardial damage induced by a HF diet. Wild-type C57 BL/6J mice were fed a HF diet or control diet for 16 weeks. ALDH2 overexpression was achieved by injecting a lentiviral ALDH2 expression vector into the left ventricle. Consumption of a HF diet induced metabolic syndrome and myocardial remodeling, and these deleterious effects were attenuated by ALDH2 overexpression. In addition, ALDH2 overexpression attenuated the cellular apoptosis and insulin resistance associated with a HF diet. Mechanistically, ALDH2 overexpression inhibited the expression of c-Jun N-terminal kinase (JNK)-1, activated protein 1 (AP-1), insulin receptor substrate 1 (IRS-1), 4- hydroxynonenal, caspase 3, transforming growth factor β1, and collagen I and III, and enhanced Akt phosphorylation. ALDH2 may effectively attenuate myocardial remodeling and contractile defects induced by a HF diet through the regulation of the JNK/AP-1 and IRS-1/Akt signaling pathways. Our study demonstrates that ALDH2 plays an essential role in protecting cardiac function from lipotoxic cardiomyopathy.


Spontaneous rupture of utero-ovarian vessels in pregnancy.
Spontaneous rupture of utero-ovarian vessels in pregnancy is rare and usually involves utero-ovarian veins. Presenting symptoms include acute-onset abdominal pain and maternal hypovolemic shock secondary to haemoperitoneum. Although this condition had been documented over a century ago, an accurate diagnosis is rarely reached prior to laparotomy due to a multitude of other surgical and obstetrical presentations that may pose a similar clinical picture. In such an event an emergency exploratory laparotomy followed by caesarean section with ligation of the uterine vessels can help in preventing a maternal mortality.


Peripheral effects of fenfluramine.
1 The peripheral cardiovascular effects of the centrally acting anorexigenic agent, fenfluramine hydrochloride, have been investigated in the rat. 2 After intravenous administration of fenfluramine, an immediate hypotensive response, followed by a reflex rise in blood pressure was recorded. This was followed by a prolonged fall in blood pressure which frequently failed to return to pre-drug levels. 3 The antagonists, propranolol and atropine, failed to inhibit this hypotensive effect of fenfluramine. 4 The effects of 5 mg/kg fenfluramine for 1h on the blood pressure responses to the sympathomimetic amines, tyramine, methoxamine and metaraminol were studied. 5 The responses to the indirectly acting tyramine were reduced by 50% following fenfluramine, while those to the directly acting methoxamine remained unaffected by the drug. Responses to metaraminol, an amine with both direct and indirect actions, were also unaffected to a significant degree by fenfluramine. 6 Studies on rat isolated vas deferens again showed that responses to tyramine are greatly reduced following fenfluramine. 7 In addition fenfluramine itself produced spontaneous contractions of the vas deferens. These contractions were blocked by the alpha-adrenoceptor blocking agents phentolamine and thymoxamine. 8 It is suggested that fenfluramine exerts an effect at the adrenergic nerve terminal, either by displacing noradrenaline stores or by inhibition of the amine uptake process.


Curcumin Supplementation Alleviates Polymyxin E-Induced Nephrotoxicity.
The last-line agent for gram-negative bacteria that have developed resistance towards commonly used antibiotics is polymyxin E (PolyE). The renal toxicity attributed to this agent limits its use, proper dosing, and eventually its clinical efficacy. Although the exact mechanism of PolyE-induced nephrotoxicity is not obvious, some investigations suggest the role of oxidative stress and its associated events in this complication. Curcumin (CUR) is a potent antioxidant molecule. The aim of the current investigation was the evaluation of the potential nephroprotective properties of CUR in PolyE-treated mice. Mice were randomly allocated into five groups (n = 8 per group). PolyE (15 mg/kg/day, i.v, for 7 days) alone or in combination with CUR (10, 100 and 200 mg/kg, i.p) were administered to mice. Renal injury biomarkers, in addition to markers of oxidative stress and kidney histopathological alterations, were evaluated. Plasma creatinine (Cr) and blood urine nitrogen (BUN) significantly raised in PolyE group. Oxidative stress biomarkers consisting of reactive oxygen species (ROS) and lipid peroxidation (LPO) also increased, and concomitantly GSH and antioxidant capacity of renal cells significantly decreased following the use of PolyE. Interstitial nephritis, tissue necrosis, and glomerular atrophy were all induced by the use of PolyE in the mice kidney. CUR (10, 100, and 200 mg/kg, i.p) treatment alleviated PolyE-induced oxidative stress and histopathological alterations in the kidney tissue significantly. According to the results of this study, CUR has a protective role against renal toxicity induced by PolyE. Hence, more research is necessary until this compound could be clinically applicable to alleviate PolyE-induced renal injury.


Funding for U.S. biomedical research: the case for the scientist-advocate.
The U.S. biomedical research community finds itself at a particularly consequential moment. Since the end of the Fiscal Year (FY) 1998-2003 NIH budget doubling period, brought to fruition with bipartisan leadership, the Federal investment in biomedical research has been declining. The NIH budget has actually decreased in constant dollars since FY 2004. Across-the-board cuts included in the Budget Control Act of 2011 would result in a loss of $2.4 billion and roughly 2,300 research project grants in FY 2013 alone, unless Congress acts to intervene before January 2013. Many of the beneficiaries of NIH support view advocacy for research funding as "someone else's job". The case to reverse this mindset must be made. Members of Congress and their staffers are open to consideration of the case for sustaining Federal investments in science, even during these difficult budget times. However, the advocacy effort must be broad-based and repeatedly presented to effect change. The figures on economic return from spending on biomedical research are compelling, but they do not tell the entire story. The results of biomedical research improve and save lives every single day, a fact that should not be lost on our elected leaders.


Exploiting new potential targets for anti-hepatitis B virus drugs.
Based on the recent studies of HBV strains with different replication efficiency, several new potential targets for anti-HBV replication have been presented. These include the viral and cellular regulatory factors associated with HBV replication and the process for encapsidation of viral genome and budding into endoplasmic reticulum (ER). A putative regulatory domain has been reported at the carboxyl-end of reverse transcriptase (RT) and when serine is substituted for proline at residue 652 of RT, replication efficiency of HBV is decreased. Substitution of proline for threonine at the 2798 nucleotide of the terminal protein (TP) gene, renders the mutant completely replication deficient. Expression of TP blocks the interferon (IFN) pathway and inhibits the responsive state of cells to interferons ( IFN) alpha and gamma. Interference of HBV capsid assembly drastically affects the encapsidation of viral genome, a crucial process for reverse transcription and viral DNA synthesis. Small molecules (bis-ANS) have been reported to act as a "wedge" to misdirect the polymerization of capsid, resulting in inhibition of virus replication. Another new group of compounds (HAP) has been shown to inhibit virus replication and also inhibit the assembly of viral capsid (core particle). Finally the capsids containing HBV genome are enveloped by budding into endoplasmic reticulum and release from virus infected cells, and this morphogenesis and secretion of HBV is dependent on glucosidases in the ER of host cells. Competitive inhibition of these glucosidases has been suggested as strategy against HBV replication.


The influence of rapamycin on the early cardioprotective effect of hypoxic preconditioning on cardiomyocytes.
The purpose of this study was to examine the effects of rapamycin on the cardioprotective effect of hypoxic preconditioning (HPC) and on the mammalian target of rapamycin (mTOR)-mediated hypoxia-inducible factor 1 (HIF-1) signaling pathway. Primary cardiomyocytes were isolated from rat pups and underwent rapamycin and/or HPC, followed by hypoxia/re-oxygenation (H/R) injury. Cell viability and cell injury were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, and qRT-PCR was used to measure HIF-1α and mTOR mRNA expression. A Langendorff heart perfusion model was conducted to observe the effect of rapamycin. Rapamycin treatment nearly abolished the cardioprotective effect of HPC in cardiomyocytes, reduced cell viability (p = 0.007) and increased cell damage (p = 0.032). HIF-1α and mTOR mRNA expression increased in cardiomyocytes undergoing I/R injury within 2 h after HPC. After rapamycin treatment, mTOR mRNA expression and HPC-induced HIF-1α mRNA expression were both reduced (p < 0.001). A Langendorff heart perfusion model in rat hearts showed that rapamycin greatly attenuated the cardioprotective effect of HPC in terms of heart rate, LVDP, and dp/dtmax (all, p < 0.029). Rapamycin, through inhibition of mTOR, reduces the elevated HIF-1α expression at an early stage of HPC, and attenuates the early cardioprotective effect of HPC.


Lysosomal enzyme release from human monocytes by particulate activators is mediated by beta-glucan inhibitable receptors.
Human peripheral blood monocytes ingest particulate activators and generate leukotrienes via a trypsin-sensitive, beta-glucan-inhibitable receptor. The incubation of monolayers of monocytes with from 4 X 10(5) to 2 X 10(8) zymosan or glucan particles resulted in a dose-dependent release of up to 9% +/- 1.9 and 17.8% +/- 5.3 (mean +/- SD, n = 3) of the lysosomal enzyme, N-acetylglucosaminidase, into the culture medium. Lysosomal enzyme release occurred throughout the 2-hr period studied, with the greatest rate of N-acetyl-glucosaminidase release occurring during the first hour; the presence of 5 micrograms/ml of cytochalasin B accelerated this process when zymosan was the agonist. The preincubation of monocytes with from 0.5 to 500 micrograms/ml of soluble yeast beta-glucan inhibited N-acetylglucosaminidase release by 4 X 10(7) zymosan and glucan particles in a dose-dependent manner, with 50% inhibition occurring with 50 micrograms/ml of soluble yeast beta-glucan (mean +/- SD, n = 3). Preincubation with as much as 5 mg/ml of yeast mannan had no inhibitory effect on N-acetylglucosaminidase release. The pretreatment for 30 min of monolayers of monocytes with 50 micrograms/ml of affinity-purified trypsin, which selectively inactivates the monocyte-phagocytic response to particulate activators, also fully inhibited lysosomal enzyme release induced by zymosan and glucan particles. The inhibitory effects of a soluble ligand, yeast beta-glucan, and of trypsin pretreatment on lysosomal enzyme release correspond to the inhibitory effect of these agents on monocyte phagocytosis of zymosan and glucan particles and thus indicates ligand specificity for the beta-glucan receptor in the release of stored intracellular mediators.


Long-term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO-3 study.
Tenapanor, a first-in-class, minimally systemic inhibitor of intestinal sodium/hydrogen exchanger isoform 3 (NHE3), is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults based on two randomized, placebo-controlled, phase III studies (T3MPO-1 [NCT02621892], T3MPO-2 [NCT02686138]). The open-label T3MPO-3 extension study (NCT02727751) enrolled patients who completed these studies to investigate long-term safety and tolerability of tenapanor. Patients who completed T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) were eligible for enrollment in T3MPO-3. Patients in T3MPO-3 received open-label tenapanor 50 mg twice a day for up to an additional 39 (T3MPO-1) or 26 (T3MPO-2) weeks. Treatment-emergent adverse events (TEAEs) were evaluated in the entire T3MPO-3 safety population and in patients who received a total of ≥52 weeks of tenapanor. A total of 312 patients were enrolled in T3MPO-3; 90 received ≥52 weeks of tenapanor. TEAEs were reported in 117 (37.5%) patients in the safety population and in 52 (57.8%) patients who received ≥52 weeks of tenapanor. Diarrhea was the most common TEAE, occurring in 10.6% of the safety population and in 11.1% of patients who received ≥52 weeks of tenapanor. Most cases were mild or moderate in severity, with only two severe cases reported in the safety population. No deaths occurred during the T3MPO-3 study. Tenapanor was tolerable over ≥52 weeks of treatment and showed similar safety to that seen in shorter studies. Combined results of the T3MPO studies indicate that tenapanor is a valuable new treatment option for patients with IBS-C.


Reactivity of Zinc Thiolate Bonds: Oxidative Organopolysulfide Formation and S3 Insertion.
Zinc thiolate bonds are intriguing targets of study because of their redox noninnocence and prevalence in bioinorganic sites. A five-coordinate zinc dithiolate complex [Et4N]2[LZn] (H4L = N,N'-di(2-sulfhydrylphenyl)-pyridine-2,6-dicarboxamide) was synthesized to study the oxidative reactivity of zinc thiolate bonds. Multiple chemically reversible reactions of the zinc thiolate bonds were identified. Oxidation of [Et4N]2[LZn] with iodine resulted in structural rearrangement to a bimetallic disulfide-bridged complex. In contrast, the addition of elemental sulfur to [Et4N]2[LZn] resulted in the insertion of a neutral S3 fragment into the Zn-thiolate bond to selectively form an unusual monometallic tetrasulfanido complex. When oxidized, this tetrasulfanido compound rearranged to form a bimetallic trisulfide-bridged complex. The observed diversity of zinc thiolate reactivity, particularly with sulfur, is likely important in biological contexts.


Alexia without agraphia.
This typical case of alexia without agraphia, caused by an astrocytoma, is the first recorded case in the literature of alexia without agraphia with a right homonymous hemianopia caused by a tumor. This case differs from previously reported cases of the syndrome by its fluctuating clinical course and its slow progression. All but one of previously reported cases had been of vascular or surgical etiology. This course and the associated radiographic findings should differentiate the neoplastic from the vascular etiology of this most fascinating syndrome.


Methylation dynamics during folliculogenesis and early embryo development in sheep.
Genome-wide DNA methylation reprogramming occurs during mammalian gametogenesis and early embryogenesis. Post-fertilization demethylation of paternal and maternal genomes is considered to occur by an active and passive mechanism respectively, in most mammals but sheep; in this species no loss of methylation was observed in either pronucleus. Post-fertilization reprogramming relies on methylating and demethylating enzymes and co-factors that are stored during oocyte growth, concurrently with the re-methylation of the oocyte itself. The crucial remodelling of the oocyte epigenetic baggage often overlaps with potential interfering events such as exposure to assisted reproduction technologies or environmental changes. Here, we report a temporal analysis of methylation dynamics during folliculogenesis and early embryo development in sheep. We characterized global DNA methylation and hydroxymethylation by immunofluorescence and relatively quantified the expression of the enzymes and co-factors mainly responsible for their remodelling (DNA methyltransferases (DNMTs), ten-eleven translocation (TET) proteins and methyl-CpG-binding domain (MBD) proteins). Our results illustrate for the first time the patterns of hydroxymethylation during oocyte growth. We observed different patterns of methylation and hydroxymethylation between the two parental pronuclei, suggesting that male pronucleus undergoes active demethylation also in sheep. Finally, we describe gene-specific accumulation dynamics for methylating and demethylating enzymes during oocyte growth and observe patterns of expression associated with developmental competence in a differential model of oocyte potential. Our work contributes to the understanding of the methylation dynamics during folliculogenesis and early embryo development and improves the overall picture of early rearrangements that will originate the embryo epigenome.


S1 and KH domains of polynucleotide phosphorylase determine the efficiency of RNA binding and autoregulation.
To better understand the roles of the KH and S1 domains in RNA binding and polynucleotide phosphorylase (PNPase) autoregulation, we have identified and investigated key residues in these domains. A convenient pnp::lacZ fusion reporter strain was used to assess autoregulation by mutant PNPase proteins lacking the KH and/or S1 domains or containing point mutations in those domains. Mutant enzymes were purified and studied by using in vitro band shift and phosphorolysis assays to gauge binding and enzymatic activity. We show that reductions in substrate affinity accompany impairment of PNPase autoregulation. A remarkably strong correlation was observed between β-galactosidase levels reflecting autoregulation and apparent KD values for the binding of a model RNA substrate. These data show that both the KH and S1 domains of PNPase play critical roles in substrate binding and autoregulation. The findings are discussed in the context of the structure, binding sites, and function of PNPase.


Efficient Z-scheme photocatalyst from simultaneous decoration of In2S3 nanosheets and WO3 nanorods on graphene sheets.
Inspired by natural photosynthesis, the Z-scheme photocatalyst is a promising approach to extend the absorption spectra of photocatalysts and reduce the recombination of photo-generated electrons and holes. However, the fabrication of well-structured efficient multi-component Z-scheme photocatalysts is still a big challenge. We report here a facile one-pot method to synthesize graphene-based Z-scheme photocatalysts. The one-pot method guarantees good distribution of well-structured individual components on thin-layered rGO sheets with excellent connections. With inactive WO3 nanorods and inactive β-In2S3 nanosheets attached to the surface of the rGO sheets, the synthesized In2S3/WO3/rGO tertiary nanocomposite shows excellent visible-light catalytic activity for hydrogen production at 1524 μmol g(-1) h(-1), demonstrating unambiguously the Z-scheme catalytic mechanism. To prevent cross-reactions and interferences, our strategy was to choose no more than one ionic precipitation reaction for the one-pot process, as unwanted cross-reactions could become inevitable if many cations and anions were present. This fabrication strategy should be applicable generally to synthesize other multiple-component nanocomposites, as demonstrated also by the preliminary results of the successful synthesis of the BiVO4/WO3/rGO nanocomposite (one ionic precipitation reaction and one hydrolysis reaction) and WO3/TiO2/rGO nanocomposite (two hydrolysis reactions).


[PI3K/Akt signaling pathway mediates the protective effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats].
To investigate the role of PI3K/Akt signaling pathway in mediating the protective effect of endomorphin-1 against myocardial ischemia-reperfusion (IR) injury. Fifty SD male rats were randomly divided into sham operation group, myocardial IR group, endomorphin-1 post-treatment group (EM50 group), endomorphin-1+wortmannin (a PI3K/Akt signaling pathway inhibitor) treatment group (EM50+Wort group), and wortmannin treatment group (Wort group). Rat models of myocardial IR injury were established by ligation of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. The heart rate and mean arterial pressure were monitored during the experiment. Plasma levels of LDH, CK-MB, cTnI, IL-6, TNF-α, SOD and MDA were measured after reperfusion. The mRNA expression of Bax and Bcl-2 was detected using RT-PCR, and the expression of apoptosis-related protein cleaved caspase-3, phosphorylated Akt protein and total Akt protein in myocardial tissue was detected using Western blotting. Myocardial IR injury significantly decreased heart rate and blood pressure of the rats in comparison with the sham operation (P < 0.05). Compared with those in the IR group, the rats in EM50 group showed significantly increased heart rate and blood pressure (P < 0.05) with decreased plasma LDH, CK-MB, cTnI, IL-6, TNF-α and MDA levels (P < 0.05), increased SOD activity (P < 0.05), increased expression of p-Akt protein and Bcl-2 mRNA (P < 0.05), and decreased expression of Bax mRNA and cleaved caspase-3 protein (P < 0.05). In EM50+Wort group, the heart rate and blood pressure were significantly lowered (P < 0.05), plasma LDH, CK-MB, cTnI, IL-6, TNF-α and MDA levels increased (P < 0.05), SOD activity decreased (P < 0.05), the expression of p-Akt protein and Bcl-2 mRNA was reduced (P < 0.05), and the expression of Bax mRNA and cleaved caspase-3 protein increased (P < 0.05) as compared with those in EM50 group. EM-1 postconditioning can regulate cardiac myocyte apoptosis and reduce myocardial IR injury in rats. The PI3K/Akt signaling pathway may play a role in mediating the myocardial protective effects of EM-1 postconditioning.


THE EVOLUTION OF DISTYLY: POLLEN TRANSFER IN ARTIFICIAL FLOWERS.
A recent model by Lloyd and Webb derives conditions necessary for the evolution of distyly based on pollen-transfer probabilities between ancestral morphs and invading mutants. We used bumblebees visiting artificial flowers to measure the parameters of the model. Our findings supported the first evolutionary step proposed by the model, establishment of a stigma-height polymorphism. Conditions for the subsequent establishment of an anther-height polymorphism were not satisfied by pollen-transfer patterns alone. Because conditions for the first step are considered more onerous, however, and because the second stage depends on inbreeding depression as well as pollen-transfer patterns, we interpret our results as supporting the plausibility of the Lloyd-Webb model. Video images of bees visiting glass-sided artificial flowers demonstrate a mechanism for disassortative pollination between the ancestral and mutant morph. In general, pollen-transfer probabilities were negatively correlated with the height difference between anthers of the donor and stigma of the recipient. Style length affects bee feeding posture in such a way that disassortative pollination could feasibly occur in the absence of an anther-height polymorphism.


Should we perform routine prophylactic central neck dissection in patients with thyroid papillary microcarcinoma?
Cervical lymph node (LN) metastases in papillary thyroid cancer (PTC) are common in tumors especially that are larger than 1cm. Ipsilateral central neck dissection (CND) is usually preferred even in the absence of a palpable LN. This study aims to clarify the incidence and predictive factors for occult ipsilateral central LN metastasis in these patients, and the management of patients without clinical evidence of metastasis. 204 PTC patients were studied. The patients were divided into two according to the tumor size of ≤5mm or larger. Patient demographics, tumor properties, LN metastasis, preoperative neck ultrasonography findings and surgical outcomes were analyzed. There were 152 patients in study group-1 (nodule > 5 mm) and 52 patients in group-2 (nodule ≤ 5 mm). The mean tumor size was 11.9 mm. Overall, preoperative neck ultrasonography showed central neck LN in 25 (12.3%) patients, however, final pathology revealed metastatic LN at central compartment in 59 (28.9%) patients. There were 56 (27.5%) patients with metastasis in group-1 compared to 3 (1.4%) patients in group-2. Prophylactic CND is advised in PTC for the reduction of recurrence in central compartment. According to our results, in patients with tumors smaller than 5 mm and without evidence of nodal metastasis in preoperative neck ultrasonography, we do not recommend prophylactic CND.


HepaDisk - A new quality of life questionnaire for HCV patients.
Since most patients with hepatitis C virus (HCV) infection now receive treatment irrespective of liver disease severity, special attention to patient quality of life (QoL), including psycho-social aspects, is required. No QoL questionnaire is specific for patients with HCV. To develop and validate a short Italian questionnaire (HepaDisk) assessing the QoL of patients affected by HCV with intuitive graphic results that is understandable by patients and physicians. A questionnaire, drafted by a steering committee, underwent a Delphi survey. A multicenter, observational study was conducted to validate the developed HepaDisk versus other tools (CLDQ-I, SF-36, WPAI:HCV), and to evaluate its correlation with disease severity in Italian patients with HCV. The 10-item questionnaire was validated in 214 patients. HepaDisk showed a high correlation with CLDQ overall score and WPAI:HCV activity impairment (Spearman's rank correlation: 0.651 and 0.595, respectively) and a lower correlation with SF-36. Strong internal consistency (Cronbach coefficient: 0.912), good test-retest reliability (Pearson's correlation coefficient: 0.789; 95% CI, 0.714-0.865), and responsiveness to changes among improved patients were demonstrated. HepaDisk is a reliable and user-friendly tool that can monitor disease impact on patient QoL over time, providing a visual representation easily understandable by both patients and physicians.


Cognitive test performance in relation to psychotic symptoms and paranoid ideation in non-demented 85-year-olds.
Clinical studies suggest that psychotic and paranoid states in late life are associated with cognitive dysfunction. However, it is not clear whether this finding would be observed in general population samples of non-demented elderly, particularly after adjustment for potential confounding factors. A representative sample of non-demented 85-year-olds living in the community or in institutions in Göteborg, Sweden (N = 347) was examined using a psychiatric and physical examination (including a medical history), key-informant interview, psychometric testing and review of medical records. Individuals with psychotic symptoms and paranoid ideation were compared with the mentally healthy regarding tests of verbal ability, inductive logical reasoning, spatial ability, perceptual speed, basic arithmetic, primary memory and secondary memory. Non-demented 85-year-olds with psychotic symptoms or paranoid ideation performed specifically worse on tests measuring verbal ability, logical reasoning and two tests of spatial ability after adjustment for sex, education, hearing impairment, visual deficits, somatic disorders, depression, 3-year-mortality rate and incident dementia. Psychotic symptoms and paranoid ideation were associated with lower performance on cognitive tests related to verbal ability, logical reasoning and spatial ability in non-demented 85-year-olds after adjustment for potential confounders.


Many-fluid Onsager density functional theories for orientational ordering in mixtures of anisotropic hard-body fluids.
The extension of Onsager's second-virial theory [L. Onsager, Ann. N.Y. Acad. Sci. 51, 627 (1949)] for the orientational ordering of hard rods to mixtures of nonspherical hard bodies with finite length-to-breadth ratios is examined using the decoupling approximations of Parsons [Phys. Rev. A 19, 1225 (1979)] and Lee [J. Chem. Phys. 86, 6567 (1987); 89, 7036 (1988)]. Invariably the extension of the Parsons-Lee (PL) theory to mixtures has in the past involved a van der Waals one-fluid treatment in which the properties of the mixture are approximated by those of a reference one-component hard-sphere fluid with an effective diameter which depends on the composition of the mixture and the molecular parameters of the various components; commonly this is achieved by equating the molecular volumes of the effective hard sphere and of the components in the mixture and is referred to as the PL theory of mixtures. It is well known that a one-fluid treatment is not the most appropriate for the description of the thermodynamic properties of isotropic fluids, and inadequacies are often rectified with a many-fluid (MF) theory. Here, we examine MF theories which are developed from the virial theorem and the virial expansion of the Helmholtz free energy of anisotropic fluid mixtures. The use of the decoupling approximation of the pair distribution function at the level of a multicomponent hard-sphere reference system leads to our MF Parsons (MFP) theory of anisotropic mixtures. Alternatively the mapping of the virial coefficients of the hard-body mixtures onto those of equivalent hard-sphere systems leads to our MF Lee (MFL) theory. The description of the isotropic-nematic phase behavior of binary mixtures of hard Gaussian overlap particles is used to assess the adequacy of the four different theories, namely, the original second-virial theory of Onsager, the usual PL one-fluid theory, and the MF theories based on the Lee (MFL) and Parsons (MFP) approaches. A comparison with the simulation data for the mixtures studied by Zhou et al. [J. Chem. Phys. 120, 1832 (2004)] suggests that the Parsons MF description (MFP) provides the most accurate representation of the properties of the isotropic-nematic ordering transition and density (pressure) dependence of the order parameters.


Bacterial orchitis and epididymo-orchitis in broiler breeders.
Two cases of orchitis and epididymo-orchitis in broiler breeders are described. The first case occurred in a 62-week-old rooster showing signs of breeding inactivity. Grossly, the left testis was abnormally shaped and had multiple yellow foci, prominent blood vessels, and a gelatinous mass on the surface. The right testis and other tissues appeared normal. A pure, heavy growth of Staphylococcus aureus was obtained on bacterial culture, and intralesional Gram-positive cocci were numerous on histopathology. The second case occurred in a 28-week-old rooster that was found dead. Both testes were abnormally shaped, swollen, firm, and had irregular, dark, depressed areas, prominent vessels, and multiple petechial haemorrhages. Epididymides were enlarged and nodular. Other lesions in this rooster included poor nutritional condition, distended cloaca, and urate scalding of the abdominal skin below the vent. Microscopically, there was extensive, severe heterophilic intratubular orchitis and epididymitis with intralesional Gram-negative bacteria. A heavy, pure growth of Escherichia coli was obtained from the testes and epididymides. In both cases, the findings suggested that the most probable route of infection was ascending via the ductus deferens.


The clinical relevance of EEG interpretation.
There is need nowadays to re-emphasize the capabilities of electroencephalography: a method representing the extremely important function/dysfunction-orientation in neurological thinking and practice. Valuable and relevant messages to the clinician naturally require solid EEG training and the resulting expertise. The idea that valuable EEG information is limited to the field of epileptology is erroneous. A plethora of clinically relevant messages can be derived from the EEG in nonepileptic conditions and, above all, in metabolic (and so called "mixed") encephalopathies where neuroimaging has almost nothing to offer. The discussion of EEG and epileptology only skirts pediatric conditions (and most of the epileptic syndromes). It is shown that EEG reading in epileptology is a lot more than simply "hunting spikes." A strong plea is being made against the presently fashionable overuse of the term "non-convulsive status epilepticus." Continuing neglect of functional/dysfunctional orientation can seriously endanger the entire field of Neurology.


Psychopathology in Substance Use Disorder Patients with and without Substance-Induced Psychosis.
Background. Substance-induced psychotic disorder (SIPD) is a diagnosis constructed to distinguish substance-induced psychotic states from primary psychotic disorders. A number of studies have compared SIPD persons with primary psychotic patients, but there is little data on what differentiates substance use disorder (SUD) individuals with and without SIPD. Here, we compared psychopathology, sociodemographic variables, and substance use characteristics between SUD patients with and without SIPD. Methods. A retrospective chart review was conducted on newly admitted patients at a rehabilitation centre between 2007 and 2012. Results. Of the 379 patients included in the study, 5% were diagnosed with SIPD (n = 19) and 95% were diagnosed with SUDs without SIPD (n = 360). More SIPD patients reported using cannabis and psychostimulants, and fewer SIPD patients reported using alcohol than SUDs patients without SIPD. SIPD patients scored higher on the "schizophrenia nuclear symptoms" dimension of the SCL-90R psychoticism scale and exhibited more ClusterB personality traits than SUD patients without SIPD. Discussion. These data are consistent with previous studies suggesting that psychopathology, substance type, and sociodemographic variables play important role in the development of SIPD. More importantly, the results highlight the need for paying greater attention to the types of self-reported psychotic symptoms during the assessment of psychotomimetic effects associated with psychoactive substances.


Arginine Methylation Regulates Self-Assembly of Peptides.
Bio-inspired design of peptides represents one facile strategy for development of supramolecular monomers for self-assembly into well-defined nanostructures. Inspired by methylation of arginine during post-translational modification for manipulating protein functions, herein, the controllable self-assembly of peptides via rational incorporation of methylated arginine residues into bola-amphiphilic peptides is reported. A series of bola-amphiphilic peptides are designed and synthesized either containing natural arginine or methylated arginine and investigate the influence of arginine methylation on peptide assembly. This study finds that incorporation of symmetrically di-methylated arginine into oppositely charged hexapeptide hex-SDMAE leads to distinct assembling performance compare to natural peptide hex-RE. The findings demonstrate that the methylation of rationally designed peptide sequences allows for regulation of self-assembly of peptides, thus implying the great potential of arginine methylation in establishing controllable peptide assembling systems and creating in situ formulation of biomedical materials in the future.


Voluntary medication error reporting program in a Japanese national university hospital.
In Japan, as in other countries, medical accidents arising from human error can seriously damage public confidence in medical services, as well as being intrinsically undesirable. Errors voluntarily reported by the healthcare practitioners in our institution (Kanazawa University Hospital) were considered to assess the contributory factors by using the accumulated error database in the hospital information system. Medical errors in our institution during the period from July 1, 2000, to June 30, 2002, were counted using the error reporting system database and were classified. The number of errors reported during the investigation period was 1378, of which 78% were reported by nursing staff. Medication errors involving administration of injectable or oral drugs to inpatients, dispensing, and prescription accounted for about 50% of that number. Among dispensing errors, 53% were detected by patients or their families and 36% by nurses. The best method of error prevention is to learn from previous errors. For this purpose, the error reporting program is effective. In patient safety management, it is important to take into account the potential risks of future errors, as well as to capture information about errors that have already happened. For safety management, adoption of appropriate information technology (e.g., implementation of a prescription order entry system) is effective in reducing medication errors. However, it is important to note that serious errors can also arise in computer-based systems.


The immune adherence receptor: dissociation between the expression of erythrocyte and mononuclear cell C3b receptors.
Human erythrocytes have a surface receptor for the third component of complement (C3b). This receptor mediates the immune adherence (IA) reaction. In this study, erythrocytes from over 100 normal donors and from donors with rare blood group types were examine for IA reactivity. All donors had red cells with high titer IA activity, with the exception of one Rh null individual whose erythrocytes had barely detectable IA activity. Five other Rh null donors had normal IA titers. Because of the apparent defect in the expression of the red cell C3b receptor in this one individual, the mononuclear cell C3b receptors of this donor were studied and found to be normal. These findings suggest that expression of the erythrocyte C3b receptor may be controlled by factors which differ from those determining expression of the mononuclear cell C3b receptor.


Mapping the global football field: a sociological model of transnational forces within the world game.
This paper provides a sociological model of the key transnational political and economic forces that are shaping the 'global football field'. The model draws upon, and significantly extends, the theory of the 'global field' developed previously by Robertson. The model features four quadrants, each of which contains a dominant operating principle, an 'elemental reference point', and an 'elemental theme'. The quadrants contain, first, neo-liberalism, associated with the individual and elite football clubs; second, neo-mercantilism, associated with nation-states and national football systems; third, international relations, associated with international governing bodies; and fourth, global civil society, associated with diverse institutions that pursue human development and/or social justice. We examine some of the interactions and tensions between the major institutional and ideological forces across the four quadrants. We conclude by examining how the weakest quadrant, featuring global civil society, may gain greater prominence within football. In broad terms, we argue that our four-fold model may be utilized to map and to examine other substantive research fields with reference to globalization.


Visible-light photoresponse of gold nanoparticles supported on TiO2 : a combined photocatalytic, photoelectrochemical, and transient spectroscopy study.
In the context of gaining understanding on the origin of the visible-light photoresponse of TiO2 containing gold nanoparticles, the photocurrent spectra and photocatalytic H2 evolution of titania (P25) and Au-P25 were compared. Whereas no photocurrent was detected upon visible-light irradiation for either of the two photocatalysts, Au-P25 exhibited photocatalytic H2 evolution for wavelengths between 400 and 575 nm. This contradictory behavior under visible-light irradiation of Au-P25 was rationalized by transient absorption spectroscopy. It was suggested that photocatalytic H2 generation results from methanol quenching of the charge-separation state in each semiconductor nanoparticle, but the lack of photocurrent is due to the short lifetime of the charge separation, which makes interparticle charge migration for micrometric distances unlikely.


SWI/SNF Complex Alterations in Tumors with Rhabdoid Features: Novel Therapeutic Approaches and Opportunities for Adoptive Cell Therapy.
The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy.


Intravitreal gas injection without vitrectomy for macular detachment associated with an optic disk pit.
To evaluate the clinical outcomes after gas tamponade without vitrectomy for retinal detachment associated with an optic disk pit using optical coherence tomography. Intravitreal gas injection was performed on 8 consecutive patients (mean age, 35.0 years; range, 15-74 years) with unilateral macular detachment associated with an optic disk pit. A 0.3-mL injection of 100% sulfur hexafluoride 6 gas was carried out without an anterior chamber tap. Patients treated with gas injection were instructed to remain facedown for 5 days. Complete retinal reattachment after only gas tamponade was achieved in four out of eight eyes. The mean number of gas injections was 1.8. The mean best-corrected visual acuity before and after the treatment with gas tamponade was approximately 30/100 and 20/20, respectively. The period required for reattachment after final gas treatment was 12 months. There were no incidences of recurrence after complete reattachment by gas tamponade in any of the cases during the 94-month average follow-up period (range, 64-132 months). Gas tamponade appears to be an effective alternative method for macular detachment associated with an optic disk pit, even though the mechanisms of optic disk pit maculopathy are still unknown.


EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery.
Glioblastoma is the most aggressive malignant brain tumor among all primary brain and central nervous system tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Thus, there is an urgent need to develop more efficient therapeutics to improve the poor survival rates of patients with glioblastoma. To address this need, we have developed a novel tumor-targeted immunotoxin (IT), D2C7-(scdsFv)-PE38KDEL (D2C7-IT), by fusing the single chain variable fragment (scFv) from the D2C7 monoclonal antibody (mAb) with the Pseudomonas Exotoxin (PE38KDEL). D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and EGFR variant III (EGFRvIII), two onco-proteins frequently amplified or overexpressed in glioblastomas. Surface plasmon resonance and flow cytometry analyses demonstrated a significant binding capacity of D2C7-IT to both EGFRwt and EGFRvIII proteins. In vitro cytotoxicity data showed that D2C7-IT can effectively inhibit protein synthesis and kill a variety of EGFRwt-, EGFRvIII-, and both EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells and human tumor cell lines. Furthermore, D2C7-IT exhibited a robust anti-tumor efficacy in orthotopic mouse glioma models when administered via intracerebral convection-enhanced delivery (CED). A preclinical toxicity study was therefore conducted to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect-level (NOAEL) of D2C7-IT via intracerebral CED for 72 hours in rats. Based on this successful rat toxicity study, an Investigational New Drug (IND) application (#116855) was approved by the Food and Drug Administration (FDA), and is now in effect for a Phase I/II D2C7-IT clinical trial (D2C7 for Adult Patients with Recurrent Malignant Glioma, https://clinicaltrials.gov/ct2/show/NCT02303678). While it is still too early to draw conclusions from the trial, results thus far are promising.


ECG and EEG based detection and multilevel classification of stress using machine learning for specified genders: A preliminary study.
Mental health, especially stress, plays a crucial role in the quality of life. During different phases (luteal and follicular phases) of the menstrual cycle, women may exhibit different responses to stress from men. This, therefore, may have an impact on the stress detection and classification accuracy of machine learning models if genders are not taken into account. However, this has never been investigated before. In addition, only a handful of stress detection devices are scientifically validated. To this end, this work proposes stress detection and multilevel stress classification models for unspecified and specified genders through ECG and EEG signals. Models for stress detection are achieved through developing and evaluating multiple individual classifiers. On the other hand, the stacking technique is employed to obtain models for multilevel stress classification. ECG and EEG features extracted from 40 subjects (21 females and 19 males) were used to train and validate the models. In the low&high combined stress conditions, RBF-SVM and kNN yielded the highest average classification accuracy for females (79.81%) and males (73.77%), respectively. Combining ECG and EEG, the average classification accuracy increased to at least 87.58% (male, high stress) and up to 92.70% (female, high stress). For multilevel stress classification from ECG and EEG, the accuracy for females was 62.60% and for males was 71.57%. This study shows that the difference in genders influences the classification performance for both the detection and multilevel classification of stress. The developed models can be used for both personal (through ECG) and clinical (through ECG and EEG) stress monitoring, with and without taking genders into account.


Physical mechanisms of cell damage in microcarrier cell culture bioreactors.
The negative effects of excessive agitation on tissue cells in microcarrier culture have often been ascribed to "shear." Analysis of the fluid mechanics occurring suggests that there are actually three potential damage mechanisms: collisions of a cell-covered microcarrier with other beads, collisions with parts of the reactor (primarily the impeller), and interaction with turbulent eddies the size of the microcarrier beads. Review of the available quantitative information on agitation effects in cell cultures does not establish which mechanism is predominant; the range of experimental variables reported emphasizes power input over the other reactor and impeller parameters. The bead-bead collision model is tentatively supported by the available data, but the other mechanisms may still be significant in some systems. The formation of bead aggregates by cellular bridging provides a parallel means of damaging cells. Breaking of these bridges by any of the three means identified earlier can cause cell destruction and/or the net transfer of cells to formerly bare beads. High concentrations of bridges are favored by lower agitation rates, presumably because the bridges are not as quickly destroyed after formation.


Concurrent chemoradiotherapy with or without adjuvant chemotherapy in intermediate and locoregionally advanced nasopharyngeal carcinoma.
Concurrent chemoradiotherapy (CCRT) showed a significant improvement in disease control and clinical outcome in patients with intermediate and locoregionally advanced nasopharyngeal carcinoma (NPC) (stage II, III and IVA+B). However, there has been debate about the contribution and application of additional adjuvant chemotherapy (AC) to a CCRT regime. This study aims to evaluate the additional value of AC in the treatment of intermediate and locally advanced NPC with regard to toxicity and clinical outcomes. A total of 189 patients with American Joint Committee on Cancer (AJCC) stage II to stage IVB NPC were retrospectively identified. Patient characteristics, toxicity, compliance with treatment and clinical outcomes, including response to treatment, overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), freedom from local recurrence (FLR) and freedom from distant metastasis (FDM), were analyzed. The overall response rate of CCRT and CCRT/AC groups was 97.92 % and 97.83 %, respectively (P=0.643). The 5-year OS rate was 68.2 % in the CCRT group and 75.9 % in the CCRT/AC group (P=0.53). The 5-year PFS rate was 66.7 % and 71.4 % in CCRT and CCRT/AC groups, respectively (P=0.96). This study showed no evidence of an additional value of AC in CCRT treatment in disease control and clinical outcomes in patients with locally advanced NPC in endemic regions. Moreover, three additional cycles of AC after CCRT appeared to be poorly tolerated in patients. Therefore, AC should not be routinely used for treatment, although clinical trials may be justified.


Natural history and imaging of subtalar and midfoot joint disease in rheumatoid arthritis.
Foot involvement is not uncommon and occurs early in the disease course of rheumatoid arthritis (RA). Inflammation and ongoing synovitis of foot joints lead to joint destruction and instability, tendon dysfunction, and eventually collapse of the medial longitudinal arch and pes planovalgus that contributes to difficulty in walking and gait abnormalities. This article reviews foot-related problems in patients with RA, focusing on the prevalence, natural history and role of imaging in both diagnosis and management of midfoot and subtalar joint disease in RA.


Anisotropic diffusion limited aggregation in three dimensions: universality and nonuniversality.
We explore the macroscopic consequences of lattice anisotropy for diffusion limited aggregation (DLA) in three dimensions. Simple cubic and bcc lattice growths are shown to approach universal asymptotic states in a coherent fashion, and the approach is accelerated by the use of noise reduction. These states are strikingly anisotropic dendrites with a rich hierarchy of structure. For growth on an fcc lattice, our data suggest at least two stable fixed points of anisotropy, one matching the bcc case. Hexagonal growths, favoring six planar and two polar directions, appear to approach a line of asymptotic states with continuously tunable polar anisotropy. The more planar of these growths visually resembles real snowflake morphologies. Our simulations use a new and dimension-independent implementation of the DLA model. The algorithm maintains a hierarchy of sphere coverings of the growth, supporting efficient random walks onto the growth by spherical moves. Anisotropy was introduced by restricting growth to certain preferred directions.


Rates of childhood trauma in a sample of university students in Greece: The Greek version of the Early Trauma Inventory-Self Report.
The self-report Early Trauma Inventory (ETI-SR-SF) was developed by Bremner et al in 2007 and has been proven a valid tool for the assessment of childhood trauma. The inventory covers four types of traumatic experiences: general trauma, physical abuse, emotional abuse and sexual abuse. The primary aim of the present study was to assess the internal consistency, test-retest reliability, convergent validity and factor structure of the Greek version of the ETI-SR-SF. The study sample consisted of 605 individuals (402 women), undergraduate and postgraduate students of Athens universities with a mean age of 24.3 years. All participants completed a questionnaire on demographic characteristics, the Greek version of the ETI-SR-SF and the Greek version of the Trauma Symptoms Checklist (TSC-40). Both ETI-SR-SF and TSC-40 were re-administered to 56 participants after three to four weeks. ETI-SR-SF was found to display high levels of internal consistency (Cronbach's α=0.91) and test-retest reliability (ICC=0.93). In addition, the internal structure of every subscale was examined by the means of factor analysis, which revealed that the items in every subscale contribute to a single factor explaining a great proportion of the variance. The correlation between total scores of ETI-SR-SF and TSC-40 was significantly strong (r=0.42, p<0.001), indicating satisfactory convergent validity. The most frequently reported type of childhood trauma was corporal punishment, at a rate of 89.9%, followed by emotional abuse (67.2%) and sexual abuse (27%). These rates are higher than those found in the international literature indicating that the various types of early traumatic experience are very common phenomena in the Greek student population. This finding should alert the experts and requires replication and further investigation by studies with larger samples. The findings of the present study suggest that the Greek version of the self-report Early Trauma Inventory (ETI-SR-SF) is a valid and reliable tool useful for future studies on childhood traumatic experiences in Greek populations. Moreover, according to our preliminary findings further investigation of the childhood trauma in Greece appears to be very much warranted.


Textiloma in the leg.
Textiloma is defined as a tumor formed due to retained gauze. It is rarely reported in the musculoskeletal system. We are presenting a case with a soft tissue swelling over the lateral aspect of the lower third of the leg, come for implant removal of the distal tibia and fibular fracture. We removed the soft tissue mass enbloc thinking it to be a benign tumor. On cutting the mass on the operation table, a gauze piece encased by fibrous tissue was found. Textiloma can present as tumoral forms and can mimic as a pseudo-tumor.


Effect of analgesia administration timing on early post-operative period characteristics: a randomized, double-blind, controlled study.
This study investigated the effect of time of analgesia administration in 64 patients undergoing total abdominal hysterectomy. Patients received standard general anaesthesia and were divided randomly into two equal groups. At the time of fascia closure, patients in the intra-operative (Iop) group received 0.5 mg/kg pethidine intravenously. On arrival in the post-anaesthesia care unit, the same dose of pethidine was given to patients in the post-operative (Pop) group. All patients then used a patient-controlled analgesia pump to administer pethidine analgesia as required. Times to extubation, response to verbal stimulation and orientation, post-operative pain scores and analgesic consumption were recorded. Times to extubation and response to verbal stimulation were significantly longer in the Iop group. Pain scores, analgesic consumption and additional analgesic requirements were significantly higher in the Pop group in the first 2 h post-operatively. In conclusion, intra-operative administration of pethidine provided better pain management than post-operative administration.


Dimethyl fumarate ameliorates endotoxin-induced acute kidney injury against macrophage oxidative stress.
Characterized by macrophage infiltration, renal inflammation during septic acute kidney injury (AKI) reveals a ubiquitous human health problem. Unfortunately, effective therapies with limited side effects are still lacking. This study is aiming to elucidate the role of Dimethyl fumarate (DMF) in macrophages against oxidative stress of septic AKI. Balb/c mice were gavaged by 50 mg/kg DMF then injected with 10 mg/kg LPS by i.p. We examined LPS-induced renal dysfunction and histological features in murine kidneys. Raw264.7 macrophage cells were also treated with DMF and then induced by LPS. The mitotracker staining was used to follow mitochondria integrity by confocal microscopy. Flow cytometry measured the production of ROS by DCF-HDA and the expression of iNOS. Western blot detected the expression of Nrf-2 and Sirt1. Co-IP measured the interaction between Sirt1 and Nrf-2. Confocal microscopy observed the colocalization of Sirt1 and Nrf-2 in LPS-treated Raw264.7 macrophage cells. DMF ameliorated murine LPS nephritis with reduced blood urea nitrogen and serum creatinine, as well as decreased the histological alterations compared to the normal control. DMF significantly inhibited the expression of iNOS and reduced the production of nitrite in Raw264.7 cells following LPS treatment. Our study also revealed the role of DMF in protecting against intracellular ROS accumulation and mitochondria dysfunction in LPS-induced nephritis. DMF facilitated colocalization and interaction between Sirt1 and Nrf-2 in LPS-treated cells. This study showed that DMF alleviated LPS-induced nephritis, indicating protective effects of DMF on macrophage against oxidative stress induced by LPS potentially involving Nrf-2-mediated pathway.


The predictive value of the extensor grip test for the effectiveness of bracing for tennis elbow.
Tennis elbow is a common complaint. Several treatment strategies, such as corticosteroid injections and physical therapy and braces, have been described. The extensor grip test has predictive value in assessing the effectiveness of bracing in tennis elbow. Cohort study (prognosis); Level of evidence, 1. Patients with tennis elbow complaints were randomized into 3 groups: brace only, physical therapy, and combination brace and physical therapy. The extensor grip test was performed before randomization on all patients. Outcome measures at 6-week follow-up were success rate, severity of complaints, pain, disability, inconvenience during daily life, and satisfaction. In the brace-only group, significant differences were identified between patients with a positive test result and patients with a negative test result for 3 outcome measures. The success rate in the test-negative group was 23% (5/22) compared to 47% (21/45) in the test-positive group. Mean decrease in pain was 23 (95% confidence interval, -3 to 49) in the test-positive group compared to 11 (95% confidence interval, -6 to 28) in the test-negative group, and mean satisfaction in the test-positive group was 71 (95% confidence interval, 48 to 94) compared to 51 (95% confidence interval, 24 to 78) in the test-negative group. In the physical therapy and combination groups, no differences were identified between test-positive and test-negative patients. The extensor grip test seems valuable as a predictive factor for the effectiveness of bracing as treatment for tennis elbow over the short term.


Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells.
Autophagy is mostly a nonselective bulk degradation system within cells. Recent reports indicate that autophagy can act both as a protector and killer of the cell depending on the stage of the disease or the surrounding cellular environment (for review see Cuervo, A.M. 2004. Trends Cell Biol. 14:70-77). We found that cytoplasmic vacuoles induced in pancreatic acinar cells by experimental pancreatitis were autophagic in origin, as demonstrated by microtubule-associated protein 1 light chain 3 expression and electron microscopy experiments. To analyze the role of macroautophagy in acute pancreatitis, we produced conditional knockout mice lacking the autophagy-related 5 gene in acinar cells. Acute pancreatitis was not observed, except for very mild edema in a restricted area, in conditional knockout mice. Unexpectedly, trypsinogen activation was greatly reduced in the absence of autophagy. These results suggest that autophagy exerts devastating effects in pancreatic acinar cells by activation of trypsinogen to trypsin in the early stage of acute pancreatitis through delivering trypsinogen to the lysosome.


Adjacent segmental degeneration following Wallis interspinous stabilization implantation: Biomechanical explanations and the value of magnetic resonance imaging.
Adjacent segmental degeneration (ASD) is a major issue after pedicular fixation. This study examined the degeneration of the adjacent levels due to the insertion of the Wallis interspinous stabilization system compared with discectomy, using magnetic resonance imaging (MRI).Thirty-eight patients diagnosed with lumbar degeneration disorders at L4-L5 were reviewed: 19 patients underwent discectomy and Wallis system implantation (group A), and 19 patients underwent discectomy (group B). The Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) were assessed preoperatively and postoperatively. ASD was evaluated by MRI.There was no difference in the preoperative ODI scores between the 2 groups (non-normal distribution, median, 50 (40, 50) vs 50 (50, 50), P = .331), but the postoperative ODI scores were different (non-normal distribution, median, 0 (0, 32) vs 20 (20, 30), P < .005). Similar results were observed for VAS. In group A, ASD occurred in 4 patients (21.1%) in the disc and 8 (42.1%) in the facet joint at L3/4, and in 4 (21.1%) in the disc and 5 (26.3%) in the facet joint at L5/S1. In Group B, ASD occurred in 3 patients (15.8%) in the disc at L3/4, and in 4 (21.1%) in the disc at L5/S1. In general, there was no difference between the 2 groups (P > .05), except at L3/4 (P = .015).ASD of the facet joint in the cranial segment occurred after Wallis system implantation, suggesting that the Wallis system cannot prevent ASD of the facet joint, but could have some other benefits for the discs.


Specific characteristics of CK2β regulatory subunits in plants.
In all eukaryotes, the typical CK2 holoenzyme is an heterotetramer composed of two catalytic (CK2α and CK2α') and two regulatory (CK2β) subunits. One of the distinctive traits of plant CK2 is that they present a greater number of genes encoding for CK2α/β subunits than animals or yeasts, for instance, in Arabidopsis and maize both CK2α/β subunits belong to multigenic families composed by up to four genes. Here, we conducted a genome-wide survey examining 34 different plant genomes in order to investigate if the multigenic property of CK2β genes is a common feature through the entire plant kingdom. Also, at the level of structure, the plant CK2β regulatory subunits present distinctive features as (i) they lack about 20 aminoacids in the C-terminal domain, (ii) they present a specific N-terminal extension of about 90 aminoacids that shares no homology with any previously characterized functional domain, and (iii) the acidic loop region is poorly conserved at the aminoacid level. Since there is no data about CK2β or holoenzyme structure in plants, in this study, we use human CK2β as a template to predict a structure for Zea mays CK2β1 by homology modeling and we discuss about possible structural changes in the acidic loop region that could affect the enzyme regulation.


The decrease in body fat in mice fed conjugated linoleic acid is due to increases in energy expenditure and energy loss in the excreta.
We carried out energy balance studies in four groups of young, growing, 5-wk-old Balb-C mice (n = 12/group) that were either food restricted or nonrestricted and fed high fat diets (38 energy%) with or without 0.93 g/100 g conjugated linoleic acid (CLA) for 39 d. The energy in carcasses, excreta and food was measured in a bomb calorimeter. CLA lowered the percentage of the energy intake that was stored in the body from 1.9 +/- 0.8 to -2.3 +/- 0.7% (mean +/- SD, P < 0.05) in the nonrestricted mice and from 1.4 +/- 1.3 to -2.9 +/- 0.7% (P < 0.05) in the restricted mice. Thus, the CLA-treated mice had a net loss of body energy. The percentage of the energy intake eliminated in the excreta increased from 7.6 +/- 0.9% in controls to 8.7 +/- 1.0% (P < 0.05) in the CLA-treated mice that were nonrestricted and from 7.3 +/- 0.8 to 8.4 +/- 0.6 (P < 0.05) in the restricted mice. The amount of energy ingested minus the amount retained in carcasses and excreta equals the energy expenditure. The percentage of the energy intake that was expended as heat increased from 90.5 +/- 1.2 in controls to 93.6 +/- 1.5% (P < 0.05) in the CLA-treated nonrestricted mice and from 91.3 +/- 1.5 to 94.5 +/- 1.0% (P < 0.05) in the restricted mice. The lower energy storage in the CLA-fed mice was accounted for by an increase in the energy expenditure (74%) and by an increase in energy lost in the excreta (26%). Feeding CLA also increased liver weight, which may warrant further studies on the safety of CLA.


Nucleotide sequence of mouse L19 ribosomal protein cDNA isolated in screening with tre oncogene probes.
A cDNA library was prepared from cytoplasmic poly(A)RNA from mouse NIH-3T3 cells carrying a transfected human tre oncogene. Screening with tre gene probes identified a tre cDNA clone 11-4 and a co-purifying weakly hybridizing cDNA clone 11-5. The 11-5-specific RNA was expressed in both nontransfected and tre-transfected NIH-3T3 cells, showing it is of mouse rather than tre gene origin. Its nucleotide sequence was 717 bp long and contained, starting from the first nucleotide, an open reading frame of 588 bp followed by a 3' noncoding region and 26 A residues at the 3' terminus. Comparison with the GenBank data base revealed 93.7% homology with cDNA encoding the rat L19 ribosomal protein. Furthermore, the 196-amino-acid polypeptide deduced from 11-5 was of the same length and contained only one amino acid difference compared with the rat L19 protein. Comparison with the weakly hybridizing tre gene probe showed stretches of homology that were, however, too short to be taken into consideration. We conclude that the 11-5 sequence encodes the mouse L19 ribosomal protein.


Immunochemical characterization of antigenic domains on human interferon-beta: spatially distinct epitopes are associated with both antiviral and antiproliferative activities.
The use of a panel of monoclonal antibodies (mAb) raised against recombinant (serine-17) human interferon-beta (rHuIFN-beta ser) has permitted the identification of three epitopes on HuIFN-beta, designated as sites I, II and III, based solely on functional differences, i.e., the neutralization of antiviral and antiproliferative activities of natural and recombinant HuIFN-beta (Redlich, P.N. and Grossberg, S. E., J. Immunol. 1989. 143: 1887). Site I- and II-directed mAb possessed neutralizing activity whereas none was noted by mAb recognizing site III. To characterize further these epitopes by immunochemical means, we studied their (a) spatial relationship by competitive binding assays, (b) antigenic structure by Western blotting, and (c) sensitivity to chemical modification by the measurement of mAb reactivity after radioiodination. Competitive antibody binding studies revealed site II to be spatially distinct from sites I and III. Furthermore, site I- and II-directed mAb could easily recognize rHuIFN-beta ser on a Western blot, suggesting that both these epitopes are primarily sequential in structure or denaturation resistant. Chemical modification by radioiodination, which did not alter the biologic activity of rHuIFN-beta ser, had likewise little effect on mAb reactivity to site I; however, reactivity to site II was diminished and reactivity to site III was minimal following the radioiodination process. Both site I- and II-directed mAb inhibited the binding of 125I-rHuIFN-beta ser to intact Daudi cells, suggesting that inhibition of receptor binding is their mechanism of neutralization. Thus, we conclude that epitopes I and II, which are associated with both antiviral and antiproliferative activities of rHuIFN-beta, are spatially and immunochemically distinct.


Hypertension depresses but exercise training restores both Mfsd2a expression and blood-brain barrier function within PVN capillaries.
Hypertension augments while exercise training corrects the increased vesicle trafficking (transcytosis) across the blood-brain barrier (BBB) within preautonomic areas and the autonomic imbalance. There is no information on a possible mechanism(s) conditioning these effects. Knowing that Mfsd2a is the major transporter of docosahexaenoic acid (DHA) and that Mfsd2a knockout mice exhibited leaky BBB, we sought to identify its possible involvement in hypertension- and exercise-induced transcytosis across the BBB. Spontaneously hypertensive rats (SHR) and Wistar rats were submitted to treadmill training (T) or kept sedentary (S) for 4 wk. Resting hemodynamic/autonomic parameters were recorded in conscious chronically cannulated rats. BBB permeability within the hypothalamic paraventricular nucleus (PVN) was evaluated in anesthetized rats. Brains were harvested for Mfsd2a and caveolin-1 (an essential protein for vesicle formation) expression. SHR-S versus Wistar-S exhibited elevated arterial pressure (AP) and heart rate (HR), increased vasomotor sympathetic activity, reduced cardiac parasympathetic activity, greater pressure variability, reduced HR variability, and depressed baroreflex control. SHR-S also showed increased BBB permeability, reduced Mfsd2a, and increased caveolin-1 expression. SHR-T versus SHR-S exhibited increased Mfsd2a density, reduced caveolin-1 protein expression, and normalized PVN BBB permeability, which were accompanied by resting bradycardia, partial AP drop, reduced sympathetic and normalized cardiac parasympathetic activity, increased HR variability, and reduced pressure variability. No changes were observed in Wistar-T versus Wistar-S. Training is an efficient tool to rescue Mfsd2a expression, which by transporting DHA into the endothelial cell reduces caveolin-1 availability and vesicles' formation. Exercise-induced Mfsd2a normalization is an important mechanism to correct both BBB function and autonomic control in hypertensive subjects.


Can high social capital at the workplace buffer against stress and musculoskeletal pain?: Cross-sectional study.
Work-related musculoskeletal pain and stress are both highly prevalent in the working environment and relate well to the biopsychosocial model. While the onset of musculoskeletal pain is often dependent on the biological element of the biopsychosocial model, chronic pain is often influenced by psychological and social factors. Similarly, stress is also influenced by biological, psychological, and social factors. This study investigates the possibility of social capital being a buffer for stress and musculoskeletal pain in a group of female laboratory technicians.Female laboratory technicians (n = 500) replied to questions about stress (Cohens Perceived Stress Scale-10), musculoskeletal pain (0-10 visual analog scale), and social capital at the workplace (bonding [in teams], bridging [between teams], and linking [between teams and leaders]). Outcome variables were stress and musculoskeletal pain and the predictor variable was social capital. General linear models tested the association of the 3 types of social capital (predictor variables) with stress and pain (mutually adjusted outcome variables). Analyses were controlled for age, lifestyle (body mass index, smoking), seniority, and working hours per week.For stress as outcome, moderate and high bonding social capital were different from low social capital with -2.04 (95% confidence interval [CI] -3.33 to -0.76) and -4.56 (95% CI -5.84 to -3.28) points on the Perceived Stress Scale of 0 to 42, respectively. Similarly, moderate and high bridging social capital were different from low social capital with -1.50 (95% CI -2.76 to -0.24) and -4.39 (95% CI -5.75 to -3.03), respectively. For linking, only high social was significantly different from low with -2.94 (95% CI -4.28 to -1.60). None of the 3 types of social capital was associated with musculoskeletal pain.Higher levels of social capital at the workplace appear to buffer against stress, but not against musculoskeletal pain. Intervention studies should investigate whether improving bonding, bridging, and linking social capital at the workplace may be a viable strategy to prevent or reduce work-related stress.


[The interaction of GABA-A receptors with the serotoninergic system of the brain in regulating the testosterone level by the negative feedback mechanism].
A unilateral hemicastration decreased the serotonin and 5-hydroxyindolacetic acid levels in the Wistar rat mediobasal hypothalamus, but not in the midbrain. These neurotransmitters were shown to interact in the process of androgen restoration after the hemicastration. The maximal contribution of GABAergic mechanisms in the testosterone feedback regulation involves the GABA effect via the central GABA-A receptors of the mediobasal hypothalamus' serotoninergic neurons, thus activating the hormone level restoration. The GABA seems to induce a serotonin-independent inhibition of the testosterone level stabilising after hemicastration.


[Isolation of bone marrow-derived rat osteoclast-like cells with the digestion of trypsin].
To obtain highly enriched osteoclasts in vitro. The bone marrow cells of 1-day, 12-day, 24-day and 36-day old Sprague-Dawley (SD) rats were separately cultured with the presence of 1,25-(OH)2D3 and dexamethasone, and the osteoclast-like cells were identified by Trap staining and scanning electron microscope observation and were purified by trypsin digestion. The count of Trap positive osteoclast-like cells was analyzed statistically. The osteoclast-like cells of each group were Trap positive cells and could form the bone absorption lacunas in vitro. The amounts of osteoclast-like cells were different statistically between the groups (P < 0.05) except between the groups of 1-day old and 12-day old (P > 0.05). Highly enriched osteoclast-like cells were harvested by the digestion of 0.25% trypsin and 0.02% EDTA. It's indicated that a large amount of highly enriched osteoclast-like cells could be obtained through the culture of bone marrow cells of 10-day and 12-day old SD rats with 1,25-(OH)2D3 and dexamethasone and the digestion of trypsin/EDTA.


Pregnant with HIV before age 25: data from a large national study in Italy, 2001-2016.
Young pregnant women with HIV may be at significant risk of unplanned pregnancy, lower treatment coverage, and other adverse pregnancy outcomes. In a large cohort of pregnant women with HIV in Italy, among 2979 pregnancies followed in 2001-2016, 9·0% were in women <25 years, with a significant increase over time (2001-2005: 7·0%; 2006-2010: 9·1%; 2011-2016: 12·2%, P < 0·001). Younger women had a lower rate of planned pregnancy (23·2% vs. 37·7%, odds ratio (OR) 0·50, 95% confidence interval (CI) 0·36-0·69), were more frequently diagnosed with HIV in pregnancy (46·5% vs. 20·9%, OR 3·29, 95% CI 2·54-4·25), and, if already diagnosed with HIV before pregnancy, were less frequently on antiretroviral treatment at conception (<25 years: 56·3%; ⩾25 years: 69·0%, OR 0·58, 95% CI 0·41-0·81). During pregnancy, treatment coverage was almost universal in both age groups (98·5% vs. 99·3%), with no differences in rate of HIV viral suppression at third trimester and adverse pregnancy outcomes. The data show that young women represent a growing proportion of pregnant women with HIV, and are significantly more likely to have unplanned pregnancy, undiagnosed HIV infection, and lower treatment coverage at conception. During pregnancy, antiretroviral treatment, HIV suppression, and pregnancy outcomes are similar compared with older women. Earlier intervention strategies may provide additional benefits in the quality of care for women with HIV.


Release behaviour of drugs from tamarind seed polysaccharide tablets.
This study examines the sustained release behaviour of both water-soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water insoluble (indomethacin) drugs from tamarind seed polysaccharide isolated from tamarind kernel powder. It further investigates the effect of incorporation of diluents like microcrystalline cellulose and lactose on release of caffeine and partial cross-linking of the polysaccharide on release of acetaminophen. Applying exponential equation, the mechanism of release of soluble drugs was found to be anomalous. The insoluble drug showed near case II or zero order release mechanism. The rate of release was in the decreasing order of caffeine, acetaminophen, theophylline, salicylic acid and indomethacin. An increase in release kinetics of drug was observed on blending with diluents. However, the rate of release varied with type and amount of blend in the matrix. The mechanism of release due to effect of diluents was found to be anomalous. The rate of release of drug decreased on partial cross-linking and the mechanism of release was found to be super case II.


Potential involvement of miR-375 in the premalignant progression of oral squamous cell carcinoma mediated via transcription factor KLF5.
To elucidate the genetic effect involved in the premalignant progression of chronic inflammation to cancer, we performed microRNA and mRNA profiling in oral lichen planus (OLP), oral squamous cell carcinoma (OSCC), and normal tissue from the same patients. We demonstrate the involvement of a suppressive microRNA, miR-375, in the regulation of this premalignant progression via KLF5, a transcription factor that modulates the expression of genes contributing to proliferation and apoptosis. We found that miR-375 abundance decreased in tissues with progression from the normal state to OLP and subsequently to OSCC. Restoration of miR-375 by transduction of a synthetic mimic into OSCC cells repressed cellular proliferation and promoted apoptosis, with concomitant down-regulation of KLF5, and vice versa. The direct binding of miR-375 to the 3'-untranslated region of KLF5 was further confirmed. Additionally, Survivin (BIRC5), a target of KLF5, was also regulated by miR-375, explaining the susceptibility of miR-375-mimic transfected cells to apoptosis. Further analysis of clinical specimens suggested that expression of KLF5 and BIRC5 is up-regulated during the progression from inflammation to cancer. Our findings provide novel insights into the involvement of microRNAs in progression of inflammation to carcinoma and suggest a potential early-stage biomarker or therapy target for oral carcinoma.


Vascular activity of (-)-anonaine, (-)-roemerine and (-)-pukateine, three natural 6a(R)-1,2-methylenedioxyaporphines with different affinities for alpha1-adrenoceptor subtypes.
We have studied the mechanism of action of three 6a( R)-1,2-methylenedioxyaporphines as vasorelaxant compounds. The alkaloids assayed showed different affinities for the three human cloned alpha (1)-adrenoceptor (AR) subtypes stably expressed in rat-1 fibroblasts, showing lower affinity for alpha(1B)-AR with regard to the alpha(1A)- or alpha(1D)-subtypes. These three natural compounds are more potent inhibitors of [ (3)H]-prazosin binding than of [ (3)H]-diltiazem binding to rat cerebral cortical membranes. As all these alkaloids inhibited noradrenaline (NA)-induced [ (3)H]-inositol phosphate formation in cerebral cortex and rat tail artery, they may be safely viewed as alpha (1)-AR antagonists, as is demonstrated by the vasorelaxant responses observed in isolated rat tail artery and/or aorta precontracted with NA. The alkaloids also inhibited the contractile response evoked by KCl (80 mM) but with a lower potency than that shown against NA-induced contraction. We have also examined their ability to inhibit the different forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aortic smooth muscle and endothelial cells, with negative results. We conclude that N-methylation favours the interaction of (R)-aporphines with all alpha (1)-AR subtypes, and that the topography of the binding site recognizing the basic or protonated nitrogen atom is similar in all three alpha (1)-AR subtypes. The presence of a hydroxy group at C-11 has different effects on the affinity for each alpha (1)-AR subtype but decreases the affinity for Ca (2+) channels. These results confirm and extend the view that subtle changes in the hydroxylation patterns on the aromatic ring of the aporphine structure affect the interactions of these compounds with the three alpha (1)-AR subtypes in different ways, suggesting that the binding site recognizing the aporphine skeleton is different in each of the three subtypes.


Binding properties of the coagulation factor IX/factor X-binding protein isolated from the venom of Trimeresurus flavoviridis.
The binding properties of the coagulation factor IX/factor X-binding anticoagulant protein (IX/X-bp) isolated from the venom of Trimeresurus flavoviridis (habu snake) were investigated with an enzyme-linked immunosorbent assay. The half-maximal binding and maximal binding of IX/X-bp to both factors IX and X were observed at concentrations of Ca2+ ions of 0.4 mM and 1 mM, respectively. Concentration of IX/X-bp at half-maximal binding to solid-phase bovine factor IX and solid-phase bovine factor X were 0.4 +/- 0.1 nM and 1.1 +/- 0.4 nM, respectively, in the presence of 1 mM Ca2+ ions. The kinetics of binding activity of IX/X-bp to bovine factors IXa and Xa and to human factors IX and X resembled those of the binding to bovine factors IX and X. IX/X-bp did not bind to solid-phase coagulation factors other than factor IX/IXa and factor X/Xa, for example, prothrombin, factor VII, protein C, and protein Z, under the conditions of the experiment. To localize the binding sites of IX/X-bp on the coagulation factors, the ability of IX/X-bp to bind to various fragments derived from factors IX and X was examined. The binding of IX/X-bp to solid-phase factor IX was inhibited by a peptide containing the 4-carboxyglutamic acid (Gla) domain derived from factor IXa beta' (residues 1-42) in the liquid phase, but the binding was not inhibited by Gla-domainless factor IXa beta'. Half-maximal binding of IX/X-bp to solid-phase Gla-domain peptide of factor IX occurred at 9.2 +/- 1.9 nM. Factor X was partially reduced and the S-carboxymethylated light and heavy chains of factor X were prepared. IX/X-bp bound to the S-carboxymethylated light chain of factor X but not to the heavy chain. The binding of IX/X-bp to solid-phase factor X was inhibited by the Gla-domain peptide of factor X (residues 1-44) but not by Gla-domainless factor X. IX/X-bp bound to PCGFX, a recombinant human protein C whose Gla-domain region (residues 1-43) had been replaced by residues 1-43 of human factor X. The affinity of binding was about one tenth of that to intact human factor X. IX/X-bp was unable to bind at all to human protein C. These data indicate that IX/X-bp is a protein that binds to the Gla-domain regions of factors IX and X in the presence of Ca2+ ions.


Beyond Work-Life "Integration".
Research on the work-family interface began in the 1960s and has grown exponentially ever since. This vast amount of research, however, has had relatively little impact on workplace practice, and work-family conflict is at an all-time high. We review the work-family research to date and propose that a shift of attention is required, away from the individual experience of work and family and toward understanding how identity and status are defined at work. Several factors enshrine cherished identities around current workplace norms. The work devotion schema demands that those who are truly committed to their work will make it the central or sole focus of their lives, without family demands to distract them. Importantly, the work devotion schema underwrites valued class and gender identities: Work devotion is a key way of enacting elite class status and functions as the measure of a man--the longer the work hours and higher the demand for his attention, the better. Advocating change in the way work is done and life is lived meets resistance because it places these cherished identities at risk. Resistance to these identity threats keeps current workplace norms in place. This is why even the business case-which shows that current practices are not economically efficient-fails to persuade organizations to enact change. What is needed now is sustained attention to the implicit psychological infrastructure that cements the mismatch between today's workplace and today's workforce.


Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation.
RAS mutations occur in a broad spectrum of human hematopoietic malignancies. Activating Ras mutations in blood cells leads to hematopoietic malignancies in mice. In murine hematopoietic stem cells (HSCs), mutant N-RasG12D activates Stat5 to dysregulate stem cell function. However, the underlying mechanism remains elusive. In this study, we demonstrate that Stat5 activation induced by a hyperactive Nras mutant, G12D, is dependent on Jak2 activity. Jak2 is activated in Nras mutant HSCs and progenitors (HSPCs), and inhibiting Jak2 with ruxolitinib significantly decreases Stat5 activation and HSPC hyper-proliferation in vivo in NrasG12D mice. Activation of Jak2-Stat5 is associated with downregulation of Socs2, an inhibitory effector of Jak2/Stat5. Restoration of Socs2 blocks NrasG12D HSC reconstitution in bone marrow transplant recipients. SOCS2 downregulation is also observed in human acute myeloid leukemia (AML) cells that carry RAS mutations. RAS mutant AML cells exhibited suppression of the enhancer active marker H3K27ac at the SOCS2 locus. Finally, restoration of SOCS2 in RAS mutant AML cells mitigated leukemic growth. Thus, we discovered a novel signaling feedback loop whereby hyperactive Ras signaling activates Jak2/Stat5 via suppression of Socs2.


Pharmacokinetics of furosemide in goats following intravenous, intramuscular, and subcutaneous administrations.
Furosemide, a loop diuretic drug, is recommended for use in cases of edema, ascites, congestive heart failure, toxicosis, and acute renal failure in goats. However, its pharmacokinetics and bioavailability have not been reported yet in this species. The aim of this study was to determine the pharmacokinetics and bioavailability of furosemide in goats following intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at a dose of 2.5 mg/kg. Six clinically healthy goats received furosemide by each route in a three-way crossover pharmacokinetic design with a 15-day washout period between administrations. The plasma concentrations of furosemide were determined using the high-performance liquid chromatography-UV method and analyzed by non-compartmental analysis. The elimination half-life following IV, IM, and SC administration was 0.71 (0.67-0.76) h, 0.69 (0.61-0.74) h, and 0.70 (0.67-0.79) h, respectively. The volume of distribution at steady state and total clearance for the IV route were 0.17 (0.16-0.19) L/kg and 0.30 (0.27-0.33) L/h/kg, respectively. The peak plasma concentrations of furosemide following IM and SC administrations were 11.19 (10.33-11.95) and 6.49 (5.92-7.00) μg/ml at 0.23 (0.16-0.25) and 0.39 (0.33-0.42) h, respectively. The bioavailability was 109.84 (104.92-116.99)% and 70.80 (55.77-86.67)% for the IM and SC routes, respectively. The pharmacokinetics of furosemide following the IV, IM, and SC administrations in goats demonstrated significant differences, which may have clinical and toxicological implications requiring further investigations.


[Aluminium in the lower respiratory tract of people living in México City].
Investigating the presence of aluminium (Al) and respiratory pathologies in the lower respiratory tract of people who had lived in Mexico City for a minimum of two years. 250 respiratory tissue samples were obtained from pulmonary lobes, lymph nodes, bronchial and hilum regions during 36 individuals' autopsies. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used for quantifying Al; the samples has been previously dried, ground and digested. 13 different pathologies were identified but only three of them (pulmonary emphysema, bronchitis and anthracosis) were correlated with the presence of Al, an element being distributed in very variable concentrations (range: 2.7 to 836.1 micrograms of Al per gram of dry tissue (ì g Al/g ts)). The amount of Al found in lobes, bronchial and hilum regions was much smaller than that found in lymph nodes; such difference was statistically significant. Multivariate analysis by conglomerates revealed that the sample consisted of three classes of individuals, grouped according to the amount and distribution of Al in the lower respiratory tract, age, time spent living in Mexico City and the presence of pathologies. The Al found in the lower respiratory tract of residents of Mexico City would thus seem to have come from the air. The amount of Al and its distribution pattern depended on the time and place of residence and can lead to respiratory illness.


An efficient method for matching nucleic acid sequences.
A method of computing the fraction of matches between two nucleic acid sequences at all possible alignments is described. It makes use of the Fast Fourier Transform. It should be particularly efficient for very long sequences, achieving its result in a number of operations proportional to n ln n, where n is the length of the longer of the two sequences. Though the objective achieved is of limited interest, this method will complement algorithms for efficiently finding the longest matching parts of two sequences, and is faster than existing algorithms for finding matches allowing deletions and insertions. A variety of economies can be achieved by this Fast Fourier Transform technique in matching multiple sequences, looking for complementarity rather than identity, and matching the same sequences both in forward and reversed orientations.


A preliminary three-dimensional finite element analysis of mandibular implant overdentures.
A treatment protocol that may lead to reduced mandibular posterior residual ridge resorption in patients with overdentures retained and supported by two interforaminal implants was investigated. The treatment included the addition of short implants in the posterior edentulous mandible for the presumed purpose of favorable provision of mechanical load stimulus to alveolar bone. Three-dimensional finite element analysis was used to model cited effective strains that may stimulate bone remodeling in two selected models. Based on this laboratory study, the addition of posterior short implants has a favorable effect in maintaining bone mass under implant retained overdentures.


Archaeal lipid vaccine adjuvants for induction of cell-mediated immunity.
Liposomal vesicles (archaeosomes) composed of total polar lipids (TPL) or semi-synthetic glycerolipids, unique to the domain Archaea, constitute potent vaccine adjuvant and delivery systems. The characteristics of this adjuvant offer a novel prospect for the development of effective vaccines for emerging infections and cancers, which is reviewed in this article. Areas covered: The areas covered in this review include the chemical composition and physical characteristics, various in-vitro and in-vivo pre-clinical immunogenicity and efficacy studies for systemic immunization, induction of mucosal immunity upon modification of the formulation with cations, and the mechanism of adjuvant action following uptake by antigen presenting cells. Expert commentary: The unique features of archaeal lipids confer archaeosomes with many desirable features. With the use of semi-synthetic archaeosomes, highly defined lipids that are safe and robust for induction of cell-mediated immunity may be chosen. These adjuvants function as Toll-like receptor-independent innate immune stimulants.