Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis.
Melatonin is a very potent and efficient endogenous radical scavenger. The pineal indolamine reacts with the highly toxic hydroxyl radical and provides on-site protection against oxidative damage to biomolecules within every cellular compartment. Melatonin acts as a primary non-enzymatic antioxidative defense against the devastating actions of the extremely reactive hydroxyl radical. Melatonin and structurally related tryptophan metabolites are evolutionary conservative molecules principally involved in the prevention of oxidative stress in organisms as different as algae and rats. The rate of aging and the time of onset of age-related diseases in rodents can be retarded by the administration of melatonin or treatments that preserve the endogenous rhythm of melatonin formation. The release of excitatory amino acids such as glutamate enhances endogenous hydroxyl radical formation. The activation of central excitatory amino acid receptors suppress melatonin synthesis and is therefore accompanied by a reduced detoxification rate of hydroxyl radicals. Aged animals and humans are melatonin-deficient and more sensitive to oxidative stress. Experiments investigating the effects of endogenous excitatory amino acid antagonists and stimulants of melatonin biosynthesis such as magnesium may finally lead to novel therapeutic approaches for the prevention of degeneration and dysdifferentiation associated with diseases related to premature aging.


Involvement of the mRNA binding protein CRD-BP in the regulation of metastatic melanoma cell proliferation and invasion by hypoxia.
We have previously shown that the mRNA binding protein CRD-BP is overexpressed in human melanomas, where it promotes cell survival and resistance to chemotherapy. The present study investigates the role of hypoxia, a common characteristic of the tumor microenvironment, in the regulation of CRD-BP expression and melanoma cell responses. We found that hypoxia increases CRD-BP levels in metastatic melanoma cell lines but not in melanocytes or primary melanoma cells. Hypoxic stimulation transcriptionally regulates CRD-BP by facilitating the acetylation of histones within the CRD-BP gene and by modulating the extent of HIF1α binding to the CRD-BP promoter. Hypoxia significantly enhances the proliferative and invasive potential of metastatic melanoma cells but not that of normal or primary melanoma cells. Furthermore, inhibition of CRD-BP impairs the ability of metastatic cells to proliferate and invade in response to hypoxia. These findings identify CRD-BP as a novel effector of hypoxic responses that is relevant for the selection of metastatic cells. This work also describes a previously unknown role for CRD-BP in the regulation of melanoma cell invasion and highlights the importance of the hypoxic microenvironment in determining cell fate.


Identification of Quantitative Trait Loci Controlling Root and Shoot Traits Associated with Drought Tolerance in a Lentil (Lens culinaris Medik.) Recombinant Inbred Line Population.
Drought is one of the major abiotic stresses limiting lentil productivity in rainfed production systems. Specific rooting patterns can be associated with drought avoidance mechanisms that can be used in lentil breeding programs. In all, 252 co-dominant and dominant markers were used for Quantitative Trait Loci (QTL) analysis on 132 lentil recombinant inbred lines based on greenhouse experiments for root and shoot traits during two seasons under progressive drought-stressed conditions. Eighteen QTLs controlling a total of 14 root and shoot traits were identified. A QTL-hotspot genomic region related to a number of root and shoot characteristics associated with drought tolerance such as dry root biomass, root surface area, lateral root number, dry shoot biomass and shoot length was identified. Interestingly, a QTL (QRSratioIX-2.30) related to root-shoot ratio, an important trait for drought avoidance, explaining the highest phenotypic variance of 27.6 and 28.9% for the two consecutive seasons, respectively, was detected. This QTL was closed to the co-dominant SNP marker TP6337 and also flanked by the two SNP TP518 and TP1280. An important QTL (QLRNIII-98.64) related to lateral root number was found close to TP3371 and flanked by TP5093 and TP6072 SNP markers. Also, a QTL (QSRLIV-61.63) associated with specific root length was identified close to TP1873 and flanked by F7XEM6b SRAP marker and TP1035 SNP marker. These two QTLs were detected in both seasons. Our results could be used for marker-assisted selection in lentil breeding programs targeting root and shoot characteristics conferring drought avoidance as an efficient alternative to slow and labor-intensive conventional breeding methods.


An object-mediated updating account of insensitivity to transsaccadic change.
Recent evidence has suggested that relatively precise information about the location and visual form of a saccade target object is retained across a saccade. However, this information appears to be available for report only when the target is removed briefly, so that the display is blank when the eyes land. We hypothesized that the availability of precise target information is dependent on whether a post-saccade object is mapped to the same object representation established for the presaccade target. If so, then the post-saccade features of the target overwrite the presaccade features, a process of object mediated updating in which visual masking is governed by object continuity. In two experiments, participants' sensitivity to the spatial displacement of a saccade target was improved when that object changed surface feature properties across the saccade, consistent with the prediction of the object-mediating updating account. Transsaccadic perception appears to depend on a mechanism of object-based masking that is observed across multiple domains of vision. In addition, the results demonstrate that surface-feature continuity contributes to visual stability across saccades.


Processing Differences between Descriptions and Experience: A Comparative Analysis Using Eye-Tracking and Physiological Measures.
Do decisions from description and from experience trigger different cognitive processes? We investigated this general question using cognitive modeling, eye-tracking, and physiological arousal measures. Three novel findings indeed suggest qualitatively different processes between the two types of decisions. First, comparative modeling indicates that evidence-accumulation models assuming averaging of all fixation-sampled outcomes predict choices best in decisions from experience, whereas Cumulative Prospect Theory predicts choices best in decisions from descriptions. Second, arousal decreased with increasing difference in expected value between gambles in description-based choices but not in experience. Third, the relation between attention and subjective weights given to outcomes was stronger for experience-based than for description-based tasks. Overall, our results indicate that processes in experience-based risky choice can be captured by sampling-and-averaging evidence-accumulation model. This model cannot be generalized to description-based decisions, in which more complex mechanisms are involved.


Prioritisation by physicians in the Netherlands--the growth hormone example in drug reimbursement decisions.
Drug treatment and reimbursement is an area of ever growing complexity in health priority setting. This paper assesses the National Registry of Growth Hormone Treatment (LRG) responsible for making prioritisation decisions in the Dutch drug reimbursement system in the treatment of growth hormone, using the framework for fairness. We used qualitative research consisting of semi-structured interviews and focus group sessions combined with quantitative methods to audit the decisions of the forum. The rationing decisions of the forum demonstrate accountability for reasonableness by the conditions for transparency, relevance, and appeal. Most rationales for the decisions are public and transparent. The patients and paediatricians see decisions made by the LRG as clinical and therefore relevant decisions. They also refer to extensive appeal procedures. The case also raises important issues regarding the legitimacy of expert-based priority setting as the cyclic nature of guideline development conflicts with the need for maintaining strict rationing criteria. In 13% of the patients, the sick funds did cover treatment as the forum advised them to do, but according to guideline criteria it may be unlikely that these patients have growth hormone deficiency. According to the LRG, however, only 2% of the decisions are inconsistent with the guidelines, as some criteria on what to do in case of more uncertainty, shifted. For the forum, it seems rather unthinkable to go against the professional norms, in spite of formal national regulations. For the Health Care Insurance Board (CVZ), it was not considered possible to go against national regulations, especially as professional norms have shifted without informing policy makers and patient representatives.


Chiropractic care for nonmusculoskeletal conditions: a systematic review with implications for whole systems research.
(1) To evaluate the evidence on the effect of chiropractic care, rather than spinal manipulation only, on patients with nonmusculoskeletal conditions; and (2) to identify shortcomings in the evidence base on this topic, from a Whole Systems Research perspective. Systematic review. Databases included were PubMed, Ovid, Mantis, Index to Chiropractic Literature, and CINAHL. Search restrictions were human subjects, peer-reviewed journal, English language, and publication before May 2005. All randomized controlled trials (RCTs) were evaluated using the Scottish Intercollegiate Guidelines Network (SIGN) and Jadad checklists; a checklist developed from the CONSORT (Consolidated Standards of Reporting Trials) guidelines; and one developed by the authors to evaluate studies in terms of Whole Systems Research (WSR) considerations. The search yielded 179 papers addressing 50 different nonmusculoskeletal conditions. There were 122 case reports or case series, 47 experimental designs, including 14 RCTs, 9 systematic reviews, and 1 a large cohort study. The 14 RCTs addressed 10 conditions. Six RCTs were rated "high" on the 3 conventional checklists; one of these 6 was rated "high" in terms of WSR considerations. (1) Adverse effects should be routinely reported. For the few studies that did report, adverse effects of spinal manipulation for all ages and conditions were rare, transient, and not severe. (2) Evidence from controlled studies and usual practice supports chiropractic care (the entire clinical encounter) as providing benefit to patients with asthma, cervicogenic vertigo, and infantile colic. Evidence was promising for potential benefit of manual procedures for children with otitis media and elderly patients with pneumonia. (3) The RCT design is not necessarily incompatible with WSR. RCTs could improve generalizability by basing protocols on usual practice. (4) Case reports could contribute more to WSR by increasing their emphasis on patient characteristics and patient-based outcomes. (5) Chiropractic investigators, practitioners, and funding agencies should increase their attention to observational designs.


Eligibility for clinical trials in primary Sjögren's syndrome: lessons from the UK Primary Sjögren's Syndrome Registry.
To identify numbers of participants in the UK Primary Sjögren's Syndrome Registry (UKPSSR) who would fulfil eligibility criteria for previous/current or potential clinical trials in primary SS (pSS) in order to optimize recruitment. We did a retrospective analysis of UKPSSR cohort data of 688 participants who had pSS with evaluable data. In relation to previous/current trials, 75.2% fulfilled eligibility for the Belimumab in Subjects with Primary Sjögren's Syndrome study (Belimumab), 41.4% fulfilled eligibility for the Trial of Remicade in primary Sjögren's syndrome study (Infliximab), 35.4% for the Efficacy of Tocilizumab in Primary Sjögren's Syndrome study (Tocilizumab), 31.6% for the Tolerance and Efficacy of Rituximab in Sjögren's Disease study (Rituximab), 26.9% for the Trial of anti-B-cell therapy in pSS study (Rituximab) and 26.6% for the Efficacy and Safety of Abatacept in Patients With Primary Sjögren's Syndrome study (Abatacept). If recent measures of outcome, such as the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score ⩾5 (measure of patient symptoms) and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ⩾5 (measure of systemic disease activity) are incorporated into a study design, with requirements for an unstimulated salivary flow >0 and anti-Ro positivity, then the pool of eligible participants is reduced to 14.3%. The UKPSSR identified a number of options for trial design, including selection on ESSDAI ⩾5, ESSPRI ⩾5 and serological and other parameters.


Factors influencing the admission decision for Medical Psychiatry Units: A concept mapping approach.
Medical Psychiatry Units (MPUs), also known as Complexity Intervention Units (CIUs), provide care for complex patients suffering from both psychiatric and physical disorders. Because there is no consensus on the indications for admission to an MPU, daily practice and effectiveness research are hampered. This study therefore used a concept mapping approach to investigate which organizational and medical factors determine the decision to admit a patient to an MPU. The first step of the concept mapping approach was to create a list of factors determining MPU admission from literature. Secondly, clinical experts sorted and ranked these factors. The sorted and ranked data were then analyzed, and a draft conceptual framework was created. A final conceptual MPU admission framework was then drawn during an expert consensus meeting and recommendations for implementation were suggested. Thirteen clinical experts defined 90 factors from literature, which were sorted and ranked by 40 experts from 21 Dutch hospitals. This concept mapping approach resulted in a five-cluster solution for an MPU admission framework based on: 1. Staff competencies and organizational pre-requisites; 2. Patient context; 3. Patient characteristics; 4. Medical needs and capabilities; and 5. Psychiatric symptoms and behavioral problems. Furthermore, three inclusion and two exclusion criteria were formulated to help the clinicians decide whether or not to admit patients to an MPU. These criteria can be implemented in daily practice. Implementing the five criteria derived from this conceptual framework will help make the admission decision for complex patients with psychiatric and physical disorders to an MPU more correct, consistent, and transparent.


Sites, frequencies, and causes of self-reported fractures in 9,720 rheumatoid arthritis patients: a large prospective observational cohort study in Japan.
Sites, frequencies, and causes of self-reported fractures in Japanese patients with rheumatoid arthritis (RA) were evaluated in a prospective, observational cohort study. The incidence and cause of fracture differ by anatomical site, sex, and age. These differences may be considered in establishing custom strategies for preventing fractures in RA patients in the future. The literature contains limited data describing the details of fractures at different skeletal sites in patients with RA. We evaluated the details of fractures in Japanese RA patients on the basis of our Institute of Rheumatology Rheumatoid Arthritis cohort study in 9,720 RA patients (82 % women; mean age, 56 years) who were enrolled from 2000 to 2010. The details of fractures were obtained through biannual patient self-report questionnaires. Over a mean duration of 5.2 years, 1,317 patients (13.5 %) reported 2,323 incident fractures comprising 563 (24.2 %) clinical vertebral fractures and 1,760 (75.8 %) nonvertebral fractures. Rib fractures were the most common fractures in men, followed by clinical vertebral and hip fractures; the most common fractures in women were clinical vertebral fractures, followed by rib, foot, and hip fractures. There was a significant difference between sexes in the rates of rib, clavicle, shoulder, and ankle fractures. Spontaneous event was the primary cause of clinical vertebral fracture (65.4 %), whereas falls were the primary cause of upper extremity (76.5 %) and lower extremity (57.8 %) fractures. Rates of clinical vertebral and hip fractures increased, while those of rib and foot fractures decreased with increasing age. Incidence of falls, as causes of nonvertebral fractures, also increased in older age groups. Our results suggest that the causes of fractures may differ depending on anatomical site and that prevention of falls may be the most effective way to reduce upper and lower extremity fractures, especially in older patients with RA.


Deconstruction of science hegemony: discursive strategies of Chinese science communication on genetically modified foods.
This study analyzes Chinese online science communication and discussion about genetically modified foods (GMFs). Based on data collected from one of the largest Chinese GMFs science popularization website, it utilizes Wodak's discourse analysis to investigate how Chinese genetically modified (GM) scientific discourse is characterized by a range of discursive strategies that construct specific identity of Chinese GM scientists and explore science hegemony underlying Chinese GMFs debates. Findings show that discourse features of Chinese GM scientific discourse is objective as well as emotional, particularly conveying a strong sense of superiority realized by trope, argumentative strategies and intertextuality. The unequal power relationship between scientists and the public as well as Chinese intellectuals' knowledge hegemony could partly explain why those discursive strategies are employed in science communication practices of GMFs debates in Chinese context.


CHEK2, MGMT, SULT1E1 and SULT1A1 polymorphisms and endometrial cancer risk.
Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65-1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.


Sexual dimorphism in immunity across animals: a meta-analysis.
In animals, sex differences in immunity are proposed to shape variation in infection prevalence and intensity among individuals in a population, with females typically expected to exhibit superior immunity due to life-history trade-offs. We performed a systematic meta-analysis to investigate the magnitude and direction of sex differences in immunity and to identify factors that shape sex-biased immunocompetence. In addition to considering taxonomic and methodological effects as moderators, we assessed age-related effects, which are predicted to occur if sex differences in immunity are due to sex-specific resource allocation trade-offs with reproduction. In a meta-analysis of 584 effects from 124 studies, we found that females exhibit a significantly stronger immune response than do males, but the effect size is relatively small, and became non-significant after controlling for phylogeny. Female-biased immunity was more pronounced in adult than immature animals. More recently published studies did not report significantly smaller effect sizes. Among taxonomic and methodological subsets of the data, some of the largest effect sizes were in insects, further supporting previous suggestions that testosterone is not the only potential driver of sex differences in immunity. Our findings challenge the notion of pervasive biases towards female-biased immunity and the role of testosterone in driving these differences.


Open surgical release for contractures of the elbow.
Compared with arthroscopic release, open release is more commonly used for the treatment of stiff elbow. Flexion is recovered by releasing posterior tethering soft-tissue structures and by removing anterior impingement between the coronoid and/or radial head and the distal humerus. Extension is improved by releasing anterior soft-tissue tethers and by removing impingement between the olecranon tip and the olecranon fossa. Open elbow release is most commonly performed via ligament-sparing approaches. Ulnar nerve identification and transposition is recommended in the presence of nerve dysfunction or when correction of significant loss of elbow flexion is anticipated. Long-term improvement in flexion and extension can be expected with proper patient selection. Less predictable results are obtained in adolescent patients and in those with underlying traumatic brain injury.


Effects of a healthy Nordic diet on plasma 25-hydroxyvitamin D concentration in subjects with metabolic syndrome: a randomized, [corrected] controlled trial (SYSDIET).
At northern latitudes, vitamin D is not synthesized endogenously during winter, causing low plasma 25-hydroxyvitamin D (25(OH)D) concentrations. Therefore, we evaluated the effects of a healthy Nordic diet based on Nordic nutrition recommendations (NNR) on plasma 25(OH)D and explored its dietary predictors. In a Nordic multi-centre trial, subjects (n = 213) with metabolic syndrome were randomized to a control or a healthy Nordic diet favouring fish (≥300 g/week, including ≥200 g/week fatty fish), whole-grain products, berries, fruits, vegetables, rapeseed oil and low-fat dairy products. Plasma 25(OH)D and parathyroid hormone were analysed before and after 18- to 24-week intervention. At baseline, 45 % had vitamin D inadequacy (<50 nmol/l), whereas 8 % had deficiency (<25 nmol/l). Dietary vitamin D intake was increased by the healthy Nordic diet (P < 0.001). The healthy Nordic and the control diet reduced the prevalence of vitamin D inadequacy by 42 % (P < 0.001) and 19 % (P = 0.002), respectively, without between-group difference (P = 0.142). Compared with control, plasma 25(OH)D (P = 0.208) and parathyroid hormone (P = 0.207) were not altered by the healthy Nordic diet. Predictors for 25(OH)D were intake of vitamin D, eicosapentaenoic acids (EPA), docosahexaenoic acids (DHA), vitamin D supplement, plasma EPA and plasma DHA. Nevertheless, only vitamin D intake and season predicted the 25(OH)D changes. Consuming a healthy Nordic diet based on NNR increased vitamin D intake but not plasma 25(OH)D concentration. The reason why fish consumption did not improve vitamin D status might be that many fish are farmed and might contain little vitamin D or that frying fish may result in vitamin D extraction. Additional ways to improve vitamin D status in Nordic countries may be needed.


Social capital and change in psychological health over time.
The positive association between social capital and general health outcomes has been extensively researched over the past decade; however, studies investigating social capital and psychological health show less consistent results. Despite this, policy-makers worldwide still employ elements of social capital to promote and improve psychological health. This United Kingdom study investigates the association between changes in psychological health over time and three different individual-level proxies of social capital, measures of socio-economic status, social support and the confounders age and gender. All data are derived from the British Household Panel Survey data, with the same individuals (N = 7994) providing responses from 2000-2007. The data were split according to baseline psychological health status ('Good' or 'Poor' psychological health - the dependent variable). Using Generalised Estimating Equations, two separate models were built to investigate the association between changes from baseline psychological health over time and considered variables. An autoregressive working correlation structure was employed to derive the true influence of explanatory variables on psychological health outcomes over time. We found that generalised trust was the only social capital variable to maintain a positive and highly significant association with psychological health in multivariable models. All measures of socioeconomic status and social support were rendered insignificant, bar one. We therefore argue that the breakdown of the traditional family unit (and subsequent reduction in family capital investment), along with psychosocial pathways, demonstrate plausible mechanisms by which a decrease in generalised trust could lead to an increasing trend of worse psychological health in youth over successive birth cohorts. Policy makers, while providing welfare solutions in response to breakdown in traditional family structure, must also consider perverse incentives they provide. If perceived as a viable lifestyle choice, welfare provision could inadvertently promote further decline of trust, at even greater cost to society.


Higher event rate in patients with known CAD despite a normal myocardial perfusion scan.
The negative predictive value of a normal single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is very high. However, prognostic implication of a normal SPECT MPI in patients with known coronary artery disease (CAD) is not clear. Objective of this study was to evaluate the cardiac event rate in patients with known CAD who had a normal stress SPECT MPI. This prospective study accrued 428 consecutive patients with a history of CAD [revascularization or previous myocardial infarction (MI)] who had a normal stress (dynamic exercise or dipyridamole intervention) and rest Tc-99m-MIBI SPECT MPI. These patients were followed for 2-5 years (median: 3.1 years) for all-cause and cardiac mortality and non-fatal MI. Univariate and multivariate analyses were performed to identify predictors of outcome. During a follow-up period, all-cause mortality was found in 60 patients (14%) and 41 (10%) died of cardiac reasons. Non-fatal MI was found in 77 (18%) patients. Annualized cardiac mortality and non-fatal MI rates were 2% and 3.6% respectively. Smoking, congestive heart failure (CHF) and failure to achieve 85% age predicted heart rate were found to be predictors for all-cause and cardiac mortality. Diabetes, dyslipidemia, smoking and limited functional capacity (<7 METS) were found to be predictors for non-fatal MI. Patients with known CAD had higher cardiac event rates despite a normal stress SPECT MPI. Diabetes, dyslipidemia, smoking and limited functional capacity were the predictors for fatal and non-fatal cardiac events. A cost effective but comprehensive surveillance strategy is warranted.


Experience-dependent plasticity of neurovascularization.
Experience powerfully shapes structural and functional organization of neurons during development and in adulthood. Recent experiments in the mouse primary somatosensory cortex now suggest that experience is also a critical factor in shaping neurovasculature and promoting angiogenesis. These results support the universality of brain plasticity and show that all structural cellular components in the brain, from neuron and glia to epithelia, are shaped by experience.


Hypoxic preconditioning increases survival and angiogenic potency of peripheral blood mononuclear cells via oxidative stress resistance.
Cell-based angiogenesis is a promising treatment for ischemic diseases; however, the survival of implanted cells is impaired by oxidative stress in the ischemic microenvironment. We tested the hypothesis that hypoxic preconditioning of implanted cells enhances their resistance against oxidative stress, increasing cell survival and angiogenic potency after implantation into ischemic tissue. Mouse peripheral blood mononuclear cells (PBMNCs) were collected and subjected to hypoxic preconditioning by culture for 24 h in 2% O(2) at 33 degrees C. Hypoxic preconditioning of PBMNCs increased the expression of various genes related to antioxidant and survival signals remarkably. Compared with cells cultured under normoxia, the hypoxia-preconditioned PBMNCs showed significantly lower reactive oxygen species (ROS) accumulation and higher cell survival under oxidative stress induced by LY-83583 (a superoxide generator). Three days after intramuscular implantation into the ischemic hindlimbs of mice, survival of the hypoxia-preconditioned PBMNCs was high, whereas that of the normoxia-cultured PBMNCs was relatively low. Furthermore, 28 days after treatment microvessel density and blood flow in the ischemic hindlimbs were significantly better in the mice implanted with hypoxia-preconditioned PBMNCs than in those implanted with normoxia-cultured PBMNCs. Hypoxic preconditioning increased the survival and angiogenic potency of PBMNCs, through oxidative stress resistance mechanisms.


Spectroscopic study of the photofixation of SO2 on anatase TiO2 thin films and their oleophobic properties.
Photoinduced SO(2) fixation on anatase TiO(2) films was studied by in situ Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS). The TiO(2) films were prepared by reactive DC magnetron sputtering and were subsequently exposed to 50 ppm SO(2) gas mixed in synthetic air and irradiated with UV light at substrate temperatures between 298 and 673 K. Simultaneous UV irradiation and SO(2) exposure between 373 and 523 K resulted in significant sulfur (S) deposits on crystalline TiO(2) films as determined by XPS, whereas amorphous films contained negligible amounts of S. At substrate temperatures above 523 K, the S deposits readily desorbed from TiO(2). The oxidation state of sulfur successively changed from S(4+) for SO(2) adsorbed on crystalline TiO(2) films at room temperature without irradiation to S(6+) for films exposed to SO(2) at elevated temperatures with simultaneous irradiation. In situ FTIR was used to monitor the temporal evolution of the photoinduced surface reaction products formed on the TiO(2) surfaces. It is shown that band gap excitation of TiO(2) results in photoinduced oxidation of SO(2), which at elevated temperatures become coordinated to the TiO(2) lattice through interactions with O vacancies and form sulfite and sulfate surface species. These species makes the surface acidic, which is manifested in nondetectable adherence of stearic acid to the modified surface. The modified films show good chemical stability as evidenced by sonication and repeated recycling of the films. The results suggest a new method to functionalize wide band gap oxide surfaces by means of photoinduced reactions in reactive gases at elevated substrate temperatures. In the case of anatase TiO(2) in reactive SO(2) gas, we here show that such functionalization yields surfaces with excellent oleophobic properties, as probed by adhesion of stearic acid.


Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness.
Targeted mutagenesis in embryonic stem cells was used to generate mice deficient in lymphotoxin-alpha (LT-alpha). Mice lacking LT-alpha -/- (LT-alpha -/- mice) exhibit a phenotype dominated by defects in secondary lymphoid organ development. LT-alpha -/- mice lack lymph nodes and Peyer's patches, and possess spleens in which the usual architecture is disrupted. However, in a few of the mutants, abnormal lymph node-like structures were observed, mainly within the mesenteric fat. Abnormal clusters of lymphocytes were also found to accumulate in the periportal and perivascular regions of the liver and lung of LT-alpha -/- mice. Yet, lymphocytes from LT-alpha -/- mice appeared phenotypically normal, expressing the expected ratios of B and T cell surface markers as well as the lymphocyte homing marker, L-selectin. In addition, bone marrow cells from LT-alpha -/- mice were able to successfully reconstitute the lymphoid organs of severe combined immunodeficient mice. However, LT-alpha -/- mutant mice examined for humoral immune responsiveness were found to be impaired in their ability to respond to different Ag. These data illustrate the utility of this mouse model as a system for understanding lymphoid organ development and its effects on immune responsiveness.


Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates.
Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with α-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries. In vitro generated α-syn oligomers and fibrils were characterized using atomic force microscopy and the thioflavin T binding assay. These toxic oligomers or fibrils administered alone (0.48 mg/kg) or their 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behavior was tested on days 0, 15 and 28 of the protocol. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e., 14 days after treatment completion) induced rigidity, hypokinesia and immobility. This was accompanied by elevated nigral but not striatal DA, DOPAC and HVA concentrations in response to dual administration of α-syn oligomers plus fibrils but not the oligomers by themselves. α-Syn fibrils intensified not only the hypokinesia and immobility 14 days post treatment, but also reduced vertical rearing and enhanced DA levels in the substantia nigra. Only nigral DA turnover (DOPAC/DA but not HVA/DA ratio) was augmented in response to fibril treatment but there were no changes in the striatum. Compilation of these novel behavioral and neurochemical findings substantiate the validity of the α-syn nasal vector model for investigating parkinsonian-like symptoms.


Is implicit Theory of Mind real but hard to detect? Testing adults with different stimulus materials.
Recently, Theory of Mind (ToM) research has been revolutionized by new methods. Eye-tracking studies measuring subjects' looking times or anticipatory looking have suggested that implicit and automatic forms of ToM develop much earlier in ontogeny than traditionally assumed and continue to operate outside of subjects' awareness throughout the lifespan. However, the reliability of these implicit methods has recently been put into question by an increasing number of non-replications. What remains unclear from these accumulating non-replication findings, though, is whether they present true negatives (there is no robust phenomenon of automatic ToM) or false ones (automatic ToM is real but difficult to tap). In order to address these questions, the current study implemented conceptual replications of influential anticipatory looking ToM tasks with a new variation in the stimuli. In two separate preregistered studies, we used increasingly realistic stimuli and controlled for potential confounds. Even with these more realistic stimuli, previous results could not be replicated. Rather, the anticipatory looking pattern found here remained largely compatible with more parsimonious explanations. In conclusion, the reality and robustness of automatic ToM remains controversial.


Long-term treatment with angiotensin converting enzyme inhibitor restores reduced calcitonin gene-related peptide-containing vasodilator nerve function in mesenteric artery of spontaneously hypertensive rats.
Effects of long-term treatment with angiotensin converting enzyme (ACE) inhibitor on decreased function of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRP nerves) in mesenteric resistance artery were investigated in spontaneously hypertensive rats (SHR). Eight-week-old SHR were treated for 7 weeks with 0.1% captopril, 0.01% temocapril, 0.05% pindolol or 0.005% hydralazine in drinking water. Long-term treatment with each drug significantly lowered mean blood pressure of SHR. In isolated and perfused mesenteric vascular beds with active tone, periarterial nerve stimulation (PNS) (0.5 to 8 Hz) produced frequency-dependent vasodilations, which were abolished by CGRP(8-37) (CGRP-receptor antagonist) and significantly smaller in SHR than in normotensive Wistar Kyoto rats. Treatment of SHR with captopril and temocapril but not with pindolol and hydralazine resulted in significantly greater PNS-induced vasodilation than in non-treated SHR, but ACE-inhibitor treatment did not affect vasodilation induced by exogenous CGRP. In captopril-treated SHR preparations, PNS evoked significantly larger CGRP-like immunoreactive release than in non-treated SHR. In non-treated 15-week-old SHR preparations, direct perfusion of captopril or temocapril (0.1 microM and 1 microM) did not modify frequency-dependent vasodilation in response to PNS. These results suggest that long-term ACE inhibitor treatment prevents or restores CGRP nerve function reduction in SHR.


Bioactive compounds and pharmacological and food applications of Syzygium cumini - a review.
The present review explores the nutritional, phytochemical and pharmacological potential as well as diverse food usages of Syzygium cumini. S. cumini is a traditional medicinal plant with various bioactive compounds distributed in all parts of the plant. The major bioactive compounds present in the edible part are myricetin, oxalic acid, gallic acid, citronellol, cyanidin diglucoside, hotrienol, phytosterols, flavonoids, carotenoids and polyphenols as well as micronutrients, accounting for numerous health benefits. The potential benefits of these bioactive compounds are to prevent/reduce metabolic abnormalities and various diseases. The health protective effects and functional properties of the plant were proved by different in vitro and in vivo pharmacological studies. All parts of the plant have good health benefits like hypoglycemic, anti-inflammatory, antianemic, antibacterial, antioxidant, antiallergic, hepatoprotective, hypolipidemic and antipyretic properties. The fruit of S. cumini can be consumed raw or processed in the form of jam, jellies, wine, fermented beverages and many other value added food products.


Follow-up urodynamics in patients with neurogenic bladder.
Neurogenic bladder patients are at long-term risk of secondary upper urinary tract damage. Symptoms are unreliable and follow-up urodynamics is the only method of ascertaining safety of bladder pressures. This review examines the recommendations, shortcomings and utilization of existing guidelines. The evidence with regard to follow-up urodynamics in different settings relevant to neurogenic bladder is evaluated and an algorithm is proposed. A pubmed search was conducted for studies on follow-up urodynamics in patients with neurogenic bladder. Additional search was made of secondary sources including reviews and guidelines. The need for follow-up urodynamics should be considered in all patients undergoing an initial assessment and weighed against the risks. Existing guidelines, while unanimous in their recommendation of its utilization, give scant details regarding its incorporation in clinical management. Follow-up urodynamics can document efficacy and identify the need for escalation of therapy in patients on intermittent catheterization and antimuscarinics. Patients with spinal injury, spinal dysraphism and anorectal malformations are at higher risk for upper tract damage. Follow-up urodynamics can help identify patients suitable for intravesical botulinum and mark those destined for failure. Patients undergoing augmentation cystoplasty may be candidates for less aggressive urodynamic follow-up. Neurogenic bladder is managed by a broad cross-section of physicians. Clear recommendations and a management algorithm are important for improving patient care. Follow-up urodynamics can identify patients at risk, prevent renal dysfunction and improve the quality of life. There is an urgent need for more evidence on this important subject.


The level of H₂O₂ type oxidative stress regulates virulence of Theileria-transformed leukocytes.
Theileria annulata infects predominantly macrophages, and to a lesser extent B cells, and causes a widespread disease of cattle called tropical theileriosis. Disease-causing infected macrophages are aggressively invasive, but this virulence trait can be attenuated by long-term culture. Attenuated macrophages are used as live vaccines against tropical theileriosis and via their characterization one gains insights into what host cell trait is altered concomitant with loss of virulence. We established that sporozoite infection of monocytes rapidly induces hif1-α transcription and that constitutive induction of HIF-1α in transformed leukocytes is parasite-dependent. In both infected macrophages and B cells induction of HIF-1α activates transcription of its target genes that drive host cells to perform Warburg-like glycolysis. We propose that Theileria-infected leukocytes maintain a HIF-1α-driven transcriptional programme typical of Warburg glycolysis in order to reduce as much as possible host cell H2 O2 type oxidative stress. However, in attenuated macrophages H2O2 production increases and HIF-1α levels consequently remained high, even though adhesion and aggressive invasiveness diminished. This indicates that Theileria infection generates a host leukocytes hypoxic response that if not properly controlled leads to loss of virulence.


Hypoglossal canal dural arteriovenous fistula: incidence and the relationship between symptoms and drainage pattern.
The purpose of this study was to evaluate the incidence, radiographic findings, relationship between presenting symptoms for treatment and drainage pattern, and treatment outcomes of hypoglossal canal dural arteriovenous fistula (HC-dAVF). During a 16-year period, 238 patients underwent endovascular treatment for cranial dAVF at a single center. The incidence, radiographic findings, relationship between presenting symptoms for treatment and drainage pattern, and treatment outcomes of HC-dAVF were retrospectively evaluated. The incidence of HC-dAVF was 4.2% (n = 10). Initial symptoms were tinnitus with headache (n = 6), tinnitus only (n = 1), ocular symptoms (n = 1), otalgia (n = 1), and congestive myelopathy (n = 1). Presenting symptoms requiring treatment included ocular symptoms (n = 4), hypoglossal nerve palsy (n = 4), aggravation of myelopathy (n = 1), and aggravation of tinnitus with headache (n = 1). While the affected HC was widened in 4 of 10 patients, hypersignal intensity on source images was conspicuous in all 7 patients who underwent MR angiography (MRA). All ocular symptoms and congestive myelopathy were associated with predominant drainage to superior ophthalmic or perimedullary veins due to antegrade drainage restriction. All patients who underwent transvenous coil embolization (n = 8) or transarterial N-butyl cyanoacrylate (NBCA) embolization (n = 1) improved without recurrence. One patient who underwent transarterial particle embolization had a recurrence 12 months posttreatment and was retreated with transvenous embolization. The incidence of HC-dAVF was 4.2% of all cranial dAVF patients who underwent endovascular treatment. Source images of MRA helped to accurately diagnose HC-dAVF. More aggressive symptoms may develop as a result of a change in the predominant drainage route due to the development of venous stenosis or obstruction over time. Transvenous coil embolization appears to be the first treatment of choice.


Assessment of Economic Impact Among In-Patients with Non-Communicable Diseases in a Private Tertiary Care Hospital in Southern India.
Non-communicable diseases (NCDs) are currently responsible for tremendous economic impact on households. This study was done to estimate the direct, indirect and total costs incurred by households of in-patients with non-communicable diseases admitted in a Private tertiary care hospital. It was a cross-sectional study conducted in a private tertiary care hospital of Mangalore city in June 2012 by interviewing 30 patients and their attenders using a validated interview schedule. Direct cost constituted 58.6% of the total expenses during the course of stay in the hospital. Mean direct cost was more among patients with cancers (p=0.049). Indirect cost was associated with educational status (p=0.04), occupational status (p<0.001) and socio economic status (ses) (p<0.001) of patients. Total cost was more among patients from upper middle ses households (p=0.012). Direct and indirect cost constituted 5-10% each and total cost > 20% of the annual income of majority of households. Medical insurance scheme was not availed by 26 (86.7%) patients due to ignorance. Economic burden imposed by a single admission among inpatients with NCDs was tremendous on their households. Hence, information on various medical insurance schemes needs to be popularized among people to improve its utilization. Health care providers need to introduce more financial schemes to minimize health care costs among poor households.


Maximization of production of secreted recombinant proteins in Pichia pastoris fed-batch fermentation.
Pontryagin's Maximum Principle has been applied for optimization of secreted proteins from Pichia pastoris fed-batch fermentation. The objective of this work is to maximize the total accumulated product per unit operation time under different given conditions and system constraints. To obtain optimal solutions, an automated curve-fitting software, Table Curve 2D, was employed to construct the necessary mathematical models and solve the complicated functions. In the solution processes, the end of the glycerol batch phase was defined as the initial state of the system, the end of the methanol fed-batch phase as the final state, the cell mass produced along with product accumulated as state variables, and the specific growth rate (mu) as the control variable. Initially, a relationship between the specific production rate (rho) and mu was established. Then, according to Pontryagin's Maximum Principle, the admissible range of mu and its trajectories for the optimal operations were determined. Four representative cases with different combinations of the operation time along with the initial and final states were evaluated. A close correlation was obtained between the predicted values of the model equation with the experimental results from the Pichia pastoris fed-batch fermentations producing secreted alpha-galactosidase. The approaches proposed here greatly simplify the computational processes and validate the optimization strategy as a generalized approach to maximize the yield from fed-batch fermentations.


Acute hemolytic transfusion reaction due to anti-Le(b).
Anti-Le(b) is usually a clinically insignificant antibody of immunoglobulin M subclass most often found in the sera of pregnant women or individuals that are Le(a-b-). We report a case of an acute hemolytic transfusion reaction due to a hemolytic anti-Le(b) that was not seen in the pretransfusion antibody detection test, but was strongly reactive in posttransfusion testing. A 30-year-old African-American woman with metastatic renal cell carcinoma was receiving chemotherapy. She was anemic with hemoglobin (Hb) of 7.2 g/dL and had a negative antibody detection test by the solid-phase red blood cell adherence method. She was transfused with 2 RBC units without incident. Nine days later her Hb was 7.9 g/dL again with a negative antibody detection test. Transfusion of an additional RBC unit was begun. During the transfusion she developed chills, nausea, hypertension, and red-brown urine. The posttransfusion sample plasma was grossly hemolyzed with a strongly positive direct antiglobulin test (DAT) by gel. By comparison the pretransfusion plasma was normal appearing and the DAT was weaker. The eluate was negative on both occasions. Anti-Le(b) was detected in the posttransfusion sample by MTS gel (Ortho Diagnostics). Both RBC units she had received before the RBC unit that caused the reaction were Le(b+) as was the implicated RBC unit. This case illustrates that anti-Le(b) which is usually clinically insignificant can occasionally cause severe hemolytic transfusion reactions. Only three other reported cases of anti-Le(b) causing hemolytic transfusion reactions could be found in the literature, two of which were in abstract form only.


A powerful team: the family physician advocating for patients with a rare disease.
Rare diseases are characteristically difficult to diagnose and for the majority, there are no effective treatments or evidence-based management guidelines. Although it is unrealistic to expect family physicians to recognise the wide clinical spectrum of rare diseases, their longitudinal and holistic approach to medicine place them in a unique position to consider the possibility of a rare disease. This article outlines the challenges faced by the rare disease community, and the role of the primary care physician to advocate for answers as their patients transition through the healthcare system. The road to the diagnosis of a rare disease can test the doctor-patient relationship. Patients often struggle for answers and family physicians are stymied by a lack of information. At the same time, the availability of cyber-based health information and online rare-disease patient groups has led to the emergence of the 'expert' patient, who seeks a collaborative and empowering relationship with their physician. Following diagnosis, the family physician plays a crucial part in providing continuity of care, advocating access to expert healthcare, coordinating complex management and becoming a source of psychological support.


Work-life balance among shift workers: results from an intervention study about self-rostering.
The aims of the study were to explore the effects of the implementation of IT-based tools for planning of rosters among shift workers on work-family-related outcomes and to interpret the results in light of the different implementation processes. A quasi-experimental intervention study was conducted with 12-month follow-up at 14 intervention and 14 reference worksites in Denmark. Workplaces planning to introduce IT-supported self-rostering were recruited, and three different kinds of interventions were implemented. Intervention A and B aimed at increasing workers satisfaction and well-being, while intervention C was designed to optimize the personnel resources. Questionnaire data were collected from 840 employees at baseline and 784 at follow-up. Process evaluation encompassed interviews with about 25 employees and 15 managers at baseline and follow-up. Work-family-related outcomes were work-life conflicts, work-life facilitation, marital conflicts and time with children. An overall decline in work-family conflicts and increase in work-family facilitation were found in the total intervention group. More specifically, in group B, work-family conflicts and marital conflicts decreased while work-family facilitation increased. In group C, work-family conflicts increased while work-family facilitation and time spend with children decreased, and no significant changes were observed in the reference group and in group A. An overall positive effect of the implementation of self-rostering was found on the balance between work and private life. However, results from the process evaluation suggested that the organizational aim with the intervention was crucial for the effect.


Counting and cardinal understanding in children with Down syndrome and typically developing children.
This study compares the procedural counting ability (independently and with parental support) and conceptual understanding of cardinality of a group of children with Down syndrome and a group of typically developing children, matched for non-verbal mental age. Participants were 23 children with Down syndrome (chronological age range: 3.5-7 years; mental age range: 2.5-4 years) and 20 typically developing children (chronological age range: 2-4 years; mental age range: 2.5-4 years), and their main caregiver. The children were asked to count sets of toys (assessing procedural counting skills) and to give sets of toys (assessing understanding of cardinality), with set sizes between 2 and 18 items. The counting task was performed in two conditions, with and without parental support. The children were also asked to say the count word sequence aloud, to assess sequence production independent from object counting. The typically developing children produced significantly more number words altogether, longer standard number sequences and could count larger sets than the children with Down syndrome. Support from an adult improved performance on the count task significantly for both groups of children, and there was no significant difference between the groups in the degree of improvement, i.e. the zone of proximal development. No significant differences were found between the frequency of children (approximately one third) in each group who used counting to solve the give task, indicating an understanding of cardinality.


Geographic Variations and Time Trends in Cancer Treatments in Taiwan.
Targeted therapies have become important treatment options for cancer care in many countries. This study aimed to examine recent trends in utilization of antineoplastic drugs, particularly the use of targeted therapies for treatment of cancer, by geographic region in Taiwan (northern, midwestern, southern, and eastern regions and the outer islands). This was a retrospective observational study of antineoplastic agents using 2009-2012 quarterly claims data from Taiwan's National Health Insurance Research Database. Yearly market shares by prescription volume and costs for targeted therapies among total antineoplastic agents by region were estimated. We used multivariate regression model and ANOVA to examine variations in utilization of targeted therapies between geographic regions and used ARIMA models to estimate longitudinal trends. Population-adjusted use and costs of antineoplastic drugs (including targeted therapies) were highest in the southern region of Taiwan and lowest in the outer islands. We found a 4-fold difference in use of antineoplastic drugs and a 49-fold difference in use of targeted therapies between regions if the outer islands were included. There were minimal differences in use of antineoplastic drugs between other regions with about a 2-fold difference in use of targeted therapies. Without considering the outer islands, the market share by prescription volume and costs of targeted therapies increased almost 2-fold (1.84-1.90) and 1.5-fold (1.26-1.61) respectively between 2009 and 2012. Furthermore, region was not significantly associated with use of antineoplastic agents or use of targeted therapies after adjusting for confounders. Region was associated with costs of antineoplastic agents but it was not associated with costs of targeted therapies after confounding adjustments. Use of antineoplastic drugs overall and use of targeted therapies for treatment of cancer varied somewhat between regions in Taiwan; use was notably low in the outer islands. Strategies might be needed to ensure access to cancer care in each region as economic burden of cancer care increase due to growing use of targeted therapies.


Assessment of groundwater vulnerability using integrated remote sensing and GIS techniques for the West Bengal coast, India.
Groundwater in the coastal districts of West Bengal, India is highly susceptible to various factors such as over-pumping, variations in rainfall, lower elevation and risk due to sea level rise. In addition to these factors, tropical cyclone induced storm surge and saltwater intrusion also induce potential risks to the quality of the coastal aquifers. There are several knowledge gaps, as many of these factors have not previously been systematically and rigorously analysed; furthermore, up-to-date information is either unavailable or insufficient. Accordingly, the present study analysed the groundwater vulnerability during the pre- and post-monsoon months for the period from 2001 to 2010 at three main coastal districts of West Bengal: East Midnapore, South 24 Parganas and North 24 Parganas (administrative regions). The GALDIT index-based model was employed to assess salt-water intrusion into the groundwater using Geographic Information System (GIS). Spatial distribution maps were also generated to identify highly vulnerable groundwater locations. Map removal and single parameter sensitivity analyses were performed to understand the sensitivity of the parameters. The study reveals that the depth of ground-water levels for the three districts increased and also the rainfall exerts a significant effect on the groundwater depth. The chemical constituents TDS and chloride contents in groundwater during the period 2004 to 2010 were analysed. The average TDS range values for pre- and post-monsoon seasons were observed to vary in the range between 100 and 3874 mg/l and 83-1929 mg/l respectively. Reports indicate that, groundwater in the area is highly saturated with iron containing minerals like Fe(OH)3, goethite, and hematite and is also moderately saturated with the calcite, chalcedony, dolomite and quartz, whereas under-saturated with anhydrite and gypsum. The implications of the research points to the urgent need for remedial action and appropriate responses at policy-level to protect groundwater.


Expression of leukotriene receptors in the rat dorsal root ganglion and the effects on pain behaviors.
Leukotrienes (LTs) belong to the large family of lipid mediators implicated in various inflammatory conditions such as asthma and rheumatoid arthritis. Four distinct types (BLT1, BLT2, CysLT1 and CysLT2) of G-protein-coupled receptors for LTs have been identified. Several studies have reported that LTs are involved in inflammatory pain, but the mechanism and the expression of LT receptors in the nociceptive pathway are unknown. We investigated the precise expression of these four types of LT receptors in the adult rat dorsal root ganglion (DRG) using reverse transcription-polymerase reaction (RT-PCR) and radioisotope-labeled in situ hybridization histochemistry (ISHH). We detected mRNAs for BLT1 and CysLT2 in the DRG, but not for BLT2 and CysLT1. CysLT2 mRNA was preferentially expressed by small sized DRG neurons (about 36% of total neurons), whereas BLT1 mRNA was expressed by non-neuronal cells. Double labeling analysis of CysLT2 with NF-200, calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), transient receptor potential vanilloid subfamily 1 (TRPV1) and P2X3 receptor revealed that many CysLT2-labeled neurons were localized with unmyelinated and non-peptidergic neurons, and interestingly, CysLT2 mRNA heavily co-localized with TRPV1 and P2X3-positive neurons. Intraplantar injection of LTC4, a CysLT2 receptor agonist, itself did not induce the thermal hyperalgesia, spontaneous pain behaviors or swelling of hind paw. However, pretreatment of LTC4 remarkably enhanced the painful behaviors produced by alpha, beta-methylene adenosine 5'-triphosphate (αβ-me-ATP), a P2X3 receptor agonist. These data suggests that CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to a potentiation of the neuronal activity following peripheral inflammation.


Kinship and social bonds in female chimpanzees (Pan troglodytes).
A large body of theoretical and empirical research suggests that kinship influences the development and maintenance of social bonds among group-living female mammals, and that human females may be unusual in the extent to which individuals form differentiated social relationships with nonrelatives. Here we combine behavioral observations of party association, spatial proximity, grooming, and space use with extensive molecular genetic analyses to determine whether female chimpanzees form strong social bonds with unrelated individuals of the same sex. We compare our results with those obtained from male chimpanzees who live in the same community and have been shown to form strong social bonds with each other. We demonstrate that party association is as good a predictor of spatial proximity and grooming in females as it is in males, that the highest party association indices are consistently found between female dyads, that the sexes do not differ in the long-term stability of their party association patterns, and that these results cannot be explained as a by-product of the tendency of females to selectively range in particular areas of the territory. We also show that close kin (i.e. mother-daughter and sibling dyads) are very rare, indicating that the vast majority of female dyads that form strong social bonds are not closely related. Additional analyses reveal that "subgroups" of females, consisting of individuals who frequently associate with one another in similar areas of the territory, do not consist of relatives. This suggests that a passive form of kin-biased dispersal, involving the differential migration of females from neighboring communities into subgroups, was also unlikely to be occurring. These results show that, as in males, kinship plays a limited role in structuring the intrasexual social relationships of female chimpanzees.


[Clinical studies on sulbactam/ampicillin in the field of pediatrics].
During 8 months from October 1986 to May 1987, the clinical efficacy of sulbactam/ampicillin (SBT/ABPC) was evaluated in 63 pediatric inpatients with various infections. Clinical efficacies were evaluable in 58 patients among them (consisting of 2 patients with sepsis, 3 with tonsillitis, 12 with bronchitis, 6 with bronchopneumonia, 24 with pneumonia, 1 with phlegmon, 2 with lymphadenitis, 1 with impetigo and 7 with urinary tract infection) and were excellent in 40 patients and good in 17 with an overall efficacy rate of 98.3%. Bacteriological efficacies were assessed in 25 patients and 27 strains of organisms (consisting of 3 strains of Staphylococcus aureus, 2 Streptococcus pneumoniae, 1 Streptococcus pyogenes, 2 beta-Streptococcus, 1 Gram-positive cocci, 5 Escherichia coli, 1 Enterobacter aerogenes, 7 Haemophilus influenzae, 2 Haemophilus parainfluenzae, 1 Branhamella catarrhalis, 1 Proteus mirabilis and 1 Salmonella subgenus I). Bacteriological eradication rates were 88.9% for Gram-positive organisms, 66.7% for Gram-negative organisms and 74.1% overall. No superinfection was observed in any of patients treated. Side effects and clinical laboratory parameter abnormalities observed consisted of diarrhea in 7 (11.1%) of the 63 patients, eosinophilia in 2 (3.3%) of 61 tested, thrombocytosis in 3 (5.5%) of 55, elevation of direct bilirubin in 1 (3.3%) of 30, elevation of total bilirubin in 1 (3.1%) of 32, elevation of GOT in 4 (6.8%) of 59 and elevation of GPT in 1 (1.7%) of 59 patients tested. As an effect on the hemostatic mechanism of this drug, PIVKA II was detected in 1 patient (4.2%) of 24 tested, but findings of other coagulation tests were normal and none of patients showed bleeding tendency or inhibition of platelet aggregation. From the above results, it appears that SBT/ABPC is an efficacious and safe drug in the treatment of bacterial infections of pediatric patients.


Pharmacodynamic model for acute tolerance development to the electroencephalographic effects of alfentanil in the rat.
This investigation was carried out to characterize the rate and extent of acute tolerance development to the pharmacodynamics of alfentanil in the rat with the electroencephalogram (EEG) as a measure of alfentanil's effects on the central nervous system. Alfentanil was administered by use of three different drug infusion strategies in order to develop a pharmacokinetic-pharmacodynamic model for acute tolerance: I) intravenous infusion of 0.5 mg/kg in 10 min, achieving peak alfentanil concentrations of 750 ng/ml; II) computer-controlled infusion to rapidly achieve and maintain a constant drug level of 750 ng/ml, followed by washout; III) computer-controlled infusion to step through multiple constant drug levels (up to 1500 ng/ml), followed by washout. Frequent arterial plasma samples were taken and assayed for alfentanil. EEG signals were continuously recorded until effects returned to base-line values. The amplitudes in the 0.5- to 3.5-Hz (delta) frequency band were calculated by aperiodic analysis and used as an EEG effect measure. The pharmacokinetic data were characterized by a three-compartment model with nonlinear clearance. Nonlinear kinetics was apparent from the multiple steady-state protocol III. Clearance values ranged from (S.E.) 49.7 (2.8) ml/min/kg at low alfentanil concentrations to a minimum value of 29.3 (0.8) ml/min/kg at high concentrations. The pharmacodynamic data showed profound acute tolerance development reflected as proteresis in the concentration-effect pairs after protocol I and a rapidly declining effect in the presence of stable alfentanil concentrations after protocols II and III. The effect stabilized within 15 min after a change in target concentration. A physiological tolerance model was developed to characterize the rate and extent of tolerance development to the effects of alfentanil. The models are generally applicable and consider the physiological homeostatic mechanisms responsible for the tolerance development to be an integral part of the pharmacodynamic system. Tolerance was modeled as a negative feedback control of the drug-induced effect with a first-order transfer function. The model required only two tolerance parameters to quantify the rate and extent of tolerance development and allowed for a rebound effect. Maximum tolerance diminished alfentanil's effect by 46% and was achieved with a half-life of 7.0 min.


PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells.
Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator-activated receptor (PPAR)β/δ inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells. Wild-type and transgenic mice with reduced PPARβ/δ expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARβ/δ agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARβ/δ activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARβ/δ in knockout mice induced ER stress in the heart. Moreover, PPARβ/δ knockout mice also displayed a reduction in autophagic markers. Our data indicate that PPARβ/δ activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy.


Implanted cell-dense prevascularized tissues develop functional vasculature that supports reoxygenation after thrombosis.
Achieving adequate vascularization within implanted engineered tissues is a significant obstacle to maintaining viability and functionality. In vitro prevascularization of engineered tissues has been explored as a potential solution to this challenge. The traditional paradigm of in vitro prevascularization is to implant an engineered tissue with a preformed vascular network that is perfused after anastomosis with the host circulation. We investigated the efficacy of this strategy by implanting cell-dense prevascularized tissues created via cell-mediated contraction and composed of collagen and a collagen-fibrin mixture into dorsal window chambers surgically prepared on immunocompromised mice. We found that host-implant anastomosis takes place in 2-6 days and that perfusion of vessels within the implants is subsequently restricted by thrombosis. However, by day 7, a functional vascular network composed of host and implant vessels developed. Prevascularization enhanced intra-implant pO2 significantly as early as 2 days postimplantation, reaching a maximum of 55 mmHg by day 8, which was significantly greater than the maximum within cellularized control tissues (18 mmHg). By day 14, collagen tissues supported ∼ 0.51 × 10(9) implanted and host-derived cells per mL. Our findings elucidate key features of in vitro prevascularization that can be used toward the design of larger and more functionally complex engineered tissues.


An unusual cause of acute abdomen in adults: giant cystic lymphangioma of the pancreatic head. A clinical case and literature review.
Cystic lymphangioma of the pancreas presenting as acute abdomen in adults has not been reported before. We report the case of a young man who presented with severe pain in the upper abdomen and abdominal swelling. On imaging, he was found to have a giant multiseptate cystic lesion occupying almost the entire abdomen anterior to the pancreas. On exploration, a cystic mass involving the head of the pancreas and densely adherent to the antrum, and the second and third parts of the duodenum was found and a classic Whipple pancreaticoduodenectomy was done. Histology revealed a diagnosis of cystic lymphangioma. Cystic lymphangioma is a rare benign tumor of the pancreas and this is the first reported case in an adult presenting with acute abdomen. Though rarely diagnosed preoperatively, this entity should also be considered in the differential diagnosis of cystic lesions of the pancreas. Complete surgical excision is curative.


Using the Relating to Older People Evaluation tool to measure ageism in higher education.
The global population is ageing and this trend is expected to continue. Attitudes towards older people differ worldwide. Ageism is a complex, multifaceted concept that includes attitudes and behaviours. In the UK, ageism and discriminatory practices exist in nursing, and educationalists and clinicians need to address ageist attitudes and promote the care of older people. In nursing there is a lack of synthesised evidence measuring ageism among nursing students. To explore the use of the Relating to Older People Evaluation (ROPE) questionnaire in different student populations in higher education, including nursing students. A systematic search was conducted for articles written in English describing the use of ROPE, published between 2007 and 2017. Six quantitative studies were identified that met the inclusion criteria. Statistical analysis was not possible and a thematic analysis of these studies was completed. Two themes emerged: attitudes predict behaviour and socialisation to ageism in higher education. Ageist attitudes were correlated with negative ageist behaviours and the socialisation of nursing students in clinical practice increased ageist attitudes. Ageism and the ageist attitudes of nursing students must continue to be explored. ROPE is a suitable tool to measure nursing students' ageist attitudes and behaviours.


Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors.
We have crystallized Drosophila melanogaster acetylcholinesterase and solved the structure of the native enzyme and of its complexes with two potent reversible inhibitors, 1,2,3,4-tetrahydro-N-(phenylmethyl)-9-acridinamine and 1,2,3,4-tetrahydro-N-(3-iodophenyl-methyl)-9-acridinamine--all three at 2.7 A resolution. The refined structure of D. melanogaster acetylcholinesterase is similar to that of vertebrate acetylcholinesterases, for example, human, mouse, and fish, in its overall fold, charge distribution, and deep active-site gorge, but some of the surface loops deviate by up to 8 A from their position in the vertebrate structures, and the C-terminal helix is shifted substantially. The active-site gorge of the insect enzyme is significantly narrower than that of Torpedo californica AChE, and its trajectory is shifted several angstroms. The volume of the lower part of the gorge of the insect enzyme is approximately 50% of that of the vertebrate enzyme. Upon binding of either of the two inhibitors, nine aromatic side chains within the active-site gorge change their conformation so as to interact with the inhibitors. Some differences in activity and specificity between the insect and vertebrate enzymes can be explained by comparison of their three-dimensional structures.


Primary Flexor Tendon Repair with Early Active Motion: Experience in Europe.
The protocol for primary flexor tendon repair in zones 1 and 2 of the hand is changing. This article discusses recent changes. Immediate repair within 48 hours is performed whenever possible. A 6-strand core suture is performed using the M modification of Tang's technique. The pulleys are divided to allow free excursion of the repaired tendon within the tendon sheath. To avoid repaired structures within the sheath being too bulky, the authors generally repair only half of the flexor digitorum superficialis. In some cases, the flexor digitorum superficialis is excised completely. Rehabilitation remains based on controlled active motion.


Staging of the axilla in breast cancer: accurate in vivo assessment using positron emission tomography with 2-(fluorine-18)-fluoro-2-deoxy-D-glucose.
To evaluate the ability of positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) to determine noninvasively axillary lymph node status in patients with breast cancer. The presence of axillary lymph node metastasis is the most important prognostic factor in women with breast cancer. It signifies the presence of occult metastatic disease and indicates the need for adjuvant therapy. The only reliable way in which this important prognostic information may be obtained is by performing axillary dissection, which may be associated with significant complications and delay in discharge from the hospital. PET with 18F-FDG can visualize primary cancers in the breast and metastatic tumor deposits. Fifty patients with untreated breast cancer had clinical examination of their axilla performed (graded as positive or negative), followed by PET of the axilla and midthorax. PET data were analyzed blindly and graded as positive or negative, depending on the presence or absence of axillary nodal metastases. Cytopathologic assessment of the axillary nodes was carried out within 1 week of PET, by fine-needle aspiration cytology in 5 patients and axillary dissection in 45; the excised specimens were examined by a single pathologist. The overall sensitivity of PET in 50 patients was 90% and the specificity was 97%. Clinical examination of the same patients had an overall sensitivity of 57% and a specificity of 90%. In the 24 patients with locally advanced breast cancer (T3, T4, TxN2), PET had a sensitivity of 93% and a specificity of 100%. In T1 tumors (seven patients), the sensitivity and specificity were 100%. PET had a high predictive value (>90%) and accuracy (94%) in staging the axilla. PET is a sensitive and specific method of staging the axilla in patients with breast cancer. It may obviate the need for axillary surgery in women with small primary tumors, define the women likely to benefit from axillary dissection, or allow radiotherapy to be substituted for surgery, particularly in post-menopausal women.


Anterior cingulate gyrus volume and glucose metabolism in autistic disorder.
This study reports the first paired measurements of glucose metabolism and volume of the anterior cingulate gyrus in autism. Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans of seven high-functioning autistic patients and seven sex- and age-matched normal volunteers were coregistered. After the anterior cingulate gyri were outlined on the MRI images, the volumes of the structures were measured and corrected for brain volume. The volumes were then applied to the PET images and metabolic maps were obtained. Right anterior cingulate area 24' was significantly smaller in relative volume, and both area 24 and area 24' were metabolically less active, in the autistic patients than in the normal subjects. Autism may be characterized by structural and functional alterations in the anterior cingulate gyrus.


Immunologically induced lung disease in guinea pigs. A comparison of ovalbumin and pigeon serum as antigens.
This study was conducted to compare the capacity of pigeon serum (PS), an antigen (Ag) associated with hypersensitivity pneumonitis (HP), and ovalbumin (OA) in the induction of immunologic lung disease in guinea pigs (gp). Whereas OA was very effective in inducing a severe pneumonitis, PS failed to produce significant disease. A determination of the antibody (Ab) responses in OA- or PS-sensitized GP revealed that total Ab activity, as well as specific IgG1, and IgG2 responses, were not significantly different in the two groups. There was, however, a markedly higher IgE-like Ab response to OA than to PS. Thus, there was a striking correlation between specific IgE synthesis and the production of immunologic lung disease. The disease resembled immune complex disease histologically, and we suggest that the IgE antibody may function as a preceding "anaphylactic trigger" mechanism for the lodging of complement-fixing Ag-Ab complexes in the vasculature of the lung. It is further suggested that PS may be a poor Ag for the induction of IgE synthesis in guinea pigs.


Paragonimus skrjabini Chen, 1959 (Digenea: Paragonimidae) and related species in eastern Asia: a combined molecular and morphological approach to identification and taxonomy.
A molecular and morphometric investigation is reported on the species complex of mammalian lungflukes of which Paragonimus skrjabini Chen, 1959 and P. miyazakii Kamo, Nishida, Hatsushika & Tomimura, 1961 are the best-known examples. This species complex (here called the P. skrjabini complex) is shown to be monophyletic using DNA sequences from the nuclear ITS2 region and the mitochondrial cox1 gene. The latter marker permits the discrimination of populations, some previously named as distinct species, from various geographical locations in China and Japan. Morphometric analysis of a number of variables accords remarkably closely with the molecular results. Main findings are that (1) nominal P.skrjabini from Fujian Province in eastern China is phylogenetically very close to P. miyazakii from Japan. It is proposed that both taxa should be referred to the same subspecies as P. krjabini miyazakii. (2) Populations from Guangdong Province, Guangxi Zhuang Autonomous Region, Sichuan and Hubei should be referred to P. skrjabini skrjabini. Specimens of P. skrjabini from the Yangtze basin in Sichuan and Hubei are remarkably similar to one another according to genetic and morphometric data, but are not so different from Guangdong populations that they should be referred to a different subspecies at this stage. Specimens of P. skrjabini from Yunnan have not been assigned to a subspecies at this stage. (3) Partly following earlier studies, we regard the following as synonyms of P. skrjabini: P. miyazakii (reduced to subspecific status); P. szechuanensis Chung & Tsao, 1962 (probably belongs to P. s. skrjabini); and P. hueitungensis Chung, Hsu, Ho, Kao, Shao, Chiu, Pi, Liu, Ouyang, Shen, Yi & Yao, 1975 (probably belongs to P.s.skrjabini ); P. veocularis (Chen & Li, 1979) (specimens from Fujian regarded as belonging to this species should be referred to P.skrjabini miyazakii: the subspecific status of specimens from the type-locality in northern Sichuan is unclear). A number of questions remain unresolved. The name P. hokuoensis Ho & Chung, 1964 was proposed for two individual metacercariae of distinctive appearance from southern Yunnan. DNA sequences from very similar metacercariae from the same locality place this nominal species within, or sister to, the P. skrjabini complex. As yet, nothing is known regarding adult morphology or biology of this taxon and we retain it here as a distinct species. P. heterorchis (Zhou, Pang & Hsiang, 1982) might be a synonym of P. skrjabini: the form of the metacercaria provides evidence against this view and further work is required. P. macrorchis Chen, 1962 has probably been confused with P. skrjabiniin China. Within China, the former probably occurs only on Hainan Island, although P. fukienensis Tang & Tang, 1962 from Fujian Province could be a synonym.


Polyhydroxyalkanoate production potential of heterotrophic bacteria in activated sludge.
This study was conducted to evaluate the polyhydroxyalkanoate (PHA) production potential of cultivable heterotrophic bacteria in activated sludge by genotypic and phenotypic characterizations. A total of 114 bacterial strains were isolated from four activated sludge samples taken from a lab-scale sequencing batch reactor and three wastewater treatment processes of two municipal wastewater treatment plants. PCR detection of the phaC genes encoding class I and II PHA synthase revealed that 15% of the total isolates possessed phaC genes, all of which had the closest similarities to known phaC genes of α- and β-Proteobacteria and Actinobacteria. PHA production experiments under aerobic and nitrogen-limited conditions showed that 68% of the total isolates were capable of producing PHA from at least one of the six substrates used (acetate, propionate, lactate, butyrate, glucose and glycerol). Genotypic and phenotypic characterizations revealed that 75% of the activated sludge bacteria had PHA production potential. Our results also indicated that short-chain fatty acids would be the preferable substrates for PHA production by activated sludge bacteria, and that there might be a variety of unidentified phaC genes in activated sludge.


Changes in dental plaque microbial richness and oral behavioral habits during caries development in young Chinese children.
To detect changes in the microbial richness of dental plaque and oral behaviors during caries development in young Chinese children. Supragingival plaque samples and a survey of oral behaviors of 130 children aged 3 at baseline were analyzed at 6 months and 12 months. Total DNA was isolated from all samples and PCR-denaturing gradient gel electrophoresis analysis was conducted. In the follow-up, 44 children had caries or cavity fillings at 6 months, a further 28 children had caries or cavity fillings at 12 months. The other 58 children remained caries-free at 12 months. According to the changes in caries status at the 12-month follow-up, all participants were divided into three groups: caries-free, caries at 6 months and caries at 12 months. The changes in oral behaviors during the 12-month follow-up were not significantly different in the three groups. The frequency of eating sweets and eating sweets before sleeping was significantly different among the three groups at baseline. At baseline, the average detectable bands of caries in the 12-month caries group were similar to those of the caries-free group; both of them were higher than that of the 6-month caries group. At 6 months, the average detectable bands of the 12-month caries group were significantly lower than that of the caries-free group although the children of the 12-month caries group were caries-free at that time. For young Chinese children, the high frequency of eating sweets and eating sweets before sleeping are risk factors of caries onset, and the decrease in microbial richness could occur 6 months before the onset of caries.


Infant formula.
Although the American Academy of Pediatrics and the American Academy of Family Physicians recommend breast milk for optimal infant nutrition, many parents still choose formula as an acceptable alternative. The wide variety of available formulas is confusing to parents and physicians, but formulas can be classified according to three basic criteria: caloric density, carbohydrate source, and protein composition. Most infants require a term formula with iron. There is insufficient evidence to recommend supplementation with docosahexaenoic acid or arachidonic acid. Soy formulas are indicated for congenital lactase deficiency and galactosemia, but are not recommended for colic because of insufficient evidence of benefit. Hypoallergenic formulas with extensively hydrolyzed protein are effective for the treatment of milk protein allergy and the prevention of atopic disease in high-risk infants. Antireflux formulas decrease emesis and regurgitation, but have not been shown to affect growth or development. Most infants with reflux require no treatment. Family physicians can use these guidelines to counsel parents about infant formula, countering consumer advertising that is not evidence-based.


Bedside Breath-Wise Visualization of Bronchospasm by Electrical Impedance Tomography Could Improve Perioperative Patient Safety: A Case Report.
Bronchospasm appears in up to 4% of patients with obstructive lung disease or respiratory infection undergoing general anesthesia. Clinical examination alone may miss bronchospasm. As a consequence, subsequent (mis)treatment and ventilator settings could lead to pulmonary hyperinflation, hypoxia, hypercapnia, hypotension, patient-ventilator asynchrony, volutrauma, or barotrauma. Electrical impedance tomography (EIT), a new noninvasive technique, can potentially identify bronchospasms by determining regional expiratory time constants (τ) for each one of the pixels of a functional EIT image. We present the first clinical case that highlights the potential of breath-wise EIT-based τ images of the lung to quickly identify bronchospasm at the bedside, which could improve perioperative patient management and safety.


A microfluidic design to provide a stable and uniform in vitro microenvironment for cell culture inspired by the redundancy characteristic of leaf areoles.
The leaf venation is considered to be an optimal transportation system with the mesophyll cells being divided by minor veins into small regions named areoles. The transpiration of water in different regions of a leaf fluctuates over time making the transportation of water in veins fluctuate as well. However, because of the existence of multiple paths provided by the leaf venation network and the pits on the walls of the vessels, the pressure field and nutrient concentration in the areoles that the mesophyll cells live in are almost uniform. Therefore, inspired by such structures, a microfluidic design of a novel cell culture chamber has been proposed to obtain a stable and uniform microenvironment. The device consists of a novel microchannel system imitating the vessels in the leaf venation to transport the culture medium, a cell culture chamber imitating the areole and microgaps imitating the pits. The effects of the areole and pit on flow fields in the cell culture chamber have been discussed. The results indicate that the bio-inspired microfluidic device is a robust platform to provide an in vivo like fluidic microenvironment.


Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival.
Preorthotopic liver transplantation locoregional therapy (LRT) for hepatocellular carcinoma (HCC) reduces drop-out rates in patients awaiting orthotopic liver transplantation (OLT). In this study, we investigated the efficacy of LRT as a strategy to improve longterm survival after transplantation. A retrospective analysis of prospectively collected data identified 100 patients with HCC who underwent OLT between 1985 and 2005. Of these, 46 received LRT in the form of transarterial chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or a combination of these. The 1-, 3-, and 5-year survivals, regardless of LRT, were 81.3%, 66.1%, and 61.3%, respectively. Demographic data and waiting time for OLT were similar between LRT and untreated groups. Pre-OLT radiologic stage was comparable (LRT: 2.11 +/- 0.74 versus Untreated: 2.39 +/- 0.94; p = 0.16). At the time of transplantation, the LRT group had notable tumor downstaging (1.50 +/- 1.34 versus 2.49 +/- 1.17; p = 0.008). The LRT group had better 5-year survival (82.4% versus 51.8%; p = 0.01), but this improvement was observed in patients with HCC stages II, III, and IV (77.6% versus 37.4%; p = 0.016). Sixteen LRT patients, and none untreated, revealed complete tumor necrosis with no viable tumor cells on explant pathology (pT0). These patients did not experience any longterm recurrence, in contrast to those with similar pre-OLT tumors. OLT is a viable treatment option for primary HCC. LRT substantially downstages the primary tumor and improves longterm survival in patients with advanced disease. Complete tumor necrosis with LRT is associated with excellent longterm recurrence-free survival.


The Role of Supportive Treatment in the Management of Hyperammonemia in Neonates and Infants.
The objective of this study is to investigate the efficacy of continuous renal replacement therapy (CRRT), mainly continuous venovenous hemodiafiltration (CVVHDF), and evaluate vasoactive requirements in hyperammonemic neonates and infants. Patients who underwent CRRT for hyperammonemia were retrospectively analyzed. Patients in 7 of the encounters were treated solely by CVVHDF. During 3 encounters, patients who received continuous venovenous hemodialysis (CVVHD) were transitioned to CVVHDF. CVVHD was used in 3 encounters. The median 50% reduction time for ammonia was 8 h (range 3-15 h). The median duration of CRRT treatment was 40 h (range 24-89 h). Survival to hospital discharge occurred in 12 encounters (92.3%). Eleven encounters (84.6%) were treated with different vasoactive agents. In those encounters, the median vasoactive medications' start time was the 6th hours (range 2-60 h) of CRRT. There was no association between the vasoactive index score and pre-dialysis ammonia concentration. CRRT achieves timely control of hypeammonemic states. Hemodynamic instability necessitating intervention with vasoactive medications is a common finding in patients with hyperammonemia.


The mechanical and pharmacological regulation of glioblastoma cell migration in 3D matrices.
The invasion of glioblastoma is a complex process based on the interactions of tumor cells and the extracellular matrix. Tumors that are engineered using biomaterials are more physiologically relevant than a two-dimensional (2D) cell culture system. Matrix metalloproteinases and the plasminogen activator generated by tumor cells regulate a tumor's invasive behavior. In this study, microtumors were fabricated by encapsulating U87 glioma cells in Type I collagen and then glioma cell migration in the collagen hydrogels was investigated. Crosslinking of collagen with 8S-StarPEG increased the hydrogel viscosity and reduced the tumor cell migration speed in the hydrogels. The higher migration speed corresponded to the increased gene expression of MMP-2, MMP-9, urokinase plasminogen activator (uPA), and tissue plasminogen activator (tPA) in glioma cells grown in non-crosslinked collagen hydrogels. Inhibitors of these molecules hindered U87 and A172 cell migration in collagen hydrogels. Aprotinin and tranexamic acid did not inhibit U87 and A172 migration on the culture dish. This study demonstrated the differential effect of pharmacologic molecules on tumor cell motility in either a 2D or three-dimensional culture environment.


Cardiovascular disease in HIV infection.
The survival of patients with HIV infection who have access to highly active antiretroviral therapy has dramatically increased. In HIV-infected persons, cardiovascular disease can be associated with HIV infection, opportunistic infections or neoplasias, use of antiretroviral drugs or treatment of opportunistic complications, mode of HIV acquisition (such as intravenous drug use), or with the classic non-HIV-related cardiovascular risk factors (such as smoking or age). Diseases of the heart associated with HIV infection or its opportunistic complications include pericarditis and myocarditis. Pericarditis may lead to pericardial effusion rarely causing tamponade. Cardiomyopathy is often clinically silent with asymptomatic left ventricular systolic dysfunction. Endocarditis is mainly the consequence of intravenous drug abuse, possibly leading to life-threatening valvular insufficiency with the need for cardiac surgery. A further serious condition associated with HIV infection is pulmonary hypertension potentially leading to right heart failure. The cardiovascular complications of HIV infection such as cardiomyopathy and pericarditis have been reduced by highly active antiretroviral therapy, but premature coronary atherosclerosis is now a growing problem because antiretroviral drugs can lead to serious metabolic disturbances resembling those in the metabolic syndrome. Lipodystrophy, a clinical syndrome of peripheral fat wasting, central adiposity, dyslipidemia, and insulin resistance, is most prevalent among patients treated with protease inhibitors. These patients should thus be screened for hyperlipidemia, hyperglycemia, and hypertension, and they may be candidates for lipid-lowering therapies. When initiating lipid-lowering therapy, interactions between statins and HIV protease inhibitors affecting cytochrome P450 function must be considered. Restenosis rate after percutaneous coronary intervention may be unexpectedly high.


Treatment of cheese whey by a cross-flow anaerobic membrane bioreactor: Biological and filtration performance.
Whey, produced in large quantities during cheese production, is a rapidly fermentable high strength wastewater characterized by a high biodegradability and low alkalinity. In this study, a lab-scale cross-flow anaerobic membrane bioreactor was used to address the commonly experienced difficulties such as unstable reactor performance and unexpected biomass losses when treating whey wastewater with conventional anaerobic reactors. The anaerobic membrane bioreactor provided a stable treatment performance, i.e. more than 90% chemical oxygen demand removal, and moderate membrane fluxes between 8 and 11 L m-2 h-1 could be obtained, applying a low cross-flow velocity of about 0.5 m s-1. Short term critical flux tests revealed that higher fluxes up to 36 L m-2 h-1 are possible at elevated cross-flow velocities and/or reduced mixed liquor suspended solids concentrations. Sludge filterability indicated by capillary suction time and specific resistance to filtration deteriorated throughout the study. Chemical cleaning efficiency gradually decreased, indicating irreversible membrane fouling during long term operation.


Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease.
Controversies surround the usefulness of Coenzyme Q10 (CoQ10) in Huntington's disease (HD), an autosomal dominant, fatal, neurodegenerative disease with no cure or disease modifying treatment. CoQ10, an endogenous substrate for electron transport and an anti-oxidant, has been shown in some but not all studies to improve symptoms and survival in mouse models of HD. Previous studies have been conducted in fast-progressing models that better mimic the juvenile forms of HD than the much more common middle-age onset form, possibly accounting for mixed results. Establishing the usefulness of CoQ10 to alter HD disease course in a model that better recapitulates the progressive features of the human disorder is important because clinical trials of CoQ10, which is safe and well tolerated, are being planned in patients. The CAG140 knock-in (KI) mouse model of HD in which an expanded (approximately 120) CAG repeat is inserted in the mouse gene provides a model of the mutation in the proper genomic and protein context. These mice display progressive motor, cognitive and emotional anomalies, transcriptional disturbances and late striatal degeneration. Homozygote mutant CAG140 KI mice and wild-type littermates were fed CoQ10 (0.2%, 0.6%) in chow, and behavioral and pathological markers of disease were examined. CoQ10 improved early behavioral deficits and normalized some transcriptional deficits without altering huntingtin aggregates in striatum. The lower dose (0.2%) was more beneficial than 0.6%. Similar to previous studies, this low dose also induced deleterious effects in open field and rotarod in WT mice, however these effects are of unclear clinical significance in view of the excellent safety profile of CoQ10 in humans. These data confirm that CoQ10 may be beneficial in HD but suggest that maximum benefit may be observed when treatment is begun at early stages of the disease and that dosage may be critical.