A Study of the Prevalence of Psychiatric Disorders in Patients with Methamphetamine-Induced Psychosis.
The abuse of narcotic drugs and psychotropic substances such as amphetamines and ecstasy has had a growing trend. Tachycardia, increased blood pressure, hallucinations, panic attacks, and psychosis are the negative effects of methamphetamine abuse. The present study aimed to assess psychiatric disorders associated with methamphetamine-induced psychotic disorder. This cross-sectional study was performed from October 2013 to March 2014 on 165 patients hospitalized at Shahid Beheshti Hospital in Kerman, Iran, and diagnosed with psychosis induced by methamphetamine abuse within the previous 6 months. Study subjects were selected via census method. Based on the exclusion criteria and due to the lack of cooperation of some patients, 121 patients were enrolled in the study. Research data were gathered using clinical interviews, the Yale-Brown obsessive compulsive scale (Y-BOCS), Hamilton anxiety scale (HAM-A) and Hamilton rating scale for depression (HRSD), Young mania rating scale (YMRS), substance dependence severity scale (SDSS), positive and negative syndrome scale (PANSS), and clinical global impression (CGI) scale. The data analysis was performed using SPSS software, descriptive statistics, and ANOVA. Among the 121 patients of the sample group, 4 patients (3.3%) had anxiety, 58 patients (47.9%) depression, 30 patients (24.8%) obsessive-compulsive disorder (OCD), 20 patients (16.5%) bipolar mood disorder (BMD), 8 patients (6.6%) persistent psychotic symptoms, 85 patients (70.2%) personality disorder, and 36 patients (29.8%) had no personality disorders. The highest prevalence was related to borderline personality disorder (35.5%). However, 45 patients (37.2%) had no impairment associated with methamphetamine-induced psychosis. It seems that there is comorbidity between psychiatric disorders, including mood disorders, especially depressive disorder, childhood history of attention deficit hyperactivity disorder (ADHD), bipolar disorder, and personality disorders such as borderline personality disorder, and antisocial personality disorders, and methamphetamine abuse.


Extract of Pyrus nivalis enhances phagocytosis in lungs after particles matter exposure in BALB/c mice.
During past few decades, studies have demonstrated that particulate matter (PM) is the most serious environmental pollutant in industrial countries which mainly contributes for increasing prevalence of chronic respiratory inflammatory diseases. Healthy food supplements to prevent the inflammatory diseases are common and show notable effects. The effects of the extract of Pyrus nivalis, a common fruit and herbal medicine in Taiwan, on PM-induced airway inflammation in mice were investigated by feeding the extract orally for 21 days. Results obtained from lung histology and bronchial alveolar lavage fluid (BALF) cell profile showed that oral feeding of P. nivalis extract did not affect the airway inflammation. However, it increased the phagocytic activity in BALF cells and induced M1-dominant macrophage differentiation in lungs. Our study showed that extract of P. nivalis might present the beneficial and therapeutic potential for clearance of PM and pathogens in airway. PRACTICAL APPLICATIONS: Pyrus nivalis is a common fruit and also used extensively in Chinese herbology. The pharmacological effects of P. nivalis have been reported in ancient Chinese Medical literature and known to possess anti-asthma and anti-cough properties as well as to enhance function of lungs. In this study, we found that orally feeding the extract of P. nivalis did not induce airway inflammation and affect particulate matter (PM)-induced inflammatory cells infiltration in lungs but increased phagocytosis with or without PM treatment which might indicate its therapeutic potential for clearance of PM and pathogens in airway.


Neuroendocrine and behavioural responses to exposure to an infant in male prairie voles.
Paternal behaviour and pair-bond formation are defining characteristics of social monogamy. However, in comparison to pair-bonding, the endocrine factors associated with the male care of young are not well studied. In the present study, plasma concentrations of oxytocin, vasopressin and corticosterone (CORT) were measured in reproductively naïve male prairie voles as a function of exposure to an infant or control manipulations (i.e. handling or exposure to a wooden dowel). Plasma oxytocin concentrations were transiently elevated within 10 min of pup exposure. Although plasma CORT concentration typically increases after handling, after 10 min of pup exposure, the concentration of plasma CORT was not increased, suggesting an attenuation of CORT release by pup exposure. Group differences in the concentrations of plasma hormones were no longer detected at 20 or 60 min after treatment. These patterns of rapid change in the concentrations of plasma oxytocin and CORT were observed in both juvenile and adult males but not detected after control procedures. Plasma vasopressin, assessed only in adult males, did not vary as a function of pup exposure or other manipulations. In the paraventricular nucleus of the hypothalamus, pup exposure also increased activation (as assessed by the measurement of c-Fos) of neurones that stained for either oxytocin or vasopressin, whereas it decreased c-Fos expression in neurones stained for corticotrophin-releasing hormone. In addition, brief pup exposure (20 min) facilitated subsequent partner preference formation when alloparental males and pup attackers were considered as a group. In the context of other studies, these data support the hypothesis that neuroendocrine changes associated with male alloparental behaviour are related to those implicated in pair-bonding.


Long-term survival and outgrowth of mechanically engineered nervous tissue constructs implanted into spinal cord lesions.
While most approaches to repair spinal cord injury (SCI) rely on promoting axon outgrowth, the extensive distance that axons would have to grow to bridge SCI lesions remains an enormous challenge. In this study, we used a new tissue-engineering technique to create long nervous tissue constructs spanned by living axon tracts to repair long SCI lesions. Exploiting the newfound process of extreme axon stretch growth, integrated axon tracts from dorsal root ganglia (DRG) neurons were mechanically elongated in vitro to 10 mm over 7 days and encased in a collagen hydrogel to form a nervous tissue construct. In addition, a modified lateral hemisection SCI model in the rat was developed to create a 1 cm long cavity in the spinal cord. Ten days following SCI, constructs were transplanted into the lesion and the animals were euthanized 4 weeks post-transplantation for histological analyses. Through cell tracking methods and immunohistochemistry, the transplanted elongated cultures were consistently found to survive 4 weeks in the injured spinal cord. In addition, DRG axons were observed extending out of the transplanted construct into the host spinal cord tissue. These results demonstrate the promise of nervous tissue constructs consisting of stretch-grown axons to bridge even extensive spinal cord lesions.


Back-to-front: improved tactile discrimination performance in the space you cannot see.
We investigated any differences in people's ability to reconstruct the appropriate spatiotemporal ordering of multiple tactile stimuli, when presented in frontal space (a region where visual inputs tend to dominate) versus in the space behind the back (a region of space that we rarely see) in professional piano players and in non-musicians. Even though tactile temporal order judgments were much better in the musicians overall, both groups showed a much reduced crossed-hands deficit when their hands were crossed behind their backs rather than at the front. These results suggest that because of differences in the availability of visual input, the spatiotemporal representation of non-visual stimuli in front versus rear space is different.


Test-retest reliability and sensitivity of the Concept2 Dyno dynamometer: practical applications.
Strength assessment is often part of the objective periodical observation of teams, squads, or large groups of athletes. Equipment that provides assessment that is mobile and is easy to use will reduce the impact on the athletes' training and competitive calendar. However, any equipment used must be reliable to allow accurate monitoring of performance. The aim of this study was to examine the reliability of the Concept2 Dyno dynamometer. Forty-six competitive athletes (males: n = 36, age 23.3 ± 6.8 years, height 1.80 ± 0.09 m, body mass 82.3 ± 15.6 kg; females, n = 10, age 20.7 ± 1.4 years, height 1.65 ± 0.09 m, body mass 62.7 ± 11.8 kg), with a strength training background of more than 2 years, performed a familiarization session and 3 experimental sessions with 1 week intervening each. Each experimental session consisted of 3 maximal efforts of seated chest press (CPress), seated row (SRow), and seated leg press (LPress) exercises. Reliability was assessed examining systematic bias, intraclass correlation coefficient, coefficient of variation (CV), and 95% limits of agreement (95% LoA) between sessions. No systematic bias was found for any of the exercises. Intraclass correlation coefficients were high (0.89-0.98) with relatively low CV (6.2-4.3%). Finally, 95% LoA indicated that subsequent testing could underestimate by a factor of 0.87 or overestimate by a factor of 1.17, on average. These results indicate that Concept2 Dyno dynamometer is reliable and can be used in the field to efficiently monitor strength performance. Coaches and researchers should use "analytical goals" to help decide as to the use of Concept2 Dyno for their purposes.


491 nm generation by sum-frequency mixing of diode pumped neodymium lasers.
We present three different dual-wavelength laser architectures to obtain cw blue radiations. They are based on diode-pumped Nd-doped crystals lasing on the 4F3/2-4I11/2 and 4F3/2-4I9/2 transitions. Blue radiations were achieved by intracavity sum frequency operation in a BiB3O6 crystal. We report a maximum output blue power of 303 mW at 491 nm for a pump power of 10 W.


Accuracy of DLPNO-CCSD(T) method for noncovalent bond dissociation enthalpies from coinage metal cation complexes.
The performance of the domain based local pair-natural orbital coupled-cluster (DLPNO-CCSD(T)) method has been tested to reproduce the experimental gas phase ligand dissociation enthalpy in a series of Cu(+), Ag(+), and Au(+) complexes. For 33 Cu(+)-noncovalent ligand dissociation enthalpies, all-electron calculations with the same method result in MUE below 2.2 kcal/mol, although a MSE of 1.4 kcal/mol indicates systematic underestimation of the experimental values. Inclusion of scalar relativistic effects for Cu either via effective core potential (ECP) or Douglass-Kroll-Hess Hamiltonian, reduces the MUE below 1.7 kcal/mol and the MSE to -1.0 kcal/mol. For 24 Ag(+)-noncovalent ligand dissociation enthalpies, the DLPNO-CCSD(T) method results in a mean unsigned error (MUE) below 2.1 kcal/mol and vanishing mean signed error (MSE). For 15 Au(+)-noncovalent ligand dissociation enthalpies, the DLPNO-CCSD(T) methods provides larger MUE and MSE, equal to 3.2 and 1.7 kcal/mol, which might be related to poor precision of the experimental measurements. Overall, for the combined data set of 72 coinage metal ion complexes, DLPNO-CCSD(T) results in a MUE below 2.2 kcal/mol and an almost vanishing MSE. As for a comparison with computationally cheaper density functional theory (DFT) methods, the routinely used M06 functional results in MUE and MSE equal to 3.6 and -1.7 kcal/mol. Results converge already at CC-PVTZ quality basis set, making highly accurate DLPNO-CCSD(T) estimates affordable for routine calculations (single-point) on large transition metal complexes of >100 atoms.


Do children have the same vulnerability to metabolic drug–drug interactions as adults? A critical analysis of the literature.
Many drug–drug interactions (DDIs) in the pediatric population are managed based on data generated in adults. However, due to developmental changes in elimination pathways from birth to adolesence, and variable weight‐adjusted dose of interacting drugs, the assumption of DDIs being similar in adults and pediatrics might not be correct. This study compares the magnitude of reported DDIs in pediatric and adult populations. A systematic literature review was undertaken to identify reports of DDIs in pediatric subjects. A total of 145 reports of DDIs were identified over the age range of birth to 20 years. The magnitude of DDIs for 24 drug pairs from 31 different pediatric studies could be assessed and compared with those in adults where corresponding data existed. The magnitude of the DDI, as measured by a relevant parameter (e.g., AUC, CL) in the presence and absence of inhibitor,were higher (>1.25‐fold), similar (0.8‐ to 1.25‐fold) or lower (<0.8‐fold) than the corresponding ratio in adults in 10, 15, and 8 cases respectively. An age‐related trend in the magnitude of DDIs could not be established. However, the study highlighted the clear paucity of the data in children younger than 2 years. Care should be exercised when applying the knowledge of DDIs from adults to children younger than 2 years of age.


Extracellular matrix heparan sulfate proteoglycans modulate the mitogenic capacity of acidic fibroblast growth factor.
Confluent cultures of human endothelial cells deposit into extracellular matrix (ECM) distinct heparan sulfate proteoglycans (HSPG) which modulate acidic fibroblast growth factor's (aFGF) ability to stimulate human endothelial cell mitogenic capacity. Extracellular matrix 35S-HSPG were isolated from cultures metabolically labelled with Na235SO4 by DEAE-Sepharose, Sepharose CL-4B, and aFGF-Affi-Gel 15 column chromatography and identified by resistance to chondroitinase ABC and sensitivity to nitrous acid. Fifty to sixty percent of the 35S-HSPG deposited into ECM do not bind aFGF. The bound 35S-HSGP (40-50% of the total counts applied) eluted from the aFGF-Affi-Gel column after the addition of buffer containing 2 M NaCl. aFGF-binding and aFGF-nonbinding 35S-HSPG were individually pooled and further purified by Sepharose CL-4B column chromatography. 35S-HSPG which bind aFGF, designated HSPGP, were 100-fold superior to heparin in augmenting the mitogenic efficacy of aFGF in sparse proliferating cultures. In contrast, however, 35S-HSPG, which did not bind aFGF, designated HSPG1, inhibited aFGF-stimulated proliferation in both sparse and subconfluent endothelial cell cultures. The majority of the biological activity of both aFGF-potentiating HSPGP and aFGF-inhibitory HSPG1 was contained in the glycosaminoglycan chains released by alkaline borohydride treatment of intact HSPGP or HSPG1, respectively. 3H-Core protein derived from HSPGP or HSPG1 contained only minor biological activity. The ability of heparitinase or heparinase (Flavobacterium heparinum) to abolish biological activity differed, depending upon the HSPG tested, also suggested that these are two distinct HSPGs.


System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.
The term systems pharmacology describes a field of study that uses computational and experimental approaches to broaden the view of drug actions rooted in molecular interactions and advance the process of drug discovery. The aim of this work is to stick out the role that the systems pharmacology plays across the multi-target drug discovery from natural products for cardiovascular diseases (CVDs). Firstly, based on network pharmacology methods, we reconstructed the drug-target and target-target networks to determine the putative protein target set of multi-target drugs for CVDs treatment. Secondly, we reintegrated a compound dataset of natural products and then obtained a multi-target compounds subset by virtual-screening process. Thirdly, a drug-likeness evaluation was applied to find the ADME-favorable compounds in this subset. Finally, we conducted in vitro experiments to evaluate the reliability of the selected chemicals and targets. We found that four of the five randomly selected natural molecules can effectively act on the target set for CVDs, indicating the reasonability of our systems-based method. This strategy may serve as a new model for multi-target drug discovery of complex diseases.


3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study.
During the past 15 years there has been an exponential increase in the number of prescriptions for lipid-lowering drugs. Uncertainties remain about the long-term impact of these medications on cancer, which is particularly bothersome given that the duration of these treatments may extend for several decades. To explore the association between 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and cancer incidence. Using the administrative health databases of the Régie de l'Assurance-Maladie du Québec we performed a nested case-control study. We selected a cohort of 6721 beneficiaries of the health care plan of Quebec who were free of cancer for at least 1 year at cohort entry, 65 years and older, and treated with lipid-modifying agents. Cohort members were selected between 1988 and 1994 and were followed up for a median period of 2.7 years. From the cohort, 542 cases of first malignant neoplasm were identified, and 5420 controls were randomly selected. Users of HMG-CoA reductase inhibitors were compared with users of bile acid-binding resins as to their risk of cancer. Specific cancer sites were also considered. Users of HMG-CoA reductase inhibitors were found to be 28% less likely than users of bile acid-binding resins to be diagnosed as having any cancer (rate ratio, 0.72; 95% confidence interval, 0.57-0.92). All specific cancer sites under study were found to be not or inversely associated with the use of HMG-CoA reductase inhibitors. The results of our study provide some degree of reassurance about the safety of HMG-CoA reductase inhibitors.


Short-chain carboxylic-acid-stimulated, PMN-mediated gingival inflammation.
This communication reviews the effects of short-chain carboxylic acids on human cells of importance to the periodontium. The central hypothesis is that these acids can alter both cell function and gene expression, and thus contribute to the initiation and prolongation of gingival inflammation. Short-chain carboxylic acids [CH3-(CH2)x-COOH, x < 3] are metabolic intermediates with a broad range of apparently paradoxical biological effects. For example, lactic acid (CH3-CHOH-COOH), a 3-carbon alpha-hydroxy-substituted acid, is widely recognized for its cariogenicity. Lactic acid, however, also occurs in tropical fruits, and is the active ingredient in a variety of anti-wrinkle creams developed by dermatologists. In marked contrast, the unsubstituted 3-carbon propionic acid (CH3-CH2-COOH) is used as a food preservative and is the active principle for one class of non-steroidal anti-inflammatory agents. Interestingly, the addition of one carbon to propionic acid dramatically changes the biological effects. The unsubstituted 4-carbon butyric acid (CH3-CH2-CH2-COOH) is used by hematologists as a de-differentiating agent for the treatment of sickle cell anemia, but by oncologists as a differentiating agent for cancer chemotherapy. Finally, acting either individually or in concert, these acids can increase vascular dilation. Clearly, these acids, while metabolically derived, have a number of very divergent activities which are cell-type-specific (Fig. 1). It may be telling that periodontal bacteria produce these acids in millimolar concentrations, and that these bacteria can be characterized by their acid production profiles. It is no less interesting that these acids occur in the gingival crevices of human subjects with severe periodontal disease at millimolar levels which are > 10-fold higher than those found in mildly diseased subjects, and are undetectable in healthy subjects. Further, when applied directly to healthy human gingiva, short-chain carboxylic acids stimulate a gingival inflammatory response and inflammatory cytokine release. At the cellular level, these acids inhibit proliferation of gingival epithelial and endothelial cells, and inhibit leukocyte apoptosis and function, but can stimulate leukocyte cytokine release. At the molecular level, these acids can stimulate neutrophil gene transcription, translation, and protein expression. Thus, the likelihood is high that these acids, in addition to their cariogenic activity, can promote and prolong gingival inflammation. Our challenge will be to identify the cell or cells of the periodontium which respond to short-chain carboxylic acids, to delineate their responses and the molecular mechanism(s) of these effects, and to categorize the aspects of the inflammatory components which damage and those which protect the host. With this information, it may be possible to begin to rationally identify and test pharmaceutical agents which diminish the harmful aspects, while enhancing the beneficial components, of the inflammatory response.


Residential Socioeconomic Environments and Areca Nut Use in Taiwan: A Comparison with Alcohol and Tobacco Use in Multilevel Analysis.
While the association between residential socioeconomic environments and the use of globally common substances such as alcohol and tobacco has been well documented in Western countries, it remains little known about regionally important substances, such as areca nut in Asia. Objective: This study was aimed to develop residential environmental indicators in the context of Taiwan and examine their associations with areca nut use, in comparison to alcohol and tobacco use. Methods: Data were drawn from 13,392 adults across 168 townships in the 2014 National Survey on Substance Use in Taiwan. Residential socioeconomic environment variables were derived from the census and analyzed using factor analysis. Multilevel logistic regression models were used to examine the association of individual- and residential-level factors with the use of areca nut (use/nonuse), alcohol (harmful use, low-risk use, or nonuse), and tobacco (nicotine dependence, regular active use, or nonuse). Results: A three-factor structure of socioeconomic environments derived from 16 residential-level variables consisted of Rural Disadvantage, Affluence, and Family Fragmentation. Multilevel analyses showed that areca nut use was associated with both individual-level (male sex, age group 35-44 years, being divorced/widowed/separated, low educational attainment, and the occupational group of labors) and residential-level (Rural Disadvantaged and Family Fragmented) variables; such a profile was most similar to that of nicotine dependence. Conclusions: A three-factor structure could be derived for the residential-level socioeconomic environments in the Taiwanese context. Rural Disadvantaged and Family Fragmented were associated with areca nut use, which have implications for interventions targeted at the community level.


In vitro growth of four individual human gut bacteria on oligosaccharides produced by chemoenzymatic synthesis.
The present study aimed at examining oligosaccharides (OS) for potential stimulation of probiotic bacteria. Nineteen structurally well-defined candidate OS covering groups of β-glucosides, α-glucosides and α-galactosides with degree of polymerization 2-4 were prepared in >100 mg amounts by chemoenzymatic synthesis (i.e. reverse phosphorolysis or transglycosylation). Fourteen of the OS are not naturally occurring and five (β-D-glucosyl-fructose, β-D-glucosyl-xylitol, α-glucosyl-(1,4)-D-mannose, α-glucosyl-(1,4)-D-xylose; α-glucosyl-(1,4)-L-fucose) have recently been synthesized for the first time. These OS have not been previously tested for effects of bacterial growth and here the ability of all 19 OS to support growth of four gastrointestinal bacteria: three probiotic bacteria Bifidobacterium lactis, Bifidobacterium longum, and Lactobacillus acidophilus, and one commensal bacterium, Bacteroides vulgatus has been evaluated in monocultures. The disaccharides β-D-glucosyl-xylitol and β-D-glucosyl-(1,4)-xylose noticeably stimulated growth yields of L. acidophilus NCFM, and additionally, β-D-glucosyl-(1,4)-xylose stimulated B. longum Bl-05. α-Glucosyl-(1,4)-glucosamine and α-glucosyl-(1,4)-N-acetyl-glucosamine enhanced the growth rate of B. animalis subsp. lactis and B. longum Bl-05, whereas L. acidophilus NCFM and Bac. vulgatus did not grow on these OS. α-Galactosyl-(1,6)-α-galactosyl-(1,6)-glucose advanced the growth rate of B. animalis subsp. lactis and L. acidophilus NCFM. Thus several of the structurally well-defined OS supported growth of beneficial gut bacteria. This reflects a broad specificity of their sugar transporters for OS, including specificity for non-naturally occurring OS, hence showing promise for design of novel prebiotics.


Genetic algorithms, path relinking, and the flowshop sequencing problem.
In a previous paper, a simple genetic algorithm (GA) was developed for finding (approximately) the minimum makespan of the n-job, m-machine permutation flowshop sequencing problem (PFSP). The performance of the algorithm was comparable to that of a naive neighborhood search technique and a proven simulated annealing algorithm. However, recent results have demonstrated the superiority of a tabu search method in solving the PFSP. In this paper, we reconsider the implementation of a GA for this problem and show that by taking into account the features of the landscape generated by the operators used, we are able to improve its performance significantly.


Ezrin enhances line tension along transcellular tunnel edges via NMIIa driven actomyosin cable formation.
Transendothelial cell macroaperture (TEM) tunnels control endothelium barrier function and are triggered by several toxins from pathogenic bacteria that provoke vascular leakage. Cellular dewetting theory predicted that a line tension of uncharacterized origin works at TEM boundaries to limit their widening. Here, by conducting high-resolution microscopy approaches we unveil the presence of an actomyosin cable encircling TEMs. We develop a theoretical cellular dewetting framework to interpret TEM physical parameters that are quantitatively determined by laser ablation experiments. This establishes the critical role of ezrin and non-muscle myosin II (NMII) in the progressive implementation of line tension. Mechanistically, fluorescence-recovery-after-photobleaching experiments point for the upstream role of ezrin in stabilizing actin filaments at the edges of TEMs, thereby favouring their crosslinking by NMIIa. Collectively, our findings ascribe to ezrin and NMIIa a critical function of enhancing line tension at the cell boundary surrounding the TEMs by promoting the formation of an actomyosin ring.


Maternal Consumption of Seafood in Pregnancy and Child Neuropsychological Development: A Longitudinal Study Based on a Population With High Consumption Levels.
Seafood consumption during pregnancy is thought to be beneficial for child neuropsychological development, but to our knowledge no large cohort studies with high fatty fish consumption have analyzed the association by seafood subtype. We evaluated 1,892 and 1,589 mother-child pairs at the ages of 14 months and 5 years, respectively, in a population-based Spanish birth cohort established during 2004-2008. Bayley and McCarthy scales and the Childhood Asperger Syndrome Test were used to assess neuropsychological development. Results from multivariate linear regression models were adjusted for sociodemographic characteristics and further adjusted for umbilical cord blood mercury or long-chain polyunsaturated fatty acid concentrations. Overall, consumption of seafood above the recommended limit of 340 g/week was associated with 10-g/week increments in neuropsychological scores. By subtype, in addition to lean fish, consumption of large fatty fish showed a positive association; offspring of persons within the highest quantile (>238 g/week) had an adjusted increase of 2.29 points in McCarthy general cognitive score (95% confidence interval: 0.42, 4.16). Similar findings were observed for the Childhood Asperger Syndrome Test. Beta coefficients diminished 15%-30% after adjustment for mercury or long-chain polyunsaturated fatty acid concentrations. Consumption of large fatty fish during pregnancy presents moderate child neuropsychological benefits, including improvements in cognitive functioning and some protection from autism-spectrum traits.


The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis.
The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis.


Association Between Progranulin and Gaucher Disease.
Gaucher disease (GD) is a genetic disease caused by mutations in the GBA1 gene which result in reduced enzymatic activity of β-glucocerebrosidase (GCase). This study identified the progranulin (PGRN) gene (GRN) as another gene associated with GD. Serum levels of PGRN were measured from 115 GD patients and 99 healthy controls, whole GRN gene from 40 GD patients was sequenced, and the genotyping of 4 SNPs identified in GD patients was performed in 161 GD and 142 healthy control samples. Development of GD in PGRN-deficient mice was characterized, and the therapeutic effect of rPGRN on GD analyzed. Serum PGRN levels were significantly lower in GD patients (96.65±53.45ng/ml) than those in healthy controls of the general population (164.99±43.16ng/ml, p<0.0001) and of Ashkenazi Jews (150.64±33.99ng/ml, p<0.0001). Four GRN gene SNPs, including rs4792937, rs78403836, rs850713, and rs5848, and three point mutations, were identified in a full-length GRN gene sequencing in 40 GD patients. Large scale SNP genotyping in 161 GD and 142 healthy controls was conducted and the four SNP sites have significantly higher frequency in GD patients. In addition, "aged" and challenged adult PGRN null mice develop GD-like phenotypes, including typical Gaucher-like cells in lung, spleen, and bone marrow. Moreover, lysosomes in PGRN KO mice exhibit a tubular-like appearance. PGRN is required for the lysosomal appearance of GCase and its deficiency leads to GCase accumulation in the cytoplasm. More importantly, recombinant PGRN is therapeutic in various animal models of GD and human fibroblasts from GD patients. Our data demonstrates an unknown association between PGRN and GD and identifies PGRN as an essential factor for GCase's lysosomal localization. These findings not only provide new insight into the pathogenesis of GD, but may also have implications for diagnosis and alternative targeted therapies for GD.


Are Females More Resistant to Extreme Neuromuscular Fatigue?
Despite interest in the possibility of females outperforming males in ultraendurance sporting events, little is known about the sex differences in fatigue during prolonged locomotor exercise. This study investigated possible sex differences in central and peripheral fatigue in the knee extensors and plantar flexors resulting from a 110-km ultra-trail-running race. Neuromuscular function of the knee extensors and plantar flexors was evaluated via transcranial magnetic stimulation (TMS) and electrical nerve stimulation before and after an ultra-trail-running race in 20 experienced ultraendurance trail runners (10 females and 10 males matched by percent of the winning time by sex) during maximal and submaximal voluntary contractions and in relaxed muscle. Maximal voluntary knee extensor torque decreased more in males than in females (-38% vs -29%, P = 0.006) although the reduction in plantar flexor torque was similar between sexes (-26% vs -31%). Evoked mechanical plantar flexor responses decreased more in males than in females (-23% vs -8% for potentiated twitch amplitude, P = 0.010), indicating greater plantar flexor peripheral fatigue in males. Maximal voluntary activation assessed by TMS and electrical nerve stimulation decreased similarly in both sexes for both muscle groups. Indices of knee extensor peripheral fatigue and corticospinal excitability and inhibition changes were also similar for both sexes. Females exhibited less peripheral fatigue in the plantar flexors than males did after a 110-km ultra-trail-running race and males demonstrated a greater decrease in maximal force loss in the knee extensors. There were no differences in the magnitude of central fatigue for either muscle group or TMS-induced outcomes. The lower level of fatigue in the knee extensors and peripheral fatigue in the plantar flexors could partly explain the reports of better performance in females in extreme duration running races as race distance increases.


DNA release and uptake associated with the development of pleomorphic cells in mammalian skin autotransplants.
Although several in vitro studies have demonstrated active release of DNA by living cells, there is still doubt. There are no such in vivo studies (1). The following experiment is an in vivo study to determine whether DNA release and uptake by cells and tissues occur and can be related to normal growth and differentiation, abnormal growth and cancer Epidermal and full-thickness ear-skin grafts were separately autotransplanted into two groups of mice. In a second group, host mice were labelled with tritiated thymidine and autografted separately, with unlabelled epidermal and full-thickness ear-skin grafts. Animals were sacrificed regularly in both cases. Full thickness grafts revealed cysts in 15 out of 16 grafts, with well-differentiated squamous epidermis, DNA labelling of dermalfibroblasts and no DNA labelling of epidermal cells. Epidermal grafts revealed cysts in six out of 20 grafts, with epidermal cells variable in shape and arrangement; some appeared normal but others were two to four times larger, forming solid nests of cells. In some grafts, there were spindle-shaped pleomorphic cells loosely interconnected. DNA labelling was observed in occasional epidermal cell. Two lung adenocarcinomas were found. These results suggest active release of DNA by host cells and DNA uptake by grafted cells. This phenomenon and the differential uptake of DNA labelling of epidermal and dermal cells in the epidermal and full-thickness grafts suggest an association with abnormal, even pleomorphic epidermal cell behaviour due to the interference of dermal/epidermal interacting factors.


Interaction between motor ability and skill learning in children: Application of implicit and explicit approaches.
The benefits of implicit and explicit motor learning approaches in young adults have been studied extensively, but much less in children. This study investigated the relationship between fundamental motor ability and implicit/explicit learning in children using the errorless learning paradigm. First, the motor ability of 261 children (142 boys, 119 girls) aged 9-12 years (M = 9.74, SD = 0.67) was measured. Second, children with motor ability scores in the upper and lower quartile learned a golf-putting skill in either an errorless (implicit) or errorful (explicit) learning condition. Four groups were formed: Errorless High-Ability (n = 13), Errorless Low-Ability (n = 11), Errorful High-Ability (n = 10), and Errorful Low-Ability (n = 11). Learning consisted of 300 practice trials, while testing included a 50-trial retention test, followed by a 50-trial secondary task transfer test, and another 50-trial retention test. The results showed that for high- and low-ability errorless learners, motor performance was unaffected by the secondary task, as was the case for high-ability errorful learners. Low-ability errorful learners performed worse with a secondary task and were significantly poorer than the corresponding high-ability group. These results suggest that implicit motor learning (errorless) may be beneficial for children with low motor ability. The findings also show a trend that children of high motor ability might benefit from learning explicitly (errorful). Further research is recommended to examine the compatibility of implicit and explicit approaches for children of different abilities.


Molecular probes for diagnosis of fungal infections.
We have developed 21 specific nucleic acid probes which target the large subunit rRNA genes from Aspergillus flavus, Aspergillus fumigatus, Aspergillus glaucus, Aspergillus niger, Aspergillus terreus, Blastomyces dermatitidis, Candida albicans, Candida (Torulopsis) glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Coccidioides immitis, Cryptococcus neoformans var. gattii, Cryptococcus neoformans var. neoformans, Filobasidiella neoformans var. bacillispora, Filobasidiella neoformans var. neoformans, Histoplasma capsulatum, Pseudallescheria boydii, and Sporothrix schenckii. A section of the 28S rRNA gene from approximately 100 fungi, representing about 50 species of pathogens and commonly encountered saprophytes, was sequenced to develop universal PCR primers and species-specific oligonucleotide probes. Each step in the process of detection and identification was standardized to a common set of conditions applicable without modification to all fungi of interest and all types of clinical specimens. These steps consist of DNA extraction by boiling specimens in an alkaline guanidine-phenol-Tris reagent, amplification of a variable region of the 28S rRNA gene with universal primers, and amplicon identification by probe hybridization or DNA sequencing performed under conditions identical for all fungi. The results obtained by testing a panel of fungal isolates and a variety of clinical specimens indicate a high level of specificity.


[(18)F]-FLT PET to predict early response to neoadjuvant therapy in KRAS wild-type rectal cancer: a pilot study.
This pilot study evaluated the utility of 3'-deoxy-3'[18F]-fluorothymidine ([(18)F]-FLT) positron emission tomography (PET) to predict response to neoadjuvant therapy that included cetuximab in patients with wild-type KRAS rectal cancers. Baseline [(18)F]-FLT PET was collected prior to treatment initiation. Follow-up [(18)F]-FLT was collected after three weekly infusions of cetuximab, and following a combined regimen of cetuximab, 5-FU, and radiation. Imaging-matched biopsies were collected with each PET study. Diminished [(18)F]-FLT PET was observed in 3/4 of patients following cetuximab treatment alone and in all patients following combination therapy. Reduced [(18)F]-FLT PET following combination therapy predicted disease-free status at surgery. Overall, [(18)F]-FLT PET agreed with Ki67 immunoreactivity from biopsy samples and surgically resected tissue, and was predictive of treatment-induced rise in p27 levels. These results suggest that [(18)F]-FLT PET is a promising imaging biomarker to predict response to neoadjuvant therapy that included EGFR blockade with cetuximab in patients with rectal cancer.


Immunogenicity and safety of a mixed vaccination schedule with one dose of nonavalent and one dose of bivalent HPV vaccine versus two doses of nonavalent vaccine - A randomized clinical trial.
Limited data is available on the use of different HPV vaccines in the same subjects. We evaluated the immunogenicity and safety of a mixed vaccination schedule with one dose of nonavalent (9vHPV) and one dose of bivalent vaccine (2vHPV) administered in different order versus two doses of 9vHPV vaccine. 371 girls and boys aged 9-10 years were randomized (1:1) to receive (I) two doses of 9vHPV or (II) a mixed schedule of 2vHPV + 9vHPV or 9vHPV + 2vHPV with a 6 month interval. Antibodies to HPV were tested by ELISA in blood samples collected one or six months post-first dose and one month post-second dose. Post-first dose of 9vHPV 99.4-100% of subjects were seropositive to 9 HPV types included in the vaccine. GMTs varied from 5.0 to 73.6 IU(AU)/ml depending on HPV type. Post-first dose of 2vHPV all subjects were seropositive to HPV16 and 18 (GMTs 16.7 and 11.7 IU/ml, respectively) and 50.0-76.7% were seropositive to 7 types not included in 2vHPV (GMTs varied from 0.3 to 17.5 AU/ml depending on type). Post-second dose all subjects, regardless of the study group, were seropositive to 9 HPV types included in 9vHPV. Anti-HPV16 and 18 GMTs were higher in subjects with the mixed schedule and for the other 7 HPV types higher in subjects who received two doses of 9vHPV vaccine. A higher proportion of subjects who received 2vHPV reported local or systemic adverse events than those who received 9vHPV as the first dose. Post-second dose there were no differences in reported adverse events between the two vaccines. The results show the mixed HPV vaccination schedules used in this study are immunogenic and have an acceptable safety profile. Although the seroprotective threshold of antibodies remains unknown the 100% seropositivity to all 9 HPV types included in 9vHPV and the increase of GMTs observed in all study groups post-second dose administration are reassuring and suggest protection might be achieved regardless of the schedule used. Clinicaltrials.gov NCT02567955.


Motor-independent targeting of CLASPs to kinetochores by CENP-E promotes microtubule turnover and poleward flux.
Efficient chromosome segregation during mitosis relies on the coordinated activity of molecular motors with proteins that regulate kinetochore attachments to dynamic spindle microtubules [1]. CLASPs are conserved kinetochore- and microtubule-associated proteins encoded by two paralog genes, clasp1 and clasp2, and have been previously implicated in the regulation of kinetochore microtubule dynamics [2-4]. However, it remains unknown how CLASPs work in concert with other proteins to form a functional kinetochore microtubule interface. Here we have identified mitotic interactors of human CLASP1 via a proteomic approach. Among these, the microtubule plus-end-directed motor CENP-E [5] was found to form a complex with CLASP1 that colocalizes to multiple structures of the mitotic apparatus in human cells. We found that CENP-E recruits both CLASP1 and CLASP2 to kinetochores independently of its motor activity or the presence of microtubules. Depletion of CLASPs or CENP-E by RNA interference in human cells causes a significant and comparable reduction of kinetochore microtubule poleward flux and turnover rates and rescues spindle bipolarity in Kif2a-depleted cells. We conclude that CENP-E integrates two critical functions that are important for accurate chromosome movement and spindle architecture: one relying directly on its motor activity, and the other involving the targeting of key microtubule regulators to kinetochores.


Guidelines for animal surgery in research and teaching. AVMA Panel on Animal Surgery in Research and Teaching, and the ASLAP (American Society of Laboratory Animal Practitioners).
The direct or delegated authority for activities involving animals used in research and teaching programs lies with the attending veterinarian. These duties and responsibilities cannot be abrogated by others in the organization. The veterinarian is the single individual with the broadest range of knowledge of animals used in biomedical research, testing, and teaching. Federal regulations and policy require that the Institutional Animal Care and Use Committee (IA-CUC) ensure that the use of animals will be ethically justifiable and humane and that all individuals who perform surgery on animals will be appropriately qualified and trained. The attending veterinarian also has specific responsibilities under law and must take an active role in providing this assurance. In recognition of this, the Council on Research of the AVMA created a Panel on Animal Surgery in Research and Teaching to develop a report on guidelines for performing animal surgery in a research or teaching setting. Drafts of the panel report were sent through an extensive review process that included representative groups in veterinary medicine, human health, government, biomedical research, and animal welfare. The report of the panel was referred to the American Society of Laboratory Animal Practitioners (ASLAP). As an organization, the major focus of which is the role of the veterinarian in research using animals, it is appropriate that the ASLAP further refine this report into a set of guidelines for the research community. The ASLAP committee wishes to acknowledge the AVMA for recognizing the need for these guidelines and providing the financial support to convene the initial panel. This document was compiled with expectations for change in future revisions. Intended to complement other pertinent guidelines and regulations on animal surgery, these guidelines are designed to help individuals charged with the stewardship of animals used in research and teaching.


Risk Stratification for Immediate Postoperative Hearing Loss by Preoperative BAER (Brainstem Auditory Evoked Response) and Audiometry in NF2-Associated Vestibular Schwannomas.
Both brainstem auditory evoked potentials (BAEP) and audiometry play a crucial role in neuro-oncological treatment decisions in Neurofibromatosis Type 2 associated (NF2) vestibular schwannoma (VS) as hearing preservation is the major goal. In this study, we investigated the risk of immediate postoperative hearing deterioration (>15 dB and/or 15% loss in pure-tone average [PTA]/ speech discrimination score [SDS] in a cohort of 100 operated VS (ears) in 72 NF2 patients by retrospective analysis of pre- and postoperative hearing data (PTA, SDS, American Association of Otolaryngology-Head and Neck Surgery [AAO-HNS], and brainstem auditory evoked potential [BAEP] class) taking into account relevant influencing factors, particularly preoperative audiometry and BAEP status and the extent of resection. Immediately after surgery, the hearing was preserved in 73% of ears and approximately ~60% of ears kept their hearing classes. Preoperative BAEP (p = 0.015) and resection amount (p = 0.048) significantly influenced postoperative hearing outcome. The prediction model for postoperative hearing deterioration/loss between preoperative BAEP and AAO-HNS class showed increased risk by increasing BAEP class. Twenty-one tumors/ears were identified with large BAEP and AAO-HNS class discrepancies (≥2 points) and were associated with a high (48-100%) risk of deafness after surgery in ears with preoperative available hearing. Overall, the results were heterogeneous but the better both BAEP and audiometry class before surgery, the higher the chance of hearing maintenance afterwards. Large resection amounts (e.g., 100% risk in near-total resections) exhibit a significant (p < 0.05) higher risk compared to smaller amounts (e.g., 10/20% in laser-coagulated/partially resected tumors). Our results emphasized the indispensable role of both hearing monitoring in form of audiometry and neurophysiology (BAEP) in the pre-and perioperative monitoring of NF2-associated VS. Both BAEP and audiometry are good prognostic markers for the postoperative hearing outcome. The extent of resection should be strictly guided by and adjusted to the intraoperative neurophysiological monitoring.


Internal body state influences topographical plasticity of sensory representations in the rat gustatory cortex.
Primary sensory cortices are remarkably organized in spatial maps according to specific sensory features of the stimuli. These cortical maps can undergo plastic rearrangements after changes in afferent ("bottom-up") sensory inputs such as peripheral lesions or passive sensory experience. However, much less is known about the influence of "top-down" factors on cortical plasticity. Here, we studied the effect of a visceral malaise on taste representations in the gustatory cortex (GC). Using in vivo optical imaging, we showed that inducing conditioned taste aversion (CTA) to a sweet and pleasant stimulus induced plastic rearrangement of its cortical representation, becoming more similar to a bitter and unpleasant taste representation. Using a behavior task, we showed that changes in hedonic perception are directly related to the maps plasticity in the GC. Indeed imaging the animals after CTA extinction indicated that sweet and bitter representations were dissimilar. In conclusion, we showed that an internal state of malaise induces plastic reshaping in the GC associated to behavioral shift of the stimulus hedonic value. We propose that the GC not only encodes taste modality, intensity, and memory but extends its integrative properties to process also the stimulus hedonic value.


A novel approach to fit testing the N95 respirator in real time in a clinical setting.
The instant measurements provided by the Portacount fit-test instrument have been used as the gold standard in predicting the protection of an N95 respirator in a laboratory environment. The conventional Portacount fit-test method, however, cannot deliver real-time measurements of face-seal leakage when the N95 respirator is in use in clinical settings. This research was divided into two stages. Stage 1 involved developing and validating a new quantitative fit-test method called the Personal Respiratory Sampling Test (PRST). In Stage 2, PRST was evaluated in use during nursing activities in clinical settings. Eighty-four participants were divided randomly into four groups and were tested while performing bedside nursing procedures. In Stage 1, a new PRST method was successfully devised and validated. Results of Stage 2 showed that the new PRST method could detect different concentrations and different particle sizes inside the respirator while the wearer performed different nursing activities. This new fit-test method, PRST, can detect face seal leakage of an N95 respirator being worn while the wearer performs clinical activities. Thus, PRST can help ensure that the N95 respirator actually fulfils its function of protecting health-care workers from airborne pathogens.


Association of DNA polymerase alpha and beta with rough endoplasmic reticulum in sea-urchin eggs and changes in subcellular distribution during early embryogenesis.
The subcellular distribution of DNA polymerase alpha and beta was examined in unfertilized eggs and embryos of the sea-urchin, Hemicentrotus pulcherrimus. In unfertilized egg homogenates, prepared in sucrose solution containing 5 mM 2-mercaptoethanol and 5 mM MgCl2, DNA polymerases equilibrated in isospycnic centrifugation as a single peak at a buoyant density of 1.261 g/cm3 (band I). This indicates that DNA polymerases associate with a cytoplasmic organelle. Band I was converted to bands II (1.227 g/cm3), III (1.177 g/cm3) and IV (1.146 g/cm3) by EDTA treatment. The RNA content of bands I, II, III and IV was approximately 0.34, 0.25, 0.10 and 0.04 mg/mg protein respectively. In isokinetic and isopycnic centrifugations both DNA polymerase and RNA cosedimented and coequilibrated. These results suggest that bands I, II, III and IV contain various amounts of ribosomes on a common structure. Examination by electron microscopy indicated that bands I, II, III and IV contained mainly monolayered membrane vesicles with different amounts of bound ribosomes. The content of ribosomes varied in the order: band I > band II > band III > band IV. Each band contained DNA polymerase with sedimentation coefficients of 5.8-7.6 S (sensitive to N-ethylmaleimide and aphidicolin) and 3.2 S (insensitive to these drugs). We conclude that almost all of DNA polymerases alpha and beta are localized on the rough endoplasmic reticulum in unfertilized eggs. Mixing experiments suggest that the association is specific and is not an artifact of homogenization. During development of embryos DNA polymerases associated with the membrane decreased with concomitant increase in the nuclear fraction. This suggests that the enzymes migrate from the cytoplasm to the nucleus. It is discussed that the role of the endoplasmic reticulum as a storage site of DNA polymerases in unfertilized eggs and the mechanism of translocation of DNA polymerases from the cytoplasm to the nucleus during early embryogenesis.


Particulate matter air pollution disrupts endothelial cell barrier via calpain-mediated tight junction protein degradation.
Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation. We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction. Changes in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 μm). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured. PM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and β-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro. These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM-induced lung damage and adverse cardiovascular outcomes.


Cannabis and psychosis. Is there epidemiological evidence for an association?
A review of the evidence shows that there is no convincing support for a separate clinical diagnosis of 'cannabis psychosis'. Cannabis can, however, produce brief acute organic reactions and, in moderate to heavy doses, psychotic episodes in clear consciousness. Ingestion in naive users or increasingly heavy use in habitual users can precipitate a schizophreniform episode. Heavy users may have an increased risk of developing schizophrenia in the subsequent 15 years. Well controlled, longitudinal studies are required to explore these associations further and their possible aetiological significance.


Developmental Expression Patterns of GABAA Receptor Subunits in Layer 3 and 5 Pyramidal Cells of Monkey Prefrontal Cortex.
Cortical pyramidal neuron activity is regulated in part through inhibitory inputs mediated by GABAA receptors. The subunit composition of these receptors confers distinct functional properties. Thus, developmental shifts in subunit expression will likely influence the characteristics of pyramidal cell firing and the functional maturation of processes that depend on these neurons. We used laser microdissection and PCR to quantify postnatal developmental changes in the expression of GABAA receptor subunits (α1, α2, α5, β2, γ2, and δ) in layer 3 pyramidal cells of monkey prefrontal cortex, which are critical for working memory. To determine the specificity of these changes, we examined glutamate receptor subunits (AMPA Glur1 and NMDA Grin1) and conducted the same analyses in layer 5 pyramidal cells. Expression of GABAA receptor subunit mRNAs changed substantially, whereas glutamate receptor subunit changes were modest over postnatal development. Some transcripts (e.g., GABAA α1) progressively increased from birth until adulthood, whereas others (e.g., GABAA α2) declined with age. Changes in some transcripts were present in only one layer (e.g., GABAA δ). The development of GABAA receptor subunit expression in primate prefrontal pyramidal neurons is protracted and subunit- and layer-specific. These trajectories might contribute to the molecular basis for the maturation of working memory.


Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota.
Transplantation began at the University of Minnesota in 1963. Treatment of diabetes and its complications has been emphasized since 1966, when the first pancreas-kidney transplant was done. Of 3,640 kidneys transplanted by 1992, 1,373 were for diabetic recipients, including 658 from living donors and 715 from cadaver donors. The results progressively improved; since 1984, survival rates of kidney grafts have been similar for diabetic and nondiabetic recipients, with three fourths of the grafts functioning at 4 years. As of 1992, 501 pancreas transplants had been done, including 170 simultaneous with a kidney, 142 after a kidney, and 188 alone for nonuremic diabetic patients; again, the results have improved: by the 1990s, graft survival rates were similar in the 3 recipient categories. Successful pancreas transplants have been shown by our coworkers to stabilize or improve neuropathy and prevent recurrence of diabetic nephropathy in kidney grafts. In an attempt to simplify endocrine replacement therapy, we have done 63 human islet transplants, 34 as allografts for patients with type I diabetes and 29 as autografts after total pancreatectomy to treat chronic pancreatitis. Insulin independence occurs for about 50% of islet autograft recipients. Two recent islet allograft recipients treated with 15-deoxyspergualin have had sustained insulin independence. We anticipate that endocrine replacement therapy by transplantation will become routine for diabetic patients as methods to prevent rejection are refined.


Improved Real-Time PCR Diagnosis of Citrus Stubborn Disease by Targeting Prophage Genes of Spiroplasma citri.
Spiroplasma citri is a phloem-limited bacterium causing citrus stubborn disease (CSD). Isolation and culturing of S. citri is technically demanding and time consuming. S. citri is typically low in titer and unevenly distributed in citrus, making reliable detection challenging. The current preferred detection method is polymerase chain reaction (PCR) assays with primers developed from sequences of S. citri housekeeping genes. Recent genome sequencing of S. citri revealed that the bacterium harbors multiple copies of prophage genes. Therefore, targeting multicopy prophage genes was hypothesized to improve sensitivity of PCR detection. Two primer sets, Php-orf1 and Php-orf3, were developed from conserved prophage sequences in the S. citri genome. These primer sets were used to evaluate detection sensitivity in SYBR Green-based quantitative PCR (qPCR) assays with 18 S. citri in cultures isolated from different hosts and locations. Prophage primer set Php-orf1 increased detection sensitivity by 4.91 and 3.65 cycle threshold (Cq) units compared with housekeeping gene primers for spiralin and P58 putative adhesin gene, respectively. Detection was slightly less sensitive for the Php-orf3 primer set at 3.02 and 1.76 Cq units, respectively, over the same housekeeping gene primers. The prophage primer sets were validated for qPCR detection with field samples from three citrus orchards in California's San Joaquin Valley collected from 2007 to 2013. The data showed that S. citri prophage sequences improved sensitivity for qPCR detection of S. citri-infected trees at least 10-fold and reduced the number of false-negative results. No false-positive samples were detected with any of the primer sets. The enhanced sensitivity resulted from the higher copy number of prophage genes in the S. citri genome and, thus, improved CSD diagnosis from field samples.


Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia.
Chromosome 3p21-22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28-6.31) among four major AIDS-defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.


Tuning oxygen electrocatalysis via strain on LaNiO3(001).
The slow kinetics of the oxygen evolution (OER) and oxygen reduction (ORR) reactions hamper the development of renewable energy storage and conversion technologies. Transition-metal oxides (TMOs) are cost-effective replacements to conventional noble metal catalysts for driving these electrochemical systems. Strain is known to greatly affect the electronic structure of TMO surfaces, leading to significant changes in their electrocatalytic activities. In this study, we explore the influence of strain on the OER and ORR mechanisms on the LaNiO3(001) surface using density functional theory (DFT). Through a comparison of the overpotential and the largest change in Gibbs free energy (ΔG) in the reaction pathway, we determined that the OER activity on the LaNiO3 surface is directly related to the desorption of -H from the surface, which can be tuned as a function of strain. Moreover, tensile strain shuts off the reaction pathway to forming the -O2H intermediate state, due to the dissociation of -O2H into -O2 and -H. This is largely a consequence of the strong binding of H to the surface O, leading to a significant increase in the largest ΔG for the ORR on the tensile-strained surfaces by promoting an alternative reaction pathway. Overall, our results show that tensile strain on LaNiO3(001) leads to a decrease in both OER and ORR activities. Interestingly, in both cases, we find that the reaction is driven by the interactions with surface O ions, thus calling for a reinterpretation of the role that Ni eg orbital polarization plays in defining the OER and ORR catalytic activity on the TMO surfaces. Here, it is an indirect measure of changes in Ni-O hybridization, which controls the binding of -H species to the surface. As such, these results highlight the importance of surface O ions; particularly as it relates to defining molecule-surface interactions that ultimately tune and enhance the electrocatalytic efficiency of perovskite materials through the modulation of strains.


Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.
Ataxia-telangiectasia mutated and Rad3 related (ATR)-Seckel syndrome and autosomal recessive primary microcephaly (MCPH) syndrome share clinical features. RNA interference (RNAi) of MCPH1 have implicated the protein it encodes as a DNA-damage response protein that regulates the transcription of Chk1 and BRCA1, two genes involved in the response to DNA damage. Here, we report that truncating mutations observed in MCPH-syndrome patients do not impact on Chk1 or BRCA1 expression or early ATR-dependent damage-induced phosphorylation events. However, like ATR-Seckel syndrome cells, MCPH1-mutant cell lines show defective G2-M checkpoint arrest and nuclear fragmentation after DNA damage, and contain supernumerary mitotic centrosomes. MCPH1-mutant and ATR-Seckel cells also show impaired degradation of Cdc25A and fail to inhibit Cdc45 loading onto chromatin after replication arrest. Additionally, microcephalin interacts with Chk1. We conclude that MCPH1 has a function downstream of Chk1 in the ATR-signalling pathway. In contrast with ATR-Seckel syndrome cells, MCPH1-mutant cells have low levels of Tyr 15-phosphorylated Cdk1 (pY15-Cdk1) in S and G2 phases, which correlates with an elevated frequency of G2-like cells displaying premature chromosome condensation (PCC). Thus, MCPH1 also has an ATR-independent role in maintaining inhibitory Cdk1 phosphorylation, which prevents premature entry into mitosis.


Use of Complementary Health Approaches for Chronic Low-Back Pain: A Pain Research Registry-Based Study.
Objectives: To measure the use of complementary health approaches (CHAs) recommended in recent clinical practice guidelines relating to low-back pain, multivariate factors associated with their use, and clinical outcomes of CHA users and nonusers. Design: Observational cross-sectional study. Settings/Location: The Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation. Subjects: A total of 568 patients with chronic low-back pain. Interventions: Massage therapy, spinal manipulation, yoga, and acupuncture. Outcome measures: The numerical rating scale for low-back pain intensity, Roland-Morris Disability Questionnaire for back-related disability, and the Patient-Reported Outcomes Measurement Information System with 29 items for quality-of-life deficits relating to sleep disturbance, pain interference with activities, anxiety, depression, and low energy/fatigue. Results: The distribution of the number of different CHAs used by patients for low-back pain was as follows: 0, 179 (31.5%); 1, 139 (24.5%); 2, 160 (28.2%); 3, 70 (12.3%); and 4, 20 (3.5%). The numbers of patients using the specific CHAs were as follows: massage therapy, 271 (47.7%); spinal manipulation, 238 (41.9%); yoga, 144 (25.4%); and acupuncture, 96 (16.9%). Opioids had been used for low-back pain by 415 (73.1%) patients. Higher levels of education and higher pain self-efficacy scores were associated with greater use of any CHA, whereas increasing age and being Black were associated with lesser use of any CHA. Any CHA use was associated with lesser low-back pain intensity and lesser back-related disability. Patients who used massage therapy reported better clinical outcomes across all three dimensions. Patient pain self-efficacy also enhanced the effect of CHA use. Conclusions: The use of CHAs relative to opioids for low-back pain was inconsistent with recommendations from recent clinical practice guidelines despite clinical benefits with CHA use in this study. More research is needed on ways to improve the uptake of CHAs recommended for low-back pain, particularly among older and Black patients.


The effects of mobilization with movement on dorsiflexion range of motion, dynamic balance, and self-reported function in individuals with chronic ankle instability.
Previous studies have examined the effectiveness of a manual therapy intervention known as Mobilization with Movement (MWM) to increase dorsiflexion range of motion (ROM) in individuals with chronic ankle instability (CAI). While a single talocrural MWM treatment has increased dorsiflexion ROM in these individuals, examining the effects of multiple treatments on dorsiflexion ROM, dynamic balance, and self-reported function would enhance the clinical application of this intervention. This study sought to determine if three treatment sessions of talocrural MWM would improve dorsiflexion ROM, Star Excursion Balance Test (SEBT) reach distances, and self-reported function using the Foot and Ankle Ability Measure (FAAM) in individuals with CAI. Eleven participants with CAI (5 Males, 6 Females, age: 21.5 ± 2.2 years, weight: 83.9 ± 15.6 kg, height: 177.7 ± 10.9 cm, Cumberland Ankle Instability Tool: 17.5 ± 4.2) volunteered in this repeated-measures study. Subjects received three MWM treatments over one week. Weight-bearing dorsiflexion ROM (cm), normalized SEBT reach distances (%), and self-reported function (%) were assessed one week before the intervention (baseline), prior to the first MWM treatment (pre-intervention), and 24–48 h following the final treatment (post-intervention). No significant changes were identified in dorsiflexion ROM, SEBT reach distances, or the FAAM-Activities of Daily Living scale (p > 0.05). Significant changes were identified on the FAAM-Sport (p = 0.01). FAAM-Sport scores were significantly greater post-intervention (86.82 ± 9.18%) compared to baseline (77.27 ± 11.09%; p = 0.01) and pre-intervention (79.82 ± 13.45%; p = 0.04). These results indicate the MWM intervention did not improve dorsiflexion ROM, dynamic balance, or patient-centered measures of activities of daily living. However, MWM did improve patient-centered measures of sport-related activities in individuals with CAI.


REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease.
REM sleep behavior disorder (RBD) has been reported with various neurodegenerative disorders, most frequently in disorders with Lewy body pathology. RBD often precedes the onset of PD, and a recent prospective study showed that 38% of patients with RBD eventually developed PD. We identified 37 patients with degenerative dementia and a history of bursts of vigorous movement of the arms and legs with vocalization during sleep and associated with dream recall. Patients with and without two or more signs of parkinsonism were compared. Clinical, laboratory, and neuropsychometric features were analyzed, and criteria for the clinical diagnosis of dementia with Lewy bodies (DLB) were applied to all patients. Thirty-four of the 37 patients were male with mean age at onset of 61.5 years for RBD and 68.1 years for cognitive decline. RBD commenced before or concurrently with dementia in all patients but two. Parkinsonism (two or more signs) occurred in 54% of the sample (20/37), with a mean age at onset of 69.1 years. Polysomnography (PSG) confirmed RBD in all patients studied. Neuropsychological testing demonstrated impaired perceptual-organizational skills, verbal fluency, and marked constructional dyspraxia in more than one-half the patients. There were no statistically significant differences in the frequency of clinical features or in neuropsychological performance between patients with and without parkinsonism. Thirty-four patients (92%) met criteria for clinically possible or probable DLB. Three patients were autopsied; all had limbic with or without neocortical Lewy bodies. We report a group of predominantly male patients with a characteristic association of RBD and degenerative dementia. The clinical and neuropsychometric features of the groups of patients with and without parkinsonism are similar. We hypothesize that the underlying pathology in these patients is DLB.


Patterns of DSM-IV alcohol abuse and dependence symptoms in adolescent drinkers.
Diagnostic criteria for alcohol use disorders have largely been developed from research and clinical experience with adults. This research was designed to describe patterns of DSM-IV alcohol use disorder symptoms, and other problem domains, in adolescents with alcohol problems. A modified version of the Structured Clinical Interview for the DSM (SCID) was used to assess DSM-IV alcohol abuse and alcohol dependence symptoms in 91 male and 90 female adolescent drinkers with various levels of alcohol consumption and alcohol-related problems. The SCID was expanded to assess other alcohol problem domains thought to be relevant for adolescents. DSM-IV dependence symptoms showed moderate to high covariation, supporting the utility of the alcohol dependence construct in adolescence. Compared to previous reports from adult samples, some symptoms were relatively infrequent (e.g., withdrawal, medical problems). Tolerance had low specificity for the diagnosis of alcohol dependence. There was significant heterogeneity in the symptomatology of subjects with DSM-IV alcohol abuse. Although they are not in the DSM-IV criteria, alcohol-related blackouts, craving and risky sexual behavior were common in adolescents with DSM-IV alcohol dependence and abuse diagnoses. The data generally support the utility of DSM-IV criteria for alcohol dependence among adolescents. However, tolerance, withdrawal and medical problems appear to present differently in adolescents than has been reported in adults. Those with DSM-IV alcohol abuse diagnoses had very heterogeneous patterns of symptomatology, suggesting limitations of the criteria for DSM-IV alcohol abuse in adolescence. Alcohol-related blackouts, craving and risky sexual behavior are common among adolescents with alcohol use disorders and are an important focus for assessment and treatment efforts.


Safety, efficacy, and patient-perceived satisfaction of peripherally inserted central catheters in terminally ill cancer patients: a prospective multicenter observational study.
The purpose of this study was to investigate the safety, efficacy, and subjective satisfaction of peripherally inserted central catheters (PICCs) in terminally ill cancer patients. All PICCs were inserted by an interventional radiologist with radiological guidance. We monitored the occurrence of PICC-related complication and evaluated the patient-perceived satisfaction for PICC using semi-structured questionnaire. A total of 36 terminally ill cancer patients underwent PICC. Three patients had 2 PICC insertions; hence, finally 39 episodes during 829 PICC days were analyzed. All procedures were completed without any procedure-related complication. The median catheter life span was 19.0 days (95 % CI, 14.1-23.9). Thirty-four cases maintained the PICC until the intended time, while the other 5 cases (12.8 %; 6.1/1000 PICC days) were premature PICC removals. Totally 10 complications (25.6 %; 12.3/1000 PICC days) were reported including premature removals (n = 5), trivial bleedings (n = 3), and thrombophlebitis (n = 2). Patients reported that the procedure was not distressing (42 %), a little distressing (36 %), or distressing (21 %). Of 30 patients who had preserved cognitive function at fifth day, most patients (n = 25, 83 %) reported more comfort although the other 5 patients reported no change (n = 3) or less comfort (n = 2). PICCs were safely inserted and showed favorable maintenance rate with acceptable complications. Additionally, most of the patients felt that parenteral access became much comfortable after PICC insertion. When considering the characteristics of terminally ill cancer patients, poor general condition and a limited period of survival, PICC could be a safe and effective method for intravenous access.


A model of underlying socioeconomic vulnerability in human populations: evidence from variability in population health and implications for public health.
Drawing from insights into the variability of complex biologic systems we propose that the health of human populations reflects the interrelationship between underlying vulnerabilities (determined by population-level social and economic factors; e.g., income distribution) and capacities (determined by population-level salutary resources, e.g., social capital) and how populations, shaped by these vulnerabilities and capacities, respond to intermittent stressors (e.g., economic downturns) and protective events (e.g., introduction of a school). Monitoring this dynamic at the population-level can be accomplished by examining not only rates of illness and mortality, but variability in rates, either between populations or within populations over time. We used mortality data from New York City neighborhoods between 1990 and 2001 to test two related hypotheses consistent with this model of population health: (a) There is greater variability in mortality rates at a point in time between neighborhoods that are characterized by socioeconomic vulnerability; and (b) there is greater variability in mortality rates over time within neighborhoods that are characterized by socioeconomic vulnerability. We found that neighborhoods characterized by social and economic vulnerability displayed substantial variability in particular mortality rates. Mortality rates displaying the greatest variability were from causes that may be sensitive to social conditions (e.g., homicide or HIV/AIDS rates). Variability in population health existed both between neighborhoods with underlying vulnerability at one point in time and within vulnerable neighborhoods over time. The results of this analysis are consistent with a theory of underlying socioeconomic vulnerabilities of human populations and suggest that variability in population health may be an important consideration in population health assessment.


Intrastromal epithelial accretion follows deep excimer annular keratectomy.
The purpose of this study was to evaluate corneal reepithelialization and wound healing following annular excimer keratectomy. Two sets of experiments were performed on 35 rabbit eyes. In the first set of experiments, experiment I, deep Fresnel excimer keratectomy was performed, with a 6-mm outer and 3-mm inner diameter. Animals were sacrificed at 1, 5, 12, and 16 weeks, and corneas were examined by light and electron microscopy. In experiment II, the central epithelium was left intact, and superficial and deep mid-peripheral excimer annular keratectomies were performed measuring 6 mm in outer and 3 mm in inner diameter. Animals were sacrificed at 1 week, and corneas were examined by light microscopy. Following deep Fresnel excimer keratectomy (experiment I), corneas showed stromal edema in the central 3-mm zone. Intrastromal islands of epithelial cells with PAS positive basement membrane-like structures were seen histologically at 1 week. Electron microscopy showed loss of stromal collagen in areas adjacent to epithelial islands; in areas distant from the epithelial islands, the stromal collagen appeared normal. The overlying central stroma sloughed after 5 weeks. Anterior stromal scarring was observed. In experiment II (mid-peripheral annular keratectomy), intrastromal epithelial accretion was present in corneas with deep annular keratectomy but not in superficial annular keratectomy. Intrastromal epithelial accretion follows deep excimer annular keratectomy and is associated with adjacent stromal degradation.


Follow-up imaging after pediatric pyeloplasty.
The duration, methods and frequency of radiographic follow-up after pediatric pyeloplasty is not well-defined. We prospectively evaluated a cohort of children undergoing pyeloplasty to determine the method for follow-up. Between 2000 and 2008, children undergoing pyeloplasty for unilateral ureteropelvic junction obstruction were evaluated for this study. All patients were evaluated preoperatively with protocol ultrasound (USG) and diuretic renal scan (RS). On the basis of preoperative split renal function (SRF), these patients were divided into four groups - Group I: SRF > 40%, Group II: SRF 30-39%, Group III: SRF 20-29%, and Group IV: SRF 10-19%. In follow-up, USG and RS were done at 3 months and repeated at 6 months, 1 year, and then yearly after surgery for a minimum period of 5 years. Improvement, stability, or worsening of hydronephrosis was based on the changes in anteroposterior (AP) diameter of pelvis and caliectasis on USG. Absolute increase in split renal function (SRF) >5% was considered significant. Failure was defined as increase in AP diameter of pelvis and decrease in cortical thickness on 3 consecutive USG, t½ >20 min with obstructive drainage on RS and/or symptomatic patient. 145 children were included in the study. Their mean age was 3.26 years and mean follow-up was 7.5 years. Pre- and post-operative SRF remain unchanged within 5% range in 35 of 41 patients (85%) in Group I. While 9 of 20 patients (45%) in Group II, 23 of 50 patients (46%) in Group III, and 14 of 34 patients (41%) in Group IV exhibited changes >5% after surgery. 5 patients failed, 2 in Group III, and 3 in Group IV. None of the patients deteriorated in Group I and II. After pyeloplasty in children with a baseline split GFR >30%, if a diuretic renogram and USG performed 3 months postoperatively shows nonobstructive drainage with t½ <20 min and decreased hydronephrosis, no further follow-up is required.


Gender, health inequalities and welfare state regimes: a cross-national study of 13 European countries.
This study is the first to examine the relationship between gender and self-assessed health (SAH), and the extent to which this varies by socioeconomic position in different European welfare state regimes (Liberal, Corporatist, Social Democratic, Southern). The EUROTHINE harmonised data set (based on representative cross-sectional national health surveys conducted between 1998 and 2004) was used to analyse SAH differences by gender and socioeconomic position (educational rank) in different welfare states. The sample sizes ranged from 7124 (Germany) to 118 245 (Italy) and concerned the adult population (aged >or=16 years). Logistic regression analysis (adjusting for age) identified significant gender differences in SAH in nine European welfare states. In the UK (OR 0.88; 95% CI 0.78 to 0.99) and Finland (OR 0.85; 95% CI 0.77 to 0.95), men were significantly more likely to report "bad" or "very bad" health. In Denmark, Sweden, Norway, Holland, Italy, Spain and Portugal, a significantly higher proportion of women than men reported that their health was "bad" or "very bad". The increased risk of poor SAH experienced by women from these countries ranged from a 23% increase in Denmark (OR 1.23; 95% CI 1.08 to 1.39) to more than a twofold increase in Portugal (OR 2.01; 95% CI 1.87 to 2.15). For some countries (Italy, Portugal, Sweden), women's relatively worse SAH tended to be most prominent in the group with the highest level of education. Women in the Social Democratic and Southern welfare states were more likely to report worse SAH than men. In the Corporatist countries, there were no gender differences in SAH. There was no consistent welfare state regime patterning for gender differences in SAH by socioeconomic position. These findings constitute a challenge to regime theory and comparative social epidemiology to engage more with issues of gender.


Sensitization of Radioresistant Prostate Cancer Cells by Resveratrol Isolated from Arachis hypogaea Stems.
Resveratrol (RV, 3,4',5-trihydroxystilbene) is naturally produced by a wide variety of plants including grapes and peanuts (Arachis hypogaea). However, the yield of RV from peanut stem and its potential radiosensitizing effects in prostate cancer (PCa) have not been well investigated. In this study, we characterized RV in peanut stem extract (PSE) for the first time and showed that both RV and PSE dose-dependently induced cell death in DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells with the radioresistant phenotype. Furthermore, the combination of radiation with either RV or PSE induced the death of radioresistant PCa cells through delayed repair of radiation-induced DNA double-strand break (DSB) and prolonged G2/M arrest, which induced apoptosis. The administration of RV and PSE effectively enhanced radiation therapy in the shDAB2IP PCa xenograft mouse model. These results demonstrate the promising synergistic effect of RV and PSE combined with radiation in the treatment of radioresistant PCa.


Ambulatory blood pressure measurements are related to albumin excretion and are predictive for risk of microalbuminuria in young people with type 1 diabetes.
The relationship between BP and microalbuminuria in young people with type 1 diabetes is not completely clear. As microalbuminuria is preceded by a gradual rise in albumin excretion within the normal range, we hypothesised that ambulatory BP (ABP) may be closely related to albumin excretion and progression to microalbuminuria. ABP monitoring (ABPM) was performed in 509 young people with type 1 diabetes (age median [range]: 15.7 [10.7-22.6] years) followed with annual assessments of three early morning urinary albumin:creatinine ratios (ACRs) and HbA(1c). Systolic BP (SBP) and diastolic BP (DBP) and the nocturnal fall in BP were analysed in relation to ACR. All ABPM variables were significantly related to baseline log(10) ACR (p < 0.001). After the ABPM evaluation, 287 patients were followed for a median of 2.2 (1.0-5.5) years. ABP at baseline was independently related to mean ACR during follow-up. Nineteen initially normoalbuminuric patients developed microalbuminuria after 2.0 (0.2-4.0) years and their baseline daytime DBP was higher than in normoalbuminuric patients (p < 0.001). After adjusting for baseline ACR and HbA(1c), there was an 11% increased risk of microalbuminuria for each 1 mmHg increase in daytime DBP. Forty-eight per cent of patients were non-dippers for SBP and 60% for DBP; however, ACR was not different between dippers and non-dippers and there were no differences in the nocturnal fall in BP between normoalbuminuric and future microalbuminuric patients. In this cohort of young people with type 1 diabetes, ABP was significantly related to ACR, and daytime DBP was independently associated with progression to microalbuminuria. Increasing albumin excretion, even in the normal range, may be associated with parallel rises in BP.


Estimating and explaining the effect of education and income on head and neck cancer risk: INHANCE consortium pooled analysis of 31 case-control studies from 27 countries.
Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 - 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 - 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.


PET Tracers for Clinical Imaging of Breast Cancer.
Molecular imaging of breast cancer has undoubtedly permitted a substantial development of the overall diagnostic accuracy of this malignancy in the last years. Accurate tumour staging, design of individually suited therapies, response evaluation, early detection of recurrence and distant lesions have also evolved in parallel with the development of novel molecular imaging approaches. In this context, positron emission tomography (PET) can be probably seen as the most interesting molecular imaging technology with straightforward clinical application for such purposes. Dozens of radiotracers for PET imaging of breast cancer have been tested in laboratory animals. However, in this review we shall focus mainly in the smaller group of PET radiopharmaceuticals that have lead through into the clinical setting. PET imaging can be used to target general metabolic phenomena related to tumoural transformation, including glucose metabolism and cell proliferation, but can also be directed to specific hormone receptors that are characteristic of the breast cancer cell. Many other receptors and transport molecules present in the tumour cells could also be of interest for imaging. Furthermore, molecules related with the tumour microenvironment, tumour induced angiogenesis or even hypoxia could also be used as molecular biomarkers for breast cancer imaging.


Mental health consequences and correlates of reported medical student abuse.
To assess the prevalence, correlates, and mental health consequences of reported medical training-related abuses. A longitudinal cohort study of 137 students surveyed from medical school entrance (time 1) through the winter of the fourth training year (time 4). A state college of medicine. Reported training-related abuses (measured at time 4) and mental health status measured at times 1 and 4 (depressive and anxiety symptoms, hostility, problem drinking, escapist drinking, alcohol consumption levels, and gender role orientations). Seventy-two percent of students reported at least one abusive experience during medical training. Females were significantly more likely than males to report gender discrimination, exclusion from informal settings, discomfort from sexual humor, and unwanted sexual advances. Abuse was significantly related to most psychopathological outcomes, controlling for pre-existing psychopathology. Males low in masculinity and females low in femininity were most likely to report abuse. The data provide further support for the assumption that a high proportion of medical students not only experience the training process as abusive in nature but also suffer measurable psychopathological consequences. Efforts should be made to reform medical education, with a prominent focus on gender role-related issues.


Effects of ingestion of collagen peptide on collagen fibrils and glycosaminoglycans in the dermis.
In order to investigate the effects of collagen peptide ingestion on fibroblasts and the extracellular matrix in the dermis, collagen peptide was administered orally to pigs at 0.2 g/kg body weight/d for 62 d, and its effects were compared with those of lactalbumin and water controls. Fibroblast density, and diameter and density of collagen fibrils were significantly larger in the collagen peptide group than in the lactalbumin and water control groups. The two major components of dermal glycosaminoglycans, hyaluronic acid and dermatan sulfate, which are present in the inter-fibrillar space, did not differ significantly among the three groups. However, the ratio of dermatan sulfate, which is derived from fibril-bound decorin, was largest in the collagen peptide group. These results suggest that ingestion of collagen peptide induces increased fibroblast density and enhances formation of collagen fibrils in the dermis in a protein-specific manner.


Positron emission tomography/computed tomography for target delineation in head and neck cancers.
Radiation and concurrent chemoradiation are essential in the treatment of head and neck cancers because they allow a potentially curative organ preservation approach in a manner that greatly affects quality of life. Greater doses of radiation to areas of gross disease have invariably led to greater loco-regional control. Radiation delivery has undergone great strides, especially in the era of intensity-modulated radiotherapy and related technologies. With the ability to sculpt out areas of higher and lower doses of radiation to millimeter accuracy, the role of imaging to better direct the radiation beam to its target via improved localization has become an issue of great promise. The use of (18)F-fluorodeoxyglucose-positron emission tomography (PET) with computed tomography (CT) as a means of noninvasively staging many head and neck cancers has become increasingly popular. With its role as a functional assay of tumor metabolic activity, it is often used in conjunction with physical examination and other imaging modalities to determine levels of nodal metastases as well as the site of head and neck involvement. Several groups have used images derived from PET/CT to outline areas of gross disease to receive definitive doses of radiotherapy. Generally, no statistically significant difference exists in the volumes delineated on CT alone versus PET/CT. However, in the studied populations there is often important and significant wide individual variability. The tumors on PET/CT are either larger or smaller than tumors outlined on CT scan only, in the majority of patients. Although areas of controversy include threshold definition and image resolution, the utility of a functional assay in defining target volume helps determine areas to receive higher doses of radiation in cancers of the head and neck. Exciting new functional modalities are emerging to image other parameters including tumor hypoxia, which presents a new target with the same challenges in target delineation as PET/CT.


Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges.
Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.


Acute renal failure owing to paraphenylene diamine hair dye poisoning in Sudanese children.
Paraphenylene diamine (PPD) has traditionally been used as a dark-coloured hair dye. In Sudan, it is used by women to colour their hair and as a body dye when added to henna (Lawasonia alba). Accidental or deliberate ingestion causes severe systemic toxicity. Although a wide variety of complications has been described, there are few reports in children. To describe the clinical features, management and outcome of PPD intoxication in Sudanese children. Data for a 3-year period (2006-2008) were extracted from the medical records of the Paediatric Nephrology Unit, Soba University Hospital. Information included the circumstances of poisoning, gender, age distribution, clinical presentation, biochemical findings and outcome. Over the 3-year period, 17 children (16 female) were admitted to the Paediatric Nephrology Unit with PPD intoxication. Mean age was 13.8 yrs (range 2-18). Thirteen (76.4%) had attempted suicide, three (17.6%) were poisoned as a result of attempted murder and one poisoning (5.8%) was accidental. Eight children (47%) required tracheostomy for severe angioneurotic oedema. Of 12 (71%) who developed acute renal failure (ARF), nine required dialysis and three were managed conservatively. Two children (12%) died and the other 15 recovered with normal renal function. PPD intoxication is a life-threatening condition with significant morbidity and mortality in children. Clinical manifestations and outcome are similar to those in adults. Mortality can be reduced by early recognition, prompt referral and aggressive supportive treatment.