Isolated high serum triiodothyronine levels. Clinical relevance after sodium iodide I 131 therapy.
Ten of 25 thyrotoxic patients treated with sodium iodine I 131 had thyroid function test results that indicated a high triiodothyronine (T3) level, with normal thyroxine (T4) and thyroid-stimulating hormone (TSH) levels, within 15 months of treatment. This pattern was usually transitional and lasted a variable time, eventually leading to euthyroidism, hyperthyroidism, or hypothyroidism. It is concluded that an isolated elevation of T3 levels after radioactive iodine therapy can be associated with any clinical pattern of thyroid function and has no clear prognostic value. No specific treatment is needed for this abnormality.


Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study.
To prospectively establish the specificity, sensitivity, and positive predictive value (PPV) of a basal 17-hydroxyprogesterone (17-HP) level for the screening of 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) among hyperandrogenic women. Prospective observational trial. Tertiary care academic medical centers. Eight healthy controls, 20 patients with NCAH, and 284 consecutively seen patients with hyperandrogenism. All controls and patients with NCAH, and select patients with hyperandrogenism, underwent acute ACTH (1-24) stimulation. Specificity was determined by measuring 17-HP every other day during one menstrual cycle in 8 healthy women with normal ovulation (107 samples). Sensitivity was determined by measuring 17-HP between 7 and 9 A.M. and 3 and 5 P.M. on the same day in 20 patients with genetically confirmed NCAH. The PPV was determined by prospectively measuring 17-HP in 284 consecutively seen hyperandrogenic women at their initial evaluation. The diagnosis of NCAH was established by a stimulated 17-HP level of >10 ng/mL. Among controls, 17-HP levels of <2, <3, and <4 ng/mL all had a specificity of 100% when obtained in the follicular phase; when obtained in the luteal phase, they had specificities of 53%, 82%, and 82%, respectively. Among patients with NCAH, 17-HP levels of >2, >3, and >4 ng/mL had sensitivities of 100%, 90%, and 90%, respectively, for the detection of the disorder when obtained in the morning, and sensitivities of 95%, 90%, and 85%, respectively, when obtained in the afternoon. Among the 284 consecutively seen hyperandrogenic women, the PPVs of the first and second 17-HP levels were 7.3% and 19% for a cutoff level of >2 ng/mL, 13% and 43% for a cutoff level of >3 ng/mL, and 33% and 40% for a cutoff level of >4 ng/mL, respectively. A basal 17-HP level is a useful screening tool for NCAH. A cutoff level of 4 ng/mL has maximum specificity and PPV, with little loss in sensitivity if testing is performed in the morning and during the follicular phase. However, a lower cutoff level (e.g., 2 or 3 ng/mL) is preferable if testing is performed at odd hours of the day, as is common in many practices, and maximum sensitivity is desired.


In vivo administration of flt3 ligand markedly stimulates generation of dendritic cell progenitors from mouse liver.
The study of liver dendritic cells (DC) and their progenitors is restricted by the small numbers that can be isolated or propagated from normal hepatic tissue. We examined the ex vivo growth, phenotype, and function of these cells after the administration to mice of the recently cloned hemopoietic growth factor flt3 ligand (FL), which is highly effective in mobilizing stem/progenitor cells. FL treatment (10 microg/day for 10 days) resulted in a mean 14-fold increase in the absolute number of nonparenchymal cells recovered from collagenase-digested livers compared with the control value. Culture of these nonparenchymal cells in granulocyte-macrophage CSF (GM-CSF; 1000 U/ml) resulted in the early formation of proliferating cell clusters and maximal release (within 4-5 days) of markedly increased numbers of nonadherent, low buoyant density cells per liver. Maximal release of low buoyant density cells propagated from control livers was at the later time of 6 to 8 days. Cells from both sources were DEC-205+, CD11c+, MHC class II+, CD80(low) (i.e., low level of CD80), CD86(low) and CD40(low). This immature phenotype was linked to poor T cell allostimulatory activity, indicative of DC progenitors. Propagation of cells from livers of FL-treated mice in GM-CSF and IL-4 resulted in a more mature DC phenotype and function. Maturational changes were also observed following exposure of the GM-CSF-stimulated progenitors to type 1 collagen for 3 additional days. The ability of FL to boost production of large numbers of liver DC progenitors provides opportunities for the further study of these important APC in normal liver immunobiology and in immune-mediated hepatic disorders.


Compliance in a randomized controlled trial: the implementation of emotion-orientated care in psycho-geriatric facilities.
The aim of this study was to gain insight into compliance with the introduction of a new care model [emotion-orientated care (EOC)] as part of an intervention study (RCT) in psycho-geriatric care. The success of the implementation (compliance), as well as the expectations and experiences concerning the training were studied. Observations were conducted in four intervention homes and four control homes, and care-plans of residents were also analysed to see whether the implementation had succeeded. Semi-structured interviews were conducted with four persons in each of the four intervention sites (a total of 16 interviews) to study the experiences with the training and implementation. The observations showed no clear differences between intervention and control homes with regard to the interactions between residents and professional caregivers. Analysis of the reporting systems revealed differences within, as well as between, the intervention and control homes. The content of the reports showed no differences between the intervention and control homes. The interviewees had different expectations of the EOC training, depending on their disciplinary background. The caregivers regarded the training as a confirmation of their current practice. They experienced some changes at the individual level and some of them reported that the co-operation between units had become better. At the home-level no changes were reported. Every interviewee indicated that the implementation of EOC was difficult and laborious and that there were (mainly organizational) obstacles that could hinder the implementation of the EOC training. Observations and the analysis of the reporting systems indicated that there was no clear difference between intervention homes and control homes as to the actual implementation of the intervention, indicating that the compliance with the new care model was not optimal. The interviews gave some insight into factors that caused lack of compliance.


Potential uses of intravenous proton pump inhibitors to control gastric acid secretion.
Proton pump inhibitors are the most effective agents for suppressing gastric acidity and are the preferred therapy for many acid-related conditions. While proton pump inhibitors have been accessible in intravenous formulations in several European countries, they have been available only as oral drugs in the United States. In the near future, the proton pump inhibitor pantoprazole is likely to become available in an intravenous formulation for American patients. Potential uses for intravenous proton pump inhibitors include treatment of Zollinger-Ellison syndrome and peptic ulcers complicated by bleeding or gastric outlet obstruction, as well as prevention of stress ulcers and acid-induced lung injury. These intravenous proton pump inhibitors are also likely to be beneficial to patients undergoing long-term maintenance with oral proton pump inhibitors who cannot take oral therapy for a period of time. Intravenous pantoprazole is especially distinguished in its lack of clinically relevant drug interactions, and it requires no dosage adjustment for patients with renal insufficiency or with mild to moderate hepatic dysfunction. Both omeprazole and pantoprazole are well tolerated in both oral and intravenous forms. Although further studies are needed to define their roles clearly, the availability of intravenous formulations of proton pump inhibitors will certainly assist with the treatment of gastric acid-related disorders.


The HAWK2 program: a computer-based drug prevention intervention for Native American youth.
American Indians and Alaska Natives (AI/ANs) have some of the highest rates of substance use compared with other ethnic groups. Native American youth start experimenting with drugs at younger ages, continue to use them after initial experimentation, and thus seem to mirror the same drug use patterns as their older peers. Despite the seriousness of the problem, there is a lack of evidence-based drug prevention interventions for AI/AN youth. This review article describes the process by which an existing evidence-based, culturally relevant drug prevention intervention was transformed into a low-cost, computerized intervention digitized in order to extend its reach to Native American youth in reservations and rural locations. The intervention, titled HAWK(2) (Honoring Ancient Wisdom and Knowledge(2): Prevention and Cessation) is aimed at young Native children in elementary school settings (grades 4 and 5) and uses engaging multimedia features such as games, animations, and video clips to impart substance abuse prevention knowledge and skills training. The development of this intervention was a collaborative process involving the participation of community experts, research scientists, school teachers, and practitioners, as well as Native youth. Specific examples are provided to illustrate the development processes. Initial feedback from practitioners and youth suggest the feasibility and acceptability of computer-based interventions by Native youth and practitioners. Computer-based interventions are a cost-effective way of engaging youth in prevention programming. Future studies of HAWK(2) will provide an important means of testing the long-term effectiveness of self-administered, computer-based interventions for AI/AN youth.


Persistent hyperactivity and distinctive strategy features in the Morris water maze in 3xTg-AD mice at advanced stages of disease.
Search strategies in the Morris water maze provide useful insights on cognitive function that may reveal genotype differences not reflected by escape latency or distance. Its analysis is pointed out as a complementary tool to better define the phenotype and the effect of treatments in animal models in which both cognitive impairment and behavioral symptoms reproduce the clinical complexity of the Alzheimer's disease patient. Here, we studied the performance of 13-month-old male 3xTg-AD mice in 3 different paradigms (cue learning, place task, and probe trial) and as compared with age-matched nontransgenic mice. The quantitative analysis (escape latency, distance, and speed) showed that in all tasks, the cognitive performance of 3xTg-AD mice was interfered with by a persistent hyperactive pattern. Their worse cognitive function was revealed by the qualitative features of nonsearch behaviors (floating and circling) and search strategies (single and /mixed, goal directed and nongoal directed). The search pattern was based on mixed and nongoal-directed strategies, in contrast to the single and goal-directed strategies used by controls. In the place task, poor cognitive flexibility of 3xTg-AD mice was also shown in persistence of search in the cue-trained position and the need to correct the strategy to find the new location. Trials involving a naïve situation (first trial of the cue task) or the difficulty of a new task (first trial of the place task and the probe trial) were the most suitable to show the deficits. This qualitative analysis may also be useful in the assessment of preventive or therapeutical treatments.


Early kinetics of innate and adaptive immune responses during hepatitis B virus infection.
Innate immunity appears to be silent in acutely hepatitis B virus (HBV)-infected chimpanzees, as shown by microarray analysis of intrahepatic gene expression. Whether this observation also applies to HBV pathogenesis in man remains undefined. The aim of this study was thus to characterise natural killer (NK) and CD56(+) natural T (NT) cell responses early after human HBV infection and their relationship to the induction of adaptive immunity. Two HBV-seronegative blood donors who became hepatitis B surface antigen (HBsAg) and HBV DNA positive but had persistently normal alanine aminotransferase (ALT) were followed from a very early stage of HBV infection. The phenotype (CD69 and NKG2D) and function (cytotoxicity and interferon gamma (IFN gamma) production) of NK and NT cells were analysed. CD4- and CD8-mediated responses were studied in parallel with overlapping peptides covering the entire HBV sequence by ex vivo intracellular cytokine staining (ICS) for IFN gamma, interleukin 2 (IL2), IL4 and IL10, and by ex vivo Elispot for IFN gamma. Healthy subjects, and patients with chronic and acute HBV infection were studied for comparison. An early induction of both innate and adaptive responses was observed. NK and NT cells showed faster kinetics than HBV-specific T cells with an earlier peak of activity, while CD4(+) and CD8(+) cell responses were mounted with a similar profile, with higher frequencies of IFN gamma-producing CD8(+) cells at the peak of the response. The innate immune system is able to sense HBV infection, as shown by the early development of NK and NT cell responses, which probably contribute to contain the HBV infection and to allow timely induction of adaptive responses.


ALK-immunoreactive neoplasms.
Since the first discovery of anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) by Morris et al in 1994, the number of ALK-positive neoplasms, either in the form of translocation or gain-of-function mutations, have been dramatically expanded from ALCL of T- and NK-cell origin, to diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor (IMT), neuroblastoma, non-small cell lung carcinoma (NSCLC), undifferentiated anaplastic thyroid carcinoma, and rare type of sarcomas. This review covers the major aspects of ALK-immunoreactive neoplasms with emphasis on the pathogenesis of ALK-positive neoplasms. The new advances and rapid-evolving practices using ALK inhibitors for therapy are also discussed at the end of this review. ALK(+) articles published in English literature are retrieved and critically reviewed. ALK(+) neoplasia is a rapidly growing field and the list of ALK(+) neoplasms is being expanded continuously. Accurate and correct diagnosis of ALK(+) neoplasms is of paramount importance in guiding the appropriate treatment in the era of personalized medicine using specific ALK inhibitor.


Nitrate decreases methane production also by increasing methane oxidation through stimulating NC10 population in ruminal culture.
Studies proved that addition of nitrate in rumen could lead to reduction of methane emission. The mechanism of this function was involved in the competition effect of nitrate on hydrogen consumption and the inhibitory effect of generated nitrite on methanogen proliferation. The present study investigated an alternative mechanism that denitrifying anaerobic methane oxidizing (DAMO) bacteria, DAMO archaea and anammox bacteria may co-exist in rumen, therefore, more methane can be oxidized when addition of nitrate. Ruminal batch culture model was used to test the effects of addition of 5 mM NaNO3, 4 mM NH4Cl, or both into the culture substrate on methane production, fermentation patterns, and population of methanogens, NC10 and anaerobic methanotrophic-2d (ANME-2d). Our results showed that NC10 in the ruminal culture was detected by polymerase chain reaction (PCR) when using NC10 special primer sets, and addition of nitrate reduced methane production and the relative proportions of methanogen, whereas increased the relative proportion of NC10. A combined addition of ammonia salt and nitrate did not show further inhibitory effect on methane production but accelerated nitrate removal. We did not detect DAMO archaea in ruminal culture by real-time PCR when using ANME-2d special primer sets. The present study may encourage researchers to pay more attention to methane oxidation performed by anaerobic methanotroph when studying the strategies of inhibiting ruminal methane emission.


Cardiac morphofunctional characteristics of transgenic rats with overexpression of the bradykinin B1 receptor in the endothelium.
Our aim was to evaluate whether endothelial overexpressing of the bradykinin B1 receptor could be associated with altered left ventricular and myocardial performance. Echocardiography and hemodynamic were employed to assess left ventricular morphology and function in Sprague Dawley transgenic rats overexpressing the endothelial bradykinin B1 receptor (Tie2B1 rats). The myocardial inotropism was evaluated on papillary muscles contracting in vitro. In Tie2B1 animals, an enlarged left ventricular cavity and lower fractional shortening coupled with a lower rate of pressure change values indicated depressed left ventricular performance. Papillary muscle mechanics revealed that both Tie2B1 and wild-type rat groups had the same contractile capacities under basal conditions; however, in transgenic animals, there was accentuated inotropism due to post-pause potentiation. Following treatment with the Arg(9)-BK agonist, Tie2B1 papillary muscles displayed a reduction in myocardial inotropism. Endothelial B1 receptor overexpression has expanded the LV cavity and worsened its function. There was an exacerbated response of papillary muscle in vitro to a prolonged resting pause, and the use of a B1 receptor agonist impairs myocardial inotropism.


Disruption of cooperation between Ras and MycN in human neuroblastoma cells promotes growth arrest.
Our aim was to examine whether active Ras and MycN cooperation contributes to the malignant phenotype of human neuroblastoma with amplified MycN gene, an aggressive incurable tumor. Human neuroblastoma LAN-1 cells, in which the MycN gene is amplified, were used to examine the impact of the Ras inhibitor farnesylthiosalicylic acid on cell growth, on the levels Ras and MycN proteins, and on profiles of gene expression. We show that LAN-1 cells express relatively large amounts of MycN and active Ras-GTP. Inhibition of active Ras by farnesylthiosalicylic acid led to attenuation of the Raf-MEK-ERK and phosphoinositide 3-kinase-Akt-glycogen synthase-3 (GSK-3) pathways, to reduction in cyclin D1, phospho-retinoblastoma, and E2F, and to increase in the cyclin-dependent kinase inhibitor p27 and in retinoblastoma-binding protein-1, an inhibitor of E2F transcriptional activity. Ras inhibition by farnesylthiosalicylic acid or by a dominant-negative Ras also led to complete disappearance of MycN protein from the nuclei of LAN-1 cells. This was a result of blocking of Akt inactivation of GSK-3, leading to GSK-3-dependent phosphorylation with consequent proteosomal degradation of MycN. Loss of active Ras and of MycN in LAN-1 cells was manifested in profiles of gene expression that could be expected from the loss of MycN transcriptional activity and of Ras signaling. These changes explain the farnesylthiosalicylic acid-induced inhibition of LAN-1 cell growth. Active Ras is needed to block MycN degradation, promoting cooperative Ras- and MycN-dependent cell cycle progression in LAN-1 cells. Ras inhibitors are therefore likely candidates for the treatment of advanced neuroblastoma characterized by high expression of MycN.


Same same, but different: effects of likelihood framing on concerns about a medical disease in patients with somatoform disorders, major depression, and healthy people.
Research has shown that patients with somatoform disorders (SFD) have difficulty using medical reassurance (i.e. normal results from diagnostic testing) to revise concerns about being seriously ill. In this brief report, we investigated whether deficits in adequately interpreting the likelihood of a medical disease may contribute to this difficulty, and whether patients' concerns are altered by different likelihood framings. Patients with SFD (N = 60), patients with major depression (N = 32), and healthy volunteers (N = 37) were presented with varying likelihoods for the presence of a serious medical disease and were asked how concerned they are about it. The likelihood itself was varied, as was the format in which it was presented (i.e. negative framing focusing on the presence of a disease v. positive framing emphasizing its absence; use of natural frequencies v. percentages). Patients with SFD reported significantly more concern than depressed patients and healthy people in response to low likelihoods (i.e. 1: 100 000 to 1:10), while the groups were similarly concerned for likelihoods ⩾1:5. Across samples, the same mathematical likelihood caused significantly different levels of concern depending on how it was framed, with the lowest degree of concern for a positive framing approach and higher concern for natural frequencies (e.g. 1:100) than for percentages (e.g. 1%). The results suggest a specific deficit of patients with SFD in interpreting low likelihoods for the presence of a medical disease. Positive framing approaches and the use of percentages rather than natural frequencies can lower the degree of concern.


[Working conditions and health-related measures in the processing of waste products of phosphorus-containing mineral fertilizers].
In the processing of the waste products of phosphorus containing fertilizer production, several major health-related factors were identified depending on the industrial site's peculiarities: unfavourable microclimate conditions (both cold and heat), relative temperature differences, noise and vibration caused by the equipment, semi-product's, additives' and finished product's dusts, fluorine- and phosphorus-containing substances' affects and poor illumination. The proposed data were used for health-related improvements in the occupational conditions.


Epigenomic programming contributes to the genomic drift evolution of the F-Box protein superfamily in Arabidopsis.
Comparisons within expanding sequence databases have revealed a dynamic interplay among genomic and epigenomic forces in driving plant evolution. Such forces are especially obvious within the F-Box (FBX) superfamily, one of the largest and most polymorphic gene families in land plants, where its frequent lineage-specific expansions and contractions provide an excellent model to assess how genetic variation impacted gene function before and after speciation. Previous phylogenetic comparisons based on orthology, diversity, and expression patterns identified three plant FBX groups--Common, Lineage-Specific, and Pseudo(genized)--whose emergences are consistent with genomic drift evolution. Here, we examined this variance within Arabidopsis thaliana by evaluating SNPs for all 877 FBX loci from 432 naturally occurring accessions and their relationships to variations in natural selection, expression, and DNA/histone methylation. In line with their phenotypic importance, Common FBX loci have low polymorphism but high deleterious mutation rates indicative of stringent functional constraints. In contrast, the Lineage-Specific and Pseudo groups are enriched in genes with basal expression and higher SNP density and more correlated with methylation marks (RNA-directed DNA methylation and histone H3K27 trimethylation) that promote transcriptional silencing. Taken together, we propose that reversible epigenomic modifications helped shape FBX gene evolution by transcriptionally suppressing the adverse effects of gene dosage imbalance and harmful FBX alleles that arise during genomic drift, while simultaneously allowing innovations to emerge through epigenomic reprogramming.


Clipping of incidental aneurysm of middle cerebral artery through small temporal craniotomy and linear skin incision.
The authors introduced a new approach for clipping of the incidental aneurysm of the middle cerebral artery (MCA) and reported the clinical results. We retrospectively reviewed 26 patients with 27 incidental MCA aneurysms who were treated from January 2010 to December 2012. All clippings were performed through a small temporal craniotomy and linear skin incision. Follow-up imaging showed complete occlusion of 26 aneurysms (96.3%), residual neck in one (3.7%). In one case, residual neck of the aneurysm did not grow on serial follow up. In one of 26 cases (3.8%), approach-related complication was retraction injury of the temporal cortex. Two patients developed postoperative infarction on the MCA territories due to vasospasm and on the cerebellum due to unknown causes. These were not approach-related complications. Operation time was 95 min-250 min (mean 143 min). There were no complications of temporal muscle atrophy, scar deformity, paresthesia, or pain around the scalp incision and frontalis palsy. This approach offers good surgical possibilities and little approach related morbidity in the clipping of incidental MCA aneurysms.


Hippocampal Proteome of Rats Subjected to the Li-Pilocarpine Epilepsy Model and the Effect of Carisbamate Treatment.
In adult rats, the administration of lithium-pilocarpine (LiPilo) reproduces most clinical and neuropathological features of human temporal lobe epilepsy (TLE). Carisbamate (CRS) possesses the property of modifying epileptogenesis in this model. Indeed, about 50% of rats subjected to LiPilo status epilepticus (SE) develop non-convulsive seizures (NCS) instead of motor seizures when treated with CRS. However, the mechanisms underlying these effects remain unknown. The aim of this study was to perform a proteomic analysis in the hippocampus of rats receiving LiPilo and developing motor seizures or NCS following CRS treatment. Fifteen adult male Sprague-Dawley rats were used. SE was induced by LiPilo injection. CRS treatment was initiated at 1 h and 9 h after SE onset and maintained for 7 days, twice daily. Four groups were studied after video-EEG control of the occurrence of motor seizures: a control group receiving saline (CT n = 3) and three groups that underwent SE: rats treated with diazepam (DZP n = 4), rats treated with CRS displaying NCS (CRS-NCS n = 4) or motor seizures (CRS-TLE n = 4). Proteomic analysis was conducted by 2D-SDS-PAGE. Twenty-four proteins were found altered. In the CRS-NCS group, proteins related to glycolysis and ATP synthesis were down-regulated while proteins associated with pyruvate catabolism were up-regulated. Moreover, among the other proteins differentially expressed, we found proteins related to inflammatory processes, protein folding, tissue regeneration, response to oxidative stress, gene expression, biogenesis of synaptic vesicles, signal transduction, axonal transport, microtubule formation, cell survival, and neuronal plasticity. Our results suggest a global reduction of glycolysis and cellular energy production that might affect brain excitability. In addition, CRS seems to modulate proteins related to many other pathways that could significantly participate in the epileptogenesis-modifying effect observed.


Managing immune diseases in the smartphone era: how have apps impacted disease management and their future?
Immunology, similar to other areas of clinical science, is a data-rich discipline that involves a great deal of interaction between healthcare professionals and their patients. The focus of this editorial is to review the challenges and opportunities for mobile healthcare applications within immunology. It is clear that further research is required to fully maximize the potential of mobile apps (e.g., regulations and guidelines, electronic health). However, it is equally clear that mobile healthcare applications have had a positive impact on patient outcomes (better response rates, more efficient usage of time and more accurate diagnosis). Overall, healthcare applications have a fundamental role to play in the future management of diseases as they will help to ensure that we deliver more effective patient care.


[3H] melatonin binding in membrane and cytosol fractions from rat and calf brain.
The binding characteristics of the tritiated pineal hormone, [3H] melatonin, were studied in brain tissues using in vitro binding techniques. In synaptosomal membranes prepared from rat hippocampus and subjected to preincubation at 37 degrees C and multiple washings, high-affinity binding of [3H] melatonin significantly exceeds that previously reported for membrane or cytosol fractions from mammalian brain. Scatchard analysis of saturation binding data indicates that binding affinities are similar in membrane (Kd = 15 nM) and cytosol (Kd = 11 nM) preparations. However, binding is about sevenfold greater in membranes than in cytosol prepared by centrifugation of homogenates at 104,000g for 60 min. Specific binding is also present in both particulate and soluble fractions from calf brain. Inhibition experiments, in rat hippocampal membranes, indicate that norepinephrine is the most potent inhibitor of about 55% of total binding. Serotonin also exhibited high affinity for about 25% of total binding, suggesting that [3H] melatonin labels both adrenergic and serotonergic sites in this brain region. Further studies are required to characterize the serotonergic and adrenergic sites labelled by [3H] melatonin and to determine whether these sites are functionally important receptors for melatonin.


[Scientific activity of the most productive Spanish research teams in pharmacology and pharmacy during the period 1986-1993 as covered by the Science Citation Index (SCI)].
Bibliometric analyses at the research team level in the pharmacology and pharmacy (F&F) subfield allow in-depth analysis of the findings obtained at higher aggregation levels. Publications of Spanish authors in pharmacological journals covered by the Science Citation Index (SCI) are studied and the most productive Spanish teams during 1986-1989 and 1990-1993 are identified through in-house programmes based on co-authorship analysis. Team composition is defined and team size, scientific output, productivity, expected impact factor and collaboration pattern of the most productive teams are analysed as well as its evolution over time. The observed annual increasing rate in the number of publications and authors in the field (11%) was similar to that of the number of researchers in the Spanish scientific system (8%). The number of highly productive teams doubled from the first to the second period (28 and 61 teams, respectively). The average team size was 8 researchers, showing an average scientific output of 3 documents/year and an average, productivity of 1.7 publications per author and team in each period. Over the years, an increase in the expected impact factor (EIF) of the publication journals and significant changes in the team composition were observed. A total of 13 stable teams were identified, with a greater size and output than the rest of the groups, and showing an upward trend in their expected impact factor and international collaboration rate. Stable teams did not show the negative correlation between team size and productivity observed for the total of the highly productive teams. The F&F subfield is in a very dynamic stage, with a great increase in the number of researchers, starting of new teams and consolidation of others. A trend was observed towards the concentration of activity in the most productive teams, that are the most visible internationally both in number of publications in the SCI and in the impact factor of the publication journals.


Genetic effects on alcohol consumption patterns and problems in women.
We review evidence that genetic factors play no less important a role in the etiology of alcoholism in women than in men. Potential mediators of this genetic influence (differences in personality or alcohol sensitivity) exhibit equal heritability in men and women. Genetically determined differences in alcohol preference (or consumption level), a phenotype widely used in animal models of alcoholism, have been neglected as a mechanism of alcoholism inheritance. Using data from the 1992-3 interview survey of the Australian twin panel (N = 5995 twins), we have reexamined the mediating role of personality and alcohol consumption variables. By comparing the non-alcoholic co-twins of alcoholic twins, and twins from concordant unaffected pairs (separately for MZ and DZ pairs), we have avoided the problem of obtaining consumption and personality assessments that are contaminated by history of alcoholism. In MZ pairs, in both genders, co-twin's heavy alcohol exposure (drinking 5+ drinks in one day) and co-twin's Novelty Seeking score, are both predictive of alcoholism in the respondent. The effect of co-twin's heavy alcohol exposure remains significant even when the respondent's personality variables are controlled for, implying that there are genetic effects on alcoholism risk mediated through consumption pattern that are independent of those mediated through personality differences.


Clinical experience with superior vena caval Greenfield filters.
To evaluate the results of superior vena caval (SVC) Greenfield filters in patients at risk for pulmonary embolism (PE) secondary to upper extremity deep venous thrombosis (UEDVT). Over a 46-month period, 26 patients (10 men, mean age 67 years, range 25 to 89) with UEDVT in whom anticoagulation was contraindicated (n = 22) or ineffective in preventing recurrent PE or extension of the thrombus (n = 4) were treated with placement of SVC Greenfield filters. One SVC filter was misplaced into the innominate vein but left in place; this vein remains patent after 2 months without evidence of filter migration. Follow-up ranged from 10 days to 46 months (mean 7.8 months). Fifteen (58%) patients died inhospital of causes unrelated to the SVC filter or recurrent thromboembolism (mean time to death 36 days). Of the 11 survivors, follow-up ranged from 1 to 38 months (mean 22). Sequential chest roentgenograms in 9 (82%) patients revealed no filter migration or displacement. No evidence of PE was found in any of the survivors over the course of follow-up. Insertion of SVC Greenfield filters is a safe and feasible therapy to prevent recurrent thromboembolism in patients with UEDVT who are refractory to or inappropriate for anticoagulation therapy.


Impulsivity trait and proactive cognitive control: An fMRI study.
The ability to flexibly regulate our behavior is a fundamental feature of human cognition and requires efficient functioning of cognitive control. During movement preparation, proactive inhibitory control plays a crucial role in regulating the excitatory activity carried out by alertness. The balance between alertness and proactive inhibition could be altered in people with motor impulsivity trait, determining the typical failure in the inhibition of prepotent motor responses. To test this hypothesis, 36 young adults were administered the Barratt Impulsiveness Scale to assess motor impulsivity trait and underwent fMRI acquisition during the execution of an event-related Go/Nogo task. To investigate motor preparation processes, we analyzed the "readiness" period, in which subjects were waiting and preparing for the upcoming stimulus (Go or Nogo). We found a positive significant correlation between motor impulsivity scores and the activation of left sensorimotor cortices. This result indicates that motor impulsivity trait might be associated with a disinhibition of the motor system, characterized by a diminished reactivity threshold and a reduced control over covert urges. Furthermore, we observed a positive significant correlation between motor impulsivity scores and the activation in left inferior and superior parietal lobule, which might be related to a more pronounced proactive control, probably reflecting a compensatory mechanism implemented by participants with a higher degree of motor impulsivity trait to reach a correct inhibition. Current findings provide a rationale for further studies aiming to better understand proactive control functioning in healthy impulsive subjects and under clinical conditions.


Activation and upregulation of keratinocyte and epidermal transglutaminases are associated with depletion of their substrates in psoriatic lesions.
Psoriasis is a chronic skin disorder caused by abnormal interactions between epidermal and immune cells. Thus, the interplay between the proliferation and differentiation of epidermal components should be tightly regulated to protect against psoriasis. The differentiation process is primarily controlled by transglutaminases (TGs). However, studies on TG enzymes and their molecular alterations in psoriatic skin lesions are limited. Therefore, this study aimed to investigate TG activity and gene and protein expression in human psoriatic and normal skin tissues. Keratinocyte TG (TG1), and epidermal TG (TG3) activity, localization, protein levels, and gene expression in human psoriatic skin were determined by immunohistochemistry and RT-qPCR. The expression of TG substrates (loricin and involucrin - IVL) was also investigated using RT-qPCR. TG1 and TG3 enzymatic activities and gene expression were significantly higher in psoriatic skin tissue than in normal skin tissue. However, both TGs were present in the same location and were equally highly expressed. Moreover, the expression of two TG substrates (loricin and involucrin) was significantly decreased compared to that in psoriatic and healthy skin samples. The activation and upregulation of TG1 and TG3 result from the depletion of their substrates (loricin and involucrin), both of which play a major role in the pathogenicity of psoriatic skin tissue and are necessary for proper skin development.


Second positive phototropism results from coordinated co-action of the phototropins and cryptochromes.
Phototropism and hypocotyl growth inhibition are modulated by the coaction of different blue-light photoreceptors and their signaling pathways. How seedlings integrate the activities of the different blue-light photoreceptors to coordinate these hypocotyl growth responses is still unclear. We have used time-lapse imaging and a nontraditional mathematical approach to conduct a detailed examination of phototropism in wild-type Arabidopsis and various blue-light photoreceptor mutants. Our results indicate that high fluence rates of blue light (100 micro mol m(-)(2) s(-)(1)) attenuate phototropism through the coaction of the phototropin and cryptochrome blue-light photoreceptors. In contrast, we also demonstrate that phototropins and cryptochromes function together to enhance phototropism under low fluence rates (<1.0 micro mol m(-)(2) s(-)(1)) of blue light. Based on our results, we hypothesize that phototropins and cryptochromes regulate phototropism by coordinating the balance between stimulation and inhibition of growth of the hypocotyl depending on the fluence rate of blue light.


Challenging DESs and ILs in the valorization of food waste: a case study.
In this study, the efficacy of two of the best performing green solvents for the fractionation of lignocellulosic biomass, cholinium arginate (ChArg) as biobased ionic liquid (Bio-IL) and ChCl:lactic acid (ChCl:LA, 1:10) as natural deep eutectic solvent (NADES), was investigated and compared in the pretreatment of an agri-food industry waste, apple fibers (90°C for 1 h). For the sake of comparison, 1-butyl-3-methylimidazolium acetate (BMIM OAc) as one of the best IL able to dissolve cellulose was also used. After the pretreatment, two fractions were obtained in each case. The results gathered through FTIR and TG analyses of the two materials and the subsequent DNS assay performed after enzymatic treatment led to identify ChArg as the best medium to delignify and remove waxes, present on the starting apple fibers, thus producing a material substantially enriched in cellulose (CRM). Conversely, ChCl:LA did not provide satisfactorily results using these mild conditions, while BMIM OAc showed intermediate performance probably on account of the reduced crystallinity of cellulose after the dissolution-regeneration process. To corroborate the obtained data, FTIR and TG analyses were also performed on the residues collected after the enzymatic hydrolysis. At the end of the pretreatment, ChArg was also quantitatively recovered without significant alterations.


Assessing the impact of the 13 valent pneumococcal vaccine on childhood empyema in Australia.
Empyema is a serious complication of pneumonia frequently caused by Streptococcus pneumoniae (SP). We assessed the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema after inclusion in the Australian National Immunisation Program. For bacterial pneumonia and empyema hospitalisations, we ascertained incidence rates (IRs) using the National Hospital Morbidity Database International Statistical Classification of Disease discharge codes and relevant population denominators, and calculated incidence rate ratios (IRR) comparing the 13vPCV period (June 2012-May 2017) with the 7vPCV period (June 2007-May 2011). Blood and pleural fluid (PF) cultures and PF PCR of 401 children with empyema from 11 Australian hospitals during the 13vPCV period were compared with our previous study in the 7vPCV period. Across 7vPCV and 13vPCV periods, IRs per million children (95% CIs) were 1605 (1588 to 1621) and 1272 (1259 to 1285) for bacterial pneumonia, and 14.23 (12.67 to 15.79) and 17.89 (16.37 to 19.42) for empyema hospitalisations. IRRs were 0.79 (0.78 to 0.80) for bacterial pneumonia and 1.25 (1.09 to 1.44) for empyema. Of 161 empyema cases with SP serotypes, 147 (91.3%) were vaccine types. ST3 accounted for 76.4% of identified serotypes in the 13vPCV period, more than double than the 7vPCV period (p<0.001); ST19A decreased from 36.4% to 12.4%. No cases of ST1 empyema were identified in the 13vPCV period versus 14.5% in the 7vPCV period. 13vPCV resulted in a significant reduction in all-cause hospitalisations for bacterial pneumonia but empyema hospitalisations significantly increased, with emergence of pneumococcal ST3 as the dominant serotype in empyema. Australian and New Zealand Clinical Trial Registry ACTRN 12614000354684.


18β-Glycyrrhetinic-acid-mediated unfolded protein response induces autophagy and apoptosis in hepatocellular carcinoma.
18β-Glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicine, Glycyrrhrzae Radix et Rhizoma. Here, we explored the effects of GA on hepatocellular carcinoma (HCC) in vitro and in vivo and the underlying molecular mechanisms. We confirmed that GA suppressed proliferation of various HCC cell lines. Treatment of GA caused G0/G1 arrest, apoptosis and autophagy in HCC cells. GA-induced apoptosis and autophagy were mainly due to the unfolded protein response. We compared the roles of the ATF4/CHOP and IRE1α/XBP1s UPR pathways, which were both induced by GA. The ATF4/CHOP cascade induced autophagy and was indispensable for the induction of apoptosis in GA-treated HCC cells. In contrast, the IRE1α/XBP1s cascade protected HCC cells from apoptosis in vitro and in vivo induced by GA. Despite this, activation of autophagy protected HCC cells from apoptosis induced by GA. We concluded that pharmacological inhibition of autophagy or IRE1α may be of benefit to enhance the antitumor activity of GA.


Laser streaming: Turning a laser beam into a flow of liquid.
Transforming a laser beam into a mass flow has been a challenge both scientifically and technologically. We report the discovery of a new optofluidic principle and demonstrate the generation of a steady-state water flow by a pulsed laser beam through a glass window. To generate a flow or stream in the same path as the refracted laser beam in pure water from an arbitrary spot on the window, we first fill a glass cuvette with an aqueous solution of Au nanoparticles. A flow will emerge from the focused laser spot on the window after the laser is turned on for a few to tens of minutes; the flow remains after the colloidal solution is completely replaced by pure water. Microscopically, this transformation is made possible by an underlying plasmonic nanoparticle-decorated cavity, which is self-fabricated on the glass by nanoparticle-assisted laser etching and exhibits size and shape uniquely tailored to the incident beam profile. Hydrophone signals indicate that the flow is driven via acoustic streaming by a long-lasting ultrasound wave that is resonantly generated by the laser and the cavity through the photoacoustic effect. The principle of this light-driven flow via ultrasound, that is, photoacoustic streaming by coupling photoacoustics to acoustic streaming, is general and can be applied to any liquid, opening up new research and applications in optofluidics as well as traditional photoacoustics and acoustic streaming.


[Localization of c-myc gene protein in hepatoma cells].
Localization of c-myc gene protein was investigated in human hepatoblastoma cells (Hep G2) and its derived tumor tissue in nude mice by using immunohistochemical method. Revealing by double staining technique, c-myc protein was located in the nuclei of tumor cells at a site different from where the nucleic acid accumulated but disappeared in the mitotic nucleus. It was confirmed to be in the nuclei, next to the chromatin by immunoelectron microscopy. This pattern was not influenced by HBsAg expression in tumor tissue derived from 2.2.15 cells (transfected Hep G2 cell line with HBV genome) and the intensity of c-myc protein became lower in those tumor cells with expression of HBcAg in the nuclei. Significance of the location of c-myc protein is briefly discussed.


Rejection Sensitivity as a Transdiagnostic Risk Factor for Internalizing Psychopathology Among Gay and Bisexual Men.
Gay and bisexual men are at increased risk for mood and anxiety (internalizing) disorders relative to heterosexual men. Rejection sensitivity (RS), or the anxious expectation of rejection, is associated with depression and social anxiety symptoms among lesbians and gay men as well as generalized anxiety symptoms among sexual minority women. However, it remains unclear if it is associated with other internalizing symptoms, such as panic and posttraumatic stress symptoms. Further, research on the comorbidity of mental disorders suggests that a latent transdiagnostic internalizing factor (INT) accounts for the co-occurrences between mood and anxiety disorders. Although previous research has found that the associations between discrimination and mental disorders can be explained by INT, research has yet to examine if this extends to the associations between RS and internalizing symptoms. Using a sample of young gay and bisexual men (N = 101), we examined the associations between RS and internalizing symptoms (depression, social anxiety, generalized anxiety, panic, and posttraumatic stress). Additionally, we examined the extent to which these associations were mediated by INT. Results indicated that RS was significantly associated with social anxiety, generalized anxiety, and posttraumatic stress symptoms, and that INT fully mediated these associations. As such, findings support RS as a transdiagnostic risk factor for internalizing symptoms among gay and bisexual men.


Laparoendoscopic single-site plus one port nephroureterectomy: single center initial experience.
Nephroureterectomy (NU) with bladder cuff excision is the gold standard treatment for patients with upper urinary tract urothelial cancer. We report our initial experience with laparoendoscopic single-site plus one port (LESS POP) technique for NU and bladder cuff excision. We retrospectively reviewed the records of consecutive patients undergoing LESS POP NU between 2011 and 2012. We describe in detail our surgical technique and summarized the outcomes in this initial series. Ten patients (7 male, 3 female) aged 55 to 84 years underwent LESS POP NU. There were no conversions to open technique or additions of conventional laparoscopic ports. Median (range) operative time was 217 minutes. Specimens were extracted through the umbilical incision in five patients and through an extension of the lower quadrant port in five. One patient experienced urine leak followed by umbilical wound dehiscence (Clavien grade IIIb complication). In this series, LESS POP NU was feasible with encouraging outcomes. We believe that it is possible to extend the benefits of LESS to patients with upper tract tumors while adhering to strict oncologic principles.


Depression, fatigue, and health-related quality of life among people with advanced multiple sclerosis: results from an exploratory telerehabilitation study.
This study reports on secondary data, depression, fatigue and health-related quality of life (HRQOL), collected on people with advanced multiple sclerosis (MS) as part of a larger study of the impact of a telerehabilitation intervention on people with severe mobility impairment. People with spinal cord injuries (SCIs) (n=111) and the prevention of pressure sores were the primary group of interest of the project. The focus here is on data collected from people with advanced MS (n=27), who were included as an exploratory cohort, as they experience increased risk of pressure ulcer development as their level of mobility declines. The study consisted of a nine-week intervention with three randomized groups: video, telephone, and standard care. Aside from information on pressure sores, data were also collected on fatigue, depression, and HRQOL for a two-year follow-up period. For the video group HRQOL scores trended higher and fatigue and depression scores lower for 24 months. Fatigue scores were significantly lower for the video group at month six, 12, and 18. In the sample overall, fatigue symptoms were far more prominent than depressive symptoms and affected 100% higher rates of depression than women. At baseline, controlling for Extended Disability Status Score (EDSS), depression and fatigue were correlated. However, contrary to indications from previous cross-sectional studies, no consistent relationship was observed over time between the two. Telerehabilitation interventions for people with advanced MS warrant further investigation. Findings here suggest that such interventions may be beneficial, although the results need affirmation through larger samples. In addition, the higher prevalence of male depression merits serious attention.


An approach to analysis of large-scale correlations between genome changes and clinical endpoints in ovarian cancer.
This report describes analyses of associations of genome copy number abnormalities in ovarian cancers with clinical features using genome-wide graphical and analytical procedures. These studies show that tumor grade is a better indicator of the extent of genomic progression than stage, that loss of chromosome 4 occurs preferentially in high-grade tumors, and that gains of 3q26-qter, 8q24-qter, and 20q13-qter occur frequently in low-grade and low-stage tumors and thus may be early events in ovarian cancer development. In addition, loss of chromosome 16q24 and a total number of independent genome copy number aberrations >7 are associated with reduced survival duration. The association of loss of 16q24 (D16S3026) with decreased survival duration was confirmed by quantitative PCR. Regions that frequently are abnormal and associated with altered survival duration are strong candidates for higher resolution analysis and gene discovery and may be useful markers for prediction of clinical outcome.


Graphical representation of ribosomal RNA probe accessibility data using ARB software package.
Taxon specific hybridization probes in combination with a variety of commonly used hybridization formats nowadays are standard tools in microbial identification. A frequently applied technology, fluorescence in situ hybridization (FISH), besides single cell identification, allows the localization and functional studies of the microbial community composition. Careful in silico design and evaluation of potential oligonucleotide probe targets is therefore crucial for performing successful hybridization experiments. The PROBE Design tools of the ARB software package take into consideration several criteria such as number, position and quality of diagnostic sequence differences while designing oligonucleotide probes. Additionally, new visualization tools were developed to enable the user to easily examine further sequence associated criteria such as higher order structure, conservation, G+C content, transition-transversion profiles and in situ target accessibility patterns. The different types of sequence associated information (SAI) can be visualized by user defined background colors within the ARB primary and secondary structure editors as well as in the PROBE Match tool. Using this tool, in silico probe design and evaluation can be performed with respect to in situ probe accessibility data. The evaluation of proposed probe targets with respect to higher-order rRNA structure is of importance for successful design and performance of in situ hybridization experiments. The entire ARB software package along with the probe accessibility data is available from the ARB home page http://www.arb-home.de


Studies on the virulence of tubercle bacilli; isolation and biological properties of a constituent of virulent organisms.
The bacillary cords characteristic for virulent tubercle bacilli are readily disrupted when wet bacilli are suspended in hydrocarbons such as paraffin oil or petroleum ether. The disruption of cords is due to the removal of a material coating the surface of the bacilli and causing them to adhere to each other. This material can be obtained from virulent bacilli by extracting them with petroleum ether. It is a lipid. Avirulent variants of tubercle bacilli do not yield a similar material after extraction in the same manner; only little of it is obtained from BCG bacilli. The following properties of the fraction obtained by petroleum ether extraction are described: (a) It inhibits the migration of leukocytes in vitro. (b) If repeatedly injected in small doses into mice, it is toxic, whereas a single high dose does not give rise to toxic manifestations. (c) The susceptibility of mice to the toxic action of repeated injections parallels to some extent their degree of susceptibility to infection with the strain of tubercle bacilli from which the fraction was obtained. (d) The injection of the extracted material into guinea pigs does not induce a state of allergic reactivity toward tuberculin. Likewise, tuberculin-positive guinea pigs do not show hypersensitivity against injections of the extracted substance. Bacilli extracted with petroleum ether do not lose their viability. They grow out normally in vitro, and they are still pathogenic. However, the removal of the petroleum ether-soluble lipid from the bacilli results in a loss of the ability of the organisms to inhibit the migration of polymorphonuclear leukocytes. Moreover, mice and guinea pigs infected with extracted bacilli may develop tuberculosis considerably slower than animals injected with comparable amounts of unextracted organisms. The significance of these findings is discussed in relation to the problem of the virulence of tubercle bacilli.


Adenocarcinoma in a Tailgut Cyst: A Rare Case Report.
Developmental cysts are the most common retrorectal area cysts observed in adults. Tailgut cysts tend to be multicystic, and their lining epithelium may display the characteristics of columnar, musin-secreting columnar, ciliated, transitional or squamous epithelia. While the large majority of cysts tend to be benign, several malignant cases have been reported, with adenocarcinoma and carcinoid tumors constituting the more common types of malignant tailgut cysts. A 55-year-old female patient presented to our hospital with complaints of swelling in the gluteal region. Following morphological, histomorphological and immunohistochemical evaluations, a diagnosis of a moderately differentiated adenocarcinoma arising from a tailgut cyst was made. Tailgut cysts are infrequent diseases but adenocarcinoma arising from a tailgut cyst is extremely rare. In rare cases, developmental cysts may undergo malignant transformation that warrants an accurate morphological and histomorphological assessment, as well as numerous samplings, for an accurate diagnosis.


The effect of neurotoxin on rabies virus binding to mouse neuroblastoma cells.
Mouse neuroblastoma cells were exposed to alpha bungarotoxin, a neurotoxin known to inhibit rabies virus binding to the nicotinic acetylcholine receptor located at the neuromuscular junction in muscle tissue. The total amount of 3H-CVS virus that bound to neurotoxin treated cells was separated into specific and non-specific binding using a cold competition assay. Comparison of untreated and neurotoxin treated cells demonstrated that the majority of cell-associated virus in untreated cells was of a specific nature whereas the majority of the cell-associated virus in neurotoxin treated cells was due to non-specific binding.


Super-Resolution Genome Mapping in Silicon Nanochannels.
Optical genome mapping in nanochannels is a powerful genetic analysis method, complementary to deoxyribonucleic acid (DNA) sequencing. The method is based on detecting a pattern of fluorescent labels attached along individual DNA molecules. When such molecules are extended in nanochannels, the labels create a fluorescent genetic barcode that is used for mapping the DNA molecule to its genomic locus and identifying large-scale variation from the genome reference. Mapping resolution is currently limited by two main factors: the optical diffraction limit and the thermal fluctuations of DNA molecules suspended in the nanochannels. Here, we utilize single-molecule tracking and super-resolution localization in order to improve the mapping accuracy and resolving power of this genome mapping technique and achieve a 15-fold increase in resolving power compared to currently practiced methods. We took advantage of a naturally occurring genetic repeat array and labeled each repeat with custom-designed Trolox conjugated fluorophores for enhanced photostability. This model system allowed us to acquire extremely long image sequences of the equally spaced fluorescent markers along DNA molecules, enabling detailed characterization of nanoconfined DNA dynamics and quantitative comparison to the Odijk theory for confined polymer chains. We present a simple method to overcome the thermal fluctuations in the nanochannels and exploit single-step photobleaching to resolve subdiffraction spaced fluorescent markers along fluctuating DNA molecules with ∼100 bp resolution. In addition, we show how time-averaging over just ∼50 frames of 40 ms enhances mapping accuracy, improves mapping P-value scores by 3 orders of magnitude compared to nonaveraged alignment, and provides a significant advantage for analyzing structural variations between DNA molecules with similar sequence composition.


Alterations of the human vestibulo-ocular reflex in a simulated dive at 62 ATA.
In an attempt to investigate some aspects of the high pressure nervous syndrome, the vestibulo-ocular reflex (VOR) gain was measured in two professional divers undergoing a simulated dive at 62 ATA. The aquanauts in a seated position were rotated sinusoidally around the vertical axis at a frequency of about 0.3 Hz over a 20 degrees range. Tests were performed at regular intervals prior to, during, and after the compression/decompression period. The rotations were applied either in total darkness or with a visual target rotating with the chair or with a target fixed to the chair-supporting frame. An infrared photoelectric system monitored eye movements. The results showed no spontaneous nystagmus, but two definite changes in VOR gain: (1) a slight but significant increase related to pressure increase, which may be due to an increase of the vestibular system excitability or a decrease of the cerebellar inhibition exerted upon the vestibular nuclei, and (2) an intermittently appearing increase (VOR gain between 1 and 1.3) during brief periods. The latter finding, not related to pressure, was interpreted as the expression of an underwater-adapted mode that may developed in professional divers submitted to the intensive use of magnifying diving-optical systems.


A novel AVPR2 missense mutation in an Asian family with inherited nephrogenic diabetes insipidus: A case report.
X-linked nephrogenic diabetes insipidus (NDI) is a rare inherited disease, and is characterized by renal resistance to arginine vasopressin (AVP). Its diagnosis can be clinically challenging. The application of molecular genetic analysis can provide a rapid and definitive diagnosis. A 75-year-old woman presented with recurrent nausea and vomiting was admitted to the Department of Gastroenterology. The patient had a strong family history of polydipsia and polyuria. Sequencing analysis of the antidiuretic hormone arginine vasopressin receptor 2 (AVPR2) revealed the novel missense mutation p. Trp164Cys (c.492G>G/C) in exon 2. There was a heterozygous mutation in the patient's sister and niece, while there was a mutation in her sons, brother and nephews. The locus is located on the X chromosome Xq28, and its mutation can lead to X linked recessive NDI. The p. Trp164Cys mutation of AVPR2 gene has not been reported in literature before. The mutation was predicted to be probably damaging by several prediction methods, including SIFT and PolyPhen-2. There was no significant abnormal variation in other detection regions of the gene. And there was also no abnormal variation in AVP and AQP2 genes in this family. X-linked NDI was diagnosed according to the patient's family history and DNA sequencing analysis. After treated with desmopressin, antiemetic drugs and massive infusion glucose transfusion, the patient's urine volume decreased and electrolyte disturbance was corrected, and the symptoms of nausea and vomiting gradually disappeared. The patients with suspected congenital NDI should undergo genetic sequencing analysis of AVPR2, AVP and AQP2 genes. A definitive diagnosis can benefit patient and avoid unnecessary investigations.


Long-term impacts of parental migration on Chinese children's psychosocial well-being: mitigating and exacerbating factors.
Prolonged separation from migrant parents raises concerns for the well-being of 60 million left behind children (LBC) in rural China. This study aimed to investigate the impact of current and previous parental migration on child psychosocial well-being, with a focus on emotional and behavioral outcomes, while considering factors in family care and support. Children were recruited from schools in migrant-sending rural areas in Zhejiang and Guizhou provinces by random stratified sampling. A self-administered questionnaire measured children's psychosocial well-being, demographics, household characteristics, and social support. Multiple linear regression models examined the effects of parental migration and other factors on psychosocial difficulties. Data from 1930 current, 907 previous, and 701 never LBC were included (mean age 12.4, SD 2.1). Adjusted models showed both previous and current parental migration was associated with significantly higher overall psychosocial difficulties, involving aspects of emotion, conduct, peer relationships, hyperactivity, and pro-social behaviors. Parental divorce and lack of available support demonstrated a strong association with greater total difficulties. While children in Guizhou had much worse psychosocial outcomes than those in Zhejiang, adjusted subgroup analysis showed similar magnitude of between-province disparities regardless of parental migration status. However, having divorced parents and lack of support were greater psychosocial risk factors for current and previous-LBC than for never LBC. Parental migration has an independent, long-lasting adverse effect on children. Psychosocial well-being of LBC depends more on the relationship bonds between nuclear family members and the availability of support, rather than socioeconomic status.


Rebalance of striatal NMDA/AMPA receptor ratio underlies the reduced emergence of dyskinesia during D2-like dopamine agonist treatment in experimental Parkinson's disease.
Dopamine replacement with levodopa (L-DOPA) represents the mainstay of Parkinson's disease (PD) therapy. Nevertheless, this well established therapeutic intervention loses efficacy with the progression of the disease and patients develop invalidating side effects, known in their complex as L-DOPA-induced dyskinesia (LID). Unfortunately, existing therapies fail to prevent LID and very few drugs are available to lessen its severity, thus representing a major clinical problem inPDtreatment. D2-like receptor (D2R) agonists are a powerful clinical option as an alternative to L-DOPA, especially in the early stages of the disease, being associated to a reduced risk of dyskinesia development. D2R agonists also find considerable application in the advanced stages of PD, in conjunction with L-DOPA, which is used in this context at lower dosages, to delay the appearance and the extent of the motor complications. In advanced stages of PD, D2R agonists are often effective in delaying the appearance and the extent of motor complications. Despite the great attention paid to the family of D2R agonists, the main reasons underlying the reduced risk of dyskinesia have not yet been fully characterized. Here we show that the striatal NMDA/AMPAreceptor ratio and theAMPAreceptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while L-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia.


In ovo exposure to brominated flame retardants Part I: Assessment of effects of TBBPA-BDBPE on survival, morphometric and physiological endpoints in zebra finches.
Tetrabromobisphenol A bis(2,3-dibromopropyl) ether (TBBPA-BDBPE) is an additive flame retardant used in polyolefins and polymers. It has been detected in biota, including in avian eggs, yet little is known of its effects. We assessed the pattern of TBBPA-BDBPE concentrations in songbird eggs over the incubation period, and the effects of embryonic exposure to TBBPA-BDBPE in a model songbird species, the zebra finch (Taeniopygia guttata). To assess concentrations during embryo development, eggs were injected on the day they were laid with the vehicle control (safflower oil) or 100 ng TBBPA-BDBPE/g egg, and whole egg contents were collected throughout embryonic development on day 0 (unincubated), 5, 10 and 13. To evaluate effects of embryonic exposure to TBBPA-BDBPE, eggs were injected at Hamburger-Hamilton stage 18 (∼80 h after initiation of incubation) with safflower oil only, 10, 50 or 100 ng TBBPA-BDBPE/g egg (albumin injection volume 1 μl/g). Eggs were monitored for hatching success, and nestlings were monitored for growth and survival. At 15 days post-hatch, tissues were collected to assess physiological effects. TBBPA-BDBPE was incorporated into the egg as the embryo developed, and concentrations started declining in late incubation, suggesting biotransformation by the embryo. There were no effects on hatching success, nestling survival, growth, organ somatic indices, or thyroid hormone homeostasis; however, there was evidence that body condition declined in a dose-dependent manner towards the end of the rapid nestling growth phase. This decreased body condition could be a delayed effect of early developmental exposure, or it may be the result of increased exposure to biotransformation products of TBBPA-BDBPE produced over the nestling period, which are predicted to be more bioaccumulative and toxic than the parent compound.


Polyelectrolyte complexation via viscoelastic phase separation results in tough and self-recovering porous hydrogels.
Polyelectrolyte complexation between oppositely charged polyelectrolytes forms coacervates in dilute solutions and thin films in concentrated solutions. It is difficult to obtain macroscopically uniform bulk polyelectrolyte complex (PEC) materials, since the two polymers form insoluble complexes quickly at the contact interface during mixing, resulting in heterogeneous aggregates. Here, we succeeded in preparing bulk PEC materials based on desalting-induced polyelectrolyte complexation via viscoelastic phase separation. With a high ionic strength aqueous medium, a homogeneous and concentrated solution containing oppositely charged polyelectrolytes is prepared. Desalting of the counter-ions and co-ions of the solution through semi-permeable membranes induces viscoelastic phase separation of the solution to form a physical hydrogel with open pore structure. Regulating the charge ratio of the two oppositely charged polymers results in significant changes in the porous morphology and mechanical properties. The charge-balanced PEC hydrogels show unique properties including high toughness and self-recovery due to the reversible ionic associations. The porous yet tough properties of bulk PEC hydrogels makes them potential candidates for applications such as cell scaffolds.


Alpha 1-adrenoceptor blockade in renal hypertensive rats with low and high renin levels.
A total of 75 male Wistar rats with one-kidney, one-clip renal hypertension was maintained on either a regular (RNa) or a low-salt (LNa) diet for 3 wk after clipping. Blood pressure in the unanesthetized rats was equally elevated independent of sodium intake. Plasma renin activity was higher in LNa animals, and blood pressure was renin dependent only in this group, as evidenced by the blood pressure response to 10 mg/kg captopril iv. There was no significant difference in plasma catecholamines between RNa and LNa rats, although in the former the sympathetic nervous system is believed to play a major role in sustaining high blood pressure. The acute intravenous administration of 0.5 mg/kg prazosin did not induce a more pronounced blood pressure fall in the RNa rats. Prazosin enhanced plasma norepinephrine levels similarly in both groups, but epinephrine levels only rose in the LNa animals. Prazosin also markedly stimulated plasma renin activity rendering blood pressure renin dependent even in RNa rats. Thus, using alpha 1-adrenoceptor blockade, it has not been possible to demonstrate that the blood pressure elevation of salt-repleted one-kidney, one-clip renal hypertensive rats is due to an enhanced sympathetic nerve activity. Data obtained with sympatholytic agents must be interpreted with great caution if renin activity cannot be kept unchanged.


Preimplantation genetic diagnosis.
Embryo biopsy for preimplantation genetic diagnosis can be performed on the oocyte/zygote, cleavage stage embryo, or blastocyst, but the majority of centres perform cleavage stage biopsy. Single-cell diagnosis is undertaken by the polymerase chain reaction or fluorescent in-situ hybridization. Technical difficulties have arisen with preimplantation genetic diagnosis, such as allele dropout and chromosomal mosaicism. However, it is hoped that these difficulties can be overcome in the future with the advent of new techniques.


Requirement for C-terminal extension to the RNA binding domain for efficient RNA binding by ribosomal protein L2.
Ribosomal protein L2 is a primary 23S rRNA binding protein in the large ribosomal subunit. We examined the contribution of the N- and C-terminal regions of Bacillus stearothermophilus L2 (BstL2) to the 23S rRNA binding activity. The mutant desN, in which the N-terminal 59 residues of BstL2 were deleted, bound to the 23S rRNA fragment to the same extent as wild type BstL2, but the mutation desC, in which the C-terminal 74 amino acid residues were deleted, abolished the binding activity. These observations indicated that the C-terminal region is involved in 23S rRNA binding. Subsequent deletion analysis of the C-terminal region found that the C-terminal 70 amino acids are required for efficient 23S rRNA binding by BstL2. Furthermore, the surface plasmon resonance analysis indicated that successive truncations of the C-terminal residues increased the dissociation rate constants, while they had little influence on association rate constants. The result indicated that reduced affinities of the C-terminal deletion mutants were due only to higher dissociation rate constants, suggesting that the C-terminal region primarily functions by stabilizing the protein L2-23S rRNA complex.


Bioaccumulation of petroleum hydrocarbons in arctic amphipods in the oil development area of the Alaskan Beaufort Sea.
An objective of a multiyear monitoring program, sponsored by the US Department of the Interior, Bureau of Ocean Energy Management was to examine temporal and spatial changes in chemical and biological characteristics of the Arctic marine environment resulting from offshore oil exploration and development activities in the development area of the Alaskan Beaufort Sea. To determine if petroleum hydrocarbons from offshore oil operations are entering the Beaufort Sea food web, we measured concentrations of hydrocarbons in tissues of amphipods, Anonyx nugax, sediments, Northstar crude oil, and coastal peat, collected between 1999 and 2006 throughout the development area. Mean concentrations of polycyclic aromatic hydrocarbons (PAH), saturated hydrocarbons (SHC), and sterane and triterpane petroleum biomarkers (StTr) were not significantly different in amphipods near the Northstar oil production facility, before and after it came on line in 2001, and in amphipods from elsewhere in the study area. Forensic analysis of the profiles (relative composition and concentrations) of the 3 hydrocarbon classes revealed that hydrocarbon compositions were different in amphipods, surface sediments where the amphipods were collected, Northstar crude oil, and peat from the deltas of 4 North Slope rivers. Amphipods and sediments contained a mixture of petrogenic, pyrogenic, and biogenic PAH. The SHC in amphipods were dominated by pristane derived from zooplankton, indicating that the SHC were primarily from the amphipod diet of zooplankton detritus. The petroleum biomarker StTr profiles did not resemble those in Northstar crude oil. The forensic analysis revealed that hydrocarbons in amphipod tissues were not from oil production at Northstar. Hydrocarbons in amphipod tissues were primarily from their diet and from river runoff and coastal erosion of natural diagenic and fossil terrestrial materials, including seep oils, kerogens, and peat. Offshore oil and gas exploration and development do not appear to be causing an increase in petroleum hydrocarbon contamination of the Beaufort Sea food web.


[High-resolution computed tomography in malformations of the cochlear and vestibular organs].
Twenty-one patients with congenital deformities of the petrous bones were examined by high resolution computed tomography. This allows an accurate description of the extent of the malformation in all parts of the cochlear and vestibular organs; only localised changes in the auditory ossicles, such as fixation of the stapes and changes in the soft tissue portions of the labyrinth, cannot be shown. Improved demonstration of soft tissues while using less radiation makes high resolution CT preferable to conventional polytomography. It is also easier to perform and provides axial projections which are essential for the elucidation of malformations of the middle and inner ear.


Environmentally Responsive Dual-Targeting Nanoparticles: Improving Drug Accumulation in Cancer Cells as a Way of Preventing Anticancer Drug Efflux.
Drug targeting and stimuli-responsive drug release are 2 active areas of cancer research and hold tremendous potential in the management of cancer drug resistance. In this study, I addressed this issue and focused on the synthesis and characterization of pH-responsive Fe3O4@SiO2(FITC)-BTN/folic acid/DOX multifunctional nanoparticles aiming to increase drug accumulation in malignancies with both dual active targeting and endosomal drug release properties. Dye-doped silica magnetic-fluorescent composite was constructed by a simple coprecipitation of Fe+2/Fe+3 salts followed by sol-gel formation and dual-targeting function was obtained by conjugating folate and biotin moieties on the silica surface of nanoparticles via an esterification reaction. Doxorubicin was then successfully attached on the amine-functionalized nanoparticles using a pH-sensitive Schiff-base formation. The physicochemical characterization of the structure was performed by dynamic light scattering, zeta potential measurement, X-ray diffraction, Fourier transform infrared spectroscopy, electron microscopy techniques, and an in vitro pH-dependent release study. Cellular uptake and cytotoxicity experiments demonstrated an enhanced intracellular delivery and reduction of cancer cell viability in the cervical carcinoma HeLa cell line. Furthermore, proapoptotic studies showed that the nanoparticles increased the apoptotic rates within the same cancer cells. The preliminary cell tests confirm the potential of these multifunctional nanoparticles against the development of drug resistance in cancer cells.


The HOMA-IR Performance to Identify New Diabetes Cases by Degree of Urbanization and Altitude in Peru: The CRONICAS Cohort Study.
Prognostic thresholds to identify new type 2 diabetes mellitus (T2DM) cases using the HOMA-IR have not been defined. We studied the HOMA-IR performance to identify incident T2DM cases and to assess if the thresholds varied according to urbanization and altitude in Peru. Longitudinal analysis. The outcome was incident T2DM cases: self-report diagnosis and fasting glucose. The exposure was the HOMA-IR. Receiver operating characteristic (ROC) curves were plotted, and the area under the ROC curve (AUC) was estimated with 95% confidence intervals (95% CIs). Results are presented overall and stratified by study site (Lima, Tumbes, urban Puno, and rural Puno), rurality (urban, semiurban, and rural), and altitude (low and high). A total of 3120 participants (mean age: 55.6 years, 51.2% females) contributed data to this analysis. The median baseline HOMA-IR was 1.7 (IQR 1.0-2.9), with median values ranging from 1.1 in rural Puno to 2.0 in Lima and Tumbes (p < 0.001). Overall for incident T2DM, the AUC was 0.69 (95% CI: 0.64-0.74) with an empirical threshold of 2.8 yielding a positive likelihood ratio of 2.30 and a negative one of 0.61; the positive and negative predictive values were 14.6% and 95.7%, respectively. The empirical thresholds varied within the variables of interest, for example, from 0.9 in urban Puno to 2.9 in Lima. Using the HOMA-IR to identify incident T2DM cases seems to yield moderate accuracy. The HOMA-IR could help improve identifying people at high risk of T2DM.


[The long-term results of brace treatment in Perthes disease].
We evaluated the long-term radiological outcomes of the patients with Perthes disease who were conservatively treated with brace. Thirty-three hips of 27 skeletally mature patients (21 males, 6 females; mean age 25.2±3.4 years; range 20 to 32 years) treated with modified Thomas splint were included in this study. The results were evaluated according to the Stulberg classification. The mean age of the patients was 6.3±2.2 (range 3-12) years at the onset of the disease and the mean follow-up was 18.6±3.2 (range 7.2-24.1) years. According to onset of the disease, good results were obtained for the patients who were less than six-years-old as 77.7%, between 6-9 years old as 84.2%, after nine years old as 40%. However, 100% of the Herring group A hips, 79.2% of the group B hips and 50% of the group C hips were healed with Stulberg class I or II results. We obtained satisfactory results after conservative treatment with Thomas splint in patients who were between 6-9 years old at onset of the disease with Herring group B involvement. It is hard to say whether the good results were stemmed from having good prognosis of these patients, or stemmed from positive effect of using brace on treatment.


Gut-Brain Axis and Behavior.
In the last 5 years, interest in the interactions among the gut microbiome, brain, and behavior has exploded. Preclinical evidence supports a role of the gut microbiome in behavioral responses associated with pain, emotion, social interactions, and food intake. Limited, but growing, clinical evidence comes primarily from associations of gut microbial composition and function to behavioral and clinical features and brain structure and function. Converging evidence suggests that the brain and the gut microbiota are in bidirectional communication. Observed dysbiotic states in depression, chronic stress, and autism may reflect altered brain signaling to the gut, while altered gut microbial signaling to the brain may play a role in reinforcing brain alterations. On the other hand, primary dysbiotic states due to Western diets may signal to the brain, altering ingestive behavior. While studies performed in patients with depression and rodent models generated by fecal microbial transfer from such patients suggest causation, evidence for an influence of acute gut microbial alterations on human behavioral and clinical parameters is lacking. Only recently has an open-label microbial transfer therapy in children with autism tentatively validated the gut microbiota as a therapeutic target. The translational potential of preclinical findings remains unclear without further clinical investigation.


[Hemodynamic effect of a mitral valve prosthesis].
Hemodynamic findings are analysed in 113 patients with different types of mitral prosthesis. Catheterization of the heart was carried out before the operation and during the late post-operative period. The gradient through the prosthesis was estimated for patients with different types of mitral valve prosthesis during the operation. According to our data, the tilting-disc valve prosthesis MKC-59 and the ball valve prosthesis MKC-25 are associated with the best gradients. Mitral prosthesis improves hemodynamic activity, but does not normalize it. The heart index remains lowered, while the pressure inside the pulmonary capillaries and pulmonary artery remains elevated, as compared to normal levels. Signs of mitral stenosis become more apparent during exercise.


PB1-mediated virulence attenuation of H5N1 influenza virus in mice is associated with PB2.
H5N1 avian influenza viruses demonstrate different phenotypes, such as pathogenicity after one or serial passages in mammalian hosts or cells. To establish the molecular basis of these phenotypes, we cloned isolates from the lungs of mice infected with human A/Vietnam/1194/2004 (H5N1) influenza virus. Large-plaque isolates were less pathogenic to mice than small-plaque isolates. Genome sequencing revealed that the small-plaque and large-plaque isolates differed in several amino acids. In order to assess their effects on pathogenicity in mice, two amino acid changes common to attenuated isolates, one in PB2 (I63T) and the other in PB1 (T677M), were inserted into a wild-type recombinant virus construct. The PB2 (I63T) or PB1 (T677M) mutations alone did not alter the phenotype of H5N1 virus, whereas recombinant virus with both mutations was less pathogenic than the wild-type recombinant virus. Furthermore, the PB1 (T677M) mutation showed a lower replication efficiency, although it had higher polymerase activity. The recombinant virus with the PB2 (63T) mutation replicated as well as the wild-type recombinant virus. These results suggest that the C terminus of PB1 of H5N1 influenza virus mediates virulence attenuation of H5N1 influenza virus in mice, associating with the N terminus of PB2. However, the role of the N terminus of PB2 in virulence attenuation in mice remains unclear.


Acute cadmium exposure causes systemic and thromboembolic events in mice.
Cadmium (Cd), an environmental and industrial pollutant, poses a potential threat and affects many systems in human and animals. Although several reports on Cd toxicity were presented, the acute effect of Cd on systemic and thrombotic events was not reported so far. Cd (2.284 mg/kg) or saline (control) was injected intraperitoneally (ip), and the systemic parameters were assessed in mice. Compared to control group, acute intraperitoneal injection of Cd, in mice showed significant quickening of platelet aggregation (P<0.001) leading to pial cerebral thrombosis. Likewise, Cd exposure caused a significant increase in white blood cell numbers (P<0.05) indicating the occurrence of systemic inflammation. Also, alanine aminotransferase (ALT) (P<0.05) and creatinine (P<0.01) levels were both significantly increased. Interestingly, the superoxide dismutase activity was significantly decreased in Cd treated group compared to control group (P<0.001), suggesting the occurrence of oxidative stress. We conclude that the Cd exposure in mice causes acute thromboembolic events, oxidative stress and alter liver and kidney functions.


The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A.
Excessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumor suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130-CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A. These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension.


Perioperative complications after live-donor hepatectomy.
Current studies of complications following donor hepatectomy may not be generalizable to all hospitals performing this procedure. To address this, live liver donors were identified in the Nationwide Inpatient Sample (2000-2008). Complications after donor hepatectomy were categorized using International Classification of Diseases, Ninth Revision codes and risk factors for complications were tested using logistic regression. Negative binomial regression models were used to estimate the increase in length of stay and hospital charge associated with complications. Among 555 donors (representing 2783 donors nationwide), 23% had 1 or more complications and 5% had a major complication. The most common complications were ileus (27%) and atelectasis (26%). No patient or hospital factors were associated with complications. Having any complication was associated with increased length of stay (incidence rate ratio, 1.36; 95% CI, 1.16-1.58; P < .001) and hospital charge (incidence rate ratio, 1.25; 95% CI, 1.09-1.44; P = .002). Approximately 25% of liver donors have complications immediately postoperatively but most are minor, lending support to current practices in live liver donation and donor selection.


Longitudinal changes in memory and executive functioning are associated with longitudinal change in instrumental activities of daily living in older adults.
Impaired everyday function is a diagnostic criterion for dementia, and a determinant of healthcare utilization and caregiver burden. Although many previous studies have demonstrated a cross-sectional relationship between cognition (particularly executive functions and memory) and everyday function in older adults, very little is known about longitudinal relationships between these domains. This study examined the association between longitudinal change in episodic memory (MEM) and executive functioning (EXEC) and change in everyday function. Participants were a cognitively heterogeneous group of 100 elderly persons including those with normal cognition, as well as those with mild cognitive impairment and dementia. They were followed for an average of 5 years. Random effects modeling showed that change in both MEM and EXEC were independently associated with rate of change in informant-rated instrumental activities of daily living (IADLs), even after controlling for age, education, and gender. Findings indicate that declines in MEM and EXEC over time make unique and independent contributions to declines in older adults' ability to function in daily life.


Photocatalytic Reduction of CO2 to CO in Aqueous Solution under Red-Light Irradiation by a Zn-Porphyrin-Sensitized Mn(I) Catalyst.
This work demonstrates photocatalytic CO2 reduction by a noble-metal-free photosensitizer-catalyst system in aqueous solution under red-light irradiation. A water-soluble Mn(I) tricarbonyl diimine complex, [MnBr(4,4'-{Et2O3PCH2}2-2,2'-bipyridyl)(CO)3] (1), has been fully characterized, including single-crystal X-ray crystallography, and shown to reduce CO2 to CO following photosensitization by tetra(N-methyl-4-pyridyl)porphyrin Zn(II) tetrachloride [Zn(TMPyP)]Cl4 (2) under 625 nm irradiation. This is the first example of 2 employed as a photosensitizer for CO2 reduction. The incorporation of -P(O)(OEt)2 groups, decoupled from the core of the catalyst by a -CH2- spacer, afforded water solubility without compromising the electronic properties of the catalyst. The photostability of the active Mn(I) catalyst over prolonged periods of irradiation with red light was confirmed by 1H and 13C{1H} NMR spectroscopy. This first report on Mn(I) species as a homogeneous photocatalyst, working in water and under red light, illustrates further future prospects of intrinsically photounstable Mn(I) complexes as solar-driven catalysts in an aqueous environment.


Diagnostic detection of human lung cancer-associated antigen using a gold nanoparticle-based electrochemical immunosensor.
The development of rapid and sensitive methods for the detection of immunogenic tumor-associated antigen is important not only for understanding their roles in cancer immunology but also for the development of clinical diagnostics. Alpha-enolase (ENO1), a p48 molecule, is widely distributed in a variety of tissues, whereas gamma-enolase (ENO2) and beta-enolase (ENO3) are found exclusively in neuron/neuroendocrine and muscle tissues, respectively. Because ENO1 has been correlated with small cell lung cancer, nonsmall cell lung cancer, and head and neck cancer, it can be used as a potential diagnostic marker for lung cancer. In this study, we developed a simple, yet novel and sensitive, electrochemical sandwich immunosensor for the detection of ENO1; it operates through physisorption of anti-ENO1 monoclonal antibody on polyethylene glycol-modified disposable screen-printed electrode as the detection platform, with polyclonal secondary anti-ENO1-tagged, gold nanoparticle (AuNP) congregates as electrochemical signal probes. The immunorecognition of the sample ENO1 by the congregated AuNP@antibody occurred on the surface of the electrodes; the electrochemical signal from the bound AuNP congregates was obtained after oxidizing them in 0.1 M HCl at 1.2 V for 120 s, followed by the reduction of AuCl(4-) in square wave voltammetry (SWV) mode. The resulting sigmoidally shaped dose-response curves possessed a linear dynamic working range from 10(-8) to 10(-12) g/mL. This AuNP congregate-based assay provides an amplification approach for detecting ENO1 at trace levels, leading to a detection limit as low as 11.9 fg (equivalent to 5 microL of a 2.38 pg/mL solution).


Performance of extended Lagrangian schemes for molecular dynamics simulations with classical polarizable force fields and density functional theory.
Iterative energy minimization with the aim of achieving self-consistency is a common feature of Born-Oppenheimer molecular dynamics (BOMD) and classical molecular dynamics with polarizable force fields. In the former, the electronic degrees of freedom are optimized, while the latter often involves an iterative determination of induced point dipoles. The computational effort of the self-consistency procedure can be reduced by re-using converged solutions from previous time steps. However, this must be done carefully, as not to break time-reversal symmetry, which negatively impacts energy conservation. Self-consistent schemes based on the extended Lagrangian formalism, where the initial guesses for the optimized quantities are treated as auxiliary degrees of freedom, constitute one elegant solution. We report on the performance of two integration schemes with the same underlying extended Lagrangian structure, which we both employ in two radically distinct regimes-in classical molecular dynamics simulations with the AMOEBA polarizable force field and in BOMD simulations with the Onetep linear-scaling density functional theory (LS-DFT) approach. Both integration schemes are found to offer significant improvements over the standard (unpropagated) molecular dynamics formulation in both the classical and LS-DFT regimes.


Identification of biological mechanisms underlying a multidimensional ASD phenotype using machine learning.
The complex genetic architecture of Autism Spectrum Disorder (ASD) and its heterogeneous phenotype makes molecular diagnosis and patient prognosis challenging tasks. To establish more precise genotype-phenotype correlations in ASD, we developed a novel machine-learning integrative approach, which seeks to delineate associations between patients' clinical profiles and disrupted biological processes, inferred from their copy number variants (CNVs) that span brain genes. Clustering analysis of the relevant clinical measures from 2446 ASD cases in the Autism Genome Project identified two distinct phenotypic subgroups. Patients in these clusters differed significantly in ADOS-defined severity, adaptive behavior profiles, intellectual ability, and verbal status, the latter contributing the most for cluster stability and cohesion. Functional enrichment analysis of brain genes disrupted by CNVs in these ASD cases identified 15 statistically significant biological processes, including cell adhesion, neural development, cognition, and polyubiquitination, in line with previous ASD findings. A Naive Bayes classifier, generated to predict the ASD phenotypic clusters from disrupted biological processes, achieved predictions with a high precision (0.82) but low recall (0.39), for a subset of patients with higher biological Information Content scores. This study shows that milder and more severe clinical presentations can have distinct underlying biological mechanisms. It further highlights how machine-learning approaches can reduce clinical heterogeneity by using multidimensional clinical measures, and establishes genotype-phenotype correlations in ASD. However, predictions are strongly dependent on patient's information content. Findings are therefore a first step toward the translation of genetic information into clinically useful applications, and emphasize the need for larger datasets with very complete clinical and biological information.


Overweight and obesity may lead to under-diagnosis of airflow limitation: findings from the Copenhagen City Heart Study.
The prevalence of obesity has increased during the last decades and varies from 10-20% in most European countries to approximately 32% in the United States. However, data on how obesity affects the presence of airflow limitation (AFL) defined as a reduced ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) are scarce. Data was derived from the third examination of the Copenhagen City Heart Study from 1991 until 1994 (n = 10,135). We examine the impact of different adiposity markers (weight, body mass index (BMI), waist circumference, waist-hip ratio, and abdominal height) on AFL. AFL was defined in four ways: FEV1/FVC ratio < 0.70, FEV1/FVC ratio < lower limit of normal (LLN), FEV1/FVC ratio <0.70 including at least one respiratory symptom, and FEV1/FVC ratio < LLN and FEV1% of predicted < LLN. All adiposity markers were positively and significantly associated with FEV1/FVC independent of age, sex, height, smoking status, and cumulative tobacco consumption. Among all adiposity markers, BMI was the strongest predictor of FEV1/FVC. FEV1/FVC increased with 0.04 in men and 0.03 in women, as BMI increased with 10 units (kg · m-2). Consequently, diagnosis of AFL was significantly less likely in subjects with BMI ≥ 25 kg · m-2 with odds ratios 0.63 or less compared to subjects with BMI between 18.5-24.9 kg · m-2 when AFL was defined as FEV1/FVC < 0.70. High BMI reduces the probability of AFL. Ultimately, this may result in under-diagnosis and under-treatment of COPD among individuals with overweight and obesity.