A two-year study on the efficacy and tolerability of policosanol in patients with type II hyperlipoproteinaemia.
This is a report of the results of a two years' randomized, double-blind placebo-controlled study of the efficacy, safety, and tolerability of policosanol administered at 5 mg twice-a-day in the treatment of type II hyperlipoproteinaemia. The study included 69 patients from both sexes, in whom total cholesterol and low-density-lipoprotein cholesterol (LDL-C) were not controlled sufficiently by diet. The treatment effect on total cholesterol and LDL-C was maintained during the 2-year follow up. Thus, percent reductions 24 months after therapy were 25% (LDL-C) and 18% (cholesterol). All comparisons with placebo were significant. Similarly, ratios of LDL-C to HDL-C and cholesterol to HDL-C were significantly reduced and such decreases were maintained during the study. Policosanol raised significantly the values of high-density lipoprotein cholesterol (HDL-C) during the study and maximal increases were reached 12 months after therapy (+21%). From this time the increases mildly declined to +14% and +11.2% respectively at 18 and 24 months after therapy. No significant changes in triglycerides were observed as compared with baseline or placebo. No patient withdrew from the study because of adverse effects. No drug-related clinical or biochemical adverse side-effects were observed. Any adverse experiences reported were mild and transient; moreover, no significant differences were obtained when compared with those reported by the placebo group. The results indicate that policosanol administered for two years to patients with type II hypercholesterolaemia shows a maintained efficacy as well as very good safety and tolerability.


Downregulation of ribophorin II suppresses tumor growth, migration, and invasion of nasopharyngeal carcinoma.
It has been reported that ribophorin II (RPN2) expression is increased in many cancers, but the role of RPN2 in nasopharyngeal carcinoma (NPC) remains unclear. This study found that the expression of RPN2 is increased dramatically in NPC tissues of patients compared with that in the adjacent normal tissues. This study attempted at understanding the effect of siRNA-RPN2 treatment on the migration and invasion of NPC cell lines CNE2 and HNE1. RT-PCR and Western blotting showed that RPN2 was highly expressed in CNE2 and HNE1 cells. siRNA-RPN2 treatment significantly inhibited cell viability at 24 and 48 h compared with the control group. Results of the transwell assay showed that, compared to the control groups, migration and invasion of the cells treated with siRNA-RPN2 decreased markedly. In addition, compared to the control groups, caspase-3, caspase-9, and E-cadherin expression levels increased and MMP 2 expression decreased significantly in the siRNA-RPN2-treated group. Phosphorylation of AKT and PI3K was also inhibited after siRNA-RPN2 treatment. siRNA-RPN2 can effectively inhibit the invasion and migration of human NPC cells via AKT/PI3K signaling. This can serve as a novel strategy for NPC treatment.


Screening and evaluation of antiviral compounds against Equid alpha-herpesviruses using an impedance-based cellular assay.
Equid alpha-herpesviruses (EHV) are responsible for different diseases in equine population. EHV-1 causes respiratory diseases, abortions and nervous disorders, EHV-4 causes respiratory diseases and sporadic abortion, while EHV-3 is responsible of equine coital exanthema. In view of the lack of efficacy of vaccines against EHV-1 and EHV-4 and in the absence of vaccines against EHV-3, the use of antiviral treatment is of great interest. In this study, we documented the interest of the Real-Time Cell Analysis (RTCA) technology to monitor the cytopathic effects induced by these viruses on equine dermal cells, and established the efficacy of this method to evaluate the antiviral effect of aciclovir (ACV) and ganciclovir (GCV). In addition, the RTCA technology has also been found appropriate for the high-throughput screening of small molecules against EHV, allowing the identification of spironolactone as a novel antiviral against EHV.


[EEG spectral characteristics in the dynamics of planned movements].
The spectral characteristics of the EEG in 11 healthy right-handed volunteers with no neurological disorders in dynamics of the unusual finger movements of both hands in random rhythm have been investigated. In particular, it is shown that the preparation and execution of voluntary finger movements compared to the rest were accompanied by a reduction level of activation within almost all the surface of cerebral cortex, except for right frontal lobe. It has been experimentally demonstrated that a significant increasing EEG activity of the right frontal area in high-frequency domain power spectrum was independent of the working limb. This might testify the direct participation of this cortical area in the processes of voluntary muscular activity planning, initiation and control.


A screening, prevention, and restoration model for saving the injured brain in intensive care unit survivors.
We face a profound and emerging public health problem in the form of acute and chronic brain dysfunction. This affects both young and elderly intensive care unit survivors and is altering the landscape of society. Two-thirds of intensive care unit patients develop delirium, and this is associated with longer stays, increased costs, and excess mortality. In addition, over half of intensive care unit survivors suffer a dementia-like illness that impacts their physical and cognitive functional abilities and which appears to be related to the duration of their intensive care unit delirium. A new paradigm of how intensivists handle the brain is required. We propose a three-step approach to address this emerging epidemic, which includes Screening, Prevention, and Restoration of brain function (SPR). Screening combines risk factor identification and delirium assessment using validated instruments. Prevention of acute and chronic brain dysfunction requires implementation of a core model of care that combines evidence-based practices: awakening and breathing, coordination with target-based sedation, delirium monitoring, and exercise/early mobility (ABCDE). Restoration introduces strategies of ongoing screening and treatment for intensive care unit survivors at high risk of ongoing brain dysfunction. This practical system applying many evidence-based concepts incorporates personalized medicine, systems-based practice, and continuing research and development toward improving acute and chronic cognitive outcomes.


[Alcohol consumption and self esteem in adolescents].
The aim of this study was to analyze the relationship of levels of self esteem and alcohol consumption in adolescents, by carrying out a transversal, descriptive study, in a college of nursing of Queretaro in Mexico, in the month of July 2008, with a sample of 109 adolescents, between 17 and 20 years old. For attainment of the data two instruments were applied: AUDIT and the Rosemberg self esteem scale. The majority of the participating adolescents had high self esteem (94.5%) and none presented low self esteem. Of the adolescents in the study 80.7% did not consume alcohol hazardously. It was concluded that the adolescents presented high self esteem and low alcohol consumption. Therefore, it is necessary to implement preventive programs related to alcohol consumption and to identify the protective factors to guarantee the maintenance of healthy habits for the adolescents.


Transformation of meaning perspectives in clients with rheumatoid arthritis.
The purpose of this qualitative study was to examine the process of transformation of personal beliefs, values, feelings, and knowledge (meaning perspectives) underlying occupational change in a small group of clients with rheumatoid arthritis during home-based rehabilitation. A grounded theory approach used to collect and analyze data concurrently included: (1) a sample of five adult clients diagnosed with rheumatoid arthritis in occupational therapy, (2) data collection through 28 semi-directed interviews, and (3) data analysis using the constant comparison method. The study identified meaning perspectives of these clients with rheumatoid arthritis and explored the transformation of perspectives related to the modification of occupational performance. The study suggests that the exploration of meaning perspective transformation by clients and therapists could be a potential part of rehabilitation intervention.


In vitro and in vivo oncogenic potential of bovine leukemia virus G4 protein.
In addition to the genes involved in the structure of the viral particle, the bovine leukemia virus (BLV) genome contains a region called X which contains at least four genes. Among them, the tax and rex genes, respectively, are involved in transcriptional and posttranscriptional regulation of viral transcription. Two other genes, R3 and G4, were identified after cloning of the corresponding mRNAs from BLV-infected lymphocytes. Although the function of the two latter genes is still unknown, they appear to have important roles, since deletion of them restricts viral propagation in vivo. In order to assess the oncogenic potential of the R3 and G4 proteins, we first analyzed their ability to immortalize and/or transform primary rat embryo fibroblasts (Refs). In this assay, the G4 but not the R3 protein cooperated with the Ha-ras oncogene to induce tumors in nude mice. It thus appears that G4 exhibited oncogenic potential in vitro. To extend these observations in vivo, the pathology induced by recombinant viruses with mutations in G4 and in R3 and G4 was next evaluated with the sheep animal model. Viral propagation, as measured by semiquantitative PCR, appeared to be reduced when the R3 and G4 genes were deleted. These observations confirm and extend our previous data underlining the biological function of these genes. In addition, we present the results of a clinical survey that involves 39 sheep infected with six different BLV recombinants. Over a period of 40 months, 83% of the sheep infected with a wild-type virus developed leukemias and/or lymphosarcomas. In contrast, none out of 13 sheep infected with viruses with mutations in G4 or in R3 and G4 developed disease. We conclude that in addition to its oncogenic potential in vitro, G4 is required for pathogenesis in vivo. These observations should help us gain insight into the process of leukemogenesis induced by the related human T-cell leukemia virus type 1.


Renal function decline in recipients and donors of kidney grafts: role of aortic stiffness.
Renal function decreases over time as a result of reduction in the number of functioning nephrons with age. In recipients and donors of kidney grafts, renal function decline may be linked differently to various parameters, namely arterial stiffness. We conducted a prospective cohort study including 101 recipients of kidney grafts and their donors aiming at determining the factors correlated to the renal function decline over time. Aortic stiffness was evaluated by the non-invasive measurement of aortic pulse wave velocity. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease (MDRD) equation and the annualized change was determined. Decline in renal function was estimated at 1-year post-transplantation and annually thereafter (median follow-up 8 years, range 3.6-18.3), as the mean of the annualized decrease in the glomerular filtration rate. In recipients, filtration rate decreased by 4.8 ± 19.7 ml/min/1.73 m(2) the first post-transplant year and at a yearly rate of 2.2 ± 3.8 ml/min/1.73 m(2) thereafter. The first-year decline was related to smoking and acute rejection. Later decline was significantly associated with donor age and aortic stiffness. In living donors, renal function decline after the first year corresponded to 0.7 ml/min/1.73 m(2), was significantly lower than that of recipients (p < 0.001), and was determined by donor age at nephrectomy. Recipients of kidney grafts show a glomerular filtration rate decline over time that is significantly associated with donor age and aortic stiffness after the first post-transplant year, while donors demonstrate a lower decline that is mostly determined by age at nephrectomy.


Tenosynovial giant cell tumor of the thigh: positron emission tomography findings.
Tenosynovial giant cell tumors (TGCTs) are pigmented villonodular proliferative lesions originating from the synovium, bursa, or joint. TGCTs tend to be locally aggressive, and there is a chance for multiple occurrences, which often lead to impairment of joint function. In this article, we report the case of a diffuse-type extra-articular TGCT found in the thigh of a 36-year-old woman. Surveillance F-18 fluorodeoxyglucose positron emission tomography detected increased activity within the left thigh. This activity was confirmed with magnetic resonance imaging and with surgical excision and histopathologic determination of the tumor. This patient's case suggests that TGCTs may be discovered and followed after resection with positron emission tomography.


Impact of vascular disease in predicting stroke and death in patients with atrial fibrillation: the Danish Diet, Cancer and Health cohort study.
The presence of vascular disease (peripheral artery disease [PAD] and/or myocardial infarction [MI]) may impact on the risk of stroke and death among patients with incident atrial fibrillation (AF). To test this hypothesis, we analyzed data from a large Danish prospective cohort, the Danish Diet, Cancer and Health (DCH) study, to assess the risk of stroke or death among those who developed AF according to concomitant presence of vascular disease. A prospective cohort study of 57, 053 persons (27, 178 men and 29, 876 women, respectively), aged between 50 and 64 years. The risk of stroke or death for patients with vascular disease was assessed amongst 3315 patients with incident AF (mean age, 67.1years; 2130 men, 1185 women) using Cox proportional hazard models, after a median follow-up of 4.8 years. Of the subjects with AF, 417 (12.6%) had 'vascular disease' (PAD and/or prior MI). The risk of the primary endpoint (stroke or death) was significantly higher in patients with vascular disease at 1-year follow-up (crude hazard ratio [HR] 2.51 [1.91-3.29]), with corresponding crude HRs for PAD and MI being 3.51 (2.40-5.13), and 1.99 (1.46-2.72), respectively. For the secondary endpoints of death or stroke individually, these risk estimates were similar (crude HR 2.48 [1.89-3.26] and 1.77 [1.18-2.66], respectively). After adjustment for risk factors within the CHADS(2) score, the adjusted HR for the primary endpoint (stroke or death) in patients with vascular disease was 1.91 (1.44-2.54), which was also significant for death (1.97 [1.48-2.62]). Vascular disease (prior MI and PAD) is an independent risk factor for the primary endpoint of 'stroke or death' in patients with AF, even after adjustment for the CHADS(2) risk score, although this is driven by the impact on mortality. This reaffirms that patients with vascular disease represent a 'high-risk' population, which necessitates proactive management of all cardiovascular risk factors and effective thromboprophylaxis (i.e. oral anticoagulation), which has been shown to significantly reduce the risk of stroke and death in AF.


Missing pelvic inflammatory disease? Substantial differences in the rate at which doctors diagnose PID.
The clinical diagnosis of pelvic inflammatory disease (PID) is subjective. Our aim was to determine if the pattern of diagnosis of PID among experienced clinicians varied compared with the diagnosis of genital warts. We conducted a retrospective study of 325 PID diagnoses made by experienced clinicians at Melbourne Sexual Health Centre, Australia (2002-2006), where doctors saw 21 785 unselected female patients in a walk-in service. We compared the proportion of female patients diagnosed as having PID and genital warts between doctors and then compared doctors above (high diagnosing) and below (low diagnosing) the mean rate of PID diagnosis. There were significant and clinically important differences in the proportion of women diagnosed with having PID (0-5.7%) across 23 doctors investigated. Estimated standard deviation in the frequency of PID diagnosis (logit scale) was 1.26 (95% CI 0.81 to 1.95)--approximately four times greater than for warts. Patients seen by high (n = 4673) and low (n = 16 787) diagnosing doctors had similar epidemiological risk profiles suggesting true distribution of PID cases across doctors was similar (p>0.13). Women diagnosed with having PID by high diagnosing doctors compared with low diagnosing doctors were younger (odds ratio 1.7; 95% CI 1.1 to 2.8, p = 0.013) but otherwise had similar epidemiological and clinical features. Differences in diagnostic rates for PID between doctors are substantial and may be because of PID cases being missed by some doctors.


In vivo demonstration of a late depolarizing postsynaptic potential in CA1 pyramidal neurons.
Previous studies have shown that GABA can have a depolarizing and excitatory action through GABA(A) receptors in mature CNS neurons in vitro. However, it remains unknown whether this occurs under physiological conditions. In this study, using intracellular recording and staining in vivo technique, we show a late depolarizing postsynaptic potential (L-PSP) in CA1 pyramidal neurons of adult Wistar rats under halothane anesthesia. This L-PSP was elicited in approximately 70% of the recorded neurons on stimulation of the Schaffer collaterals or the contralateral commissural path. The size of L-PSP was linearly correlated to the decay time constant but not the rising slope of the initial excitatory PSP (EPSP). Intravenous administration of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 and the GABA(A) receptor blocker picrotoxin significantly reduced the size of the L-PSP. The spine density and apical dendritic branching length of the neurons that displayed L-PSPs was significantly greater than those that do not. These results indicate that NMDA receptor and GABA(A) receptor-mediated depolarizing postsynaptic potentials can be revealed in CA1 pyramidal neurons of adult rats in vivo, supporting the physiological relevance of GABA(A)-mediated depolarization in normal neuronal information processing. The difference in electrophysiological properties and morphological features between neurons that display the L-PSP and the other neurons suggest that they might represent two different subtypes of CA1 pyramidal neurons.


Amphiphilic polymer-mediated formation of laponite-based nanohybrids with robust stability and pH sensitivity for anticancer drug delivery.
The development of pH-sensitive drug delivery nanosystems that present a low drug release at the physiological pH and are able to increase the extent of the release at a lower pH value (like those existent in the interstitial space of solid tumors (pH 6.5) and in the intracellular endolysosomal compartments (pH 5.0)) is very important for an efficient and safe cancer therapy. Laponite (LP) is a synthetic silicate nanoparticle with a nanodisk structure (25 nm in diameter and 0.92 nm in thickness) and negative-charged surface, which can be used for the encapsulation of doxorubicin (DOX, a cationic drug) through electrostatic interactions and exhibit good pH sensitivity in drug delivery. However, the colloidal instability of LP still limits its potential clinical applications. In this study, we demonstrate an elegant strategy to develop stable Laponite-based nanohybrids through the functionalization of its surface with an amphiphile PEG-PLA copolymer by a self-assembly process. The hydrophobic block of PEG-PLA acts as an anchor that binds to the surface of drug-loaded LP nanodisks, maintaining the core structure, whereas the hydrophilic PEG part serves as a protective stealth shell that improves the whole stability of the nanohybrids under physiological conditions. The resulting nanocarriers can effectively load the DOX drug (the encapsulation efficiency is 85%), and display a pH-enhanced drug release behavior in a sustained way. In vitro biological evaluation indicated that the DOX-loaded nanocarriers can be effectively internalized by CAL-72 cells (an osteosarcoma cell line), and exhibit a remarkable higher anticancer cytotoxicity than free DOX. The merits of Laponite/PEG-PLA nanohybrids, such as good cytocompatibility, excellent physiological stability, sustained pH-responsive release properties, and improved anticancer activity, make them a promising platform for the delivery of other therapeutic agents beyond DOX.


Cumulative exposure to CD8+ granzyme Bhi T cells is associated with reduced lung function early after lung transplantation.
Outcomes following lung transplant remain suboptimal. This is attributable to variable posttransplant recovery of lung function, and inconsistent degrees of lung function loss after peak function is reached. Granzyme B is elevated in the blood and bronchoalveolar lavage (BAL) in acute rejection. We hypothesized that persistent exposure to T cells high in granzyme B would negatively correlate with lung function. We investigated cumulative exposure measured as the area-under-the-curve (AUC) of CD8+ T cell granzyme Bhi cells in the first year posttransplant in both BAL and blood in 24 transplant recipients. We assessed the correlation between cumulative 1-year exposure and FEV1 slope. There was a negative correlation between 1-year exposure and FEV1 slope within the first year (r=-0.63; P=.001). This relationship persisted even when adjusted for transplant type, gender, age, rejection, and indication for transplantation. In contrast, no relationship was seen with the 1-year AUC and lung function after 1 year posttransplant. In contrast to the BAL granzyme Bhi levels, granzyme Bhi levels from the blood showed no relationship with lung function. These findings suggest that CD8+ T-cell-driven factors are responsible for early improvements in lung function after transplantation.


How are cytochrome b561 electron currents controlled by membrane voltage and substrate availability?
Direct recordings of electron currents mediated by cytochromes b561 (CYB561) are not available yet, despite the importance of these proteins in a variety of physiological functions, including neurotransmitter synthesis and dietary iron uptake. Here, we used the two-electrode voltage-clamp technique applied to Xenopus oocytes to demonstrate, for the first time, the generation of electron currents by a Drosophila member of the CYB561 superfamily named stromal cell-derived receptor 2 (SDR2). This experimental method, along with the theoretical development of a three-state kinetic model, supports the hypothesis that electron donor/acceptor concentrations and transmembrane voltage mutually control SDR2-mediated electron transport activity in a complex but predictable manner.


State Support: A Prerequisite for Global Health Network Effectiveness Comment on "Four Challenges that Global Health Networks Face".
Shiffman recently summarized lessons for network effectiveness from an impressive collection of case-studies. However, in common with most global health governance analysis in recent years, Shiffman underplays the important role of states in these global networks. As the body which decides and signs international agreements, often provides the resourcing, and is responsible for implementing initiatives all contributing to the prioritization of certain issues over others, state recognition and support is a prerequisite to enabling and determining global health networks' success. The role of states deserves greater attention, analysis and consideration. We reflect upon the underappreciated role of the state within the current discourse on global health. We present the tobacco case study to illustrate the decisive role of states in determining progress for global health networks, and highlight how states use a legitimacy loop to gain legitimacy from and provide legitimacy to global health networks. Moving forward in assessing global health networks' effectiveness, further investigating state support as a determinant of success will be critical. Understanding how global health networks and states interact and evolve to shape and support their respective interests should be a focus for future research.


Measuring implementation fidelity of school-based obesity prevention programmes: a systematic review.
Until now, there is no clear overview of how fidelity is assessed in school-based obesity prevention programmes. In order to move the field of obesity prevention programmes forward, the current review aimed to 1) identify which fidelity components have been measured in school-based obesity prevention programmes; 2) identify how fidelity components have been measured; and 3) score the quality of these methods. Studies published between January 2001-October 2017 were selected from searches in PubMed, EMBASE, PsycINFO, CINAHL, Cochrane Library and ERIC. We included studies examining the fidelity of obesity prevention programmes (nutrition and/or physical activity and/or sitting) at school (children aged 4-18 year) measuring at least one component of implementation fidelity. A data extraction was performed to identify which and how fidelity components were measured. Thereafter, a quality assessment was performed to score the quality of these methods. We scored each fidelity component on 7 quality criteria. Each fidelity component was rated high (> 75% positive), moderate (50-75%) or low (< 50%). Of the 26,294 retrieved articles, 73 articles reporting on 63 different studies were included in this review. In 17 studies a process evaluation was based on a theoretical framework. In total, 120 fidelity components were measured across studies: dose was measured most often (N = 50), followed by responsiveness (N = 36), adherence (N = 26) and quality of delivery (N = 8). There was substantial variability in how fidelity components were defined as well as how they were measured. Most common methods were observations, logbooks and questionnaires targeting teachers. The quality assessment scores ranged from 0 to 86%; most fidelity components scored low quality (n = 77). There is no consensus on the operationalisation of concepts and methods used for assessing fidelity in school-based obesity prevention programmes and the quality of methods used is weak. As a result, we call for more consensus on the concepts and clear reporting on the methods employed for measurements of fidelity to increase the quality of fidelity measurements. Moreover, researchers should focus on the relation between fidelity and programme outcomes and determine to what extent adaptations to programmes have been made, whilst still being effective.


[How valid are self-reported intakes of beer, wine and spirits in population studies?].
In order to compare data on intake of wine, beer and spirits from a frequency questionnaire with intake of each type of alcoholic beverage estimated from a dietary interview, a randomly selected sub-sample of 244 women and 249 men aged 35-65 years was cross-sectionally studied. The sample was a sub-sample of the Danish MONICA study. Mean outcome measure in the study was the differences in intake of beer, wine and spirits as reported by the frequency questionnaire and the diet history interview. We found an overall agreement between the two methods, with very little or no systematic variation for all three alcoholic beverages. We conclude that compared to a more time and money consuming thorough dietary interview, the traditional frequency questionnaires seem to sufficiently capture intakes of different types of alcohol. Bias in alcohol reporting by the frequency questionnaire does not seem responsible for the recently found decreased mortality among subjects with a daily intake of wine, nor the increased mortality from drinking of spirits.


Comparison of analysis of the different prostate-specific antigen forms in serum for detection of clinically localized prostate cancer.
To compare different forms and ratios of serum prostate-specific antigen (PSA) to determine which form or ratio provides optimal diagnostic specificity and sensitivity in distinguishing between benign prostatic hyperplasia (BPH) and clinically localized prostate cancer. Serum samples were obtained from 47 patients with BPH and 39 with clinically localized prostate cancer. Patients with BPH underwent either transurethral resection of the prostate or transurethral microwave thermotherapy. Patients with prostate cancer, all of whom had no metastases on radionucleotide bone scans and no pelvic lymph node involvement, underwent either radical external beam radiation therapy or radical retropubic prostatectomy. All patients had pretreatment serum PSA levels between 1 and 20 ng/mL. The different forms of serum PSA (free PSA [PSA-F], PSA complexed to alpha 1-antichymotrypsin [PSA-ACT], and total PSA [PSA-T]) were measured using different monoclonal antibodies against PSA and ACT and immunofluorometric assay techniques. Furthermore, three ratios (PSA-F/PSA-T, PSA-ACT/PSA-T, and PSA-F/PSA-ACT) were calculated. By receiver operating characteristic curve analysis, the performance of the different forms and ratios were compared. The PSA-F/PSA-T ratio had the greatest area under the curve (AUC, 0.776), significantly larger than that for PSA-T (0.612; P = 0.024). For PSA-ACT/PSA-T, the AUC was 0.695 (P = 0.283 versus PSA-T) and 0.773 for PSA-F/PSA-ACT (P = 0.051 versus PSA-T). At a cutoff level < 0.17, PSA-F/PSA-T had a sensitivity of 79%, a specificity of 66%, and a positive predictive value of 66% compared with 74%, 38%, and 50%, respectively, for PSA-T at a cutoff level > 4.0 ng/mL. The PSA-F/PSA-T ratio gives the best diagnostic performance compared with that for other forms and ratios of PSA and will reduce the number of prostatic biopsies in patients with BPH.


Control your mind, make affordance available.
Evaluating the affordance-control interpretation of the relationship between performance and object estimation has been proposed by psychophysical and psychonomic studies. This study examined the weight estimation-performance relationship. Individuals with visual impairment or blindness put shots that varied in weight among five scales. In Experiment 1, only the perceived weight was a significant performance constraint. In Experiment 2, the weight was perceived as heavier when the participants' actions were manipulated through cognitive interpretation. The increase in perceived weight appeared to be related to performance and intrinsically scaled to the action, even when the action was only mental rather than physical. The study's findings suggest that bodily experience and action are the basis for physical judgments and likely underlie other basic cognitive interpretations of sensory stimuli. This suggestion goes hand in hand with the biofunctional approaches which assume direct experience of the integrated wholeness of one's body is fundamental for developing other kinds of awareness. Different perspectives from oriental philosophy and psychology are also discussed.


Moroccan Propolis: A Natural Antioxidant, Antibacterial, and Antibiofilm against Staphylococcus aureus with No Induction of Resistance after Continuous Exposure.
This study was performed to evaluate the total phenols, flavonoids, and antioxidant activities of twenty-four propolis samples from different regions of Morocco. In addition, two samples were screened regarding the antibacterial effect against four Staphylococcus aureus strains. Gas chromatography coupled to mass spectra (GC-MS) analysis was done for propolis samples used in antibacterial tests. The minimum inhibitory and minimum bactericidal concentration (MIC, MBC) were determined. The potential to acquire the resistance after sequential exposure of bacterial strains and the impact of adaptation to propolis on virulence using the Galleria mellonella were evaluated. Additionally, the effects of propolis extract on the bacterial adherence ability and its ability to inhibit the quorum sensing activity were also examined. Among the twenty-four extracts studied, the samples from Sefrou, Outat el Haj, and the two samples marketed in Morocco were the best for scavenging DPPH, ABTS, NO, peroxyl, and superoxide radicals as well as in scavenging of hydrogen peroxide. A strong correlation was found between the amounts of phenols, flavonoids, and antioxidant activities. Propolis extract at the MIC value (0.36 mg/mL) significantly reduced (p < 0.001) the virulence potential of S. aureus ATCC 6538 and the MRSA strains without leading to the development of resistance in the sequence of continuous exposure. It was able to impair the bacterial biofilm formation. The results have revealed that sample 1 reduces violacein production in a concentration dependent manner, indicating inhibition of quorum sensing. This extract has as main group of secondary metabolites flavonoids (31.9%), diterpenes (21.5%), and phenolic acid esters (16.5%).


Catabolism of benzoate and phthalate in Rhodococcus sp. strain RHA1: redundancies and convergence.
Genomic and proteomic approaches were used to investigate phthalate and benzoate catabolism in Rhodococcus sp. strain RHA1, a polychlorinated biphenyl-degrading actinomycete. Sequence analyses identified genes involved in the catabolism of benzoate (ben) and phthalate (pad), the uptake of phthalate (pat), and two branches of the beta-ketoadipate pathway (catRABC and pcaJIHGBLFR). The regulatory and structural ben genes are separated by genes encoding a cytochrome P450. The pad and pat genes are contained on a catabolic island that is duplicated on plasmids pRHL1 and pRHL2 and includes predicted terephthalate catabolic genes (tpa). Proteomic analyses demonstrated that the beta-ketoadipate pathway is functionally convergent. Specifically, the pad and pat gene products were only detected in phthalate-grown cells. Similarly, the ben and cat gene products were only detected in benzoate-grown cells. However, pca-encoded enzymes were present under both growth conditions. Activity assays for key enzymes confirmed these results. Disruption of pcaL, which encodes a fusion enzyme, abolished growth on phthalate. In contrast, after a lag phase, growth of the mutant on benzoate was similar to that of the wild type. Proteomic analyses revealed 20 proteins in the mutant that were not detected in wild-type cells during growth on benzoate, including a CatD homolog that apparently compensated for loss of PcaL. Analysis of completed bacterial genomes indicates that the convergent beta-ketoadipate pathway and some aspects of its genetic organization are characteristic of rhodococci and related actinomycetes. In contrast, the high redundancy of catabolic pathways and enzymes appears to be unique to RHA1 and may increase its potential to adapt to new carbon sources.


Depression strongly influences postconcussion symptom reporting following mild traumatic brain injury.
To examine the influence of depression on postconcussion symptom reporting in patients following mild traumatic brain injury (MTBI). Sixty patients referred to a specialty clinic following MTBI, 58 outpatients with Structured Clinical Interview for DSM-diagnosed depression, and 72 healthy community control participants. Participants with MTBI were divided into 2 subgroups on the basis of self-reported symptoms of depression (23 MTBI-depressed, 37 MTBI-not depressed). All participants completed a postconcussion symptom questionnaire. British Columbia Post-concussion Symptom Inventory. There were significant differences in total reported postconcussion symptoms among all 4 groups (all P < .002; Cohen's d = 0.68-3.24, large to very large effect sizes; MTBI-depressed > depressed outpatients > MTBI-no depression > healthy controls). There were significant differences in the number of symptoms endorsed (P < .05), with the highest number of symptoms endorsed by the MTBI-depressed group, followed by depressed outpatients, MTBI-no depression, and healthy controls. Patients who experience MTBIs and who have a postinjury recovery course complicated by significant depression report more postconcussion symptoms, and more severe symptoms, than (a) outpatients with depression, and (b) patients with MTBIs who do not have significant symptoms of depression.


Nano-friction behavior of phosphorene.
Nano-friction of phosphorene plays a significant role in affecting the controllability and efficiency of applying strain engineering to tune its properties. So far, the friction behavior of phosphorene has not been studied. This work studies the friction of single-layer and bilayer phosphorene on an amorphous silicon substrate by sliding a rigid tip. For the single-layer phosphorene, it is found that its friction is highly anisotropic, i.e. the friction is larger along the armchair direction than that along the zigzag direction. Moreover, pre-strain of the phosphorene also exhibits anisotropic effects. The friction increases with the pre-strain along the zigzag direction, but decreases with that along the armchair direction. Furthermore, the strong adhesion between the phosphorene and its substrate increases the friction between the phosphorene and the tip. For bilayer phosphorene, its friction highly depends on its stacking mode, which determines the contact interface with a commensurate or incommensurate pattern. This friction behavior is quite unique and greatly differs from that of graphene and molybdenum disulfide. Detailed analysis reveals that this behavior results from the combination effect of the friction contact area, the potential-energy profile of phosphorene, and its unique elongation.


Sequence specificity in DNA binding is mainly governed by association.
Sequence-specific binding of proteins to DNA is essential for accessing genetic information. We derive a model that predicts an anticorrelation between the macroscopic association and dissociation rates of DNA binding proteins. We tested the model for thousands of different lac operator sequences with a protein binding microarray and by observing kinetics for individual lac repressor molecules in single-molecule experiments. We found that sequence specificity is mainly governed by the efficiency with which the protein recognizes different targets. The variation in probability of recognizing different targets is at least 1.7 times as large as the variation in microscopic dissociation rates. Modulating the rate of binding instead of the rate of dissociation effectively reduces the risk of the protein being retained on nontarget sequences while searching.


Morphological and molecular characterisation of Gyrodactylus salmonis (Platyhelminthes, Monogenea) isolates collected in Mexico from rainbow trout (Oncorhynchus mykiss Walbaum).
Gyrodactylus salmonis (Yin et Sproston, 1948) isolates collected from feral rainbow trout, Oncorhynchus mykiss (Walbaum) in Veracruz, southeastern Mexico are described. Morphological and molecular variation of these isolates to G. salmonis collected in Canada and the U.S.A. is characterised. Morphologically, the marginal hook sickles of Mexican isolates of G. salmonis closely resemble those of Canadian specimens - their shaft and hook regions align closely with one another; only features of the sickle base and a prominent bridge to the toe permit their separation. The 18S sequence determined from the Mexican specimens was identical to two variable regions of SSU rDNA obtained from a Canadian population of G. salmonis. Internal transcribed spacer (ITS) regions (spanning ITS1, 5.8S and ITS2) of Mexican isolates of G. salmonis are identical to ITS sequences of an American population of G. salmonis and to Gyrodactylus salvelini Kuusela, Ziętara et Lumme, 2008 from Finland. Analyses of the ribosomal RNA gene of Mexican isolates of G. salmonis show 98-99% similarity to those of Gyrodactylus gobiensis Gläser, 1974, Gyrodactylus salaris Malmberg, 1957, and Gyrodactylus rutilensis Gläser, 1974. Mexican and American isolates of G. salmonis are 98% identical, as assessed by sequencing the mitochondrial cox1 gene. Oncorhynchus mykiss is one of the most widely-dispersed fish species in the world and has been shown to be an important vector for parasite/disease transmission. Considering that Mexican isolates of G. salmonis were collected well outside the native distribution range of all salmonid fish, we discuss the possibility that the parasites were translocated with their host through the aquacultural trade. In addition, this study includes a morphological review of Gyrodactylus species collected from rainbow trout and from other salmonid fish of the genus Oncorhynchus which occur throughout North America.


Electro-Quasistatic Human-Structure Coupling for Human Presence Detection and Secure Data Offloading.
The emergence of Human Body Communication (HBC), as an energy-efficient and physically secure mode of information exchange, has escalated the exploration of communication modalities between the human body and surrounding conducting objects. In this paper, we propose an Inter-Structure communication guided by Human Body while envisioning the need for non-contact sensing of biological objects such as humans with secure data offloading by analyzing the Structure-Human-Structure Interaction (SHSI) in Electro-Quasistatic (EQS) regime. Results show that the presence of a human between conducting structures (with Tx & Rx) can boost the received voltage by ~8 dB or more. Received signal level can be increased further by ~18 dB or more with a grounded receiver. Finite Element Method (FEM) based simulations are executed to study the positional variation of structure (with Rx) relative to body and earth's ground. Trends in simulation results are validated through experiments to develop an in-depth understanding of SHSI for EQS signals with low loss and enhanced physical security.


Reciprocal effects of antidepressant treatment on activity and connectivity of the mood regulating circuit: an FMRI study.
It has been hypothesized that one of the effects of antidepressants is to increase functional connectivity between the cortical mood-regulating and the limbic mood-generating regions. One consequence of this antidepressant effect is thought to be decreased limbic activation in response to negative emotional stimuli. Twelve unmedicated unipolar depressed patients and 11 closely matched healthy comparison subjects completed two magnetic resonance imaging (MRI) scanning sessions at baseline and after 6 weeks. Depressed patients received treatment with sertraline between the two sessions. During each MRI session, subjects completed a resting state functional connectivity scan and a conventional block-design negative vs. neutral pictures regional brain activation scan. After 6 weeks of sertraline treatment resting state, functional connectivity between the ACC and limbic regions increased while limbic activation in response to negative versus neutral pictures decreased. The results of this study are consistent with the hypothesis that antidepressant treatment has reciprocal effects on corticolimbic functional connectivity and limbic activation in response to emotional stimuli.


Infection after pediatric heart transplantation: results of a multiinstitutional study. The Pediatric Heart Transplant Study Group.
Detailed information regarding the spectrum and predictors of infection after heart transplantation in children is limited because of relatively small numbers of patients at any single institution. We therefore used combined data obtained from the Pediatric Heart Transplant Study Group to gain additional information regarding infectious complications in the pediatric population. To determine the time-related risk of infection and death related to infection in a large pediatric patient population, we analyzed data related to 332 pediatric patients (undergoing heart transplantation between January 1, 1993, and December 31, 1994) from 22 institutions in the Pediatric Heart Transplant Study Group. Among the 332 total patients, 276 infections were identified in 136 patients. Of those patients with development of infection, a single infection episode was reported in 54% of patients, 21% had two infections, and 25% had three or more infections. Of the 276 infections, 164 (60%) were bacterial, 51 (18%) were due to cytomegalovirus, 35 (13%) were other viral (noncytomegalovirus) infections, 19 (7%) were fungal, and 7 (2%) were protozoal. Bacterial infections were more common in infants younger than 6 months of age at time of transplantation, comprising 73% of all infections as compared with 49% in patients older than 6 months of age. The incidence of bacterial infection peaked during the first month after transplantation, with the actuarial likelihood of a bacterial infection among all patients reaching 25% at 2 months. The most common sites of bacterial infection were blood and lung (74% of bacterial infections). Cytomegalovirus accounted for 59% of viral infections, with a peak hazard occurring at 2 months after transplantation. Among all infections, cytomegalovirus was less common in infants younger than 6 months of age (8% of all infections) than in older patients (25%). By multivariate analysis, risk factors for early infection included younger recipient age (p = 0.05), mechanical ventilation at time of transplantation (p = 0.0002), positive donor cytomegalovirus serologic study result with negative recipient result (p = 0.004), and longer donor ischemic time (p = 0.04). The overall mortality rate from infection was 5%, with an actuarial freedom from death related to infection of 92% at 1 year after transplantation. The mortality rate was high in patients with fungal infections (52%), yet was low for those with cytomegalovirus infection (6%). Infections accounted for 27% of the overall mortality rate in infants younger than 6 months of age, compared with 16% for older patients. Although most infections in pediatric heart transplant recipients are successfully treated, infection remains an important cause of posttransplantation morbidity and death, especially in infants. Bacterial infections predominate within the first month after transplantation, whereas the peak hazard for viral infections occurs approximately 2 months after transplantation. Cytomegalovirus infections are common in the pediatric transplant population, but death related to cytomegalovirus is low.


Platelet-rich plasma in dermatology: boon or a bane?
There has been a recent spurt in application of platelet-rich plasma (PRP) in dermatology and aesthetic medicine. However, the details regarding use of PRP in various dermatological indications ranging from hair restoration to chronic ulcers are dispersed in literature, herein we have tried to focus all under one heading. Overall, PRP seems to be a promising therapeutic modality but the level of evidence as of now, from the available published data is low. This review will also stimulate readers to carry out well designed, larger population based trials, so as to validate its use in dermatology practice.


Factors predicting developmental outcome in premature infants with hydrocephalus due to intraventricular haemorrhage.
In a previous paper (1) we noted that premature infants developing hydrocephalus due to intraventricular haemorrhage performed considerably worse than their full term hydrocephalic, and non-hydrocephalic premature peers. Although this was an extremely small sample it was noted that some children had more handicap than others and could be roughly divided into two groups according to development outcome. 43 subjects born between 26-36 weeks gestation are now available for study. In order to determine whether there were any factors which could predict how well these children would perform developmentally, data were collected on birth history, medical problems experienced, development and treatment of the hydrocephalus. Developmental assessment was carried out at 18 months or less on all subjects and, for some, at or around 36 months and again at 60+ months. These data were statistically analysed to determine those factors which could be elicited would determine the children likely to suffer developmental or motor problems. The only significant factors which distinguished good outcome from bad outcome in these cases were when the haemorrhage took place after birth, later haemorrhage leading to poorer outcome, and an inverse relationship according to duration of ventilation. The results were discussed with relevance to future handling of similar infants.


The Fate of Chronic Burn Wounds Suspected as Marjolin's Ulcers.
Marjolin's ulcer is the malignant transformation of chronic nonhealing ulcers that have developed in burn scars or in any other chronic wound. Development of this malignancy tends to be slow and insidious, but it becomes more aggressive when the Marjolin's ulcer breaks free of the scar. We reviewed 24 cases of patients who complained of chronic burn wounds suspected to be Marjolin's ulcers. Histologically, chronic ulcer and pseudoepitheliomatous hyperplasia were 21%, respectively, and malignancy, including squamous cell carcinoma and leiomyosarcoma, were 58%. The mean latency period was 31.6 ± 13.0 years, and the majority of lesions occurred in the extremities. Pseudoepitheliomatous hyperplasia in chronic burn wounds, which is difficult to distinguish from squamous cell carcinoma and considered as a transitional state to becoming a malignant tumor, should be treated as a malignancy. An aggressive excision and reconstruction with free tissue transfer or regional flap transposition should be adopted for adequate ablation and definitive coverage, rather than skin graft and regular surveillance.


Group practice computing: the road to managing information.
Electronic information processing will have major implications for group practices in the near future, according to John T. Douglas, president and CEO of PD Medical Systems. Computer systems must be able to cope with electronic data interchange (EDI), electronic medical records (EMR) and outcome measurements to best serve groups under managed care.


Self-employment, personal values, and varieties of happiness-unhappiness.
This study compares personal values and forms of happiness between self-employed workers and those employed in an organization. Values are examined through Schwartz's (1999) established model, and happiness is measured in terms of personal flourishing and both job-specific and general hedonic well-being. In two nationally representative samples, self-employed workers are found to value self-direction and stimulation in their lives to a significantly greater degree than do organizational employees, but not to differ in other types of value. Well-being differences are predicted to depend on whether or not workers supervise others, such that any well-being advantages of self-employment are expected to occur only for self-employed workers without subordinates. As predicted, job satisfaction in self-employment is found to exceed that of organizational workers primarily for those who do not supervise others. In respect of personal flourishing, self-employed workers report significantly greater accomplishment in their lives, and that difference is again found only for workers without supervisory responsibility. However, strain experienced in a job and context-free hedonic well-being are found to be similar between self- and organizational employment. Refinements are proposed to research methods and practical procedures. (PsycINFO Database Record


Nasopharyngeal colonization with methicillin-resistant staphylococcus aureus and mortality among patients in an intensive care unit.
Nasopharyngeal colonization with Methicillin-resistant Staphylococcus aureus (MRSA) is common in critically ill patients, but its effect on patient prognosis is not fully elucidated. A retrospective cohort study was carried out enrolling 122 patients from an intensive care unit who were screened weekly for nasopharyngeal colonization with MRSA. The outcomes of interest were: general mortality and mortality by infection. Several exposure variables (severity of illness, procedures, intercurrences and MRSA nasopharyngeal colonization) were analyzed through univariate and multivariable models. Factors significantly associated with mortality in general or due to infection were: APACHE II and lung disease. The performance of surgery predicted favorable outcomes. MRSA colonization did not predict mortality in general (OR=1.02; 95%CI=0.35-3.00; p=0.97) or by infectious causes (OR=0.96; 95%CI=0.33-2.89; p=0.96). The results suggest that, in the absence of severity of illness factors, colonization with MRSA is not associated with unfavorable outcomes.


Participatory approaches and methods in gender equality and gender-based violence research with refugees and internally displaced populations: a scoping review.
Using participatory approaches or methods are often positioned as a strategy to tackle power hierarchies in research. Despite momentum on decolonising aid, humanitarian actors have struggled to describe what 'participation' of refugees and internally displaced persons (IDPs) means in practice. Efforts to promote refugee and IDP participation can be tokenistic. However, it is not clear if and how these critiques apply to gender-based violence (GBV) and gender equality-topics that often innately include power analysis and seek to tackle inequalities. This scoping review sought to explore how refugee and IDP participation is conceptualised within research on GBV and gender equality. We found that participatory methods and approaches are not always clearly described. We suggest that future research should articulate more clearly what constitutes participation, consider incorporating feminist research methods which have been used outside humanitarian settings, take more intentional steps to engage refugees and IDPs, ensure compensation for their participation, and include more explicit reflection and strategies to address power imbalances.


Mineral metabolism in male cyclists during high-intensity endurance training.
This study examined the effects of intense endurance training on basal plasma and 24-hour urinary calcium (Ca), magnesium (Mg), iron (Fe), zinc (Zn), and copper (Cu) levels in 9 male competitive cyclists. The supervised training program followed a baseline period and included a volume phase (6 weeks, averaging 87% of maximal heart rate [HR(max)]), an interval phase (18 days, 100% of HR(max)), and a 10-day unloading taper. The primary training outcome measure was 20-km time-trial cycling performance. Subjects ate unrestricted diets and maintained their weight. Compared to baseline, performance improved significantly (p < .05), while mineral metabolism was not significantly different after the volume phase. However, after the interval phase, renal Ca excretion increased (p < .05) and plasma Ca fell slightly below the clinical norm. As compared to the interval phase, urinary Ca decreased (p <.05), plasma Ca increased (p < .05), and performance further improved (p < .05) after the taper. Whereas Mg, Fe, Zn, and Cu metabolism remained unchanged throughout the study, greater renal Ca excretion was associated with very high intensity interval training.


Adding an alcohol-related risk score to an existing categorical risk classification for older adults: sensitivity to group differences.
To evaluate a new alcohol-related risk score for research use. Using data from a previously reported trial of a screening and education system for older adults (Computerized Alcohol-Related Problems Survey), secondary analyses were conducted comparing the ability of two different measures of risk to detect post-intervention group differences: the original categorical outcome measure and a new, finely grained quantitative risk score based on the same research-based risk factors. Three primary care group practices in southern California. Six hundred sixty-five patients aged 65 and older. A previously calculated, three-level categorical classification of alcohol-related risk and a newly developed quantitative risk score. Mean post-intervention risk scores differed between the three experimental conditions: usual care, patient report, and combined report (P<.001). The difference between the combined report and usual care was significant (P<.001) and directly proportional to baseline risk. The three-level risk classification did not reveal approximately 57.3% of the intervention effect detected by the risk score. The risk score also was sufficiently sensitive to detect the intervention effect within the subset of hypertensive patients (n=112; P=.001). As an outcome measure in intervention trials, the finely grained risk score is more sensitive than the trinary risk classification. The additional clinical value of the risk score relative to the categorical measure needs to be determined.


Relations between heavy drinking, gender, and substance-free reinforcement.
Behavioral economic theory and laboratory research have suggested that substance abuse may be associated with diminished engagement in enjoyable substance-free activities (substance-free reinforcement). However, college students, in particular men, have reported numerous social benefits from drinking that might mitigate the expected inverse relation between drinking and substance-free reinforcement. In this study, we examined the relations between college student heavy drinking, gender, and several categories of substance-free reinforcement (peer, dating, sexual, school, and family activities). Participants were 246 undergraduate students who were classified as a function of their reported frequency of heavy drinking during a typical week in the past month (120 heavy drinkers, 126 light drinkers). Heavy drinking was associated with significantly higher substance-free peer and sexual reinforcement. This association was gender invariant and remained significant in multiple regression models that controlled for gender, ethnicity, and fraternity or sorority membership. Substance-free reinforcement did not predict frequency of heavy drinking in models that included levels of substance-related reinforcement. The results indicate that college student heavy drinking is not associated with global deficits in substance-free reinforcement and is instead associated with increased peer and sexual activity that occurs outside the context of drinking or drug use. Prevention programs should help students to compensate for the potential loss of social reinforcement associated with reductions in drinking.


[Aiming for zero blindness].
Glaucoma is the leading cause of acquired blindness in Japan. One reason that it often leads to blindness is that it can continue to worsen even after effective medical reduction of intraocular pressure (IOP), the only evidence-based treatment. The limitations of current treatments make it critical to identify IOP-independent factors that can cause glaucoma and develop new drugs to target these factors. This is a challenging task, as the pathology of glaucoma is thought to be very complex, with different combinations of factors underlying its development and progression in different patients. Additionally, there is a deficiency in methods to efficiently perform clinical evaluations and reliably probe the state of the disease over relatively short periods. In addition, newly developed drugs need to be evaluated with clinical trials, for which human and financial resources are limited, before they can be widely used for treatment. Taking all these issues into consideration, it is evident that there are two urgent issues to consider: the development of methods to classify glaucoma in detail based on its pathology, and the improvement of clinical evaluation methods. In this review, we discuss some of our efforts to develop new neuroprotective agents for glaucoma, with a focus on the following three areas: 1. Clinical research and development of methods to classify glaucoma in detail based on IOP-independent factors, and the exploration of possibilities for the improvement of clinical evaluation of glaucoma. 2. Pathology-based research and development of new drugs for glaucoma, focusing on comprehensive gene expression analysis and the development of molecule-targeting drugs, using murine optic nerve crush as a disease model. 3. Development of next generation in vivo imaging modalities and the establishment of infrastructure enabling "big-data" analysis. First, we discuss our clinical research and the development of methods to classify glaucoma in detail based on IOP-independent factors, as well as our investigation of ways to improve the clinical evaluation of the disease. Our research was prompted by the multifactorial nature of glaucoma. There is a high degree of variability in the pattern and speed of the progression of visual field defects in individual patients, presenting a major obstacle for successful clinical trials. To overcome this, we classified the eyes of glaucoma patients into 4 types, corresponding to the 4 patterns of glaucomatous optic nerve head morphology described: by Nicolela et al. and then tested the validity of this method by assessing the uniformity of clinical features in each group. We found that in normal tension glaucoma (NTG) eyes, each disc morphology group had a characteristic location in which the loss of circumpapillary retinal nerve fiber layer thickness (cpRNFLT; measured with optical coherence tomography: OCT) was most likely to occur. Furthermore, the incidence of reductions in visual acuity differed between the groups, as did the speed of visual field loss, the distribution of defective visual field test points, and the location of test points that were most susceptible to progressive damage, measured by Humphrey static perimetry. These results indicate that Nicolela's method of classifying eyes with glaucoma was able to overcome the difficulties caused by the diverse nature of the disease, at least to a certain extent. Building on these findings, we then set out to identify sectors of the visual field that correspond to the distribution of retinal nerve fibers, with the aim of detecting glaucoma progression with improved sensitivity. We first mapped the statistical correlation between visual field test points and cpRNFLT in each temporal clock-hour sector (from 6 to 12 o'clock), using OCT data from NTG patients. The resulting series of maps allowed us to identify areas containing visual field test points that were prone to be affected together as a group. We also used a similar method to identify visual field sectors within a 10 x 10 grid displayed by an OCT map of the macula. By analyzing both the visual field and the macular map sectors, we anticipate that a more accurate and sensitive detection of glaucoma progression can become possible. We also used laser speckle flowgraphy (LSFG) to assess optic nerve blood flow. We found that compared to healthy eyes, eyes with early-stage NTG had decreased blood flow, and the peak of the blood flow wave form of each heartbeat was delayed. Finally, we used a method combining swept source OCT (SS-OCT) and newly developed analysis software to reconstruct the entire lamina cribrosa, a structure situated deep in the optic nerve head. This morphological analysis returned preliminary data suggesting that alterations in the morphology of the lamina cribrosa are already present in the early stages of glaucoma. This result indicates that axonal injury, mediated by morphological abnormalities of the lamina cribrosa, is involved in the pathogenesis of glaucoma. The next topic discussed is the pathology-based drug research and development, focusing on the use of comprehensive gene expression analysis and the development of molecule-targeting drugs in a murine model of optic nerve injury. Learning from clinical data on glaucoma and the lamina cribrosa, we carried out basic research to first determine what factors regulate axonal injury, and then develop drugs targeting these factors. Specifically, we performed a comprehensive gene expression analysis, using a next generation sequencer, and pathway analysis of retinal samples obtained from a murine model of axonal injury. This analysis revealed a characteristic upregulation of genes (such as Chop) that belongs to the endoplasmic reticulum stress pathway. An immunohistological analysis revealed that these changes in gene expression took place in the retinal ganglion cells, suggesting that endoplasmic reticulum stress molecules may be suitable therapeutic targets. Among these molecules, we chose CHOP as our primary target for drug development. Currently, we are in the process of screening a library of 1274 drugs, all of which are already used in human subjects, for CHOP inhibitors. The last topic of our discussion is future possibilities for glaucoma management. First, we discuss the development of next generation in vivo imaging modalities that allow detailed description of pathomechanisms of this multifactorial disease, glaucoma. The purpose of this research was to improve the efficacy of glaucoma diagnosis and to visualize its pathology at a cellular/molecular level and develop molecule-specific therapies. Currently available visual field tests are subjective, since they rely on a determination of the threshold of light perception, and are affected by poor reproducibility. The current dependence on visual field tests to ascertain the progression of glaucoma is thus a serious limitation on an important task of ophthalmologists. We, therefore, turned our focus to the establishment of an in vivo imaging method to detect dying retinal ganglion cells, which would highlight the pathologic state of glaucoma with high sensitivity. To this end, we used confocal scanning ophthalmoscopy to assess the usefulness of SYTOX Orange as a cell death probe. Our results showed that this probe could reveal dying retinal ganglion cells clearly, quickly and with high sensitivity. We, therefore, believe that the clinical application of probes that can sensitively detect dying retinal ganglion cells is a highly promising approach. This also applies to the use of molecular tools that can provide information on the molecular pathology of glaucoma. Finally, we would like to introduce our national collaborative work on the analysis of "big-data". The project aims to collect as wide a range of data as possible at an unprecedented scale. The data to be registered ranges from basic glaucoma data, such as IOP and visual field test results, to data from the most sophisticated comprehensive expression analyses or imaging data. This is an important area of research, since it promises to enable the exploration of targets for drug discovery and the identification of new biomarkers to efficiently detect glaucoma progression by applying new analysis strategies to the complex mass data. The project not only depends on the collaborative efforts of various types of clinical settings including private practices, medical centers and university hospitals, but also contributions of the pharmaceutical and the medical device industries. Thus, uniting a wide range of Japanese interests and resources is the key for success. In summary, in order to aim for ZERO BLINDNESS, a drastic improvement in the quality of our patient care, drug development research for unmet medical demands, and a strategic collaboration of various professionals in the ophthalmic industry are essential. With the deep appreciation we fell towards the selfless support extended during the earthquake disaster, we wish to translate our "gratitude" into "power" from Tohoku. In doing so, we as academicians are determined to keep on contributing to the society by making progress in the medicine.


C3b receptors mediate the growth factor-induced proliferation of malignant B-chronic lymphocytic leukemia lymphocytes.
We have investigated the function of C3b receptor (CR1) in the malignant lymphocytes of B-chronic lymphocytic leukemia (B-CLL) mimicking the physiological ligand C3b with the anti-CR1 monoclonal antibody CB04 covalently linked to Sepharose CL-4B (CB04-S). The binding of insolubilized CB04-S to CR1 gave a progression signal to B-CLL cells which became B cell growth factor (BCGF)-responsive. The cells of 13 of 14 cases treated with CB04-S showed an active time-dependent proliferation when BCGF was added to the culture. After 72 hr of exposure to BCGF, the growth fraction evaluated with the Ki67 monoclonal antibody was 23.4 +/- 8.9 and the proportion of cells in S phase assessed by the bromodeoxyuridine incorporation technique was 18.6 +/- 8.5%. The proper sequence of CB04-S followed by BCGF was also important since the proliferation was halved when the sequence was reversed or the two signals were delivered concomitantly. CB04-S and BCGF alone failed to induce any significant proliferation; the percentage of cycling cells was less than 1% overlapping that of control culture cells. On the contrary, the proliferation of normal tonsil B cells was triggered both by CB04-S and by BCGF used as single agents (bromodeoxyuridine+ cells 12.7 +/- 5.1% and 20.0 +/- 7.3, respectively). Together these data indicate that malignant B-CLL cells need a sequential two-step signal based upon CR1 binding in order to be activated in vitro. This is a major difference with normal tonsil B lymphocytes whose proliferation is triggered both by CB04-S and by BCGF used as single agents.


Evolution from microscopic transoral to endoscopic endonasal odontoidectomy.
The goal of this study was to compare the indications, benefits, and complications between the endoscopic endonasal approach (EEA) and the microscopic transoral approach to perform an odontoidectomy. Transoral approaches have been standard for odontoidectomy procedures; however, the potential benefits of the EEA might be demonstrated to be a more innocuous technique. The authors present their experience with 12 consecutive cases that required odontoidectomy and posterior instrumentation. Twelve consecutive cases of craniovertebral junction instability with or without basilar invagination were diagnosed at the National Institute of Neurology and Neurosurgery in Mexico City, Mexico, between January 2009 and January 2013. The EEA was used for 5 cases in which the odontoid process was above the nasopalatine line, and was compared with 7 cases in which the odontoid process was beneath the nasopalatine line; these were treated using the transoral microscopic approach (TMA). Odontoidectomy was performed after occipital-cervical or cervical posterior augmentation with lateral mass and translaminar screws. One case was previously fused (Oc-C4 fusion). The senior author performed all surgeries. American Spinal Injury Association scores were documented before surgical treatment and after at least 6 months of follow-up. Neurological improvement after odontoidectomy was similar for both groups. From the transoral group, 2 patients had postoperative dysphonia, 1 patient presented with dysphagia, and 1 patient had intraoperative CSF leakage. The endoscopic procedure required longer surgical time, less time to extubation and oral feeding, a shorter hospital stay, and no complications in this series. Endoscopic endonasal odontoidectomy is a feasible, safe, and well-tolerated procedure. In this small series there was no difference in the outcome between the EEA and the TMA; however, fewer complications were documented with the endonasal technique.


Chemokine stromal cell-derived factor 1/CXCL12 increases homing of mesenchymal stem cells to injured myocardium and neovascularization following myocardial infarction.
Heart failure due to ischemic heart disease is still a major health problem. Myocardium regeneration emerges as a novel therapeutic method for treating myocardial infarction (MI). However, it is affected by many factors. The present study was aimed to investigate the effect of chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 on mesenchymal stem cells (MSCs) homing to injured myocardium in a rat myocardial infarction model. A rat myocardial infarction model was established by permanent left anterior descending branch ligation. Mesenchymal stem cells from donor rats were cultured in IMDM and labeled with bromodeoxyuridine. The rats were divided into two groups. SDF-1 expression was measured by in situ hybridization and immunohistochemistry in the sham operated or infarcted hearts at 1, 2, 4, 7, 14 and 28 days post operation in the SDF-1 detection group. The rats in the intervention groups were injected with SDF-1, anti-SDF-1 antibody or saline 4 days after myocardial infarction. Then, a total of 5 x 10(6) cells in 2.5 ml of phosphate-buffered saline were injected through the tail vein. The number of the labeled MSCs in the infarcted hearts was counted on the 3rd day post injection. Cardiac function and blood vessel density were assessed on the 28th day post injection. Self-generating SDF-1 expression was increased at the first day post MI, peaked at the 7th day and decreased thereafter while it remained unchanged in sham operated hearts. The MSCs enrichment in the host hearts were more abundant in the MI groups than in the non-MI group (P = 0.000); the MSCs enrichment in the host hearts were more abundant in the SDF-1 injected group than in the anti-SDF-1 antibody and saline injected groups (P = 0.000). Cardiac function was improved more in the SDF-1 injected group than in the anti-SDF-1 antibody and saline injected groups (P = 0.000). Neovascularization in the SDF-1 injected group increased significantly compared to the other groups (P = 0.000). Myocardial SDF-1 expression was increased only in the early phase post MI. SDF-1 may enhance MSCs homing to the injured heart and improve cardiac function by promoting neovascularization.


Developmental instability of the Drosophila wing as an index of genomic perturbation and altered cell proliferation.
We experimentally induced different levels of instability affecting the development of specific wing regions of Drosophila melanogaster using the UAS-GAL4 system. A common index of developmental instability is fluctuating asymmetry (FA), that is, random differences between body sides of single individuals. We studied the FA in transgenic strains carrying random genomic insertions (UAS strains), as well as insertions in the regulatory region of genes involved in the organization of wing development (GAL4 strains). In addition, the expression of genes that increase (dp110 and 3622) or decrease (dPTEN) cell proliferation was ectopically induced. Our results are related to different levels of perturbation. Through the first kind of perturbation, genome integrity was compromised by the insertion of foreign DNA. In all cases, we observed a general increase in FA, although it was rarely found significant. The second kind of perturbation involved a modification of genes controlling wing development through the insertion of a GAL4 sequence in their promoter region. The third kind involved the ectopic expression of genes controlling cell proliferation. Our results show that (i) the level of FA is connected with the level of morphological perturbation induced, (ii) FA increase was higher in the wing regions that were the target of the genetic perturbation, and (iii) developmental instability was also observed in regions that were not directly addressed by the perturbation. The results were discussed on the basis of the running models about Drosophila wing development.


Association of AEBP1 and NRN1 RNA expression with Alzheimer's disease and neurofibrillary tangle density in middle temporal gyrus.
We explored RNA expression changes in the middle temporal gyrus (MTG) of Alzheimer's Disease patients (AD) by RNA sequencing the whole transcriptome of 8 AD and 8 Non-Demented (ND) controls. We used three additional expression datasets from related brain regions to validate the findings. The results highlighted the upregulation of AEBP1 and downregulation of NRN1 in AD, as well as their association with Braak staging and neurofibrillary tangles density. Furthermore, more than 400 protein-coding RNAs enriched for "Clathrin-mediated endocytosis" were validated in independent datasets from the same brain region. Finally, using in silico prediction analysis we found a signature of 52 non-protein coding RNAs that perturb key pathways involved in GABAergic transmission and peptide chain elongation. The association of AEBP1 in our data confirmed other published work examining gene expression in the hippocampus of AD patients. NRN1 is involved in neurite outgrowth, and in previous studies it has been shown to reverse synaptic defects and cognitive function impairment in Tg2576 mice. Finally, our results on non-protein coding RNAs suggest a role of these transcripts in altering synaptic and amyloid-β associated pathways.


The impact of farming on prehistoric culinary practices throughout Northern Europe.
To investigate changes in culinary practices associated with the arrival of farming, we analysed the organic residues of over 1,000 pottery vessels from hunter-gatherer-fisher and early agricultural sites across Northern Europe from the Lower Rhine Basin to the Northeastern Baltic. Here, pottery was widely used by hunter-gatherer-fishers prior to the introduction of domesticated animals and plants. Overall, there was surprising continuity in the way that hunter-gatherer-fishers and farmers used pottery. Both aquatic products and wild plants remained prevalent, a pattern repeated consistently across the study area. We argue that the rapid adaptation of farming communities to exploit coastal and lagoonal resources facilitated their northerly expansion, and in some cases, hunting, gathering, and fishing became the most dominant subsistence strategy. Nevertheless, dairy products frequently appear in pottery associated with the earliest farming groups often mixed with wild plants and fish. Interestingly, we also find compelling evidence of dairy products in hunter-gatherer-fisher Ertebølle pottery, which predates the arrival of domesticated animals. We propose that Ertebølle hunter-gatherer-fishers frequently acquired dairy products through exchange with adjacent farming communities prior to the transition. The continuity observed in pottery use across the transition to farming contrasts with the analysis of human remains which shows substantial demographic change through ancient DNA and, in some cases, a reduction in marine consumption through stable isotope analysis. We postulate that farmers acquired the knowledge and skills they needed to succeed from local hunter-gatherer-fishers but without substantial admixture.


A dispermic chimerism in a 2-year-old Caucasian boy.
Detection of two different cell populations in a child is a rare event. The following case of a dispermic chimera was diagnosed before surgery due to problems in blood group determination. A 2-year-old phenotypically male child was admitted for correction of a penoscrotal hypospadia and unilateral cryptorchism. During presurgical laboratory investigation, difficulties in blood group determination occurred. Blood group typing was performed by the DiaMed-ID Micro Typing System and by FACS. Additionally, cytogenetic analysis of lymphocytes and analysis of DNA polymorphisms in different tissues were performed. Two populations of red blood cells were detected, O cells accounting for 75% and B cells for 25%. Analysis of DNA-PCR polymorphisms in lymphocytes, nails, and in cells of the oral mucous membrane demonstrated a chimerism, with two alleles inherited from the father and one from the mother. A cytogenetic analysis of cultured lymphocytes showed a mosaic 46, XY/46,XX. Surgery revealed a prostatic utricle grade III, also called pseudovagina; genitography confirmed a vagina. Bilateral gonad biopsy showed a testis on one side and an ovary on the other. This case of chimerism represents a true hermaphroditism that most probably developed by double fertilization of one or more egg nuclei by two sperms.


Effect of Cs-4 (Cordyceps sinensis) on exercise performance in healthy older subjects: a double-blind, placebo-controlled trial.
The objective of this study was to examine the effect of Cs-4 (Cordyceps sinensis) on exercise performance in healthy elderly subjects. Twenty (20) healthy elderly (age 50-75 years) subjects were enrolled in this double-blind, placebo-controlled, prospective trial. The subjects were taking either Cs-4 333 mg or placebo capsules 3 times a day for 12 weeks. Subjects received baseline screening including physical examination and laboratory tests. Maximal incremental exercise testing was performed on a stationary cycle ergometer using breath-by-breath analysis at baseline and at the completion of the study. After receiving Cs-4 for 12 weeks, the metabolic threshold (above which lactate accumulates) increased by 10.5% from 0.83 +/- 0.06 to 0.93 +/- 0.08 L/min (p < 0.02) and the ventilatory threshold (above which unbuffered H(+) stimulates ventilation) increased by 8.5% from 1.25 +/- 0.11 to 1.36 +/- 0.15 L/min. Significant changes in metabolic or ventilatory threshold were not seen for the subjects in the placebo group after 12 weeks, and there were no changes in Vo(2) max in either group. This pilot study suggests that supplementation with Cs-4 (Cordyceps sinensis) improves exercise performance and might contribute to wellness in healthy older subjects.


Orbito-Ocular Tumours in Ibadan, South-West Nigeria.
The aim of this study was to review the cases of orbito-ocular tumors in a single tertiary health facility, and determine changes in pattern of presentation. Medical records of all patients with histologically confirmed orbito-ocular tumors between January 1992 and December 2011 in a tertiary center were reviewed. Patients' demographics, types of orbito-ocular tumor and their presentation were recorded. Records of 205 patients were analyzed with a male to female ratio of 1.1:1 and median age of seven years. Retinoblastoma was the most common tumor followed by ocular surface squamous neoplasia. Squamous cell carcinoma was the most common eyelid tumor while rhabdomyosarcoma was the most common orbital tumor. No case of melanoma was seen during the period. More than two thirds of patients had lost vision at presentation due to delay in seeking appropriate medical attention Conclusion: There appears to be a reduction in the cases of orbito-ocular tumors in Ibadan, however, there is little variation in the pattern of presentation. Encouraging early presentation to the appropriate health facility may possibly reduce the morbidity in these patients.


Sequential co-enrolment in randomised trials in neonatal intensive care medicine.
In many medical research settings, such as the neonatal intensive care unit, the number of patients who are eligible for a randomised clinical trial is relatively small and recruiting a sufficient number of patients into trials is often difficult. Furthermore, some infants may have already been enrolled into a trial as a fetus. Sequential co-enrolment of patients into more than one trial may offer a solution, yet runs the risk of contaminated results. We consider the situation of two sequential trials and describe requirements for different possible treatments effects ('estimands') to be estimated in such situations. These estimands differ regarding the extent to which participation status and treatment status in the previous trial is accounted for. Because of differences in available information about previous trials, analyses may result in estimated effects which differ in terms of interpretation and generalisability, except when in the absence of an interaction between the studied treatments. If co-enrolment cannot be ruled out, researchers should collect information about co-enrolment and treatment status in a previous or concurrent trial and mitigate the trial analysis plan in order to estimate meaningful effects.


Improvement of in vitro digestibility and thermostability of debranched waxy maize starch by sequential ethanol fractionation.
This study aimed to improve the in vitro digestibility and thermostability of debranched waxy maize starch (DWMS) by sequential fractionation. Waxy maize starch was debranched by pullulanase, followed by sequential precipitation through controlling the ratio of starch supernatants to ethanol at 1:0.5, 1:1, and 1:1.5 (v/v). Subsequently the structural, thermal, in vitro digestive properties of DWMS were investigated. In vitro digestion results showed that the secondary ethanol fractionation of 1:1 on the basis of the initial fractionation (1:0.5) induced a significant higher amount of slowly digestive starch (SDS, 30.0 %) and resistant starch (RS, 58.6 %) amongst all three fractions, along with the highest peak temperature (Tp, 106.4 °C) and the highest decomposition value (Td, 310.0 °C) in calorimetric (DSC) and thermogravimetry (TGA) measurements. Chain length distribution, surface morphology, and laser confocal micro-Raman spectroscopy (LCM-Raman) analyses revealed that medium (degree of polymerization, DP 13- 36) and long chains (DP ≥37) respectively constituting 72.0 % and 10.2 % of DWMS resulted in the formation of spheroidal crystallites with higher homogeneity and more ordered short-range structures. Overall, this work confirmed that ethanol fractionation is an efficient method for improving the in vitro digestibility and heat stability of waxy maize starch.


Faculty perceptions and use of e-learning resources for medical education and future predictions.
This study aims to investigate medical faculties' perceptions and current practice of using e-learning resources, needs and suggestions for more effective use of such resources, and future directions of e-learning in medical education. This descriptive study was conducted on full-time faculty members who were registered users of the e-learning portal of the consortium of Korean medical schools. Participants were invited to an online survey containing 45 items that addressed their perceptions and use of e-learning resources, and their predictions of future use. Descriptive analysis and reliability analysis were conducted as well as a thematic analysis of qualitative data. Ninety faculty members from 31 medical schools returned the questionnaires. Participants positively perceived e-learning resources and that they predicted their use would become increasingly popular. Still, only half of the respondents were using e-learning resources for teaching and agreed that they were willing to share their e-learning resources. Our study illustrates several barriers inhibit faculty use and sharing of e-learning resources, and a need for a more comprehensive, better-organized resource repository. Participants also pointed out the needs for more resources on multimedia assessment items, clinical videos, and virtual patients. Our study sheds light on medical faculty needs for institutional support and faculty development programs on e-learning, and institutional policies that address faculty concerns regarding ownership, intellectual property rights, and so forth on creating and sharing such resources. Collaborations among medical schools are suggested for creating a better organized around learning outcomes and more comprehensive repository of resources.


Low-grade myofibroblastic sarcoma of the gingiva.
Low-grade myofibroblastic sarcoma is a malignant tumour from myofibroblasts, which has only recently become clearly defined. It represents a rare entity developing in the soft tissues of the head and neck. About 20 cases have been reported in the oral cavity, especially in the tongue and bone, while gingiva as the primary site has been described only once to date. Diagnostic methods include histology and immunohistochemistry. The present report concerns a case of a 37-year-old man who presented with a persistent gingival ulcerated swelling that was interpreted for a long time as a gingival epulis. A low-grade myofibrosarcoma was diagnosed and the patient underwent a segmental osteotomy of the mandibular symphisys for complete excision. There was no sign of recurrence or metastatic disease during the 18-month postoperative period.


Quantitative phosphoproteomic analysis provides insights into the aluminum-responsiveness of Tamba black soybean.
Aluminum (Al3+) toxicity is one of the most important limitations to agricultural production worldwide. The overall response of plants to Al3+ stress has been documented, but the contribution of protein phosphorylation to Al3+ detoxicity and tolerance in plants is unclear. Using a combination of tandem mass tag (TMT) labeling, immobilized metal affinity chromatography (IMAC) enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS), Al3+-induced phosphoproteomic changes in roots of Tamba black soybean (TBS) were investigated in this study. The Data collected in this study are available via ProteomeXchange with the identifier PXD019807. After the Al3+ treatment, 189 proteins harboring 278 phosphosites were significantly changed (fold change > 1.2 or < 0.83, p < 0.05), with 88 upregulated, 96 downregulated and 5 up-/downregulated. Enrichment and protein interaction analyses revealed that differentially phosphorylated proteins (DPPs) under the Al3+ treatment were mainly related to G-protein-mediated signaling, transcription and translation, transporters and carbohydrate metabolism. Particularly, DPPs associated with root growth inhibition or citric acid synthesis were identified. The results of this study provide novel insights into the molecular mechanisms of TBS post-translational modifications in response to Al3+ stress.


Skin aging from ultraviolet irradiance and smoking reduces risk of melanoma: epidemiological evidence.
Long-term smoking appears to be inversely correlated with development of melanoma. Chronic ultraviolet (UV) irradiance also reduces and/or delays the development of melanoma. Thus, a common process is indicated. To examine the link between smoking and melanoma, articles reporting the relation between incidence of lung cancer and melanoma for individuals were sought. A very strong inverse correlation (r = -0.96) was found between the standardized incidence ratios for lung cancer and melanoma, passing through the value of 1 for each with a slope of -0.74. Smoking increases skin aging or elastosis in a manner similar to that of UV irradiance. Development of elastosis seems to explain why long-term smoking and chronic UV irradiance reduce the risk of melanoma. Further work is required to elucidate the mechanism whereby elastosis retards and reduces the development of melanoma.


Effects of sub-chronic exposure to terbuthylazine on DNA damage, oxidative stress and parent compound/metabolite levels in adult male rats.
Terbuthylazine is a selective pre- and post-emergency chloro-triazine herbicide used for a broad spectrum of weed control. We evaluated the potential of low doses of terbuthylazine to induce oxidative stress and cytogenetic damage in peripheral blood samples of adult male Wistar rats. Following 28-day repeated oral exposure at 0.004 mg/kg b.w./day, 0.4 mg/kg b.w./day and 2.29 mg/kg b.w./day, parameters of lipid peroxidation, total antioxidant capacity, and activities of antioxidant enzymes were measured in blood samples. Alkaline comet assay on leukocytes and erythrocyte micronucleus assay were used to measure DNA damage. In addition, the concentration of terbuthylazine and its metabolite in urine and plasma were determined using high performance liquid chromatography with UV diode-array detector (HPLC-UV-DAD). The fraction of terbuthylazine excreted in urine was negligible and was not found in plasma. Deethylterbuthylazine was only compound detected in plasma samples. Exposure to terbuthylazine did not induce significant lipid peroxidation products. The significant changes in antioxidant enzyme activities and the elevated total antioxidant capacity indicated that terbuthylazine at experimental conditions applied has potential to disturb oxidative/antioxidant balance. Results regarding the alkaline comet assay as well as micronucleated reticulocyte frequency indicated that treatment led to low-level DNA instability. Our results call for further research using other sensitive biomarkers of effect, along with different exposure scenarios.


Regulation of apical K channels in rat cortical collecting tubule during changes in dietary K intake.
Long-term adaptation to a high-K diet is known to increase the density of conducting secretory K (SK) channels in the luminal membrane of the rat cortical collecting tubule (CCT). To examine whether these channels are involved in the short-term, day-to-day regulation of K secretion, we examined the density of K channels in animals fed a high-K diet for 6 or 48 h. CCTs were isolated and split open to provide access to the luminal membrane. Cell-attached patches were formed on principal cells with 140 mM KCl in the patch-clamp pipette. SK channels were recognized from their characteristic single-channel conductance (40-50 pS) and gating patterns. Animals fed a control diet had SK channel densities of 0.40 channels/micrometer(2). When the diet was changed for one containing 10% KCl for 6 h, the channel density increased to 1.51 channels/micrometer(2). Maintaining the animals on a high-K diet for 48 h resulted in a further increase in SK channels to 2.29 channels/micrometer(2). Animals fed a low-K diet for 5 days or longer had SK densities of 0.53 channels/micrometer(2), not significantly different from control values. The presence of conducting Na channels in the luminal membrane will also affect K secretion by the CCT by altering the electrical driving force through the K channels. The density of Na channels, measured with LiCl in the pipette, was 0. 08 for controls and 1.00 and 1.08 channels/micrometer(2) after 6 h and 48 h on a high-K diet. Plasma aldosterone increased from 15 +/- 4 ng/dl (controls ) to 36 +/- 8 and 98 +/- 23 ng/dl after 6 and 48 h of K loading, respectively. The increase in K channel density could not be reproduced by infusion of the animals with aldosterone. We conclude that regulation of the density of conducting Na and K channels may contribute to day-to-day variation in the rate of renal K secretion and to the short-term maintenance of K balance.


[Cancer in siblings of children with cancer].
In some rare inherited disorders, such as Li-Fraumeni syndrome, relatives of children with cancer are at increased risk of cancer. We aimed to assess relations between childhood cancer and sibling risk, and evaluate the influence of recessive conditions in cancer causation. We did a population-based cohort study in the Nordic countries of 42,277 siblings of 25,605 children with cancer. Children with cancer were identified from records in the five Nordic cancer registries, and their siblings from nationwide population registries. Cancers in siblings were documented through record linkage with cancer registries and compared with national incidence rates. We also assessed cancer incidence in parents to identify familial cancer syndromes. 284.2 cancers were expected in siblings, whereas 353 were diagnosed (standardised incidence ratio 1.24 95% CI, 1.12-1.38). Risk ratios for siblings were highest in the first decade of life (2.59; 1.89-3.46). We excluded 56 families with genetic syndromes linked to cancer, which reduced this ratio from 1.7 to 1.0 (0.7-1.3) for siblings younger than 20 years and from 1.3 to 1.0 (0.8-1.3) for those aged 20-29 years. We found no new patterns of familial cancer that indicated inherited susceptibility, or evidence that recessive conditions might contribute to cancers not explained by syndromes. 40% of cancers in siblings that occurred before age 20 years could be attributed to known genetic factors, whereas 60% remained unexplained. Apart from rare cancer syndromes, paediatric cancer is not an indicator of increased risk in siblings.


Derivatization procedure of estradiol with a combination of MPDNP-F and 4-dimethylaminopyridine to generate product ion containing estradiol-skeleton for reliable determination of its serum/plasma concentrations by LC/ESI-MS/MS.
The quantification of serum/plasma estradiol (E2) is useful for the diagnosis, pathological analysis, and monitoring of the therapeutic efficacy of estrogen-dependent diseases. In this study, an improved derivatization method using 1-(2,4-dinitro-5-fluorophenyl)-4,4-dimethylpiperazinium iodide (MPDNP-F) was developed and combined with liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) for the sensitive and specific quantification of the serum/plasma E2. In the new method, the reaction time was reduced to 15 min from 90 min (two-step reaction in the previous method) by the direct reaction of MPDNP-F with E2 at 60°C in the presence of 4-dimethylaminopyridine (DMAP). DMAP served as the organic catalyst and had a less negative effect on the LC/ESI-MS/MS instrument compared to the non-volatile inorganic salt (NaHCO3), which was used in the previous method. The collision-induced dissociation of the molecular cation ([M]+) of the resulting derivative provided a product ion containing the E2-skeleton ([M-NO2-H]+), which significantly enhanced the assay sensitivity and specificity; compared to the dansyl chloride derivatization, which is the currently most-used derivatization procedure for the LC/ESI-MS/MS assays of E2, the MPDNP-F derivatization had significantly fewer interfering peaks and a clear and flat baseline in the serum sample analysis. The MPDNP-F derivatization-LC/ESI-MS/MS method enabled the precise and accurate quantification of E2 even at a 5.0 pg/mL concentration (lower limit of quantification) with a small sample volume (100 μL of serum/plasma) and had a tolerance for the matrix effect. This method was also proven to serve as a more sensitive and specific alternative to the clinically used chemiluminescence enzyme immunoassay.


[Interaction between antihypertensive agents and psychotropic drugs (author's transl)].
The present review paper is dealing with the interaction between antihypertensive agents and various psychotropic drugs. Various psychotropic drugs enhance certain-side-effects of the antihypertensive substances, like sedation, extrapyramidal disorders and orthostatic hypotension. On the other hand, the blood-pressure lowering effect of clonidine, guanethidine and related drugs, and possibly also that of alpha-methy-dopa is reduced by phenothiazine-neuroleptics and tricyclic antidepressants (thymoleptics), but not by benzodiazepine tranquilizers or by butyrophenone-like neuroleptics. The pharmacological background and the clinical relevance of these interaction phenomena are discussed.