A VLP library of C-terminally truncated Hepatitis B core proteins: correlation of RNA encapsidation with a Th1/Th2 switch in the immune responses of mice.
An efficient pBR327- and Ptrp-based E. coli expression system was used to generate a large-scale library of virus like particles (VLP) formed by recombinant hepatitis B virus (HBV) core (HBc) protein derivatives. To construct the library, the gene of HBc protein of the genotype D/subtype ayw2 virus was gradually truncated from the 3`-end and twenty-two HBc variants (with truncation up to 139 aa) were expressed at high levels. The proteins were purified by salt precipitation and gel filtration. Background RNA binding was observed for VLPs formed by HBc1-149, which lacked all C-terminal Arg blocks, and the addition of three Arg residues (HBc1-152) only slightly increased RNA binding. The presence of two Arg blocks (proteins HBc1-162 and HBc1-163) resulted in approximately half of the typical level of RNA binding, and the presence of three blocks (protein HBc1-171) led to approximately 85% of the typical level of binding. Only a small increase in the level of RNA binding was found for the HBc1-175 VLPs, which contained all four Arg blocks but lacked the last 8 aa of the full-length HBc protein. VLPs containing high levels of RNA had higher antigenicity according to an ELISA with anti-HBc mAbs than the VLPs formed by HBc variants without C-terminal Arg blocks and lacking RNA. The results indicate that the VLPs were stabilised by nucleic acids. The immunogenicity in BALB/c mice was comparable for VLPs formed by different HBc proteins, but a clear switch from a Th1 response to a Th2 response occurred after the loss of encapsidated RNA. We did not observe significant differences in lymphocyte proliferation in vitro for the tested VLP variants; however, the loss of RNA encapsidation correlated with a decreased level of IFN-γ induction, which is a measure of the potential CTL activity of immunogens.


Using community-led development to build health communication about rheumatic heart disease in Aboriginal children: a developmental evaluation.
A high prevalence of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) among Aboriginal children in northern Australia is coupled with low understanding among families. This has negative impacts on children's health, limits opportunities for prevention and suggests that better health communication is needed. During an RHD echocardiography screening project, Aboriginal teachers in a remote community school created lessons to teach children about RHD in their home languages, drawing on principles of community-led development. Access to community-level RHD data, previously unknown to teachers and families, was a catalyst for this innovative work. Careful, iterative discussions among speakers of four Aboriginal languages ensured a culturally coherent narrative and accompanying teaching resources. The evaluation demonstrated the importance of collective work, local Indigenous Knowledge and metaphors. As a result of the lessons, some children showed new responses and attitudes to skin infections and their RHD treatment. Language teachers used natural social networks to disseminate new information. A community interagency collaboration working to prevent RHD commenced. Conclusions and implications for public health: Action to address high rates of RHD must include effective health communication strategies that value Indigenous Knowledge, language and culture, collaborative leadership and respect for Indigenous data sovereignty.


Occupational therapy and cooking: A scoping review and future directions.
Occupational therapy (OT) has historically used cooking as an intervention and assessment approach across settings. Current practices in OT and the emergence of the multidisciplinary field of culinary medicine highlight the relationship between cooking and health. To map the current literature on OT and cooking and to identify key factors that may facilitate collaboration within culinary medicine. We conducted a scoping review using the Joanna Briggs Institute methodology to identify primary contexts and clinical settings. Publications were analysed using framework thematic analysis to identify OT themes and roles. A total of 56 studies met the criteria for inclusion. The majority of studies (n = 29, 53%) represented home/community settings and brain injury was the largest clinical group (n = 15, 27%). Primary themes related to person (n = 47, 43%), occupation (n = 30 (28%), environment (n = 19, 17%), and psychosocial wellbeing (n = 13, 12%). The primary OT role identified was that of interventionist (n = 48, 86%). OT's holistic practice places cooking within a larger context that can help identify and overcome the barriers to participation. Findings support multiple pathways in which OT can contribute to cooking initiatives for health promotion and potentially expand OT practice in population health.


Race- and Gender-Specific Associations between Neighborhood-Level Socioeconomic Status and Body Mass Index: Evidence from the Southern Community Cohort Study.
Obesity and a low socioeconomic status (SES), measured at the neighborhood level, are more common among Americans of Black race and with a low individual-level SES. We examined the association between the neighborhood SES and body mass index (BMI) using data from 80,970 participants in the Southern Community Cohort Study, a cohort that oversamples Black and low-SES participants. BMI (kg/m2) was examined both continuously and categorically using cut points defined by the CDC. Neighborhood SES was measured using a neighborhood deprivation index composed of census-tract variables in the domains of education, employment, occupation, housing, and poverty. Generally, the participants in lower-SES neighborhoods were more likely to have a higher BMI and to be considered obese. We found effect modification by race and sex, where the neighborhood-BMI association was most apparent in White female participants in all the quintiles of the neighborhood SES (ORQ2 = 1.55, 95%CI = 1.34, 1.78; ORQ3 = 1.71, 95%CI = 1.48, 1.98; ORQ4 = 1.76, 95%CI = 1.52, 2.03; ORQ5 = 1.64, 95%SE = 1.39, 1.93). Conversely, the neighborhood-BMI association was mostly null in Black male participants (ORQ2 = 0.91, 95%CI = 0.72, 1.15; ORQ3 = 1.05, 95%CI = 0.84, 1.31; βQ4 = 1.00, 95%CI = 0.81, 1.23; ORQ5 = 0.76, 95%CI = 0.63, 0.93). Within all the subgroups, the associations were attenuated or null in participants residing in the lowest-SES neighborhoods. These findings suggest that the associations between the neighborhood SES and BMI vary, and that other factors aside from the neighborhood SES may better predict the BMI in Black and low-SES groups.


Effects of burst stimulation during ventricular fibrillation on cardiac function after defibrillation.
The purpose of defibrillation is to rapidly restore blood flow and tissue perfusion following ventricular fibrillation (VF) and shock delivery. We tested the hypotheses that 1) a series of 1-ms pulses of various amplitudes delivered before the defibrillation shock can improve hemodynamics following the shock, and 2) this hemodynamic improvement is due to stimulation of cardiac or thoracic sympathetic nerves. Ten anesthetized pigs received a burst of either 15 or 30 1-ms pulses (0.1-10 A in strength) during VF, after which defibrillation was performed. ECG, arterial blood pressure, and left ventricular (LV) pressure were recorded. Defibrillation shocks and burst pulses were delivered from a right ventricular coil electrode to superior vena cava coil and left chest wall electrodes. Sympathetic blockade was induced with 1 mg/kg timolol and trials were repeated. The first half of this protocol was repeated in two animals that were pretreated with reserpine. Heart rate (HR) after 1-, 2-, 5-, and 10-A pulses was significantly higher than after control shocks without preceding pulse therapy. Mean and peak LV pressure measurements increased 38 and 72%, respectively, following shocks preceded by 5- and 10-A pulses compared with shocks preceded by no burst pulses. Mean and peak arterial pressures increased 36 and 43%, respectively, following shocks preceded by 5- and 10-A pulses compared with shocks preceded by no burst pulses. After beta-blockade, HR, mean and peak arterial pressures, and mean LV pressure were not significantly different after pulses of any strength compared with control shocks. LV peak pressure following the 10-A pulses was significantly higher than with no burst pulses but was significantly lower than the response to the 10-A pulses delivered without beta-blockade. HR, mean and peak arterial pressures, and mean and peak LV pressure responses after 15 or 30 5- or 10-A pulses were similar to the responses to the same pulses after beta-blockade. We conclude that a burst of 15-30 1-ms pulses delivered during VF can increase HR, arterial pressure, and LV pressure following defibrillation. beta-Blockade or reserpine pretreatment prevents most of this postshock increase in HR, arterial pressure, and LV pressure.


Intravenous injection of thalidomide in pregnant rabbits.
When administered orally to pregnant strain III rabbits, thalidomide is teratogenic to their fetuses. However, when the drug is injected intravenously to females of the same genetically controlled stock, it has no observable effect. This finding indicates that a metabolite of thalidomide formed in the intestinal tract may be the real teratogenic agent.


CBESW: sequence alignment on the Playstation 3.
The exponential growth of available biological data has caused bioinformatics to be rapidly moving towards a data-intensive, computational science. As a result, the computational power needed by bioinformatics applications is growing exponentially as well. The recent emergence of accelerator technologies has made it possible to achieve an excellent improvement in execution time for many bioinformatics applications, compared to current general-purpose platforms. In this paper, we demonstrate how the PlayStation 3, powered by the Cell Broadband Engine, can be used as a computational platform to accelerate the Smith-Waterman algorithm. For large datasets, our implementation on the PlayStation 3 provides a significant improvement in running time compared to other implementations such as SSEARCH, Striped Smith-Waterman and CUDA. Our implementation achieves a peak performance of up to 3,646 MCUPS. The results from our experiments demonstrate that the PlayStation 3 console can be used as an efficient low cost computational platform for high performance sequence alignment applications.


Shorter length of stay is associated with worse functional outcomes for medicare beneficiaries with stroke.
Understanding of the potential impact that length of stay (LOS) may have on Medicare beneficiaries' poststroke discharge function and discharge destination since implementation of a prospective payment system is lacking. This study examined the trends and associations between LOS and discharge outcomes in Medicare beneficiaries with stroke treated in inpatient rehabilitation facilities (IRFs). A serial, cross-sectional analysis of the Inpatient Rehabilitation Facility Patient Assessment Instrument dataset was conducted. The sample consisted of 371,211 patients with stroke who were over 65 years of age in all IRFs in the United States between January 1, 2002, and June 30, 2007. Annual trends for means of LOS, admission and discharge Functional Independence Measure (FIM) scores, and percent community discharge were examined using generalized estimating equations (GEEs) with facility level control and post hoc testing. The association between discharge FIM scores and LOS was examined using a continuous, multivariate GEE model. The association between community discharge and LOS was examined using a logistic, multivariate GEE model. Time trends showed mean LOS decreased 1.8 days; admission and discharge FIM scores declined 4.4 points and 3.6 points, respectively; and mean community discharges declined 5.4%. Controlling for study year and covariates, each day was associated with an increase of 0.50 discharge FIM points (95% confidence interval=0.48, 0.52). Each day also was associated with a 0.3% decrease in odds of community discharge (95% confidence interval=0.994, 0.999). Reliability and validity of the Inpatient Rehabilitation Facility Patient Assessment Instrument (IRF-PAI) are lacking. Results may have been biased by a lack of control at the patient and facility levels. Medicare beneficiaries with stroke treated in IRFs experienced shorter LOS, had worsening admission and discharge function, and had fewer community discharges. Worsening admission function and shorter LOS may contribute to worsening discharge outcomes, which may indicate a lack of readiness for IRF treatment and that facility-level factors may be playing a role in shorter LOS.


Current update of adoptive immunotherapy using cytokine-induced killer cells to eliminate malignant gliomas.
The therapeutic outcome for those with malignant glioma is poor, even though diverse therapeutic modalities have been developed. Immunotherapy has emerged as a therapeutic approach for malignant gliomas, making it possible to selectively treat tumors while sparing normal tissue. Here, we review clinical trials of adoptive immunotherapy approaches for malignant gliomas. We also describe a clinical trial that examined the efficacy and safety of autologous cytokine-induced killer (CIK) cells along with concomitant chemoradiotherapy for newly diagnosed glioblastoma. These CIK cells identify and kill autologous tumor cells. This review focuses on the use of adoptive immunotherapy for malignant gliomas and reviews the current literature on the concept of antitumor activity mediated by CIK cells.


[Nonviral gene transfer in vivo in gene therapy].
Recent findings connected with in vivo use of artificial macromolecular complexes (genosomes) for functional gene transfer and delivery are discussed in the paper. Non-viral methods are the most safe for the purpose of human gene delivery. The cationic liposomes containing cholesterol are the most suitable for this purpose, because they possess high biodegradability and stability in blood stream. The DNA-liposome complexes should: (i) contain DNA in the condition at most protected from environmental influence, (ii) be rather homogeneous and of small size (40-80 nm). Injections of complexes into blood are the most effective; in a respect of organospecifity may be achieved by appropriate ligand selection. It is the most perspectively to increase the expression level by combining liposomes with viral peptides.


Optimal Pessary Care: A Modified Delphi Consensus Study.
Support pessaries are an important, low-risk treatment option for women with vaginal prolapse but evidence to inform optimal practice is lacking. Currently, gynecologists, urologists, and urogynecologists recommend silicone vaginal support pessaries as first-line treatment for symptomatic vaginal prolapse in women of all ages. It is unknown how many providers who are not physicians prescribe and care for women using pessaries. For this study we attempted to collect opinions of expert nurse providers who fit pessaries on topics related to pessary care and management in an effort to develop consensus to guide practice. A 4-round modified Delphi technique was utilized and included one series of online surveys, 2 rounds of anonymous online questionnaires, and one series of face-to-face meetings at conferences. Respondents were invited to participate in all opportunities to provide opinion. For the first 3 rounds respondents were asked to rate statements on a 3-point scale, (agree, disagree, neutral) and provide written comments for those statements with which they did not agree. The goal of additional rounds was 80% agreement between participants, including no less than 6 nurse pessary experts. Greater than 80% consensus was achieved for 22 statements related to patient and provider education, terminology for documentation, pessary management, and follow-up care. Use of vaginal estrogen, antimicrobials, and prevention and management of mechanical injury were areas where no consensus was reached. Expert pessary providers were able to develop consensus recommendations to inform provider education and clinical care where the evidence base remains sparse. Areas where consensus was not achieved inform the future pessary-related research agenda needed to identify optimal cost-effective pessary care and educational methods for new pessary providers.


Failure to detect bovine immunodeficiency virus contamination of stud bull spermatozoa, blood leukocytes, or semen leukocytes in samples supplied by artificial insemination centers.
To determine whether bovine immunodeficiency virus (BIV) infection could be detected in spermatozoa, blood leukocytes, or semen leukocytes from stud bulls in artificial insemination centers. 30 bulls at 3 artificial insemination centers. Polymerase chain reaction testing that used 3 sets of primer pairs targeting pol and env regions of the BIV proviral genome was performed on DNA extracted from semen leukocytes, spermatozoa, and blood leukocytes from each bull. Southern blot analysis was performed to increase sensitivity of detection. Western blot analysis of plasma samples was used to detect antibodies against BIV. BIV provirus was not detected in DNA samples obtained from semen leukocytes, spermatozoa, or blood leukocytes, and antibodies against BIV were not detected. Contrary to our report of high point prevalence of BIV contamination of semen from a single artificial insemination center, bulls of the study reported here did not appear to be infected. Maximum risk of BIV infection in similar bulls was estimated at 10% with a confidence level of 95%.


Effects of the hormone relaxin on the metabolism of the glycosaminoglycans in the mouse symphysis pubis.
The influence of the peptide hormone relaxin on the glycosaminoglycan (GAG) metabolism was investigated in the pubic ligament of the symphysis pubis and in serum of the virgin mouse. Fresh weight DNA and GAG content per 1 ligament is significantly increased, the level of water soluble protein is not affected. A shift in the electrophoretic GAG pattern by an increasing amount of hyaluronic acid and a decreasing amount of chondroitin sulfate and dermatan sulfate can be observed. Concerning GAG-splitting enzymes (N-acetylglucosaminidase, arylsulfatase, beta-glucuronidase) the N-acetylglucosaminidase reveals a significant increase of its activity in the interpubic ligament and in the serum. The data demonstrate that relaxin treatment induces some changes in the GAG metabolism.


L-lysine reduces nonenzymatic glycation of glomerular basement membrane collagen and albuminuria in diabetic rats.
In this study, we examined the hypothesis whether exogenous administration of L-lysine in drinking water would reduce nonenzymatic glycation of glomerular basement membrane (GBM) collagen and thus albuminuria in streptozotocin-diabetic rats. The rationale is that the administered lysine would combine with the circulating glucose and make it unavailable to react with epsilon-amino groups of lysine of various proteins in these diabetic rats. Lysine (0.1%) was given to diabetic rats 7 days (early treatment) or 90 days (late treatment) after induction of hyperglycemia. The treatment was continued for 60 days. Diabetic rats had significantly higher glucose, glycosylated HbA(1), kidney weight, nonenzymatic glycation of GBM collagen, albuminuria, and systolic blood pressure than normal rats. Early treatment with lysine prevented the rise in glycosylated HbA(1) (normal 6.98 +/- 0.71% vs. diabetic - early treatment - 7.78 +/- 1.50%; p = NS), reduced glycosylation of GBM collagen by 86%, and significantly improved albuminuria. There was no significant effect on plasma glucose and systolic blood pressure. However, late treatment reduced the glycosylation of GBM collagen by 46% with a significant improvement in albuminuria. Plasma creatinine levels were not different between normal and untreated diabetic or lysine-treated diabetic rats; however, the creatinine clearance was significantly higher in all groups of diabetic rats (normal 0.45 +/- 0.09 vs. diabetic 2.02 +/- 0.39 ml/min; p < 0.001). The data suggest that early rather than late treatment is more beneficial in reducing nonenzymatic glycation of collagen, although both treatments significantly reduced albuminuria. There was no nephrotoxicity as assessed by plasma creatinine levels or creatinine clearances. These beneficial effects occurred independent of changes either in blood pressure or plasma insulin concentration.


[The effects of hydroxyethyl starch on lipopolysaccharide-induced endothelial injury in rat mesenteric venules].
To investigate the effect of hydroxyethyl starch (HES, 130/0.4) on lipopolysaccharide (LPS)-induced endothelial injury in rat mesenteric venules. Thirty-six Wistar rats weighing 200 - 250 g were randomly divided into 3 groups, n = 12 for each group. Rats were given LPS (2 mg/kg) and followed by normal saline 16 ml x kg(-1) x h(-1) in LPS group or HES 16 ml x kg(-1) x h(-1) in HES group for 60 min. Rats in control group received equal volume of saline. The dynamic changes in diameters of postcapillary venules, red blood cell velocities in venules, and hydrogen peroxide released from venules were evaluated. The ultrastructure of postcapillary venule was observed by electron microscopy. Mesenteric venular RBC velocities, vascular diameters and shear rates on the venular wall remained constant in any of the groups during the observation (P > 0.05). The hydrogen peroxide generation from venules increased in both HES and LPS groups (P < 0.05). In HES group, the hydrogen peroxide generation and cytoplasmic caveolae in postcapillary venule induced by LPS were significantly inhibited compared with LPS group (P < 0.05). Hydroxyethyl starch (130/0.4) could reduce the LPS-induced endothelial injury in rat mesentery. The effect was related to the inhibition of hydrogen peroxide generation on venular wall.


Effectiveness of intensive care of very low birth-weight infants.
Perinatal/neonatal intensive care can be evaluated in terms of its efficacy, effectiveness and efficiency. There is good experimental evidence from randomized controlled clinical trials that intensive-care interventions in the perinatal period are efficacious in reducing perinatal/neonatal mortality and fetal/neonatal morbidity. The effectiveness of intensive care programs in large populations has not been tested experimentally. However, population surveys show that perinatal/neonatal mortality is declining and it is likely that this is due in large part to improved perinatal care. Moreover, low birth-weight infants born in Level 3 hospitals have a lower neonatal mortality rate than LBW infants born in hospitals that are less well staffed and equipped. The true size of the reduction in fetal/neonatal mortality that is attributable to perinatal interventions is difficult to estimate from the experience of referral hospitals because of selection bias (both postnatal and prenatal). Thus, the size of the reduction in mortality resulting from the intensive care of VLBW infants is quite striking in hospital-based studies, but more modest in area-based studies. The efficiency of perinatal interventions in reducing death and disability takes into consideration both the health outcomes and the costs attributable to perinatal intensive care. Although neonatal intensive care saves lives, it is doubtful that the rate of handicap in very low birth-weight infants has been much affected. The immediate and long-term costs of neonatal intensive care are high, but a systematic economic evaluation has not yet been published.


Scattered UV beneath public shade structures during winters.
Broadband field measurements were conducted beneath three different-sized public shade structures, small, medium and large, during winter in the Southern Hemisphere. These measurements were compared with the diffuse UV to quantify the relationship of the UV under and around the shade structures to the diffuse UV. For the shade structures, a relationship between the diffuse UV and the UV in the shade has been provided for clear skies and solar zenith angles (SZA) of 49-76 degrees. This allows the prediction of the UV in the shade of these structures if the diffuse UV is known. The ultraviolet protection factors for the three shade structures ranged from 1.5 to 5.4 for decreasing SZA. For the greater SZA of 70-76 degrees, the erythemal UV in the shade was 65%, 59% and 51% of that in full sun for the small, medium and large structures, respectively. For the smaller SZA of 50-53 degrees the erythemal UV in the shade was 35%, 41% and 18% for the small, medium and large shade structures, respectively. From this research it can be concluded that the UV radiation levels in the shade in winter could cause erythema and other sun-related disorders.


A hierarchical screening approach to enantiomeric separation.
The screening of a number of chiral stationary phases (CSPs) with different modifiers in supercritical fluid chromatography to find a chromatographic method for separation of enantiomers can be time-consuming. Computational methods for data analysis were utilized to establish a hierarchical screening strategy, using a dataset of 110 drug-like chiral compounds with diverse structures tested on 15 CSPs with two different modifiers. This dataset was analyzed using a combinatorial algorithm, principal component analysis (PCA), and a correlation matrix. The primary goal was to find a set of eight columns resolving a large number of compounds, but also having complementary enantioselective properties. In addition to the hereby defined hierarchical experimental strategy, quantitative structure enantioselective models (QSERs) were evaluated. The diverse chemical space and relatively limited size of the training set reduced the accuracy of the QSERs. However, including separation factors from other CSPs increased the accuracies of the QSERs substantially. Hence, such combined models can support the experimental strategy in prioritizing the CSPs of the second screening phase, when a compound is not separated by the primary set of columns.


Hypothalamic-pituitary-adrenal axis tonus is associated with hippocampal microstructural asymmetry.
It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since there is growing evidence for hemispheric lateralization in brain systems regulating arousal and emotion. Here we tested the hypotheses that individual variations in basal morning and afternoon/evening cortisol levels would be associated with the degree of hemispheric asymmetry in hippocampal microstructure. Fifty healthy adults aged 19 to 86 years were included in the analyses. Diffusion-weighted imaging was acquired from all subjects. Hippocampal mean diffusivity (MD) and volume was extracted. Cortisol measures were based on 5 morning and 3 afternoon/evening saliva samples. Higher left relative to right hippocampus MD was associated with higher basal cortisol levels. Associations were anatomically specific and not attributable to hippocampal volume asymmetry. No correlation between hippocampal volume and MD was observed, suggesting that MD and volume index distinct biological properties of the hippocampus. Observed associations raise a number of possibilities, among them an asymmetric role of the hippocampus on HPA-axis regulation, or conversely, that individual variations in secreted cortisol, perhaps associated with stress, may have lateralized effects on hippocampal microstructure. Our results point to an important relationship between the limbic system and neuroendocrine function in terms of left-right asymmetries, raising additional questions about how the limbic system is related to neuroendocrine functions.


Elevated NAD(P) glycohydrolase activity: a possible enzymatic marker for malignancy in Burkitt's lymphoma cells.
A comparative analysis of enzymatic activities has been performed on 47 human continuous lymphoid lines: 22 tumors derived from Burkitt's lymphoma lines, 6 other lymphomatous long-term cultures, and 19 nonmalignant ties determined on the cell extracts. 4 showed no significant differences between the various lines. They included adenosine diphosphoribose incorporation, glucose-6-phosphate dehydrogenase, cyclic-AMP phosphodiesterase, and glutathione reductase. However, striking differences of activity were found for the enzyme, NAD(P) glycohydrolase (EC 18.104.22.168). Activity levels were, as a mean, four times higher in Burkitt's lymphoma-derived cell lines than in nonmalignant control lines, and the difference was highly significant (p less than 0.02). All Burkitt cell lines containing translocations of chromosome 8 with either chromosomes 2, 14 or 22 showed an increased activity. The specificity and significance of this possible enzymatic marker of Burkitt's lymphoma cells is discussed.


Apoptosis in temporomandibular joint disc with internal derangement involves mitochondrial-dependent pathways. An in vivo study.
Two main apoptosis pathways have been identified: an extrinsic (or death receptor-mediated) and an intrinsic (or mitochondrial) pathway. Apoptotic cell death through the extrinsic pathway has just been described in temporomandibular joint disc (TMJ) with internal derangement (ID); in contrast, no data are available on the involvement of the intrinsic pathway in this tissue. The aim of this work was to investigate whether the intrinsic pathway participates in apoptosis activation in patients with TMJ ID and anterior disc displacement without reduction. Apoptosis activation was studied in TMJ discs from 15 patients with ID and in six unaffected discs using bcl-2-associated X protein (bax), B-cell lymphoma 2 (bcl-2), cytochrome c and caspase 9 immunohistochemistry. A correlation was sought between immunohistochemical findings and degree of disc damage. None of the pathological TMJ disc sections were immunopositive for bcl-2; negative bcl-2 immunostaining was detected in affected discs; cytochrome c and caspase 9 immunoreactivity was greater in pathological compared to unaffected discs; the difference was significant and correlated with histopathological degeneration score data (Spearman's rho = 0.617). The present findings suggest that in-human TMJ with ID and anterior disc displacement without reduction of cell apoptosis occurs, at least partly, via the mitochondrial pathway, which contributes to the subsequent disc degeneration. These data may have clinical implications and could help devise improved treatment strategies.


Full-Endoscopic Procedures Versus Traditional Discectomy Surgery for Discectomy: A Systematic Review and Meta-analysis of Current Global Clinical Trials.
Traditional discectomy surgery (TDS) provides good or excellent results in clinical surgical discectomy but may induce neural adhesion, spinal structural damage, instability, and other complications. The potential advantages of full-endoscopic (FE) procedures over standard TDS include less blood loss, less postoperative pain, shorter hospitalization, and an earlier return to work. However, more evidence is needed to support this new technology in clinical applications. The aim of this systematic review and meta-analysis was to compare the safety and efficacy of FE and TDS. Comprehensive systematic review and meta-analysis of the literature. Electronic databases, including PubMed, EMBASE, SinoMed, and Cochrane Library, were searched to identify clinical therapeutic trials comparing FE to TDS for discectomy. Six trials comprising 730 patients were included, and the overall quality of the literature was moderate, including 4 Grade I levels of evidence (4 randomized controlled trials, [RCTs]) and 2 Grade II levels (2 non-RCTs). The pooled data revealed no difference in reoperation rates between FE and TDS (P = 0.94), but the complication rate was significantly lower in the FE group (3.86%) than in the TDS group (11.4%). Perioperative parameters (operation time, blood loss, hospitalization time, and return to work days) were significantly lower in the FE group (P < 0.05 for all groups using either score). Postoperative pain and neurology score assessments were conducted at 4 different time points at 3 months, 6 months, 12 months, and 24 months. Significant differences were detected in the following: lumbar North American Spine Society (NASS) pain at 6 months (P = 0.008); cervical NASS neurology at 6 months (P = 0.03); visual analog scale (VAS) score in leg at 3 months (P < 0.001); VAS score in arm at 24 months (P = 0.002); VAS score in neck at 3 months, 6 months, and 12 months after therapy (P = 0.003, P = 0.004, P = 0.01); and VAS score in neck at 3 months and 6 months (P = 0.01, P = 0.004). Moreover, the pooled data revealed no statistically significant differences in improvements in the Oswestry disability index (ODI), instability (X-ray), and Hilibrand criteria (P > 0.05 for all groups). Only 6 studies were included, 4 of which had the same authors. Between-study heterogeneity due to differences in socioeconomic factors, nutrition, and matching criteria is difficult to avoid. Based on this meta-analysis of 24 months of clinical results, we conclude that the FE procedure is as effective as TDS but has the additional benefits of lower complication rates and superior perioperative parameters. In addition, patients may experience less pain with FE techniques due to a smaller incision and less operative injury. However, large-volume, well-designed RCTs with extensive follow-up are needed to confirm and update the findings of this analysis.


Perforating granuloma annulare.
With more than 3 years' follow-up, dramatic clinical transfiguration of granuloma annulare was observed in a 59-year-old man with perforating granuloma annulare. The eruption was at first localized, then became generalized, developed perforations, and subsided in parallel with the improvement of associated diabetes mellitus. After reviewing 23 cases of perforating granuloma annulare from the literature, the authors divided the eruptions into two types according to their clinical features, naming one type papular perforating type (P-type) and the other ulcerative perforating type (U-type). U-type is strongly correlated with diabetes; patients with this type require detailed laboratory examination for the presence of diabetes mellitus.


Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice.
The aim of this study was to investigate the role of the cytosolic form of phosphoenolpyruvate carboxykinase (Pck1) in the development of insulin resistance. Previous studies have shown that the roles of Pck1 in white adipose tissue (WAT) in glyceroneogenesis and reesterification of free fatty acids (FFA) to generate triglyceride are vital for the prevention of diabetes. We hypothesized that insulin resistance develops when dysregulation of Pck1 occurs in the triglyceride/fatty acid cycle, which regulates lipid synthesis and transport between adipose tissue and the liver. We examined this by analyzing mice with a deletion of the PPARgamma binding site in the promoter of Pck1 (PPARE(-/-)). This mutation reduced the fasting Pck1 mRNA expression in WAT in brown adipose tissue (BAT). To analyze insulin resistance, we performed hyperinsulinemic-euglycemic glucose clamp analyses. PPARE(-/-) mice were profoundly insulin resistant and had more FFA and glycerol released during the hyperinsulinemic-euglycemic clamp compared with wild-type mice (WT). Finally, we analyzed insulin secretion in isolated islets. We found a 2-fold increase in insulin secretion in the PPARE(-/-) mice at 16.7 mM glucose. Thus, the PPARE site in the Pck1 promoter is essential for maintenance of lipid metabolism and glucose homeostasis and disease prevention.


What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review.
The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings.


Feasibility evaluation of a pilot scribe-training program in an Australian emergency department.
Objective Medical scribes have an emerging and expanding role in health, particularly in Emergency Medicine in the US. Scribes assist physicians with documentation and clerical tasks at the bedside while the physician consults with his or her patient. Scribes increase medical productivity. The aim of the present study was to examine the feasibility of a pilot hospital-administered scribe-training program in Australia and to evaluate the ability of an American training course (Medical Scribe Training Systems) to prepare trainee scribes for clinical training in an emergency department in Australia. Methods The present study was a pilot, prospective, observational cohort study from September 2015 to February 2016 at Cabrini Emergency Department, Melbourne. Scribe trainees were enrolled in the pre-work course and then trained clinically. Feasibility of training scribes and limited efficacy testing of the course was undertaken. Results The course was acceptable to users and demand for training exists. There were many implementation tasks and issues experienced and resources were required to prepare the site for scribe implementation. Ten trainees were enrolled for preclinical training. Six candidates undertook clinical training, five achieved competency (required seven to 16 clinical shifts after the preclinical course). The training course was helpful and provided a good introduction to the scribe role. The course required adaptation to a non-US setting and the specific hospital setting. In addition, it needed more detail in some common emergency department topics. Conclusion Training scribes at a hospital in Australia is feasible. The US training course used can assist with preclinical training. Course modification is required. What is known about the topic? Scribes increase emergency physician productivity in Australia. There is no previous work on how to train scribes in Australia. What does this paper add? We show that implementing a scribe-training program is feasible and that a training package can be purchased from the US to train scribes in Australia and that it is useful. We also show the adaptation that the course may require to meet Australian emergency department needs. What are the implications for practitioners? Scribes could become an additional member of the emergency department team in Australia and can be trained locally.


Proton electrochemical gradient: Driving and regulating neurotransmitter uptake.
Accumulation of neurotransmitters in the lumen of synaptic vesicles (SVs) relies on the activity of the vacuolar-type H+ -ATPase. This pump drives protons into the lumen, generating a proton electrochemical gradient (ΔμH+ ) across the membrane. Recent work has demonstrated that the balance between the chemical (ΔpH) and electrical (ΔΨ) components of ΔμH+ is regulated differently by some distinct vesicle types. As different neurotransmitter transporters use ΔpH and ΔΨ with different relative efficiencies, regulation of this gradient balance has the potential to influence neurotransmitter uptake. Nevertheless, the underlying mechanisms responsible for this regulation remain poorly understood. In this review, we provide an overview of current neurotransmitter uptake models, with a particular emphasis on the distinct roles of the electrical and chemical gradients and current hypotheses for regulatory mechanisms.


Patient-controlled sedation for colonoscopy: a randomized trial comparing patient-controlled administration of propofol and alfentanil with physician-administered midazolam and pethidine.
Patient-controlled sedation (PCS) using propofol and alfentanil provides effective sedation for colonoscopy, with the advantage of a shorter recovery time in comparison with diazepam and pethidine. However, most endoscopy units in the United Kingdom are currently using midazolam (a shorter-acting benzodiazepine) as a sedative agent. This study compares the efficacy of sedation and recovery times between PCS and a combination of midazolam and pethidine. Sixty-seven patients undergoing colonoscopy were randomly assigned prospectively to receive sedation with either PCS, using propofol and alfentanil, or a bolus of midazolam and pethidine. Sedation and pain scores were recorded during the procedure by one specialist nurse. Patients' recollection of pain was recorded after the procedure. Recovery was assessed using number connection tests. The impact on subsequent activities and the level of amnesia, as well as overall satisfaction, were established by telephone call after 24 h. The sedation method had no impact on the success, difficulty, or duration of the colonoscopy. PCS could be set up by the specialist nurse without affecting the time between cases. Patients in the PCS group recovered significantly faster (median 5 min vs 35 min; P < 0.0001) and left the department more quickly (median 40 min vs 75 min; P < 0.0001). Patients in the PCS group had significantly higher pain scores and significantly more recall than those in the midazolam and pethidine group. All patients were satisfied with the sedation they received. PCS provides an acceptable alternative to sedation with midazolam and pethidine with the advantage of significantly faster recovery times, which are of relevance in the outpatient setting.


Multivariable association discovery in population-scale meta-omics studies.
It is challenging to associate features such as human health outcomes, diet, environmental conditions, or other metadata to microbial community measurements, due in part to their quantitative properties. Microbiome multi-omics are typically noisy, sparse (zero-inflated), high-dimensional, extremely non-normal, and often in the form of count or compositional measurements. Here we introduce an optimized combination of novel and established methodology to assess multivariable association of microbial community features with complex metadata in population-scale observational studies. Our approach, MaAsLin 2 (Microbiome Multivariable Associations with Linear Models), uses generalized linear and mixed models to accommodate a wide variety of modern epidemiological studies, including cross-sectional and longitudinal designs, as well as a variety of data types (e.g., counts and relative abundances) with or without covariates and repeated measurements. To construct this method, we conducted a large-scale evaluation of a broad range of scenarios under which straightforward identification of meta-omics associations can be challenging. These simulation studies reveal that MaAsLin 2's linear model preserves statistical power in the presence of repeated measures and multiple covariates, while accounting for the nuances of meta-omics features and controlling false discovery. We also applied MaAsLin 2 to a microbial multi-omics dataset from the Integrative Human Microbiome (HMP2) project which, in addition to reproducing established results, revealed a unique, integrated landscape of inflammatory bowel diseases (IBD) across multiple time points and omics profiles.


Low median fluorescence intensity could be a nonsafety concept of immunologic risk evaluation in patients with shared molecular eplets in kidney transplantation.
Human leukocyte antigen (HLA) antibodies are usually "epitope" and not "antigen" specific. This work presents an interesting case concerning Luminex median fluorescence intensity (MFI) levels in antibodies considered low risk (<1,000), but producing humoral rejection. These low-titer antibodies could play an important role in transplantation. A 42-year-old woman was retransplanted with a deceased donor with negative complement-dependent cytotoxicity cross-matching. Our patient was pretransplant (PrT) sensitized to HLA antigens (single antigens (SA) = 31%) for 1 previous transplant. Thus, the formerly detected sensitized antigens were A32, A30, A31, cross-reacting group 5C, and DQ3 with a MFI(max) ≈ 4,127. In the posttransplantation period (PTP), the patient exhibited important instability in renal function and we detected an increased SA percentage (61%) with MFI(max) = 15,029 (A*32) with other antigens (detected with a low PrT MFI [<1,000]) as anti-A*03 (MFI(max) = 13,301) and anti-A*11 (MFI(max) = 13,714) specificities. Anti-A*03 was a donor-specific antibody (DSA). Renal biopsy was compatible with humoral rejection. The patient was pulsed with methylprednisolone, plasmapheresis, and intravenous immunoglobulin without improvement. Thus, we added anti-CD20 and the initial clinical response was highly favorable. Biopsies resulted in suggestive rejection reversion. MFI A*03 DSA decreased to 6,908 and later to MFI(max) = 5,505. After a 6-month PTP, the patient is well with MFI(max) = 3,124. It was possible to define exactly the potential immunizing epitope eplets whose recognition determined the specific antibody production. A*32:01, A*30:01, A*31:01 (detected PrT), A*11:01, and A*03:01 (detected PTP) alleles have several shared eplets (62QE, 70AQS, and 76VGT), with 62QE being the only eplet present on all alleles. In conclusion, low MFI levels in antibodies considered low risk could be important in posttransplant humoral rejection, although the patient's renal function can be restored. Thus, specific shared eplets should always be investigated with respect to previous transplant mismatches.


Metallacyclocumulenes: a theoretical perspective on the structure, bonding, and reactivity.
Conspectus Transition metals help to stabilize highly strained organic fragments. Metallacycles, especially unsaturated ones, provide much variety in this area. We had a sustained interest in understanding new C-C bond formation reactions affected by binuclear transition metal fragments Cp2M. One such study led to the exploration of the bimetallic C-C cleavage and coupled complexes, where the acetylide ligands bridge two metal atoms. The underlying M-C interaction in these complexes inspired the synthesis of a five-membered cyclocumulene complex, which opened a new phase in organometallic chemistry. The metallacyclocumulene produces a variety of C-C cleavage and coupled products including a radialene complex. Group 4 metallocenes have thus unlocked a fascinating chemistry by stabilizing strained unsaturated C4 organic fragments in the form of five-membered metallacyclocumulenes, metallacyclopentynes, and metallacycloallenes. Over the years, we have carried out a comprehensive theoretical study to understand the unusual stability and reactivity of these metallacycles. The unique (M-Cβ) interaction of the internal carbon atoms with the metal atom is the reason for unusual stability of the metallacycles. We have also shown that there is a definite dependence of the C-C coupling and cleavage reactions on the metal of metallacyclocumulenes. It demonstrates unexpected reaction pathways for these reactions. Based on this understanding, we have predicted and unraveled the stabilization factors of an unusual four-membered metallacycloallene complex. Indeed, our prediction about a four-membered heterometallacycle has led to an interesting bonding situation, which is experimentally realized. This type of M-C bonding is intriguing from a fundamental perspective and has great relevance in synthesizing unusual structures with interesting properties. In this Account, we first give a short prologue of what led to the present study and describe the salient features of the structure and bonding of the metallacyclocumulenes. The unusual reaction pathway of this metallacycle is explored next. Similar features of the metallacyclopentynes and metallacycloallenes are briefly mentioned. Then, we discuss the exploitation of the unique M-C bonding to design some exotic molecules such as a four-membered metallacycloallene complex. Our efforts to build a conceptual framework to understand these metallacycles and to exploit their chemistry continue.


Predicting the outcome of persistent sciatica using conditioned pain modulation: 1-year results from a prospective cohort study.
Background and aims Recovery in patients hospitalised with severe sciatica is unpredictable. Prognostic tools to aid clinicians in the early identification of patients at risk of developing chronic sciatic pain are warranted. Conditioned pain modulation (CPM) is a psychophysical measure of the endogenous pain modulatory pathways. Several studies have suggested CPM as a potentially important predictive biomarker for the development of chronic pain. The aim of the study was to determine whether CPM effect in patients still suffering from leg pain 6 weeks after hospital discharge for severe sciatica is associated with persistent leg pain at 12 months. A potential association would suggest that measuring CPM effect could be a valuable prognostic tool in the hospital management of sciatica. Methods A prospective cohort study in which CPM effect was measured 6 weeks after hospital discharge following an acute admission with sciatica as the main complaint. The impact of CPM effect on the outcome was analysed using logistic regression. The outcome measured was self-reported leg pain score of ≥1 in the past week on a 0-10 numeric rating scale (NRS) at 12 months post discharge. Results A total of 111 patients completed the entire study, 51 of whom received non-randomised surgical treatment. Crude and confounder adjusted analyses showed no significant association between CPM effect and leg-pain measured at 12 months, crude Odds Ratio 0.87, 95% CI 0.7-1.1, p = 0.23. Conclusions Our results suggest that CPM assessment has limited prognostic value for the long-term outcome in severe sciatica when measured 6 weeks after hospital discharge. Implications The present study adds important knowledge concerning the limited clinical use of late CPM testing in sciatica patients. The heterogeneity in patients, the wide range of treatments received and a generally favourable outcome are factors that may affect CPM's clinical value as a prognostic factor for severe sciatica.


Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts.
Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.


Physiology and interaction of nitrate and nitrite reduction in Staphylococcus carnosus.
Staphylococcus carnosus reduces nitrate to ammonia in two steps. (i) Nitrate was taken up and reduced to nitrite, and nitrite was subsequently excreted. (ii) After depletion of nitrate, the accumulated nitrite was imported and reduced to ammonia, which again accumulated in the medium. The localization, energy gain, and induction of the nitrate and nitrite reductases in S. carnosus were characterized. Nitrate reductase seems to be a membrane-bound enzyme involved in respiratory energy conservation, whereas nitrite reductase seems to be a cytosolic enzyme involved in NADH reoxidation. Syntheses of both enzymes are inhibited by oxygen and induced to greater or lesser degrees by nitrate or nitrite, respectively. In whole cells, nitrite reduction is inhibited by nitrate and also by high concentrations of nitrite (> or = 10 mM). Nitrite did not influence nitrate reduction. Two possible mechanisms for the inhibition of nitrite reduction by nitrate that are not mutually exclusive are discussed. (i) Competition for NADH nitrate reductase is expected to oxidize the bulk of the NADH because of its higher specific activity. (ii) The high rate of nitrate reduction could lead to an internal accumulation of nitrite, possibly the result of a less efficient nitrite reduction or export. So far, we have no evidence for the presence of other dissimilatory or assimilatory nitrate or nitrite reductases in S. carnosus.


Sense of coherence and physical health. A "Copenhagen interpretation" of Antonovsky's SOC concept.
According to Antonovsky's (Aaron Antonovsky, 1923-1994) sense of coherence (SOC) model, persons with a high SOC have the ability to benefit from their general defense mechanisms in order to overcome stressful situations. In a health-disease continuum, this leads to the development towards health. However, Antonovsky's global hypothesis that the strength of the SOC may influence the physical health status of a person could not be proven. Flensborg-Madsen et al. from Copenhagen were able to provide a new access regarding SOC and health. They investigated the mixture of emotional aspects and mental constructions as a possible cause for fairly low correlation between SOC and physical health. Thus, in an empirical way, they described "emotional coherence" in relation to physical health, while "mental coherence" was linked to psychological health. These authors introduced the idea of applying a shortened version of the original 29-item SOC questionnaire, but have not yet developed or tested the shortened questionnaire. Backed by their important findings, it appears to be promising to consider the use of the SOC questionnaire as standardized by Antonovsky, but cleared of the items regarding "predictability", i.e., Flensborg-Madsen et al. suggested that the items on "predictability" be excluded from the SOC scale when a correlation to physical health is to be investigated. Further investigations in this area of research will be of high impact, not only for health sciences, but also for medical practice.


Exercise levels and preferences on exercise counselling and programming among older cancer survivors: A mixed-methods study.
To assess exercise levels and exercise counselling /programming preferences among older cancer survivors. A mixed-methods study design was employed. Quantitative instruments on exercise levels, exercise counselling and programming preferences, frailty status, and cancer-related symptoms were administered to 290 post-treatment older cancer survivors aged ≥65. Twelve participants with different exercise levels and different views on exercise counselling and programming were purposively selected to participate in semi-structured interviews. Overall, 58.3% of participants did not meet the recommended exercise guidelines, and 44.1% were not engaging in any vigorous or moderate exercise. Frail survivors were less likely to meet the guidelines (aOR = 0.194, 95%CI = 0.053, 0.712) compared to their robust counterparts. However, 66.9% and 62.8% of participants expressed a definite or possible interest in receiving exercise counselling and participating in an exercise program, respectively. Particularly, survivors who are male, did not receive chemotherapy, are less educated, and have higher symptom burden were less likely to show interest. Most preferred low-intensity exercise (59.8%) and wanted to start the exercise program after treatment (68.2%), which differs from the literature on general adult survivors. The major trigger to initiate and maintain exercise behaviors was the benefits of exercise and a common barrier to exercising was lack of time. Most older cancer survivors did not meet the recommended exercise guidelines, but they were open to exercise counselling and programming. Reviewing education on the benefits of exercise is especially important after treatment completion to promote healthy lifestyles.


Microstructural analysis of Au/TiO2-SBA-15 nanocomposite.
Properties of gold nanoparticles (AuNPs) are very different from bulk gold, in particular, highly dispersed AuNPs exhibit high catalytic activities on metal oxide supports. Catalytic activities of AuNPs are strongly dependent on: (i) size and morphology; (ii) synthesis methods; (iii) nature of the support; (iv) interaction between AuNPs and the support; and (v) oxidation state of AuNPs in the synthesized catalysts. A goal is to maintain the size and to prohibit aggregation of AuNPs, since aggregations deteriorate catalytic activities. Some strong interactions are therefore required between AuNPs and their supports to prevent the movement of AuNPs. SBA-15 is a promising material for the support of AuNPs since it has ordered two-dimensional hexagonal pore channels, uniform pore size ranging from 5 to 30 nm, narrow pore size distribution, thick amorphous walls ranging from 3 to 6 nm, and high surface area. In this study, SBA-15, TiO2-SBA-15 and TiO2-SBA-15-AuNP nanocomposites were synthesized by the sol-gel method and microstructural characterizations were carried out by both X-ray diffraction analysis and electron microscopy.


A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab.
First-line chemotherapy regimens that include bevacizumab (Bev) have been hypothesized to improve outcomes in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC). Although approved to treat NSCLC in 2009, insufficient data exist on the clinical uses of Bev in Japan. The present study prospectively evaluated the efficacy and safety of Bev-containing combination chemotherapy. Eligible patients exhibited histologically or cytologically documented advanced or recurrent non-sq NSCLC. Patients were administered 15 mg/kg Bev with standard chemotherapy followed by maintenance Bev. The primary endpoints were progression-free survival (PFS) and safety. A total of 102 patients with non-sq NSCLC were enrolled, 44.1% of whose tumor carried epidermal growth factor receptor (EGFR) mutations. The overall response rate to the intervention was 44.1%, and the median PFS was 8.3 months [95% confidence interval (CI)=6.4-10.2 months]. The median overall survival was 26.3 months (95% CI=22.2-30.4 months). The incidence of Bev-associated severe adverse events was similar to those in previous trials, excluding a grade 3-4 hypertension rate of 30.4% in the present study. Multivariate analysis revealed that a higher TNM classification of malignant tumor staging-T factor, adjusted hazard ratio (HR)=1.33 (95% CI=1.10-1.61), and poor performance status [adjusted HR=1.63 (1.02-2.60)] were associated with significantly shorter PFS, whilst the EGFR exon 19 deletion was significantly associated with prolonged PFS [adjusted HR=0.47 (0.25-0.87)]. Bev-containing chemotherapy was safe and effective for patients with non-sq NSCLC in clinical settings in Japan. The EGFR exon 19 deletion was suggested as a positive predictive factor for the efficacy of Bev-containing chemotherapy.


[Trigeminal evoked potentials in migraine].
Trigeminal evoked potentials (TEP) were studied in 19 patients with migraine without aura. Significant shortening of latent periods of early and late TEP components was observed during stimulation on the side of headache as compared with the same indices during stimulation on nonalgesic side. Hyperreactivity of trigeminal vascular system in patients with migraine without aura during the period between the attacks is discussed. Asymmetry of laten TEP periods may determine the preferential side of headache, on the one hand, and may reflect the changes in trigeminal system following the repeated lateralized fits of migraine, on the other hand. Administration of 1 g of aspirin resulted in increase (normalization) of the latentions of TEP components. After efferalgan administration TEP changes were not registered. The suggestion is made that inhibitory influence of aspirin on the truncal trigeminal system is one of the central mechanisms of its action.


Effect of SARS-CoV-2 seropositivity on antigen - specific cytokine and chemokine responses in latent tuberculosis.
SARS-CoV-2 and latent Mycobacterium tuberculosis infection are both highly co-prevalent in many parts of the globe. Whether exposure to SARS-CoV-2 influences the antigen specific immune responses in latent tuberculosis has not been investigated. We examined the baseline, mycobacterial antigen and mitogen induced cytokine and chemokine responses in latent tuberculosis (LTBI) individuals with or without SARS-CoV-2 seropositivity, LTBI negative individuals with SARS-CoV-2 seropositivity and healthy control (both LTBI and SARS-CoV-2 negative) individuals. Our results demonstrated that LTBI individuals with SARS-CoV-2 seropositivity (LTBI+/IgG +) were associated with increased levels of unstimulated and TB-antigen stimulated IFNγ, IL-2, TNFα, IL-17, IL-1β, IL-6, IL-12, IL-4, CXCL1, CXCL9 and CXCL10 when compared to those without seropositivity (LTBI+/IgG-). In contrast, LTBI+/IgG+ individuals were associated with decreased levels of IL-5 and IL-10. No significant difference in the levels of cytokines/chemokines was observed upon mitogen stimulation between the groups. SARS-CoV-2 seropositivity was associated with enhanced unstimulated and TB-antigen stimulated but not mitogen stimulated production of cytokines and chemokines in LTBI+ compared to LTBI negative individuals. Finally, most of these significant differences were not observed when LTBI negative individuals with SARS-CoV-2 seropositivity and controls were examined. Our data clearly demonstrate that both baseline and TB - antigen induced cytokine responses are augmented in the presence of SARS-CoV-2 seropositivity, suggesting an augmenting effect of prior SARS-CoV-2 infection on the immune responses of LTBI individuals.


[Congenital dilatation of extrahepatic bile ducts].
The authors present 3 cases of congenital dilatation of extrahepatic bile ducts and performed a review of the bibliography of this frequent pathology. They concluded that the diagnosis could be difficult in the pre-operatory and the cholangeographic methods are the beds. The treatment of choice in the actuality is the ++quistectomy with hepaticojejunostomy in "Y of Roux".


Myasthenia gravis.
Myasthenia gravis (MG) is a rare, autoimmune neuromuscular junction disorder. Contemporary prevalence rates approach 1/5,000. MG presents with painless, fluctuating, fatigable weakness involving specific muscle groups. Ocular weakness with asymmetric ptosis and binocular diplopia is the most typical initial presentation, while early or isolated oropharyngeal or limb weakness is less common. The course is variable, and most patients with initial ocular weakness develop bulbar or limb weakness within three years of initial symptom onset. MG results from antibody-mediated, T cell-dependent immunologic attack on the endplate region of the postsynaptic membrane. In patients with fatigable muscle weakness, the diagnosis of MG is supported by: 1. pharmacologic testing with edrophonium chloride that elicits unequivocal improvement in strength; 2. electrophysiologic testing with repetitive nerve stimulation (RNS) studies and/or single-fiber electromyography (SFEMG) that demonstrates a primary postsynaptic neuromuscular junctional disorder; and 3. serologic demonstration of acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) antibodies. Differential diagnosis includes congenital myasthenic syndromes, Lambert Eaton syndrome, botulism, organophosphate intoxication, mitochondrial disorders involving progressive external ophthalmoplegia, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), motor neuron disease, and brainstem ischemia. Treatment must be individualized, and may include symptomatic treatment with cholinesterase inhibitors and immune modulation with corticosteroids, azathioprine, cyclosporine, and mycophenolate mofetil. Rapid, temporary improvement may be achieved for myasthenic crises and exacerbations with plasma exchange (PEX) or intravenous immunoglobulin (IVIg). Owing to improved diagnostic testing, immunotherapy, and intensive care, the contemporary prognosis is favorable with less than five percent mortality and nearly normal life expectancy.


Tocotrienols Attenuate White Adipose Tissue Accumulation and Improve Serum Cholesterol Concentration in High-Fat Diet-Treated Mice.
Tocotrienols (T3s), which are vitamin E homologs, have not only antioxidant function but also inhibitory effects on body weight gain and hepatic lipid droplet accumulation. However, the mechanisms of the anti-obesity effects of T3s are not yet understood. In this study, C57BL/6 mice were fed a high-fat diet in the presence or absence of T3s. Treatment with T3s inhibited white adipose tissue accumulation and elevation of serum cholesterol concentrations. Additionally, to clarify the relationship between obesity-induced cognitive dysfunction and the neuroprotective effect of T3s, cognitive function, brain oxidation, and protein expression levels of brain-derived neurotrophic factor (BDNF), which is strongly involved in neuronal growth and differentiation, were measured. Although mice behaviors were improved by oral T3 intake, there were no significant differences in brain oxidation levels and BDNF expression. These results suggest that T3s attenuate obesity via inhibition of body fat and serum cholesterol increase.


Facilitation of visual perception in head direction: visual attention modulation based on head direction.
People usually see things using frontal viewing, and avoid lateral viewing (or eccentric gaze) where the directions of the head and eyes are largely different. Lateral viewing interferes with attentive visual search performance, probably because the head is directed away from the target and/or because the head and eyes are misaligned. In this study, we examined which of these factors is the primary one for interference by conducting a visual identification experiment where a target was presented in the peripheral visual field. The critical manipulation was the participants' head direction and fixation position: the head was directed to the fixation location, the target position, or the opposite side of the fixation. The performance was highest when the head was directed to the target position even when there was misalignment of the head and eye, suggesting that visual perception can be influenced by both head direction and fixation position.


[Blood antigens in the AB0 system and susceptibility of humans to diphtheria].
The analysis of a large number of diphtheria cases (1326) at the peak of diphtheria morbidity in Russia (1993-1994) revealed that the intensity of antidiphtheria antitoxic immunity was age-dependent with a sharp immunodeficiency in the population aged 35 years and older. As adaptive capacity of the organism decreases, the positive associative links between immunity to diphtheria and the AB0 blood groups become evident. Populations with phenotype B (III) had the largest diphtheria immune stratum at the age of 35 years and over as compared to 3 other phenotypes. The genotypic analysis of serological data may be of practical importance for the detection of the degree of predisposition of humans to infectious diseases.


Circulating Th22 cells, as well as Th17 cells, are elevated in patients with renal cell carcinoma.
T-helper (Th) 22 cells serve an essential role in different types of tumors and autoimmune diseases. No research has been conducted to study the role of Th22 cells in the pathogenesis of renal cell carcinoma (RCC). We aimed to evaluate the prognostic value of circulating Th22, Th17, and Th1 cells in RCC patients. Thirty-two newly diagnosed RCC patients and thirty healthy controls were enlisted in the research. Their peripheral blood was collected, and the frequencies of circulating Th22, Th17, and Th1 cells were detected by flow cytometry. Plasma IL-22 concentrations were examined by an enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to identify the mRNA expression levels of aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) in peripheral blood mononuclear cells (PBMC). Compared with the healthy control group, the frequency of circulating Th22 and Th17 cells and concentrations of plasma IL-22 were significantly increased in RCC patients. However, there was no significant difference in the frequency of Th1 cells. A positive correlation between Th22 cells and plasma IL-22 levels was found in RCC patients. Also, there was a significant positive correlation between Th22 and Th17 cells in RCC patients. An up-regulated expression of AHR and RORC transcription factors were also observed in RCC patients. As tumor stage and grade progressed, the frequencies of Th22 and Th17 cells and the level of plasma IL-22 significantly increased. Meanwhile, there was a positive correlation between Th22 and Th17 cells and RCC tumor stage or grade. Furthermore, patients with high Th22 or Th17 cells frequency displayed a decreased trend in survival rate. Our research indicated that the increased circulating Th22 and Th17 cells and plasma IL-22 may be involved in the pathogenesis of RCC and may be involved in the occurrence and development of tumors. Th22 cells, plasma IL-22, and Th17 cells may be promising new clinical biomarkers and may be used as cellular targets for RCC therapeutic intervention.


Fault Detection and Diagnosis in Multi-Robot Systems: A Survey.
The use of robots has increased significantly in the recent years; rapidly expending to numerous applications. These sophisticated machines are susceptible to different types of faults that might endanger the robot or its surroundings. These faults must be detected and diagnosed in time to allow continual operation. The field of Fault Detection and Diagnosis (FDD) has been studied for many years. This research has given birth to many approaches that are applicable to different types of physical machines. However, the domain of robotics poses unique requirements that challenge traditional FDD approaches. The study of FDD for robotics is relatively new; only few surveys were presented. These surveys have focused on the single robot scenario. To the best of our knowledge, there is no survey that focuses on FDD for Multi-Robot Systems (MRS). In this paper we set out to fill this gap. This paper provides detailed insights to the world of FDD for MRS. We first describe how different attributes of MRS pose different challenges for FDD. With respect to these challenges, we survey different FDD approaches applicable for MRS. We conclude with a description of research opportunities in this field. With these contributions it is the authors' intention to provide detailed insights to the world of FDD for MRS.


Stimulation of thymocyte proliferation by phosphorothioate DNA oligonucleotides.
DNA is a complex macromolecule the immunological properties of which depend on short sequence motifs called CpG motifs or immunostimulatory sequences (ISS). These sequences are mitogenic for B cells and can stimulate macrophage cytokine production. While these sequences do not directly activate T cells, they can augment effects of stimulation via the TCR. Furthermore, ISS can affect T cells because of macrophage production of IL-12 and IFN-alpha/beta. In these studies, we further evaluated the immune effects of DNA on T cells, testing the possibility that certain T cell populations can respond directly to this stimulus. We therefore tested the in vitro responses of thymocytes to a series of phosphodiester (Po) and phosphorothioate (Ps) oligonucleotides (ODNs) varying in sequence. In in vitro cultures, phosphorothioate ODNs (sODNs) containing CpG motifs induced significant proliferation of murine thymocytes, although phosphodiester compounds lacked activity. The magnitude of stimulation varied with sequences flanking the CpG motifs, as both dA and dT sequences enhanced the stimulatory capacity of the CpG motif. Furthermore, CpG sODNs were strong costimulators of anti-CD3-mediated thymocyte activation, increasing proliferation compared to anti-CD3 in the absence of DNA. This activation was only partially inhibited by cyclosporine A and was not dependent on a calcium influx. Together, these results indicate that phosphorothioate oligonucleotides containing CpG motifs can directly induce thymocyte proliferation as well as augment TCR activation. These observations thus extend the range of actions of CpG DNA and suggest additional mechanisms for its function as an immunomodulatory agent or adjuvant.


Girl's and women's experiences of seeking mental health support for symptoms associated with psychosis. A narrative review.
Women are more likely than men to experience symptoms associated with psychosis, such as voice hearing, and more likely to seek mental health support. However, little is known about the emotional experiences of girls and young women who seek help for symptoms of psychosis to inform gender sensitive services and access routes. The current review offers the first focused insights into barriers and facilitators relating to help seeking for girls and women experiencing symptoms of psychosis. OneSearch, PubMed, and PsychINFO databases were searched for suitable papers in relation to the research question between November 2021 and February 2022; 139 papers were found, of which eight met the inclusion criteria for review. Across the eight papers reviewed, participants were aged 15- to 71-years-old. From the participant numbers available, data from a total of 54,907 participants from a range of demographic groups were included in the review. Results and findings sections from the eight papers were reviewed for themes, and four overarching themes emerged: (1) The emotional cost of seeking help, (2) voice hearing for girls and women, (3) side effects of treatment, and (4) facilitators to accessing support. Engagement in talking therapies can be difficult when services minimize the experience of psychosis-related symptoms. Women may be more likely to have their symptom-related distress diagnosed as a mood disorder, rather than symptoms of psychosis being identified, preventing timely tailored intervention. Normalization, psychoeducation, social support, and validation were recommended as helpful interventions.


Sex and relationship dysfunction in neurological disability.
(1) to ascertain how many people with neurological disability experience sexual or relationship problems; (2) to examine the interplay of neurological disability and sexual function within the context of the dyadic relationship; (3) to consider the implications of the results for service provision. A survey of outpatients attending Hunters Moor Regional Rehabilitation Centre, Newcastle upon Tyne over a 6 month period. Standardised measures of sexual function and concern, relationship satisfaction, disability, and mental health were used. Seventy people were interviewed (18% of the potential study population). Prevalence figures therefore refer to this self selected sample. Fifty one per cent had experienced a change in sexual function and 27% were concerned about this change. Of those in cohabiting relationships 25% were experiencing difficulties. Gender was significantly associated with concern about sexual function, men being more concerned. A high score on the marital adjustment scale indicating relationship dissatisfaction was the best predictor of change in and concern about sexual function. Change in sexual function and duration of illness were the most powerful predictors of relationship dissatisfaction. If concern is taken as an indication of a desire for help more than one in four of this sample required help for sexual dysfunction. Sexual and relationship functioning were very closely associated and dysfunction in either of these areas was the best predictor of dysfunction in the other area. The dyadic relationship is an important institution in the management of disability. Sexual dysfunction can be predictive of difficulties within a relationship. Any service designed to address sexual health should also address relationship issues.


Applying an Open-Source Segmentation Algorithm to Different OCT Devices in Multiple Sclerosis Patients and Healthy Controls: Implications for Clinical Trials.
Background. The lack of segmentation algorithms operative across optical coherence tomography (OCT) platforms hinders utility of retinal layer measures in MS trials. Objective. To determine cross-sectional and longitudinal agreement of retinal layer thicknesses derived from an open-source, fully-automated, segmentation algorithm, applied to two spectral-domain OCT devices. Methods. Cirrus HD-OCT and Spectralis OCT macular scans from 68 MS patients and 22 healthy controls were segmented. A longitudinal cohort comprising 51 subjects (mean follow-up: 1.4 ± 0.9 years) was also examined. Bland-Altman analyses and interscanner agreement indices were utilized to assess agreement between scanners. Results. Low mean differences (-2.16 to 0.26 μm) and narrow limits of agreement (LOA) were noted for ganglion cell and inner and outer nuclear layer thicknesses cross-sectionally. Longitudinally we found low mean differences (-0.195 to 0.21 μm) for changes in all layers, with wider LOA. Comparisons of rate of change in layer thicknesses over time revealed consistent results between the platforms. Conclusions. Retinal thickness measures for the majority of the retinal layers agree well cross-sectionally and longitudinally between the two scanners at the cohort level, with greater variability at the individual level. This open-source segmentation algorithm enables combining data from different OCT platforms, broadening utilization of OCT as an outcome measure in MS trials.


Dynamic Contrast-Enhanced Magnetic Resonance Imaging Suggests Normal Perfusion in Normal-Appearing White Matter in Multiple Sclerosis.
Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and has been associated with reduced perfusion in normal-appearing white matter (NAWM). The magnitude of this hypoperfusion is unclear. The present study aims to quantify NAWM perfusion with dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in patients with relapsing-remitting (RR) MS and in a control group. The statistical power of a DCE-MRI acquisition to reveal hypoperfusion in MS was estimated using a Monte Carlo simulation: synthetic tissue curves with a contrast-to-noise ratio of 8 were generated for MS patients and control group using perfusion values reported in previous studies. A compartment-uptake model was fitted to these curves, yielding estimates of cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability-surface area product (PS). This was repeated 1000 times. Mean and standard deviation of the resulting distributions were used to calculate the statistical power of a DCE-MRI study to detect perfusion differences between 16 control subjects and 24 MS subjects.In an institutional review board-approved study, patients with RR-MS (n = 24; mean age, 36 years; 17 women, mean Enhanced Disability Status Scale score, 3.25) and patients without history or symptoms of neurological disorder (n = 16; mean age, 49 years; 9 women) underwent a DCE-MRI examination with a previously established MRI protocol (3D SPGR sequence; 2.1 seconds temporal resolution; 44 slices; spatial resolution, 1.7 × 1.7 × 3 mm). Regions were defined manually in the middle cerebral artery; in the frontal, periventricular, and occipital NAWM; in the pons; and in the thalamus, and CBF, CBV, and PS were quantified using a compartment-uptake model.Parameter differences between MS and control groups were evaluated using a mixed linear model with subjects as random effect and controlling for age and sex. A P value of less than 0.05 was considered to indicate statistical significance. For all but one of previously reported effect sizes, the simulation study estimated a statistical power of 80% to 100% to detect reduced CBF in MS. In the patient study, mean (standard deviation) CBF in NAWM was 11.0 (15.1) and 10.4 (8.2) mL/100 mL per minute in the MS and control groups, respectively. Mean CBV in NAWM was 0.50 (0.45) mL/100 mL in the MS group and 0.48 (0.28) mL/100 mL in the control group. Mean values of PS in NAWM were 0.002 mL (0.027)/100 mL per minute in the control group and -0.001 (0.015) mL/100 mL per minute in the MS patients. Differences between patient groups were not statistically significant for CBF, CBV, mean transit time, and PS (P = 0.44, P = 0.20, P = 0.78, P = 0.66, respectively). In both groups, the influence of age on any parameter was nonsignificant. Cerebral blood flow and CBV in the thalamus and pons were significantly higher than in NAWM regions (P < 1e-4); mean transit time was significantly shorter than in NAWM (P < 1e-4). Permeability-surface area product was not significantly different from zero (P > 0.25) in all evaluated regions. Despite high statistical power, we could not confirm previous reports of NAWM hypoperfusion in MS. This indicates that, at least in our patient cohort, potential hypoperfusion is much less pronounced than reported in previous studies.


Impact of transgenerational host switch on gut bacterial assemblage in generalist pest, Spodoptera littoralis (Lepidoptera: Noctuidae).
Diet composition is vital in shaping gut microbial assemblage in many insects. Minimal knowledge is available about the influence of transgenerational diet transition on gut microbial community structure and function in polyphagous pests. This study investigated transgenerational diet-induced changes in Spodoptera littoralis larval gut bacteriome using 16S ribosomal sequencing. Our data revealed that 88% of bacterial populations in the S. littoralis larval gut comprise Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. The first diet transition experiment from an artificial diet (F0) to a plant diet (F1), cabbage and cotton, caused an alteration of bacterial communities in the S. littoralis larval gut. The second transgenerational diet switch, where F1 larvae feed on the same plant in the F2 generation, displayed a significant variation suggesting further restructuring of the microbial communities in the Spodoptera larval gut. F1 larvae were also challenged with the plant diet transition at the F2 generation (cabbage to cotton or cotton to cabbage). After feeding on different plant diets, the microbial assemblage of F2 larvae pointed to considerable differences from other F2 larvae that continued on the same diet. Our results showed that S. littoralis larval gut bacteriome responds rapidly and inexplicably to different diet changes. Further experiments must be conducted to determine the developmental and ecological consequences of such changes. Nevertheless, this study improves our perception of the impact of transgenerational diet switches on the resident gut bacteriome in S. littoralis larvae and could facilitate future research to understand the importance of symbiosis in lepidopteran generalists better.


Redox properties of structural Fe in clay minerals. 1. Electrochemical quantification of electron-donating and -accepting capacities of smectites.
Clay minerals often contain redox-active structural iron that participates in electron transfer reactions with environmental pollutants, bacteria, and biological nutrients. Measuring the redox properties of structural Fe in clay minerals using electrochemical approaches, however, has proven to be difficult due to a lack of reactivity between clay minerals and electrodes. Here, we overcome this limitation by using one-electron-transfer mediating compounds to facilitate electron transfer between structural Fe in clay minerals and a vitreous carbon working electrode in an electrochemical cell. Using this approach, the electron-accepting and -donating capacities (Q(EAC) and Q(EDC)) were quantified at applied potentials (E(H)) of -0.60 V and +0.61 V (vs SHE), respectively, for four natural Fe-bearing smectites (i.e., SWa-1, SWy-2, NAu-1, and NAu-2) having different total Fe contents (Fe(total) = 2.3 to 21.2 wt % Fe) and varied initial Fe(2+)/Fe(total) states. For every SWa-1 and SWy-2 sample, all the structural Fe was redox-active over the tested E(H) range, demonstrating reliable quantification of Fe content and redox state. Yet for NAu-1 and NAu-2, a significant fraction of the structural Fe was redox-inactive, which was attributed to Fe-rich smectites requiring more extreme E(H)-values to achieve complete Fe reduction and/or oxidation. The Q(EAC) and Q(EDC) values provided here can be used as benchmarks in future studies examining the extent of reduction and oxidation of Fe-bearing smectites.


Efficacy of continuous renal replacement therapy in the treatment of severe acute pancreatitis associated acute respiratory distress syndrome.
To investigate the efficacy of the treatment of severe acute pancreatitis (SAP) complicated by acute respiratory distress syndrome (ARDS) using continuous renal replacement therapy (CRRT) by evaluating the effect of CRRT on respiratory and circulatory function as well as serum cytokines level. Fifty four randomly selected patients with confirmed SAP complicated by ARDS after being admitted to intensive care unit (ICU) within 72 hr of onset were included in the study. Patients received mechanical respiratory support and CRRT. Arterial blood gas analysis was conducted and serum cytokine levels, including tumor necrosis factor alpha (TNF-α), interleukin 4 (IL-4) and interleukin 6 (IL-6), as well as C reactive protein (CRP) were evaluated respectively both before and 6h, 12h, and 24h after CRRT therapy. Peak inspiratory pressure and pulmonary compliance were also recorded. Arterial oxygen tension (PaO2), oxygenation index (OI) as well as dynamic pulmonary compliance were all elevated significantly, whereas peak inspiratory pressure significantly decreased at 6h, 12h and 24h after CRRT respectively; serum cytokine level and CRP significantly decreased (p < 0.05). CRRT can effectively reduce the level of inflammatory mediators, and improve respiratory and circulatory function.


In the Beginning was the Genome: Genomics and the Bi-textuality of Human Existence.
This paper addresses the cultural impact of genomics and the Human Genome Project (HGP) on human self-understanding. Notably, it addresses the claim made by Francis Collins (director of the HGP) that the genome is the language of God and the claim made by Max Delbrück (founding father of molecular life sciences research) that Aristotle must be credited with having predicted DNA as the soul that organises bio-matter. From a continental philosophical perspective I will argue that human existence results from a dialectical interaction between two types of texts: the language of molecular biology and the language of civilisation; the language of the genome and the language of our socio-cultural, symbolic ambiance. Whereas the former ultimately builds on the alphabets of genes and nucleotides, the latter is informed by primordial texts such as the Bible and the Quran. In applied bioethics deliberations on genomics, science is easily framed as liberating and progressive, religious world-views as conservative and restrictive (Zwart 1993). This paper focusses on the broader cultural ambiance of the debate to discern how the bi-textuality of human existence is currently undergoing a transition, as not only the physiological, but also the normative dimension is being reframed in biomolecular and terabyte terms.


Prediction of perinatal depression from adolescence and before conception (VIHCS): 20-year prospective cohort study.
Perinatal depression is a neglected global health priority, affecting 10-15% of women in high-income countries and a greater proportion in low-income countries. Outcomes for children include cognitive, behavioural, and emotional difficulties and, in low-income settings, perinatal depression is associated with stunting and physical illness. In the Victorian Intergenerational Health Cohort Study (VIHCS), we aimed to assess the extent to which women with perinatal depressive symptoms had a history of mental health problems before conception. VIHCS is a follow-up study of participants in the Victorian Adolescent Health Cohort Study (VAHCS), which was initiated in August, 1992, in the state of Victoria, Australia. In VAHCS, participants were assessed for health outcomes at nine timepoints (waves) from age 14 years to age 29 years. Depressive symptoms were measured with the Revised Clinical Interview Schedule and the General Health Questionnaire. Enrolment to VIHCS began in September, 2006, during the ninth wave of VAHCS; depressive symptoms at this timepoint were measured with the Composite International Diagnostic Interview. We contacted women every 6 months (from age 29 years to age 35 years) to identify any pregnancies. We assessed perinatal depressive symptoms with the Edinburgh Postnatal Depression Scale (EPDS) by computer-assisted telephone interview at 32 weeks of gestation, 8 weeks after birth, and 12 months after birth. We defined perinatal depression as an EPDS score of 10 or more. From a stratified random sample of 1000 female participants in VAHCS, we enrolled 384 women with 564 pregnancies. 253 (66%) of these women had a previous history of mental health problems at some point in adolescence or young adulthood. 117 women with a history of mental health problems in both adolescence and young adulthood had 168 pregnancies, and perinatal depressive symptoms were reported for 57 (34%) of these pregnancies, compared with 16 (8%) of 201 pregnancies in 131 women with no preconception history of mental health problems (adjusted odds ratio 8·36, 95% CI 3·34-20·87). Perinatal depressive symptoms were reported at one or more assessment points in 109 pregnancies; a preconception history of mental health problems was reported in 93 (85%) of these pregnancies. Perinatal depressive symptoms are mostly preceded by mental health problems that begin before pregnancy, in adolescence or young adulthood. Women with a history of persisting common mental disorders before pregnancy are an identifiable high-risk group, deserving of clinical support throughout the childbearing years. Furthermore, the window for considering preventive intervention for perinatal depression should extend to the time before conception. National Health and Medical Research Council (Australia), Victorian Health Promotion Foundation, Colonial Foundation, Australian Rotary Health Research and Perpetual Trustees.


Self-mutilation and suicide attempts: relationships to bipolar disorder, borderline personality disorder, temperament and character.
Self-mutilation has traditionally been associated with borderline personality disorder, and seldom examined separately from suicide attempts. Clinical experience suggests that self-mutilation is common in bipolar disorder. A family study was conducted on the molecular genetics of depression and personality, in which the proband had been treated for depression. All probands and parents or siblings were interviewed with a structured interview and completed the Temperament and Character Inventory. Fourteen per cent of subjects interviewed reported a history of self-mutilation, mostly by wrist cutting. Self-mutilation was more common in bipolar I disorder subjects then in any other diagnostic groups. In multiple logistic regression self-mutilation was predicted by mood disorder diagnosis and harm avoidance, but not by borderline personality disorder. Furthermore, the relatives of non-bipolar depressed probands with self-mutilation had higher rates of bipolar I or II disorder and higher rates of self-mutilation. Sixteen per cent of subjects reported suicide attempts and these were most common in those with bipolar I disorder and in those with borderline personality disorder. On multiple logistic regression, however, only mood disorder diagnosis and harm avoidance predicted suicide attempts. Suicide attempts, unlike self-mutilation, were not familial. Self-mutilation and suicide attempts are only partially overlapping behaviours, although both are predicted by mood disorder diagnosis and harm avoidance. Self-mutilation has a particularly strong association with bipolar disorder. Clinicians need to think of bipolar disorder, not borderline personality disorder, when assessing an individual who has a history of self-mutilation.


The effects of augmented visual feedback during balance training in Parkinson's disease: study design of a randomized clinical trial.
Patients with Parkinson's disease often suffer from reduced mobility due to impaired postural control. Balance exercises form an integral part of rehabilitative therapy but the effectiveness of existing interventions is limited. Recent technological advances allow for providing enhanced visual feedback in the context of computer games, which provide an attractive alternative to conventional therapy. The objective of this randomized clinical trial is to investigate whether a training program capitalizing on virtual-reality-based visual feedback is more effective than an equally-dosed conventional training in improving standing balance performance in patients with Parkinson's disease. Patients with idiopathic Parkinson's disease will participate in a five-week balance training program comprising ten treatment sessions of 60 minutes each. Participants will be randomly allocated to (1) an experimental group that will receive balance training using augmented visual feedback, or (2) a control group that will receive balance training in accordance with current physical therapy guidelines for Parkinson's disease patients. Training sessions consist of task-specific exercises that are organized as a series of workstations. Assessments will take place before training, at six weeks, and at twelve weeks follow-up. The functional reach test will serve as the primary outcome measure supplemented by comprehensive assessments of functional balance, posturography, and electroencephalography. We hypothesize that balance training based on visual feedback will show greater improvements on standing balance performance than conventional balance training. In addition, we expect that learning new control strategies will be visible in the co-registered posturographic recordings but also through changes in functional connectivity.


Clinical comparision of intravesical hyaluronic acid and hyaluronic acid-chondroitin sulphate therapy for patients with bladder pain syndrome/interstitital cystitis.
Patients with a history of bladder pain syndrome/interstitial cystitis (BPS/IC) and who responded poorly or unsatisfactorily with previous treatment were compared taking intravesical hyaluronic acid (HA) or hyaluronic acid-chondroitin sulphate (HA-CS). Patients were treated with intravesical instillation with 50 mL sterile sodium hyalurinic acid (Hyacyst, Syner-Med, Surrey, UK) (n = 32) and sodium hyaluronate 1.6% sodium chondroitin sulphate 2% (Ialuril, Aspire Pharma, UK) (n = 33). Intravesical instillations were performed weekly in first month, every 15 days in the second month and monthly in third and fourth months, for a total of 8 doses. Patients were evaluated using a visual analog pain scale (VAS), interstitial cystitis symptom index (ICSI), interstitial cystitis problem index (ICPI), voiding diary for frequency/nocturia, cystometric bladder capacity and voided volume at the beginning and at 6 months. All patients had a potassium sensitivity test (PST) initially. Wilcoxon and Mann-Whitney U tests were used for statistical analysis. In total, 53 patients met the study criteria. There were 30 patients in the HA-CS group (mean age: 48.47) and 23 patients in the HA group (mean age: 49.61) (p > 0.05). The initial PST was positive in 71.7% patients (38/53) overall with no difference between groups (p > 0.05). Responses for VAS, ICCS, ICPS, 24-hour frequency/nocturia statistically improved in both groups at 6 months. There was no significant difference in symptomatic improvement (p > 0.05). Eight patients had mild adverse events. HA and HA/CS instillation can be effective in BPS/IC patients who do not respond to conservative treatment. An important limitation of our study is that the HA dosage of the 2 treatment arms were different. It would be more appropriate with same HA dosage in both groups; however, there was no commercially available glycosaminoglycan (GAG) substance with same HA dosage for single and combination therapy. Large, long-term randomized studies are required to determine if there is a difference between these treatments.