Measuring Disability: Comparing the Impact of Two Data Collection Approaches on Disability Rates.
The usual approach in disability surveys is to screen persons with disability upfront and then ask questions about everyday problems. The objectives of this paper are to demonstrate the impact of screeners on disability rates, to challenge the usual exclusion of persons with mild and moderate disability from disability surveys and to demonstrate the advantage of using an a posteriori cut-off. Using data of a pilot study of the WHO Model Disability Survey (MDS) in Cambodia and the polytomous Rasch model, metric scales of disability were built. The conventional screener approach based on the short disability module of the Washington City Group and the a posteriori cut-off method described in the World Disability Report were compared regarding disability rates. The screener led to imprecise rates and classified persons with mild to moderate disability as non-disabled, although these respondents already experienced important problems in daily life. The a posteriori cut-off applied to the general population sample led to a more precise disability rate and allowed for a differentiation of the performance and needs of persons with mild, moderate and severe disability. This approach can be therefore considered as an inclusive approach suitable to monitor the Convention on the Rights of Persons with Disabilities.


Results of surgical correction of upper eyelid retraction in Graves' Orbitopathy.
Anterior levator disinsertion/reinsertion and Müllerectomy (ALDM) is generally performed to correct upper eyelid retraction in patients with Graves' orbitopathy (GO). We studied the outcome of this procedure and its correlation with clinical parameters. Retrospective analysis of results of ALDM in 305 consecutive euthyroid patients with burnt-out GO treated in our hospital between 1 January 2000 and 1 January 2016. From the patient files, we recorded data on age, gender, laterality of surgery, smoking history and previous interventions. For outcome analysis, we used a qualitative scoring system with subdivision into three categories (good (MRD-1 of 4-5 mm, smooth upper eyelid contour and left-right difference of < 1 mm); acceptable (MRD-1 of 3-<4 or> 5-6 mm), smooth upper eyelid contour and left-right difference of < 2 mm; poor: if none of the above criteria was met). We analysed the outcome per eyelid as well as per patient. Of the 305 patients (471 eyelids), 166 underwent bilateral and 139 unilateral surgery. Regarding eyelids, the outcome of surgery was good in 71.6% (337/471) acceptable in 15.7% (74/471) and poor in 12.7% (60/471). Regarding patients, the outcome was good in 64.3% (196/305), acceptable in 15.7% (48/305) and poor in 20% (61/305). Concerning bilateral and unilateral surgery, the outcome was good in 60.8% (101/166) and acceptable in 16.9% (28/166) of patients after bilateral surgery, and good in 68.3% (95/139) and acceptable in 14.4% (20/139) of the patients after unilateral surgery (p = 0.17). Reoperation was performed in 16% (75 of 471) of eyelids and in 22 % (66 of 305) of patients. After secondary surgery, the cumulative success percentage was good in 78.6% (370/471) of eyelids and in 79% (241/305) of patients. We found no relation between surgical outcome and any other studied parameter, such as age, gender, smoking history and previous intervention such as extraocular muscle surgery and/or orbital decompression. Correction of upper eyelid retraction yields a good result in 64.3% of patients and 71.6% of eyelids. With one additional procedure, the procedure proved was successful in 79% of patients and eyelids. We found no relation between the outcome of surgery and any other parameter, such as previous disease severity, previous interventions or smoking history. For comparative analysis, we recommend to report the outcome per patient rather than per eyelid.


Effects of long-term culture on human embryonic stem cell aging.
In recent years, human embryonic stem (hES) cells have become a promising cell source for regenerative medicine. Although hES cells have the ability for unlimited self-renewal, potential adverse effects of long-term cell culture upon hES cells must be investigated before therapeutic applications of hES cells can be realized. Here we investigated changes in molecular profiles associated with young (<60 passages) and old (>120 passages) cells of the H9 hES cell line as well as young (<85 passages) and old (>120 passages) cells of the PKU1 hES cell line. Our results show that morphology, stem cell markers, and telomerase activity do not differ significantly between young and old passage cells. Cells from both age groups were also shown to differentiate into derivatives of all 3 germ layers upon spontaneous differentiation in vitro. Interestingly, mitochondrial dysfunction was found to occur with prolonged culture. Old passage cells of both the H9 and PKU1 lines were characterized by higher mitochondrial membrane potential, larger mitochondrial morphology, and higher reactive oxygen species content than their younger counterparts. Teratomas derived from higher passage cells were also found to have an uneven preference for differentiation compared with tumors derived from younger cells. These findings suggest that prolonged culture of hES cells may negatively impact mitochondrial function and possibly affect long-term pluripotency.


Resolving the Complex Genetic Basis of Phenotypic Variation and Variability of Cellular Growth.
In all organisms, the majority of traits vary continuously between individuals. Explaining the genetic basis of quantitative trait variation requires comprehensively accounting for genetic and nongenetic factors as well as their interactions. The growth of microbial cells can be characterized by a lag duration, an exponential growth phase, and a stationary phase. Parameters that characterize these growth phases can vary among genotypes (phenotypic variation), environmental conditions (phenotypic plasticity), and among isogenic cells in a given environment (phenotypic variability). We used a high-throughput microscopy assay to map genetic loci determining variation in lag duration and exponential growth rate in growth rate-limiting and nonlimiting glucose concentrations, using segregants from a cross of two natural isolates of the budding yeast, Saccharomyces cerevisiae We find that some quantitative trait loci (QTL) are common between traits and environments whereas some are unique, exhibiting gene-by-environment interactions. Furthermore, whereas variation in the central tendency of growth rate or lag duration is explained by many additive loci, differences in phenotypic variability are primarily the result of genetic interactions. We used bulk segregant mapping to increase QTL resolution by performing whole-genome sequencing of complex mixtures of an advanced intercross mapping population grown in selective conditions using glucose-limited chemostats. We find that sequence variation in the high-affinity glucose transporter HXT7 contributes to variation in growth rate and lag duration. Allele replacements of the entire locus, as well as of a single polymorphic amino acid, reveal that the effect of variation in HXT7 depends on genetic, and allelic, background. Amplifications of HXT7 are frequently selected in experimental evolution in glucose-limited environments, but we find that HXT7 amplifications result in antagonistic pleiotropy that is absent in naturally occurring variants of HXT7 Our study highlights the complex nature of the genotype-to-phenotype map within and between environments.


Most hydrocarbonoclastic bacteria in the total environment are diazotrophic, which highlights their value in the bioremediation of hydrocarbon contaminants.
Eighty-two out of the 100 hydrocarbonoclastic bacterial species that have been already isolated from oil-contaminated Kuwaiti sites, characterized by 16S rRNA nucleotide sequencing, and preserved in our private culture collection, grew successfully in a mineral medium free of any nitrogenous compounds with oil vapor as the sole carbon source. Fifteen out of these 82 species were selected for further study based on the predominance of most of the isolates in their specific sites. All of these species tested positive for nitrogenase using the acetylene reduction reaction. They belonged to the genera Agrobacterium, Sphingomonas, and Pseudomonas from oily desert soil and Nesiotobacter, Nitratireductor, Acinetobacter, Alcanivorax, Arthrobacter, Marinobacter, Pseudoalteromonas, Vibrio, Diatzia, Mycobacterium, and Microbacterium from the Arabian/Persian Gulf water body. A PCR-DGGE-based sequencing analysis of nifH genes revealed the common occurrence of the corresponding genes among all the strains tested. The tested species also grew well and consumed crude oil effectively in NaNO3 -containing medium with and without nitrogen gas in the top space. On the other hand, these bacteria only grew and consumed crude oil in the NaNO3 -free medium when the top space gas contained nitrogen. We concluded that most hydrocarbonoclastic bacteria are diazotrophic, which allows for their wide distribution in the total environment. Therefore, these bacteria are useful for the cost-effective, environmentally friendly bioremediation of hydrocarbon contaminants.


High-density lipoprotein proteome dynamics in human endotoxemia.
A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome. Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants. This study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS.


VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.
Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget's disease, or a combination of these. The disease mechanism is unknown. We developed a Drosophila model of VCP mutation-dependent degeneration. The phenotype is reminiscent of PINK1 and parkin mutants, including a pronounced mitochondrial defect. Indeed, VCP interacts genetically with the PINK1/parkin pathway in vivo. Paradoxically, VCP complements PINK1 deficiency but not parkin deficiency. The basis of this paradox is resolved by mechanistic studies in vitro showing that VCP recruitment to damaged mitochondria requires Parkin-mediated ubiquitination of mitochondrial targets. VCP recruitment coincides temporally with mitochondrial fission, and VCP is required for proteasome-dependent degradation of Mitofusins in vitro and in vivo. Further, VCP and its adaptor Npl4/Ufd1 are required for clearance of damaged mitochondria via the PINK1/Parkin pathway, and this is impaired by pathogenic mutations in VCP.


Retrovirally transduced bone marrow stromal cells isolated from a mouse model of human osteogenesis imperfecta (oim) persist in bone and retain the ability to form cartilage and bone after extended passaging.
Bone marrow stromal cells isolated from a model of osteogenesis imperfecta (oim) mice, were transduced with a retrovirus (BAG) carrying the LacZ and neor genes after passage 21. The transduced cells retained the ability to express alkaline phosphatase activity in vitro when treated with recombinant human bone morphogenetic protein two (rhBMP-2), formed cartilage in vitro in aggregate cultures and formed bone in ceramic cubes after 6 weeks of implantation in nude mice. X-gal staining of ceramic cubes seeded with the transduced cells demonstrated the presence of LacZ-positive cells on the edges of bone and also in the lacunae of the newly formed bone 6 weeks after implantation. After infusion into femurs of oim mice, the transduced cells were detected in the marrow cavity and on the edges of the trabecular bone of the injected and contralateral femurs by X-gal staining and PCR analysis at 4, 10, 20, 30 and 40 days after injection. The LacZ gene was also detected in the lung and liver of the recipient mice at 4 and 10 days after injection but not at later time-periods. The present findings suggest that long-term cultured bone marrow stromal cells from osteogenesis imperfecta (OI) animals have the potential to traffic through the circulatory system, home to bone, form bone and continue to express exogenous genes. These findings open the possibility of using these cells as vehicles to deliver normal genes to bone as an alternative approach for the treatment of some forms of OI and certain other bone acquired and genetic diseases.


Hematologic reference intervals and age effect in European Strigiformes.
The clinical importance of hematologic testing in avian veterinary medicine is reflected in the increasing number of studies for the establishment of hematologic RIs of Strigiformes and other species. Age is an important physiologic factor in birds and the effect on hematology variable should be understood. The objective of this study was to determine baseline data of hematologic variables in 5 species of Iberian Strigiformes in different age classes. Nocturnal birds of prey were sampled at Wildlife Health Centers. Packed cell volume was determined by the microhematocrit centrifugation method, and RBC and WBC counts were determined using the direct hemocytometer count method with Natt and Herrick solution. Hemoglobin concentration was measured spectrophotometrically. The MCV, MCHC, and MHC were calculated using the standard formulas. The differential WBC count was performed by the routine microscopic evaluation of 200 cells on a blood smear manually stained with Wright stain. Thrombocyte blood count estimate was obtained from the blood film. No differences were observed between juveniles and adults for any variable evaluated in Tawny owl, Little owl, Scops owl, Long-eared owl, and Barn owl. In addition, PCV, RBC, and HGB of chicks were statistically significantly lower than in juveniles and adults, and total WBC was significantly higher in Tawny owl, Little owl, Scops owl, and Long-eared owl. Our findings provide evidence that laboratory data from chicks of Strigiformes are different compared to juveniles and adults; therefore, separate RIs were defined.


Polyamines as Snake Toxins and Their Probable Pharmacological Functions in Envenomation.
While decades of research have focused on snake venom proteins, far less attention has been paid to small organic venom constituents. Using mostly pooled samples, we surveyed 31 venoms (six elapid, six viperid, and 19 crotalid) for spermine, spermidine, putrescine, and cadaverine. Most venoms contained all four polyamines, although some in essentially trace quantities. Spermine is a potentially significant component of many viperid and crotalid venoms (≤0.16% by mass, or 7.9 µmol/g); however, it is almost completely absent from elapid venoms assayed. All elapid venoms contained larger molar quantities of putrescine and cadaverine than spermine, but still at levels that are likely to be biologically insignificant. As with venom purines, polyamines impact numerous physiological targets in ways that are consistent with the objectives of prey envenomation, prey immobilization via hypotension and paralysis. Most venoms probably do not contain sufficient quantities of polyamines to induce systemic effects in prey; however, local effects seem probable. A review of the pharmacological literature suggests that spermine could contribute to prey hypotension and paralysis by interacting with N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, nicotinic and muscarinic acetylcholine receptors, γ-Aminobutyric acid (GABA) receptors, blood platelets, ryanodine receptors, and Ca2+-ATPase. It also blocks many types of cation-permeable channels by interacting with negatively charged amino acid residues in the channel mouths. The site of envenomation probably determines which physiological targets assume the greatest importance; however, venom-induced liberation of endogenous, intracellular stores of polyamines could potentially have systemic implications and may contribute significantly to envenomation sequelae.


Advanced imaging and hospice use in end-of-life cancer care.
Advanced imaging can inform prognosis and may be a mechanism to de-escalate unnecessary end-of-life care in patients with cancer. Associations between greater use of advanced imaging and less-aggressive end-of-life care in real-world practice has not been examined. We conducted a retrospective analysis of SEER-Medicare data on patients who died from breast, lung, colorectal, or prostate cancer between 2002 and 2007. Hospital referral region (HRR)-level use of computerized tomography (CT), magnetic resonance imaging, and positron emission tomography was categorized by tertile of imaging use and correlated with hospice enrollment overall and late hospice enrollment using multivariable logistic regression. A total of 55,058 patients met study criteria. Hospice use ranged from 50.8% (colorectal cancer) to 62.1% (prostate cancer). In multivariable analyses, hospital referral regions (HRRs) with high rates of CT imaging were associated with lower odds of hospice enrollment (odds ratio, 0.80; 95% CI, 0.70-0.90) and late enrollment among those who did enroll (odds ratio, 1.49; 95% CI, 1.26-1.76). HRRs with the highest rates of CT use were predominantly located in the Midwest and Northeast and associated with higher percentage population of black patients (14.5 vs 5.6%), greater comorbidity (28.4 vs 23.7%), metropolitan residence (93.9 vs 78.5%), and less than high school education (26.4 vs 19.3%). In this population-based retrospective study, we did not observe evidence that overall and timely hospice are associated with higher rates of imaging near the end of life. An observed association between higher rates of imaging, particularly CT, may be explained in part by HRR-level differences in practice patterns and patient demographic characteristics. Further research is warranted to explore the ability of oncologic imaging to appropriately de-escalate care.


Can prebiotics and probiotics improve therapeutic outcomes for undernourished individuals?
It has become clear in recent years that the human intestinal microbiota plays an important role in maintaining health and thus is an attractive target for clinical interventions. Scientists and clinicians have become increasingly interested in assessing the ability of probiotics and prebiotics to enhance the nutritional status of malnourished children, pregnant women, the elderly, and individuals with non-communicable disease-associated malnutrition. A workshop was held by the International Scientific Association for Probiotics and Prebiotics (ISAPP), drawing on the knowledge of experts from industry, medicine, and academia, with the objective to assess the status of our understanding of the link between the microbiome and under-nutrition, specifically in relation to probiotic and prebiotic treatments for under-nourished individuals. These discussions led to four recommendations: (1) The categories of malnourished individuals need to be differentiated To improve treatment outcomes, subjects should first be categorized based on the cause of malnutrition, additional health-concerns, differences in the gut microbiota, and sociological considerations. (2) Define a baseline "healthy" gut microbiota for each category Altered nutrient requirement (for example, in pregnancy and old age) and individual variation may change what constitutes a healthy gut microbiota for the individual. (3) Perform studies using model systems to test the effectiveness of potential probiotics and prebiotics against these specific categories These should illustrate how certain microbiota profiles can be altered, as members of different categories may respond differently to the same treatment. (4) Perform robust well-designed human studies with probiotics and/or prebiotics, with appropriate, defined primary outcomes and sample size These are critical to show efficacy and understand responder and non-responder outcomes. It is hoped that these recommendations will lead to new approaches that combat malnutrition. This report is the result of discussion during an expert workshop titled "How do the microbiota and probiotics and/or prebiotics influence poor nutritional status?" held during the 10th Meeting of the International Scientific Association for Probiotics and Prebiotics (ISAPP) in Cork, Ireland from October 1-3, 2012. The complete list of workshop attendees is shown in Table 1.


Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment.
This study reports the scintigraphy, histopathology, sole treatment with high-dose radioactive iodine and outcome of eight cases of feline thyroid carcinoma. Scintigraphic findings were variable and in 7/8 cases scintigraphic features could not reliably distinguish whether the thyroid tissue was malignant. Histopathology revealed typical criteria of malignancy in all cases, with mitotic activity described most frequently (7/8 cases), followed by infiltration of local tissues (4/8 cases). Cellular pleomorphism was infrequently observed. Single high-dose (1100MBq I(131)) radioiodine therapy was successful in 6/8 cases, with complete resolution of hyperthyroidism, and was associated with prolonged survival times (181-2381 days). Sole treatment with high-dose radioiodine is a safe and effective treatment for functional thyroid carcinoma. The prognosis for feline thyroid carcinoma successfully treated with radioiodine is good, with extended survival times commonly achieved.


Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
The authors conducted a randomized, controlled, multicenter trial, in which they assigned well-controlled hypertensive participants aged 55 years and older with moderate hypercholesterolemia to receive pravastatin (n=5170) or usual care (n=5185) for 4 to 8 years, when trial therapy was discontinued. Passive surveillance using national databases to ascertain deaths and hospitalizations continued for a total follow-up of 8 to 13 years to assess whether mortality and morbidity differences persisted or new differences developed. During the post-trial period, fatal and nonfatal outcomes were available for 98% and 64% of participants, respectively. The primary outcome was all-cause mortality and the secondary outcomes included cardiovascular mortality, coronary heart disease (CHD), stroke, heart failure, cardiovascular disease, and end-stage renal disease. No significant differences appeared in mortality for pravastatin vs usual care (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03) or other secondary outcomes. Similar to the previously reported in-trial result, there was a significant treatment effect for CHD in black patients (HR, 0.79; 95% CI, 0.64-0.98). However, the in-trial result showing a significant treatment by race effect did not remain significant during the entire follow-up (P=.08). These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in black patients.


Pancreatic stone protein/regenerating protein (PSP/reg): a novel secreted protein up-regulated in type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) has insulin resistance (IR) or reduced β-cell mass, partially due to an increased β-cell apoptosis rate. Pancreatic stone protein/regenerating protein (PSP/reg) is a secretory protein produced in the pancreas and up-regulated dramatically during pancreatic disease. Recent studies revealed that β-cells undergoing apoptosis induce PSP/reg expression in surviving neighboring cells. Further experiments demonstrated that PSP/reg was elevated during disease progression in type 1 diabetes mellitus (T1DM). However, the association between PSP/reg and T2DM patients is unknown. The aim of this pilot study was to investigate PSP/reg in different clinical stages of T2DM and evaluate its correlation with chronic complications of diabetes. A total of 1,121 participants (479 males, 642 females; age range 23-80 years) were enrolled in this study. PSP/reg serum values were measured by a newly developed enzyme-linked immunosorbent assay (ELISA). We analyzed its correlation with clinical and biochemical parameters in subjects with T2DM at different clinical phases. Statistical analyses were conducted using SPSS 17.0 software. Correlations of PSP/reg and clinical parameters were performed using Spearman's rank correlation coefficient. Differences between groups were determined by Nemenyi test. PSP/reg was elevated in high-risk and impaired glucose regulation (IGR) patients (p<0.05). PSP/reg was significantly up-regulated in newly diagnosed T2DM patients and long-term diabetes patients with complications (p<0.001). PSP/reg levels correlated with the duration of diabetes (p<0.001). The area under the curve (AUC) for presence of diabetes-onset and its chronic complications was 0.640 and 0.754, respectively. PSP/reg is significantly up-regulated in T2DM patients, and PSP/reg levels are related to the duration of diabetes. Therefore, PSP/reg might be useful as a predictor of T2DM and disease progression.


Neurotoxic potential of ingested ZnO nanomaterials on bees.
The honey bee is among most important pollinators threatened by environmental pollution, pest control and potentially, by products of nanotechnologies. The aim of the current study was an analysis of the neurotoxic potential of ingested zinc oxide nanomaterials (ZnO NMs) or zinc ions (Zn(2+)) on honey bees. We analysed a variety of biomarkers, including metabolic impairment, feeding rate, and survival, as well as the activities of a stress-related enzyme glutathione S-transferase, and the neurotoxicity biomarker acetylcholinesterase. Acetylcholinesterase activity was found to be elevated in bees exposed to either of the tested substances. In addition, we observed increased feeding rate in the group treated with Zn(2+) but not with ZnO NMs or control group. The observed effects we relate primarily to Zn(2+) ions. Here we provide evidence that zinc ions either originating from Zn salt or Zn-based NPs have a neurotoxic potential and thus might contribute to colony survival.


Auxin transport into cotyledons and cotyledon growth depend similarly on the ABCB19 Multidrug Resistance-like transporter.
ABCB19 of Arabidopsis thaliana (formerly known as MDR1 and PGP19) belongs to the Multidrug Resistance-like (MDR) or B group of the ATP-binding cassette (ABC) transporter superfamily, and mediates polar auxin transport in stems and roots. Here we have investigated the role of ABCB19 and auxin distribution in cotyledon development. During embryogenesis, confocal microscopy showed ABCB19 protein to be present in cotyledons during their main growth phase, but not later. Analysis of ProDR5:GFP expression patterns showed a significantly diminished and restricted auxin distribution pattern in abcb19 cotyledons. Nonetheless, development of abcb19 embryonic cotyledons was very similar to that of wild-type. Post-germination, ABCB19 was present in the plasma membrane of cotyledon epidermal, mesophyll and petiole cells during blade expansion. Post-germination cotyledon blade expansion in abcb19 was 65% slower than in wild-type, although the epidermal cell area was reduced by only 17%. The growth rate reduction quantitatively correlated with reduced auxin levels rather than auxin sensitivity as indicated by quantitative ProDR5:GUS assays and direct auxin measurements, and may be explained by the 50% reduction in the import of auxin through the petioles of abcb19 cotyledons during the period of maximum expansion. Taken together, these data indicate that cotyledon expansion during the establishment of photoautotrophic growth depends on ABCB19-mediated auxin import.


Adverse tissue reaction to corrosion at the neck-stem junction after modular primary total hip arthroplasty.
Complications related to the neck-stem junction of modular stems used for total hip arthroplasty (THA) are generating increasing concern. A 74-year-old male had increasing pain and a cutaneous reaction around the scar 1 year after THA with a modular neck-stem. Imaging revealed osteolysis of the calcar and a pseudo-tumour adjacent to the neck-stem junction. Serum cobalt levels were elevated. Revision surgery to exchange the stem and liner and to resect the pseudo-tumour was performed. Analysis of the stem by scanning electron microscopy and by energy dispersive X-ray and white light interferometry showed fretting corrosion at the neck-stem junction contrasting with minimal changes at the head-neck junction. Thus, despite dry assembly of the neck and stem on the back table at primary THA, full neck-stem contact was not achieved, and the resulting micromotion at the interface led to fretting corrosion. This case highlights the mechanism of fretting corrosion at the neck-stem interface responsible for adverse local tissue reactions. Clinical and radiological follow-up is mandatory in patients with dual-modular stems.


Sickle Cell Trait and Renal Function in Hispanics in the United States: The Northern Manhattan Study.
Sickle cell anemia (SCA) is a common hematological disorder among individuals of African descent in the United States; the disorder results in the production of abnormal hemoglobin. It is caused by homozygosity for a genetic mutation in HBB; rs334. While the presence of a single mutation (sickle cell trait, SCT) has long been considered a benign trait, recent research suggests that SCT is associated with renal dysfunction, including a decrease in estimated glomerular filtration rate (eGFR) and increased risk of chronic kidney disease (CKD) in African Americans. It is currently unknown whether similar associations are observed in Hispanics. Therefore, our study aimed to determine if SCT is associated with mean eGFR and CKD in a sample of 340 Dominican Hispanics from the Northern Manhattan Study. Using regression analyses, we tested rs334 for association with eGFR and CKD, adjusting for age and sex. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and CKD was defined as eGFR < 60 mL/min/1.73 m2. Within our sample, there were 16 individuals with SCT (SCT carriers). We found that SCT carriers had a mean eGFR that was 12.12 mL/min/1.73m2 lower than non-carriers (P=.002). Additionally, SCT carriers had 2.72 times higher odds of CKD compared with non-carriers (P=.09). Taken together, these novel results show that Hispanics with SCT, as found among African Americans with SCT, may also be at increased risk for kidney disease.


The Governance of Genomic Information: Will it Come of Age?
The completion of the Human Genome Project has opened up unprecedented possibilities in healthcare, but also ethical and social dilemmas in terms of how these can be achieved. Genomic information can be seen as a "global public good" (GPG), in that it is represented by knowledge in the public domain and across national boundaries. Lack of investment, infrastructure and expertise in developing countries means that they are unable to take advantage of these GPG characteristics to address their health needs, fuelling fears of a growing "genomics divide". Some have suggested an international knowledge sharing and capacity building network, a Global Genomics Initiative, as a means to harness the potential of genomics to reduce inequalities in health between North and South. Three UNESCO declarations also call for cooperation between developed and developing countries in genomics research and science and technology in general. Using international relations theories around global governance and networks as a conceptual framework, this paper examines whether these initiatives are likely to succeed in providing effective governance of genomics.


The benefits and harms of breast cancer screening: an independent review.
Whether breast cancer screening does more harm than good has been debated extensively. The main questions are how large the benefit of screening is in terms of reduced breast cancer mortality and how substantial the harm is in terms of overdiagnosis, which is defined as cancers detected at screening that would not have otherwise become clinically apparent in the woman's lifetime. An independent Panel was convened to reach conclusions about the benefits and harms of breast screening on the basis of a review of published work and oral and written evidence presented by experts in the subject. To provide estimates of the level of benefits and harms, the Panel relied mainly on findings from randomised trials of breast cancer screening that compared women invited to screening with controls not invited, but also reviewed evidence from observational studies. The Panel focused on the UK setting, where women aged 50-70 years are invited to screening every 3 years. In this Review, we provide a summary of the full report on the Panel's findings and conclusions. In a meta-analysis of 11 randomised trials, the relative risk of breast cancer mortality for women invited to screening compared with controls was 0·80 (95% CI 0·73-0·89), which is a relative risk reduction of 20%. The Panel considered the internal biases in the trials and whether these trials, which were done a long time ago, were still relevant; they concluded that 20% was still a reasonable estimate of the relative risk reduction. The more reliable and recent observational studies generally produced larger estimates of benefit, but these studies might be biased. The best estimates of overdiagnosis are from three trials in which women in the control group were not invited to be screened at the end of the active trial period. In a meta-analysis, estimates of the excess incidence were 11% (95% CI 9-12) when expressed as a proportion of cancers diagnosed in the invited group in the long term, and 19% (15-23) when expressed as a proportion of the cancers diagnosed during the active screening period. Results from observational studies support the occurrence of overdiagnosis, but estimates of its magnitude are unreliable. The Panel concludes that screening reduces breast cancer mortality but that some overdiagnosis occurs. Since the estimates provided are from studies with many limitations and whose relevance to present-day screening programmes can be questioned, they have substantial uncertainty and should be regarded only as an approximate guide. If these figures are used directly, for every 10,000 UK women aged 50 years invited to screening for the next 20 years, 43 deaths from breast cancer would be prevented and 129 cases of breast cancer, invasive and non-invasive, would be overdiagnosed; that is one breast cancer death prevented for about every three overdiagnosed cases identified and treated. Of the roughly 307,000 women aged 50-52 years who are invited to begin screening every year, just over 1% would have an overdiagnosed cancer in the next 20 years. Evidence from a focus group organised by Cancer Research UK and attended by some members of the Panel showed that many women feel that accepting the offer of breast screening is worthwhile, which agrees with the results of previous similar studies. Information should be made available in a transparent and objective way to women invited to screening so that they can make informed decisions.


Broca's area and the origins of human vocal skill.
Chimpanzees appear to be unable to learn to speak. It is usual to attribute their lack of vocal skill to limitations of their vocal tract, and to the absence in their neocortex of any area corresponding to Broca's area in the human brain. The first signs of Broca's area in hominid endocasts are therefore taken to represent an evolutionary development of great significance. There are two outstanding questions. First, what exactly does Broca's area do? Secondly, why does Broca's area in one hemisphere play a much greater role in controlling speech than does the corresponding area in the other hemisphere? The following answers are proposed. (1) Broca's area seems to be concerned not with the production of individual sounds but with the regulation of sequences of sounds. Chimpanzees have no need for such an area because their natural calls are not made up by varying the sequential order of elementary units. (2) Cerebral dominance for speech may result from the fact that the vocal cords are innervated in the same way as other central organs, such as the tongue. Each hemisphere sends a projection, and the two projections overlap extensively so that either hemisphere can assume full control. It is argued that it is most efficient for a single hemisphere to dominate where a complex sequence of movements must be programmed. This reorganization has occurred for the production of song in some songbirds and for the control of the vocal cords in human speech.


State humanitarian verticalism versus universal health coverage: a century of French international health assistance revisited.
The French contribution to global public health over the past two centuries has been marked by a fundamental tension between two approaches: State-provided universal free health care and what we propose to call State humanitarian verticalism. Both approaches have historical roots in French colonialism and have led to successes and failures that continue until the present day. In this paper, the second in The Lancet's Series on France, we look at how this tension has evolved. During the French colonial period (1890s to 1950s), the Indigenous Medical Assistance structure was supposed to bring metropolitan France's model of universal and free public health care to the colonies, and French State imperial humanitarianism crystallised in vertical programmes inspired by Louis Pasteur, while vying with early private humanitarian activism in health represented by Albert Schweitzer. From decolonisation to the end of the Cold War (1960-99), French assistance to newly independent states was affected by sans frontièrisme, Health for All, and the AIDS pandemic. Since 2000, France has had an active role in development of global health initiatives and favoured multilateral action for health assistance. Today, with adoption of the 2030 Sustainable Development Goals and the challenges of non-communicable diseases, economic inequality, and climate change, French international health assistance needs new direction. In the context of current debate over global health as a universal goal, understanding and acknowledging France's history could help strengthen advocacy in favour of universal health coverage and contribute to advancing global equity through income redistribution, from healthy populations to people who are sick and from wealthy individuals to those who are poor.


Drought tolerance in potato (S. tuberosum L.): Can we learn from drought tolerance research in cereals?
Drought tolerance is a complex trait of increasing importance in potato. Our knowledge is summarized concerning drought tolerance and water use efficiency in this crop. We describe the effects of water restriction on physiological characteristics, examine the main traits involved, report the attempts to improve drought tolerance through in vitro screening and marker assisted selection, list the main genes involved and analyze the potential interest of native and wild potatoes to improve drought tolerance. Drought tolerance has received more attention in cereals than in potato. The review compares these crops for indirect selection methods available for assessment of drought tolerance related traits, use of genetic resources, progress in genomics, application of water saving techniques and availability of models to anticipate the effects of climate change on yield. It is concluded that drought tolerance improvement in potato could greatly benefit from the transfer of research achievements in cereals. Several promising research directions are presented, such as the use of fluorescence, reflectance, color and thermal imaging and stable isotope techniques to assess drought tolerance related traits, the application of the partial root-zone drying technique to improve efficiency of water supply and the exploitation of stressful memory to enhance hardiness.


Media debates and 'ethical publicity' on social sex selection through preimplantation genetic diagnosis (PGD) technology in Australia.
This paper offers a critical discourse analysis of media debate over social sex selection in the Australian media from 2008 to 2014. This period coincides with a review of the National Health and Medical Research Council's Ethical Guidelines on the Use of Assisted Reproductive Technology in Clinical Practice and Research (2007), which underlie the regulation of assisted reproductive clinics and practice in Australia. I examine the discussion of the ethics of pre-implatation genetic diagnosis (PGD) within the media as 'ethical publicity' to the lay public. Sex selection through PGD is both exemplary of and interconnected with a range of debates in Australia about the legitimacy of certain reproductive choices and the extent to which procreative liberties should be restricted. Major themes emerging from media reports on PGD sex selection in Australia are described. These include: the spectre of science out of control; ramifications for the contestation over the public funding of abortion in Australia; private choices versus public authorities regulating reproduction; and the ethics of travelling overseas for the technology. It is concluded that within Australia, the issue of PGD sex selection is framed in terms of questions of individual freedom against the principle of sex discrimination - a principle enshrined in legislation - and a commitment to publically-funded medical care.


Premature mortality of epilepsy in low- and middle-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy.
To determine the magnitude of risk factors and causes of premature mortality associated with epilepsy in low- and middle-income countries (LMICs). We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank-defined LMICs. We assessed the quality of the studies based on representativeness; ascertainment of cases, diagnosis, and mortality; and extracted data on standardized mortality ratios (SMRs) and mortality rates in people with epilepsy. We examined risk factors and causes of death. The annual mortality rate was estimated at 19.8 (range 9.7-45.1) deaths per 1,000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3-7.2) among higher-quality population-based studies. Clinical cohort studies yielded 7.1 (range 1.6-25.1) deaths per 1,000 people. The weighted median SMRs were 5.0 in male and 4.5 in female patients; relatively higher SMRs within studies were measured in children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5-75.5%) derived from population-based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5 to 56.6%, and sudden unexpected death in epilepsy (SUDEP), with reported PMRs ranging from 1 to 18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Epilepsy in LMICs has a significantly greater premature mortality, as in high-income countries, but in LMICs the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries, and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs.


Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis.
Increasing evidence implicates serine proteinases in pathologic tissue turnover. The aim of this study was to assess the role of the transmembrane serine proteinase matriptase in cartilage destruction in osteoarthritis (OA). Serine proteinase gene expression in femoral head cartilage obtained from either patients with hip OA or patients with fracture to the neck of the femur (NOF) was assessed using a low-density array. The effect of matriptase on collagen breakdown was determined in cartilage degradation models, while the effect on matrix metalloproteinase (MMP) expression was analyzed by real-time polymerase chain reaction. ProMMP processing was determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis/N-terminal sequencing, while its ability to activate proteinase-activated receptor 2 (PAR-2) was determined using a synovial perfusion assay in mice. Matriptase gene expression was significantly elevated in OA cartilage compared with NOF cartilage, and matriptase was immunolocalized to OA chondrocytes. We showed that matriptase activated proMMP-1 and processed proMMP-3 to its fully active form. Exogenous matriptase significantly enhanced cytokine-stimulated cartilage collagenolysis, while matriptase alone caused significant collagenolysis from OA cartilage, which was metalloproteinase-dependent. Matriptase also induced MMP-1, MMP-3, and MMP-13 gene expression. Synovial perfusion data confirmed that matriptase activates PAR-2, and we demonstrated that matriptase-dependent enhancement of collagenolysis from OA cartilage is blocked by PAR-2 inhibition. Elevated matriptase expression in OA and the ability of matriptase to activate selective proMMPs as well as induce collagenase expression make this serine proteinase a key initiator and inducer of cartilage destruction in OA. We propose that the indirect effects of matriptase are mediated by PAR-2, and a more detailed understanding of these mechanisms may highlight important new therapeutic targets for OA treatment.


Chemical synthesis and translesion replication of a cis-syn cyclobutane thymine-uracil dimer.
The cytosine base in DNA undergoes hydrolytic deamination at a considerable rate when UV radiation induces formation of a cyclobutane pyrimidine dimer (CPD) with an adjacent pyrimidine base. We have synthesized a phosphoramidite building block of a cis-syn cyclobutane thymine-uracil dimer (T[]U), which is the deaminated form of the CPD at a TC site, and incorporated it into oligodeoxyribonucleotides. The previously reported method for synthesis of the thymine dimer (T[]T) was applied, using partially protected thymidylyl-(3'-5')-2'-deoxyuridine as the starting material, and after triplet- sensitized irradiation, the configuration of the base moiety in the major product was determined by NMR spectroscopy. Presence of the cis-syn cyclobutane dimer in the obtained oligonucleotides was confirmed by UV photoreversal and reaction with T4 endonuclease V. Using a 30mer containing T[]U, translesion synthesis by human DNA polymerase eta was analyzed. There was no difference in the results between the templates containing T[]T and T[]U and pol eta bypassed both lesions with the same efficiency, incorporating two adenylates. This enzyme showed fidelity to base pair formation, but this replication causes a C-->T transition because the original sequence is TC.


Origin of Flowback and Produced Waters from Sichuan Basin, China.
Shale gas extraction through hydraulic fracturing and horizontal drilling is increasing in China, particularly in Sichuan Basin. Production of unconventional shale gas with minimal environmental effects requires adequate management of wastewater from flowback and produced water (FP water) that is coextracted with natural gas. Here we present, for the first time, inorganic chemistry and multiple isotope (oxygen, hydrogen, boron, strontium, radium) data for FP water from 13 shale gas wells from the Lower Silurian Longmaxi Formation in the Weiyuan gas field, as well as produced waters from 35 conventional gas wells from underlying (Sinian, Cambrian) and overlying (Permian, Triassic) formations in Sichuan Basin. The chemical and isotope data indicate that the formation waters in Sichuan Basin originated from relics of different stages of evaporated seawater modified by water-rock interactions. The FP water from shale gas wells derives from blending of injected hydraulic fracturing water and entrapped saline (Cl ∼ 50,000 mg/L) formation water. Variations in the chemistry, δ18O, δ11B, and 87Sr/86Sr of FP water over time indicate that the mixing between the two sources varies with time, with a contribution of 75% (first 6 months) to 20% (>year) of the injected hydraulic fracturing water in the blend that compose the FP water. Mass-balance calculation suggests that the returned hydraulic fracturing water consisted of 28-49% of the volume of the injected hydraulic fracturing water, about a year after the initial hydraulic fracturing. We show differential mobilization of Na, B, Sr, and Li from the shale rocks during early stages of operation, which resulted in higher Na/Cl, B/Cl, Li/Cl, and 87Sr/86Sr and lower δ11B of the FP water during early stages of FP water formation relative to the original saline formation water recorded in late stages FP water. This study provides a geochemical framework for characterization of formation waters from different geological strata, and thus the ability to distinguish between different sources of oil and gas wastewater in Sichuan Basin.


Identifying Sub-Acute Rehabilitation Needs Among Individuals After Transient Ischaemic Attack Using Rehab-Compass as a Simple Screening Tool in the Outpatient Clinic.
To evaluate comprehensive unmet rehabilitation needs by using a novel graphic screening tool, Rehab-Compass, among individuals in the sub-acute stage after first-ever transient ischaemic attack. A pilot prospective cohort study investigated 47 individuals with first-ever transient ischaemic attack in an outpatient clinic setting. By using Rehab-Compass, based on well-validated patient-reported outcome measure questionnaires, this study examined comprehensive unmet rehabilitation needs among individuals at 4-month follow-up after the onset of transient ischaemic attack. Rehab-Compass identified that most participants were independent in their daily lives (modified Rankin Scale; mRS 0-1) with a relatively good quality of life (median EuroQol 5 dimensions (EQ-5D) 0.85), but certain limitations in participation in their daily lives. Rehab-Compass showed that, at 4 months after transient ischaemic attack, the most common condition affected was mood (reported by 89% of participants), followed by bladder function (70%), sexual life (52%), strength (51%) and fatigue (26%). Symptoms of depression and anxiety were reported by 6% and 17% of participants, respectively. This pilot study indicates that RehabCompass might be a suitable simple screening tool for use in the outpatient clinic setting to identify the multidimensional rehabilitation needs of individuals after transient ischaemic attack.


Maternal prenatal anxiety and child COMT genotype predict working memory and symptoms of ADHD.
Maternal prenatal anxiety is an important risk factor for altered child neurodevelopment but there is uncertainty concerning the biological mechanisms involved and sources of individual differences in children's responses. We sought to determine the role of functional genetic variation in COMT, which encodes catechol-O-methyltransferase, in the association between maternal prenatal anxiety and child symptoms of ADHD and working memory. We used the prospectively-designed ALSPAC cohort (n = 6,969) for our primary data analyses followed by replication analyses in the PREDO cohort (n = 425). Maternal prenatal anxiety was based on self-report measures; child symptoms of ADHD were collected from 4-15 years of age; working memory was assessed from in-person testing at age 8 years; and genetic variation in COMT at rs4680 was determined in both mothers and children. The association between maternal prenatal anxiety and child attention/hyperactivity symptoms and working memory was moderated by the child's rs4680 genotype, with stronger effects obtained for the val/val (G:G) genotype relative to val/met (A:G) (all p<0.01) and met/met (A:A) groups (all p<0.05). Similar findings were observed in the PREDO cohort where maternal prenatal anxiety interacted with child rs4680 to predict symptoms of ADHD at 3.5 years of age. The findings, from two cohorts, show a robust gene-environment interaction, which may contribute to inter-individual differences in the effects of maternal prenatal anxiety on developmental outcomes from childhood to mid-adolescence.


Localization and Characterization of alpha-Glucosidase Activity in Lactobacillus brevis.
Lactobacillus brevis is found together with the yeast Brettanomyces lambicus during the overattenuation process in spontaneously fermented lambic beer. An isolated L. brevis strain has been shown to produce an alpha-glucosidase with many similarities to the glucosidase earlier found in B. lambicus. The enzyme was purified by ammonium sulfate precipitation, gel (Sephadex G-150 and Ultrogel AcA-44) filtration, and ion-exchange chromatography (DEAE-Sephadex A-50). The molecular weights of the enzyme, as determined by gel chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were about 50,000 and 60,000, respectively. Optimum catalytic activity was obtained at 40 degrees C and pH 6.0. The enzyme showed a decrease of hydrolysis with an increase in the degree of polymerization of the substrate. The K(m) values for p-nitrophenyl-alpha-d-glucopyranoside, maltose, and maltotriose were 0.51, 3.0, and 5.2 mM, respectively. There was lack of inhibition by 0.15 mM acarbose and 0.5 M turanose, but the enzyme was inhibited by Tris (K(i) value of 25 mM). The alpha-glucosidase of L. brevis together with the enzyme of B. lambicus seems to be a key factor in the overattenuation of lambic beer, although the involvement of other lactic acid bacteria (pediococci) cannot be excluded.


Association of reproductive disorders and male congenital anomalies with environmental exposure to endocrine active pesticides.
There is growing evidence that environmental exposure to pesticides may increase the risk of developing reproductive and developmental disorders. This study determined the prevalence and risk of developing gestational disorders and male congenital genitourinary malformations in areas with distinct exposure to pesticides, many of them with potential endocrine disrupting properties. A population-based case-control study was carried out on pregnant women and male children living in ten health districts of Andalusia classified as areas of high and low environmental exposure to pesticides according to agronomic criteria. The study population included 45,050 cases and 950,620 controls matched for age and health district. Data were collected from computerized hospital records between 1998 and 2005. Prevalence rates and risk of miscarriage, low birth weight, hypospadias, cryptorchidism and micropenis were significantly greater in areas with higher use of pesticides in relation to those with lower use, thus supporting and extending previous information.


Nearly degenerate wavelength-multiplexed polarization entanglement by cascaded optical nonlinearities in a PPLN ridge waveguide device.
In this paper we report the generation of wavelength-multiplexed polarization-entangled photon pairs in the 1.5-μm communication wavelength band by using cascaded optical second nonlinearities (sum-frequency generation and subsequent spontaneous parametric down-conversion, c-SFG/SPDC) in a periodically poled LiNbO(3) ridge waveguide device. The c-SFG/SPDC method makes it possible to fully use the broad spectral bandwidth of SPDC in nearly frequency-degenerate conditions, and can provide more than 50 pairs of wavelength channels for the entangled photon pairs in the 1.5-μm wavelength band, using only standard optical resources in the telecom field. Visibilities higher than 98% were clearly observed in two-photon interference fringes for all the wavelength channels under investigation (eight pairs). We further performed a detailed experimental investigation of the cross-talk characteristics and the impact of detuning the pump wavelengths.


Endopeptidase 24.15 from rat testes. Isolation of the enzyme and its specificity toward synthetic and natural peptides, including enkephalin-containing peptides.
Endopeptidase 24.15, a metalloendopeptidase (EC 184.108.40.206) with an Mr of about 70,000, was purified to homogeneity from rat testes. The enzyme cleaves preferentially bonds on the carboxyl side of hydrophobic amino acids. Secondary enzyme-substrate interactions at sites removed from the scissile bond are indicated by the finding that a hydrophobic or bulky residue in the P3' position greatly contributes to substrate binding and catalytic efficiency. The isolated enzyme is inhibited by metal chelators and by thiols. Loss of enzymic activity after dialysis against EDTA can be restored by low concentrations of Zn2+ and Co2+ ions. The rate of reaction of the Co2+ enzyme with a synthetic substrate was higher than that of the Zn2+ enzyme. These results are consistent with the classification of the enzyme as a metalloendopeptidase. N-Carboxymethyl peptides that fulfil the binding requirements of the substrate recognition site of the enzyme act as potent competitive inhibitors. Biologically active peptides such as luteinizing hormone-releasing hormone, bradykinin and neurotensin are cleaved at sites consistent with the specificity of the enzyme deduced from studies with synthetic peptides. Dynorphin A (1-8)-peptide, beta-neoendorphin, metorphamide, and Metenkephalin-Arg6-Gly7-Leu8 are rapidly converted to the corresponding enkephalins. The testis enzyme is catalytically and immunologically closely related to the previously identified brain enzyme.


Cinnamon extract induces tumor cell death through inhibition of NFkappaB and AP1.
Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8+ T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFkappaB and AP1 in mouse melanoma model. Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model. Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFkappaB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro. Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFkappaB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers.


A Multicenter, Randomized, Controlled Phase IIb Trial of Avoidance of Hyperoxemia during Cardiopulmonary Bypass.
Cardiac surgery utilizing cardiopulmonary bypass (CPB) is one of the most common forms of major surgery. Cardiac surgery-associated multiorgan dysfunction (CSA-MOD) is well recognized and includes acute kidney injury (AKI), hepatic impairment, myocardial damage, and postoperative neurologic deficit. Pathophysiology of CSA-MOD involves numerous injurious pathways linked to the use of CPB including oxidative stress and formation of reactive iron species. During cardiac surgery with CPB, arterial return blood is oxygenated to supranormal levels. This study aimed to determine whether the avoidance of arterial hyperoxemia decreased oxidative stress and reduced the severity of the multiorgan dysfunction in patients undergoing cardiac surgery utilizing CPB. The study was a multicenter, open-label, parallel-group, randomized controlled study of the avoidance of arterial hyperoxemia versus usual care in patients undergoing cardiac surgery involving CPB. Primary outcome was the incidence and severity of AKI. Secondary outcomes included serum biomarkers for CSA-MOD, duration of mechanical ventilation, and length of intensive care and hospital stay. A total of 298 patients were randomized and analyzed at two hospitals in New Zealand and Australia. Mean PaO2 was significantly different between groups during CPB. There was no difference in the development of AKI (intervention arm 72.0% vs. usual care 66.2%; difference, -5.8% [95% CI, -16.1 to 4.7%]; P = 0.28), other markers of organ damage, or intensive care unit and hospital length of stay. Avoiding modest hyperoxemia during CPB failed to demonstrate any difference in AKI, markers of organ damage, or length of stay.


Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins.
Long interspersed nuclear elements (LINEs or L1 elements) are targeted for epigenetic silencing during early embryonic development and remain inactive in most cells and tissues. Here we show that E2F-Rb family complexes participate in L1 elements epigenetic regulation via nucleosomal histone modifications and recruitment of histone deacetylases (HDACs) HDAC1 and HDAC2. Our experiments demonstrated that (i) Rb and E2F interact with human and mouse L1 elements, (ii) L1 elements are deficient in both heterochromatin-associated histone marks H3 tri methyl K9 and H4 tri methyl K20 in Rb family triple knock out (Rb, p107, and p130) fibroblasts (TKO), (iii) L1 promoter exhibits increased histone H3 acetylation in the absence of HDAC1 and HDAC2 recruitment, (iv) L1 expression in TKO fibroblasts is upregulated compared to wild type counterparts, (v) L1 expression increases in the presence of the HDAC inhibitor TSA. On the basis of these findings we propose a model in which L1 sequences throughout the genome serve as centers for heterochromatin formation in an Rb family-dependent manner. As such, Rb proteins and L1 elements may play key roles in heterochromatin formation beyond pericentromeric chromosomal regions. These findings describe a novel mechanism of L1 reactivation in mammalian cells mediated by failure of corepressor protein recruitment by Rb, loss of histone epigenetic marks, heterochromatin formation, and increased histone H3 acetylation.


Involvement of T44 molecules in an antigen-independent pathway of T cell activation. Analysis of the correlations to the T cell antigen-receptor complex.
Prior studies indicate that the 9.3 monoclonal antibody (mAb) which defines a 44 kD T lineage-specific glycoprotein (T44) enhances the proliferative response of peripheral blood T lymphocytes to phytohemagglutinin (PHA) or allogeneic cells. The T44 molecule was expressed in both resting and activated T lymphocytes and in a subset of thymocytes, as assessed by indirect immunofluorescence and flow cytofluorometry. In view of the potential importance of T44 in T cell activation, we investigated the ability of the 9.3 (anti-T44) antibody to stimulate peripheral blood T lymphocytes under culture conditions giving optimal proliferative responses to anti-T3 mAb. Like UCHT1 (anti-T3) mAb, the 9.3 (anti-T44 mAb) promoted strong proliferative responses of purified T cells, provided that adherent cells were added to the culture. Maximal proliferation in response to 9.3 antibody was consistently detected at day 5 (at day 3 with anti-T3 or PHA). Moreover, triggering of T lymphocytes with 9.3 antibody (in the presence of adherent cells) resulted in strong IL-2 production that peaked at 48 h. Analysis of the physical and functional relationship between the T44 molecule and other molecules involved in T cell activation, including the clonotypically restricted Ti and the monomorphic T3 or T11 molecules, was carried out on a mutagenized jurkat T leukemia cell line. This mutant, termed JA3 (surface phenotype: T11+, T3+, 3A1+, T4-, T8-, DR-, Tac-, 4F2+, T44+) produced large amounts of IL-2 upon stimulation with PHA, anti-T3, or anticlonotypic mAb in conjunction with phorbol myristate acetate (or adherent cells). The molecules precipitated by anti-T44 mAb from 125I-labeled JA3 cells appeared as a diffuse band of Mr 40-45,000 under reducing conditions; under nonreducing conditions, a prominent band of Mr 80-85,000 was observed, while the Mr 40-45,000 band was greatly reduced. Thus, T44 molecules in both reducing and nonreducing conditions had relative molecular weights similar to that of molecules carrying clonotypic (Ti) determinants. In addition, like anti-Ti or anti-T3 mAb, anti-T44 antibody induced JA3 cells to produce large amounts of IL-2 in the presence of phorbol myristate acetate. Other similarities between T44 and molecules carrying clonotypic structures included the susceptibility to antibody-induced modulation and the late reexpression (72 h) at the cell surface after modulation. Taken together, these experiments suggest that anti-T44 mAb might recognize a monomorphic determinant of the T cell receptor molecule or be physically or functionally linked to the T3-Ti complex.(ABSTRACT TRUNCATED AT 400 WORDS)


Cell-based cancer gene therapy: breaking tolerance or inducing autoimmunity?
This review examines the mechanisms involved in anti-tumor immunity and how peptides present in many tumor types (tumor-associated antigens) are recognized by T cells from tumor-bearing cancer patients. Tumor-associated antigens are derived from proteins that are also expressed in normal cells. It is predicted that immune responses to such peptides will be compromised by self-tolerance or that stimulation of effective immune responses will be accompanied by autoimmunity. We also consider that the immunity induced against two autoantigens, which are highly conserved in vertebrates, involve qualitatively different mechanisms, such as the production of antibodies and cell-mediated immune responses. However, both pathways lead to tumor immunity and identical phenotypic manifestations of autoimmunity. Appropriate selection of the optimal tumor antigen is critical for the induction of an anti-tumor immune response. Thus, we stress that the methods for antigen presentation using dendritic cells play a critical role in the development of tumor vaccines, to break immune tolerance and induce a strong immune response against them. The viability and feasibility of expansion of canine dendritic cells from bone marrow and peripheral blood ex vivo for the treatment of spontaneous cancers in dogs is also discussed.


The neurovascular triad: mixed cavernous, capillary, and venous malformations of the brainstem.
The four types of cerebrovascular malformations may sometimes be combined and more often occur in pairs; triads are exceptional. The authors present six patients with the clinicoradiographic profile of mixed vascular malformations of the brainstem, including cavernous malformation (CM), capillary telangiectasia, and developmental venous anomaly (DVA). Five patients (one of whom was a child) suffered from hemorrhage, suggesting that this complex association has a high bleeding potential. Progressive growth, rebleeding, and de novo occurrence of the associated CM were documented in three cases. Magnetic resonance imaging of the brain was obtained in all patients by using one or more of the following modalities: T1-weighted sequences before and after gadolinium administration; T2-weighted sequences; T2-weighted fluid attenuated Inversion recovery; T1-weighted fast spin echo; and diffusion weighted, diffusion tensor, and perfusion imaging in three cases. Three patients were surgically treated with the intention of excising the hemorrhagic lesion, but only two patients had their malformations successfully removed. In the third case, diffuse pontine telangiectasia precluded the safe excision of the CM. Histological examination demonstrated a blended pathological milieu characterized by coalescent telangiectasia and venules associated with loculated endothelial chambers resembling an immature or de novo CM. Three patients were treated conservatively; recurrent minor hemorrhage occurred in one case. The authors found these malformations to be arranged in two basic relationships: CM inside the telangiectasia and CM in the radicles of the DVA. Stenosis of the main venous collector and dilation of the medullary veins were important findings. The pathogenesis of this malformation may be referred to a developmental deviance of the brainstem capillary-venous network associated with transitional vessels and loculated endothelial vascular spaces related to genetic and acquired origins, probably in a restrictive venous outflow milieu.


Influence of early mobilization on respiratory and peripheral muscle strength in critically ill patients.
To evaluate the effects of an early mobilization protocol on respiratory and peripheral muscles in critically ill patients. A randomized controlled clinical trial was conducted with 59 male and female patients on mechanical ventilation. The patients were divided into a conventional physical therapy group (control group, n=14) that received the sector's standard physical therapy program and an early mobilization group (n=14) that received a systematic early mobilization protocol. Peripheral muscle strength was assessed with the Medical Research Council score, and respiratory muscle strength (determined by the maximal inspiratory and expiratory pressures) was measured using a vacuum manometer with a unidirectional valve. Systematic early mobilization was performed on five levels. Significant increases were observed for values for maximal inspiratory pressure and the Medical Research Council score in the early mobilization group. However, no statistically significant improvement was observed for maximal expiratory pressure or MV duration (days), length of stay in the intensive care unit (days), and length of hospital stay (days). The early mobilization group showed gains in inspiratory and peripheral muscle strength.


Prognostic biomarkers in uveal melanoma: evidence for a stem cell-like phenotype associated with metastasis.
Uveal melanomas frequently metastasize and cause patient death. Many clinical, histopathologic, molecular, and genetic factors have been linked to metastasis. We hypothesized that understanding the relationships between, and relative prognostic significance of these factors would provide new insights into the pathogenesis of metastasis. To this end, we collected clinical, pathologic, and molecular data for 65 uveal melanomas, including patient age, sex, tumor size, location, cell type, vasculogenic mimicry looping matrix patterns, gene expression profiles, and immunohistochemistry for cytokeratin-18, vascular endothelial cadherin, E-cadherin, beta-catenin, and hypoxia-inducible factor 1alpha. In addition, we used Gene Set Enrichment Analysis to identify statistically significant overlap in genes that were differentially expressed in metastasizing tumors and those expressed in other well-characterized biological systems. Our results show that the class 2 gene expression signature was the most accurate predictor of metastasis (P=0.0001) and that the biomarkers most strongly associated with the class 2 signature included epithelioid cell type, beta-catenin, E-cadherin, and hypoxia-inducible factor 1alpha (P< or =0.001 for each). Thus, the class 2 gene expression signature continues to be the most accurate predictor of uveal melanoma metastasis and can, therefore, serve as a benchmark for evaluating other biomarkers. Importantly, Gene Set Enrichment Analysis showed a significant association between genes expressed in class 2 tumors and those expressed in primitive ectodermal and neural stem cells. Taken together with the constellation of biomarkers associated with the class 2 signature, this suggests the presence of cancer cells with a primitive neural/ectodermal stem cell-like phenotype that may be responsible for metastasis in these highly aggressive tumors.


Enabling Ambipolar to Heavy n-Type Transport in PbS Quantum Dot Solids through Doping with Organic Molecules.
PbS quantum dots (QDs) are remarkable semiconducting materials, which are compatible with low-cost solution-processed electronic device fabrication. Understanding the doping of these materials is one of the great research interests, as it is a necessary step to improve the device performance as well as to enhance the applicability of this system for diverse optoelectronic applications. Here, we report the efficient doping of the PbS QD films with the use of solution-processable organic molecules. By engineering the energy levels of the donor molecules and the PbS QDs through the use of different cross-linking ligands, we are able to control the characteristics of PbS field-effect transistors (FETs) from ambipolar to strongly n-type. Because the doping promotes trap filling, the charge carrier mobility is improved up to 0.64 cm2 V-1 s-1, which is the highest mobility reported for low-temperature processed PbS FETs employing SiO2 as the gate dielectric. The doping also reduces the contact resistance of the devices, which can also explain the origin of the increased mobility.


Creating a patient-based condition-specific outcome measure for Temporomandibular Disorders (TMDs): Oral Health Impact Profile for TMDs (OHIP-TMDs).
The aim of this study was to generate a putative patient-based outcome measure specifically for Temporomandibular Disorders (TMDs) using a mixed-method approach. A combined quantitative-qualitative methodology was used to identify the most relevant items in the Oral Health Impact Profile (OHIP-49) for TMDs. The quantitative study involved 110 patients with TMDs diagnosed using the Research Diagnostic Criteria for TMDs (RDC/TMD) and 110 age- and sex-matched controls. All subjects completed the OHIP-49. The qualitative study involved semi-structured interviews with a separate sample of patients with TMDs (n = 29). The two resultant data sets were analysed blinded and separately. Each data set used predetermined rules to select candidate items for the putative OHIP for TMDs. The two sets of selected items were then compared using a priori rules to make a final item selection for OHIP TMDs. Eighteen pre-existing items were selected through the quantitative process and fourteen by the qualitative process. On comparison of the two selections all but two of the items selected by the qualitative process had also been selected by the quantitative process. Two new candidate items emerged from the qualitative data that were not covered by OHIP-49. A 22 item putative OHIP-TMDs outcome measure emerged from the final selection process. A putative OHIP-TMDs outcome measure has been generated which requires further testing especially in relation to its responsiveness to change.


Feasibility study of a scalable optical interconnection network for massively parallel processing systems.
The theoretical modeling of a novel topology for scalable optical interconnection networks, called optical multimesh hypercube (OMMH), is developed to predict size, bit rate, bit-error rate, power budget, noise, efficiency, interconnect distance, pixel density, and misalignment sensitivity. The numerical predictions are validated with experimental data from commercially available products to assess the effects of various thermal, system, and geometric parameters on the behavior of the sample model. OMMH is a scalable network architecture that combines positive features of the hypercube (small diameter, regular, symmetric, and fault tolerant) and the mesh (constant node degree and size scalability). The OMMH is implemented by a free-space imaging system incorporated with a space-invariant hologram for the hypercube links and fiber optics to provide the mesh connectivity. The results of this work show that the free-space links can operate at 368 Mbits/s and the fiber-based links at 228 Mbits/s for a bit-error rate of 10(-17) per channel. The predicted system size for 32 nodes in the OMMH is 4.16 mm × 4.16 mm × 3.38 cm. Using 16-bit, bit-parallel transmission per node, the system can operate at a bit rate of up to 5.88 Gbits/s for a size of 1.04 cm × 1.04 cm × 3.38 cm.


How to build an effective research network: lessons from two decades of the GARNet plant science community.
Successful collaborative research is dependent on excellent ideas and innovative experimental approaches, as well as the provision of appropriate support networks. Collaboration requires venues, infrastructures, training facilities, and, perhaps most importantly, a sustained commitment to work together as a community. These activities do not occur without significant effort, yet can be facilitated and overseen by the leadership of a research network that has a clearly defined role to help build resources for their community. Over the past 20 years, this is a role that the UKRI-BBSRC-funded GARNet network has played in the support of the UK curiosity-driven, discovery-led plant science research community. This article reviews the lessons learnt by GARNet in the hope that they can inform the practical implementation of current and future research networks.


Long-term health of children following the Eyjafjallajökull volcanic eruption: a prospective cohort study.
Background: More than 500 million people worldwide live within exposure range of an active volcano and children are a vulnerable subgroup of such exposed populations. However, studies on the effects of volcanic eruptions on children's health beyond the first year are sparse. Objective: To examine the effect of the 2010 Eyjafjallajökull eruption on physical and mental health symptoms among exposed children in 2010 and 2013 and to identify potential predictive factors for symptoms. Method: In a population-based prospective cohort study, data was collected on the adult population (N = 1615) exposed to the 2010 Eyjafjallajökull eruption and a non-exposed group (N = 697). The exposed group was further divided according to exposure level. All participants answered questionnaires assessing their children´s and their own perceived health status in 2010 and 2013. Results: In 2010, exposed children were more likely than non-exposed children to experience respiratory symptoms (medium exposed OR 1.47; 95% CI 1.07-2.03; high exposed OR 1.52; 95% CI 1.03-2.24) and anxiety/worries (medium exposed OR 2.39; 95% CI 1.67-3.45; high exposed OR 2.77; 95% CI 1.81-4.27). Both genders had an increased risk of symptoms of anxiety/worries but only exposed boys were at increased risk of experiencing headaches and sleep disturbances compared to non-exposed boys. Within the exposed group, children whose homes were damaged were at increased risk of experiencing anxiety/worries (OR 1.62; 95% CI 1.13-2.32) and depressed mood (OR 1.55; 95% CI 1.07-2.24) than children whose homes were not damaged. Among exposed children, no significant decrease of symptoms was detected between 2010 and 2013. Conclusions: Adverse physical and mental health problems experienced by the children exposed to the eruption seem to persist for up to a three-year period post-disaster. These results underline the importance of appropriate follow-up for children after a natural disaster.


Development and initial evaluation of a self-report form of the DSM-5 Level of Personality Functioning Scale.
The DSM-5 presents an Alternative Model for Personality Disorder (AMPD) recommending the assessment of impairments in core personality functions as well as clinically relevant personality traits. Although a self-report assessment instrument has been provided corresponding to the trait model proposed in the AMPD, no comparable instrument provides a direct assessment of the specific indicators of core personality functions described in that model. The goal of this paper is to provide preliminary reliability and validity data for a measure that directly corresponds to core personality pathology as operationalized in the AMPD. Self-report questions were generated to capture each diagnostic indicator provided in the Level of Personality Functioning Scale, a clinician rating guide provided in the AMPD that describes characteristic impairments in identity, self-direction, empathy, and intimacy at 5 different levels of personality functioning. These questions were administered to a community sample of 306 participants, with the resulting scale examined for internal consistency, unidimensionality, and concurrent validity with 4 other self-report measures of global personality dysfunction. Items representing the 4 subcomponents of personality dysfunction were found to manifest high degrees of internal consistency, and were highly related to each other, supporting the AMPD contention that these core dysfunctions reflect a single dimension of personality dysfunction. Correlations with concurrent validity measures were large, with associations at the global level of dysfunction often exceeding .80. The developed instrument is reprinted in the supplementary materials, with the goal of encouraging additional refinement and development by other investigators as part of the call for additional research on the AMPD. (PsycINFO Database Record


Use of Decision Models in the Development of Evidence-Based Clinical Preventive Services Recommendations: Methods of the U.S. Preventive Services Task Force.
The U.S. Preventive Services Task Force (USPSTF) develops evidence-based recommendations about preventive care based on comprehensive systematic reviews of the best available evidence. Decision models provide a complementary, quantitative approach to support the USPSTF as it deliberates about the evidence and develops recommendations for clinical and policy use. This article describes the rationale for using modeling, an approach to selecting topics for modeling, and how modeling may inform recommendations about clinical preventive services. Decision modeling is useful when clinical questions remain about how to target an empirically established clinical preventive service at the individual or program level or when complex determinations of magnitude of net benefit, overall or among important subpopulations, are required. Before deciding whether to use decision modeling, the USPSTF assesses whether the benefits and harms of the preventive service have been established empirically, assesses whether there are key issues about applicability or implementation that modeling could address, and then defines the decision problem and key questions to address through modeling. Decision analyses conducted for the USPSTF are expected to follow best practices for modeling. For chosen topics, the USPSTF assesses the strengths and limitations of the systematically reviewed evidence and the modeling analyses and integrates the results of each to make preventive service recommendations.


Best practices in implementing inpatient pediatric asthma pathways: a qualitative study.
Objective: Clinical pathways (operational versions of practice guidelines) can improve guideline adherence and quality of care for children hospitalized with asthma. However, there is limited guidance on how to implement pathways successfully. Our objective was to identify potential best practices in pathway implementation.Methods: In a previous observational study, we identified higher and lower performing children's hospitals based on hospital-level changes in asthma patient length of stay after implementation of a pathway. In this qualitative study, we conducted semi-structured interviews with a purposive sample of healthcare providers involved in pathway implementation at these hospitals. We used constant comparative methods to develop a conceptual model of potential best practices in implementation.Results: Healthcare providers (n = 24) from 6 higher performing and 2 lower performing hospitals were interviewed about pathway implementation. We identified several practices that addressed barriers and promoted successful pathway implementation: (1) utilizing quality improvement (QI) methodology and a data-driven approach helped overcome inertia of current practice; (2) getting teams to commit to shared goals around asthma care helped overcome disagreements in the implementation process; (3) integrating pathways into the electronic medical record decreased some burdens of implementation; (4) leveraging multidisciplinary teams by developing protocols for nurses and/or respiratory therapists to titrate medications reduced variability in provider practice; and (5) engaging hospital leaders with pathway implementation teams helped secure crucial resources.Conclusions: We identified several potential best practices to support pathway implementation. Hospitals implementing pathways should consider applying these strategies to better ensure success in improving quality of asthma care for children.


Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones.
The new antitubercular drug candidate 2-[2-S-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one (BTZ043) targets the DprE1 (Rv3790) subunit of the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase. To monitor the potential development of benzothiazinone (BTZ) resistance, a total of 240 sensitive and multidrug-resistant Mycobacterium tuberculosis clinical isolates from four European hospitals were surveyed for the presence of mutations in the dprE1 gene and for BTZ susceptibility. All 240 strains were susceptible, thus establishing the baseline prior to the introduction of BTZ043 in clinical trials.


Bioaerosols in the Barcelona subway system.
Subway systems worldwide transport more than 100 million people daily; therefore, air quality on station platforms and inside trains is an important urban air pollution issue. We examined the microbiological composition and abundance in space and time of bioaerosols collected in the Barcelona subway system during a cold period. Quantitative PCR was used to quantify total bacteria, Aspergillus fumigatus, influenza A and B, and rhinoviruses. Multitag 454 pyrosequencing of the 16S rRNA gene was used to assess bacterial community composition and biodiversity. The results showed low bioaerosol concentrations regarding the targeted microorganisms, although the bacterial bioburden was rather high (104 bacteria/m3 ). Airborne bacterial communities presented a high degree of overlap among the different subway environments sampled (inside trains, platforms, and lobbies) and were dominated by a few widespread taxa, with Methylobacterium being the most abundant genus. Human-related microbiota in sequence dataset and ascribed to potentially pathogenic bacteria were found in low proportion (maximum values below 2% of sequence readings) and evenly detected. Hence, no important biological exposure marker was detected in any of the sampled environments. Overall, we found that commuters are not the main source of bioaerosols in the Barcelona subway system.


The association of lipid abnormalities with tissue pathology in human osteoarthritic articular cartilage.
Articular cartilage is one of very few body tissues uniquely characterized as having substantial stores of lipid deposits. Lipid droplets are naturally accumulated by chondrocytes and individual fatty acids have been shown to have protective as well as deleterious effects on cartilage degradation in animal models of degenerative joint disease. As a means to better assess the role of lipids in human joint pathology, a comparative analysis of fatty acids was undertaken in small segments of osteoarthritic articular cartilage. The data were assessed in terms of chondrocyte synthetic activity and histological determination of disease severity. The distribution profile of individual fatty acids in normal and osteoarthritic specimens remained constant, with palmitic, oleic, and linoleic acids representing 85% of the total fatty acids. In contrast, levels of total fatty acids were markedly increased in association with increasing degree of lesion severity. Compared with tissue from normal-aged joints, grade 0 to 1 mild lesions had elevated levels of total fatty acids, essential fatty acids, and chondrocyte synthetic activity of 80%, 312%, and 393%, respectively. More severe tissue involvement (grade 6 to 9), was associated with even greater increases of 440%, 1,100%, and 1,150%, respectively. No change was noted in cholesterol content in any tissue. The accumulation of arachidonic acid was greater than the proportional increase in total fatty acid content and was primarily distributed into the neutral lipid fraction, where it constituted almost 62% of the fatty acid level in tissues of moderate lesion severity. There was an association of lipid accumulation in general and arachidonic acid in particular with histological severity.(ABSTRACT TRUNCATED AT 250 WORDS)


Neuron to astrocyte communication via cannabinoid receptors is necessary for sustained epileptiform activity in rat hippocampus.
Astrocytes are integral functional components of synapses, regulating transmission and plasticity. They have also been implicated in the pathogenesis of epilepsy, although their precise roles have not been comprehensively characterized. Astrocytes integrate activity from neighboring synapses by responding to neuronally released neurotransmitters such as glutamate and ATP. Strong activation of astrocytes mediated by these neurotransmitters can promote seizure-like activity by initiating a positive feedback loop that induces excessive neuronal discharge. Recent work has demonstrated that astrocytes express cannabinoid 1 (CB1) receptors, which are sensitive to endocannabinoids released by nearby pyramidal cells. In this study, we tested whether this mechanism also contributes to epileptiform activity. In a model of 4-aminopyridine induced epileptic-like activity in hippocampal slice cultures, we show that pharmacological blockade of astrocyte CB1 receptors did not modify the initiation, but significantly reduced the maintenance of epileptiform discharge. When communication in astrocytic networks was disrupted by chelating astrocytic calcium, this CB1 receptor-mediated modulation of epileptiform activity was no longer observed. Thus, endocannabinoid signaling from neurons to astrocytes represents an additional significant factor in the maintenance of epileptiform activity in the hippocampus.


A psychometric evaluation of the Chinese version of the Hospital Anxiety and Depression Scale in patients with coronary heart disease.
To evaluate further the psychometric properties of the Chinese version of the Hospital Anxiety and Depression Scale (HADS) as a screening instrument for anxiety and depression in Chinese patients with coronary heart disease (CHD) in Xian, China. There is considerable evidence that anxiety and depression are common in patients with CHD and are associated with increased morbidity and mortality. A valid, reliable and sensitive screening tool that can be used readily on this group of patients would be useful for assessment, intervention and outcome evaluation. A single group, cross-sectional study. Measurement performance was tested on 314 Chinese patients with CHD and repeated on 173 of them two weeks later. The Chinese version of HADS (C-HADS) had acceptable internal consistency and test-retest reliability, with a Cronbach's alpha of 0.85 and intraclass correlation coefficient of 0.90, respectively. There was acceptable concurrent validity with significant (p < 0.05) correlations between the anxiety and depression subscales of the C-HADS and CHD patients' perceived health status as measured by the Chinese-Mandarin version of the Short Form-36 health survey (CM:SF-36). Principal components analysis revealed a three-factor solution accounting for 53% of the total variance. The three underlying sub-scale dimensions are depression, psychic anxiety and psychomotor anxiety. The responsiveness of the C-HADS was also satisfactory with significant correlation between the changes in the C-HADS score and the changes in the mental health domain of the CM:SF-36 (p < 0.01). Finally, over one-third of the patients demonstrated psychological distress. Empirical data support the C-HADS as a reliable and valid screening instrument for the assessment of anxiety and depression in Chinese-speaking patients with CHD. A tri-dimensional scoring approach should be considered as potentially clinically useful for this group of patients. The C-HADS can guide and evaluate the delivery of psychological care for Chinese patients with CHD.


Baseline Susceptibility to Pyrethroid and Organophosphate Insecticides in Two Old World Sand Fly Species (Diptera: Psychodidae).
Phlebotomine sand flies are blood-feeding insects that transmit Leishmania parasites that cause various forms of cutaneous and visceral leishmaniasis and sand fly fever viruses (Phlebovirus; Bunyaviridae) in humans. Sand flies pose a significant threat to US military personnel deployed to Leishmania-endemic and sand fly fever endemic regions which include Europe, the Mediterranean basin, Middle East, Central Asia, Southwest Asia, and Africa. A research project supported by the Department of Defense Deployed Warfighter Protection Program was initiated to evaluate the susceptibility of 2 Old World sand fly species, Phlebotomus papatasi and P duboscqi, to a number of commonly used pyrethroid and organophosphate insecticides. A new glass vial bioassay technique based on the CDC bottle assay was developed for this study. The exposure time-mortality relationship at a given insecticide concentration was determined for each insecticide, and their relative toxicity against the 2 sand fly species was ranked based on bioassay results. This study validated the new bioassay technique and also generated baseline insecticide susceptibility data to inform future insecticide resistance monitoring work.


Aspirin use and risk of fatal cancer.
Aspirin and other nonsteroidal antiinflammatory drugs inhibit prostaglandin synthesis and tumor growth in many experimental systems, but it is unclear which of these tumor models are relevant to humans. We have reported reduced risk of fatal colon cancer among persons who used aspirin in a large prospective study. This analysis examines other fatal cancers in relation to aspirin among 635,031 adults in that study who provided information in 1982 on the frequency and duration of their aspirin use and did not report cancer. Death rates were measured through 1988. Death rates decreased with more frequent aspirin use for cancers of the esophagus, stomach, colon, and rectum but not generally for other cancers. For each digestive tract cancer, death rates were approximately 40% lower among persons who used aspirin 16 times/month or more for at least 1 year compared to those who used no aspirin. The trend of decreasing risk with more frequent aspirin use was strongest among persons who had used aspirin for 10 years or more; it remained statistically significant, except for esophageal cancer, in multivariate analyses that adjusted for other known risk factors. Biases such as early detection or aspirin avoidance among cases do not appear to explain the results. Our data suggest that regular, prolonged use of aspirin may reduce the risk of fatal cancer of the esophagus, stomach, colon, and rectum. Future epidemiological and basic research should examine all digestive tract cancers in considering the chemopreventive or therapeutic potential of nonsteroidal antiinflammatory drugs.