Formation of the sural nerve in foetal cadavers.
The purpose of this study was to provide a morphologic description and assessment on the formation level of the sural nerve (SN) and its components. Also we aimed to reveal histological features of the SN components. An anatomical study of the formation of the SN was carried out on 100 limbs from 50 embalmed foetuses. The results showed that the SN was formed by the union of the medial sural cutaneous nerve (MSCN) and the peroneal communicating branch (PCB) in 71% of the cases (Type A); the MSCN and PCB are branches of the tibial and common peroneal nerve (CPN) or lateral sural cutaneous nerves (LSCN), respectively. Formation level of the SN was at the distal third of the leg in 43% of the cases, at the middle third of the leg in 46% of the cases, and at the upper third of the leg in 11% of the cases. The PCB originated in the CPN in 68% and the PCB originated in the LSCN in 3% of the cases. The SN was formed only by the MSCN in 20% of the cases (Type B). Type C was divided into four subgroups: in the first group the PCB and fibres of the posterior femoral cutaneous nerve joined the MSCN in 4% of cases; in the second group the MSCN, PCB, and sciatic nerve did not unite and coursed separately in 1% of cases; in the third group the SN arose directly from the sciatic nerve alone and the MSCN made a little contribution in 2% of cases; and in the fourth group the PCB, fibres of the sciatic nerve, and the MSCN formed the SN in 1% of the cases. The SN was formed only by the PCB in 1% of the cases (Type D). Distances of the formation level of the SN to the intercondylar line and the lateral malleolus were measured and also noted. A detailed knowledge of the anatomy of the SN and its contributing nerves are important in many interventional procedures.


The recognition, diagnosis, and treatment of mental disorders by primary care physicians.
A valid and reliable vignette-based measure of DSM-III psychiatric diagnostic knowledge was administered to practicing primary care physicians (PCPs; generally, internal and family practice medicine) and mental health professionals (MHPs, in psychiatry and psychology). Recognition, diagnosis, and treatment recommendations were measured for 14 different disorders. Contrary to other reports, PCPs consistently recognized the presence of mental disorder and did so virtually as well as MHPs, although both PCPs and MHPs showed more under-recognition than over-recognition. Diagnostic accuracy, however, was substantially lower, with that of MHPs exceeding PCPs for the general classes of affective, anxiety, somatic, and personality disorders, but not for the organic disorders. In making specific diagnoses, significantly fewer PCPs than MHPs gave an accurate diagnosis for eight of the 14 disorders: dysthymic disorder, major depression with psychotic features, agoraphobia with panic attacks (marginally), generalized anxiety disorder, adjustment disorder with anxious mood (marginally), psychologic factors affecting physical condition, and two personality disorders. Overall, PCPs were most accurate in identifying organic disorders (81% correct), least accurate in identifying the personality disorders (14%), and intermediate in identifying the affective (47%), anxiety (49%), and somatic disorders (49%). In most cases, both PCPs and MHPs preferred referral to treatment in primary care, but more PCPs than MHPs recommended treatment in primary care for certain anxiety and somatic disorders. Some differences in the recommended use of antidepressants in primary care were also found. Implications for the provision of mental health care by primary care physicians are discussed.


Processing objects at different levels of specificity.
How objects are represented and processed in the brain is a central topic in cognitive neuroscience. Previous studies have shown that knowledge of objects is represented in a feature-based distributed neural system primarily involving occipital and temporal cortical regions. Research with nonhuman primates suggest that these features are structured in a hierarchical system with posterior neurons in the inferior temporal cortex representing simple features and anterior neurons in the perirhinal cortex representing complex conjunctions of features (Bussey & Saksida, 2002; Murray & Bussey, 1999). On this account, the perirhinal cortex plays a crucial role in object identification by integrating information from different sensory systems into more complex polymodal feature conjunctions. We tested the implications of these claims for human object processing in an event-related fMRI study in which we presented colored pictures of common objects for 19 subjects to name at two levels of specificity - basic and domain. We reasoned that domain-level naming requires access to a coarser-grained representation of objects, thus involving only posterior regions of the inferior temporal cortex. In contrast, basic-level naming requires finer-grained discrimination to differentiate between similar objects, and thus should involve anterior temporal regions, including the perirhinal cortex. We found that object processing always activated the fusiform gyrus bilaterally, irrespective of the task, whereas the perirhinal cortex was only activated when the task required finer-grained discriminations. These results suggest that the same kind of hierarchical structure, which has been proposed for object processing in the monkey temporal cortex, functions in the human.


Ultrasonographic and histologic evaluation of medial and middle patellar ligaments in exercised horses following injection with ethanolamine oleate and 2% iodine in almond oil.
To describe the ultrasonographic and quantitative histologic effect of injecting 2% iodine in almond oil (IAO) and ethanolamine oleate (EO) in the medial and middle patellar ligaments of horses and to determine whether a difference in response exists between IAO and EO treatment. 10 healthy horses. In 5 horses, the medial and middle patellar ligaments of 1 limb were injected with EO, whereas IAO was injected in the medial and middle patellar ligaments of another 5 horses. Ultrasonographic evaluation was performed on the experimental and control limb before injection of IAO and EO and prior to euthanasia to determine cross-sectional area and evaluate fiber pattern. The patellar ligaments were harvested 2 weeks after injection and examined histologically to evaluate the inflammatory response, fibroplasia, and chondroid metaplasia. Injection of the patellar ligaments with IAO resulted in a greater increase in cross-sectional area on ultrasonography than EO. Both agents caused a decrease in echogenicity of the ligament. Histologically, significantly greater infiltration of inflammatory cells and fibroplasia developed after injection with IAO, compared with EO. Both agents resulted in significantly greater fibroplasia relative to control specimens. Injection of the medial and middle patellar ligaments with IAO induces more severe inflammation and fibroplasia than EO. Maturation of the inflammatory and fibrous response may contribute to resolution or attenuation of upward fixation of the patella by subsequent stiffening of the ligaments.


Stages in axon formation: observations of growth of Aplysia axons in culture using video-enhanced contrast-differential interference contrast microscopy.
The regenerative growth in culture of the axons of two giant identified neurons from the central nervous system of Aplysia californica was observed using video-enhanced contrast-differential interference contrast microscopy. This technique allowed the visualization in living cells of the membranous organelles of the growth cone. Elongation of axonal branches always occurred through the same sequence of events: A flat organelle-free veil protruded from the front of the growth cone, gradually filled with vesicles that entered by fast axonal transport and Brownian motion from the main body of the growth cone, became more voluminous and engorged with organelles (vesicles, mitochondria, and one or two large, irregular, refractile bodies), and, finally, assumed the cylindrical shape of the axon branch with the organelles predominantly moving by bidirectional fast axonal transport. The veil is thus the nascent axon. Because veils appear to be initially free of membranous organelles, addition of membrane to the plasmalemma by exocytosis is likely to occur in the main body of the growth cone rather than at the leading edge. Veils almost always formed with filopodial borders, protruding between either fully extended or growing filopodia. Therefore, one function of the filopodia is to direct elongation by demarcating the pathway along which axolemma flows. Models of axon growth in which the body of the growth cone is pulled forward, or in which advance of the leading edge is achieved by filopodial shortening or contraction against an adhesion to the substrate, are inconsistent with our observations. We suggest that, during the elongation phase of growth, filopodia may act as structural supports.


Adult soft tissue sarcomas. A pattern of care survey of the American College of Surgeons.
A nationwide survey of the clinical presentation, pathology, and management of soft tissue sarcomas in adults was carried out under the auspices of the Commission on Cancer of the American College of Surgeons. Two separate 2-year periods were used to allow assessment of changes in patterns of care. Data were obtained from 504 hospitals in 1977-1978 (2355 patients) and 645 institutions in 1983-1984 (3457 patients). Pretreatment findings of interest included some evidence of physician delay in diagnosis, overuse of excisional biopsy as opposed to the generally preferred approach of incisional biopsy, a low rate of usage of the American Joint Committee for Cancer Staging (AJCSS) system, and major reliance on CT for pretreatment patient evaluation. Operation was the primary treatment, with or without adjuvant therapies, in approximately three fourths of the patients. The other one fourth were primarily patients with distant metastasis at the time of diagnosis. Some increase in multimodal therapy did occur in the second period but the rate of amputation was low (approximately 10%) in both periods studied. Survival curves support the prognostic validity of the AJCCS system and the value of complete resection of soft tissue sarcomas. Adverse prognostic factors included positive surgical margins, large tumors, retroperitoneal or mediastinal primary sites, some histologic types, and the perceived need for adjuvant therapy. Patients receiving adjuvant radiation or chemotherapy had less favorable survival data than those treated by operation alone due to criteria used for selecting patients for these therapies. Approximately one half of the treatment failures in the 1977-1978 series were locoregional, whereas 18% were limited to lung metastasis. Salvage therapy for these two forms of treatment failure yielded 61% and 21% 5-year survival rates.


3-D object retrieval and recognition with hypergraph analysis.
View-based 3-D object retrieval and recognition has become popular in practice, e.g., in computer aided design. It is difficult to precisely estimate the distance between two objects represented by multiple views. Thus, current view-based 3-D object retrieval and recognition methods may not perform well. In this paper, we propose a hypergraph analysis approach to address this problem by avoiding the estimation of the distance between objects. In particular, we construct multiple hypergraphs for a set of 3-D objects based on their 2-D views. In these hypergraphs, each vertex is an object, and each edge is a cluster of views. Therefore, an edge connects multiple vertices. We define the weight of each edge based on the similarities between any two views within the cluster. Retrieval and recognition are performed based on the hypergraphs. Therefore, our method can explore the higher order relationship among objects and does not use the distance between objects. We conduct experiments on the National Taiwan University 3-D model dataset and the ETH 3-D object collection. Experimental results demonstrate the effectiveness of the proposed method by comparing with the state-of-the-art methods.


Systematic review and meta-analysis of randomized controlled trials evaluating intraoral orthopedic appliances for temporomandibular disorders.
To conduct a systematic review with meta-analysis of randomized controlled trials (RCTs) that have assessed the efficacy of intraoral orthopedic appliances to reduce pain in patients with temporomandibular disorders affecting muscle and joint (TMJD) compared to subjects receiving placebo control, no treatment, or other treatments. A search strategy of MEDLINE, the Cochrane Library, the Cochrane CENTRAL Register, and manual search identified all English language publications of RCTs for intraoral appliance treatment of TMJD pain during the years of January 1966 to March 2006. Two additional studies from 2006 were added during the review process. Selection criteria included RCTs assessing the efficacy of hard and soft stabilization appliances, anterior positioning appliances, anterior bite appliances, and other appliance types for TMJD pain. Pain relief outcome measures were used in the meta-analyses, and the QUORUM criteria for data abstraction were used. A quality analysis of the methods of each RCT was conducted using the CONSORT criteria. The review findings were expressed both as a qualitative review and, where possible, as a mathematical synthesis using meta-analysis of results. A total of 47 publications citing 44 RCTs with 2,218 subjects were included. Ten RCTs were included in two meta-analyses. In the first meta-analysis of seven studies with 385 patients, a hard stabilization appliance was found to improve TMJD pain compared to non-occluding appliance. The overall odds ratio (OR) of 2.46 was statistically significant (P = .001), with a 95% confidence interval of 1.56 to 3.67. In the second meta-analysis of three studies including 216 patients, a hard stabilization appliance was found to improve TMJD pain compared to no-treatment controls. The overall OR of 2.15 was positive but not statistically significant, with a 95% confidence interval of 0.80 to 5.75. The quality (0 to 1) of the studies was moderate, with a mean of 55% of quality criteria being met, suggesting some susceptibility to systematic bias may have existed. Hard stabilization appliances, when adjusted properly, have good evidence of modest efficacy in the treatment of TMJD pain compared to non-occluding appliances and no treatment. Other types of appliances, including soft stabilization appliances, anterior positioning appliances, and anterior bite appliances, have some RCT evidence of efficacy in reducing TMJD pain. However, the potential for adverse events with these appliances is higher and suggests the need for close monitoring in their use.


Functional heterogeneity of CD44 molecules in ovarian cancer cell lines.
We have previously shown that CD44 partly mediates ovarian cancer cell attachment to peritoneal mesothelium through recognition of mesothelial-associated hyaluronate. CD44 is a major receptor for hyaluronate and exists as a standard 90-180-kDa form (CD44H), as well as several higher molecular mass variant forms produced by alternative splicing. To determine whether functional differences exist between CD44H and its variants we have investigated the relationship between CD44 isoform expression and mesothelial adhesion in 12 ovarian cancer cell lines. Eight lines were CD44 positive (range, 83-94%) and demonstrated significant binding to mesothelium and hyaluronate, whereas two lines showed reduced CD44 levels (3-13%) and demonstrated decreased binding. Interestingly, two other lines (OVC-3 and SW626) expressed CD44 in the majority of cells (>93%) and yet bound weakly to mesothelium. Mean linear fluorescence intensity of CD44 expressed by OVC-3 and SW626 cells was approximately one-half that of strongly binding cell lines, suggesting that the ability to adhere may be partly related to CD44 surface density. However, immunoprecipitation and immunoblot analyses revealed that standard CD44H represented only 23-31% of total CD44 in weakly binding cells, with the majority of species being comprised of CD44 variants. Indirect immunofluorescence of OVC-3 and SW626 cells confirmed the presence of CD44 variants containing exons v3, v6, and v9. In contrast, CD44H represented the majority (75-86%) of total CD44 expressed by strongly binding cell lines such as CAOV-3 and UPN36T. Transfection of CD44H cDNA into weakly binding OVC-3 cells restored significant mesothelial binding which was partly blocked by anti-CD44 antibody. These data suggest that the expression of CD44 is necessary but not sufficient for mediating attachment of ovarian cancer cells to mesothelium. Although CD44 variants may constitute the major CD44 species in certain ovarian cancer cell lines, it appears that these CD44 species are not always capable of mediating significant binding to mesothelium or hyaluronate. Rather, an adequate level of CD44H is the critical determinant of binding in this system. The role of CD44 variants in the process of ovarian cancer metastasis will require further investigation.


Relationship between insulin resistance and nonmodulating hypertension: linkage of metabolic abnormalities and cardiovascular risk.
Insulin resistance is a feature common to patients with diabetes and to some with hypertension. It is assumed that this feature confers the increased metabolic risk in hypertension. However, the state of the renin-angiotensin system might contribute to cardiovascular risk, although there is no clear mechanistic explanation. Our recent observation that insulin levels are increased in a specific subset of patients with normal/high-renin hypertension, the nonmodulators, provided the background for the current hypothesis: to ascertain whether abnormalities in lipid and carbohydrate metabolism are observed in the same patients in whom alterations in sodium transport, sodium homeostasis, and the renin-aniotensin system response have been identified. Exploration of a family history of cardiovascular risk was a secondary goal. Insulin sensitivity (assessed by a 75-g oral glucose load), lipid levels, and two defects in the renin-angiotensin system were assessed in 62 hypertensive and 14 normotensive subjects placed on a high (210 mmol/l) and a low (10 mmol/l) sodium intake for 2 weeks, to classify them as low-renin, nonmodulator, or modulating hypertensive subjects. Only in nonmodulators were the following cardiovascular risk factors significantly increased: fasting insulin (P < 0.01); increment in post-glucose load insulin (P < 0.01); total, LDL, and VLDL cholesterol and triglyceride levels (P < 0.05); and erythrocyte Na+/Li+ countertransport activity (P < 0.001). Both nonmodulators and low-renin hypertensive subjects had a significantly (P < 0.01) increased frequency of a family history of hypertension by questionnaire compared with subjects with intact modulation. However, only nonmodulators had a significantly (P < 0.02) higher frequency of a family history of myocardial infarction. Thus, there is a clustering of metabolic abnormalities in a discrete subset of the essential hypertensive population with a specific dysregulation of the renin-angiotensin system--nonmodulation. The absence of this cluster in low-renin hypertensive subjects may explain their relatively diminished cardiovascular risk. Its presence in nonmodulators likely contributes to the increased cardiovascular risk observed in normal/high-renin hypertension.


Interactions of omeprazole-based analogues with cytochrome P450 2C19: a computational study.
Cytochrome P450 2C19 (CYP2C19) is one of 57 drug metabolizing enzymes in humans and is responsible for the metabolism of ∼7-10% of drugs in clinical use. Recently omeprazole-based analogues were reported to be the potent inhibitors of CYP2C19 and have the potential to be used as the tool compounds for studying the substrate selectivity of CYP2C19. However, the binding modes of these compounds with CYP2C19 remain to be elucidated. In this study, a combination of molecular docking, molecular dynamics (MD), and MM/GBSA calculations was employed to systematically investigate the interactions between these compounds and CYP2C19. The binding modes of these analogues were analyzed in detail. The results indicated that the inclusion of explicit active site water molecules could improve binding energy prediction when the water molecules formed a hydrogen bonding network between the ligand and protein. We also found that the effect of active site water molecules on binding free energy prediction was dependent on the ligand binding modes. Our results unravel the interactions of these omeprazole-based analogues with CYP2C19 and might be helpful for the future design of potent CYP2C19 inhibitors with improved metabolic properties.


Development of Questionnaire for Auditory Localization.
Localization plays an important role in identifying the source of the stimuli. Aural localization is based on the phase (period-related time), intensity level, and spectral differences between the sounds at each ear. Various behavioral measures are available to check the interaural level, time, and frequency differences, which provide information on an individual's ability to localize the sound source. This might vary depending on the audibility and amplification devices. Although these behavioral measures are available, the perceptual quality of localization cannot be obtained using these measures. This study aimed to develop a questionnaire for auditory localization. A questionnaire was prepared, the content validated, and administered on 120 individuals in the age range of 18-50 years who were divided into three different groups. The results of the descriptive and item analysis revealed a significant difference between the groups, with group I showing better localization ability. No significant difference was observed between the groups II and III. The receiver operating curve and cut-off scores were obtained. Individuals with a score of <42.5 on the questionnaire have better or good localization ability. The area covered under the curve is 0.987; therefore, the sensitivity and specificity of the questionnaire is also high. It can be concluded that this questionnaire is a simple, valid, and preliminary measure for the auditory localization ability of an individual.


Rapid, sensitive detection of Mycoplasma pneumoniae in simulated clinical specimens by DNA amplification.
The polymerase chain reaction (PCR) was investigated as a means of diagnosing Mycoplasma pneumoniae infections. The target DNA sequence was a 375-bp segment of the P1 virulence protein. This DNA segment was amplified in pure cultures of five different strains of M. pneumoniae but not in other species of Mycoplasma, Acholeplasma, or Ureaplasma that were tested. Simulated clinical specimens were used to compare PCR, culture, and the gene probe. The sensitivity of PCR was between 1 and 10 organisms. The sensitivity of culture was approximately 10(3) organisms, and the gene probe detected between 10(4) and 10(5) organisms. These results indicate that PCR has significant potential as a rapid, sensitive method for detecting M. pneumoniae in clinical specimens.


Short-term consumption of probiotic lactobacilli has no effect on acid production of supragingival plaque.
Acidogenicity and the levels of mutans streptococci (MS) in dental plaque after the use of Lactobacillus rhamnosus GG (LGG) and Lactobacillus reuteri were determined. The study had a randomised, double-blind, crossover design. Thirteen volunteers used tablets containing LGG or a combination of L. reuteri SD2112 and PTA 5289 for 2 weeks. At baseline and at the end of each tablet period, all available supragingival plaque was collected. Lactic acid production was determined from a fixed volume (8 μl) of fresh plaque and the rest of the plaque was used for culturing MS and lactobacilli. The retention of probiotics to the plaque was assessed using PCR techniques. No probiotic-induced changes were found in the acidogenicity of plaque. Also, MS counts remained at the original level. The number of subjects with lactobacilli in plaque increased in the L. reuteri group (p = 0.011) but not in the LGG group. PCR analysis of plaque revealed the presence of LGG in four and L. reuteri in six subjects after the use of the probiotic. The use of the lactobacilli did not affect the acidogenicity or MS levels of plaque. Short-term consumption of LGG and L. reuteri appeared not to influence the acidogenicity of plaque.


Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size.
The defining process in the evolution of primates and particularly humans is the dramatic expansion of the brain. While many types of genes could potentially contribute to this process, genes that specifically regulate brain size during development may be especially relevant. Here, we examine the evolution of the microcephalin gene, whose null mutation in humans causes primary microcephaly, a congenital defect characterized by severe reductions in brain size without other gross abnormalities. We show that the evolution of microcephalin's protein sequence is highly accelerated throughout the lineage from simian ancestors to humans and chimpanzees, with the most pronounced acceleration seen in the early periods of this lineage. We further demonstrate that this accelerated evolution is coupled with signatures of positive selection. Statistical analysis suggests that about 45 advantageous amino acid changes in microcephalin might have fixed during the 25-30 million years of evolution from early simian progenitors to modern humans. These observations support the notion that the molecular evolution of microcephalin may have contributed to brain expansion in the simian lineage leading to humans. We have recently shown that ASPM, another gene linked to primary microcephaly, experienced strong positive selection in the ape lineage leading to humans. We therefore propose that genes regulating brain size during development may have the general propensity to contribute to brain evolution in primates and particularly humans.


Attitudes and knowledge regarding health care policy and systems: a survey of medical students in Ontario and California.
Canada and the United States have similar medical education systems, but different health care systems. We surveyed medical students in Ontario and California to assess their knowledge and views about health care policy and systems, with an emphasis on attitudes toward universal care. A web-based survey was administered during the 2010-2011 academic year to students in 5 medical schools in Ontario and 4 in California. The survey collected demographic data and evaluated attitudes and knowledge regarding broad health care policy issues and health care systems. An index of support for universal health care was created, and logistic regression models were used to examine potential determinants of such support. Responses were received from 2241 students: 1354 from Ontario and 887 from California, representing 42.9% of eligible respondents. Support for universal health care coverage was higher in Ontario (86.8%) than in California (51.1%), p < 0.001. In California, females, self-described nonconservatives, students with the intent to be involved in health care policy as physicians and students with a primary care orientation were associated with support for universal coverage. In Ontario, self-described liberals and accurate knowledge of the Canadian system were associated with support. A single-payer system for practice was preferred by 35.6% and 67.4% of students in California and Ontario, respectively. The quantity of instruction on health care policy in the curriculum was judged too little by 73.1% and 57.5% of students in California and Ontario, respectively. Medical students in Ontario are substantially more supportive of universal access to health care than their California counterparts. A majority of students in both regions identified substantial curricular deficiencies in health care policy instruction.


Foot Function, Foot Pain, and Falls in Older Adults: The Framingham Foot Study.
Although foot pain has been linked to fall risk, contributions of pain severity, foot posture, or foot function are unclear. These factors were examined in a cohort of older adults. The purpose of this study was to examine the associations of foot pain, severity of foot pain, and measures of foot posture and dynamic foot function with reported falls in a large, well-described cohort of older adults from the Framingham Foot Study. Foot pain, posture, and function were collected from Framingham Foot Study participants who were queried about falls over the past year (0, 1, and ≥2 falls). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of falls with foot pain, pain severity, foot posture, and foot function adjusting for covariates. The mean age of the 1,375 participants was 69 years; 57% were female, and 21% reported foot pain (40% mild pain, 47% moderate pain, and 13% severe pain). One-third reported falls in the past year (1 fall: n = 263, ≥2 falls: n = 152). Foot pain was associated with a 62% increased odds of recurrent falls. Those with moderate and severe foot pain showed increased odds of ≥2 falls (OR 1.78, CI 1.06-2.99, and OR 3.25, CI 1.65-7.48, respectively) compared to those with no foot pain. Foot function was not associated with falls. Compared to normal foot posture, those with planus foot posture had 78% higher odds of ≥2 falls. Higher odds of recurrent falls were observed in individuals with foot pain, especially severe foot pain, as well as in individuals with planus foot posture, indicating that both foot pain and foot posture may play a role in increasing the risk of falls among older adults.


Tumour necrosis factor-alpha gene promoter polymorphism in chronic obstructive pulmonary disease.
Tumour necrosis factor(TNF)-alpha levels are elevated in airways of patients with chronic obstructive pulmonary disease (COPD) and may contribute to its pathogenesis. A guanine to adenine substitution at position -308 of the TNF-alpha gene promoter (TNF1/2) has been associated with chronic bronchitis of various aetiologies in a Taiwanese population. The authors performed a study investigating association of the polymorphism with smoking-related COPD in Caucasians. Frequencies of TNF1/2 alleles in 86 Caucasians (52 males) with COPD were compared with 63 (52 males) asymptomatic smoker/exsmoker control subjects and a population control of 199 (99 males) blood donors. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism technique on genomic deoxyribonucleic acid (DNA) obtained from peripheral blood. There were no significant differences in TNF1/2 allele frequencies between groups: 0.85/0.15 in COPD, 0.85/0.15 in smoker control subjects, 0.83/0.17 in population control subjects. Within the COPD group there was no association of TNF1/2 alleles with indices of airflow obstruction (% predicted forced expiratory volume in one second (FEV1) and % predicted FEV1/vital capacity ratio) nor gas transfer (% predicted carbon monoxide transfer coefficient and % predicted carbon monoxide diffusing capacity of the lung). It is concluded that: 1) the tumour necrosis factor gene promoter allele does not influence the risk of developing chronic obstructive pulmonary disease in a Caucasian population of smokers; and 2) there is no association of the tumour necrosis factor gene promoter genotype with severity of airflow obstruction nor degree of emphysema in chronic obstructive pulmonary disease.


Simulating posterior parietal damage in a biologically plausible framework: neuropsychological tests of the search over time and space model.
The search over time and space (sSoTS) model attempts to simulate both the spatial and the temporal aspects of human visual search using spiking level neurons, which incorporate some biologically plausible aspects of neuronal firing. The model contains pools of units that (a) code basic features of objects, presumed to reside in the ventral visual stream, and (b) respond in a feature-independent way to stimulation at their location, presumed to operate in the posterior parietal cortex. We examined the effects of selective lesioning neurons responding to one side of the location map. Unilateral damage introduced spatial biases into selection that affected conjunction more than single-feature search. In addition, there was an impaired ability to segment stimuli over time as well as space (e.g., in preview search). These results match previously reported data on patients with posterior parietal lesions. In addition we show that spatial biases in selection increase under conditions in which there is decreased activity from excitatory neurotransmitters, mimicking effects of reduced arousal. Further simulations explored the effects of time and of visual grouping on extinction, generating predictions that were then tested empirically. The model provides a framework for linking behavioural data from patients with neural-level determinants of visual attention.


Six-Month Effectiveness of Remote Activity Monitoring for Persons Living With Dementia and Their Family Caregivers: An Experimental Mixed Methods Study.
This study aimed to evaluate if and how remote activity monitoring (RAM) improves caregiver outcomes for family members providing care for persons living with Alzheimer's disease or a related dementia (ADRD). We conducted an embedded experimental mixed methods study of 132 persons living with ADRD and their family caregivers (n = 64 randomly assigned to RAM treatment condition). In addition to baseline and 6-month quantitative survey data on context of care, primary objective stressors, resources, self-efficacy/competence, and distress collected from caregivers, 6-month RAM review checklists contained open-ended, qualitative information on perceived acceptability of the technology. The RAM system did not exert statistically significant effects on caregiving outcomes over a 6-month period. However, qualitative analyses identified several potential moderators of RAM technology effectiveness that were subsequently tested in post-hoc repeated measures analyses of variance. Caregivers who utilized RAM technology and cared for relatives with: (a) less severe cognitive impairment; and (b) difficulty navigating around the home were more likely to indicate statistically significant increases in competence and self-efficacy, respectively. We found that the early months spent calibrating and modifying RAM are potentially challenging for families, which may prevent this technology from improving caregiving outcomes during initial months of use. Remote activity monitoring may work optimally for caregivers of persons living with ADRD in specific situations (e.g., earlier stages of dementia; wandering risk), which suggests the need for appropriate needs assessments that can better target such innovations.


Pediatric Intraosseous Access Performed by Emergency Department Nurses Using Semiautomatic Devices: A Randomized Crossover Simulation Study.
No study has examined the performance of emergency department (ED) nurses in establishing intraosseous access (IO) access. This study aimed to evaluate ED nurses' success rate in establishing pediatric IO access using semiautomatic devices. A randomized crossover simulation study was conducted. The success rates of ED nurses were compared with those of paramedics with similar years of experience. The study instruments were the new spring-loaded injector (NIO) and the battery power drill (EZ-IO). Uncooked piglets' bones were used as the study model. All attempts were filmed by a video camera. Successful placement was defined as the visualization of flow from the marrow cavity. Participants recorded their ranking of the "ease of use" of each device. No differences in 1-attempt success rate was found between nurses and paramedics (27/34 [79.4%] vs 25/30 [83.3%], P = 0.68). Nurses and paramedics had similar success rates with the 2 semiautomatic IO devices (12/17 vs 12/15 with the spring-loaded injector, P = 0.69, and 15/17 vs 13/15 with the battery power drill, P = 0.9). The number of failed attempts and the causes for failure were equally distributed between nurses and paramedics. Median ease-of-use Likert-scale scores of the spring-loaded injector and the battery power drill were 4 (interquartile range [IQR] = 3-4) and 5 (IQR = 5-5) (P < 0.04) for the nurses and 5 (IQR = 4-5) and 5 (IQR = 4-5) (P = 0.44) for the paramedics, respectively. Emergency department nurses and paramedics had a similarly high insertion success rates on a pediatric bone model. This pilot study suggests that ED nurses can successfully perform this procedure.


The role of capsid maturation on adenovirus priming for sequential uncoating.
Adenovirus assembly concludes with proteolytic processing of several capsid and core proteins. Immature virions containing precursor proteins lack infectivity because they cannot properly uncoat, becoming trapped in early endosomes. Structural studies have shown that precursors increase the network of interactions maintaining virion integrity. Using different biophysical techniques to analyze capsid disruption in vitro, we show that immature virions are more stable than the mature ones under a variety of stress conditions and that maturation primes adenovirus for highly cooperative DNA release. Cryoelectron tomography reveals that under mildly acidic conditions mimicking the early endosome, mature virions release pentons and peripheral core contents. At higher stress levels, both mature and immature capsids crack open. The virus core is completely released from cracked capsids in mature virions, but it remains connected to shell fragments in the immature particle. The extra stability of immature adenovirus does not equate with greater rigidity, because in nanoindentation assays immature virions exhibit greater elasticity than the mature particles. Our results have implications for the role of proteolytic maturation in adenovirus assembly and uncoating. Precursor proteins favor assembly by establishing stable interactions with the appropriate curvature and preventing premature ejection of contents by tightly sealing the capsid vertices. Upon maturation, core organization is looser, particularly at the periphery, and interactions preserving capsid curvature are weakened. The capsid becomes brittle, and pentons are more easily released. Based on these results, we hypothesize that changes in core compaction during maturation may increase capsid internal pressure to trigger proper uncoating of adenovirus.


Protective effect of fruits of Morinda citrifolia L. on scopolamine induced memory impairment in mice: a behavioral, biochemical and cerebral blood flow study.
Noni (Morinda citrifolia L.) is widely used for different illnesses including CNS disorders. Recently Noni has been reported to prevent amyloid beta induced memory impairment in mice. However, the influence of Noni on cholinergic system has not been explored so far. Therefore, present study was designed to investigate effect of Noni fruit on memory, cerebral blood flow (CBF), oxidative stress and acetylcholinesterase (AChE) activity in scopolamine induced amnesia model. Mice were orally treated with ethanolic extract of Noni fruit and chloroform, ethyl acetate and butanol fractions of ethanolic extract for three days. Scopolamine was administered 5 min prior to acquisition trial and memory function was evaluated by passive avoidance test. CBF was measured by laser doppler flowmetry. AChE activity and oxidative stress parameters were estimated in mice brain at the end of behavioral studies. Further, effect of ethanolic extract and its fractions (5-400 μg/ml) on AChE activity was measured in vitro. Scopolamine caused memory impairment along with reduced CBF, increased AChE activity and oxidative stress in mice brain. Ethanolic extract of Noni fruits and its chloroform and ethyl acetate fractions significantly improved memory and CBF. However, butanol fraction had no effect. Further, increased oxidative stress and AChE activity following scopolamine was significantly attenuated by ethanolic extract of Noni and its fractions. Moreover ethanolic extract and its fractions showed dose dependent inhibition of AChE activity in vitro. These observations suggest that Noni may be useful in memory impairment due to its effect on CBF, AChE and oxidative stress.


Lack of contextual-word predictability during reading in patients with mild Alzheimer disease.
In the present work we analyzed the effect of contextual word predictability on the eye movement behavior of patients with mild Alzheimer disease (AD) compared to age-matched controls, by using the eyetracking technique and lineal mixed models. Twenty AD patients and 40 age-matched controls participated in the study. We first evaluated gaze duration during reading low and highly predictable sentences. AD patients showed an increase in gaze duration, compared to controls, both in sentences of low or high predictability. In controls, highly predictable sentences led to shorter gaze durations; by contrary, AD patients showed similar gaze durations in both types of sentences. Similarly, gaze duration in controls was affected by the cloze predictability of word N and N+1, whereas it was the same in AD patients. In contrast, the effects of word frequency and word length were similar in controls and AD patients. Our results imply that contextual-word predictability, whose processing is proposed to require memory retrieval, facilitated reading behavior in healthy subjects, but this facilitation was lost in early AD patients. This loss might reveal impairments in brain areas such as those corresponding to working memory, memory retrieval, and semantic memory functions that are already present at early stages of AD. In contrast, word frequency and length processing might require less complex mechanisms, which were still retained by AD patients. To the best of our knowledge, this is the first study measuring how patients with early AD process well-defined words embedded in sentences of high and low predictability. Evaluation of the resulting changes in eye movement behavior might provide a useful tool for a more precise early diagnosis of AD.


(Alpha)3(beta)1 integrin regulates epithelial cytoskeletal organization.
Epithelial cell morphology and cytoskeletal organization are determined by interactions, with both adjacent cells and the extracellular matrix, which are mediated by integrins and cadherins. Little is known, however, of the relative contributions of integrins and cadherins to maintaining the sub-cortical cytoskeleton characteristic of epithelial cells. Since most studies that utilize integrin-blocking antibodies result in a loss of both cell-cell adhesion and sub-cortical cytoskeletal organization, it has been difficult to distinguish whether integrins and cadherins both mediate cytoskeletal assembly in epithelial cells. Therefore, cells derived from kidney collecting ducts of (alpha)3(beta)1 integrin-deficient mice were used to examine the role of integrins in epithelial cell morphology and cytoskeletal organization. In primary cell culture, (alpha)3(beta)1 integrin-deficient kidney collecting duct cells maintain cadherin-mediated cell-cell adhesions but fail to form the sub-cortical cytoskeleton that is characteristic of epithelial cells, and instead assemble actin stress fibers. Moreover, the cell-cell junctions in mutant cells were irregular, rather than being uniformly oriented perpendicular to the culture substrate. These results demonstrated that integrins have an primary and essential function in establishing and maintaining the sub-cortical cytoskeleton that is characteristic of epithelial cells. To further study the role of (alpha)3(beta)1 integrin in establishing and maintaining cytoskeletal organization in tubular epithelial cells, we derived immortalized cell lines from wild-type and (alpha)3(beta)1 integrin-deficient kidney collecting ducts that duplicated the cytoskeletal and cadherin organization observed in primary cells. E-cadherin and (alpha)- and (beta)-catenin were complexed together in equal amounts in membranes of wild-type and (alpha)3(beta)1 integrin-deficient cells. However, association of the cadherin:catenin complex with (alpha)-actinin was greatly decreased in mutant cells, indicating that integrin-mediated assembly of the sub-cortical cytoskeleton is essential for subsequent association of the cytoskeleton with the cadherin:catenin complex. These results present direct evidence for integrin:cadherin cross-regulation in which cadherin function is dependent on the presence of an integrin.


Sodium bicarbonate ingestion prior to training improves mitochondrial adaptations in rats.
We tested the hypothesis that reducing hydrogen ion accumulation during training would result in greater improvements in muscle oxidative capacity and time to exhaustion (TTE). Male Wistar rats were randomly assigned to one of three groups (CON, PLA, and BIC). CON served as a sedentary control, whereas PLA ingested water and BIC ingested sodium bicarbonate 30 min prior to every training session. Training consisted of seven to twelve 2-min intervals performed five times/wk for 5 wk. Following training, TTE was significantly greater in BIC (81.2 +/- 24.7 min) compared with PLA (53.5 +/- 30.4 min), and TTE for both groups was greater than CON (6.5 +/- 2.5 min). Fiber respiration was determined in the soleus (SOL) and extensor digitorum longus (EDL), with either pyruvate (Pyr) or palmitoyl carnitine (PC) as substrates. Compared with CON (14.3 +/- 2.6 nmol O(2).min(-1).mg dry wt(-1)), there was a significantly greater SOL-Pyr state 3 respiration in both PLA (19.6 +/- 3.0 nmol O(2).min(-1).mg dry wt(-1)) and BIC (24.4 +/- 2.8 nmol O(2).min(-1).mg dry wt(-1)), with a significantly greater value in BIC. However, state 3 respiration was significantly lower in the EDL from both trained groups compared with CON. These differences remained significant in the SOL, but not the EDL, when respiration was corrected for citrate synthase activity (an indicator of mitochondrial mass). These novel findings suggest that reducing muscle hydrogen ion accumulation during running training is associated with greater improvements in both mitochondrial mass and mitochondrial respiration in the soleus.


Regional soft tissue pains: alias myofascial pain?
This chapter deals with four main questions: what is the evidence that 'myofascial pain' syndromes exist?; what is the evidence that the myofascial pain concept is clinically useful?; what is the evidence that managing patients in terms of the myofascial pain diagnosis confers benefits?; and what is the evidence-based management of myofascial pain? The purpose of a diagnosis is to provide boundaries around subgroups of illness in a population since each subgroup presumably has a different mechanism, natural history, prognosis, course and response to treatment. The current literature is divided in its conceptual approach to the problem of regional musculoskeletal pain. Some authors regard myofascial pain as being distinct from regional musculoskeletal pain while others regard these as synonymous. A postulated theory of the pathophysiology of myofascial pain is discussed. This contrasts with a view that regional myofascial pain represents a non-specific localized pain arising from multiple regional, systemic and psychosocial factors. In order to consider myofascial pain as a distinct diagnosis, it would be necessary to resolve reliability issues in the identification of its critical diagnostic features. Beyond reliability issues, there are also problems of sensitivity and specificity--i.e. of the patient population that it identifies--which must be resolved if controlled trials are to be conducted. The clinical usefulness of the myofascial pain diagnosis is considered with regard to what is believed about the course of healing, the determinants of disability, the course of regional versus widespread musculoskeletal pain, the relationship of musculoskeletal injury to pain, and the evidence-based management of musculoskeletal pain. An epidemiological perspective is proposed with regard to regional musculoskeletal pain. This allows for the identification of operationally defined strata of regional musculoskeletal pain and permits studies in course, prognosis and treatment, even though some conceptual issues such as the 'myofascial pain diagnosis' remain to be clarified.


6-gingerol ameliorates age-related hepatic steatosis: Association with regulating lipogenesis, fatty acid oxidation, oxidative stress and mitochondrial dysfunction.
The prevalence of NAFLD increases with age. As the main active ingredient of ginger, 6-gingerol significantly improves lipid metabolism abnormalities in adult rodents. However, few studies have reported its effect on age-related NAFLD. This study was to investigate the effects of 6-gingerol on age-related hepatic steatosis and its potential targets. As expected, 6-gingerol dramatically normalized the hepatic triglyceride content, plasma insulin and HOMA-IR index of ageing rats. Mechanistically, 6-gingerol affected lipid metabolism by increasing β-oxidation and decreasing lipogenesis through activation of PPARα and CPT1α and inhibition of DGAT-2. Furthermore, 6-gingerol reversed the decreases in citrate, Cs and ATP, lessened the damage caused by ROS, and upregulated mitochondrial marker enzymes NOX, SDH, and SIRT3 in the ageing liver, indicating its ability to strengthen mitochondrial function. Our results showed 6-gingerol exerted a positive effect on insulin sensitivity by regulating Akt. In conclusion, the hepatic anti-steatotic effect of 6-gingerol is associated with inhibition of de novo lipogenesis, upregulation of fatty acid oxidation, reduction in oxidative stress and synergistic enhancement of mitochondrial function.


Measurement of dijet azimuthal decorrelation in pp collisions at [Formula: see text].
A measurement of the decorrelation of azimuthal angles between the two jets with the largest transverse momenta is presented for seven regions of leading jet transverse momentum up to 2.2[Formula: see text]. The analysis is based on the proton-proton collision data collected with the CMS experiment at a centre-of-mass energy of 8[Formula: see text] corresponding to an integrated luminosity of 19.7[Formula: see text]. The dijet azimuthal decorrelation is caused by the radiation of additional jets and probes the dynamics of multijet production. The results are compared to fixed-order predictions of perturbative quantum chromodynamics (QCD), and to simulations using Monte Carlo event generators that include parton showers, hadronization, and multiparton interactions. Event generators with only two outgoing high transverse momentum partons fail to describe the measurement, even when supplemented with next-to-leading-order QCD corrections and parton showers. Much better agreement is achieved when at least three outgoing partons are complemented through either next-to-leading-order predictions or parton showers. This observation emphasizes the need to improve predictions for multijet production.


Risk factors for intracerebral and subarachnoid hemorrhage among Hispanics and non-Hispanic whites in a New Mexico community.
A higher incidence of spontaneous intracerebral and subarachnoid hemorrhage among Hispanics than non-Hispanic whites has been measured in Bernalillo County, New Mexico. In an attempt to explain these differences, we compared historical vascular risk factors between Hispanics and non-Hispanic whites living in this community. An ongoing telephone survey, the Behavioral Risk Factor Surveillance System, collected annual data about vascular risk factors among non-institutionalized, randomly selected adults. Data covering 6 years, 1988-1993, were analyzed. There were 843 Hispanic and 1,635 non-Hispanic white residents of Bernalillo County, New Mexico, who participated in this survey. Because Hispanics were significantly younger than non-Hispanic whites (37.7 vs. 43.4 years, p < 0.001), all other comparisons were adjusted for age. Prevalence of hypertension was similar between these ethnic groups (15-17%). Prevalence of alcohol drinking considered risky for abuse was similar between these ethnic groups (5-6%), but was significantly higher among Hispanic men than women (8.5 vs. 1.6%, p < 0.001). The quantity of alcohol consumption among those at risk for abuse was similar between these ethnic groups. Prevalence of current cigarette smoking was similar between these ethnic groups (22-23%), but Hispanics smoked significantly less than non-Hispanic whites (11.4 vs. 15.2 cigarettes per day, p < 0.001) and among non-Hispanic whites, men smoked significantly more than women (17.0 vs. 13.4 cigarettes per day, p = 0.001). The vascular risk factors which we compared between Hispanics and non-Hispanic whites do not help to explain the higher incidence of hemorrhagic strokes among the Hispanics in Bernalillo County, New Mexico. Additional risk factors for hemorrhagic strokes in these two ethnic groups should be studied.


Comparison of Parental and Transgenic Alfalfa Rhizosphere Bacterial Communities Using Biolog GN Metabolic Fingerprinting and Enterobacterial Repetitive Intergenic Consensus Sequence-PCR (ERIC-PCR).
> Abstract Rhizosphere bacterial communities of parental and two transgenic alfalfa (Medicago sativa L.) of isogenic background were compared based on metabolic fingerprinting using Biolog GN microplates and DNA fingerprinting of bacterial communities present in Biolog GN substrate wells by enterobacterial repetitive intergenic consensus sequence-PCR (ERIC-PCR). The two transgenic alfalfa expressed either bacterial (Bacillus licheniformis) genes for alpha-amylase or fungal (Phanerochaete chrysosporium) genes for Mn-dependent lignin peroxidase (Austin S, Bingham ET, Matthews DE, Shahan MN, Will J, Burgess RR, Euphytica 85:381-393). Cluster analysis and principal components analysis (PCA) of the Biolog GN metabolic fingerprints indicated consistent differences in substrate utilization between the parental and lignin peroxidase transgenic alfalfa rhizosphere bacterial communities. Cluster analysis of ERIC-PCR fingerprints of the bacterial communities in Biolog GN substrate wells revealed consistent differences in the types of bacteria (substrate-specific populations) enriched from the rhizospheres of each alfalfa genotype. Comparison of ERIC-PCR fingerprints of bacterial strains obtained from substrate wells to substrate community ERIC-PCR fingerprints suggested that a limited number of populations were responsible for substrate oxidation in these wells. Results of this study suggest that transgenic plant genotype may affect rhizosphere microorganisms and that the methodology used in this study may prove a useful approach for the comparison of bacterial communities.


Oxidation of allylic and benzylic alcohols to aldehydes and carboxylic acids.
An oxidation of allylic and benzylic alcohols to the corresponding carboxylic acids is effected by merging a Cu-catalyzed oxidation using O2 as a terminal oxidant with a subsequent chlorite oxidation (Lindgren oxidation). The protocol was optimized to obtain pure products without chromatography or crystallization. Interception at the aldehyde stage allowed for Z/E-isomerization, thus rendering the oxidation stereoconvergent with respect to the configuration of the starting material.


APOBEC3G is a single-stranded DNA cytidine deaminase and functions independently of HIV reverse transcriptase.
In the absence of the viral vif gene, human immunodeficiency virus (HIV) may be restricted by the APOBEC3G gene on chromosome 22. The role of the HIV Vif protein is to exclude host cell APOBEC3G from the budding virion. As APOBEC3G shows sequence homology to cytidine deaminases, it is presumed that in the absence of Vif, cytidine residues in the cDNA are deaminated yielding uracil. It is not known if additional proteins mediate APOBEC3G function or if deamination occurs in concert with reverse transcription. This report describes an in vitro assay showing that Baculovirus derived APOBEC3G alone extensively deaminates cDNA independently of reverse transcriptase. It reproduces the dinucleotide context typical of G --> A hypermutants derived from a Delta(vif) virus. By using an RNaseH- form of reverse transcriptase, it was shown that the cDNA has to be free of its RNA template to allow deamination. APOBEC3G deamination of dC or dCTP was not detected. In short, APOBEC3G is a single-stranded DNA cytidine deaminase capable of restricting retroviral replication.


Effect of renin angiotensin system inhibitors on long-term major cardiovascular outcomes in patients with high atherosclerotic cardiovascular risk.
The advantage of angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) in patients with preserved LV systolic function is uncertain. We aimed to investigate the effects of ACEI/ARB in high atherosclerotic risk patients without overt heart failure (HF) on long-term major cardiovascular outcomes (MACEs). The Cohort Of patients with high Risk for cardiovascular Events (CORE-Thailand) registry is a prospective, multicenter, observational, longitudinal study of Thai patients with high atherosclerotic risk. The patients with ejection fraction < 50% were excluded. Among 8513 recruited patients, there were 4246 patients included into final analysis after propensity score matching. At 5-years follow-up, Cox regression analysis showed that ACEI/ARB was significantly associated with reduced risk of all-cause mortality or non-fatal myocardial infarction, non-fatal stroke and HF hospitalization (HR 0.82, 95% CI 0.70-0.96, P = 0.011). The benefit was driven by the reduced all-cause mortality and HF. Subgroup analysis demonstrated that ACEI/ARB decreased risk of long-term MACEs in patients with diabetes (HR 0.77, 95% CI 0.63-0.94, P = 0.011) and patients not taking statin (HR 0.57, 95% CI 0.40-0.82, P = 0.002). We demonstrated that the use of ACEI/ARB was associated with reduced risk of long-term MACEs in a large cohort of high atherosclerotic risk patients. Reduction of all-cause mortality and HF were likely the main contributors to the benefit of ACEI/ARB.


The curious relation between theory of mind and sharing in preschool age children.
Young children have long been known to act selfishly and gradually appear to become more generous across middle childhood. While this apparent change has been well documented, the underlying mechanisms supporting this remain unclear. The current study examined the role of early theory of mind and executive functioning in facilitating sharing in a large sample (N = 98) of preschoolers. Results reveal a curious relation between early false-belief understanding and sharing behavior. Contrary to many commonsense notions and predominant theories, competence in this ability is actually related to less sharing. Thus, the relation between developing theory of mind and sharing may not be as straightforward as it seems in preschool age children. It is precisely the children who can engage in theory of mind that decide to share less with others.


Identification of QTLs that modify peripheral neuropathy in NOD.H2b-Pdcd1-/- mice.
The non-obese diabetic (NOD) mouse strain is prone to developing various autoimmune syndromes including type I diabetes mellitus (T1DM), sialadenitis, thyroiditis and pancreatitis. Although the genetic basis of T1DM has been extensively analyzed, genetic factors that modify the other autoimmune phenotypes are largely unknown. We have recently reported that NOD mice with anti-diabetogenic MHC haplotype (H-2(b)) and programmed cell death 1 (PD-1) deficiency (NOD.H2(b)-Pdcd1(-/-) mice) are protected from T1DM but develop various tissue-specific autoimmune diseases including peripheral neuropathy due to autoimmune neuritis, sialadenitis and gastritis. In the present study, we generated [(C57BL/6 x NOD.H2(b))(F1) x NOD-H2(b)](BC1)-Pdcd1(-/-) mice to screen non-MHC quantitative trait loci (QTLs) that modify autoimmune phenotypes other than T1DM. We identified seven QTLs for peripheral neuropathy and neuritis, one QTL for insulitis, four QTLs for gastritis, two QTLs for sialadenitis and seven QTLs for vasculitis throughout the genome and designated them as Annp loci for autoimmunity due to polymorphisms of non-MHC genes in NOD mice and PD-1 deficiency. Annp1, 5, 6 and 7 overlapped with reported loci for T1DM (Idd3, 9, 15 and 2, respectively), suggesting that these loci modify not only T1DM but also other autoimmune phenotypes. NOD allele was promotive at 9 of 14 Annp loci, while NOD allele was protective at the other loci. Half of Annp loci associated with a single phenotype, while the other seven loci associated with more than two phenotypes. These results indicate that NOD genetic background harbors various QTLs that modify autoimmune phenotypes either by organ-specific or by organ-non-specific manner.


Physical Inactivity From Adolescence to Young Adulthood: The Relevance of Various Dimensions of Inequality in a Swedish Longitudinal Sample.
As physical inactivity may track from adolescence to adulthood, it is important to identify social determinants of physical inactivity in early life. However, most studies have measured socioeconomic position as one dimension. We examine whether multiple dimensions of socioeconomic position, in addition to other dimensions of inequality (i.e., gender, immigrant background), associate with physical inactivity at two time points in youth. Longitudinal data were drawn from the Swedish Level of Living Survey ( N = 765) and analysed by gender-stratified logistic regression. Among girls, low parental social class (odds ratio [OR] = 2.63, 95% confidence interval [CI; 1.28, 5.42]) and income (OR = 2.28, 95% [CI 1.12, 4.65]) were associated with physical inactivity, while immigrant background (OR = 2.33, 95% CI [1.03, 5.23]) and a low level of parental education (OR = 3.38, 95% CI [1.15, 9.95]) predicted physical inactivity among women. Among boys, low parental income (OR = 3.27, 95% CI [1.39, 7.69]) was associated with physical inactivity, whereas immigrant background (OR = 2.29, 95% CI [1.04, 5.03]) predicted physical inactivity among men. Our results suggest that physical inactivity is socially patterned, but different dimensions of social stratification should not be considered interchangeable as they may operate independently, through intersection with gender, and at different time points in youth in increasing the risk of physical inactivity.


Short introns interrupting the Oct-2 POU domain may prevent recombination between POU family genes without interfering with potential POU domain 'shuffling' in evolution.
Transcription factors are often encoded by gene families that share the same type of DNA binding domain. The POU domain genes are one such paradigm. We compared the genomic DNA encoding the POU domain of the Oct-2 genes in human and mouse. In both species this domain is split into a cluster of four exons by short, highly diverged introns. We postulate that the main role of these introns is to prevent ectopic homologous recombination with other members of the POU gene family, with its potentially deleterious effects in somatic and germline cells. Such rapidly diverging introns may generally promote evolution by facilitating the maintenance of duplicated genes. The use of different codons for the same protein domain among members of a gene family may be a slower process that serves a similar purpose. Introns that split conserved domains such as the POU domain do not conform to the exon shuffling hypothesis originally put forward by W. Gilbert (1978). However, we note that the introns flanking the POU domain are in the same phase, i.e. interrupt codons in the same reading frame. Thus we propose that the entire POU domain, which is encoded by a tight cluster of exons, has been shuffled together during evolution as a functional unit, or 'shufflon'.


Manitoba's population-based databases and long-term planning: beyond the hospital databases.
The Manitoba Centre for Health Policy and Evaluation (MCHPE) conducts health services research focusing on Manitoba's administrative databases. Administrative databases contain information which is routinely and systematically collected for administrative purposes such as hospital and physician claims and funding requirements. This article describes the MCHPE's five major databases, their strengths and limitations, and the development of the Population Health Information System (PHIS). Four modules from PHIS illustrate how the data are used to provide useful information for health care planners, administrators and policy analysts. Finally, future projects and directions for using administrative databases are explored.


The quality of communication about older patients between hospital physicians and general practitioners: a panel study assessment.
Optimal care of patients is dependent on good professional interaction between general practitioners and general hospital physicians. In Norway this is mainly based upon referral and discharge letters. The main objectives of this study were to assess the quality of the written communication between physicians and to estimate the number of patients that could have been treated at primary care level instead of at a general hospital. This study comprised referral and discharge letters for 100 patients above 75 years of age admitted to orthopaedic, pulmonary and cardiological departments at the city general hospital in Trondheim, Norway. The assessments were done using a Delphi technique with two expert panels, each with one general hospital specialist, one general practitioner and one public health nurse using a standardised evaluation protocol with a visual analogue scale (VAS). The panels assessed the quality of the description of the patient's actual medical condition, former medical history, signs, medication, Activity of Daily Living (ADL), social network, need of home care and the benefit of general hospital care. While information in the referral letters on actual medical situation, medical history, symptoms, signs and medications was assessed to be of high quality in 84%, 39%, 56%, 56% and 39%, respectively, the corresponding information assessed to be of high quality in discharge letters was for actual medical situation 96%, medical history 92%, symptoms 60%, signs 55% and medications 82%. Only half of the discharge letters had satisfactory information on ADL. Some two-thirds of the patients were assessed to have had large health benefits from the general hospital care in question. One of six patients could have been treated without a general hospital admission. The specialists assessed that 77% of the patients had had a large benefit from the general hospital care; however, the general practitioners assessment was only 59%. One of four of the discharge letters did not describe who was responsible for follow-up care. In this study from one general hospital both referral and discharge letters were missing vital medical information, and referral letters to such an extent that it might represent a health hazard for older patients. There was also low consensus between health professionals at primary and secondary level of what was high benefit of care for older patients at a general hospital.


TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort.
Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A. This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.


Measurement properties of the smartphone-based B-B Score in current shoulder pathologies.
This study is aimed at the determination of the measurement properties of the shoulder function B-B Score measured with a smartphone. This score measures the symmetry between sides of a power-related metric for two selected movements, with 100% representing perfect symmetry. Twenty healthy participants, 20 patients with rotator cuff conditions, 23 with fractures, 22 with capsulitis, and 23 with shoulder instabilities were measured twice across a six-month interval using the B-B Score and shoulder function questionnaires. The discriminative power, responsiveness, diagnostic power, concurrent validity, minimal detectable change (MDC), minimal clinically important improvement (MCII), and patient acceptable symptom state (PASS) were evaluated. Significant differences with the control group and significant baseline-six-month differences were found for the rotator cuff condition, fracture, and capsulitis patient groups. The B-B Score was responsive and demonstrated excellent diagnostic power, except for shoulder instability. The correlations with clinical scores were generally moderate to high, but lower for instability. The MDC was 18.1%, the MCII was 25.2%, and the PASS was 77.6. No floor effect was observed. The B-B Score demonstrated excellent measurement properties in populations with rotator cuff conditions, proximal humerus fractures, and capsulitis, and can thus be used as a routine test to evaluate those patients.


A geometric diffuse-interface method for droplet spreading.
This paper exploits the theory of geometric gradient flows to introduce an alternative regularization of the thin-film equation valid in the case of large-scale droplet spreading-the geometric diffuse-interface method. The method possesses some advantages when compared with the existing models of droplet spreading, namely the slip model, the precursor-film method and the diffuse-interface model. These advantages are discussed and a case is made for using the geometric diffuse-interface method for the purpose of numerical simulations. The mathematical solutions of the geometric diffuse interface method are explored via such numerical simulations for the simple and well-studied case of large-scale droplet spreading for a perfectly wetting fluid-we demonstrate that the new method reproduces Tanner's Law of droplet spreading via a simple and robust computational method, at a low computational cost. We discuss potential avenues for extending the method beyond the simple case of perfectly wetting fluids.


Development and application of an urban tree air quality score for photochemical pollution episodes using the Birmingham, United Kingdom, area as a case study.
An atmospheric chemistry model (CiTTyCAT) is used to quantify the effects of trees on urban air quality in scenarios of high photochemical pollution. The combined effects of both pollutant deposition to and emission of biogenic volatile organic compounds (BVOC) from the urban forest are considered, and the West Midlands, metropolitan area in the UK is used as a case study. While all trees can be beneficial to air quality in terms of the deposition of O3, NO2, CO, and HNO3, some trees have the potential to contribute to the formation of O3 due to the reaction of BVOC and NOx. A number of model scenarios are used to develop an urban tree air quality score (UTAQS) that ranks trees in order of their potential to improve air quality. Of the 30 species considered, pine, larch, and silver birch have the greatest potential to improve urban air quality, while oaks, willows, and poplars can worsen downwind air quality if planted in very large numbers. The UTAQS classification is designed with practitioners in mind, to help them achieve sustainable urban air quality. The UTAQS classification is applicable to all urban areas of the UK and other mid-latitude, temperate climate zones that have tree species common to those found in UK urban areas. The modeling approach used here is directly applicable to all areas of the world given the appropriate input data. It provides a tool that can help to achieve future sustainable urban air quality.


Electrophoretic build-up of alternately multilayered films and micropatterns based on graphene sheets and nanoparticles and their applications in flexible supercapacitors.
Graphene nanosheets and metal nanoparticles (NPs) have been used as nano-building-blocks for assembly into macroscale hybrid structures with promising performance in electrical devices. However, in most graphene and metal NP hybrid structures, the graphene sheets and metal NPs (e.g., AuNPs) do not enable control of the reaction process, orientation of building blocks, and organization at the nanoscale. Here, an electrophoretic layer-by-layer assembly for constructing multilayered reduced graphene oxide (RGO)/AuNP films and lateral micropatterns is presented. This assembly method allows easy control of the nano-architecture of building blocks along the normal direction of the film, including the number and thickness of RGO and AuNP layers, in addition to control of the lateral orientation of the resultant multilayered structures. Conductivity of multilayered RGO/AuNP hybrid nano-architecture shows great improvement caused by a bridging effect of the AuNPs along the out-of-plane direction between the upper and lower RGO layers. The results clearly show the potential of electrophoretic build-up in the fabrication of graphene-based alternately multilayered films and patterns. Finally, flexible supercapacitors based on multilayered RGO/AuNP hybrid films are fabricated, and excellent performance, such as high energy and power densities, are achieved.


[Epidemiology of overweight in Switzerland: results of the Swiss National Health Survey 1992-93].
In many western countries more than half of the population is considered overweight (BMI > or = 25). Data from the first national representative health survey for Switzerland (conducted 1992/93), including 7930 men and 7358 women (response rate 71%) aged 15 and over, were used. Means and percentiles of body weight, body height and BMI were calculated for men and women of different age groups. Overweight was defined as a BMI > or = 25, graded as overweight grade I (25.00-29.99), grade II (30.00-39.99), and grade III (BMI > or = 40.00) and analyzed according to gender, age, etc. Mean values for height decreases with increasing age, and body weight increases up to the age of 55-64 years in men and women. BMI values of all percentiles and age groups are lower for women than for men with the exception of age groups of 55 years or older and the 90 percentile. The prevalence of grade I overweight is 33.1% for men and 17.1% for women, of grade II overweight 5.8% and 4.5%, and of grade III overweight 0.3% and 0.2% respectively. Overall prevalence of overweight is 21.8% for women and 39.2% for men. Increasing age is associated with a higher prevalence of overweight. The prevalence of overweight in men increases with age up to 55-64 years, then levels off. In women, prevalence continues to rise. Overweight is more common in men of all age groups than in women. Periodic studies of the national prevalence of overweight are essential for monitoring the magnitude, and changes in the magnitude, of this serious public health problem.


High-strength resorbable brushite bone cement with controlled drug-releasing capabilities.
Brushite cements differ from apatite-forming compositions by consuming a lot of water in their setting reaction whereas apatite-forming cements consume little or no water at all. Only such cement systems that consume water during setting can theoretically produce near-zero porosity ceramics. This study aimed to produce such a brushite ceramic and investigated whether near elimination of porosity would prevent a burst release profile of incorporated antibiotics that is common to prior calcium phosphate cement delivery matrices. Through adjustment of the powder technological properties of the powder reactants, that is particle size and particle size distribution, and by adjusting citric acid concentration of the liquid phase to 800mM, a relative porosity of as low as 11% of the brushite cement matrix could be achieved (a 60% reduction compared to previous studies), resulting in a wet unprecompacted compressive strength of 52MPa (representing a more than 100% increase to previously reported results) with a workable setting time of 4.5min of the cement paste. Up to 2wt.% of vancomycin and ciprofloxacin could be incorporated into the cement system without loss of wet compressive strength. It was found that drug release rates could be controlled by the adjustable relative porosity of the cement system and burst release could be minimized and an almost linear release achieved, but the solubility of the antibiotic (vancomycin>ciprofloxacin) appeared also to be a crucial factor.


Reinforcement Learning in Sparse-Reward Environments With Hindsight Policy Gradients.
A reinforcement learning agent that needs to pursue different goals across episodes requires a goal-conditional policy. In addition to their potential to generalize desirable behavior to unseen goals, such policies may also enable higher-level planning based on subgoals. In sparse-reward environments, the capacity to exploit information about the degree to which an arbitrary goal has been achieved while another goal was intended appears crucial to enabling sample efficient learning. However, reinforcement learning agents have only recently been endowed with such capacity for hindsight. In this letter, we demonstrate how hindsight can be introduced to policy gradient methods, generalizing this idea to a broad class of successful algorithms. Our experiments on a diverse selection of sparse-reward environments show that hindsight leads to a remarkable increase in sample efficiency.


Breast reconstruction with the latissimus dorsi flap: women's preference for scar location.
Refinements made in latissimus dorsi breast reconstruction have improved the aesthetic appearance of the breast without changing the donor-site location. The optimal location for donor-site placement, from a patient's perspective, is still unknown. The purpose of this study was to assess women's preference for the latissimus dorsi donor-site location; the reasons for donor-site choice; and the correlation between donor-site location preference and factors such as, age, body mass index, body image, and clothing options. Two hundred fifty women between the ages of 20 and 80 years were surveyed. Participants analyzed patients' pictures and ranked the scar locations from most desirable to least desirable. The reason for preference and additional factors were assessed. The data were then collected and analyzed using contingency tables with p < 0.005. The low and middle transverse donor sites were the most preferred sites, 54 percent and 22 percent, respectively. The most common reasons for choosing a donors site were ability to conceal the scar in a low-back top and contour improvement. Women younger than 50 years were more concerned about the ability to conceal the scar (64 percent). Women older than 50 years were focused on contour improvement (40 percent) and concealing the scar while clothed (42 percent) (p < 0.05). No direct correlation with age, body mass index, body image, or clothing options was seen. Women overwhelmingly prefer the low and middle transverse scar locations. Physicians should consider using these locations primarily in suitable patients, as this may improve overall patient satisfaction following breast reconstruction.


A Pilot Study of the Effect of Aloe barbadensis Mill. Extract (AVH200®) in Patients with Irritable Bowel Syndrome: a Randomized, Double-Blind, Placebo-Controlled Study.
Few effective treatment options exist for patients with irritable bowel syndrome (IBS), and many patients state the use of aloe vera products reduce their symptoms. The aim of this pilot study was to investigate the effect of Aloe barbadensis Mill. Extract (AVH200®) in adult patients with IBS in a randomized, double-blind, placebo controlled study. Sixty-eight adult patients diagnosed with IBS according to the Rome III criteria were randomized to receive AVH200® or matching placebo for four weeks. Symptom questionnaires were completed on a weekly basis and the patients were asked if they had had adequate relief of their gastrointestinal symptoms. A tendency towards a higher proportion of responders in the aloe vera group (55%) vs. placebo (31%), (p=0.09) was observed, and the proportion of subjects who reported adequate relief at least 50% of the weeks during the treatment period tended to be larger in the aloe vera vs. placebo group (33% vs. 14%; p=0.12). The overall severity of the gastrointestinal symptoms was reduced in the aloe vera group (314+/-83 vs. 257+/-107; p=0.003) but not the placebo group (276+/-88 vs. 253+/-100; NS), without difference between the groups (p=0.10). AVH200® was well tolerated and no serious adverse events were observed. Even though the primary endpoint was not met, AVH200® seems to be a promising treatment option for patients with IBS owing to the positive results seen within the secondary endpoints. This study may have been underpowered to detect a clinically meaningful difference between the treatment groups, and therefore larger randomized, controlled studies are required to confirm these results and to elucidate potential mechanisms explaining its effect.


The detrimental effects of emotional process dysregulation on decision-making in substance dependence.
Substance dependence is complex and multifactorial, with many distinct pathways involved in both the development and subsequent maintenance of addictive behaviors. Various cognitive mechanisms have been implicated, including impulsivity, compulsivity, and impaired decision-making. These mechanisms are modulated by emotional processes, resulting in increased likelihood of initial drug use, sustained substance dependence, and increased relapse during periods of abstinence. Emotional traits, such as sensation-seeking, are risk factors for substance use, and chronic drug use can result in further emotional dysregulation via effects on reward, motivation, and stress systems. We will explore theories of hyper and hypo sensitivity of the brain reward systems that may underpin motivational abnormalities and anhedonia. Disturbances in these systems contribute to the biasing of emotional processing toward cues related to drug use at the expense of natural rewards, which serves to maintain addictive behavior, via enhanced drug craving. We will additionally focus on the sensitization of the brain stress systems that result in negative affect states that continue into protracted abstinence that is may lead to compulsive drug-taking. We will explore how these emotional dysregulations impact upon decision-making controlled by goal-directed and habitual action selections systems, and, in combination with a failure of prefrontal inhibitory control, mediate maladaptive decision-making observed in substance dependent individuals such that they continue drug use in spite of negative consequences. An understanding of the emotional impacts on cognition in substance dependent individuals may guide the development of more effective therapeutic interventions.


Formative Evaluation of a Text Messaging Intervention to Promote Varenicline Adherence Among Tobacco-Dependent Persons with HIV.
Few published studies describe processes in the development of mobile health interventions. This study reports data from a formative evaluation of a text messaging intervention being developed to increase adherence to smoking cessation medication (varenicline) among tobacco-dependent persons with HIV/AIDS. Four focus groups were conducted (N = 29) using a mixed-methods approach to assess: (a) beliefs and preferences regarding the use of varenicline, (b) preferences for receiving tobacco-related texts, and (c) the acceptability of draft text messages. Themes that emerged from the focus groups were that (a) participants were cautious and wanted to discuss varenicline carefully with health care providers, (b) participants preferred simple messages that were positive and encouraging, (c) messages should emphasize tobacco cessation and not varenicline adherence, and (d) texts would serve as a reminder about goals and foster support and connectedness with the health care team. Overall, 47 out of the 100 messages received a grade of C or less (rated on a 5-point grade scale: A, B, C, D, or F), the majority of which focused on medication adherence. All participants reported that they were likely to read the messages. The majority (64%) indicated that they preferred receiving 2 or more messages per day. Gathering systematic participant feedback provides critical input in intervention planning.


Ethanol metabolism and effects: nitric oxide and its interaction.
Ethanol (EtOH) in alcoholic beverages is consumed by a large number of individuals and its elimination is primarily by oxidation. The role of nitric oxide (NO) in EtOH's effects is important since NO is one of the most prominent biological factors in mammals. NO is constantly formed endogenously from L-arginine. Dose and length of EtOH exposure, and cell type are the main factors affecting EtOH effects on NO production. Either acute or chronic EtOH ingestion affects inducible NO synthase (iNOS) activity. However it seems that EtOH suppresses induced-NO production by inhibition of iNOS in different cells. On the other hand, it is clear that acute low doses of EtOH increase both the release of NO and endothelial NOS (eNOS) expression, and augment endothelium-mediated vasodilatation, whereas higher doses impair endothelial functions. EtOH selectively affects neuronal NOS (nNOS) activity in different brain cells, which may relate to various behavioral interactions. Therefore, there is an excellent chance for EtOH and NO to react with each other. Effects of EtOH on NO production and NOS activity may be important to EtOH modification of cell or organ function. Nitrosated compounds (alkyl nitrites) are often found as the interaction products, which might be one of the minor pathways of EtOH metabolism. NO also inhibits EtOH metabolizing enzymes. Furthermore, NO is involved in EtOH induced liver damage and has a role in fetal development during EtOH exposure in pregnancy. The mechanisms underlying these effects are only partially understood. Hence, the current discussion of the interaction of EtOH and NO is presented.


The new immunosuppression.
New knowledge on how lymphocytes become tolerant to antigens is now enabling novel tolerance-harnessing strategies to enter the clinical arena. In the field of transplantation, monoclonal antibodies used either to deplete lymphocytes or to block T-cell function can induce tolerance in mice and non-human primates. Understanding the mechanisms underlying tolerance should enable application to the clinic. Harnessing of tolerance mechanisms may enable more judicious use of conventional immunosuppressive agents even to the point of maintenance monotherapy, so limiting drug side effects and ensuring compliance.


MO-C-BRCD-01: Towards Personalized Medicine: Integration of Imaging into Therapy.
A significant advance in cancer therapy is currently underway with the evolution from a population-based to a personalized patient-based prescription. Rapid developments in imaging, particularly adoption of molecular imaging, offer unprecedented opportunities for accurate characterization of tumor biology, as well as early assessment of treatment response. Accurate characterization of tumor biology enables effective selection of appropriate therapy or even a design of purposefully non-uniform tumor-specific treatment plans, tailored to the spatial distribution of biological properties of each patient's tumor. Early assessment of treatment response enables treatment adaptation, potentially intensifying or reducing the treatment dose to provide more efficacious and less toxic therapies. However, integration of imaging into therapeutic applications requires a high level of image quantification, well beyond what is currently required in diagnostic imaging applications. This lecture will provide an overview of imaging applications in therapy, ranging from target selection totreatment response assessment. Potential roadblocks, as well as research opportunities on the path to personalization of cancer therapy, will be highlighted. 1. Understand the role of imaging in target definition and treatment response assessment 2. Understand the requirements for establishing imaging as a biomarker 3. Learn about research opportunities on the interface between imaging and therapy.


Experiences with community engagement and informed consent in a genetic cohort study of severe childhood diseases in Kenya.
The potential contribution of community engagement to addressing ethical challenges for international biomedical research is well described, but there is relatively little documented experience of community engagement to inform its development in practice. This paper draws on experiences around community engagement and informed consent during a genetic cohort study in Kenya to contribute to understanding the strengths and challenges of community engagement in supporting ethical research practice, focusing on issues of communication, the role of field workers in 'doing ethics' on the ground and the challenges of community consultation. The findings are based on action research methods, including analysis of community engagement documentation and the observations of the authors closely involved in their development and implementation. Qualitative and quantitative content analysis has been used for documentation of staff meetings and trainings, a meeting with 24 community leaders, and 40 large public and 70 small community group meetings. Meeting minutes from a purposive sample of six community representative groups have been analysed using a thematic framework approach. Field workers described challenges around misunderstandings about research, perceived pressure for recruitment and challenges in explaining the study. During consultation, leaders expressed support for the study and screening for sickle cell disease. In community meetings, there was a common interpretation of research as medical care. Concerns centred on unfamiliar procedures. After explanations of study procedures to leaders and community members, few questions were asked about export of samples or the archiving of samples for future research. Community engagement enabled researchers to take account of staff and community opinions and issues during the study and adapt messages and methods to address emerging ethical challenges. Field workers conducting informed consent faced complex issues and their understanding, attitudes and communication skills were key influences on ethical practice. Community consultation was a challenging concept to put into practice, illustrating the complexity of assessing information needs and levels of deliberation that are appropriate to a given study.


Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression.
Inappropriate discontinuation of drug treatment and noncompliance are a leading cause of long-term morbidity during treatment of depression. Increasing evidence supports an association between depressive illness and disturbances in brain glutamate activity, nitric oxide synthesis, and gamma-amino butyric acid. Animal models also confirm that suppression of glutamate N-methyl-D-aspartate receptor activity or inhibition of the nitric oxide-cyclic guanosine monophosphate pathway, as well as increasing brain levels of gamma-amino butyric acid, may be key elements in antidepressant action. Imaging studies demonstrate, for the most part, decreased hippocampal volume in patients with depression, which may worsen with recurrent depressive episodes. Preclinical models link this potentially neurodegenerative pathology to continued stress-evoked synaptic remodeling, driven primarily by the release of glucocorticoids, glutamate, and nitric oxide. These stress-induced structural changes can be reversed by antidepressant treatment. In patients with depression, antidepressant withdrawal after chronic administration is associated with a stress response as well as functional and neurochemical changes. Preclinical data also show that antidepressant withdrawal evokes a behavioral stress response that is associated with increased hippocampal N-methyl-D-aspartate receptor density, with both responses dependent on N-methyl-D-aspartate receptor activation. Drawing from both clinical and preclinical studies, this article proposes a preliminary molecular perspective and hypothesis on the neuronal implications of adherence to and discontinuation of antidepressant medication.


Effects of oocyte activation and sperm preparation on the development of porcine embryos derived from in vitro-matured oocytes and intracytoplasmic sperm injection.
The objective was to determine the effects of various methods of oocyte activation and sperm pretreatment on development of porcine embryos derived from in vitro-matured oocytes and intracytoplasmic sperm injection (ICSI). The second polar body was extruded in the majority (>78.4%) of in vitro-matured (IVM) oocytes 4h after electrical pulse activation. In embryos generated by ICSI and sham-ICSI, a combination of an electrical pulse, with various chemical activators 4 h later, improved (P < 0.05) blastocyst formation rate compared to activation only with a pulse. Treatment with 6-dimethylaminopurine (DMAP) after electrical activation significantly increased the oocyte activation rate. The effects of exposure of sperm to repeated freeze-thaw cycles (without cryoprotectant) on oocyte activation and the effects of sperm pre-incubated with dithiothreitol (DTT) or Triton X-100 on early embryo development were also examined. Blastocyst formation rates after ICSI did not differ between motile sperm and those rendered immotile by one-time freezing and thawing without cryoprotectant. However, sperm rendered immotile by three cycles of freezing/thawing without cryoprotectant had a significantly lower blastocyst formation rate. Although oocytes injected with sperm pre-incubated with Triton X-100 had a higher normal fertilization rate than those pre-incubated with DTT or one-time frozen/thawed sperm, rates of blastocyst formation and cell numbers were similar among the three groups. In conclusion, various methods of oocyte activation and sperm preparation significantly affected the developmental capacity of early porcine embryos derived from IVM and ICSI.


The M1 and pre-M1 segments contribute differently to ion selectivity in ASICs and ENaCs.
The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological function. Members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily of trimeric ion channels are typically sodium selective, but to a surprisingly variable degree. While acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium ratio ∼10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). This discrepancy may be expected to originate from differences in the pore-lining second transmembrane segment (M2). However, these show a relatively high degree of sequence conservation between ASICs and ENaCs, and previous functional and structural studies could not unequivocally establish that differences in M2 alone can account for the disparate degrees of ion selectivity. By contrast, surprisingly little is known about the contributions of the first transmembrane segment (M1) and the preceding pre-M1 region. In this study, we used conventional and noncanonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in hENaC show that these regions contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work suggests that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. These results further highlight how M1 and pre-M1 are likely to differentially affect pore structure in these related channels.