Sialoliths or phleboliths?
Salivary gland obstruction caused by vascular malformation with phleboliths is relatively uncommon and may be masquerading as sialolithiasis. This article presents the case of a patient who suffered from vascular malformation with phleboliths that caused submandibular gland obstruction and was once misdiagnosed as sialolithiasis. Illustrative case report and review of the literature. Our patient was presented with recurrent episodes of right submandibular swelling and pain at mealtime for two years. The radiopacities in the X-ray film were misdiagnosed as multiple sialoliths. The sialendoscopic surgery ruled out the sialoliths, and an impressively expanded vascular network consisting of capillaries was detected all over the ductal lumen. We diagnosed vascular malformation with phleboliths. A search of the MEDLINE database (from 1948 to February 2009) was performed. The patient was treated with sclerotherapy. The clinical outcome was satisfactory during a follow-up of 28 months, with no evidence of recurrence. The results of the extensive literature review showed that vascular malformation with phleboliths that leads to submandibular gland obstruction is rare with a total of three cases reported, including this patient. Vascular malformation with phleboliths must be included in the differential diagnosis of salivary gland obstruction.


Connecticut's 'Money Follows The Person' Yields Positive Results For Transitioning People Out Of Institutions.
A centerpiece of federal and state efforts to rebalance long-term services and supports to enhance consumer choice and contain costs, the federal Money Follows the Person Rebalancing Demonstration helps qualified individuals living in institutions make the transition to life in the community. The Connecticut Money Follows the Person program is an unusually rich source of data, with information on the 2,262 people who transitioned to the community under that state's program during 2008-14. Responses to participant surveys completed before and six, twelve, and twenty-four months after transition indicate that, for the majority of respondents who remained in the community, quality of life and life satisfaction improved significantly after transition, and they stayed high. About half of the participants visited hospitals or emergency departments after transition; however, only 14 percent had returned to an institution one year after transition. Predictors of reinstitutionalization included some not previously observed: mental health disability, difficulties with family members before transition, and not exercising choice and control in daily life. These and other findings suggest multiple ways in which policy makers can target efforts to strengthen transition programs that can meaningfully improve people's lives while containing costs.


Mathematical simulation of cerebral blood flow in focal ischemia.
A computer model was developed to describe regional cerebral blood flow and tissue oxygenation with autoregulation during focal ischemia produced by occlusion of th middle cerebral artery (MCA). This steady state model described the distribution of blood flow in the cerebral arterial system including the circle of Willis as well as the pial arterial anastomoses, and included a simplified form of autoregulation based on the local control of pressure and flow in the pial and intracerebral arteries, respectively. Preliminary simulation studies with the model yielded the following results. Less effective autoregulation was predicted by the model at low blood pressure in focal ischemia. Passive dilatation of the pial vasculature produced a leftward shift in the autoregulatory curve. Simulations with occlusion of the MCA revealed the ultimate importance of the pial anastomoses in providing adequate blood and oxygen supply in the ischemic territories including the specially vulnerable lenticulostriate area. The volume of the ischemic (pO2 less than 1 mmHg) brain tissue in the MCA-cortex estimated by using a concurrent Krogh cylinder model was 50% when the pial anastomoses were 80 micrometers in diameter and the ischemic area disappeared at 170 micrometers diameter. With relatively small anastomoses (less than 200 m) the model demonstrated intracerebral steal during intracerebral vasodilation. Passive dilation of the pial arteries including the pial anastomoses caused the steal to disappear and to reverse. These results suggest that both autoregulatory shift and steal reversal can be explained by passive dilatation of the pial vasculature.


Moderate-level resistance to glycopeptide LY333328 mediated by genes of the vanA and vanB clusters in enterococci.
Three of five natural plasmids carrying a wild-type vanA gene cluster did not confer LY333328 glycopeptide resistance on Enterococcus faecalis JH2-2 (MIC = 2 microg/ml). The two remaining plasmids conferred resistance to the drug (MIC, 8 microg/ml). The vanB gene cluster did not confer resistance to LY333328, since this antibiotic was not an inducer. Mutations in the vanS(B) sensor gene that allowed induction by teicoplanin or constitutive expression of the vanB cluster led to LY333328 resistance (MIC, 8 to 16 microg/ml). Overproduction of the VanH, VanA, and VanX proteins for D-alanyl-D-lactate (D-Ala-D-Lac) synthesis and D-Ala-D-Ala hydrolysis was sufficient for resistance to LY333328 (MIC, 16 microg/ml). Mutations in the host D-Ala:D-Ala ligase contributed to LY333328 resistance in certain VanA- and VanB-type strains, but the MICs of the antibiotic did not exceed 16 microg/ml. Addition of D-2-hydroxybutyrate in the culture medium of mutants that did not produce the VanH D-lactate dehydrogenase led to incorporation of this D-2-hydroxy acid at the C-terminal ends of the peptidoglycan precursors and to LY333328 resistance (MIC, 64 microg/ml). The vanZ gene of the vanA cluster conferred resistance to LY333328 (MIC, 8 microg/ml) by an unknown mechanism. These data indicate that VanA- and VanB-type enterococci may acquire moderate-level resistance to LY333328 (MIC </= 16 microg/ml) in a single step by various mechanisms.


Systemic resistance to gray mold induced in tomato by benzothiadiazole and Trichoderma harzianum T39.
Gray mold (Botrytis cinerea) is an important disease of tomato (Solanum lycopersicum). This study examined defense-related gene expression involved in the resistance to B. cinerea that is induced in tomato plants by benzothiadiazole and Trichoderma harzianum T39 soil drench. In whole plants, transcriptional changes related to salicylic acid and ethylene were induced by the application of a 0.01% benzothiadiazole solution, whereas changes related to jasmonic acid were induced by the application of a 0.4% T39 suspension. On detached leaves, soil treatment by T39 led to enhanced resistance to B. cinerea infection that was proportional to the concentration of the T39 suspension. By 5 days after pathogen inoculation, the plants that had received the 0.04% T39 drench exhibited 62% less severe disease than the untreated plants. The 0.4% T39 drench led to an 84% reduction in disease severity. Observations of B. cinerea infection in leaves harvested from plants grown in the treated soils revealed that drenching with a T39 suspension induces systemic resistance against B. cinerea and primes salicylic acid- and ethylene-related gene expression in a manner proportional to the concentration of the biocontrol agent. Benzothiadiazole treatment induced resistance to gray mold independently of salicylic acid and led to strong priming of two genes known to be involved in defense against B. cinerea, Pti5 and PI2.


Electrochemical measurement of transport into scoliotic intervertebral discs in vivo using nitrous oxide as a tracer.
An in vivo study measuring nitrous oxide concentrations in scoliotic intervertebral discs during surgery. To determine pathways for nutrient transport into scoliotic human discs in vivo. The intervertebral disc is the largest avascular structure in the body. Disc cells in the nucleus rely on the blood supply from the vertebral bodies for supply of nutrients and removal of waste. Loss of nutrient supply is thought to lead to disc degeneration, but solute transport has not been measured in vivo in humans. We measured solute transport into the disc using N2O as a tracer, in 19 human discs from five patients with neuromuscular scoliosis (6-19 years of age) during surgery for correction of scoliotic deformities. During anesthesia N2O diffuses into the disc at a rate governed by effective permeability of the vertebral body-disc interface. Intradiscal N2O concentrations were measured amperometrically using silver needle microelectrodes, which were inserted into the discs once they were exposed by an anterior approach. For all spines N2O concentrations were very low in the disc at the curve apex (6% those expected from unimpeded diffusion) and, although still low, were significantly higher 2 discs below or above the apex. Because flux into the apical disc is most restricted, the decrease in solute transport is possibly induced by changes in mechanical stress on the disc; microfocal radiographs of a scoliotic spine suggest that increased endplate calcification could be partly responsible for limiting solute diffusion.


Estimating Marginal Returns to Education.
This paper estimates marginal returns to college for individuals induced to enroll in college by different marginal policy changes. The recent instrumental variables literature seeks to estimate this parameter, but in general it does so only under strong assumptions that are tested and found wanting. We show how to utilize economic theory and local instrumental variables estimators to estimate the effect of marginal policy changes. Our empirical analysis shows that returns are higher for individuals with values of unobservables that make them more likely to attend college. We contrast our estimates with IV estimates of the return to schooling.


Factors influencing the degree of eating ability among people with dementia.
To explore the degree of eating ability in people with dementia and identify what factors affect their eating ability. Appropriate food consumption is important to human life. Although eating difficulties are common among people with dementia, little is known about what factors might influence their eating ability. Descriptive, cross-sectional study. A total of 149 people with dementia residing in nursing facilities in Seoul or the Gyeonggi area of Korea were evaluated using the Korean Mini-Mental State Examination, Korean Activities of Daily Living Scale and Eating Behaviour Scale. Data were analysed using descriptive statistics, one-way analysis of variance, Pearson correlation coefficient and multiple regression analysis. The participants showed a moderate level of dependency with respect to eating ability and were most dependent on the use of utensils. There were significant differences in eating ability according to general characteristics such as duration of residence, duration of illness, degree of visual impairment, eating place, and diet type. The eating ability of the participants was significantly correlated with cognitive function and physical function. Cognitive function, physical function, duration of illness, eating place (living room or dining room), and diet type (soft or liquid) significantly predicted eating ability in people with dementia. The findings of this study suggest that it is necessary to thoroughly assess the eating ability of people with dementia and to develop appropriate training programs to maintain or improve their remaining eating ability. The creation of a pleasurable physical and social environment for eating might also be helpful. These findings would be able to serve a useful basis in the development of materials for nursing intervention programs for people with dementia during mealtimes by improving the techniques and care qualities of nursing caregivers.


PTFOS: flexible and absorbable intracranial electrodes for magnetic resonance imaging.
Intracranial electrocortical recording and stimulation can provide unique knowledge about functional brain anatomy in patients undergoing brain surgery. This approach is commonly used in the treatment of medically refractory epilepsy. However, it can be very difficult to integrate the results of cortical recordings with other brain mapping modalities, particularly functional magnetic resonance imaging (fMRI). The ability to integrate imaging and electrophysiological information with simultaneous subdural electrocortical recording/stimulation and fMRI could offer significant insight for cognitive and systems neuroscience as well as for clinical neurology, particularly for patients with epilepsy or functional disorders. However, standard subdural electrodes cause significant artifact in MRI images, and concerns about risks such as cortical heating have generally precluded obtaining MRI in patients with implanted electrodes. We propose an electrode set based on polymer thick film organic substrate (PTFOS), an organic absorbable, flexible and stretchable electrode grid for intracranial use. These new types of MRI transparent intracranial electrodes are based on nano-particle ink technology that builds on our earlier development of an EEG/fMRI electrode set for scalp recording. The development of MRI-compatible recording/stimulation electrodes with a very thin profile could allow functional mapping at the individual subject level of the underlying feedback and feed forward networks. The thin flexible substrate would allow the electrodes to optimally contact the convoluted brain surface. Performance properties of the PTFOS were assessed by MRI measurements, finite difference time domain (FDTD) simulations, micro-volt recording, and injecting currents using standard electrocortical stimulation in phantoms. In contrast to the large artifacts exhibited with standard electrode sets, the PTFOS exhibited no artifact due to the reduced amount of metal and conductivity of the electrode/trace ink and had similar electrical properties to a standard subdural electrode set. The enhanced image quality could enable routine MRI exams of patients with intracranial electrode implantation and could also lead to chronic implantation solutions.


Reconstitution of papillomavirus E2-mediated plasmid maintenance in Saccharomyces cerevisiae by the Brd4 bromodomain protein.
The papillomavirus E2 protein functions in viral transcriptional regulation, DNA replication, and episomal genome maintenance. Viral genomes are maintained in dividing cells by attachment to mitotic chromosomes by means of the E2 protein. To investigate the chromosomal tethering function of E2, plasmid stability assays were developed in Saccharomyces cerevisiae to determine whether the E2 protein could maintain plasmids containing the yeast autonomous replication sequence replication element but with the centromeric element replaced by E2-binding sites. E2 expression was not sufficient to maintain such plasmids, but plasmid stability could be rescued by expression of the mammalian protein Brd4. In the presence of both Brd4 and E2 proteins, plasmids with multiple E2-binding sites were stable without selection. S. cerevisiae encodes a homolog of Brd4 named Bdf1 that does not contain the C-terminal domain that interacts with the E2 protein. A fusion protein of Bdf1 and the Brd4 C-terminal "tail" could support E2-mediated plasmid maintenance in yeast. Using a panel of mutated E2 proteins, we determined that plasmid stability required the ability of E2 to bind DNA and to interact with Brd4 and mammalian mitotic chromosomes but did not require its replication initiation and transactivation functions. The S. cerevisiae-based plasmid maintenance assays described here are invaluable tools for dissecting mechanisms of episomal viral genome replication and screening for additional host protein factors involved in plasmid maintenance.


Abdominal Incision Injection of Liposomal Bupivacaine and Opioid Use After Laparotomy for Gynecologic Malignancies.
To investigate opioid use and pain scores associated with incisional injection of liposomal bupivacaine compared with bupivacaine hydrochloride after laparotomy for gynecologic malignancies. A retrospective cohort study was conducted to compare abdominal incision infiltration with liposomal bupivacaine with bupivacaine hydrochloride after modification of a pre-existing enhanced recovery pathway. Patients undergoing staging laparotomy or complex cytoreductive surgery under the updated pathway were compared with patients treated under the original pathway (historic controls). Endpoints included cumulative opioid use (primary outcome) in oral morphine equivalents and cumulative pain score. In the complex cytoreductive cohort, median oral morphine equivalents were lower in the liposomal bupivacaine group through 24 hours (30 compared with 53.5 mg, P=.002), 48 hours (37.5 compared with 82.5 mg, P=.005), and the length of stay (62 compared with 100.5 mg, P=.006). Fewer liposomal bupivacaine patients required intravenous rescue opioids (28.9% compared with 55.6%, P<.001) or patient-controlled analgesia (4.1% compared with 33.3%, P<.001). Cumulative pain score was no different between groups through 48 hours (161 compared with 158, P=.69). Postoperative nausea and ileus were less frequent in patients receiving liposomal bupivacaine. Median hospital stay was 5 days in both groups. In the staging laparotomy cohort, cumulative opioids and cumulative pain score were no different between groups (through 48 hours: 162 compared with 161, P=.62; 38 compared with 38, P=.68, respectively). Intravenous rescue opioids (15.3% compared with 28.6%, P=.05) and patient-controlled analgesia (1.4% compared with 8.3%, P=.05) were used less frequently in the liposomal bupivacaine group. Median hospital stay was 4 days in both groups. Despite the higher cost of liposomal bupivacaine, total pharmacy costs did not differ between groups. Abdominal incision infiltration with liposomal bupivacaine was associated with less opioid and patient-controlled analgesia use with no change in pain scores compared with bupivacaine hydrochloride after complex cytoreductive surgery for gynecologic malignancies. Improvements were also seen in patients undergoing staging laparotomy.


The metagenomics of disease-suppressive soils - experiences from the METACONTROL project.
Soil teems with microbial genetic information that can be exploited for biotechnological innovation. Because only a fraction of the soil microbiota is cultivable, our ability to unlock this genetic complement has been hampered. Recently developed molecular tools, which make it possible to utilize genomic DNA from soil, can bypass cultivation and provide information on the collective soil metagenome with the aim to explore genes that encode functions of key interest to biotechnology. The metagenome of disease-suppressive soils is of particular interest given the expected prevalence of antibiotic biosynthetic clusters. However, owing to the complexity of soil microbial communities, deciphering this key genetic information is challenging. Here, we examine crucial issues and challenges that so far have hindered the metagenomic exploration of soil by drawing on experience from a trans-European project on disease-suppressive soils denoted METACONTROL.


REWARD: Design, Optimization, and Evaluation of a Real-Time Relative-Energy Wearable R-Peak Detection Algorithm.
Wearable devices are an unobtrusive, cost-effective means of continuous ambulatory monitoring of chronic cardiovascular diseases. However, on these resource-constrained systems, electrocardiogram (ECG) processing algorithms must consume minimal power and memory, yet robustly provide accurate physiological information. This work presents REWARD, the Relative-Energy-based WeArable R-Peak Detection algorithm, which is a novel ECG R-peak detection mechanism based on a nonlinear filtering method called Relative-Energy (Rel-En). REWARD is designed and optimized for real-time execution on wearable systems. Then, this novel algorithm is compared against three state-of-the-art real-time R-peak detection algorithms in terms of accuracy, memory footprint, and energy consumption. The Physionet QT and NST Databases were employed to evaluate the algorithms' accuracy and robustness to noise, respectively. Then, a 32-bit ARM Cortex-M3-based microcontroller was used to measure the energy usage, computational burden, and memory footprint of the four algorithms. REWARD consumed at least 63% less energy and 32% less RAM than the other algorithms while obtaining comparable accuracy results. Therefore, REWARD would be a suitable choice of R-peak detection mechanism for wearable devices that perform more complex ECG analysis, whose algorithms require additional energy and memory resources.


Extended pancreaticoduodenectomy with vascular resection for pancreatic cancer: a systematic review.
This systematic review objectively evaluates the safety and outcomes of extended pancreaticoduodenectomy with vascular resection for pancreatic cancer involving critical adjacent vessels namely the superior mesenteric-portal veins, hepatic artery, superior mesenteric artery, and celiac axis. Electronic searches were performed on two databases from January 1995 to August 2009. The end points were: firstly, to evaluate the safety through reporting the mortality rate and associated complications and, secondly, the outcome by reporting the survival after surgery. This was synthesized through a narrative review with full tabulation of results of all included studies. Twenty-eight retrospective studies comprising of 1,458 patients were reviewed. Vein thrombosis and arterial involvement were reported as contraindications to surgery in 62% and 71% of studies, respectively. The median mortality rate was 4% (range, 0% to 17%). The median R0 and R1 rates were 75% (range, 14% to 100%) and 25% (range, 0% to 86%), respectively. In high volume centers, the median survival was 15 months (range, 9 to 23 months). Nine of 10 (90%) studies comparing the survival after extended pancreaticoduodenectomy with vascular resection versus standard pancreaticoduodenectomy reported statistically similar (p > 0.05) survival outcomes. Undertaking vascular resection was not associated with a poorer survival. The morbidity, mortality, and survival outcome after undertaking extended pancreaticoduodenectomy with vascular resection for pancreatic cancer with venous involvement and/or limited arterial involvement is acceptable in the setting of an expert referral center and should not be a contraindication to a curative surgery.


Selective interaction of PEGylated polyglutamic acid nanocapsules with cancer cells in a 3D model of a metastatic lymph node.
Metastases are the most common reason of cancer death in patients with solid tumors. Lymph nodes, once invaded by tumor cells, act as reservoirs before cancer cells spread to distant organs. To address the limited access of intravenously infused chemotherapeutics to the lymph nodes, we have developed PEGylated polyglutamic acid nanocapsules (PGA-PEG NCs), which have shown ability to reach and to accumulate in the lymphatic nodes and could therefore act as nanotransporters. Once in the lymphatics, the idea is that these nanocapsules would selectively interact with cancer cells, while avoiding non-specific interactions with immune cells and the appearance of subsequent immunotoxicity. The potential of the PGA-PEG NCs, with a mean size of 100 nm and a negative zeta potential, to selectively reach metastatic cancer cells, has been explored in a novel 3D model that mimics an infiltrated lymph node. Our 3D model, a co-culture of cancer cells and lymphocytes, allows performing experiments under dynamic conditions that simulate the lymphatic flow. After perfusion of the nanocarriers, we observe a selective interaction with the tumor cells. Efficacy studies manifest the need to develop specific therapies addressed to treat metastatic cells that can be in a dormant state. We provide evidence of the ability of PGA-PEG NCs to selectively interact with the tumor cells in presence of lymphocytes, highlighting their potential in cancer therapeutics. We also state the importance of designing precise in vitro models that allow performing mechanistic assays, to efficiently develop and evaluate specific therapies to confront the formation of metastasis.


Optimizing time histograms for non-Poissonian spike trains.
The time histogram is a fundamental tool for representing the inhomogeneous density of event occurrences such as neuronal firings. The shape of a histogram critically depends on the size of the bins that partition the time axis. In most neurophysiological studies, however, researchers have arbitrarily selected the bin size when analyzing fluctuations in neuronal activity. A rigorous method for selecting the appropriate bin size was recently derived so that the mean integrated squared error between the time histogram and the unknown underlying rate is minimized (Shimazaki & Shinomoto, 2007 ). This derivation assumes that spikes are independently drawn from a given rate. However, in practice, biological neurons express non-Poissonian features in their firing patterns, such that the spike occurrence depends on the preceding spikes, which inevitably deteriorate the optimization. In this letter, we revise the method for selecting the bin size by considering the possible non-Poissonian features. Improvement in the goodness of fit of the time histogram is assessed and confirmed by numerically simulated non-Poissonian spike trains derived from the given fluctuating rate. For some experimental data, the revised algorithm transforms the shape of the time histogram from the Poissonian optimization method.


Top 20 Research Studies of 2014 for Primary Care Physicians.
A team of primary care clinicians with expertise in evidence-based medicine performed monthly surveillance of more than 110 English-language clinical research journals during 2014, and identified 255 studies that had the potential to change how family physicians practice. Each study was critically appraised and summarized, focusing on its relevance to primary care practice, validity, and likelihood that it could change practice. A validated tool was used to obtain feedback from members of the Canadian Medical Association about the clinical relevance of each POEM (patient-oriented evidence that matters) and the benefits they expect for their practice. This article, the fourth installment in this annual series, summarizes the 20 POEMs based on original research studies judged to have the greatest impact on practice for family physicians. Key studies for this year include advice on symptomatic management and prognosis for acute respiratory infections; a novel and effective strengthening treatment for plantar fasciitis; a study showing that varenicline plus nicotine replacement is more effective than varenicline alone; a network meta-analysis concluding that angiotensin-converting enzyme inhibitors are preferred over angiotensin II receptor blockers; the clear benefits of initial therapy with metformin over other agents in patients with diabetes mellitus; and important guidance on the use of anticoagulants.


Human genetic data reveal contrasting demographic patterns between sedentary and nomadic populations that predate the emergence of farming.
Demographic changes are known to leave footprints on genetic polymorphism. Together with the increased availability of large polymorphism data sets, coalescent-based methods allow inferring the past demography of populations from their present-day patterns of genetic diversity. Here, we analyzed both nuclear (20 noncoding regions) and mitochondrial (HVS-I) resequencing data to infer the demographic history of 66 African and Eurasian human populations presenting contrasting lifestyles (nomadic hunter-gatherers, nomadic herders, and sedentary farmers). This allowed us to investigate the relationship between lifestyle and demography and to address the long-standing debate about the chronology of demographic expansions and the Neolithic transition. In Africa, we inferred expansion events for farmers, but constant population sizes or contraction events for hunter-gatherers. In Eurasia, we inferred higher expansion rates for farmers than herders with HVS-I data, except in Central Asia and Korea. Although isolation and admixture processes could have impacted our demographic inferences, these processes alone seem unlikely to explain the contrasted demographic histories inferred in populations with different lifestyles. The small expansion rates or constant population sizes inferred for herders and hunter-gatherers may thus result from constraints linked to nomadism. However, autosomal data revealed contraction events for two sedentary populations in Eurasia, which may be caused by founder effects. Finally, the inferred expansions likely predated the emergence of agriculture and herding. This suggests that human populations could have started to expand in Paleolithic times, and that strong Paleolithic expansions in some populations may have ultimately favored their shift toward agriculture during the Neolithic.


The FGF and FGFR Gene Family and Risk of Cleft Lip With or Without Cleft Palate.
Background : Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods : We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results : Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion : Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.


The Relationships Between Internal and External Measures of Training Load and Intensity in Team Sports: A Meta-Analysis.
The associations between internal and external measures of training load and intensity are important in understanding the training process and the validity of specific internal measures. We aimed to provide meta-analytic estimates of the relationships, as determined by a correlation coefficient, between internal and external measures of load and intensity during team-sport training and competition. A further aim was to examine the moderating effects of training mode on these relationships. We searched six electronic databases (Scopus, Web of Science, PubMed, MEDLINE, SPORTDiscus, CINAHL) for original research articles published up to September 2017. A Boolean search phrase was created to include search terms relevant to team-sport athletes (population; 37 keywords), internal load (dependent variable; 35 keywords), and external load (independent variable; 81 keywords). Articles were considered for meta-analysis when a correlation coefficient describing the association between at least one internal and one external measure of session load or intensity, measured in the time or frequency domain, was obtained from team-sport athletes during normal training or match-play (i.e., unstructured observational study). The final data sample included 122 estimates from 13 independent studies describing 15 unique relationships between three internal and nine external measures of load and intensity. This sample included 295 athletes and 10,418 individual session observations. Internal measures were session ratings of perceived exertion (sRPE), sRPE training load (sRPE-TL), and heart-rate-derived training impulse (TRIMP). External measures were total distance (TD), the distance covered at high and very high speeds (HSRD ≥ 13.1-15.0 km h-1 and VHSRD ≥ 16.9-19.8 km h-1, respectively), accelerometer load (AL), and the number of sustained impacts (Impacts > 2-5 G). Distinct training modes were identified as either mixed (reference condition), skills, metabolic, or neuromuscular. Separate random effects meta-analyses were conducted for each dataset (n = 15) to determine the pooled relationships between internal and external measures of load and intensity. The moderating effects of training mode were examined using random-effects meta-regression for datasets with at least ten estimates (n = 4). Magnitude-based inferences were used to interpret analyses outcomes. During all training modes combined, the external load relationships for sRPE-TL were possibly very large with TD [r = 0.79; 90% confidence interval (CI) 0.74 to 0.83], possibly large with AL (r = 0.63; 90% CI 0.54 to 0.70) and Impacts (r = 0.57; 90% CI 0.47 to 0.64), and likely moderate with HSRD (r = 0.47; 90% CI 0.32 to 0.59). The relationship between TRIMP and AL was possibly large (r = 0.54; 90% CI 0.40 to 0.66). All other relationships were unclear or not possible to infer (r range 0.17-0.74, n = 10 datasets). Between-estimate heterogeneity [standard deviations (SDs) representing unexplained variation; τ] in the pooled internal-external relationships were trivial to extremely large for sRPE (τ range = 0.00-0.47), small to large for sRPE-TL (τ range = 0.07-0.31), and trivial to moderate for TRIMP (τ range= 0.00-0.17). The internal-external load relationships during mixed training were possibly very large for sRPE-TL with TD (r = 0.82; 90% CI 0.75 to 0.87) and AL (r = 0.81; 90% CI 0.74 to 0.86), and TRIMP with AL (r = 0.72; 90% CI 0.55 to 0.84), and possibly large for sRPE-TL with HSRD (r = 0.65; 90% CI 0.44 to 0.80). A reduction in these correlation magnitudes was evident for all other training modes (range of the change in r when compared with mixed training - 0.08 to - 0.58), with these differences being unclear to possibly large. Training mode explained 24-100% of the between-estimate variance in the internal-external load relationships. Measures of internal load derived from perceived exertion and heart rate show consistently positive associations with running- and accelerometer-derived external loads and intensity during team-sport training and competition, but the magnitude and uncertainty of these relationships are measure and training mode dependent.


Modelling calcium microdomains using homogenisation.
Microdomains of calcium (i.e., areas on the nanometer scale that have qualitatively different calcium concentrations from that in the bulk cytosol) are known to be important in many situations. In cardiac cells, for instance, a calcium microdomain between the L-type channels and the ryanodine receptors, the so-called diadic cleft, is where the majority of the control of calcium release occurs. In other cell types that exhibit calcium oscillations and waves, the importance of microdomains in the vicinity of clusters of inositol trisphosphate receptors, or between the endoplasmic reticulum (ER) and other internal organelles or the plasma membrane, is clear. Given the limits of computational power, it is not currently realistic to model an entire cellular cytoplasm by incorporating detailed structural information about the ER throughout the entire cytoplasm. Hence, most models use a homogenised approach, assuming that both cytoplasm and ER coexist at each point of the domain. Conversely, microdomain models can be constructed, in which detailed structural information can be incorporated, but, until now, methods have not been developed for linking such a microdomain model to a model at the level of the entire cell. Using the homogenisation approach we developed in an earlier paper [Goel, P., Friedman, A., Sneyd, J., 2006. Homogenization of the cell cytoplasm: the calcium bidomain equations. SIAM J. Multiscale Modeling Simulation, in press] we show how a multiscale model of a calcium microdomain can be constructed. In this model a detailed model of the microdomain (in which the ER and the cytoplasm are separate compartments) is coupled to a homogenised model of the entire cell in a rigorous way. Our method is illustrated by a simple model of the diadic cleft of a cardiac half-sarcomere.


High-risk human papillomavirus is sexually transmitted: evidence from a follow-up study of virgins starting sexual activity (intercourse).
Genital human papillomavirus (HPV) infection is generally considered to be sexually transmitted. However, nonsexual spread of the virus has also been suggested. The goal of this study was to assess: (a) the role of sexual intercourse in the transmission of HPV; (b) the determinants for seroconversion; and (c) the correlation between HPV DNA, abnormal cervical cytology, and serological response to HPV16. One hundred virgins and 105 monogamous women were randomly selected from a population-based cohort study in Copenhagen, Denmark, in which the women were examined twice with 2-year interval (interview, cervical swabs, Pap smear, blood samples). The presence of HPV DNA was determined by GP5+/6+ primers based HPV-PCR-EIA. HPV 16 virus-like particles (VLP) antibodies were detected by ELISA. All of the virgins were both HPV DNA negative and seronegative to VLP16, except for one woman who was weakly HPV 6 DNA positive. Only those virgins who initiated sexual activity became HPV DNA positive and/or VLP16 positive. The most important determinant of HPV DNA acquisition was the number of partners between the two examinations. The only significant risk factor for HPV 16 VLP seroconversion among women acquiring HPV DNA was HPV type. Our results show that sexual intercourse is important in the transmission of HPV, and that HPV 16 VLP seroconversion and the development of cervical lesions only occur after HPV transmission. Remarkably, no cervical lesions were found in HPV 16 DNA positive women who had seroconverted. Although based on small numbers, this may suggest that the development of antibodies had a protective effect.


Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.
The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease. Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66-1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy. This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.


Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains.
Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain. To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology. Expression of AQP4 was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact "young" individuals aged younger than 60 years (range, 33-57 years), cognitively intact "aged" individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwent Western blot analysis (15 young, 24 aged, and 21 with AD). Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated. Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = -2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage (R2 = 0.14; P = .006). In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.


Bactericidal activity of curcumin I is associated with damaging of bacterial membrane.
Curcumin, an important constituent of turmeric, is known for various biological activities, primarily due to its antioxidant mechanism. The present study focused on the antibacterial activity of curcumin I, a significant component of commercial curcumin, against four genera of bacteria, including those that are Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa). These represent prominent human pathogens, particularly in hospital settings. Our study shows the strong antibacterial potential of curcumin I against all the tested bacteria from Gram-positive as well as Gram-negative groups. The integrity of the bacterial membrane was checked using two differential permeabilization indicating fluorescent probes, namely, propidium iodide and calcein. Both the membrane permeabilization assays confirmed membrane leakage in Gram-negative and Gram-positive bacteria on exposure to curcumin I. In addition, scanning electron microscopy and fluorescence microscopy were employed to confirm the membrane damages in bacterial cells on exposure to curcumin I. The present study confirms the broad-spectrum antibacterial nature of curcumin I, and its membrane damaging property. Findings from this study could provide impetus for further research on curcumin I regarding its antibiotic potential against rapidly emerging bacterial pathogens.


Using the RE-AIM framework to evaluate a physical activity intervention in churches.
Health-e-AME was a 3-year intervention designed to promote physical activity at African Methodist Episcopal churches across South Carolina. It is based on a community-participation model designed to disseminate interventions through trained volunteer health directors. We used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework to evaluate this intervention through interviews with 50 health directors. Eighty percent of the churches that had a health director trained during the first year of the intervention and 52% of churches that had a health director trained during the second year adopted at least one component of the intervention. Lack of motivation or commitment from the congregation was the most common barrier to adoption. Intervention activities reached middle-aged women mainly. The intervention was moderately well implemented, and adherence to its principles was adequate. Maintenance analyses showed that individual participants in the intervention's physical activity components continued their participation as long as the church offered them, but churches had difficulties continuing to offer physical activity sessions. The effectiveness analysis showed that the intervention produced promising, but not significant, trends in levels of physical activity. Our use of the RE-AIM framework to evaluate this intervention serves as a model for a comprehensive evaluation of the health effects of community programs to promote health.


Quality of life of parents of mentally-ill children: a systematic review and meta-analysis.
To examine the quality of life (QOL) of parents of children with a specific mental disorder (any age). Relevant articles were searched using different databases. Articles were included that compared the QOL of parents with mentally-ill children to parents of healthy controls or norm values or provided the required data for this comparison. A meta-analysis was conducted to obtain an overall mean effect size estimate. Additional analyses were performed to assess publication bias and moderation. Twenty-six out of 10 548 articles met the pre-defined inclusion criteria. Most of these studies focused on attention-deficit/hyperactivity disorder or autism spectrum disorder, used clinical samples that mainly included males and young children and studied the QOL of mothers. The meta-analysis revealed that parents of mentally-ill children are experiencing a clinically relevant reduction in their QOL relative to parents of healthy children and norm values (g = -0.66). The compromised QOL of parents of mentally-ill children needs to be considered and addressed by health professionals who are in contact with them. The paper provides insights into existing research gaps and suggests improvements for subsequent work.


A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer.
Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines are bioactive, but limited by disease burden and immune tolerance. Cyclophosphamide augments vaccine activity in tolerant neu mice and in patients with metastatic breast cancer. HER2-specific monoclonal antibodies (mAb) enhance vaccine activity in neu mice. We hypothesized that cyclophosphamide-modulated vaccination with HER2-specific mAb safely induces relevant HER2-specific immunity in neu mice and patients with HER2+ metastatic breast cancer. Adding both cyclophosphamide and the HER2-specific mAb 7.16.4 to vaccination maximized HER2-specific CD8+ T-cell immunity and tumor-free survival in neu transgenic mice. We, therefore, conducted a single-arm feasibility study of cyclophosphamide, an allogeneic HER2+ GM-CSF-secreting breast tumor vaccine, and weekly trastuzumab in 20 patients with HER2+ metastatic breast cancer. Primary clinical trial objectives were safety and clinical benefit, in which clinical benefit represents complete response + partial response + stable disease. Secondary study objectives were to assess HER2-specific T-cell responses by delayed type hypersensitivity (DTH) and intracellular cytokine staining. Patients received three monthly vaccinations, with a boost 6 to 8 months from trial entry. This combination immunotherapy was safe, with clinical benefit rates at 6 months and 1 year of 55% [95% confidence interval (CI), 32%-77%; P = 0.013] and 40% (95% CI, 19%-64%), respectively. Median progression-free survival and overall survival durations were 7 months (95% CI, 4-16) and 42 months (95% CI, 22-70), respectively. Increased HER2-specific DTH developed in 7 of 20 patients [of whom 4 had clinical benefit (95% CI, 18-90)], with a trend toward longer progression-free survival and overall survival in DTH responders. Polyfunctional HER2-specific CD8+ T cells progressively expanded across vaccination cycles. Further investigation of cyclophosphamide-modulated vaccination with trastuzumab is warranted.


Cytogenetic studies in human blood lymphocytes exposed in vitro to radiofrequency radiation at a cellular telephone frequency (835.62 MHz, FDMA).
Freshly collected peripheral blood samples from four healthy human volunteers were diluted with RPMI 1640 tissue culture medium and exposed in sterile T-75 tissue culture flasks in vitro for 24 h to 835.62 MHz radiofrequency (RF) radiation, a frequency employed for customer-to-base station transmission of cellular telephone communications. An analog signal was used, and the access technology was frequency division multiple access (FDMA, continuous wave). A nominal net forward power of 68 W was used, and the nominal power density at the center of the exposure flask was 860 W/m(2). The mean specific absorption rate in the exposure flask was 4.4 or 5.0 W/kg. Aliquots of diluted blood that were sham-exposed or exposed in vitro to an acute dose of 1.50 Gy of gamma radiation were used as negative or positive controls. Immediately after the exposures, the lymphocytes were stimulated with a mitogen, phytohemagglutinin, and cultured for 48 or 72 h to determine the extent of genetic damage, as assessed from the frequencies of chromosomal aberrations and micronuclei. The extent of alteration in the kinetics of cell proliferation was determined from the mitotic indices in 48-h cultures and from the incidence of binucleate cells in 72-h cultures. The data indicated no significant differences between RF-radiation- and sham-exposed lymphocytes with respect to mitotic indices, incidence of exchange aberrations, excess fragments, binucleate cells, and micronuclei. In contrast, the response of the lymphocytes exposed to gamma radiation was significantly different from both RF-radiation- and sham-exposed cells for all of these indices. Thus, under the experimental conditions tested, there is no evidence for the induction of chromosomal aberrations and micronuclei in human blood lymphocytes exposed in vitro for 24 h to 835.62 MHz RF radiation at SARs of 4.4 or 5.0 W/kg.


Modular and selective biosynthesis of gasoline-range alkanes.
Typical renewable liquid fuel alternatives to gasoline are not entirely compatible with current infrastructure. We have engineered Escherichia coli to selectively produce alkanes found in gasoline (propane, butane, pentane, heptane, and nonane) from renewable substrates such as glucose or glycerol. Our modular pathway framework achieves carbon-chain extension by two different mechanisms. A fatty acid synthesis route is used to generate longer chains heptane and nonane, while a more energy efficient alternative, reverse-β-oxidation, is used for synthesis of propane, butane, and pentane. We demonstrate that both upstream (thiolase) and intermediate (thioesterase) reactions can act as control points for chain-length specificity. Specific free fatty acids are subsequently converted to alkanes using a broad-specificity carboxylic acid reductase and a cyanobacterial aldehyde decarbonylase (AD). The selectivity obtained by different module pairings provides a foundation for tuning alkane product distribution for desired fuel properties. Alternate ADs that have greater activity on shorter substrates improve observed alkane titer. However, even in an engineered host strain that significantly reduces endogenous conversion of aldehyde intermediates to alcohol byproducts, AD activity is observed to be limiting for all chain lengths. Given these insights, we discuss guiding principles for pathway selection and potential opportunities for pathway improvement.


Helping northern Ethiopian communities reduce childhood mortality: population-based intervention trial.
More than 10 million children die each year mostly from preventable causes and particularly in developing countries. WHO guidelines for the Integrated Management of Childhood Illness (IMCI) are intended to reduce childhood mortality and are being implemented in Ethiopia. As well as specific clinical interventions, the role of the community in understanding and acting on childhood sickness is an important factor in improving survival. This trial sought to assess the effect on survival of community-based health promotion activities. Two districts in northern Ethiopia were studied, each with a random sample of more than 4000 children less than 5 years old. Regular six-monthly visits were made to document deaths among children. After the first year, communities in one district were educated about issues of good childcare and caring for sick children while the other district received this information only after the trial ended. Although overall mortality was higher in the post-intervention period, most of the increase was seen in the control area. A Cox proportional hazards model gave an adjusted hazard ratio of 0.66 (95% confidence interval = 0.46-0.95) for the intervention area compared with the control area in the post-intervention period, with no significant pre-intervention difference. Significant survival advantages were found for females, children of younger fathers, those with married parents, those living in larger households, and those whose nearest health facility was a health centre. For all of the children who died, only 44% of parents or caregivers had sought health care before the child's death. This non-specific community-based public health intervention, as an addition to IMCI strategies in local health facilities, appears to have significantly reduced childhood mortality in these communities. The possibility that such interventions may not effectively reach certain social groups (for example single parents) is an important consideration for implementation of similar strategies in future. The synergy between community awareness and the availability of effective peripheral health services is also an issue that needs further exploration.


The cohesin subunit Rad21 is required for synaptonemal complex maintenance, but not sister chromatid cohesion, during Drosophila female meiosis.
Replicated sister chromatids are held in close association from the time of their synthesis until their separation during the next mitosis. This association is mediated by the ring-shaped cohesin complex that appears to embrace the sister chromatids. Upon proteolytic cleavage of the α-kleisin cohesin subunit at the metaphase-to-anaphase transition by separase, sister chromatids are separated and segregated onto the daughter nuclei. The more complex segregation of chromosomes during meiosis is thought to depend on the replacement of the mitotic α-kleisin cohesin subunit Rad21/Scc1/Mcd1 by the meiotic paralog Rec8. In Drosophila, however, no clear Rec8 homolog has been identified so far. Therefore, we have analyzed the role of the mitotic Drosophila α-kleisin Rad21 during female meiosis. Inactivation of an engineered Rad21 variant by premature, ectopic cleavage during oogenesis results not only in loss of cohesin from meiotic chromatin, but also in precocious disassembly of the synaptonemal complex (SC). We demonstrate that the lateral SC component C(2)M can interact directly with Rad21, potentially explaining why Rad21 is required for SC maintenance. Intriguingly, the experimentally induced premature Rad21 elimination, as well as the expression of a Rad21 variant with destroyed separase consensus cleavage sites, do not interfere with chromosome segregation during meiosis, while successful mitotic divisions are completely prevented. Thus, chromatid cohesion during female meiosis does not depend on Rad21-containing cohesin.


Evaluating the criterion validity of hierarchical psychopathology dimensions across models: Familial aggregation and associations with research domain criteria (sub)constructs.
The Hierarchical Taxonomy of Psychopathology (HiTOP) posits that psychopathology is a hierarchy of correlated dimensions. Numerous studies have examined the validity of these dimensions using bifactor models, in which each disorder loads onto both a general and specific factor (e.g., internalizing, externalizing). Although bifactor models tend to fit better than alternative models, concerns have been raised about bifactor model selection, factor reliability, and interpretability. Therefore, we compared the reliability and validity of several higher-order HiTOP dimensions between bifactor and correlated factor models using familial aggregation and associations with Research Domain Criteria (RDoC; sub)constructs as validators. Lifetime psychopathology was assessed in a community sample (N = 504) using dimensional disorder severity scales calculated from semistructured interview data. A series of unidimensional, correlated factor, and bifactor models were fit to model several HiTOP dimensions. A bifactor model with two specific factors (internalizing and disinhibited externalizing) and a correlated two-factor model provided the best fit to the data. HiTOP dimensions had adequate reliability in the correlated factor model, but suboptimal reliability in the bifactor model. The disinhibited externalizing dimension was highly correlated across the two models and was familial, yet largely unrelated to RDoC (sub)constructs in both models. The internalizing dimension in the correlated factor model and the general factor in the bifactor model were highly correlated and had similar validity patterns, suggesting the general factor was largely redundant with the internalizing dimension in the correlated factor model. These findings support concerns about the interpretability of psychopathology dimensions in bifactor models. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Dentists' perceptions of barriers to providing dental care to pregnant women.
The purpose of the study was to understand US dentists' attitudes, knowledge, and practices regarding dental care for pregnant women and to determine the impact of recent papers on oral health and pregnancy and guidelines disseminated widely. In 2006 and 2007, the investigators conducted a mailed survey of all 1,604 general dentists in Oregon; 55.2% responded). Structural equation modeling was used to estimate associations between dentists' attitudes toward providing care to pregnant women, dentists' knowledge about the safety of dental procedures, and dentists' current practice patterns. Dentist's perceived barriers have the strongest direct effect on current practice and might be the most important factor deterring dentists from providing care to pregnant patients. Five attitudes (perceived barriers) were associated with providing less dental services: time, economic, skills, dental staff resistance, and peer pressure. The final model shows a good fit with a chi-square of 38.286 (p = .12; n = 772; df = 52) and a Bentler-Bonett normed fit index of .98 and a comparative fit index of .993. The root mean square error of approximation is .02. Findings suggest that attitudes are significant determinants of accurate knowledge and current practice. Multidimensional approaches are needed to increase access to dental care and protect the oral health of women during pregnancy. Despite current clinical recommendations to deliver all necessary care to pregnant patients during the first, second, and third trimesters, dentists' knowledge of the appropriateness of procedures continues to lag the state of the art in dental science.


EFNS guidelines on neurostimulation therapy for neuropathic pain.
Pharmacological relief of neuropathic pain is often insufficient. Electrical neurostimulation is efficacious in chronic neuropathic pain and other neurological diseases. European Federation of Neurological Societies (EFNS) launched a Task Force to evaluate the evidence for these techniques and to produce relevant recommendations. We searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions. Spinal cord stimulation (SCS) is efficacious in failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS) type I (level B recommendation). High-frequency transcutaneous electrical nerve stimulation (TENS) may be better than placebo (level C) although worse than electro-acupuncture (level B). One kind of repetitive transcranial magnetic stimulation (rTMS) has transient efficacy in central and peripheral neuropathic pains (level B). Motor cortex stimulation (MCS) is efficacious in central post-stroke and facial pain (level C). Deep brain stimulation (DBS) should only be performed in experienced centres. Evidence for implanted peripheral stimulations is inadequate. TENS and r-TMS are non-invasive and suitable as preliminary or add-on therapies. Further controlled trials are warranted for SCS in conditions other than failed back surgery syndrome and CRPS and for MCS and DBS in general. These chronically implanted techniques provide satisfactory pain relief in many patients, including those resistant to medication or other means.


Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis.
The Mycobacterium smegmatis genome contains many genes encoding putative drug efflux pumps. Yet with the exception of lfrA, it is not clear whether these genes contribute to the intrinsic drug resistance of this organism. We showed first by reverse transcription (RT)-PCR that several of these genes, including lfrA as well as the homologues of Mycobacterium tuberculosis Rv1145, Rv1146, Rv1877, Rv2846c (efpA), and Rv3065 (mmr and emrE), were expressed at detectable levels in the strain mc(2)155. Null mutants each carrying an in-frame deletion of these genes were then constructed in M. smegmatis. The deletions of the lfrA gene or mmr homologue rendered the mutant more susceptible to multiple drugs such as fluoroquinolones, ethidium bromide, and acriflavine (two- to eightfold decrease in MICs). The deletion of the efpA homologue also produced increased susceptibility to these agents but unexpectedly also resulted in decreased susceptibility to rifamycins, isoniazid, and chloramphenicol (two- to fourfold increase in MICs). Deletion of the Rv1877 homologue produced some increased susceptibility to ethidium bromide, acriflavine, and erythromycin. The upstream region of lfrA contained a gene encoding a putative TetR family transcriptional repressor, dubbed LfrR. The deletion of lfrR elevated the expression of lfrA and produced higher resistance to multiple drugs. Multidrug-resistant single-step mutants, independent of LfrA and attributed to a yet-unidentified drug efflux pump (here called LfrX), were selected in vitro and showed decreased accumulation of norfloxacin, ethidium bromide, and acriflavine in intact cells. Finally, use of isogenic beta-lactamase-deficient strains showed the contribution of LfrA and LfrX to resistance to certain beta-lactams in M. smegmatis.


Knowledge, attitudes, and behaviors of parents towards varicella and its vaccination.
The aims of this cross-sectional survey were to examine the knowledge, the attitudes, and the behavior regarding the varicella infection and its vaccination and to get insight into their determinants among parents of children in Italy. From May to June 2015 in the geographic area of Naples (Italy) a random sample of 675 parents of children aged 4-7 years received a self-administered anonymous questionnaire about socio-demographic characteristics, knowledge, attitudes, and behaviors towards varicella and its vaccination. A total of 414 parents responded to the questionnaire, for a response rate of 61.3%. A history of varicella was reported in 163 children (39.6%). Only 26.6% parents knew that the vaccine was available and the number of doses and this knowledge was significantly higher in those who had a university degree, in those who had received information on the vaccination from a health care provider, and in those who had vaccinated their child. The perceived utility towards vaccination had a mean value of 5.7. The positive attitude towards the utility of the vaccination was higher in parents with a level of education not higher than middle school, in those who had vaccinated their child, in those who considered the varicella a dangerous disease, and in those who had received information from a health care provider. More than one-third had vaccinated their child. Immunization was more frequent in parents who had knowledge about the vaccination, who beliefs that the immunization was useful, who believed that the disease was not dangerous, and who had not a history of varicella among their children. Educational programs are needed among parents as support to improve knowledge about vaccination and immunization coverage.


Knowledge, attitudes and practices (kap) regarding influenza A (H1N1) among a population living along Thai-Myanmar border, Ratchaburi Province, Thailand.
The 2009 influenza A (H1N1) outbreaks in Thailand was successfully controlled, partly through the use of electronic media to educate the public. People living along the Thai-Myanmar border may have less access to this electronic media or might have health beliefs that differ from the general Thai population with potential to impact an influenza outbreak. We conducted a survey to assess the knowledge, attitudes and practices regarding influenza among people living along the Thai-Myanmar boder in Ratchaburi Province, Thailand. Of 110 house- holds surveyed, 96% were Karen ethnicity. Greater than 50% were uneducated and most had a low family income. Knowledge about influenza was low. Attitudes regarding infection were mostly negative among the elderly in this area. Practices regarding influenza were moderately good. Education level was associated with knowledge and practice. Income level and wealth indicators were associated with knowledge and having a radio or TV was associated with good practices. Preventive behavior was associated with good knowledge but not with attitudes about influenza. Health education campaigns are needed in these communities to help people adopt desired changes in behavior to improve personal hygiene.


Modeling colitis-associated cancer with azoxymethane (AOM) and dextran sulfate sodium (DSS).
Individuals with inflammatory bowel disease (IBD), such as Crohn's disease (CD) or ulcerative colitis (UC) are at increased risk of developing colorectal cancer (CRC) over healthy individuals. This risk is proportional to the duration and extent of disease, with a cumulative incidence as high as 30% in individuals with longstanding UC with widespread colonic involvement. Colonic dysplasia in IBD and colitis associated cancer (CAC) are believed to develop as a result of repeated cycles of epithelial cell injury and repair while these cells are bathed in a chronic inflammatory cytokine milieu. While spontaneous and colitis-associated cancers share the quality of being adenocarcinomas, the sequence of underlying molecular events is believed to be different. This distinction argues the need for specific animal models of CAC. Several mouse models currently exist for the study of CAC. Dextran sulfate sodium (DSS), an agent with direct toxic effects on the colonic epithelium, can be administered in drinking water to mice in multiple cycles to create a chronic inflammatory state. With sufficient duration, some of these mice will develop tumors. Tumor development is hastened in this model if administered in a pro-carcinogenic setting. These include mice with genetic mutations in tumorigenesis pathways (APC, p53, Msh2), as well as mice pre-treated with genotoxic agents (azoxymethane [AOM], 1,2-dimethylhydrazine [DMH]). The combination of DSS with AOM as a model for colitis associated cancer has gained popularity for its reproducibility, potency, low price, and ease of use. Though they have a shared mechanism, AOM has been found to be more potent and stable in solution than DMH. While tumor development in other models generally requires several months, mice injected with AOM and subsequently treated with DSS develop adequate tumors in as little as 7-10 weeks. Finally, AOM and DSS can be administered to mice of any genetic background (knock out, transgenic, etc.) without cross-breeding to a specific tumorigenic strain. Here, we demonstrate a protocol for inflammation-driven colonic tumorigenesis in mice utilizing a single injection of AOM followed by three seven-day cycles of DSS over a 10 week period. This model induces tumors with histological and molecular changes closely resembling those occurring in human CAC and provides a highly valuable model for the study of oncogenesis and chemoprevention in this disease.


Cold smoking of Atlantic salmon (Salmo salar) fillets with smoke condensate--an alternative processing technology for the production of smoked salmon.
Two different protocols for the production of cold smoked salmon were investigated. All fillets were dry salted (18 h, 4 degrees C) before being allotted to a smoke condensate/liquid smoke protocol (SCP), which included drenching (1 min) in smoke condensate [1:3 (v/v) smoke:water] and drying (150 min, 28.4 +/- 2.2 degrees C) or a wood chips protocol (WCP) that included drying and smoking in a regular smoking chamber (23 degrees C, 480 min) using wood chips for smoke production. Quality assessments were performed on the smoked fillets at day 0 and after 7, 14, and 31 d of storage (3.4 +/- 0.7 degrees C). Application of the SCP resulted in a significantly higher (P<0.01) processing yield (89.6% +/- 0.7%) as compared to the WCP (88.6% +/- 0.5%). On day 0, the SCP fillets were significantly (P<0.01) less light (L*) and yellow (b*) and had a lower chroma (C*) and hue (h*) compared to the fillets processed with WCP. From 7 d until the end of storage time, small differences in color were observed. After 31 d of storage, the SCP fillets had a significantly higher (P<0.05) intensity of oily texture and lower intensity of salty and smoke taste. Texture profile analysis (TPA) showed few significant differences between the processing protocols, although the WCP fillets were significantly harder than the SCP fillets when recording the force at 60% compression of the fillet height. The use of smoke condensate and drenching technology is a way of producing cold smoked salmon with quality characteristics quite similar to those found in commercial "traditional" products, although processors who want to use this technology have to optimize the drying step and the smoke condensate formulation to their specifications.


Structure-based design of targeted covalent inhibitors.
Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non-covalent small molecule inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery scientists the ability to increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional groups designed to covalently bind to specific sites in a target. In this tutorial review we introduce the broader concept of covalent inhibition, discuss the potential benefits and challenges of such an approach, and provide an overview of the current status of the field. We also describe some strategies and computational tools to enable successful covalent drug discovery.


Longer booking intervals in general practice: effects on doctors' stress and arousal.
A controlled trial was carried out to determine whether longer booking intervals at surgeries affected general practitioners' self-assessed levels of stress and arousal. Sixteen general practitioners from 10 practices took part. Surgery sessions with patients booked at 10 minute intervals (experimental sessions) were compared with the doctors' usual booking intervals of between 7.5 and 5.0 minutes (control sessions). Stress and arousal were assessed by the general practitioner before and after each surgery session using a mood adjective check list. The study included 109 experimental and 184 control sessions. The median consultation length increased from six minutes in the control sessions to seven minutes in the experimental sessions. At the end of the experimental sessions, stress scores were lower, and arousal scores higher than at the end of the control sessions (P less than 0.001). There were no significant differences between experimental and control sessions in stress or arousal at the start of the sessions. Favourable mood changes were seen more consistently in the experimental sessions than control sessions, with less than a quarter of doctors showing increased stress or decreased arousal after sessions relative to before. It is concluded that longer booking intervals are of psychological advantage to general practitioners.


Characterizing occupational heat-related mortality in the United States, 2000-2010: an analysis using the Census of Fatal Occupational Injuries database.
Occupational heat-related mortality is not well studied and risk factors remain largely unknown. This paper describes the epidemiological characteristics of heat-related deaths among workers in the US 2000-2010. Fatality data were obtained at the Bureau of Labor Statistics from the confidential on-site Census of Fatal Occupational Injuries database. Fatality rates and risk ratios with 95% confidence intervals were calculated by year, sex, age group, ethnicity, race, state, and industry. Between 2000 and 2010, 359 occupational heat-related deaths were identified in the U.S., for a yearly average fatality rate of 0.22 per 1 million workers. Highest rates were found among Hispanics, men, the agriculture and construction industries, the state of Mississippi, and very small establishments. This study provides the first comprehensive national profile of heat-related deaths in the U.S. workplace. Prevention efforts should be directed at small businesses and at industries and individuals with the highest risk.


Radial n-i-p structure SiNW-based microcrystalline silicon thin-film solar cells on flexible stainless steel.
Radial n-i-p structure silicon nanowire (SiNW)-based microcrystalline silicon thin-film solar cells on stainless steel foil was fabricated by plasma-enhanced chemical vapor deposition. The SiNW solar cell displays very low optical reflectance (approximately 15% on average) over a broad range of wavelengths (400 to 1,100 nm). The initial SiNW-based microcrystalline (μc-Si:H) thin-film solar cell has an open-circuit voltage of 0.37 V, short-circuit current density of 13.36 mA/cm2, fill factor of 0.3, and conversion efficiency of 1.48%. After acid treatment, the performance of the modified SiNW-based μc-Si:H thin-film solar cell has been improved remarkably with an open-circuit voltage of 0.48 V, short-circuit current density of 13.42 mA/cm2, fill factor of 0.35, and conversion efficiency of 2.25%. The external quantum efficiency measurements show that the external quantum efficiency response of SiNW solar cells is improved greatly in the wavelength range of 630 to 900 nm compared to the corresponding planar film solar cells.


Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes.
The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.


Reading Habits of General Surgery Residents and Association With American Board of Surgery In-Training Examination Performance.
Few large-scale studies have quantified and characterized the study habits of surgery residents. However, studies have shown an association between American Board of Surgery In-Training Examination (ABSITE) scores and subsequent success on the American Board of Surgery Qualifying and Certifying examinations. To identify the quantity of studying, the approach taken when studying, the role that ABSITE preparation plays in resident reading, and factors associated with ABSITE performance. An anonymous 39-item questionnaire including demographic information, past performance on standardized examinations, reading habits, and study sources during the time leading up to the 2014 ABSITE and opinions pertaining to the importance of the ABSITE was administered August 1, 2014, to August 25, 2014, to 371 surgery residents in 15 residency programs nationwide. Scores from the 2014 ABSITE. A total of 273 residents (73.6%) responded to the survey. Seven respondents did not provide their January 2014 ABSITE score, leaving 266 for statistical analysis. Most respondents were male (162 of 266 [60.9%]), with a mean (SD) age of 29.8 (2.6) years. The median number of minutes spent studying per month was 240 (interquartile range, 120-600 minutes) for patient care or clinical duties and 120 for the ABSITE (interquartile range, 30-360 minutes). One hundred sixty-four of 266 respondents (61.7%) reported reading consistently throughout the year for patient care or clinical duties. With respect to ABSITE preparation, 72 of 266 residents (27.1%) reported reading consistently throughout the year, while 247 of 266 residents (92.9%) reported preparing between 1 and 8 weeks prior to the examination. Univariate analysis (with results reported as effect on median ABSITE percentile scores [95% CIs]) identified the following factors as positively correlated with ABSITE scores: prior United States Medical Licensing Examination (USMLE) 1 and 2 scores (per 1-point increase: USMLE 1, 0.1 [0.02-0.14], P = .03; USMLE 2, 0.3 [0.19-0.44], P < .001), prior Medical College Admission Test (MCAT) scores (per 1-point increase, 1.2 [1.3-2.0]; P = .002), high opinion of ABSITE significance (P < .001), surgical textbook use (11 [6-16]; P = .02), daily studying (13 [4-23]; P = .02), and high satisfaction with study materials (P < .001). On multivariable analysis, USMLE 2 score (per 1-point increase, 0.4 [0.2-0.6]; P < .001), MCAT score (0.6 [0.2-1.0]; P = .003), opinion of ABSITE significance (9.2 [6.9-11.6]; P < .001), and having an equal focus on patient care and ABSITE preparation during study (6.1 [0.6-11.5]; P = .03) were identified as positive predictors of ABSITE performance. Most residents reported reading consistently for patient care throughout the year. Daily studying and textbook use were associated with higher ABSITE scores on univariate analysis. Scores on the USMLE 2 and MCAT, as well as resident attitude regarding the importance of the ABSITE results, were independent predictors of ABSITE performance.


Elevated expression of heat-shock protein gene in the fibroblasts of patients with scleroderma.
1. Scleroderma is a systemic autoimmune disorder characterized by fibrosis affecting the skin, lung, kidney and other organs. The 70 kDa heat-shock protein has been implicated as essential for cell function during cell growth and differentiation. To study the molecular basis of intracellular events in sclerotic fibroblasts, we compared the expression of the hsp 70 gene in sclerotic and normal control fibroblasts by a run on nuclear transcription assay and a Northern blot assay. 2. In the run on nuclear transcription assay, sclerotic fibroblasts expressed an approximately eightfold higher level of hsp 70 transcription than normal fibroblasts in the quiescent condition after serum starvation. After stimulation with serum, the transcription level of the hsp 70 gene was almost similar in sclerotic and normal control fibroblasts. 3. In the Northern blot assay, the hsp 70 gene transcript, which was present in increased amounts in sclerotic fibroblasts, exhibited normal size.


Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders.
There have been no recent assessments of the economic burden of sinusitis in the peer-reviewed literature. We sought to estimate the 1996 total direct health care expenditures for the treatment of sinusitis. This study determined (1) direct expenditures of medical and surgical encounters in which sinusitis was the primary diagnosis and (2) attributable expenditures when related airway diseases were the primary diagnosis and sinusitis was a comorbid condition. An expert panel used the Delphi consensus-building technique to determine the proportions for the latter. Overall health care expenditures attributable to sinusitis in 1996 were estimated at $5.8 billion, of which $1.8 billion (30.6%) was for children 12 years or younger. A primary diagnosis of acute or chronic sinusitis accounted for 58.7% of all expenditures ($3.5 billion). About 12% each of the costs for asthma and chronic otitis media and eustachian tube disorders were attributed to diagnosis and treatment of comorbid sinusitis. Nearly 90% of all expenditures ($5.1 billion) were associated with ambulatory or emergency department services. The economic burden of sinusitis in the United States is significant. However, the limitations of this type of evaluation suggest the $5.8 billion amount may be an underestimate of the true direct costs.


Stability of aqueous films between bubbles. Part 1. The effect of speed on bubble coalescence in purified water and simple electrolyte solutions.
Film thinning experiments have been conducted with aqueous films between two air phases in a thin film pressure balance. The films are free of added surfactant but simple NaCl electrolyte is added in some experiments. Initially the experiments begin with a comparatively large volume of water in a cylindrical capillary tube a few millimeters in diameter, and by withdrawing water from the center of the tube the two bounding menisci are drawn together at a prescribed rate. This models two air bubbles approaching at a controlled speed. In pure water, the results show three regimes of behavior depending on the approach speed; at slow speed (<1 microm/s) it is possible to form a flat film of pure water, approximately 100 nm thick, that is stabilized indefinitely by disjoining pressure due to repulsive double-layer interactions between naturally charged air/water interfaces. The data are consistent with a surface potential of -57 mV on the bubble surfaces. At intermediate approach speed (approximately 1-150 microm/s), the films are transiently stable due to hydrodynamic drainage effects, and bubble coalescence is delayed by approximately 10-100 s. At approach speeds greater than approximately 150 microm/s, the hydrodynamic resistance appears to become negligible, and the bubbles coalesce without any measurable delay. Explanations for these observations are presented that take into account Derjaguin-Landau-Verwey-Overbeek and Marangoni effects entering through disjoining pressure, surface mobility, and hydrodynamic flow regimes in thin film drainage. In particular, it is argued that the dramatic reduction in hydrodynamic resistance is a transition from viscosity-controlled drainage to inertia-controlled drainage associated with a change from immobile to mobile air/water interfaces on increasing the speed of approach of two bubbles. A simple model is developed that accounts for the boundaries between different film stability or coalescence regimes. Predictions of the model are consistent with the data, and the effects of adding electrolyte can be explained. In particular, addition of electrolyte at high concentration inhibits the near-instantaneous coalescence phenomenon, thereby contributing to increased foam film stability at high approach speeds, as reported in previous literature. This work highlights the significance of bubble approach speed as well as electrolyte concentration in affecting bubble coalescence.


Individualized Piano Instruction for Improving Cognition in Breast Cancer Survivors.
To evaluate the use of individualized piano instruction (IPI) for improving cognition among breast cancer survivors. Six participants were included in an eight-week piano program with three data collection time points at baseline, midpoint, and postintervention. Participants were recruited from the breast cancer clinic of a university cancer center in South Florida. Neurocognitive, psychosocial, and self-report assessments were conducted to determine potential benefits and program feasibility, including the NIH Toolbox® Cognition Battery, the Functional Assessment of Cancer Therapy (FACT)-Cognitive Function, the FACT-Breast, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, and a participant questionnaire. Results related to potential benefits suggest that IPI may significantly improve overall cognition in breast cancer survivors, with fluid cognition showing improvement. In addition, IPI may improve quality of life and self-reported measures of depression and anxiety, with large to moderate effect sizes, respectively. Nurses should explore different treatment options for chemotherapy-related cognitive impairment and consider including IPI in survivorship care plans.


Identification and localization of a skeletal muscle secrotonin 5-HT2A receptor coupled to the Jak/STAT pathway.
The neurotransmitter serotonin mediates a wide variety of peripheral and central physiological effects through the binding to multiple receptor subtypes (Wilkinson, L. O., and Dourish, C. T. (1991) in Serotonin Receptor Subtypes: Basic and Clinical Aspects (Peroutka, S. J., ed) Vol. 15, pp.147-210, Wiley-Liss, New York). Among them, serotonin 5-HT2A receptors are known to activate the phospholipase C-beta second messenger pathway (Peroutka, S. J. (1995) Trends Neurosci. 18, 68-69). We identified and localized in rat skeletal muscle myoblasts a functional serotonin 5-HT2A receptor. This receptor was detected on the plasma membrane, in myoblasts, and at the level of T-tubules in contracting myotubes. Binding of serotonin to its receptor increases the expression of genes involved in myogenic differentiation. Unexpectedly, the 5-HT2A receptor is able to activate another signaling pathway; it triggers a rapid and transient tyrosine phosphorylation of Jak2 kinase in response to serotonin. Jak2 auto-phosphorylation is followed by the tyrosine phosphorylation of STAT3 (signal transducers and activators of transcription) and its translocation into the nucleus. We also find that the 5-HT2A receptor and STAT3 co-precipitate with Jak2, indicating that they are physically associated. We conclude that the serotonin 5-HT2A receptor identified in skeletal muscle myoblasts is able to activate the intracellular phosphorylation pathway used by cytokines. The presence of serotonin receptors in T-tubules suggests a role for serotonin in excitation-contraction coupling and (or) an effect in skeletal muscle fiber repairing.


The bovine arterially-perfused eye: an in vitro method for the study of drug mechanisms on IOP, aqueous humour formation and uveal vasculature.
A method is reported in which the isolated bovine eye is perfused through a long posterior ciliary artery with buffered physiological saline, to provide simultaneous monitoring of drug effects on intraocular pressure (IOP), vascular resistance and the condition of the blood-aqueous barrier. With perfusion under constant pressure of 45 mm Hg, perfusate flows at 1.64 +/- 0.12 ml.min-1 (mean +/- SEM) and IOP is 7.26 +/- 0.16 mm Hg. Applying a constant flow rate of 2.25 ml.min-1, IOP averages 10.19 +/- 0.32 mm Hg and in both cases this can be maintained for around 2h. Increasing the perfusion flow rate from 1.5 to 3.5 ml.min-1 produces a 76% rise in perfusion pressure but IOP increases only insignificantly (< 10%). The inclusion in the perfusion fluid of dextran and albumin to maintain oncotic pressure similar to that of plasma makes no difference to the IOP achieved and does not affect the leakiness of the barrier. The preparation shows a net consumption of oxygen, supporting the hypothesis that the aqueous humour formed is secreted by active transport processes. Timolol (in bolus doses of 1-300 nmol) injected into the perfusing fluid is shown to induce a dose-dependent fall in IOP within 5 min, reaching a steady state within 40 min. Timolol, however, causes no significant change in vascular resistance, whether this is measured as perfusion flow rate under constant pressure or as perfusion pressure at constant flow rate, nor does it alter the permeability of the barrier. Other beta-blockers such as oxprenolol and betaxolol also induce dose-dependent decreases in IOP. By applying a fluorescein dilution technique, it is found that the aqueous formation rate (K(out) = 0.0046 min-1, or 12.9 microliters.min-1) is also reduced by timolol and, in a dose-dependent manner, by the new carbonic anhydrase inhibitor, MK-927. The bovine perfused eye offers a useful method for studying the mechanisms of action of drugs on IOP and aqueous humour formation, in isolation from the complicating influences of the CNS and the cardiovascular system and without the necessity to kill animals for experimental purposes.


A new combination of blood test and fibroscan for accurate non-invasive diagnosis of liver fibrosis stages in chronic hepatitis C.
Precise evaluation of the level of liver fibrosis is recommended in patients with chronic hepatitis C (CHC). Blood fibrosis tests and Fibroscan are now widely used for the non-invasive diagnosis of liver fibrosis. Detailed fibrosis stage classifications have been developed to provide an estimation of the liver fibrosis stage from the results of these non-invasive tests. Our aim was to develop a new and more accurate fibrosis stage classification by using new scores combining non-invasive fibrosis tests. In all, 729 patients with CHC (exploratory set: 349; validation set: 380) had liver biopsy for Metavir fibrosis (F) staging, and 6 fibrosis tests: Fibroscan, Fibrotest, FibroMeter, Hepascore, FIB-4, APRI. Exploratory set: Fibroscan and FibroMeter were the independent predictors of different diagnostic targets of liver fibrosis. New fibrosis indexes combining FibroMeter and Fibroscan were thus developed for the diagnosis of clinically significant fibrosis (CSF-index) or severe fibrosis (SF-index). The association of CSF- and SF-indexes provided a new fibrosis stage classification (CSF/SF classification): F0/1, F1/2, F2 ± 1, F2/3, F3 ± 1, F4. Validation set: CSF/SF classification had a high diagnostic accuracy (85.8% well-classified patients), significantly higher than the diagnostic accuracies of FibroMeter (69.7%, P<0.001), Fibroscan (63.3%, P<0.001), or Fibrotest (43.9%, P<0.001) classifications. The association of new fibrosis indexes combining FibroMeter and Fibroscan provides a new fibrosis stage classification. This classification is significantly more accurate than Fibrotest, FibroMeter, or Fibroscan classifications, and improves the accuracy of the non-invasive diagnosis of liver fibrosis stages to 86% without any liver biopsy.


Interaction of spatial and temporal integration in global form processing.
The mechanisms by which global structure is extracted from local orientation information are not well understood. Sensitivity to global structure can be investigated using coherence thresholds for detection of global forms of varying complexity, such as parallel and concentric arrays of oriented line elements. In this study, we investigated temporal integration in the detection of these forms and its interaction with spatial integration. We find that for concentric patterns, integration times drop as region size increases from 3 degrees to 10.9 degrees , while for parallel patterns, the reverse is true. The same spatiotemporal relationship was found for Glass patterns as for line element arrays. The two types of organization therefore show quite different spatiotemporal relations, supporting previous arguments that different types of neural mechanism underlie their detection.


Validation study of VEP vernier acuity in normal-vision and amblyopic adults.
Vernier displacement thresholds can be measured with swept-parameter visual evoked potentials (sVEPs) and may therefore be useful in pre- or nonverbal subjects. This study was conducted to test whether sVEP vernier thresholds are valid measures of the visibility of vernier offsets in two different settings. Vernier acuity thresholds were measured psychophysically and electrophysiologically using square-wave gratings containing vernier displacements modulated at 3.76 Hz. The detectability of the vernier alignment cue was degraded by introducing either gaps or standing offsets in the stimulus. These manipulations were performed in normal-vision observers. In a second experiment, psychophysical and sVEP vernier acuity were measured in amblyopic observers. sVEP thresholds and overall amplitudes in normal observers were strongly affected by the introduction of gaps or standing offsets, as were psychophysical thresholds. Psychophysical and sVEP vernier offset thresholds were significantly correlated in the amblyopic eyes, as were sVEP and optotype interocular threshold differences. sVEP amplitudes of patients with strabismus were lower than those of patients with anisometropic amblyopia, even though optotype acuities were the same in the two groups. Vernier acuity thresholds derived from the sVEP tap mechanisms that are specific for the relative position of stimulus elements, and they correlate with perceptual visibility in normal and amblyopic observers. Because of this correlation and because sVEP thresholds can be measured without the need for instruction or behavioral responses, they may be useful in assessing visual function in pre- and nonverbal patients.


Glutamate neurotoxicity in cortical cell culture.
The central neurotoxicity of the excitatory amino acid neurotransmitter glutamate has been postulated to participate in the pathogenesis of the neuronal cell loss associated with several neurological disease states, but the complexity of the intact nervous system has impeded detailed analysis of the phenomenon. In the present study, glutamate neurotoxicity was studied with novel precision in dissociated cell cultures prepared from the fetal mouse neocortex. Brief exposure to glutamate was found to produce morphological changes in mature cortical neurons beginning as quickly as 90 sec after exposure, followed by widespread neuronal degeneration over the next hours. Quantitative dose-toxicity study suggested an ED50 of 50-100 microM for a 5 min exposure to glutamate. Immature cortical neurons and glia were not injured by such exposures to glutamate. Uptake processes probably do not limit GNT in culture, as the uptake inhibitor dihydrokainate did not potentiate GNT. Possibly reflecting the lack of uptake limitation, glutamate was found to be actually more potent than kainate as a neurotoxin in these cultures, a dramatic reversal of the in vivo potency rank order. Some neurons regularly survived brief glutamate exposure; these possibly glutamate-resistant neurons had electrophysiologic properties, including chemosensitivity to glutamate, that were grossly similar to those of the original population.