Non-invasive detection of gastro-oesophageal reflux using an ambulatory system.
The aim of this study was the separate measurement of reflux of food and acid into the oesophagus in 37 healthy, ambulant subjects. This was performed by radiolabelling the food and monitoring its reflux with a small directional gamma detector, which was placed externally over the oesophagus, and connected to an ambulatory data recorder. The pH was measured with a conventional oesophageal pH electrode. This method permitted the separate characterisation of acid and neutral (food) components of gastro-oesophageal reflux. The gastric emptying characteristics of the test meal were also monitored by gamma scintigraphy in a separate experiment. The oesophageal pH fell below 4 for 3.2 + 8.6/-2.3% (mean (SD)) of the recording time. Food reflux alone occurred for 17.8 + 53.2/-13.8% of the recording time. Simultaneous food and acid reflux occurred for only 0.95 + 5.2/-1.2% of the time. Not every reflux event detected by a fall in pH was seen as an increase in counts as a result of reflux of food, and vice versa. This poor correlation of food and acid reflux implies incomplete mixing of food and acid in the stomach, and further shows the inadequacy of reflux diagnosis methods that depend on pH detection alone.


Performance of four computer-coded verbal autopsy methods for cause of death assignment compared with physician coding on 24,000 deaths in low- and middle-income countries.
Physician-coded verbal autopsy (PCVA) is the most widely used method to determine causes of death (CODs) in countries where medical certification of death is uncommon. Computer-coded verbal autopsy (CCVA) methods have been proposed as a faster and cheaper alternative to PCVA, though they have not been widely compared to PCVA or to each other. We compared the performance of open-source random forest, open-source tariff method, InterVA-4, and the King-Lu method to PCVA on five datasets comprising over 24,000 verbal autopsies from low- and middle-income countries. Metrics to assess performance were positive predictive value and partial chance-corrected concordance at the individual level, and cause-specific mortality fraction accuracy and cause-specific mortality fraction error at the population level. The positive predictive value for the most probable COD predicted by the four CCVA methods averaged about 43% to 44% across the datasets. The average positive predictive value improved for the top three most probable CODs, with greater improvements for open-source random forest (69%) and open-source tariff method (68%) than for InterVA-4 (62%). The average partial chance-corrected concordance for the most probable COD predicted by the open-source random forest, open-source tariff method and InterVA-4 were 41%, 40% and 41%, respectively, with better results for the top three most probable CODs. Performance generally improved with larger datasets. At the population level, the King-Lu method had the highest average cause-specific mortality fraction accuracy across all five datasets (91%), followed by InterVA-4 (72% across three datasets), open-source random forest (71%) and open-source tariff method (54%). On an individual level, no single method was able to replicate the physician assignment of COD more than about half the time. At the population level, the King-Lu method was the best method to estimate cause-specific mortality fractions, though it does not assign individual CODs. Future testing should focus on combining different computer-coded verbal autopsy tools, paired with PCVA strengths. This includes using open-source tools applied to larger and varied datasets (especially those including a random sample of deaths drawn from the population), so as to establish the performance for age- and sex-specific CODs.


A case-control sleep study in children with polyarticular juvenile rheumatoid arthritis.
To investigate the relationship between clinical manifestations and sleep abnormalities in patients with juvenile rheumatoid arthritis (JRA). Twenty-one patients with active polyarticular JRA and 20 healthy controls were enrolled consecutively. Pain and functional impairment were assessed with standardized, validated Brazilian questionnaires. Sleep evaluation was based on parent reporting of their child's sleep habits and polysomnography; subjects underwent an adaptation night in the sleep laboratory. Sleep architecture was analyzed and spectral analysis of non-rapid eye movement (REM) sleep was carried out by electroencephalography. Patients with JRA exhibited higher indexes of periodic leg movements (PLM; p = 0.02), isolated leg movements (LM), and arousals, as well as increases in alpha activity in non-REM sleep (all p < 0.01), in spite of similar frequency of sleep complaints in comparison to controls. Among JRA patients, greater alpha activity in non-REM sleep was observed in the participants with greater joint involvement assessed by the Escola Paulista de Medicina-Pediatric Range of Motion Scale (p = 0.03) or joint count (p = 0.02). Correlation was observed between morning stiffness and PLM and/or LM (rS = 0.75, Sr = 0.74, p < 0.001 for both), and between self-rating scores of pain and alpha activity in non-REM sleep (rS = 0.74, p < 0.001). Pain symptoms and disability are related to sleep fragmentation in patients with active polyarticular JRA.


Arachidonic acid causes lysis of blood cells and ADP-dependent platelet activation responses in platelet function tests.
The use of arachidonic acid (AA) to stimulate platelets is considered as a specific approach to study aspirin treatment efficacy. However, very high concentrations of AA are used, and it has been previously reported that AA can induce cell lysis in other settings. Several clinical studies have reported decreased responses to AA in whole blood tests in the presence of clopidogrel. Our aim was to investigate whether unspecific effects contribute to AA-induced aggregation and platelet activation in light transmission aggregometry (LTA) in platelet-rich plasma (PRP), and in assays using whole blood, multiple electrode aggregometry (MEA, Multiplate®), and flow cytometry. We report that cell lysis, especially of red blood cells, does occur at concentrations of AA used in the clinical tests and that ADP is very important for the AA-induced platelet activation responses. In flow cytometry, very limited platelet activation was detected before reaching AA concentrations in the millimolar range, where cell lysis also occurred, making it problematic to develop a reliable flow cytometry assay using AA as reagent. We conclude that cell lysis and ADP release contribute to AA-induced platelet responses, most markedly in whole blood assays. This finding could potentially explain some differences between studies comparing methods using whole blood and PRP and also how clopidogrel treatment could influence AA-induced aggregation results in previously published studies. Our findings highlight some issues with AA as reagent for platelet activation, which also have an impact on how platelet activation assays using AA should be interpreted.


Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity.
Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels. We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls. Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (⩾98 cm) had significantly lower high density lipoprotein (HDL) levels, Apo A1 and albumin values compared with the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, associated adversely with insulin levels and HOMA IR in cases but not in the controls. Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long-term health of women with PCOS.


Optimal Ozone Control with Inclusion of Spatiotemporal Marginal Damages and Electricity Demand.
Marginal damage (MD), or damage per ton of emission, is a policy metric used for effective pollution control and reducing the corresponding adverse health impacts. However, for a pollutant such as NOx, the MD varies by the time and location of the emissions, a complication that is not adequately accounted for in the currently implemented economic instruments. Policies accounting for MD information would aim to encourage emitters with large MDs to reduce their emissions. An optimization framework is implemented to account for NOx spatiotemporal MDs calculated through adjoint sensitivity analysis and to simulate power plants' behavior under emission and simplified electricity constraints. The results from a case study of U.S. power plants indicate that time-specific MDs are high around noon and low in the evening. Furthermore, an emissions reduction of about 40% and a net benefit of about $1200 million can be gained for this subset of power plants if a larger fraction of the electricity demand is supplied by power plants at low-damage times and in low-damage locations. The results also indicate that the consideration of temporal effects in NOx control policies results in a comparable net benefit to the consideration of spatial or spatiotemporal effects, thus providing a promising option for policy development.


Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies.
Differences in circulating concentrations of antiangiogenic factors sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are reported to precede the onset of preeclampsia weeks to months in low-risk pregnant women. The objective of this study was to investigate whether similar changes can be detected in pregnant women at high-risk to develop the syndrome. This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies. Serum samples were available from 194 women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and PlGF. The odds of developing preeclampsia were significantly increased among women with multiple fetuses for each 2-fold elevation in sFlt1, sEng and the ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82) between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic factors across gestation showed significant differences during the third trimester in women who develop preeclampsia compared with appropriate controls in all high-risk groups. However, when data were examined in relation to the gestational week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia. The pattern of elevated concentrations of sFlt1 and sEng, and low PlGF in high-risk pregnant subjects who develop preeclampsia is similar to that reported in low-risk pregnant women. However, differences in these factors among high-risk women who do and do not develop preeclampsia are modest, and do not appear to be clinically useful predictors in these high-risk pregnant women.


Effects of participation in a mindfulness program for veterans with posttraumatic stress disorder: a randomized controlled pilot study.
To assess outcomes associated with Mindfulness-Based Stress Reduction (MBSR) for veterans with PTSD. Forty-seven veterans with posttraumatic stress disorder (PTSD; 37 male, 32 Caucasian) were randomized to treatment as usual (TAU; n = 22), or MBSR plus TAU (n = 25). PTSD, depression, and mental health-related quality of life (HRQOL) were assessed at baseline, posttreatment, and 4-month follow-up. Standardized effect sizes and the proportion with clinically meaningful changes in outcomes were calculated. Intention-to-treat analyses found no reliable effects of MBSR on PTSD or depression. Mental HRQOL improved posttreatment but there was no reliable effect at 4 months. At 4-month follow-up, more veterans randomized to MBSR had clinically meaningful change in mental HRQOL, and in both mental HRQOL and PTSD symptoms. Completer analyses (≥ 4 classes attended) showed medium to large between group effect sizes for depression, mental HRQOL, and mindfulness skills. Additional studies are warranted to assess MBSR for veterans with PTSD.


Catalytic dehydrogenative aromatization of cyclohexanones and cyclohexenones.
Phenols and phenol derivatives serve as synthetic building blocks for the construction of compounds ranging from polymers to pharmaceuticals. Despite numerous methods for phenol synthesis, the catalytic dehydrogenation of carbocyclic compounds such as cyclohexanones and cyclohexenones to generate substituted phenol derivatives has received much attention. This review describes recent research progress concerning catalytic dehydrogenative aromatization and I2 promoted oxidative aromatization reactions in view of the types of cyclohexanone and cyclohexenone substrates and reactions, including the associated mechanisms and developments.


Rectovaginal extragastrointestinal stromal tumour (EGIST): an additional entity to be considered in the differential diagnosis of tumours of the rectovaginal septum.
Gastrointestinal stromal tumours (GISTs) are rare - and rectovaginal extragastrointestinal stromal tumours (RV-EGISTs) even rarer. We share a case of RV-EGIST, complemented by high-quality radiological and surgical images. A review of current literature pertaining to RV-EGIST is also included. Our case report highlights the diagnostic challenge presented by extragastrointestinal stromal tumours. Differentiated from overlapping pathologies only by targeted application of immunohistopathology and cytogenetics, the inclusion of RV-EGIST in the differential diagnosis of a rectovaginal tumour is essential to making this correct diagnosis. Primary surgery is the treatment of choice for RV-EGIST if complete cytoreduction can be achieved, combined with adjuvant tyrosine kinase inhibitor (TKI) therapy for those with high-risk features to further reduce rates of future recurrence.


Non-compliance and professional power.
The non-compliance of patients with prescribed treatments is considered as a barrier to effective health care. Non-compliance has implications for the health of patients, effective use of resources and assessments of the clinical efficacy of treatments. Research into non-compliance has increased over the last 30 years. This seems to indicate that it is seen as an important area of concern for all health care professionals. Definitions of non-compliance are problematic, as are methods of assessment of its nature and frequency. Many factors which may account for non-compliance have been proposed, as well as methods to improve compliance. Research into these factors however, mainly based on a positivist epistemology, has failed to provide any conclusive answers to the problem. Sound clinical reasons are suggested as the basis for the increase in interest in non-compliance. It is contended, however, that it is not only these reasons that account for the identification of non-compliance as a problem. Non-compliant behaviour is seen as problematic, because it contravenes professional beliefs, norms and expectations regarding the 'proper' roles of patients and professionals. These have formed the basis of an ideology that views patients as passive recipients of health care. It has led to an inherent tendency to 'blame' the patient and view non-compliance as irrational and deviant. The professional view of non-compliance as irrational, is exemplified in the case of individuals with mental illness, where there are inherent assumptions that non-compliance can be seen primarily as a symptom of illness. This denies the legitimacy of patient choice, and has led to attempts to control compliance via suggested legislative measures. Serious moral and ethical problems arise from such measures, and can be seen as the ultimate legitimization of an ideology of non-compliance. The maintenance of professional power and control is suggested as central to the debates surrounding non-compliance. The ideological assumptions underpinning the concept of non-compliance need questioning, and a re-conceptualization of the roles of patients and professionals is required. This must involve a view of patients as active participators in their own health care. Research based on an interpretative epistemology, aimed at understanding individual action, rather than control, would seem a more appropriate model to pursue.


Methotrexate-Associated Lymphoproliferative Disorders Mimicking Granulomatosis With Polyangiitis: A Radiological Diagnostic Challenge.
Methotrexate-associated lymphoproliferative disorders (MTX-LPD) frequently involve the extranodal organs throughout the body. Among the extranodal occurrences of MTX-LPD, pulmonary involvement is most frequent. In contrast, there are only a few reports of MTX-LPD in the nasal cavity or paranasal sinuses. Moreover, there are no previous reports of MTX-LPD mimicking granulomatosis with polyangiitis (GPA) in imaging examinations. We describe a case of a 53-year-old woman with MTX-LPD mimicking GPA in the nasal cavity and lungs. She complained of left nasal obstruction and discharge, general fatigue, and continual fever for 2 months. The patient had been diagnosed with rheumatoid arthritis and received methotrexate (MTX) for over 10 years. Contrast-enhanced computed tomography revealed unenhanced masses in the nasal cavity and multiple masses with cavitary changes in the bilateral lungs, suggesting GPA. However, histological examination of the nasal lesion and a history of MTX treatment indicated a diffuse large B-cell lymphoma type MTX-LPD. Two weeks after MTX withdrawal, prominent improvements in both lesions were observed. Complete regression of the nasal lesion was observed 3 months after discontinuation of MTX. Thus, MTX-LPD may mimic GPA in imaging examinations.


Heterotrophic monitoring at a drinking water treatment plant by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry after different drinking water treatments.
The aim of this work was to assess the suitability of matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) for routine heterotrophic monitoring in a drinking water treatment plant. Water samples were collected from raw surface water and after different treatments during two campaigns over a 1-year period. Heterotrophic bacteria were studied and isolates were identified by MALDI-TOF MS. Moreover, the diversity index and the coefficient of population similarity were also calculated using biochemical fingerprinting of the populations studied. MALDI-TOF MS enabled us to characterize and detect changes in the bacterial community composition throughout the water treatment plant. Raw water showed a large and diverse population which was slightly modified after initial treatment steps (sand filtration and ultrafiltration). Reverse osmosis had a significant impact on the microbial diversity, while the final chlorination step produced a shift in the composition of the bacterial community. Although MALDI-TOF MS could not identify all the isolates since the available MALDI-TOF MS database does not cover all the bacterial diversity in water, this technique could be used to monitor bacterial changes in drinking water treatment plants by creating a specific protein profile database for tracking purposes.


Object-centered direction selectivity in the macaque supplementary eye field.
Object-centered spatial awareness--awareness of the location, relative to an object, of its parts--plays an important role in many aspects of perception, imagination, and action. One possible basis for this capability is the existence in the brain of neurons with sensory receptive fields or motor action fields that are defined relative to an object-centered frame. In experiments described here, neuronal activity was monitored in the supplementary eye field of macaque monkeys making eye movements to the right or left end of a horizontal bar. Neurons were found to fire differentially as a function of the end of the bar to which an eye movement was made. This is direct evidence for the existence of neurons sensitive to the object-centered direction of movements.


Establishment and characterization of chicken embryo fibroblast clone LSCC-H32.
Cell line CEC-32 and clone LSCC-H32 were established from primary chicken embryo cells spontaneously but not experimentally transformed at 32 degrees C. The lines consisted of fibroblastoid and polygonal cells and had a subtetraploid karyotype of 2N = 130 to 140. The cells showed increased plating efficiency and metabolic activities as demonstrated by hexose uptake and plasminogen activator assay. The established cells produced avian lymphoid leukosis viruses of subgroups A and B. The virus released from LSCC-H32 cells induced lymphoid leukosis in inoculated chickens 18 to 22 wk post infection (PI). The cells have been carried in continuous culture for 285 passages and they appeared to grow indefinitely. They were efficiently used to propagate several animal viruses and to titrate chicken interferon.


Antibody response profiles to components of rye grass pollen extract in various strains of mice.
Using a combination of immunoprecipitation and polyacrylamide gel electrophoresis techniques, patterns of antibody responses to a number of components in rye pollen extract have been studied in hyperimmune mouse sera. Common laboratory strains of mice were investigated, including AKR, C3H/He, SwR, Ist, Asn, Balb/c, C57BL10, DBA2 and BD1:F1 hybrids. All strains responded vigorously to the immunisation protocol used (rye pollen extract/alum followed by a booster dose in aqueous media) when tested with non-discriminating assay procedures such as haemagglutination or passive cutaneous anaphylaxis directed against the whole rye pollen extract. However, markedly variable antibody responses were observed between strains and between murine and human sera when considered in relation to individual rye extract components. Particularly noteworthy was the relatively poor response of all mice to the low molecular weight rye antigen component (11,000 daltons). This material was readily detected by human sera derived from pollenosis patients. Notable also was the fact that no single rye component was detected by all mice sera. These results illustrate the complex serological response induced by heterogeneous antigen mixtures, such as grass pollen extracts.


Morphological brain differences between adult stutterers and non-stutterers.
The neurophysiological and neuroanatomical foundations of persistent developmental stuttering (PDS) are still a matter of dispute. A main argument is that stutterers show atypical anatomical asymmetries of speech-relevant brain areas, which possibly affect speech fluency. The major aim of this study was to determine whether adults with PDS have anomalous anatomy in cortical speech-language areas. Adults with PDS (n = 10) and controls (n = 10) matched for age, sex, hand preference, and education were studied using high-resolution MRI scans. Using a new variant of the voxel-based morphometry technique (augmented VBM) the brains of stutterers and non-stutterers were compared with respect to white matter (WM) and grey matter (GM) differences. We found increased WM volumes in a right-hemispheric network comprising the superior temporal gyrus (including the planum temporale), the inferior frontal gyrus (including the pars triangularis), the precentral gyrus in the vicinity of the face and mouth representation, and the anterior middle frontal gyrus. In addition, we detected a leftward WM asymmetry in the auditory cortex in non-stutterers, while stutterers showed symmetric WM volumes. These results provide strong evidence that adults with PDS have anomalous anatomy not only in perisylvian speech and language areas but also in prefrontal and sensorimotor areas. Whether this atypical asymmetry of WM is the cause or the consequence of stuttering is still an unanswered question.


Minimalist Social-Affective Value for Use in Joint Action: A Neural-Computational Hypothesis.
Joint Action is typically described as social interaction that requires coordination among two or more co-actors in order to achieve a common goal. In this article, we put forward a hypothesis for the existence of a neural-computational mechanism of affective valuation that may be critically exploited in Joint Action. Such a mechanism would serve to facilitate coordination between co-actors permitting a reduction of required information. Our hypothesized affective mechanism provides a value function based implementation of Associative Two-Process (ATP) theory that entails the classification of external stimuli according to outcome expectancies. This approach has been used to describe animal and human action that concerns differential outcome expectancies. Until now it has not been applied to social interaction. We describe our Affective ATP model as applied to social learning consistent with an "extended common currency" perspective in the social neuroscience literature. We contrast this to an alternative mechanism that provides an example implementation of the so-called social-specific value perspective. In brief, our Social-Affective ATP mechanism builds upon established formalisms for reinforcement learning (temporal difference learning models) nuanced to accommodate expectations (consistent with ATP theory) and extended to integrate non-social and social cues for use in Joint Action.


Utility of Various Bronchoscopic Modalities in Lung Cancer Diagnosis
Background: Bronchoscopy and different techniques to obtain tissue sample form the cornerstone of lung cancer diagnostics. The utility, specificity and sensitivity of various techniques are compared against each other and also in relation to the tumour type, location and morphology. Aim: To assess and compare the utility of various bronchoscopic procedures in lung malignancies. Study also compares the utility of these techniques on tumour site, morphology and cell type. Methods: One hundred and fifty six patients with suspected malignancies in whom bronchoscopy was deemed as the primary diagnostic procedure were selected. These patients underwent bronchoscopic lavage, brushings and biopsy. Samples were assessed by microbiological, cytology and histopathological analysis. Results: Bronchoscopic procedures have a high diagnostic accuracy of 81.25% in confirming lung malignancies in central tumours and also in non-accessible peripheral tumours. Bronchial brushings had the highest yield in central tumours (55.9%) and a reasonably good yield even in perpipheral tumours (40.8%). When all the modalities were compared against each other, brushings was the single most decisive technique as it alone yielded a diagnosis in a significant 33% of cases, whereas the comparative diagnosis by biopsy alone was in a minority 7.6% of cases.


Tilletia walkeri on Annual Ryegrass in Wheat Fields in the Southeastern United States.
Surveys for Tilletia walkeri on annual ryegrass (Lolium multiflorum) were conducted during 1997 and 1998 in the southeastern United States, where suspect teliospores of the Karnal bunt fungus, Tilletia indica, were found in USDA-APHIS surveys of wheat (Triticum aestivum) seed in 1996. T. walkeri is morphologically similar to T. indica. Annual ryegrass is a common weed in wheat fields in the southeastern United States. Between April and June 1997, ryegrass seed samples were collected from 190 fields of wheat in 47 counties in Georgia and from 26 fields in 17 counties in Alabama and south-central Tennessee. In 1998, 70 samples were collected from 40 counties in the same regions of the three states. The teliospores from these samples were 23 to 45 μm in diameter (average about 33 μm) and ranged from light brown to dark reddish brown. They had coarse, widely spaced cerebriform ridges on the surface and were surrounded by a gelatinous sheath. The ryegrass bunt was identified as the recently described species T. walkeri, occurring on ryegrass seed from Australia and Oregon. In 1997, teliospores of T. walkeri were found in 13 samples from eight counties in central Georgia and from one field in Tennessee. In 1998, more teliospores and bunted seeds were found, possibly due to frequent rain in the region throughout the flowering period for ryegrass. Teliospores were found in 26/70 of the samples, and among these, only a small number of bunted seed were found in 12 of 13/70 samples. In one wheat field in Morgan County, Georgia, about 50% of the ryegrass seed collected was partially bunted, and a small percentage was completely bunted. Fields with teliospores were widely distributed and generally matched the locations where teliospores were found in APHIS wheat seed surveys in 1996 to 1998. T. walkeri occurs at very low levels on ryegrass in the Southeast and is the source of teliospores, initially identified as those of T. indica, associated with wheat seed in APHIS surveys. No bunted wheat seeds or teliospores of T. indica were found in the survey.


A case of simvastatin-associated pancreatitis and review of statin-associated pancreatitis.
Reduction of low-density lipoprotein cholesterol (LDL) concentration has become the primary goal and a standard of care in the practice of cholesterol management. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most frequently prescribed lipid lowering agents on the market. As more information is learned through the results of clinical trials, LDL goals become more stringent and difficult to attain. Large doses of high-potency statins, sometimes given in combination with other lipid-lowering agents, are frequently necessary to achieve these goals. As a result, the frequency of adverse effects from statin therapy may be expected to increase, and less common adverse effects may occur more often. As statins are used more aggressively, rare and possibly dangerous adverse effects must be identified, especially those that are becoming more frequently encountered. Increased awareness may lead to earlier diagnosis and management of diseases that may be caused by the statins. We describe a 58-year-old man who was hospitalized with idiopathic pancreatitis 4 months after starting simvastatin therapy. His oral drug therapy was withheld, and he was treated with bowel rest. The patient was discharged on hospital day 5, and his oral drug regimen, including simvastatin, was resumed. He was admitted again 16 months later with a second diagnosis of acute pancreatitis and was discharged after 3 days of bowel rest with no oral drug therapy. Simvastatin was restarted on discharge, but the patient stopped taking it after experiencing muscle soreness and weakness in his arms. He recalled having similar arm pain that preceded the previous episode of acute pancreatitis. All other causes of the pancreatitis had been ruled out; thus, the correlation between simvastatin-induced myalgia and onset of acute pancreatitis on two separate occasions made simvastatin the suspected instigating agent. Pancreatitis is a rare adverse effect of statin therapy, but it has been documented in several case reports involving most of the statins. Continued reporting is necessary to increase awareness of this rare adverse effect of simvastatin so that it may be promptly managed or avoided in the future.


Comparative effect of orally administered sodium butyrate before or after weaning on growth and several indices of gastrointestinal biology of piglets.
Sodium butyrate (SB) provided orally favours body growth and maturation of the gastrointestinal tract (GIT) in milk-fed pigs. In weaned pigs, conflicting results have been obtained. Therefore, we hypothesised that the effects of SB (3 g/kg DM intake) depend on the period (before v. after weaning) of its oral administration. From the age of 5 d, thirty-two pigs, blocked in quadruplicates within litters, were assigned to one of four treatments: no SB (control), SB before (for 24 d), or after (for 11-12 d) weaning and SB before and after weaning (for 35-36 d). Growth performance, feed intake and various end-point indices of GIT anatomy and physiology were investigated at slaughter. The pigs supplemented with SB before weaning grew faster after weaning than the controls (P < 0.05). The feed intake was higher in pigs supplemented with SB before or after weaning (P < 0.05). SB provided before weaning improved post-weaning faecal digestibility (P < 0.05) while SB after weaning decreased ileal and faecal digestibilities (P < 0.05). Gastric digesta retention was higher when SB was provided before weaning (P < 0.05). Post-weaning administration of SB decreased the activity of three pancreatic enzymes and five intestinal enzymes (P < 0.05). IL-18 gene expression tended to be lower in the mid-jejunum in SB-supplemented pigs. The small-intestinal mucosa was thinner and jejunal villous height lower in all SB groups (P < 0.05). In conclusion, the pre-weaning SB supplementation was the most efficient to stimulate body growth and feed intake after weaning, by reducing gastric emptying and intestinal mucosa weight and by increasing feed digestibility.


Novel Strategy to Fabricate PLA/Au Nanocomposites as an Efficient Drug Carrier for Human Leukemia Cells in Vitro.
Poly (lactic acid) (PLA) polymer has the promising applications in the biomedical field because of its biodegradability and safe elimination. In this study, we have explored the bio-application of new nanocomposites composed with PLA nanofibers and Au nanoparticles as the potential drug carrier for an efficient drug delivery in target cancer cells. The results demonstrated that the anticancer drug daunorubicin could be efficiently self-assembled on the surface of PLA/Au nanocomposites and the synergistic enhancement of PLA/Au nanocomposites conjugated with daunorubicin into drug-sensitive K562 and drug-resistant leukemia K562/AO2 cells could be obviously observed by MTT assay and confocal fluorescence microscopy studies. These observations suggest that the new nanocomposites could readily induce daunorubicin to accumulate and uptake in target leukemia cells and increase the drug's cytotoxicity. Especially, the PLA/Au nanocomposites could significantly facilitate the cellular drug absorbtion of daunorubicin into drug-resistant K562/AO2 cells and efficiently inhibit the cancer cell proliferation. This raised the possibility to utilize the PLA/Au nanocomposites as a new effective additive agent to inhibit the drug resistance and thus as a novel strategy to sensitively track the respective cancer cells.


Are smokers with acute cough in primary care prescribed antibiotics more often, and to what benefit? An observational study in 13 European countries.
Little is known about actual clinical practice regarding management of smokers compared with ex-smokers and nonsmokers presenting with acute cough in primary care, and whether a lower threshold for prescribing antibiotics benefits smokers. This was a multicentre 13-country European prospective observational study of primary care clinician management of acute cough in consecutive immunocompetent adults presenting with an acute cough of <or=28 days duration. There was complete smoking status data for 2,549 out of 3,402 participants. 28% were smokers, 24% ex-smokers and 48% nonsmokers. Smokers and ex-smokers had more chronic respiratory conditions (18.5% and 20.5% versus 12.5%). Median symptom severity scores were similar. Smokers were prescribed antibiotics more frequently (60%) than ex-smokers (51%) and nonsmokers (53%). After adjusting for clinical presentation and patient characteristics, the odds ratio of being prescribed antibiotics for smokers compared with nonsmokers was 1.44 (95% CI 1.12-1.86; p = 0.005). Patient recovery was not significantly different for smokers and nonsmokers, after adjusting for clinical presentation and patient characteristics. Smoking status was used as an independent factor to determine whether or not to prescribe an antibiotic. Being prescribed an antibiotic was not associated with recovery in smokers.


Detection of COVID-19 using multimodal data from a wearable device: results from the first TemPredict Study.
Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.


Alteration in the erythrocyte sedimentation rate in dengue patients: analysis of 1,398 cases.
A study of the erythrocyte sedimentation rate during the first hour (ESR) in dengue patients would help determine how this parameter is affected by this disease, as well as whether it can be used for diagnosis. One thousand, three hundred and ninety-eight cases of dengue attended at the Dengue Treatment Center, Campos dos Goytacazes Rio de Janeiro, Brazil, were included. The ESR values were classified as normal or elevated and compared by gender and clinical form of the disease. Among the 1,398 cases ESR was normal in 81.25% (n = 1,136), while in 18.75% (n=262) it was elevated. In 83.92% (n=514) of the male dengue patients ESR was normal, while in 16.08% (n=98) it was elevated. Among female dengue patients, 79.17% (n=622) had normal ESR, and in 20.83% (n=164) ESR was elevated (p=0.05). Among patients with classic dengue, 77.28% (n=961) had normal ESR, while in 22.72% (n=282), it was elevated. Also in 85.81% (n=133) of patients with hemorrhagic dengue, ESR was normal, while in 14.19% (n=22) ESR was elevated (p=0.026). We concluded that ESR was within normal ranges in most dengue cases, independent of gender or clinical presentation. Given the high frequency of normality and the ease of determination of this parameter, ESR data can help in the differential diagnosis of dengue.


Coping, uncertainty and health-related quality of life as determinants of anxiety and depression on a sample of hospitalized cardiac patients in Southern Italy.
Being hospitalized often causes psychological distress and compromises patients' psychological well-being, thereby augmenting the burden of illness. The aim of this paper is to investigate two possible determinants of anxiety and depression among hospitalized cardiac patients, namely uncertainty in illness, and coping strategies, controlling for the perceived health-related quality of life, and distinguishing between borderline and pathological levels of anxiety and depression. Data on anxiety, depression, coping style, uncertainty in illness and self-assessed quality of life concerning 200 cardiac inpatients from a university hospital were collected through validated questionnaires. A biprobit analysis, whose dependent variables are hospital anxiety and depression, was carried out. Uncertainty in illness has a significant impact on the possibility of crossing the borderline level of both anxiety and depression. The coping strategy of Positive Reappraisal and Growth is inversely and significantly correlated to anxiety and depression, be it borderline or pathological; the Restraint Coping strategy is positively and significantly related to borderline anxiety. The reduction of uncertainty in illness and the development of adequate coping strategies should be promoted in order to decrease the patients' risk of crossing the borderline threshold of anxiety and depression.


scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia, Leydig and Sertoli Cells.
In December 2019, a novel coronavirus (SARS-CoV-2) was identified in COVID-19 patients in Wuhan, Hubei Province, China. SARS-CoV-2 shares both high sequence similarity and the use of the same cell entry receptor, angiotensin-converting enzyme 2 (ACE2), with severe acute respiratory syndrome coronavirus (SARS-CoV). Several studies have provided bioinformatic evidence of potential routes of SARS-CoV-2 infection in respiratory, cardiovascular, digestive and urinary systems. However, whether the reproductive system is a potential target of SARS-CoV-2 infection has not yet been determined. Here, we investigate the expression pattern of ACE2 in adult human testes at the level of single-cell transcriptomes. The results indicate that ACE2 is predominantly enriched in spermatogonia and Leydig and Sertoli cells. Gene Set Enrichment Analysis (GSEA) indicates that Gene Ontology (GO) categories associated with viral reproduction and transmission are highly enriched in ACE2-positive spermatogonia, while male gamete generation related terms are downregulated. Cell-cell junction and immunity-related GO terms are increased in ACE2-positive Leydig and Sertoli cells, but mitochondria and reproduction-related GO terms are decreased. These findings provide evidence that the human testis is a potential target of SARS-CoV-2 infection, which may have significant impact on our understanding of the pathophysiology of this rapidly spreading disease.


Topical treatments for blepharokeratoconjunctivitis in children.
Blepharokeratoconjunctivitis (BKC) is a type of inflammation of the surface of the eye and eyelids that involves changes of the eyelids, dysfunction of the meibomian glands, and inflammation of the conjunctiva and cornea. Chronic inflammation of the cornea can lead to scarring, vascularisation and opacity. BKC in children can cause significant symptoms including irritation, watering, photophobia and loss of vision from corneal opacity, refractive error or amblyopia.Treatment of BKC is directed towards modification of meibomian gland disease and the bacterial flora of lid margin and conjunctiva, and control of ocular surface inflammation. Although both topical and systemic treatments are used to treat people with BKC, this Cochrane review focuses on topical treatments. To assess and compare data on the efficacy and safety of topical treatments (including antibiotics, steroids, immunosuppressants and lubricants), alone or in combination, for BKC in children from birth to 16 years. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE ( January 1946 to 11 July 2016), Embase (January 1980 to 11 July 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 July 2016. We searched the reference lists of identified reports and the Science Citation Index to identify any additional reports of studies that met the inclusion criteria. We searched for randomised controlled trials that involved topical treatments in children up to 16 years of age with a clinical diagnosis of BKC. We planned to include studies that evaluated a single topical medication versus placebo, a combination of treatments versus placebo, and those that compared two or multiple active treatments. We planned to include studies in which participants received additional treatments, such as oral antibiotics, oral anti-inflammatories, warm lid compresses and lid margin cleaning. Two review authors independently screened the results of the literature search (titles and abstracts) to identify studies that met the inclusion criteria of the review and applied standards as expected for Cochrane reviews. We graded the certainty of the evidence using GRADE. We included one study from the USA that met the inclusion criteria. In the study, 137 children aged zero to six years old with blepharoconjunctivitis were randomised to treatment in one of four trial arms (loteprednol etabonate/tobramycin combination, loteprednol etabonate alone, tobramycin alone or placebo) for 15 days, with assessments on days 1, 3, 7 and 15. We judged the study to be at high risk of attrition bias and bias due to selective outcome reporting. The study did not report the number of children with improvement in symptoms nor with total or partial success as measured by changes in clinical symptoms.All children showed a reduction in blepharoconjunctivitis grade score, but there was no evidence of important differences between groups. Visual acuity was not fully reported but the authors stated that there was no change in visual acuity in any of the treatment groups. The study reported ocular and non ocular adverse events but was underpowered to detect differences between the groups. Ocular adverse events were as follows: loteprednol/tobramycin 1/34 (eye pain); loteprednol 4/35 (eye pain, conjunctivitis, eye discharge, eye inflammation); tobramycin 0/34; placebo (vehicle) 0/34. The evidence was limited for all these outcomes and we judged it to be very low certainty.There was no information on clinical signs (aside from grade score), disease progression or quality of life. There is no high-quality evidence of the safety and efficacy of topical treatments for BKC, which resulted in uncertainty about the indications and effectiveness of topical treatment. Clinical trials are required to test efficacy and safety of current and any future treatments. Outcome measures need to be developed which can capture both objective clinical and patient-reported aspects of the condition and treatments.


Catastrophic Health Expenditure and Impoverishment Effects of Out-of-pocket Expenses: A Comparative Study of Tannery and Non-tannery Workers of Kanpur, India.
Treatment-seeking behaviors and economic burden because of health expenditure are widely discussed issues in India, and more so in recent times. The aim of this study is to identify health problems of tannery workers and their treatment-seeking behavior and their health expenditure. The primary data used in this article were collected through a cross-sectional household survey of 284 male tannery workers in the Jajmau area of Kanpur city in the state of Uttar Pradesh, during January-June 2015. Findings of the study revealed that around 36% of the tannery workers and 42% of non-tannery workers received treatment as outpatients in government/municipal hospital in the first spell of treatment. The secondary source of treatment was pharmacy/drug stores for 30% of the tannery workers and 24% of the non-tannery workers, an indication that a substantial proportion takes treatment without consulting a qualified medical practitioner; it also highlights that almost one-third of the tannery and non-tannery workers visited private health facility despite poor economic condition. It is evident that a substantial proportion of tannery and non-tannery workers are visiting private/non-governmental organization/trust hospital despite their poor financial situation. There is an urgent need to reinstate people's faith in public health facilities by developing professionalism, integrity, and accountability among different levels of health functionaries and frontline workers with the support of credible, transparent, and responsible regulatory environment.


Semi-supervised hashing for large-scale search.
Hashing-based approximate nearest neighbor (ANN) search in huge databases has become popular due to its computational and memory efficiency. The popular hashing methods, e.g., Locality Sensitive Hashing and Spectral Hashing, construct hash functions based on random or principal projections. The resulting hashes are either not very accurate or are inefficient. Moreover, these methods are designed for a given metric similarity. On the contrary, semantic similarity is usually given in terms of pairwise labels of samples. There exist supervised hashing methods that can handle such semantic similarity, but they are prone to overfitting when labeled data are small or noisy. In this work, we propose a semi-supervised hashing (SSH) framework that minimizes empirical error over the labeled set and an information theoretic regularizer over both labeled and unlabeled sets. Based on this framework, we present three different semi-supervised hashing methods, including orthogonal hashing, nonorthogonal hashing, and sequential hashing. Particularly, the sequential hashing method generates robust codes in which each hash function is designed to correct the errors made by the previous ones. We further show that the sequential learning paradigm can be extended to unsupervised domains where no labeled pairs are available. Extensive experiments on four large datasets (up to 80 million samples) demonstrate the superior performance of the proposed SSH methods over state-of-the-art supervised and unsupervised hashing techniques.


Induced pluripotent stem cell intervention rescues ventricular wall motion disparity, achieving biological cardiac resynchronization post-infarction.
Dyssynchronous myocardial motion aggravates cardiac pump function. Cardiac resynchronization using pacing devices is a standard-of-care in the management of heart failure. Post-infarction, however, scar tissue formation impedes the efficacy of device-based therapy. The present study tests a regenerative approach aimed at targeting the origin of abnormal motion to prevent dyssynchronous organ failure. Induced pluripotent stem (iPS) cells harbour a reparative potential, and were here bioengineered from somatic fibroblasts reprogrammed with the stemness factors OCT3/4, SOX2, KLF4, and c-MYC. In a murine infarction model, within 30 min of coronary ligation, iPS cells were delivered to mapped infarcted areas. Focal deformation and dysfunction underlying progressive heart failure was resolved prospectively using speckle-tracking imaging. Tracked at high temporal and spatial resolution, regional iPS cell transplantation restored, within 10 days post-infarction, the contractility of targeted infarcted foci and nullified conduction delay in adjacent non-infarcted regions. Local iPS cell therapy, but not delivery of parental fibroblasts or vehicle, prevented or normalized abnormal strain patterns correcting the decrease in peak strain, disparity of time-to-peak strain, and pathological systolic stretch. Focal benefit of iPS cell intervention translated into improved left ventricular conduction and contractility, reduced scar, and reversal of structural remodelling, protecting from organ decompensation. Thus, in ischaemic cardiomyopathy, targeted iPS cell transplantation synchronized failing ventricles, offering a regenerative strategy to achieve biological resynchronization.


Effect of Seed Quality and Combination Fungicide-Trichoderma spp. Seed Treatments on Pre- and Postemergence Damping-Off in Cotton.
ABSTRACT Good quality seeds of cotton cultivars often escaped pre-emergence damping-off incited by Pythium spp. and Rhizopus oryzae, and they were resistant to postemergence damping-off incited by Rhizoctonia solani. Poor quality seeds, however, were highly susceptible to both phases of seedling disease and required seed treatment in order to survive. Pre-emergence damping-off incited by Pythium spp. and Rhizopus oryzae could be controlled by seed treatment with biocontrol preparations of a number of Trichoderma spp., but these treatments were much less effective in controlling postemergence disease incited by Rhizoctonia solani. Postemergence seedling disease can be controlled by fungicides, but they were much less effective in controlling the pre-emergence phase of the disease. Combination seed treatments of poor quality cotton seeds with fungicides and Trichoderma spp. preparations, followed by planting in pathogen-infested soil, indicated that this technique will control both phases of seedling disease. Seed treatment with either the fungicides or the biocontrol agents alone did not achieve this goal. The optimum combination treatment for disease control was that of chloroneb plus Trichoderma spp., followed by chloroneb plus metalaxyl (Deltacoat AD) plus T. virens strain G-6.


Averaged Propulsive Body Acceleration (APBA) Can Be Calculated from Biologging Tags That Incorporate Gyroscopes and Accelerometers to Estimate Swimming Speed, Hydrodynamic Drag and Energy Expenditure for Steller Sea Lions.
Forces due to propulsion should approximate forces due to hydrodynamic drag for animals horizontally swimming at a constant speed with negligible buoyancy forces. Propulsive forces should also correlate with energy expenditures associated with locomotion-an important cost of foraging. As such, biologging tags containing accelerometers are being used to generate proxies for animal energy expenditures despite being unable to distinguish rotational movements from linear movements. However, recent miniaturizations of gyroscopes offer the possibility of resolving this shortcoming and obtaining better estimates of body accelerations of swimming animals. We derived accelerations using gyroscope data for swimming Steller sea lions (Eumetopias jubatus), and determined how well the measured accelerations correlated with actual swimming speeds and with theoretical drag. We also compared dive averaged dynamic body acceleration estimates that incorporate gyroscope data, with the widely used Overall Dynamic Body Acceleration (ODBA) metric, which does not use gyroscope data. Four Steller sea lions equipped with biologging tags were trained to swim alongside a boat cruising at steady speeds in the range of 4 to 10 kph. At each speed, and for each dive, we computed a measure called Gyro-Informed Dynamic Acceleration (GIDA) using a method incorporating gyroscope data with accelerometer data. We derived a new metric-Averaged Propulsive Body Acceleration (APBA), which is the average gain in speed per flipper stroke divided by mean stroke cycle duration. Our results show that the gyro-based measure (APBA) is a better predictor of speed than ODBA. We also found that APBA can estimate average thrust production during a single stroke-glide cycle, and can be used to estimate energy expended during swimming. The gyroscope-derived methods we describe should be generally applicable in swimming animals where propulsive accelerations can be clearly identified in the signal-and they should also prove useful for dead-reckoning and improving estimates of energy expenditures from locomotion.


Introducing the Treatment Hierarchy Question in Network Meta-Analysis.
Comparative effectiveness research using network meta-analysis can present a hierarchy of competing treatments, from the most to the least preferable option. However, in published reviews, the research question associated with the hierarchy of multiple interventions is typically not clearly defined. Here we introduce the novel notion of a treatment hierarchy question that describes the criterion for choosing a specific treatment over one or more competing alternatives. For example, stakeholders might ask which treatment is most likely to improve mean survival by at least 2 years, or which treatment is associated with the longest mean survival. We discuss the most commonly used ranking metrics (quantities that compare the estimated treatment-specific effects), how the ranking metrics produce a treatment hierarchy, and the type of treatment hierarchy question that each ranking metric can answer. We show that the ranking metrics encompass the uncertainty in the estimation of the treatment effects in different ways, which results in different treatment hierarchies. When using network meta-analyses that aim to rank treatments, investigators should state the treatment hierarchy question they aim to address and employ the appropriate ranking metric to answer it. Following this new proposal will avoid some controversies that have arisen in comparative effectiveness research.


Quantification of effects of season and nitrogen supply on tree below-ground carbon transfer to ectomycorrhizal fungi and other soil organisms in a boreal pine forest.
*The flux of carbon from tree photosynthesis through roots to ectomycorrhizal (ECM) fungi and other soil organisms is assumed to vary with season and with edaphic factors such as nitrogen availability, but these effects have not been quantified directly in the field. *To address this deficiency, we conducted high temporal-resolution tracing of (13)C from canopy photosynthesis to different groups of soil organisms in a young boreal Pinus sylvestris forest. *There was a 500% higher below-ground allocation of plant C in the late (August) season compared with the early season (June). Labelled C was primarily found in fungal fatty acid biomarkers (and rarely in bacterial biomarkers), and in Collembola, but not in Acari and Enchytraeidae. The production of sporocarps of ECM fungi was totally dependent on allocation of recent photosynthate in the late season. There was no short-term (2 wk) effect of additions of N to the soil, but after 1 yr, there was a 60% reduction of below-ground C allocation to soil biota. *Thus, organisms in forest soils, and their roles in ecosystem functions, appear highly sensitive to plant physiological responses to two major aspects of global change: changes in seasonal weather patterns and N eutrophication.


The Fold-in, Fold-out Design for DCE Choice Tasks: Application to Burden of Disease.
Background In discrete-choice experiments (DCEs), choice alternatives are described by attributes. The importance of each attribute can be quantified by analyzing respondents' choices. Estimates are valid only if alternatives are defined comprehensively, but choice tasks can become too difficult for respondents if too many attributes are included. Several solutions for this dilemma have been proposed, but these have practical or theoretical drawbacks and cannot be applied in all settings. The objective of the current article is to demonstrate an alternative solution, the fold-in, fold-out approach (FiFo). We use a motivating example, the ABC Index for burden of disease in chronic obstructive pulmonary disease (COPD). Methods Under FiFo, all attributes are part of all choice sets, but they are grouped into domains. These are either folded in (all attributes have the same level) or folded out (levels may differ). FiFo was applied to the valuation of the ABC Index, which included 15 attributes. The data were analyzed in Bayesian mixed logit regression, with additional parameters to account for increased complexity in folded-out questionnaires and potential differences in weight due to the folding status of domains. As a comparison, a model without the additional parameters was estimated. Results Folding out domains led to increased choice complexity for respondents. It also gave domains more weight than when it was folded in. The more complex regression model had a better fit to the data than the simpler model. Not accounting for choice complexity in the models resulted in a substantially different ABC Index. Conclusion Using a combination of folded-in and folded-out attributes is a feasible approach for conducting DCEs with many attributes.


Water-soluble Complex of Curcumin with Cyclodextrins: Enhanced Physical Properties For Ocular Drug Delivery.
Curcumin, a natural hydrophobic polyphenol, has been reported to have diverse pharmacological activities. Previous studies have evaluated its efficacy using both oral and transdermal dosage forms. However, two major obstacles-poor aqueous solubility and low stability-severely limited its pharmaceutical use. The main objective of this study was to prepare curcumin eye drops that provided sustained release to allow for once daily application in retinitis pigmentosa. To achieve our goal, curcumin was complexed with β -cyclodextrin and hydroxypropyl-β- cyclodextrin in two molar ratios (1:1 and 1:2) using co-solvent, co-solvent with sonication and freezedrying filtration methods. A total of 12 complexes were prepared, then characterized using differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, solubility assessment and in vitro release studies. An improvement in curcumin aqueous solubility relative to pure curcumin was achieved for all 12 complexes. However, the freeze-drying filtration method was superior to all other methods because it produced highly water-soluble drug-CD complexes. Based on our stability analyses, pH 6.8 phosphate buffer containing 1% Tween 80 was selected as the release medium for in vitro release studies because curcumin exhibited high stability in this medium. Our F11 formulation provided sustained release of the drug for more than 96 h with a maximum amount released of drug (21.77±0.26 μg/ml). Our in vitro release data also showed that release of drug from curcumin-CDs inclusion complexes followed a Higuchi non-Fickian diffusion mechanism. Based on these results, F11 was formulated as eye drops, which provide a promising once daily novel topical delivery of this naturally derived phytochemical.


Anterior segment imaging with Spectral OCT system using a high-speed CMOS camera.
We describe a new ultrahigh speed Spectral OCT instrument making use of a CMOS camera and demonstrate high quality in vivo imaging of the anterior segment of the human eye. The high flexibility of the designed imaging system allows a wide range of imaging protocols. Two- and three-dimensional high quality OCT images of the cornea, the anterior chamber and the crystalline lens are presented. A high acquisition rate, up to 135,000 A-scans/second enables three-dimensional reconstruction of the anterior segment during lenticular accommodation, blinking and pupillary reaction to light stimulus. We demonstrate OCT tomographic real time imaging of the lens dynamics during accommodation and high quality OCT cross-sectional images of the entire anterior segment of the eye from the cornea up to posterior part of the crystalline lens.


Oxaphospholes and bisphospholes from phosphinophosphonates and α,β-unsaturated ketones.
The reaction of a {W(CO)5 }-stabilized phosphinophosphonate 1, (CO)5 WPH(Ph)P(O)(OEt)2 , with ethynyl- (2 a-f) and diethynylketones (7-11, 18, and 19) in the presence of lithium diisopropylamide (LDA) is examined. Lithiated 1 undergoes nucleophilic attack in the Michael position of the acetylenic ketones, as long as this position is not sterically encumbered by bulky (iPr)3 Si substituents. Reaction of all other monoacetylenic ketones with lithiated 1 results in the formation of 2,5-dihydro-1,2-oxaphospholes 3 and 4. When diacetylenic ketones are employed in the reaction, two very different product types can be isolated. If at least one (Me)3 Si or (Et)3 Si acetylene terminus is present, as in 7, 8, and 19, an anionic oxaphosphole intermediate can react further with a second equivalent of ketone to give cumulene-decorated oxaphospholes 14, 15, 24, and 25. Diacetylenic ketones 10 and 11, with two aromatic acetylene substituents, react with lithitated 1 to form exclusively ethenyl-bridged bisphospholes 16 and 17. Mechanisms that rationalize the formation of all heterocycles are presented and are supported by DFT calculations. Computational studies suggest that thermodynamic, as well as kinetic, considerations dictate the observed reactivity. The calculated reaction pathways reveal a number of almost isoenergetic intermediates that follow after ring opening of the initially formed oxadiphosphetane. Bisphosphole formation through a carbene intermediate G is greatly favored in the presence of phenyl substituents, whereas the formation of cumulene-decorated oxaphospholes is more exothermic for the trimethylsilyl-containing substrates. The pathway to the latter compounds contains a 1,3-shift of the group that stems from the acetylene terminus of the ketone substrates. For silyl substituents, the 1,3-shift proceeds along a smooth potential energy surface through a transition state that is characterized by a pentacoordinated silicon center. In contrast, a high-lying transition state TS(E'-F')R=Ph of 37 kcal mol(-1) is found when the substituent is a phenyl group, thus explaining the experimental observation that aryl-terminated diethynylketones 10 and 11 exclusively form bisphospholes 16 and 17.


Maternal blood pressure and hypertensive disorders during pregnancy and childhood respiratory morbidity: the Generation R Study.
Pre-eclampsia is associated with an increased risk of bronchopulmonary dysplasia, wheezing and asthma in later childhood. Currently, there are no studies available investigating maternal blood pressure measurements during multiple time-points in pregnancy and respiratory outcome measures in the child.We examined the associations of maternal blood pressure and hypertensive disorders with the risk of lower lung function, wheezing and asthma in children aged 10 years. This study among 4894 children was embedded in a population-based prospective cohort study. We used multivariate analyses, taking lifestyle and socioeconomic factors into account.We observed consistent associations per 5 mmHg higher maternal blood pressure in early pregnancy with a lower forced expiratory volume in 1 s/forced vital capacity ratio (z-score -0.03 (95% CI -0.05- -0.01)) and per 5 mmHg higher blood pressure in late pregnancy with a higher risk for current wheezing and current asthma (OR 1.07 (95% CI 1.02-1.12) and 1.06 (95% CI 1.00-1.11), respectively). We found no associations of maternal hypertensive disorders during pregnancy with child lung function, current wheezing or current asthma.Our results suggest that higher blood pressure in pregnant women is associated with lower lung function and increased risks of current wheezing and current asthma in children. The associations may be trimester specific.


Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps.
alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of carcinogenesis in experimental animal models. In these animal models, DFMO has been especially active in preventing carcinogen-induced epithelial cancers, including those of the skin, colon, breast, and urinary bladder. Although DFMO is known to exert its diverse biological effects by suppressing intracellular pools of the polyamines putrescine and spermidine, the precise mechanism by which polyamine depletion, induced by DFMO, suppresses carcinogenesis is unknown. The specific aim of our study was to determine the lowest dose of DFMO that would deplete target tissue (colorectal mucosa) levels of these polyamines in humans who had undergone prior removal of colon polyps while producing minimal toxic effects. A dose de-escalation chemoprevention trial of DFMO was conducted in 111 patients (36 female and 75 male) who were in generally good health, aged 39-79, and who had undergone colonoscopy for surgical removal of an adenomatous colon polyp greater than 3 mm within 5 years prior to entering the study. Groups of patients (12-20 patients per group) were orally treated with single, daily doses of DFMO ranging from 3.0 to 0.1 g/m2 for 4 weeks (28 days). Prior to initiation of DFMO treatment and at the end of treatment, six colorectal biopsy specimens were collected from each patient, along with serum samples. All biopsies were performed between 9 AM and noon to avoid possible effects of diurnal variations in laboratory end points. Samples for analysis of plasma DFMO levels were also collected during this time period on the day after the last day of drug administration. DFMO caused a decrease in both putrescine content and the ratio of spermidine to spermine for all dose groups down to 0.25 g/m2. Both putrescine content and the ratio of spermidine to spermine and changes in these parameters as a function of DFMO treatment decreased as a function of donor age. None of the 30 patients receiving either 0.25 or 0.5 g/m2 experienced any clinical ototoxicity in this trial. DFMO is both safe and effective in reducing colorectal mucosal polyamine contents when it is administered orally to patients at doses as low as 0.25 g/m2 for 28 days. No ototoxicity was observed at doses up to twice this amount. If DFMO is also found to be effective in suppressing polyamine contents in other target tissues, it may be useful in preventing a wide range of human epithelial cancers, including those of the prostate and breast.


Severe COVID-19 is associated with hyperactivation of the alternative complement pathway.
Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized. We aimed at assessing the contribution of complement pathways at both the protein and transcriptomic levels. To this end, we systematically assessed the RNA levels of 28 complement genes in the circulating whole blood of patients with COVID-19 and healthy controls, including genes of the alternative pathway, for which data remain scarce. We found differential expression of genes involved in the complement system, yet with various expression patterns: whereas patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in patients with a severe and critical disease, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (area under the curve = 0.82; P = .002). This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system.


Hemocytic Differentiation in Hemopoietic Organ of Bombyx mori Larvae.
Bombyx mori L. (Lepidoptera: Bombycidae) larva was investigated with a transmission electron microscopy to determine hemocytic differentiation in the hemopoietic organ located in the prothorax. Three and/or four types of stem cells in compact islets of the organ were observed. Immatured hemocytes in loose islets of the organ were more differentiated and developed than in compact islets. Four types of hemocytes such as prohemocyte, plasmatocyte, granulocyte and oenocytoid were observed in loose islets. Each type of hemocyte was differentiated from each type of stem cell. However, none of spherulocyte was observed. Each type of hemocytes matured in loose islets was discharged into hemolymph by the tearing of acellular membrane covering the islets. These observation strongly suggests that the four kinds of hemocytes except for spherulocytes first appeared in islets and then moved to the region of loose islets in matured form. The more detailed pathway of hemocytic differentiation in B. mori was represented here.


The raf oncogene is associated with a radiation-resistant human laryngeal cancer.
In order to identify the genetic factors associated with the radiation-resistant human laryngeal carcinoma cell line (SQ-20B), tumor cell DNA was transfected into NIH/3T3 cells. A high incidence (six out of six) of raf sequences was found in transfected NIH/3T3 clones and the tumorigenic potential of SQ-20B DNA could be linked to genomic fragments that represent most of the kinase domain of human c-raf-1. An apparently unaltered 3.5-kilobase pair (kb) human c-raf transcript was identified in SQ-20B cells but was not observed in the transfected NIH/3T3 cell clones. Two new transcripts (4.2 kb and 2.6 kb) were found in tumorigenic clones; the large transcript was missing in a very poorly tumorigenic clone. Cytogenetic analysis indicated that the normal autosomes of chromosome 3 were absent in SQ-20B karyotypes and had formed apparently stable marker chromosomes. Unlike the recipient NIH/3T3 cell line, 30 percent of the transformed clone-1 metaphases had minute and double-minute chromosomes representative of amplified DNA sequences. The frequency of the c-raf-1 identification by NIH/3T3 transfection of SQ-20B DNA suggests the presence of some genetic abnormality within this locus.


Diabetic mastopathy. A clinicopathologic review.
Diabetic mastopathy, an uncommon form of lymphocytic mastitis and stromal fibrosis, typically occurs in longstanding type 1 diabetes. Nineteen cases meeting predetermined histopathologic criteria for diabetic mastopathy were correlated as to clinical history and disease recurrence. Physical examination revealed palpable discrete masses or diffuse nodularity, both predominantly in the subareolar region. One nonpalpable lesion was detected incidentally during reduction mammoplasty. All cases contained lymphocytic ductitis and lobulitis with varying degrees of keloidal fibrosis, vasculitis, epithelioid fibroblasts, and lymphoid nodule formation. Single mammary lesions were found in 11 patients with type 1 diabetes, 1 with type 2 diabetes, and 3 without diabetes. Four cases were bilateral (3 patients with type 1 and 1 patient with type 2 diabetes). Six of 19 cases recurred (3 ipsilateral, 2 contralateral, and 1 bilateral). We confirm the histopathologic constellation for diabetic mastopathy. However, we question the specificity of these features because of identical findings in patients with type 2 diabetes and nondiabetic patients. We found diabetic mastopathy in men and women, as a solitary mass or bilateral disease, and recurrence in either breast, sometimes multiple. Recognition of potential recurrence is important because it might spare patients with documented diabetic mastopathy from repeated breast biopsies.


Hypertension with hemodilution prevents multifocal cerebral hypoperfusion after cardiac arrest in dogs.
Improved neurological outcome with postarrest hypertensive hemodilution in an earlier study could be the result of more homogeneous cerebral perfusion and improved O2 delivery. We explored global, regional, and local cerebral blood flow by stable xenon-enhanced computed tomography and global cerebral metabolism in our dog cardiac arrest model. Ventricular fibrillation cardiac arrest of 12.5 minutes was reversed by brief cardiopulmonary bypass, followed by life support to 4 hours postarrest. We compared control group I (n = 5; mean arterial blood pressure, 100 mm Hg; hematocrit, greater than or equal to 35%) with immediately postarrest reflow-promoted group II (n = 5; mean arterial blood pressure, 140-110 mm Hg; hypervolemic hemodilution with plasma substitute to hematocrit, 20-25%). After initial hyperemia in both groups, during the "delayed hypoperfusion phase" at 1-4 hours postarrest, global cerebral blood flow was 51-60% of baseline in group I versus 85-100% of baseline in group II (p less than 0.01). Percentages of brain tissue voxels with no flow, trickle flow, or low flow were lower (p less than 0.01) and mean regional cerebral blood flow values were higher in group II (p less than 0.01). Global cerebral oxygen uptake recovered to near baseline values at 3-4 hours postarrest in both groups. Postarrest arterial O2 content, however, in hemodiluted group II was 40-50% of that in group I. Thus, the O2 uptake/delivery ratio was increased (worsened) in both groups at 2-4 hours postarrest. After prolonged cardiac arrest, immediately induced moderate hypertensive hemodilution to hematocrit 20-25% can normalize cerebral blood flow patterns (improve homogeneity of cerebral perfusion), but does not improve cerebral O2 delivery, since the flow benefit is offset by decreased arterial O2 content. Individualized titration of hematocrit or hemodilution with acellular O2 carrying blood substitute (stroma-free hemoglobin or fluorocarbon solution) would be required to improve O2 uptake/delivery ratio.


[Pecutaneous mitral valve repair].
Over four million Europeans and a similar number Americans suffer from significant mitral regurgitation (MR). Approximately 250,000 new patients are diagnosed with the disease annually. The disorder generally evolves insidiously over many years because the heart compensates for the regurgitant volume by left atrial enlargement, left ventricular (LV) volume overload, and progressive (LV) dilatation. The most common causes of MR include ischemic heart disease, non-ischemic heart disease, and valve degeneration. Mitral valve surgery has long been the only treatment available with proven efficacy for MR. It alleviates clinical symptoms and prevents ventricular dilatation and heart failure, or attenuates further progression of this process. Surgical valve repair significantly improves clinical outcomes compared with valve replacement, reducing mortality by approximately 70%. However, patients with heart failure have both higher acute risk and significant rates of late MR recurrence after surgical repair of ischemic MR. Recently, a number of percutaneous modalities of mitral valve repair have been developed. Most of these techniques are still at early stages of clinical evaluation. The MitraClip System consists of a percutaneous edge-to-edge attachemnt system that mimics the surgical procedure. This technique creates a bridge between the anterior and posterior leaflet by means of a clip deployed through trans-septal catheterization. The growing experience show that percutaneous edge-to-edge repair using the MitraClip system is feasible, safe and, in overall, effective, with very promising clinical results when performed in carefully selected patients, The new technique does not represent a general alternative to conventional surgical valve repair, which remains the gold standard particularly in the patients with degenerative MR. However, it offers a valid option in patients unsuitable for surgery and those with functional MR secondary to advanced heart failure, where the surgical approach still remains empiric.


Abolition of reflex bradycardia by cardiac vagotomy has no effect on the regulation of oxygen uptake by Atlantic cod in progressive hypoxia.
The functional significance of chemoreflexive hypoxic bradycardia was explored in Atlantic cod Gadus morhua L. (mean mass approximately 800 g, acclimated to a seawater temperature of 11 degrees C) by investigating responses to progressive hypoxia following section of the cardiac branches of cranial nerve X. Cardiac denervation had no effect on oxygen uptake rate (MO(2)), gill ventilation rate (f(G)) or opercular pressure amplitude (P(OP)) under normoxic conditions, but caused a significant increase in heart rate (f(H)), to 50+/-1 beats min(-1) by comparison to 40+/-2 beats min(-1) in sham-operated cod (mean+/-s.e.m., n=9). Sham-operated cod exhibited transient profound bradycardia following oxygen chemoreceptor stimulation by bolus injection of sodium cyanide into the buccal cavity (2 mg in 2 ml seawater), but this cardiac chemoreflex was abolished in denervated cod. Both groups, however, exhibited similar marked transient chemoreflexive hyperventilation following NaCN. When exposed from normoxia (PO(2) approximately 18 kPa) to progressive hypoxia at nominal water PO(2)'s of 8, 6, 5, 4 and 3 kPa, both groups exhibited the same pattern of homeostatic regulation of MO(2), with no significant difference in their mean critical PO(2) (P(crit)) values, which were 7.40+/-0.81 kPa and 8.73+/-0.71 kPa, respectively (n=9). Both groups exhibited significant bradycardia during progressive hypoxia, although denervated fish always had higher mean f(H). The incipient threshold for bradycardia coincided with P(crit) in sham-operated cod whereas, in denervates, the threshold was below their P(crit) and bradycardia presumably reflected direct effects of hypoxia on the myocardium. The sham-operated group displayed a significantly more pronounced ventilatory response than denervates in hypoxia, in particular for P(OP). In sham-operated cod, peak ventilatory responses occurred in deep hypoxia below P(crit) whereas, in denervates, more modest peak responses coincided with P(crit) and, in deep hypoxia, they exhibited a significant decline in f(G) below their normoxic rate. Only a minority of shams lost equilibrium in hypoxia whereas a majority of denervates did, some of which failed to recover. The results indicate that chemoreflexive bradycardia plays no role in the homeostatic regulation of oxygen uptake by cod in hypoxia, but does contribute to maintenance of overall functional integrity below P(crit).


Placental transfer of valproic acid after liposome encapsulation during in vitro human placenta perfusion.
Valproic acid (VPA) is an antiepileptic drug that crosses the placenta freely. Because its use in pregnancy is associated with an increased incidence of fetal malformation and toxic effects, this study was designed to check whether the placental transfer of VPA entrapped in liposomes was reduced. VPA was encapsulated in dehydrated-rehydrated liposomes prepared with equimolar concentrations of phosphatidylcholine, cholesterol and alpha-tocopherol. Liposomes were analyzed for their physicochemical characteristics, their stability and percentage of encapsulation of VPA. A system of dual perfusion of an isolated lobule of term human placenta was used. Six placentas were perfused with liposome-VPA and six with free VPA for 180 min using recirculating maternal and fetal circuits. The rate of transfer and time to reach equilibrium of VPA was similar in placentas perfused with free VPA and with liposome-encapsulated VPA. Liposomes significantly reduced VPA transplacental transfer and placental uptake. This was confirmed by FMM at equilibrium, that was 0.548 +/- 0.058 in free VPA and 0.393 +/- 0.075 in liposome-VPA. The ratio of fetal to maternal concentrations at equilibrium was 0.90 +/- 0.10 in controls and 0.66 +/- 0.13 in liposome-VPA. The amount of VPA recovered in fetal circulation and in placental tissue were 28 +/- 4 and 7 +/- 3% in controls and 19 +/- 4 and 3 +/- 2% in liposome-VPA. In conclusion, our data indicate that encapsulating VPA in liposomes significantly reduces the fetal amount and exposure, and further in vitro and in vivo investigations are needed to optimize the use of liposomes, particularly in pregnancy.


Ocean acidification in the coastal zone from an organism's perspective: multiple system parameters, frequency domains, and habitats.
Multiple natural and anthropogenic processes alter the carbonate chemistry of the coastal zone in ways that either exacerbate or mitigate ocean acidification effects. Freshwater inputs and multiple acid-base reactions change carbonate chemistry conditions, sometimes synergistically. The shallow nature of these systems results in strong benthic-pelagic coupling, and marine invertebrates at different life history stages rely on both benthic and pelagic habitats. Carbonate chemistry in coastal systems can be highly variable, responding to processes with temporal modes ranging from seconds to centuries. Identifying scales of variability relevant to levels of biological organization requires a fuller characterization of both the frequency and magnitude domains of processes contributing to or reducing acidification in pelagic and benthic habitats. We review the processes that contribute to coastal acidification with attention to timescales of variability and habitats relevant to marine bivalves.


The proper splicing of RNAi factors is critical for pericentric heterochromatin assembly in fission yeast.
Heterochromatin preferentially assembles at repetitive DNA elements, playing roles in transcriptional silencing, recombination suppression, and chromosome segregation. The RNAi machinery is required for heterochromatin assembly in a diverse range of organisms. In fission yeast, RNA splicing factors are also required for pericentric heterochromatin assembly, and a prevailing model is that splicing factors provide a platform for siRNA generation independently of their splicing activity. Here, by screening the fission yeast deletion library, we discovered four novel splicing factors that are required for pericentric heterochromatin assembly. Sequencing total cellular RNAs from the strongest of these mutants, cwf14Δ, showed intron retention in mRNAs of several RNAi factors. Moreover, introducing cDNA versions of RNAi factors significantly restored pericentric heterochromatin in splicing mutants. We also found that mutations of splicing factors resulted in defective telomeric heterochromatin assembly and mis-splicing the mRNA of shelterin component Tpz1, and that replacement of tpz1+ with its cDNA partially rescued heterochromatin defects at telomeres in splicing mutants. Thus, proper splicing of RNAi and shelterin factors contributes to heterochromatin assembly at pericentric regions and telomeres.


Functional mapping of the DNA binding domain of bovine papillomavirus E1 protein.
Bovine papillomavirus type 1 (BPV-1) requires viral proteins E1 and E2 for efficient DNA replication in host cells. E1 functions at the BPV origin as an ATP-dependent helicase during replication initiation. Previously, we used alanine mutagenesis to identify two hydrophilic regions of the E1 DNA binding domain (E1DBD), HR1 (E1(179-191)) and HR3 (E1(241-252)), which are critical for sequence-specific recognition of the papillomavirus origin. Based on sequence and structure, these regions are similar in spacing and location to DNA binding regions A and B2 of T antigen, the DNA replication initiator of simian virus 40 (SV40). HR1 and A are both part of extended loops which are supported by residues from the HR3 and B2 alpha-helices. Both elements contain basic residues which may contact DNA, although lack of cocrystal structures for both E1 and T antigen make this uncertain. To better understand how E1 interacts with origin DNA, we used random mutagenesis and a yeast one-hybrid screen to select mutations of the E1DBD which disrupt sequence-specific DNA interactions. From the screen we selected seven single point mutants and one double point mutant (F175S, N184Y/K288R, D185G, V193M, F237L, K241E, R243K, and V246D) for in vitro analysis. All mutants tested in electrophoretic mobility shift assays displayed reduced sequence-specific DNA binding compared to the wild-type E1DBD. Mutants D185G, F237L, and R243K were rescued in vitro for DNA binding by the replication enhancer protein E2. We also tested the eight mutations in full-length E1 for the ability to support DNA replication in Chinese hamster ovary cells. Only mutants D185G, F237L, and R243K supported significant DNA replication in vivo which highlights the importance of E1DBD-E2 interactions for papillomavirus DNA replication. Based on the specific point mutations examined, we also assigned putative roles to individual residues in DNA binding. Finally, we discuss sequence and spacing similarities between E1 HR1 and HR3 and short regions of two other DNA tumor virus origin-binding proteins, SV40 T antigen and Epstein-Barr virus nuclear antigen 1 (EBNA1). We propose that all three proteins use a similar DNA recognition mechanism consisting of a loop structure which makes base-specific contacts (HR1) and a helix which primarily contacts the DNA backbone (HR3).


Evolution of disability in late 19th century America: Civil War pensions for Union Army veterans with musculoskeletal conditions.
This article examines the evolution of musculoskeletal (MSK) disability and its impact on mortality and work patterns in the late 19th century in America, in the context of the Civil War disability policy scheme. The study was conducted on 17,702 Union Army (UA) Civil War veterans. Of these, 10,789 were examined and diagnosed with major MSK conditions, rheumatism, sciatica, and spinal curvature, between 1862 and 1907. Analyses examine MSK (i) prevalence rates by birth cohort and age group; (ii) fatality rates as compared with other disabilities; (iii) risk rates by occupation type; and (iv) lifespan for MSK patients. MSK conditions are commonly claimed disabilities within the Civil War data set, with prevalence rates increasing with age. Regression studies show that working in clerical and professional (relative to manual labor) occupations decreases the likelihood of being examined for and diagnosed with MSK conditions. MSK patients examined at older ages tended to have longer lifespan than those examined at younger ages. The findings suggest that changes in age, environmental, and occupational conditions during the late 19th century affected MSK condition prevalence and the average lifespan of MSK patients. Implications for contemporary disability policy are discussed.


Postoperative irradiation of minor salivary gland malignancies of the head and neck.
(1) To review the Stanford experience with postoperative radiotherapy for minor salivary gland carcinomas of the head and neck. (2) To identify patterns of failure and prognostic factors for these tumors. Fifty-four patients with localized tumors were treated with curative intent at Stanford University between 1966 and 1995. The 1992 AJCC staging for squamous cell carcinomas was used to retrospectively stage these patients. Thirteen percent had stage I, 22% stage II, 26% stage III, and 39% stage IV neoplasms. Thirty-two patients (59%) had adenoid cystic carcinoma, 15 (28%) had adenocarcinoma, and seven (13%) had mucoepidermoid carcinoma. Thirty (55%) had positive surgical margins and seven (13%) had cervical lymph node involvement at diagnosis. The median follow-up for alive patients was 7.8 years (range: 25 months-28.9 years). The 5- and 10-year actuarial local control rates were 91 and 88%, respectively. Advanced T-stage (T3-4), involved surgical margins, adenocarcinoma histology, and sinonasal and oropharyngeal primaries were associated with poorer local control. The 5- and 10-year actuarial freedom from distant metastasis were 86 and 81%, respectively. Advanced T-stage (T3-4), lymph node involvement at diagnosis, adenoid cystic and high-grade mucoepidermoid histology were associated with a higher risk of distant metastases. The 10-year cause-specific survival (CSS) and overall survival (OS) were 81 % and 63%, respectively. On multivariate analysis, prognostic factors affecting survival were T-stage (favoring T1-2), and N-stage (favoring NO). When T- and N-stage were combined to form the AJCC stage, the latter became the most significant factor for survival. The 10-year OS was 86% for stage I-II vs. 52% for stage III-IV tumors. Late treatment-related toxicity was low (3/54); most complications were mild and no cranial nerve damage was noted. Surgical resection and carefully planned post-operative radiation therapy for minor salivary gland tumors is well tolerated and effective with high local control rates. AJCC stage was the most significant predictor for survival and should be used for staging minor salivary gland carcinomas.


Sleep bruxism in individuals with and without attrition-type tooth wear: An exploratory matched case-control electromyographic study.
To examine if there is a difference in possible sleep bruxism activity (SB) in subjects with or without attrition-type tooth wear. Sixteen individuals with pronounced attritional-type tooth wear were compared with sex and aged matched controls without tooth wear by means of measurement of electromyographic (EMG) activity during a minimum of four consecutive nights of sleep. Mean age and range for the study- and control- group was 23.7 years (range 19.9-28.5) and 23.6 years (range 20.3-27.9), respectively. There were 11 females and five males in each of the two groups. The attrition group presented incisal/occlusal attrition wear into dentin and matching wear facets between opposing anterior teeth. The controls had negligible signs of incisal/occlusal wear and a minimal number of matching wear facets. The prevalence of both self-reported and partner-reported SB was significantly more common in the attrition group compared to the controls (P=0.04 and P=0.007, respectively). Self-reported morning facial pain was similarly more common in the attrition group (P=0.014). Maximum opening capacity, number of muscles painful to palpation, salivary flow rate and buffering capacity were not significantly different between the groups. Interestingly, none of the measures of jaw muscle EMG activity during sleep, as recorded by the portable EMG equipment, differed significantly between the attrition group and the matched controls (P>0.05). The results from this exploratory study suggest that there is no difference in EMG activity between subjects with and without attrition-type tooth wear. Further research is needed in order to substantiate these preliminary findings.


Supramolecular motifs in s-block metal-bound sulfonated monoazo dyes, part 1: structural class controlled by cation type and modulated by sulfonate aryl ring position.
The solid-state structures of 43 Li, Na, K, Rb, Mg, Ca and Ba salts of para- and meta-sulfonated azo dyes have been examined and can be categorised into three structural classes. All form alternating organic and inorganic layers, however, the nature of the coordination network that forms these layers differs from class to class. The class of structure formed was found to be primarily governed by metal type, but can also be influenced by the nature and position of the organic substituents. Thus, for the para-sulfonated azo dyes, Mg compounds form solvent-separated ion-pair solids; Ca, Ba and Li compounds form simple coordination networks based on metal-sulfonate bonding; and Na, K and Rb compounds form more complex, higher dimensional coordination networks. Compounds of meta-sulfonated azo dyes follow a similar pattern, but here, Ca species may also form solvent-separated ion-pair solids. Significantly, this first attempt to classify such dyestuffs using the principles of supramolecular chemistry succeeds not only for the simple dyes used here as model compounds, but also for more complex molecules, similar to modern colourants.


First Report of Rhizoctonia solani AG-7 on Potato in Mexico.
Among isolates of Rhizoctonia solani Kühn collected as sclerotia from potato (Solanum tuberosum L.) tubers harvested from the Toluca Valley in 1995 was one isolate (MexND) of anastomosis group 7 (AG-7). Virulence of this and other isolates of R. solani representing AG-3 (four isolates) or AG-7 (four isolates), was determined on developing potato plants (cv. Russet Burbank) in growth chamber studies at 10 and 21°C by methods used previously (1). A control treatment was inoculated with sterile disks of potato dextrose agar (PDA). Seed tubers were placed on a layer of pasturized sand-soil mix near the bottom of 6- × 25-cm black plastic tubes, then covered with 2 to 3 cm of the sand-soil mix. Seed tubers used in virulence tests carried no R. solani as they had been surface disinfested by immersing for 2 min in a 1.85% solution of formaldehyde. Inoculum, in the form of one 7-mm agar disk cut from the growing edge of appropriate colonies growing on PDA, was placed 2 to 3 cm above the seed and covered with 7 to 10 cm of sand-soil mix (1). Each treatment had five replications. Plants were harvested after control plants had emerged, 29 days at 21°C and 36 days at 10°C, and damage to roots and shoots was assessed according to Carling and Leiner (1). All four isolates of AG-3, one from the U.S. and three from Mexico, caused major damage to roots and shoots at both temperatures. The two isolates of AG-7 from the U.S. caused superficial discoloration to shoots at both temperatures but the two isolates of AG-7 from Japan caused no damage to shoots. None of the four isolates of AG-7 damaged roots at either temperature. MexND caused no damage to roots or shoots at 21°C but produced lesions (< 1 mm in diameter) on roots and shoots at 10°C. Thus, MexND caused less damage to potato than AG-3, more damage than other isolates of AG-7, and appears more aggressive at lower temperatures. This is the first reported occurrence of R. solani AG-7 in Mexico and its first reported recovery from a potato tuber-borne sclerotium. Reference: (1) D. E. Carling and R. H. Leiner. Phytopathology 80:930, 1990.