Iron and arsenic cycling in intertidal surface sediments during wetland remediation.
The accumulation and behavior of arsenic at the redox interface of Fe-rich sediments is strongly influenced by Fe(III) precipitate mineralogy, As speciation, and pH. In this study, we examined the behavior of Fe and As during aeration of natural groundwater from the intertidal fringe of a wetland being remediated by tidal inundation. The groundwater was initially rich in Fe(2+) (32 mmol L(-1)) and As (1.81 μmol L(-1)) with a circum-neutral pH (6.05). We explore changes in the solid/solution partitioning, speciation and mineralogy of Fe and As during long-term continuous groundwater aeration using a combination of chemical extractions, SEM, XRD, and synchrotron XAS. Initial rapid Fe(2+) oxidation led to the formation of As(III)-bearing ferrihydrite and sorption of >95% of the As(aq) within the first 4 h of aeration. Ferrihydrite transformed to schwertmannite within 23 days, although sorbed/coprecipitated As(III) remained unoxidized during this period. Schwertmannite subsequently transformed to jarosite at low pH (2-3), accompanied by oxidation of remaining Fe(2+). This coincided with a repartitioning of some sorbed As back into the aqueous phase as well as oxidation of sorbed/coprecipitated As(III) to As(V). Fe(III) precipitates formed via groundwater aeration were highly prone to reductive dissolution, thereby posing a high risk of mobilizing sorbed/coprecipitated As during any future upward migration of redox boundaries. Longer-term investigations are warranted to examine the potential pathways and magnitude of arsenic mobilization into surface waters in tidally reflooded wetlands.


Networks offer new opportunities for diabetes research.
The incidence of diabetes continues to rise and demands on healthcare resources continue to grow. High quality research offers a way forward for developing new treatments and care options for people with this condition. The Diabetes Research Network represents a new approach to supporting collaborative research and has been at the vanguard of encouraging patients to get involved through its advocacy workstream. Since its inception more than 200 studies involving 25,000 volunteers have been registered in the network portfolio. An essential element for success is the involvement of primary care where benefits can accrue to patients and healthcare professionals alike.


Molecularly Imprinted Composite Membranes for Selective Detection of 2-Deoxyadenosine in Urine Samples.
An important challenge for scientific research is the production of artificial systems able to mimic the recognition mechanisms occurring at the molecular level in living systems. A valid contribution in this direction resulted from the development of molecular imprinting. In this work, a novel molecularly imprinted polymer composite membrane (MIM) was synthesized and employed for the selective detection in urine samples of 2-deoxyadenosine (2-dA), an important tumoral marker. By thermal polymerization, the 2-dA-MIM was cross-linked on the surface of a polyvinylidene-difluoride (PVDF) membrane. By characterization techniques, the linking of the imprinted polymer on the surface of the membrane was found. Batch-wise guest binding experiments confirmed the absorption capacity of the synthesized membrane towards the template molecule. Subsequently, a time-course of 2-dA retention on membrane was performed and the best minimum time (30 min) to bind the molecule was established. HPLC analysis was also performed to carry out a rapid detection of target molecule in urine sample with a recovery capacity of 85%. The experiments indicated that the MIM was highly selective and can be used for revealing the presence of 2-dA in urine samples.


Adjuvant whole-abdominal radiation therapy in uterine papillary serous carcinoma.
Nine patients from 34 to 74 years of age (median, 67 years of age) with uterine papillary serous carcinoma (UPSC) were treated with whole-abdominal radiation therapy (WART) on an adjuvant basis after cytoreductive surgery. All patients were treated with megavoltage photons to an abdominopelvic field to a median dose of 2500 cGy, with continued treatment to a whole pelvic field to a median dose of 4500 cGy. Three patients received additional boost to the vaginal apex. Follow-up time ranged from 6 to 31 months (median, 25 months) after completion of WART. Six patients had recurrent disease at 5 to 20 months (median, 7.5 months). Four of these patients died of their disease during the follow-up period. Three of six patients in whom treatment failed had disease at the vaginal apex. None of these patients received boost radiation therapy to that site. In contrast, two of three patients remaining disease free were treated with additional vaginal apex irradiation. Based on these results, the authors do not routinely recommend WART for adjuvant treatment of UPSC. They do, however, recommend vaginal apex irradiation for these patients.


Multiple toxicity from 3,4-methylenedioxymethamphetamine ("ecstasy").
There have been no published case series illustrating "ecstasy" (3,4-methylenedioxymethamphetamine [MDMA]) toxicity in a group of patients who have ingested ecstasy in the same environment. We report a series of 7 patients who ingested ecstasy in a nightclub and presented with varying degrees of MDMA toxicity. Three patients presented with features of severe MDMA toxicity. One died within an hour of hospital admission, another died 4 days later, after developing fulminant hepatic failure, and the third recovered after 12 days in intensive care. MDMA was identified in the serum of all 7 patients. High serum MDMA concentrations correlated with severe clinical and biochemical features including coma, hyperpyrexia, cardiovascular compromise, acidosis, and hyperkalaemia. "Poisoned ecstasy" was widely reported by the media as being responsible for the adverse effects observed. This report highlights a relationship between serum concentrations and toxic effects of MDMA, and the ongoing need to educate the public about the dangers of this substance.


New strategies for the elimination of polio from India.
The feasibility of global polio eradication is being questioned as a result of continued transmission in a few localities that act as sources for outbreaks elsewhere. Perhaps the greatest challenge is in India, where transmission has persisted in Uttar Pradesh and Bihar despite high coverage with multiple doses of vaccine. We estimate key parameters governing the seasonal epidemics in these areas and show that high population density and poor sanitation cause persistence by not only facilitating transmission of poliovirus but also severely compromising the efficacy of the trivalent vaccine. We analyze strategies to counteract this and show that switching to monovalent vaccine may finally interrupt virus transmission.


Mechano-sensitivity of cardiac pacemaker function: pathophysiological relevance, experimental implications, and conceptual integration with other mechanisms of rhythmicity.
Cardiac pacemaker cells exhibit spontaneous, rhythmic electrical excitation, termed automaticity. This automatic initiation of action potentials requires spontaneous diastolic depolarisation, whose rate determines normal rhythm generation in the heart. Pacemaker mechanisms have been split recently into: (i) cyclic changes in trans-sarcolemmal ion flows (termed the 'membrane-clock'), and (ii) rhythmic intracellular calcium cycling (the 'calcium-clock'). These two 'clocks'undoubtedly interact, as trans-sarcolemmal currents involved in pacemaking include calcium-carrying mechanisms, while intracellular calcium cycling requires trans-sarcolemmal ion flux as the mechanism by which it affects membrane potential. The split into separate 'clocks' is, therefore, somewhat arbitrary. Nonetheless, the 'clock' metaphor has been conceptually stimulating, in particular since there is evidence to support the view that either 'clock'could be sufficient in principle to set the rate of pacemaker activation. Of course, the same has also been shown for sub-sets of 'membrane-clock' ion currents, illustrating the redundancy of mechanisms involved in maintaining such basic functionality as the heartbeat, a theme that is common for vital physiological systems. Following the conceptual path of identifying individual groups of sub-mechanisms, it is important to remember that the heart is able to adapt pacemaker rate to changes in haemodynamic load, even after isolation or transplantation, and on a beat-by-beat basis. Neither the 'membrane-' nor the 'calcium-clock' do, as such, inherently account for this rapid adaptation to circulatory demand (cellular Ca²⁺ balance changes over multiple beats, while variation of sarcolemmal ion channel presence takes even longer). This suggests that a third set of mechanisms must be involved in setting the pace. These mechanisms are characterised by their sensitivity to the cyclically changing mechanical environment, and--in analogy to the above terminology--this might be considered a 'mechanics-clock'. In this review, we discuss possible roles of mechano-sensitive mechanisms for the entrainment of membrane current dynamics and calcium-handling. This can occur directly via stretch-activation of mechano-sensitive ion channels in the sarcolemma and/or in intracellular membrane compartments, as well as by modulation of 'standard' components of the 'membrane-' or 'calcium-clock'. Together, these mechanisms allow rapid adaptation to changes in haemodynamic load, on a beat-by-beat basis. Additional relevance arises from the fact that mechano-sensitivity of pacemaking may help to explain pacemaker dysfunction in mechanically over- or under-loaded tissue. As the combined contributions of the various underlying oscillatory mechanisms are integrated at the pacemaker cell level into a single output--a train of pacemaker action potentials--we will not adhere to a metaphor that implies separate time-keeping units ('clocks'), and rather focus on cardiac pacemaking as the result of interactions of a set of coupled oscillators, whose individual contributions vary depending on the pathophysiological context. We conclude by considering the utility and limitations of viewing the pacemaker as a coupled system of voltage-, calcium-, and mechanics-modulated oscillators that, by integrating a multitude of inputs, offers the high level of functional redundancy that is vitally important for cardiac automaticity.


A fish out of water: gill and skin remodeling promotes osmo- and ionoregulation in the mangrove killifish Kryptolebias marmoratus.
The euryhaline, amphibious mangrove killifish Kryptolebias marmoratus is known to survive weeks out of water in moist environments. We tested the hypothesis that the skin is a site of osmo- and ionoregulation in K. marmoratus. We predicted that under terrestrial conditions, gill and skin remodeling would result in an enhanced role for skin and a diminished role for the gills in osmo- and ionoregulation. Fish were exposed to water-either freshwater (FW, 1‰) or hypersaline water (saltwater [SW], 45‰)-or air over a moist surface of FW or SW for 9 d and then recovered in water. When fish were emersed for 9 d, (22)Na and (3)H-H(2)O were exchanged across the cutaneous surface. Homeostasis of whole-body Cl(-) and water levels but not of Na(+) levels was maintained over 9 d in air. In air-exposed fish, there was a significant increase in the size of skin ionocytes (in SW), a decrease in the number of skin mucous cells (in SW), and an increase in the gill interlamellar cell mass relative to those of fish in water. Gill ionocytes were mostly embedded away from the external surface in air-exposed fish, but the number and size of ionocytes increased (in FW). Interestingly, skin ionocytes formed distinct clusters of 20-30 cells. The estimated number of ionocytes over the whole skin surface was comparable to that in the gills. Overall, the findings support the hypothesis that the skin is a site of osmo- and ionoregulation in K. marmoratus in aquatic and terrestrial environments. Reversible cellular and morphological changes to the skin and gills during air exposure probably enhanced the cutaneous contribution to ion and water balance.


Drug prescription for erectile dysfunction before and after diagnosis of localized prostate cancer.
Despite the high prevalence of erectile dysfunction (ED) in men with prostate cancer, little is known about the use of ED drugs. Also, the possible influence of socioeconomic factors on ED drug use has not been studied previously. The aim of this study was to examine determinants and patterns of ED drug use before and after diagnosis in men with localized prostate cancer. Using a nationwide population-based cohort, 25,390 men with localized prostate cancer diagnosed between 2006 and 2009 and 126,944 control men were identified and followed for filled ED drug prescriptions over a 3-year period, ranging from 1 year before and up to 2 years after diagnosis. The main outcome measure was the proportion of men with at least one filled ED drug prescription after diagnosis. The number of men using ED drugs increased markedly following diagnosis. Men who underwent radical prostatectomy had the strongest increase, with a cumulative proportion of 74% for at least one filled prescription within the first 2 years after diagnosis. The corresponding proportion was 33% in men treated with radiotherapy, 21% in men on active surveillance, 10% in men on watchful waiting, and 8% in control men. Among men who underwent prostatectomy, usage attenuated over time. Determinants of postdiagnostic use were young age at diagnosis, high income, high education, and a low- or intermediate-risk cancer. Although drugs for ED are commonly prescribed after diagnosis, use among most men is transient and influenced by socioeconomic status. Posttreatment counseling and affordable ED drugs are likely to reduce treatment dropout and disparities in use and help improve sexual health and quality of life in men with prostate cancer.


A conceptual model for work-related neck and upper-limb musculoskeletal disorders.
This paper presents a conceptual model for the pathogenesis of work-related musculoskeletal disorders. The model contains sets of cascading exposure, dose, capacity, and response variables, such that response at one level can act as dose at the next. Response to one or more doses can diminish or increase the capacity for responding to successive doses. The model is used as a framework for discussing the development of work-related muscle, tendon, and nerve disorders. It is intended as a beginning, to be modified to explain new findings as they become available. In research, it can help to identify areas needing additional data for the development and expression of work-related musculoskeletal disorders. Researchers can use it to design laboratory and field studies. In practice, it demonstrates the relationship between common exposure factors and different responses. This information can be used to evaluate and design jobs for the prevention of work-related musculoskeletal disorders.


Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1.
Cytotoxic necrotizing factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra-intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work we developed a fluorescent cell-based immunoassay to screen for inhibitors of CNF1-induced Rac1 degradation among 1120 mostly approved drugs. Eleven compounds were found to prevent CNF1-induced Rac1 degradation, and five also showed a protective effect against CNF1-induced multinucleation. Finally, lasalocid, monensin, bepridil, and amodiaquine protected cells from both diphtheria toxin and CNF1 challenges. These data highlight the potential for drug repurposing to fight several bacterial infections and Rac1-based diseases.


Characterization of d-Enzyme (4-alpha-Glucanotransferase) in Arabidopsis Leaf.
Two major forms of d-enzyme (4-alpha-glucanotransferase, EC 184.108.40.206) were successfully separated from most of the amylase activity using FPLC-Mono Q column chromatography. Transfer of a maltosyl group was observed upon the incubation of d-enzyme with maltotriose and d-[U-(14) C]glucose. About 4.5% of the radioactivity was transferred to maltotriose in 2 hours. End product analysis showed the accumulation of glucose and maltopentaose from maltotriose within the first 10 minutes of the reaction. Several other maltodextrins were also observed with longer incubation times, although maltose was never produced. A quantitative measurement of maltodextrin production from the reaction of [(14) C]maltotriose with d-enzyme showed that the quantity of maltotriose decreased from 100% to 31% after 3 hours incubation, while glucose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, maltooctaose, and higher maltodextrins increased in amount. Glucose is the major product throughout the course of the reaction of d-enzyme with maltotriose. Maltotriose, in addition to glucose, are the major products in the reaction of d-enzyme with maltodextrins with a chain length greater than maltotriose. This study confirms the existence of a transglycosylase that disproportionates maltotriose and higher maltodextrins by transferring maltosyl or maltodextrinyl groups between maltodextrins resulting in the production of glucose and different maltodextrins, but not maltose, in leaf tissue with enzymic properties very similar to the previously reported d-enzyme in potato.


Efficacy of Liraglutide in clinical practice: Single centre experience.
GLP-one receptor agonists are amongst the unique antidiabetes medications that have significant metabolic and cardiovascular benefits in addition to glucose lowering effect. To best of our knowledge, there is no published data on efficacy of liraglutide use among Pakistani population.Our objective was to ascertain the efficacy of liraglutide use among type two diabetes patients. This retrospective study was conducted at the Endocrinology Clinics of Aga Khan University Hospital (AKUH) Karachi, Pakistan during the period from July 01, 2016 to 30th June, 2017. Liraglutide was prescribed to 68 obese type two diabetes patients with uncontrolled diabetes taking more than one oral medication ± insulin. Starting dose of Liraglutide was 0.6 mg, which was increased to 1.2 mg after 1-2 weeks with further increment to 1.8 mg/day based on tolerance and individual patient preference. Dose of other diabetes medications was adjusted according to clinical judgment whereas Dipeptidyl peptidase-4(DPP-4) inhibitors were discontinued. Mean age of cohort was 55 years (SD=10.94 years) with median body mass index of 36.45 kg/m2 and majority (57.35%) were on a dose of 1.2 mg of Liraglutide per day. Median HbA1c reduced to 7.50% and 7.40% at three months and six months respectively vs 8.45% at baseline. Mean reduction in weight after three month was two kilograms and at six months, it was 1.38 kilograms respectively. Liraglutide as add on therapy demonstrated favourable HbA1c and weight reduction in obese uncontrolled type two Diabetes Pakistani subjects.


Diet-beverage consumption and caloric intake among US adults, overall and by body weight.
We examined national patterns in adult diet-beverage consumption and caloric intake by body-weight status. We analyzed 24-hour dietary recall with National Health and Nutrition Examination Survey 1999-2010 data (adults aged ≥ 20 years; n = 23 965). Overall, 11% of healthy-weight, 19% of overweight, and 22% of obese adults drink diet beverages. Total caloric intake was higher among adults consuming sugar-sweetened beverages (SSBs) compared with diet beverages (2351 kcal/day vs 2203 kcal/day; P = .005). However, the difference was only significant for healthy-weight adults (2302 kcal/day vs 2095 kcal/day; P < .001). Among overweight and obese adults, calories from solid-food consumption were higher among adults consuming diet beverages compared with SSBs (overweight: 1965 kcal/day vs 1874 kcal/day; P = .03; obese: 2058 kcal/day vs 1897 kcal/day; P < .001). The net increase in daily solid-food consumption associated with diet-beverage consumption was 88 kilocalories for overweight and 194 kilocalories for obese adults. Overweight and obese adults drink more diet beverages than healthy-weight adults and consume significantly more solid-food calories and a comparable total calories than overweight and obese adults who drink SSBs. Heavier US adults who drink diet beverages will need to reduce solid-food calorie consumption to lose weight.


Identification of differentially expressed long non-coding RNAs associated with dilated cardiomyopathy using integrated bioinformatics approaches.
The aim of this study was to identify novel long non-coding RNA (lncRNA) biomarkers associated with dilated cardiomyopathy (DCM) and reveal the potential molecular mechanisms of DCM development using bioinformatics approaches. The array data of GSE5406, including 108 DCM samples and 16 non-failing control samples, were obtained from the Gene Expression Omnibus database. The differentially expressed lncRNAs were identified using limma package in R. Pearson's correlation analyses were performed between the differentially expressed lncRNAs and protein-coding genes based on their expression levels. Pathway enrichment of these lncRNAs was conducted based on the significantly co-expressed genes. From the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC) value was obtained and used for evaluating discriminatory ability. IDI2-AS1 and XIST were differentially expressed in DCM patients. A total of 510 co-expressed genes were identified. The enriched functions and pathways of the co-expressed genes mainly included NADH dehydrogenase activity, cardiac muscle contraction, and oxidative phosphorylation. The ROC curve analysis indicated that the two lncRNAs have favorable diagnostic values in DCM. The AUC values of XIST, IDI2-AS1, and the combination of XIST and IDI2-AS1 were 0.733 (95% CI: 0.646-0.809), 0.796 (95% CI: 0.715-0.863), and 0.823 (95% CI: 0.745-0.886), respectively. This study identified IDI2-AS1 and XIST lncRNAs and related pathways involved in the pathogenesis of DCM, thus providing potential diagnostic and therapeutic targets for DCM.


N-terminal pro-B-type natriuretic peptide as a predictor of incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis: the effects of age, sex and ethnicity.
Atrial fibrillation (AF) is a common source of medical costs, morbidity and mortality. NT pro-brain natriuretic peptide (BNP) is a remarkably strong predictor of AF in older whites; we aimed to assess if this biomarker was as predictive in other racial groups. We used covariate-adjusted Cox model regressions to estimate the HRs of developing AF as a function of NT proBNP, and tested for interactions of NT proBNP with age, gender and race/ethnicity. The Multi-Ethnic Study of Atherosclerosis (MESA). 5518 subjects were followed over a median of 7.6 years. During this time, 267 developed AF. NT proBNP was statistically significantly associated with incident AF; for ln NT proBNP, the adjusted HR was 2.2 (95% CI 1.9 to 2.5). Assessed by quintiles, the relationship between NT proBNP was strong and graded; the unadjusted HR for the highest quintile of NT proBNP was 23.7 (95% CI 11.1 to 50.6) and adjusted was 11.4 (95% CI 5.1 to 25.3). NT proBNP was an excellent predictor of incident AF in the younger and older age groups, in men and women and in the different race/ethnicity groups: the HR for ln NT proBNP as a predictor of incident AF ranged from 2.0 to 3.9 in each subgroup. NT proBNP is a robust predictor of incident AF; its prognostic value is more significant in younger patients and women compared with older patients and men. NT proBNP was also as strongly predictive in black patients, Hispanics and Asian/Chinese as in white patients despite a lower incidence of arrhythmia.


An Emerging Biothreat: Crimean-Congo Hemorrhagic Fever Virus in Southern and Western Asia.
Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) is endemic in numerous countries, but the epidemiology and epizoology of Crimean-Congo hemorrhagic fever (CCHF) remain to be defined for most regions of the world. Using a broad database search approach, we reviewed the literature on CCHF and CCHFV in Southern and Western Asia to better define the disease burden in these areas. We used a One Health approach, moving beyond a focus solely on human disease burden to more comprehensively define this burden by reviewing CCHF case reports, human and animal CCHFV seroprevalence studies, and human and animal CCHFV isolations. In addition, we used published literature to estimate the distribution of Hyalomma ticks and infection of these ticks by CCHFV. Using these data, we propose a new classification scheme for organizing the evaluated countries into five categories by level of evidence for CCHF endemicity. Twelve countries have reported CCHF cases, five from Southern Asia and seven from Western Asia. These were assigned to level 1 or 2. Eleven countries that have evidence of vector circulation but did not report confirmed CCHF cases were assigned to level 3 or 4. This classification scheme was developed to inform policy toward strengthening CCHF disease surveillance in the Southern and Western Asia regions. In particular, the goal of this review was to inform international organizations, local governments, and health-care professionals about current shortcomings in CCHFV surveillance in these two high-prevalence regions.


A combined experimental and theoretical study of optical rotatory dispersion for (R)-glycidyl methyl ether in aqueous solution.
The dispersive optical activity for aqueous solutions of non-rigid (R)-glycidyl methyl ether (R-GME) has been explored synergistically from experimental and theoretical perspectives. Density functional theory analyses performed with the polarizable continuum model for implicit solvation identified nine low-lying stable conformers that are interconverted by rotation about two large-amplitude torsional coordinates. The antagonistic chiroptical signatures predicted for these structural isomers were averaged under a Boltzmann-weighting ansatz to estimate the behavior expected for a thermally equilibrated ensemble. This led to optical rotatory dispersion profiles that reproduced the overall shape of observations but failed to achieve uniform agreement with measured specific-rotation values even when anharmonic vibrational corrections were applied. A mixed QM/FQ paradigm, whereby quantum-mechanical (QM) calculations of optical activity were combined with classical molecular dynamics simulations of explicit solvation that included mutual-polarization effects by means of fluctuating charges (FQ), was enlisted to elucidate the microsolvation environment and gauge its impact upon conformer distributions and response properties. Although quantitative accord with experiments remained elusive, this approach revealed strong variations in the magnitude and sign of rotatory powers for R-GME as the configuration of surrounding water molecules evolved, thereby highlighting the inherently dynamical nature of the solvated chiroptical response, calling into question the validity of "static" descriptions based on the presumption of distinct energy minima, and giving insight into the inherent complexity posed by the modeling of such properties for solvated systems.


Reply to the 'Comment on "On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility" Phys. Chem. Chem. Phys., 2018, 20, DOI: '.
In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too "small" to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole-methanol and indole-water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole-methanol-water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.


The effect of meal replacements high in glycomacropeptide on weight loss and markers of cardiovascular disease risk.
Glycomacropeptide (GMP) is a peptide that has been shown to stimulate release of cholecystokinin, which may promote satiety. The aim of this one-year study was to examine whether greater weight loss could be achieved and sustained with a GMP-enriched whey powder supplement compared with a skim milk powder supplement. In a double-blind, randomized, parallel-design study using meal replacements, weight, body composition (determined by dual-energy X-ray absorptiometry), blood pressure, fasting lipids, glucose, and insulin were measured at baseline, 6, and 12 mo. Meal replacements contained 15 g protein from GMP-enriched whey protein isolate (GMP-WPI) or skim milk powder (SMP) and 900 kJ/sachet. Volunteers consumed 2 sachets/d instead of 2 meals for 6 mo and 1 sachet/d for a further 6 mo. Of the 127 participants (95 women, 32 men, 95.5 +/- 15.4 kg, body mass index 33.4 +/- 3.4 kg/m(2), 50.0 +/- 12.4 y), 82 completed the 6-mo study and 72 of those completed the 12-mo study. At 6 mo, weight loss was 9.5 +/- 5.8 kg compared with 11.0 +/- 6.0, GMP-WPI and SMP, respectively, and 9.9 +/- 8.8 kg compared with 10.8 +/- 7.4 GMP-WPI and SMP, respectively, at 12 mo (P < 0.001 compared with baseline, at both timepoints) with no differences between treatments. Total and LDL cholesterol, triacylglycerols, glucose, insulin, and systolic and diastolic blood pressure decreased at 6 and 12 mo (all P < 0.01 compared with baseline with no difference between treatments). HDL cholesterol increased at 12 mo (P < 0.001 compared with baseline). Meal replacements containing GMP had no additional effect on the overall sustained 12-mo weight loss of 10 kg. There were improvements in cardiovascular disease risk markers.


Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies.
Squamous cell carcinomas account for about 80% of cancers of the uterine cervix, and the majority of the remainder are adenocarcinomas. There is limited evidence on the extent to which these histological types share a common etiology. The International Collaboration of Epidemiological Studies of Cervical Cancer has brought together and combined individual data on 8,097 women with invasive squamous cell carcinoma, 1,374 women with invasive adenocarcinoma and 26,445 women without cervical cancer (controls) from 12 epidemiological studies. Compared to controls, the relative risk of each histological type of invasive cervical cancer was increased with increasing number of sexual partners, younger age at first intercourse, increasing parity, younger age at first full-term pregnancy and increasing duration of oral contraceptive use. Current smoking was associated with a significantly increased risk of squamous cell carcinoma (RR = 1.50, 95% CI: 1.35-1.66) but not of adenocarcinoma (RR = 0.86 (0.70-1.05)), and the difference between the two histological types was statistically significant (case-case comparison p < 0.001). A history of screening (assessed as having had at least one previous nondiagnostic cervical smear) was associated with a reduced risk of both histological types, but the reduction was significantly greater for squamous cell carcinoma than for adenocarcinoma (RR = 0.46 (0.42-0.50) and 0.68 (0.56-0.82), respectively; case-case comparison, p = 0.002). A positive test for cervical high-risk HPV-DNA was a strong risk factor for each histological type, with 74% of squamous cell carcinomas and 78% of adenocarcinomas testing positive for HPV types 16 or 18. Squamous cell and adenocarcinoma of the cervix share most risk factors, with the exception of smoking.


Inactivation of the UGPase1 gene causes genic male sterility and endosperm chalkiness in rice (Oryza sativa L.).
A rice genic male-sterility gene ms-h is recessive and has a pleiotropic effect on the chalky endosperm. After fine mapping, nucleotide sequencing analysis of the ms-h gene revealed a single nucleotide substitution at the 3'-splice junction of the 14th intron of the UDP-glucose pyrophosphorylase 1 (UGPase1; EC188.8.131.52) gene, which causes the expression of two mature transcripts with abnormal sizes caused by the aberrant splicing. An in vitro functional assay showed that both proteins encoded by the two abnormal transcripts have no UGPase activity. The suppression of UGPase by the introduction of a UGPase1-RNAi construct in wild-type plants nearly eliminated seed set because of the male defect, with developmental retardation similar to the ms-h mutant phenotype, whereas overexpression of UGPase1 in ms-h mutant plants restored male fertility and the transformants produced T(1) seeds that segregated into normal and chalky endosperms. In addition, both phenotypes were co-segregated with the UGPase1 transgene in segregating T(1) plants, which demonstrates that UGPase1 has functional roles in both male sterility and the development of a chalky endosperm. Our results suggest that UGPase1 plays a key role in pollen development as well as seed carbohydrate metabolism.


Effect of Stimulation Current in Transcutaneous Vagus Nerve Stimulation (tVNS): A Study Using Concurrent Magnetoencephalography (MEG).
Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive method of brain stimulation that has been investigated for its use in the clinical treatment of a number of different conditions. There has been little investigation into the stimulation current that is delivered and the effect on individual variability in response to tVNS.Seventeen participants underwent tVNS, and stimulation current was determined based on individual pain threshold. To investigate individual variability, brain dynamics were measured concurrently using magnetoencephalography (MEG) in response to two different stimulation protocols of tVNS. The first protocol consisted of a sequence of equally spaced short (1ms) stimulation pulses applied 24 times per second (24 Hz), and the second consisted of a sequence of 24 pulses per second spaced according to a 6 Hz pulse frequency modulation (PFM). Both stimulation sequences were delivered to the cymba concha in the left ear.The difference in brain responses to the two sequences was initially calculated using a one-sample t-test at the group level, based on z-scoring of the data at the individual level, and no statistically significant differences were observed. Further investigation of individual variability suggested that participants fell into two groups; one that responded more strongly to 24 Hz and one that responded more strongly to the irregular spacing of pulses in the PFM protocol.We tested whether the stimulation current that the participant received could predict how they would respond to the stimulation, but we did not observe any correlation. This supports the literature that suggests that selecting stimulation current based on individual pain threshold is a suitable procedure for tVNS, and higher stimulation intensities does not correspond to stronger brain response. Further investigation into individual variability in response to different frequencies and pulse spacing of tVNS should also be investigated further and may lead to the development of personalised stimulation protocols.Clinical relevance- The stimulation current at which tVNS is delivered does not appear to influence brain response to stimulation, and the value of stimulation current should be selected based on individual participant comfort.


Patient demographic and socioeconomic characteristics in the SEER-Medicare database applications and limitations.
Users of the linked SEER-Medicare database commonly perform analyses that focus on the complex interactions among patient characteristics, cancer treatments, and outcomes. The authors review the source and scope of the patient-specific data elements, with a focus on three domains--demographic characteristics, socioeconomic characteristics, and survival status. They offer some concrete recommendations regarding the use of these data elements. In particular, they describe analyses that provide an estimate of the accuracy of the sex and age variables, and raise some cautionary notes about race and ethnicity variables. The authors describe the available measures of socioeconomic status, and recommend, with some caveats, the use of median income measures as a proxy for socioeconomic status. Finally, they describe the available data on date of death, and explain why confidence in these measures is justified.


Symptom report in detecting breast cancer-related lymphedema.
Breast cancer-related lymphedema is a syndrome of abnormal swelling coupled with multiple symptoms resulting from obstruction or disruption of the lymphatic system associated with cancer treatment. Research has demonstrated that with increased number of symptoms reported, breast cancer survivors' limb volume increased. Lymphedema symptoms in the affected limb may indicate a latent stage of lymphedema in which changes cannot be detected by objective measures. The latent stage of lymphedema may exist months or years before overt swelling occurs. Symptom report may play an important role in detecting lymphedema in clinical practice. The purposes of this study were to: 1) examine the validity, sensitivity, and specificity of symptoms for detecting breast cancer-related lymphedema and 2) determine the best clinical cutoff point for the count of symptoms that maximized the sum of sensitivity and specificity. Data were collected from 250 women, including healthy female adults, breast cancer survivors with lymphedema, and those at risk for lymphedema. Lymphedema symptoms were assessed using a reliable and valid instrument. Validity, sensitivity, and specificity were evaluated using logistic regression, analysis of variance, and areas under receiver operating characteristic curves. Count of lymphedema symptoms was able to differentiate healthy adults from breast cancer survivors with lymphedema and those at risk for lymphedema. A diagnostic cutoff of three symptoms discriminated breast cancer survivors with lymphedema from healthy women with a sensitivity of 94% and a specificity of 97% (area under the curve =0.98). A diagnostic cutoff of nine symptoms discriminated at-risk survivors from survivors with lymphedema with a sensitivity of 64% and a specificity of 80% (area under the curve =0.72). In the absence of objective measurements capable of detecting latent stages of lymphedema, count of symptoms may be a cost-effective initial screening tool for detecting lymphedema.


Effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the orexin-1 receptor.
Selective blockade of the orexin-1 receptor (OX1) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats.


Macroscopic and microscopic analysis of knife stab wounds on fleshed and clothed ribs.
Stab wounds upon bone are analyzed to interpret the weapon used and the physical context in which the attack occurred. The literature demonstrates that most research conducted pertaining to wound patterns has been carried out on defleshed and unclothed bone samples, not adequately replicating actual circumstances. For this research, six half pig torsos (Sus scrofa), fleshed (including muscle, fat, epidermis, and dermis layers) and clothed, were stabbed using three knife types, applying both straight and downward thrusts. Analysis conducted macroscopically and through a scanning electron microscope with an environmental secondary electron detector revealed a general lack of consistency in wound pattern and associated secondary effects. Consequently, it was not possible to establish wound pattern per knife type as suggested in previous research or relate it to stab motion. Advantage of microscopic analysis was evident in recognizing wound traits and observation of trace evidence not visible macroscopically.


Opioid, antipsychotic and hypnotic use in end of life in long-term care facilities in six European countries: results of PACE.
Opioids, antipsychotics and hypnotics are recommended for comfort care in dying. We studied their prescription during the last 3 days in residents deceased in the long-term care facility (LTCF). In a retrospective, cross-sectional survey in Belgium, England, Finland, Italy, the Netherlands and Poland, LTCFs, selected by proportional stratified random sampling, reported all deaths over the previous 3 months. The nurse most involved in the residents' care reviewed the chart for opioid, antipsychotic and hypnotic prescription, cause of death and comorbidities. Multivariable logistic regression was performed to adjust for resident characteristics. Response rate was 81.6%. We included 1079 deceased residents in 322 LCTFs. Opioid prescription ranged from 18.5% (95% CI: 13.0-25.8) of residents in Poland to 77.9% (95% CI: 69.5-84.5) in the Netherlands, antipsychotic prescription from 4.8% (95% CI: 2.4-9.1) in Finland to 22.4% (95% CI: 14.7-32.4) in Italy, hypnotic prescription from 7.8% (95% CI: 4.6-12.8) in Finland to 47.9% (95% CI: 38.5-57.3) in the Netherlands. Differences in opioid, antipsychotic and hypnotic prescription between countries remained significant (P < 0.001) when controlling for age, gender, length of stay, cognitive status, cause of death in multilevel, multivariable analyses. Dying from cancer showed higher odds for receiving opioids (OR 3.51; P < 0.001) and hypnotics (OR 2.10; P = 0.010). Opioid, antipsychotic and hypnotic prescription in the dying phase differed significantly between six European countries. Further research should determine the appropriateness of their prescription and refine guidelines especially for LTCF residents dying of non-cancer diseases.


[A case of cerebellar ataxia showing severe dystonia masquerading as myoclonic jerky movements on arm extension].
A 43-year-old man was admitted to our hospital due to unstable walking, head tilting to the left and difficulty in extending his arm. He was quite healthy until the age of 20 years, when these symptoms appeared and progressed slowly afterward. Due to his unstable walking, he started to use a wheelchair when he was 39 years old. He had no family history of similar disease. On admission, neurological examination revealed spasmodic torticollis, ataxic speech and marked limb and truncal ataxia. Myoclonic jerky flexion of the forearm was induced when he raised and extended his forearm. He also showed mild hyperreflexia in the lower limbs without pathological reflexes. He had weakness and atrophy of the left supraspinatus, infraspinatus, deltoid and biceps brachii muscles and mild superficial sensory impairment in the left axillary nerve territory due to cervical spondylotic radiculopathy of the left C5 root. MRI of the brain demonstrated severe bilateral atrophy of the cerebellar hemispheres and vermis but minimal atrophy of the cerebrum and brainstem. Because surface electromyography revealed continuous discharge with phasic components in the biceps and wrist flexor muscles on extending the upper limbs, the jerky flexion movement of the forearm was considered to be primarily dystonia. Although no giant SEP was observed, a C-response was detected in the long-loop reflex in response to right median nerve stimulation. Nuclear examinations showed diffuse hypoperfusion and decreased glucose metabolism in the cerebellum. Based on these findings, we hypothesized that cerebellar dysfunction may have induced severe dystonic movement resembling myoclonus. We would like to name this complicated involuntary movement an "arm thrust". This is the first case to be reported of sporadic, chronic, progressive cerebellar ataxia accompanied by severe dystonic movement, especially on stretching the forearms, that mimics myoclonic movement.


Assessing reactivity to virtual reality alcohol based cues.
The use of virtual reality (VR) programs in behavioral science research has been gaining prominence over the past several years. In the field of substance abuse, VR cue reactivity programs have been successfully tested for feasibility in nicotine and cocaine dependent samples. Seeking to expand VR applications in alcohol cue research, a novel VR alcohol cue reactivity assessment system incorporating visual, auditory, and olfactory stimuli was developed and tested. In a controlled trial, 40 non-treatment-seeking drinkers with alcohol use disorders were exposed to VR alcohol cue environments. Subjective craving, attention to alcohol cues, and level of presence (realism of experience) in VR were assessed across the environments. Overall, subjective craving for alcohol increased across the VR alcohol-related cue environments versus VR neutral cue environments. Participants reported high levels of presence in VR, indicating that the environments were perceived as realistic and compelling. These initial findings support the use of VR based cue reactivity environments for use in alcohol cue-based treatment and research.


Resistance exercise training for fibromyalgia.
Fibromyalgia is characterized by chronic widespread pain that leads to reduced physical function. Exercise training is commonly recommended as a treatment for management of symptoms. We examined the literature on resistance training for individuals with fibromyalgia. Resistance training is exercise performed against a progressive resistance with the intention of improving muscle strength, muscle endurance, muscle power, or a combination of these. To evaluate the benefits and harms of resistance exercise training in adults with fibromyalgia. We compared resistance training versus control and versus other types of exercise training. We searched nine electronic databases (The Cochrane Library, MEDLINE, EMBASE, CINAHL, PEDro, Dissertation Abstracts, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform, AMED) and other sources for published full-text articles. The date of the last search was 5 March 2013. Two review authors independently screened 1856 citations, 766 abstracts and 156 full-text articles. We included five studies that met our inclusion criteria. Selection criteria included: a) randomized clinical trial, b) diagnosis of fibromyalgia based on published criteria, c) adult sample, d) full-text publication, and e) inclusion of between-group data comparing resistance training versus a control or other physical activity intervention. Pairs of review authors independently assessed risk of bias and extracted intervention and outcome data. We resolved disagreements between the two review authors and questions regarding interpretation of study methods by discussion within the pairs or when necessary the issue was taken to the full team of 11 members. We extracted 21 outcomes of which seven were designated as major outcomes: multidimensional function, self reported physical function, pain, tenderness, muscle strength, attrition rates, and adverse effects. We evaluated benefits and harms of the interventions using standardized mean differences (SMD) or mean differences (MD) or risk ratios or Peto odds ratios and 95% confidence intervals (CI). Where two or more studies provided data for an outcome, we carried out a meta-analysis. The literature search yielded 1865 citations with five studies meeting the selection criteria. One of the studies that had three arms contributed data for two comparisons. In the included studies, there were 219 women participants with fibromyalgia, 95 of whom were assigned to resistance training programs. Three randomized trials compared 16 to 21 weeks of moderate- to high-intensity resistance training versus a control group. Two studies compared eight weeks of progressive resistance training (intensity as tolerated) using free weights or body weight resistance exercise versus aerobic training (ie, progressive treadmill walking, indoor and outdoor walking), and one study compared 12 weeks of low-intensity resistance training using hand weights (1 to 3 lbs (0.45 to 1.36 kg)) and elastic tubing versus flexibility exercise (static stretches to major muscle groups).Statistically significant differences (MD; 95% CI) favoring the resistance training interventions over control group(s) were found in multidimensional function (Fibromyalgia Impact Questionnaire (FIQ) total decreased 16.75 units on a 100-point scale; 95% CI -23.31 to -10.19), self reported physical function (-6.29 units on a 100-point scale; 95% CI -10.45 to -2.13), pain (-3.3 cm on a 10-cm scale; 95% CI -6.35 to -0.26), tenderness (-1.84 out of 18 tender points; 95% CI -2.6 to -1.08), and muscle strength (27.32 kg force on bilateral concentric leg extension; 95% CI 18.28 to 36.36).Differences between the resistance training group(s) and the aerobic training groups were not statistically significant for multidimensional function (5.48 on a 100-point scale; 95% CI -0.92 to 11.88), self reported physical function (-1.48 units on a 100-point scale; 95% CI -6.69 to 3.74) or tenderness (SMD -0.13; 95% CI -0.55 to 0.30). There was a statistically significant reduction in pain (0.99 cm on a 10-cm scale; 95% CI 0.31 to 1.67) favoring the aerobic groups.Statistically significant differences were found between a resistance training group and a flexibility group favoring the resistance training group for multidimensional function (-6.49 FIQ units on a 100-point scale; 95% CI -12.57 to -0.41) and pain (-0.88 cm on a 10-cm scale; 95% CI -1.57 to -0.19), but not for tenderness (-0.46 out of 18 tender points; 95% CI -1.56 to 0.64) or strength (4.77 foot pounds torque on concentric knee extension; 95% CI -2.40 to 11.94). This evidence was classified low quality due to the low number of studies and risk of bias assessment. There were no statistically significant differences in attrition rates between the interventions. In general, adverse effects were poorly recorded, but no serious adverse effects were reported. Assessment of risk of bias was hampered by poor written descriptions (eg, allocation concealment, blinding of outcome assessors). The lack of a priori protocols and lack of care provider blinding were also identified as methodologic concerns. The evidence (rated as low quality) suggested that moderate- and moderate- to high-intensity resistance training improves multidimensional function, pain, tenderness, and muscle strength in women with fibromyalgia. The evidence (rated as low quality) also suggested that eight weeks of aerobic exercise was superior to moderate-intensity resistance training for improving pain in women with fibromyalgia. There was low-quality evidence that 12 weeks of low-intensity resistance training was superior to flexibility exercise training in women with fibromyalgia for improvements in pain and multidimensional function. There was low-quality evidence that women with fibromyalgia can safely perform moderate- to high-resistance training.


Neuroinvasion of prions: insights from mouse models.
The prion was defined by Stanley B. Prusiner as the infectious agent that causes transmissible spongiform encephalopathies. A pathological protein accumulating in the brain of scrapie-infected hamsters was isolated in 1982 and termed prion protein (PrPSc). Its cognate gene Prnp was identified more than a decade ago by Charles Weissmann, and shown to encode the host protein PrP(C). Since the latter discovery, transgenic mice have contributed many important insights into the field of prion biology, including the understanding of the molecular basis of the species barrier for prions. By disrupting the Prnp gene, it was shown that an organism that lacks PrP(C) is resistant to infection by prions. Introduction of mutant PrP genes into PrP-deficient mice was used to investigate the structure-activity relationship of the PrP gene with regard to scrapie susceptibility. Ectopic expression of PrP in PrP knockout mice proved a useful tool for the identification of host cells competent for prion replication. Finally, the availability of PrP knockout mice and transgenic mice overexpressing PrP allows selective reconstitution experiments aimed at expressing PrP in neurografts or in specific populations of haemato- and lymphopoietic cells. The latter studies have allowed us to clarify some of the mechanisms of prion spread and disease pathogenesis.


Thai massage, and Thai herbal compress versus oral ibuprofen in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial.
The aim of this study was to verify the clinical responses to Thai massage (TM) and Thai herbal compression (THC) for treating osteoarthritis (OA) of the knee in comparison to oral ibuprofen. This study was a randomized, evaluator-blind, controlled trial. Sixty patients with OA of the knee were randomly assigned to receive either a one-hour session of TM or THC (three times weekly) or oral ibuprofen (three times daily). The duration of treatment was three weeks. The clinical assessments included visual analog scale assessing pain and stiffness, Lequesne's functional index, time for climbing up ten steps, and physician's and patient's overall opinions on improvement. In a within-group comparison, each treatment modality caused a significant improvement of all variables determined for outcome assessments. In an among group comparison, all modalities provided nearly comparable clinical efficacy after a three-week symptomatic treatment of OA of the knee, in which a trend toward greatest improvement was likely to be found in THC group. In conclusion, TM and THC generally provided comparable clinical efficacy to oral ibuprofen after three weeks of treatment and could be considered as complementary and alternative treatments for OA of the knee.


Proposal of a super trait for the optimum selection of popcorn progenies based on path analysis.
A challenge faced by popcorn breeding programs is the existence of a negative correlation between the two main traits, popping expansion and yield, which hinders simultaneous gains. The objective of this study was to investigate the use of a new variable or super trait, which favors the reliable selection of superior progenies. The super trait 'expanded popcorn volume per hectare' was introduced in the evaluation of 200 full-sib families of the eighth recurrent intrapopulation selection cycle, which were arranged in randomized blocks with three replicates in two environments. Although the inability to obtain simultaneous gains through selection via popping expansion or yield was confirmed, the super trait was positively associated with both yield and popping expansion, allowing simultaneous gains via indirect selection using 'expanded popcorn volume per hectare' as the main trait. This approach is recommended because this super trait can be used in breeding programs to optimize selective gains for the crop.


High preoperative hemoglobin A1c is a risk factor for surgical site infection after posterior thoracic and lumbar spinal instrumentation surgery.
Diabetes mellitus (DM) is reported to be a risk factor for surgical site infection (SSI), which is a serious complication after spinal surgery. The effect of DM on SSI after instrumented spinal surgery remains to be clarified. The aim was to elucidate perioperative risk factors for infection at the surgical site after posterior thoracic and lumbar spinal arthrodesis with instrumentation in patients with DM. Consecutive patients who underwent posterior instrumented thoracic and lumbar spinal arthrodesis during the years 2005-2011, who could be followed for at least 1 year after surgery, were included. These included 36 patients with DM (19 males and 17 females; mean age 64.3 years). The patients' medical records were retrospectively reviewed to determine the SSI rate. The characteristics of the DM patients were examined in detail, including the levels of serum glucose and HbA1c, which indicate the level of diabetes control. Patients with DM had a higher rate of SSI (6 of 36 patients, 16.7 %) than patients without DM (10 of 309 patients, 3.2 %). Although the perioperative serum glucose level did not differ between DM patients that did or did not develop SSI, the preoperative HbA1c value was significantly higher in the patients who developed SSI (7.6 %) than in those who did not (6.9 %). SSI developed in 0.0 % of the patients with controlled diabetes (HbA1c <7.0 %) and in 35.3 % of the patients with uncontrolled diabetes (HbA1c ≥7.0 %). DM patients whose blood glucose levels were poorly controlled before surgery were at high risk for SSI. To prevent SSI in DM patients, we recommend lowering the HbA1c to <7.0 % before performing surgery.


"Proprioceptive signature" of cursive writing in humans: a multi-population coding.
The goal of the present study was to investigate the firing behavior of populations of muscle spindle afferents in all the muscles acting on the ankle while this joint was being subjected to "writing-like" movements. First it was proposed to determine whether the ensemble of muscle spindles give rise to a unique, specific, and reproducible feedback information characterizing each letter, number or short word. Secondly, we analyzed how the proprioceptive feedback on the whole encodes the spatial and temporal characteristics of writing movements using the "vector population model". The unitary activity of 51 primary and secondary muscle spindle afferents was recorded in the tibial and common peroneal nerves at the level of the popliteal fossea, using the microneurographic method. The units recorded from belonged to the tibialis anterior, the extensor digitorum longus, the extensor hallucis longus, the peroneus lateralis, the gastrocnemius-soleus and the tibialis posterior muscles. The "writing-like" movements were randomly imposed at a "natural" velocity via a computer-controlled machine in a two-dimensional space. In general, muscle spindle afferents from any of the six muscles responded according to the tuning properties of the parent muscle, i.e. increasing their discharge rate during the phases where the direction of movement was within the preferred sensory sector of the parent muscle. The whole trajectory of the writing movements was coded in turn by the activity of Ia afferents arising from all the muscles acting on the joint. Both single afferent responses and population responses were found to be highly specific and reproducible with each graphic sign. The complex multi-muscle afferent pattern involved, with its timing and distribution in the muscle space, seems to constitute a true "proprioceptive signature" for each graphic symbol. The ensemble of muscle spindle afferents were therefore found to encode the instantaneous direction and velocity of writing movements remarkably accurately. It was concluded that the proprioceptive feedback from all the muscles with which the moving joint is equipped provides the CNS with highly specific information that might contribute to a graphic sign identification process.


Within-Trial Evaluation of Medical Resources, Costs, and Quality of Life Among Patients With Type 2 Diabetes Participating in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).
To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Medical resource use data and responses to the EuroQol 5-Dimension (EQ-5D) instrument were collected at baseline and throughout the trial. Medical resources and medications were assigned values by using U.S. Medicare payments and wholesale acquisition costs, respectively. Secondary analyses used English costs. Patients were followed for an average of 3.3 years, during which time those randomized to EQW experienced 0.41 fewer inpatient days (7.05 vs. 7.46 days; relative rate ratio 0.91; P = 0.05). Rates of outpatient medical visits were similar, as were total inpatient and outpatient costs. Mean costs for nonstudy diabetes medications over the study period were ∼$1,600 lower with EQW than with placebo (P = 0.01). Total within-study costs, excluding study medication, were lower in the EQW arm than in the placebo arm ($28,907 vs. $30,914; P ≤ 0.01). When including the estimated cost of EQW, total mean costs were significantly higher in the EQW group than in the placebo group ($42,697 vs. $30,914; P < 0.01). With English costs applied, mean total costs, including exenatide costs, were £1,670 higher in the EQW group than the placebo group (£10,874 vs. £9,204; P < 0.01). There were no significant differences in EQ-5D health utilities between arms over time. Medical costs were lower in the EQW arm than the placebo arm, but total costs were significantly higher once the cost of branded exenatide was incorporated.


Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes.
Genome-wide association studies are now identifying disease-associated chromosome regions. However, even after convincing replication, the localization of the causal variant(s) requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5' regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70-2.45; P = 1.92 x 10(-28); control frequency = 0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA (P = 6.28 x 10(-28)), suggesting that an inherited lower immune responsiveness predisposes to T1D.


VoroCrust: Voronoi Meshing Without Clipping.
Polyhedral meshes are increasingly becoming an attractive option with particular advantages over traditional meshes for certain applications. What has been missing is a robust polyhedral meshing algorithm that can handle broad classes of domains exhibiting arbitrary curved boundaries and sharp features. In addition, the power of primal-dual mesh pairs, exemplified by Voronoi-Delaunay meshes, has been recognized as an important ingredient in numerous formulations. The VoroCrust algorithm is the first provably correct algorithm for conforming Voronoi meshing for non-convex and possibly non-manifold domains with guarantees on the quality of both surface and volume elements. A robust refinement process estimates a suitable sizing field that enables the careful placement of Voronoi seeds across the surface circumventing the need for clipping and avoiding its many drawbacks. The algorithm has the flexibility of filling the interior by either structured or random samples, while all sharp features are preserved in the output mesh. We demonstrate the capabilities of the algorithm on a variety of models and compare against state-of-the-art polyhedral meshing methods based on clipped Voronoi cells establishing the clear advantage of VoroCrust output.


Arbuscular mycorrhizal fungi-assisted phytoremediation of a lead-contaminated site.
Knowledge of the behavior of plant species associated with arbuscular mycorrhizal fungi (AMF) and the ability of such plants to grow on metal-contaminated soils is important to phytoremediation. Here, we evaluate the occurrence and diversity of AMF and plant species as well as their interactions in soil contaminated with lead (Pb) from the recycling of automotive batteries. The experimental area was divided into three locations: a non-contaminated native area, a coarse rejects deposition area, and an area receiving particulate material from the chimneys during the Pb melting process. Thirty-nine AMF species from six families and 10 genera were identified. The Acaulospora and Glomus genera exhibited the highest occurrences both in the bulk (10 and 6) and in the rhizosphere soils (9 and 6). All of the herbaceous species presented mycorrhizal colonization. The highest Pb concentrations (mgkg-1) in roots and shoots, respectively, were observed in Vetiveria zizanoides (15,433 and 934), Pteris vitata (9343 and 865), Pteridim aquilinun (1433 and 733), and Ricinus communis (1106 and 625). The diversity of AMF seems to be related to the area heterogeneity; the structure communities of AMF are correlated with the soil Pb concentration. We found that plant diversity was significantly correlated with AMF diversity (r=0.645; P>0.05) in areas with high Pb soil concentrations. A better understanding of AMF communities in the presence of Pb stress may shed light on the interactions between fungi and metals taking place in contaminated sites. Such knowledge can aid in developing soil phytoremediation techniques such as phytostabilization.


Data-Powered Participatory Decision Making: Leveraging Systems Thinking and Simulation to Guide Selection and Implementation of Evidence-Based Colorectal Cancer Screening Interventions.
A robust evidence base supports the effectiveness of timely colorectal cancer (CRC) screening, follow-up of abnormal results, and referral to care in reducing CRC morbidity and mortality. However, only two-thirds of the US population is current with recommended screening, and rates are much lower for those who are vulnerable because of their race/ethnicity, insurance status, or rural location. Multiple, multilevel factors contribute to observed disparities, and these factors vary across different populations and contexts. As highlighted by the Cancer Moonshot Blue Ribbon Panel working groups focused on Prevention and Early Detection and Implementation Science inadequate CRC screening and follow-up represent an enormous missed opportunity in cancer prevention and control. To measurably reduce CRC morbidity and mortality, the evidence base must be strengthened to guide the identification of (1) multilevel factors that influence screening across different populations and contexts, (2) multilevel interventions and implementation strategies that will be most effective at targeting those factors, and (3) combinations of strategies that interact synergistically to improve outcomes. Systems thinking and simulation modeling (systems science) provide a set of approaches and techniques to aid decision makers in using the best available data and research evidence to guide implementation planning in the context of such complexity. This commentary summarizes current challenges in CRC prevention and control, discusses the status of the evidence base to guide the selection and implementation of multilevel CRC screening interventions, and describes a multi-institution project to showcase how systems science can be leveraged to optimize selection and implementation of CRC screening interventions in diverse populations and contexts.


Patients' and physicians' interpretation of chemotherapy-induced peripheral neurotoxicity.
To test if and how chemotherapy-induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI-PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation ("impossible") generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%-65% of patients; 76%-78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%-56% of them. In Group 3 strength reduction was observed in 49%-50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.


Combination therapy of an orthotopic renal cell carcinoma model using intratumoral vector-mediated costimulation and systemic interleukin-2.
Interleukin (IL)-2 therapy is currently used for therapy of renal cell carcinoma (RCC). However, it is only effective in approximately 10% to 15% of patients, showing a need for additional therapies. We have previously described a replication-defective fowlpox vector encoding three costimulatory molecules (B7-1, ICAM-1, and LFA-3), designated rF-TRICOM. Here, we show that intratumoral administration of rF-TRICOM in an orthotopic RCC model effectively enhances tumor immunogenicity and reduces tumor burden in mice and the combination of rF-TRICOM and IL-2 is more effective than either therapy alone. RCC cells were implanted under the capsule of the kidney, and mice were given rF-TRICOM intratumorally 14 days later. We compared the effect of rF-TRICOM, rF-granulocyte macrophage colony-stimulating factor (GM-CSF), and two doses of IL-2 and combinations of the above on antitumor efficacy and survival. Host CD4(+) and CD8(+) T-cell responses were also evaluated. The results show that (a) systemic IL-2 therapy was moderately effective in the reduction of tumor burden in an orthotopic RCC model; (b) a single intratumoral injection of rF-TRICOM and rF-GM-CSF significantly reduced tumor burden; (c) the addition of systemic IL-2 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in further reduction of tumor burden, decrease in the incidence of metastasis, and extended survival in tumor-bearing mice above that seen with either treatment alone; and (d) CD8(+) T cells played a critical role in the antitumor effect seen with rF-TRICOM/rF-GM-CSF + IL-2 therapy. Finally, the addition of systemic recombinant IL-15 or intratumoral vector-delivered IL-15 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in substantially more tumor-free mice than either therapy alone. These studies show that intratumoral administration of rF-TRICOM admixed with rF-GM-CSF is effective at reducing tumor burden in mice and the addition of IL-2 further contributes to this effect. These studies thus form the rationale for combination immunotherapy clinical trials in patients with RCC.


Will co-trimoxazole resistance rates ever go down? Resistance rates remain high despite decades of reduced co-trimoxazole consumption.
Several studies showed that a substantial decline in the use of co-trimoxazole did not result in a decline in resistance rates among Escherichia coli isolates. Since mathematical models have shown that it may take decades before resistance rates start to decline to relevant levels, we performed a new analysis using more recently collected data. Data were extracted from Guy's and St Thomas' Hospitals Transmission and Antimicrobial Record database which contains microbiological test results from all specimens tested between 2002 and 2014. We selected all blood samples positive for E. coli which were tested for resistance against co-trimoxazole. Prevalence of co-trimoxazole resistance among the tested samples by year was modelled by a Poisson model. Almost all (96%) of E. coli blood isolates were tested for co-trimoxazole resistance. In total, 2070 E. coli isolates were available for analyses. Resistance to co-trimoxazole fluctuated over the years, but there was no clear increasing or decreasing trend; the annual percentage change in the prevalence of co-trimoxazole resistance was 0.52 (95% confidence interval -0.75% to 1.81%). Including co-trimoxazole or trimethoprim use in the year before the sample was taken did not improve the model. The prevalence of co-trimoxazole resistance among E. coli blood isolates remained high, almost three decades after a substantial decline in co-trimoxazole use. Our results further emphasize the importance of prudent antibiotics use, as antibiotic resistance may not always be easily reversible.


Laboratory testing of clinically approved drugs against Balamuthia mandrillaris.
Balamuthia mandrillaris is a free-living protist pathogen that can cause life-threatening granulomatous amoebic encephalitis. Given the lack of effective available drugs against B. mandrillaris encephalitis with a mortality rate of more than 90%, here we screened drugs, targeting vital cellular receptors and biochemical pathways, that are already in approved clinical use for their potential clinical usefulness. Amoebicidal assays were performed by incubating B. mandrillaris with drugs (3 × 10(5) cells/0.5 mL/well) in phosphate buffered saline for 24 h and viability was determined using Trypan blue exclusion staining. For controls, amoebae were incubated with the solvent alone. To determine whether effects are reversible, B. mandrillaris were pre-exposed to drugs for 24 h, washed twice, and incubated with human brain microvascular endothelial cells, which constitute the blood-brain barrier as food source, for up to 48 h. Of the ten drugs tested, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol showed potent amoebicidal effects, while amiodarone and digoxin exhibited minimal effectiveness. When pre-treated with these drugs, no viable trophozoites re-emerged, suggesting that drugs destroyed parasite irreversibly. Based on the in vitro assay, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol are potential antimicrobials for further testing against B. mandrillaris encephalitis. These findings may provide novel strategies for therapy but further research is needed to determine clinical usefulness of aforementioned drugs against granulomatous amoebic encephalitis caused by B. mandrillaris, and other free-living amoebae, such as Acanthamoeba spp., and Naegleria fowleri.


Place and Underlying Cause of Death During the COVID-19 Pandemic: Retrospective Cohort Study of 3.5 Million Deaths in England and Wales, 2014 to 2020.
To describe the place and cause of death during the coronavirus disease 2019 (COVID-19) pandemic to assess its impact on excess mortality. This national death registry included all adult (aged ≥18 years) deaths in England and Wales between January 1, 2014, and June 30, 2020. Daily deaths during the COVID-19 pandemic were compared against the expected daily deaths, estimated with use of the Farrington surveillance algorithm for daily historical data between 2014 and 2020 by place and cause of death. Between March 2 and June 30, 2020, there was an excess mortality of 57,860 (a proportional increase of 35%) compared with the expected deaths, of which 50,603 (87%) were COVID-19 related. At home, only 14% (2267) of the 16,190 excess deaths were related to COVID-19, with 5963 deaths due to cancer and 2485 deaths due to cardiac disease, few of which involved COVID-19. In care homes or hospices, 61% (15,623) of the 25,611 excess deaths were related to COVID-19, 5539 of which were due to respiratory disease, and most of these (4315 deaths) involved COVID-19. In the hospital, there were 16,174 fewer deaths than expected that did not involve COVID-19, with 4088 fewer deaths due to cancer and 1398 fewer deaths due to cardiac disease than expected. The COVID-19 pandemic has resulted in a large excess of deaths in care homes that were poorly characterized and likely to be the result of undiagnosed COVID-19. There was a smaller but important and ongoing excess in deaths at home, particularly from cancer and cardiac disease, suggesting public avoidance of hospital care for non-COVID-19 conditions.


Pregnancy among women with physical disabilities: Unmet needs and recommendations on navigating pregnancy.
Despite concerns raised in the literature on the adverse pregnancy outcomes of women with physical disabilities, there is little information about unmet needs of women with physical disabilities during pregnancy and childbirth. This article provides an in-depth examination of unmet health care needs during and around the time of pregnancy among a sample of women with physical disabilities. It also offers recommendations to other women with physical disabilities who are considering pregnancy. Twenty-five phone interviews were conducted with women with physical disabilities from across the United States who had a baby in the past ten years. Individual semi-structured qualitative interviews lasting about 2 h were conducted. Interviews were audio-recorded, transcribed, and analyzed using an iterative, interpretive process. Women reported a wide range of disabling conditions. Analysis revealed three broad themes related to unmet needs during pregnancy among women with physical disabilities. They included (1) clinician knowledge and attitudes, (2) physical accessibility of health care facilities and equipment, (3) need for information related to pregnancy and postpartum supports. The women also provided recommendations to other women with disabilities who are currently pregnant or thinking of becoming pregnant. Recommendations related to finding a clinician one trusts, seeking peer support, self-advocating, and preparing oneself for the baby. This study sheds light on the unmet needs and barriers to care of women with mobility disabilities during pregnancy and childbirth. The study findings highlight the need for policy and practice recommendations for perinatal care of women with mobility disabilities.


NO, via its target Cx37, modulates calcium signal propagation selectively at myoendothelial gap junctions.
Gap junctional calcium signal propagation (transfer of calcium or a calcium releasing messenger via gap junctions) between vascular cells has been shown to be involved in the control of vascular tone. We have shown before that nitric oxide (NO) inhibits gap junctional communication in HeLa cells exclusively expressing connexin 37 (HeLa-Cx37) but not in HeLa-Cx40 or HeLa-Cx43. Here we studied the effect of NO on the gap junctional calcium signal propagation in endothelial cells which, in addition to Cx37, also express Cx40 and Cx43. Furthermore, we analyzed the impact of NO on intermuscle and on myoendothelial gap junction-dependent calcium signal propagation. Since specific effects of NO at one of these three junctional areas (interendothelial/ myoendothelial/ intermuscle) may depend on a differential membrane localization of the connexins, we also studied the distribution of the vascular connexins in small resistance arteries. In endothelial (HUVEC) or smooth muscle cells (HUVSMC) alone, NO did not affect gap junctional Ca2+ signal propagation as assessed by analyzing the spread of Ca2+ signals after mechanical stimulation of a single cell. In contrast, at myoendothelial junctions, it decreased Ca2+ signal propagation in both directions by about 60% (co-cultures of HUVEC and HUVSMC). This resulted in a longer maintenance of calcium elevation at the endothelial side and a faster calcium signal propagation at the smooth muscle side, respectively. Immunohistochemical stainings (confocal and two-photon-microscopy) of cells in co-cultures or of small arteries revealed that Cx37 expression was relatively higher in endothelial cells adjoining smooth muscle (culture) or in potential areas of myoendothelial junctions (arteries). Accordingly, Cx37 - in contrast to Cx40 - was not only expressed on the endothelial surface of small arteries but also in deeper layers (corresponding to the internal elastic lamina IEL). Holes of the IEL where myoendothelial contacts can only occur, stained significantly more frequently for Cx37 and Cx43 than for Cx40 (endothelium) or Cx45 (smooth muscle). NO modulates the calcium signal propagation specifically between endothelial and smooth muscle cells. The effect is due to an augmented distribution of Cx37 towards myoendothelial contact areas and potentially counteracts endothelial Ca2+ signal loss from endothelial to smooth muscle cells. This targeted effect of NO may optimize calcium dependent endothelial vasomotor function.


Induction of in vitro proliferation and maturation of human aneuploid myelogenous leukemic cells.
Human leukemic cells were induced to proliferate and mature to macrophage-like cells in primary cultures supplemented with conditioned medium (CM) from phytohemagglutinin and alloantigen-stimulated normal T lymphocytes. Blast and promyelocyte-enriched preparations, isolated after depletion of adherent phagocytic cells and lymphoid cells from samples of myelogenous leukemia patients, were suspended in liquid cultures with 30% CM. Cell cycle analysis was performed throughout the course of induced cellular maturation. Within 24 h of exposure to CM, cells with macrophage-like morphology were identified among the developing adherent cells. Approximately 15-30% of the cells in culture suspensions also developed macrophage-like morphology and esterase reactivity with alpha-napthyl acetate after incubation for 2 d. The number of these nonproliferating cells increased and became predominant in the later culture period. Flow cytometric measurement of DNA content showed that these mature cells had the same aneuploid stemline as the undifferentiated leukemic cells, indicating that genetically abnormal leukemic cells can be induced to differentiate. Reduction in the total RNA content of the macrophage-like cells was also determined by flow cytometry. Reduction in RNA and development of adherent cells served as early markers of maturation, in addition to the later acquisition of complement receptors and phagocytic capacity. Cell cycle analysis showed that CM stimulated the proliferation of immature cells. This initial proliferation may precede intertwined events of proliferation and concurrent maturation of immature cells. Later in the culture period, cellular proliferation decreased, leading to termination of the cultures.


Plasmodium vivax lineages: geographical distribution, tandem repeat polymorphism, and phylogenetic relationship.
Multi-drug resistance and severe/complicated cases are the emerging phenotypes of vivax malaria, which may deteriorate current anti-malarial control measures. The emergence of these phenotypes could be associated with either of the two Plasmodium vivax lineages. The two lineages had been categorized as Old World and New World, based on geographical sub-division and genetic and phenotypical markers. This study revisited the lineage hypothesis of P. vivax by typing the distribution of lineages among global isolates and evaluated their genetic relatedness using a panel of new mini-satellite markers. 18S SSU rRNA S-type gene was amplified from 420 Plasmodium vivax field isolates collected from different geographical regions of India, Thailand and Colombia as well as four strains each of P. vivax originating from Nicaragua, Panama, Thailand (Pak Chang), and Vietnam (ONG). A mini-satellite marker panel was then developed to understand the population genetic parameters and tested on a sample subset of both lineages. 18S SSU rRNA S-type gene typing revealed the distribution of both lineages (Old World and New World) in all geographical regions. However, distribution of Plasmodium vivax lineages was highly variable in every geographical region. The lack of geographical sub-division between lineages suggests that both lineages are globally distributed. Ten mini-satellites were scanned from the P. vivax genome sequence; these tandem repeats were located in eight of the chromosomes. Mini-satellites revealed substantial allelic diversity (7-21, AE = 14.6 ± 2.0) and heterozygosity (He = 0.697-0.924, AE = 0.857 ± 0.033) per locus. Mini-satellite comparison between the two lineages revealed high but similar pattern of genetic diversity, allele frequency, and high degree of allele sharing. A Neighbour-Joining phylogenetic tree derived from genetic distance data obtained from ten mini-satellites also placed both lineages together in every cluster. The global lineage distribution, lack of genetic distance, similar pattern of genetic diversity, and allele sharing strongly suggested that both lineages are a single species and thus new emerging phenotypes associated with vivax malaria could not be clearly classified as belonging to a particular lineage on basis of their geographical origin.


COPD in a nationally representative sample: sociodemographic factors and co-morbidity, diagnosis method, and healthcare utilization.
In 2011, the Centers for Disease Control and Prevention for the first time ever collected nationally representative prevalence data on chronic obstructive pulmonary disease (COPD), spirometry diagnosis, and healthcare utilization factors related to COPD. This research reports on that data and describes characteristics of adults with COPD who reported diagnosis by spirometry compared to those who did not report diagnosis by spirometry. Variables examined included basic elements of healthcare utilization such as emergency room visits, hospitalization or personal physician utilization. This is a cross-sectional study using novel data from the 2011 Behavioral Risk Factor Surveillance System COPD Module. Weighted multivariable logistic regression examined factors associated with (n = 13,484) and without spirometry (n = 3,131). Spirometry to diagnose COPD was reported by 78% of adults and increased with age. In multivariable modeling, spirometry was more likely in: Black, non-Hispanic compared to white non-Hispanic; current and former compared to never smokers; adults with co-morbidity including asthma, depression, and cardiovascular disease; adults with a doctor; and those who had been to emergency room/hospital for COPD. Those less likely to receive a spirometry were: Hispanic and reported exercise in the past 30 days. This study identified that adults diagnosed with COPD without a spirometry tended to be Hispanic, younger, healthier, and had less utilization of medical resources. This study is a first step in understanding the potential impact of COPD diagnosis made without spirometry.


Correlation between genotype and phenotype in patients with bi-allelic SLC26A4 mutations.
Mutation of SLC26A4 is the most common cause of prelingual hearing loss in East Asia. Patients with SLC26A4 mutations have variable phenotypes ranging from non-syndromic hearing loss to Pendred syndrome. Here, we analyzed the correlation between genotype and various inner ear phenotypes and found a possible underlying mechanism. This study included 111 patients with bi-allelic SLC26A4 mutations who had bilateral enlarged vestibular aqueduct (EVA) and hearing loss. p.H723R (61%), c.919-2A>G (24%), and p.T410M (4%) were the most common mutations in Korean patients with EVAs. Residual hearing in patients with c.919-2A>G or p.T410M mutations was better than that of patients with p.H723R homozygous mutations. Interestingly, quantitative polymerase chain reaction showed normal pendrin transcript (6-17% of normal levels) was produced from patients with c.919-2A>G homozygous mutations. Surface expression ratio of pendrin and residual anion exchange activity were higher in cells transfected with p.T410M in comparison to cells transfected with p.H723R. These results suggest that there is a correlation between degree of residual hearing and the SLC26A4 genotype commonly found in the East Asian population.


Assessment of neck pain and its associated disorders: results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders.
Best evidence synthesis. To critically appraise and synthesize the literature on assessment of neck pain. The published literature on assessment of neck pain is large and of variable quality. There have been no prior systematic reviews of this literature. The Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders conducted a critical review of the literature (published 1980-2006) on assessment tools and screening protocols for traumatic and nontraumatic neck pain. We found 359 articles on assessment of neck pain. After critical review, 95 (35%) were judged scientifically admissible. Screening protocols have high predictive values to detect cervical spine fracture in alert, low-risk patients seeking emergency care after blunt neck trauma. Computerized tomography (CT) scans had better validity (in adults and elderly) than radiographs in assessing high-risk and/or multi-injured blunt trauma neck patients. In the absence of serious pathology, clinical physical examinations are more predictive at excluding than confirming structural lesions causing neurologic compression. One exception is the manual provocation test for cervical radiculopathy, which has high positive predictive value. There was no evidence that specific MRI findings are associated with neck pain, cervicogenic headache, or whiplash exposure. No evidence supports using cervical provocative discography, anesthetic facet, or medial branch blocks in evaluating neck pain. Reliable and valid self-report questionnaires are useful in assessing pain, function, disability, and psychosocial status in individuals with neck pain. The scientific evidence supports screening protocols in emergency care for low-risk patients; and CT-scans for high-risk patients with blunt trauma to the neck. In nonemergency neck pain without radiculopathy, the validity of most commonly used objective tests is lacking. There is support for subjective self-report assessment in monitoring patients' course, response to treatment, and in clinical research.


The Effect of Topical Substance-P Plus Insulin-like Growth Factor-1 (IGF-1) on Epithelial Healing After Photorefractive Keratectomy in Rabbits.
To determine whether topical Substance-P (SP) plus insulin-like growth factor-1 (IGF-1) can improve corneal healing after photorefractive surface ablation in a rabbit. After a 9.0-mm corneal de-epithelialization using a combination of chemical (18% alcohol) and mechanical debridement, excimer photorefractive surface ablation was performed bilaterally in eight rabbits (16 eyes) with an 8.0-mm ablation zone and 70-μm depth. The right eye was treated with SP (250 μg/mL) and IGF-1 (25 ng/mL) in hyaluronic acid, one drop twice a day, and the other eye treated with only hyaluronic acid. The epithelial healing process was documented photographically twice a day until healing was complete. Six rabbits were sacrificed 6 weeks after photorefractive keratectomy (PRK) and corneas examined histologically. Seven of eight rabbit eyes treated with SP/IGF-1 healed in a shorter time than the untreated eye. For rabbit #6, both eyes healed at the same time. The average healing time (total time until wound closure) for the treated eyes was 99 hours, while the average healing time for the untreated eyes was 170 hours (P = 0.0490). A persistent epithelial defect was found in two of the nontreated eyes but none in the treated eyes. Corneal pathology showed some degree of epithelial separation in the central corneal wound in three out of six nontreated eyes and in just the treated eye of rabbit #6. Topical SP plus IGF-1 increases the epithelial healing rate after PRK. There may have been beneficial effects upon cell adhesion as well. Better and faster healing.


Glycemic control in critically ill patients before and after institution of an intensive insulin infusion protocol: circadian rhythm and the quality duration calculator.
A circadian rhythm of blood glucose values has been recently reported in critically ill patients, but there are no reports of how this rhythm is altered by a continuous intensive insulin infusion therapy protocol (IIT). We wished to examine the effect of IIT on this rhythm as well as to describe the use of the quality duration calculator (QDC) for the evaluation of glycemic control before and after IIT. This was a retrospective multihospital observational study that took place in the medical and surgical intensive care units (ICUs) of 2 tertiary care hospitals. Cohorts of consecutively admitted critically ill patients from 2-year periods before and after institution of an IIT protocol were examined. Laboratory, demographic, and outcome data were extracted from hospital databases. We studied 167,645 blood glucose measurements from 8,327 patients. We observed a circadian rhythm of blood glucose control in the pre-IIT cohort that was greatly attenuated in the post-IIT cohort. The difference between the morning and the average daily blood glucose in the pre-IIT cohort was 3.53 mg/dL (P < .001), and the difference between these values in the post-IIT cohort was 1.10 mg/dL (P = .031). In addition, the circadian nature of hyperglycemia incidence observed in the pre-IIT cohort was not seen in the post-IIT cohort. The amount of time spent in goal glycemic range increased from 23.69% (95% CI 23.01-24.38) in the pre-IIT cohort to 29.67% (95% CI 29.04-30.31) in the post-IIT cohort as estimated by the QDC. The amount of time spent in the hyperglycemic decreased from 20.17% (95% CI 19.33-20.99) in the pre-IIT cohort to 14.80% (95% CI 14.15-15.39) in the post-IIT cohort. The circadian rhythm of blood glucose control confirmed in our pre-IIT cohort was lost after institution of IIT. The morning blood glucose value appears to be a reasonable surrogate of overall glycemic control in a critically ill population on IIT, although this may vary based on the degree of control achieved. The QDC method is useful for analyzing glycemic control in patients on IIT.


Pyrroline-5-Carboxylate Reductase Is in Pea (Pisum sativum L.) Leaf Chloroplasts.
Proline accumulation is a well-known response to water deficits in leaves. The primary cause of accumulation is proline synthesis. Delta(1)-Pyrroline-5-carboxylate reductase (PCR) catalyzes the final reaction of proline synthesis. To determine the subcellular location of PCR, protoplasts were made from leaves of Pisum sativum L., lysed, and fractionated by differential and Percoll density gradient centrifugation. PCR activity comigrated on the gradient with the activity of the chloroplast stromal marker NADPH-dependent triose phosphate dehydrogenase. We conclude that PCR is located in chloroplasts, and therefore that chloroplasts can synthesize proline. PCR activities from chloroplasts and etiolated shoots were compared. PCR activity from both extracts is stimulated at least twofold by 100 millimolar KCl or 10 millimolar MgCl(2). The pH profiles of PCR activity from both extracts reveal two separate optima at pH 6.5 and 7.5. Native isoelectric focusing gels of sampies from etiolated tissue reveal a single band of PCR activity with a pl of 7.8.