Walking versus breathing: mechanical differentiation of sea urchin podia corresponds to functional specialization.
The podia of sea urchins function in locomotion, adhesion, feeding, and respiration; but different podia on a single urchin are often specialized to one or more of these tasks. We examined the morphology and material properties of podia of the green sea urchin, Strongylocentrotus droebachiensis, to determine whether, despite apparent similarities, they achieve functional specialization along the oral-aboral axis through the differentiation of distinct mechanical properties. We found that oral podia, which are used primarily for locomotion and adhesion, are stronger and thicker than aboral podia, which are used primarily for capturing drift material and as a respiratory surface. The functional role of ambital podia is more ambiguous; however, they are longer and are extended at a lower strain rate than other podial types. They are also stronger and stiffer than aboral podia. In addition, all podia become stronger and stiffer when extended at faster strain rates, in some cases by nearly an order of magnitude for an order of magnitude change in strain rate. This strain-rate dependence implies that resistance to rapid loading such as that imposed by waves is high compared to resistance to slower, self-imposed loads. Thus, the serially arranged podia of S. droebachiensis are functionally specialized along an oral-aboral axis by differences in their morphology and mechanical properties.


The role of acetylator genotype on hepatic and extrahepatic acetylation, deacetylation, and sulfation of 2-aminofluorene, 2-acetylaminofluorene, and N-hydroxy-2-acetylaminofluorene in the inbred hamster.
In vitro rates of acetylation, deacetylation, and sulfation were measured with carcinogenic arylamine, arylamide, and arylhydroxamic acid substrates using enzyme preparations derived from inbred hamster tissues of known acetylator genotype. Homozygous rapid acetylators (Bio. 87.20), heterozygous acetylators (Bio. 87.20 X Bio. 82.72/H F1), and homozygous slow acetylators (Bio. 82.73/H) did not differ significantly with respect to paraoxon-resistant intermolecular N,N-transacetylation reactions from N-hydroxy-2-acetylaminofluorene to 4-aminoazobenzene in tissue cytosol. Similarly, they did not differ with respect to paraoxon-sensitive, microsomal N-hydroxy-2-acetylaminofluorene and 2-acetylaminofluorene deacetylase, and cytosolic N-hydroxy-2-acetylaminofluorene sulfotransferase activity. However, a gene dose-response relationship was observed in the same animals for cytosolic acetyl coenzyme A-dependent 2-aminofluorene N-acetyltransferase activity. Partial purification of liver cytosol yielded two paraoxon-resistant isozyme forms of acetyltransferase activity. The rates of one isozyme were acetylator genotype dependent (polymorphic), whereas the rates of the second isozyme appeared to be acetylator genotype independent (monomorphic). Acetyl coenzyme A-dependent 2-aminofluorene N-acetyltransferase activity was catalyzed at high rates by both isozymes, whereas transacetylation of 4-aminoazobenzene by various acyl donors (N-hydroxy-2-acetylaminofluorene, N-hydroxy-4-acetylaminobiphenyl, and acetyl coenzyme A) was catalyzed primarily (but not exclusively) by the monomorphic acetyltransferase isozyme. These results provide further information concerning the importance of acetylator genotype in the metabolism of carcinogenic arylamines and their metabolites.


Accurate computational methods for two-electron atom-laser interactions.
We discuss the application of quantitatively accurate computational methods to the study of laser-driven two-electron atoms in short intense laser pulses. The fundamental importance of such calculations to the subject area is emphasized. Calculations of single- and double-electron ionization rates at 390 nm are presented.


Gamma knife radiosurgery for intracranial mature teratoma--long-term results and review of literature.
The purpose of this report is to present long-term outcomes of gamma knife radiosurgery for intracranial mature teratoma after debulking surgery. Three patients with intracranial mature teratoma had initial target volumes of 5.4, 18.7, and 5.1 cm(3), respectively, and were treated by gamma knife radiosurgery between 1993 and 2004. Marginal doses of 17, 12.5, and 13.5 Gy, respectively, were delivered to the tumors at isodose levels of 50%, 50%, and 62%, respectively. The first patient received radiosurgery after surgical removal and conventional radiotherapy. The second patient received similar management, including surgery and radiotherapy, with tumor recurrence. Two additional operations and subsequent radiosurgery were performed on this patient. Based on the favorable results of the first 2 patients, we performed radiosurgery instead of conventional radiotherapy after subtotal surgical removal in the last patient. By reviewing literatures concerning the therapeutic modalities and the long-term results of our 3 patients, we discuss the role of radiosurgery in treating intracranial mature teratoma. A follow-up period of 121, 89, and 31 months, respectively, demonstrated tumor volume reduction rates of 70%, 89%, and 48%, respectively. No evidence of further tumor progression and no radiosurgery-related complication or morbidity was noted. The school performances of the affected children are all above average. Gamma knife radiosurgery provides a safe and effective alternative as the adjuvant treatment of intracranial mature teratoma after surgical debulking. Previous conventional radiotherapy does not alter final tumor control. Radiosurgery should be considered when residual tumor growth continues with no related symptoms or evaluations of tumor markers during follow-up.


Phorbol esters target the activity-dependent recycling pool and spare spontaneous vesicle recycling.
Using electrophysiology and styryl dye imaging, we studied the effect of phorbol 12-myristate 13-acetate (PMA) on activity-dependent and spontaneous vesicle recycling. In electrophysiological experiments, we found that the PMA effect depended on the maturational state of the synapses. Spontaneous neurotransmitter release from nascent synapses without a functional readily releasable pool (RRP) was unresponsive to PMA application. In contrast, mature synapses responded robustly to PMA application, consistent with previous studies. Using styryl dye imaging, we found that there was a PMA-dependent increase in the size of the RRP when PMA was present before, during, or after activity-dependent dye uptake, suggesting that this effect involves an increase in the population of the RRP by vesicles recruited from the reserve pool. Additionally, we found that when PMA was present during spontaneous dye uptake, there was an increase in dye labeling, and these additional dye-loaded vesicles showed rapid destaining in response to strong stimulation and were also releasable by hypertonic sucrose. In contrast, these observations were not reproducible when PMA treatment was performed after spontaneous dye uptake and extracellular dye washout. Together, these findings suggest that the increased spontaneous neurotransmission in the presence of PMA was attributable to release of vesicles from the RRP rather than an effect of PMA on the spontaneously recycling pool. Thus, the phorbol esters selectively regulate the activity-dependent pool of vesicles, indicating that priming mechanisms that prepare vesicles for fusion, which are targeted by phorbol esters, are different for the spontaneous and evoked forms of fusion.


Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice.
Purpose: Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is an interesting target for cancer immune therapy, with prior studies indicating a potential to affect the tumor stroma. Our aim was to extend this earlier work through the development of a novel FAP immunogen with improved capacity to break tolerance for use in combination with tumor antigen vaccines.Experimental Design: We used a synthetic consensus (SynCon) sequence approach to provide MHC class II help to support breaking of tolerance. We evaluated immune responses and antitumor activity of this novel FAP vaccine in preclinical studies, and correlated these findings to patient data.Results: This SynCon FAP DNA vaccine was capable of breaking tolerance and inducing both CD8+ and CD4+ immune responses. In genetically diverse, outbred mice, the SynCon FAP DNA vaccine was superior at breaking tolerance compared with a native mouse FAP immunogen. In several tumor models, the SynCon FAP DNA vaccine synergized with other tumor antigen-specific DNA vaccines to enhance antitumor immunity. Evaluation of the tumor microenvironment showed increased CD8+ T-cell infiltration and a decreased macrophage infiltration driven by FAP immunization. We extended this to patient data from The Cancer Genome Atlas, where we find high FAP expression correlates with high macrophage and low CD8+ T-cell infiltration.Conclusions: These results suggest that immune therapy targeting tumor antigens in combination with a microconsensus FAP vaccine provides two-fisted punch-inducing responses that target both the tumor microenvironment and tumor cells directly. Clin Cancer Res; 24(5); 1190-201. ©2018 AACR.


Xanthelasma and lipoma in Leonardo da Vinci's Mona Lisa.
The painting Mona Lisa in the Louvre, Paris, by Leonardo da Vinci (1503-1506), shows skin alterations at the inner end of the left upper eyelid similar to xanthelasma, and a swelling of the dorsum of the right hand suggestive of a subcutaneous lipoma. These findings in a 25-30 year old woman, who died at the age of 37, may be indicative of essential hyperlipidemia, a strong risk factor for ischemic heart disease in middle age. As far as is known, this portrait of Mona Lisa painted in 1506 is the first evidence that xanthelasma and lipoma were prevalent in the sixteenth century, long before the first description by Addison and Gall in 1851.


Low pH gel intranasal sprays inactivate influenza viruses in vitro and protect ferrets against influenza infection.
Developing strategies for controlling the severity of pandemic influenza is a global public health priority. In the event of a pandemic there may be a place for inexpensive, readily available, effective adjunctive therapies to support containment strategies such as prescription antivirals, vaccines, quarantine and restrictions on travel. Inactivation of virus in the intranasal environment is one possible approach. The work described here investigated the sensitivity of influenza viruses to low pH, and the activity of low pH nasal sprays on the course of an influenza infection in the ferret model. Inactivation of influenza A and avian reassortment influenza was determined using in vitro solutions tests. Low pH nasal sprays were tested using the ferret model with an influenza A Sydney/5/97 challenge. Clinical measures were shed virus, weight loss and body temperature. The virus inactivation studies showed that influenza viruses are rapidly inactivated by contact with acid buffered solutions at pH 3.5. The titre of influenza A Sydney/5/97 [H3N2] was reduced by at least 3 log cycles with one minute contact with buffers based on simple acid mixtures such as L-pyroglutamic acid, succinic acid, citric acid and ascorbic acid. A pH 3.5 nasal gel composition containing pyroglutamic acid, succinic acid and zinc acetate reduced titres of influenza A Hong Kong/8/68 [H3N2] by 6 log cycles, and avian reassortment influenza A/Washington/897/80 X A Mallard/New York/6750/78 [H3N2] by 5 log cycles, with 1 min contact.Two ferret challenge studies, with influenza A Sydney/5/97, demonstrated a reduction in the severity of the disease with early application of low pH nasal sprays versus a saline control. In the first study there was decreased weight loss in the treatment groups. In the second study there were reductions in virus shedding and weight loss, most notably when a gelling agent was added to the low pH formulation. These findings indicate the potential of a low pH nasal spray as an adjunct to current influenza therapies, and warrant further investigation in humans.


Managing investors.
Managers and academics often lament that Wall Street's shortterm focus makes it impossible for corporations to plan for the long run. Palmisano disagrees. Yes, there are some on Wall Street, such as the sell-side analysts who dominate quarterly earnings conference calls, who can't see more than a few months out. But CEOs shouldn't participate in those calls anyway, he believes. They should instead focus their energies on the institutional investors who will embrace the long view if they are given ways to judge a company's progress. In this edited interview with one of HBR's executive editors, Palmisano describes how IBM's top management made significant changes to how the firm set goals and communicated them to investors. "The model," a rolling multi-year road map for earnings growth and cash generation, included an emphasis on R&D investment even during downturns, a plan for execution that involved every unit in the organization, and a shift toward long-term compensation. Transparency and open dialogues with large shareholders were also key. The CEO is a steward, Palmisano argues, charged with protecting a company and its returns for decades to come. But that vision need not clash with success on the visible horizon; during Palmisano's tenure, IBM's stock price soared.


The diffusive Lotka-Volterra predator-prey system with delay.
Semi-analytical solutions for the diffusive Lotka-Volterra predator-prey system with delay are considered in one and two-dimensional domains. The Galerkin method is applied, which approximates the spatial structure of both the predator and prey populations. This approach is used to obtain a lower-order, ordinary differential delay equation model for the system of governing delay partial differential equations. Steady-state and transient solutions and the region of parameter space, in which Hopf bifurcations occur, are all found. In some cases simple linear expressions are found as approximations, to describe steady-state solutions and the Hopf parameter regions. An asymptotic analysis for the periodic solution near the Hopf bifurcation point is performed for the one-dimensional domain. An excellent agreement is shown in comparisons between semi-analytical and numerical solutions of the governing equations.


Pharmacokinetics of anthocyanins and antioxidant effects after the consumption of anthocyanin-rich acai juice and pulp (Euterpe oleracea Mart.) in human healthy volunteers.
The acai berry is the fruit of the acai palm and is traditionally consumed in Brazil but has gained popularity abroad as a food and functional ingredient, yet little information exists on its health effect in humans. This study was performed as an acute four-way crossover clinical trial with acai pulp and clarified acai juice compared to applesauce and a non-antioxidant beverage as controls. Healthy volunteers (12) were dosed at 7 mL/kg of body weight after a washout phase and overnight fast, and plasma was repeatedly sampled over 12 h and urine over 24 h after consumption. Noncompartmental pharmacokinetic analysis of total anthocyanins quantified as cyanidin-3-O-glucoside showed Cmax values of 2321 and 1138 ng/L at t max times of 2.2 and 2.0 h, and AUC last values of 8568 and 3314 ng h L(-1) for pulp and juice, respectively. Nonlinear mixed effect modeling identified dose volume as a significant predictor of relative oral bioavailability in a negative nonlinear relationship for acai pulp and juice. Plasma antioxidant capacity was significantly increased by the acai pulp and applesauce. Individual increases in plasma antioxidant capacity of up to 2.3- and 3-fold for acai juice and pulp, respectively were observed. The antioxidant capacity in urine, generation of reactive oxygen species, and uric acid concentrations in plasma were not significantly altered by the treatments. Results demonstrate the absorption and antioxidant effects of anthocyanins in acai in plasma in an acute human consumption trial.


Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection.
The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.


Genomic variant sharing: a position statement.
Sharing de-identified genetic variant data is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, as well as population controls. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of pseudonomised genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine. Information robustly linking genetic variants with specific conditions is fundamental biological knowledge, not personal information, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing, with the ultimate aim of making as much information as open and de-identified as possible with appropriate consent.


Instrumental variable methods in comparative safety and effectiveness research.
Instrumental variable (IV) methods have been proposed as a potential approach to the common problem of uncontrolled confounding in comparative studies of medical interventions, but IV methods are unfamiliar to many researchers. The goal of this article is to provide a non-technical, practical introduction to IV methods for comparative safety and effectiveness research. We outline the principles and basic assumptions necessary for valid IV estimation, discuss how to interpret the results of an IV study, provide a review of instruments that have been used in comparative effectiveness research, and suggest some minimal reporting standards for an IV analysis. Finally, we offer our perspective of the role of IV estimation vis-à-vis more traditional approaches based on statistical modeling of the exposure or outcome. We anticipate that IV methods will be often underpowered for drug safety studies of very rare outcomes, but may be potentially useful in studies of intended effects where uncontrolled confounding may be substantial.


Absolute probability estimates of lethal vessel strikes to North Atlantic right whales in Roseway Basin, Scotian Shelf.
Vessel strikes are the primary source of known mortality for the endangered North Atlantic right whale (Eubalaena glacialis). Multi-institutional efforts to reduce mortality associated with vessel strikes include vessel-routing amendments such as the International Maritime Organization voluntary "area to be avoided" (ATBA) in the Roseway Basin right whale feeding habitat on the southwestern Scotian Shelf. Though relative probabilities of lethal vessel strikes have been estimated and published, absolute probabilities remain unknown. We used a modeling approach to determine the regional effect of the ATBA, by estimating reductions in the expected number of lethal vessel strikes. This analysis differs from others in that it explicitly includes a spatiotemporal analysis of real-time transits of vessels through a population of simulated, swimming right whales. Combining automatic identification system (AIS) vessel navigation data and an observationally based whale movement model allowed us to determine the spatial and temporal intersection of vessels and whales, from which various probability estimates of lethal vessel strikes are derived. We estimate one lethal vessel strike every 0.775-2.07 years prior to ATBA implementation, consistent with and more constrained than previous estimates of every 2-16 years. Following implementation, a lethal vessel strike is expected every 41 years. When whale abundance is held constant across years, we estimate that voluntary vessel compliance with the ATBA results in an 82% reduction in the per capita rate of lethal strikes; very similar to a previously published estimate of 82% reduction in the relative risk of a lethal vessel strike. The models we developed can inform decision-making and policy design, based on their ability to provide absolute, population-corrected, time-varying estimates of lethal vessel strikes, and they are easily transported to other regions and situations.


MIDSHIPS: multicentre intervention designed for self-harm using interpersonal problem-solving: protocol for a randomised controlled feasibility study.
Around 150,000 people each year attend hospitals in England due to self-harm, many of them more than once. Over 5,000 people die by suicide each year in the UK, a quarter of them having attended hospital in the previous year because of self-harm. Self-harm is a major identifiable risk factor for suicide. People receive variable care at hospital; many are not assessed for their psychological needs and little psychological therapy is offered. Despite its frequent occurrence, we have no clear research evidence about how to reduce the repetition of self-harm. Some people who have self-harmed show less active ways of solving problems, and brief problem-solving therapies are considered the most promising psychological treatments. This is a pragmatic, individually randomised, controlled, feasibility study comparing interpersonal problem-solving therapy plus treatment-as-usual with treatment-as-usual alone, for adults attending a general hospital following self-harm. A total of 60 participants will be randomised equally between the treatment arms, which will be balanced with respect to the type of most recent self-harm event, number of previous self-harm events, gender and age. Feasibility objectives are as follows: a) To establish and field test procedures for implementing the problem-solving intervention; b) To determine the feasibility and best method of participant recruitment and follow up; c) To assess therapeutic delivery; d) To assess the feasibility of obtaining the definitive trial's primary and secondary outcomes; e) To assess the perceived burden and acceptability of obtaining the trial's self-reported outcome data; f) To inform the sample size calculation for the definitive trial. The results of this feasibility study will be used to determine the appropriateness of proceeding to a definitive trial and will allow us to design an achievable trial of interpersonal problem-solving therapy for adults who self-harm. Current Controlled Trials (ISRCTN54036115).


Risk stratification of patients with chronic kidney disease: results of screening strategies incorporating clinical risk scoring and dobutamine stress echocardiography.
Cardiac disease is the principal cause of death in patients with chronic kidney disease (CKD). Ischemia at dobutamine stress echocardiography (DSE) is associated with adverse events in these patients. We sought the efficacy of combining clinical risk evaluation with DSE. We allocated 244 patients with CKD (mean age 54 years, 140 men, 169 dialysis-dependent at baseline) into low- and high-risk groups based on two disease-specific scores and the Framingham risk model. All underwent DSE and were further stratified according to DSE results. Patients were followed over 20 +/- 14 months for events (death, myocardial infarction, acute coronary syndrome). There were 49 deaths and 32 cardiac events. Using the different clinical scores, allocation of high risk varied from 34% to 79% of patients, and 39% to 50% of high-risk patients had an abnormal DSE. In the high-risk groups, depending on the clinical score chosen, 25% to 44% with an abnormal DSE had a cardiac event, compared with 8% to 22% with a normal DSE. Cardiac events occurred in 2.0%, 3.1%, and 9.7% of the low-risk patients, using the two disease-specific and Framingham scores, respectively, and DSE results did not add to risk evaluation in this subgroup. Independent DSE predictors of cardiac events were a lower resting diastolic blood pressure, angina during the test, and the combination of ischemia with resting left ventricular dysfunction. In CKD patients, high-risk findings by DSE can predict outcome. A stepwise strategy of combining clinical risk scores with DSE for CAD screening in CKD reduces the number of tests required and identifies a high-risk subgroup among whom DSE results more effectively stratify high and low risk.


Therapeutic evaluation of two different dose regimens of praziquantel in a recent Schistosoma mansoni focus in Northern Senegal.
A therapeutic trial, involving 130 Schistosoma mansoni-infected children, with no previous history of antischistosomal treatment, was carried out to evaluate the efficacy of two different dose regimens of praziquantel. The study was carried out because low cure rates were described in this recently established (1990) S. mansoni focus in northern Senegal, following treatment with a standard dosage of 40 mg/kg. The subjects were randomly allocated into two groups: one group (1) received 40 mg/kg in one oral dose, the other group (2) was treated with two oral doses of 30 mg/kg at a 6-hr interval. Parasitologic examination and circulating anodic antigen (CAA) detection were performed before, 10 days, three, six, and 21 weeks after chemotherapy. No significant differences in cure rates were found between the two groups. Six weeks after treatment, 34% and 44% of the individuals were found to be stool negative in group 1 and group 2, respectively. However, only 10-15% became completely negative according to the serum CAA antigen assay. Mean egg counts were reduced by 99% in both groups. Antigen detection confirmed the parasitologic results. Fewer side effects were observed in the group treated with 2 x 30 mg/kg, which may be explained by split dosage administration. Our study shows that the low cure rates observed in this area could not be improved by using a higher dosage of praziquantel.


Alcoholic beverage preference and characteristics of drinkers and nondrinkers in western New York (United States).
Dietary and lifestyle characteristics may differ for drinkers of specific alcoholic beverages and nondrinkers which would have important implications for studies of alcohol and disease. Our aim in this study was to describe differences in dietary and lifestyle characteristics associated with alcoholic beverage preference in a population-based sample of healthy study participants. Data were collected as part of a series of case-control studies of alcohol use, myocardial infarction, and lung, breast and prostate cancer in western New York from 1846 men and 1910 women aged 35 to 79, randomly selected from the general population of Erie and Niagara Counties. Beverage preference was defined for noncurrent vs current drinkers, and drinkers of beer, wine, liquor, and mixed beverages. Generalized linear models for continuous variables and Cochran-Mantel-Haenszel statistics for categorical variables were computed for the entire sample and stratified by gender. Participant characteristics differed by alcoholic beverage preference and drinking status. In general, wine drinkers had higher education and household incomes, lower prevalence of current smoking, higher intakes of dietary fiber, potassium, vitamin E, and total carotenoids, lower total fat intakes and higher amounts of fruits, vegetables, and grain products than consumers of other beverages. Conversely, beer and liquor drinkers had somewhat lower education and household incomes, higher rates of current smoking, higher energy and total fat intakes and consumed lower amounts of fruits, vegetables, and grain products. Finally, current nondrinkers were more likely to be older, less educated, have lower household incomes, and consume diets less consistent with dietary guidelines than current drinkers. These results suggest that usual beverage preference may encompass other health-related behaviors and underline the importance of accurate exposure measurement and use of statistical methods to accommodate these interrelationships.


Comparison of tulathromycin, azithromycin and azithromycin-rifampin for the treatment of mild pneumonia associated with Rhodococcus equi.
The objectives of the present study were to determine the relative efficacy of tulathromycin, azithromycin, or azithromycin with rifampin for the treatment of pulmonary abscesses on a farm with endemic infections caused by Rhodococcus equi. Foals with ultrasonographic evidence of pulmonary abscesses (abscess score 8.0-15 cm; n=120) were randomly allocated in four equal treatment groups: (1) tulathromycin intramuscularly; (2) azithromycin monotherapy, orally; (3) azithromycin with rifampin, orally; (4) saline intramuscularly as a placebo. Physical examination and thoracic ultrasonography were performed by individuals unaware of treatment group assignment. Foals that worsened were removed from the study. The proportion of foals that recovered without the need for a change in therapy was significantly higher for foals treated with azithromycin (29 of 30) or azithromycin with rifampin (28 of 30) than for foals treated with a placebo (20 of 30). Additionally, azithromycin or azithromycin with rifampin resulted in a significantly faster decrease in the number of abscesses and abscess score compared with a placebo. The proportion of foals treated with tulathromycin that recovered (27 of 30) was not significantly different from that of foals treated with a placebo. Azithromycin alone or in combination with rifampin was beneficial in the study population.


Carbohydrate metabolism during ascospore development in yeast.
Carbohydrate metabolism, under sporulation conditions, was compared in sporulating and non-sporulating diploids of Saccharomyces cerevisiae. Total carbohydrate was fractionated into trehalose, glycogen, mannan, and an alkali-insoluble fraction composed of glucan and insoluble glycogen. The behavior of three fractions was essentially the same in both sporulating and non-sporulating strains; trehalose, mannan, and the insoluble fraction were all synthesized to about the same extent regardless of a strain's ability to undergo meiosis or sporulation. In contrast, aspects of soluble glycogen metabolism depended on sporulation. Although glycogen synthesis took place in both sporulating and non-sporulating strains, only sporulating strains exhibited a period of glycogen degradation, which coincided with the final maturation of ascospores. We also determined the carbohydrate composition of spores isolated from mature asci. Spores contained all components present in vegetative cells, but in different proportions. In cells, the most abundant carbohydrate was mannan, followed by glycogen, then trehalose, and finally the alkali-insoluble fraction; in spores, trehalose was most abundant, followed by the alkali-insoluble fraction, glycogen, and mannan in that order.


The "justice gap" for sexual assault cases: future directions for research and reform.
Media coverage often reports "good" news about the criminal justice system's ability to effectively respond to sexual assault, concluding that the past two decades have seen an increase in rape reporting, prosecution, and conviction. The objective of this article is to examine the validity of such conclusions by critically reviewing the strengths and weaknesses of various data sources and comparing the statistics they produce. These statistics include estimates for sexual assault reporting rates and case outcomes in the criminal justice system. We conclude that such pronouncements are not currently supported by statistical evidence, and we outline some directions for future research and reform efforts to make the "good news" a reality in the United States.


Therapeutic strategies in rheumatoid arthritis over a 40-year period.
To examine trends in therapeutic strategies and to identify the determinants of starting disease modifying antirheumatic drug (DMARD) therapy over a 40-year period in a population based inception cohort of patients with rheumatoid arthritis (RA). A population based inception cohort was assembled from among all Rochester, Minnesota, residents aged > or = 18 years who were first diagnosed with RA (1987 American College of Rheumatology criteria) between January 1, 1955, and January 1, 1995. All subjects were followed longitudinally through their complete medical records until death, migration from Olmsted County, or date of abstraction (January 1, 2001, to January 1, 2003). Drug exposure data were collected on all DMARD and corticosteroid regimens. Time to DMARD initiation was examined using the Kaplan-Meier method. The influence of calendar time and disease characteristics on time from incidence to first DMARD therapy and the number of DMARD regimens were analyzed using Cox regression and proportional odds models, respectively. The study population comprised 603 patients (73% female) with a mean age of 58 years and a mean followup of 15 years. At 2 years after RA onset, 26% of patients in the 1955-74 cohort, 40% in the 1975-84 cohort, and 70% in the 1985-94 cohort had received a DMARD (log-rank p < 0.001). Age, rheumatoid factor (RF) positivity, erythrocyte sedimentation rate, large joint swelling, rheumatoid nodules, and destructive changes on radiographs were significantly associated with time to first DMARD regimen after adjustment for calendar time and sex. Patients who were older and RF positive and who did not receive CS were more likely to have received more DMARD regimens. Time to initiation of DMARD therapy has shortened markedly over the past 3-4 decades. These changes in management of early RA provide evidence for the translation of scientific evidence into clinical practice in rheumatology. Age and various disease characteristics are significantly associated with initiation and the number of DMARD regimens used. These should be considered as confounders when examining the effect of early DMARD treatment on disease progression and mortality.


Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals.
Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is currently under investigation as an anti-osteolytic agent in the treatment of a broad range of bone disorders. This study describes the absorption and disposition of the drug in laboratory animals. Following iv administration, alendronate was rapidly cleared from plasma, either taken up and sequestered in the bone or excreted by the kidney. About 30 to 40% of the dose was excreted in the urine in 24 hr, with most of the drug being excreted in the first 3 to 4 hr. There was little or no accumulation of the drug in noncalcified tissues and only a very small fraction of the dose was excreted in the bile. Most of the dose was rapidly taken up by bone tissues: 30% in 5 min, 60% in 1 hr. Absorption of alendronate was very poor. Based on the ratios in bone of the labels from the 14C-labeled oral dose and the 3H-labeled iv dose, absorption was estimated to be about 0.9% for the rat, 1.8% for the dog, and 1.7% for the monkey. Comparison of the concentrations of alendronate in bones of the same rats in fasted (3H-labeled) and fed (14C-labeled) states indicated that food caused a substantial decrease in absorption, by about 6- to 7-fold. The terminal half-life of alendronate in bone was about 200 days for the rat. Based on urinary excretion, the terminal half-life was estimated to be about 1000 days for the dog. The long persistence of alendronate in bone was likely due to its slow dissolution rate from bone tissues.


Role of M protein in pharyngeal colonization by group A streptococci in rats.
As the initial step in infection, group A streptococci (GAS) colonize either the nasopharyngeal mucosa or the skin of humans. A number of virulence factors have been implicated in the colonization phase of pathogenesis based upon their in vitro activities, but the in vivo data supporting their role in colonization of the host tissues is lacking. In this investigation, the potential requirement for M protein in pharyngeal colonization by GAS was explored by using near-isogenic strains in experimental animals studies. Fischer rats were infected by intranasal and oral inoculation with both M-positive and M-negative Streptococcus pyogenes strains. Colonization of the pharyngeal area by the streptococci was monitored at various time intervals. Both M-positive and M-negative strains colonized during the first week following infection, indicating that M protein was not necessary for this initial colonization. Two M-positive strains of S. pyogenes were recovered from the rats up to 23 weeks following inoculation, while the colonization levels for M-negative strains decreased rapidly in the second and third weeks, becoming negligible by the fourth week. This indicates a potential role for M protein in the persistence of colonization at this mucosal surface. Colonization of rats with either M-positive strain of S. pyogenes also resulted in the appearance of salivary and serum antibody responses. This in vivo model should allow further investigation into factors required for GAS disease, including the examination of the potential role of the host immune response both in modulation of the pharyngeal surface and in modulation of antigenic changes in M protein or other surface factors.


Evidence of positive selection in mitochondrial complexes I and V of the African elephant.
As species evolve, they become adapted to their local environments. Detecting the genetic signature of selection and connecting that to the phenotype of the organism, however, is challenging. Here we report using an integrative approach that combines DNA sequencing with structural biology analyses to assess the effect of selection on residues in the mitochondrial DNA of the two species of African elephants. We detected evidence of positive selection acting on residues in complexes I and V, and we used homology protein structure modeling to assess the effect of the biochemical properties of the selected residues on the enzyme structure. Given the role these enzymes play in oxidative phosphorylation, we propose that the selected residues may contribute to the metabolic adaptation of forest and savanna elephants to their unique habitats.


Influence of iron-chelated growth conditions on outer membrane protein production and virulence of Vibrio tubiashii.
Growth of two Vibrio tubiashii strains under iron-chelated conditions resulted in the production of a hydroxymate-like siderophore, and expression of outer membrane proteins with homologies to proteins in Vibrio cholerae and Vibrio vulnificus which were not seen in cells grown under non-chelated growth conditions. PCR analysis using primers based on Listonella anguillarum's ferric uptake Repressor protein (fur) gene detected a 316 bp fur gene homolog which also had sequence homology to the fur genes of V. cholerae and V. vulnificus. V. tubiashii cultured under iron-chelated growth conditions induced a greater fluid accumulation (FA) response in suckling mice than cells which were cultured under iron non-chelated growth conditions. Our observations that V. tubiashii possesses a fur-like gene homolog and expresses unique OMPs, a hydroxymate-like siderophore, and produces an increased fluid accumulation response in suckling mice when grown under iron-chelated condition support previous findings that V. tubiashii may have the essential components for the survival and establishment of infections and this report represents the first observations of competent iron acquisition system in V. tubiashii which is similar to those produced by other marine vibrios, many of which are pathogenic for humans.


Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease.
Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin. Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T2-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T2 water 1H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and alpha-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T2. Importantly, morphological, but not T2 relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model. A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T2 relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration in vivo.


LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis.
The liver receptor homolog-1 (LRH-1; NR5A2) and steroidogenic factor-1 (SF-1; NR5A1) are two orphan members of the Ftz-F1 subfamily of nuclear receptors. LRH-1 is expressed in tissues derived from endoderm, including intestine, liver and exocrine pancreas, as well as in the ovary. In these tissues, LRH-1 plays a predominant role in development, reverse cholesterol transport, bile-acid homeostasis and steroidogenesis. SF-1 expression is confined to steroidogenic tissues and the hypothalamo-pituitary-adrenal axis, where it is involved in the control of development, differentiation, steroidogenesis and sexual determination. In this article, we will review data concerning the structure, regulation and function of LRH-1. These data highlight structural similarities between LRH-1 and other Ftz-F1 members but also underscore important functional differences, assigning to LRH-1 a unique position among nuclear receptors.


Assessment of "gene-environment" interaction in cases of familial and sporadic pancreatic cancer.
Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States. This study characterizes one of the largest national registries of familial PC (FPC) and sporadic PC (SPC), focusing on demographics, clinical factors, self-reported environmental and occupational lifetime exposures, and survival status. Reported risk factors for PC include advancing age, a family history of PC, high-risk inherited syndromes, cigarette, cigar, and pipe smoking, exposure to occupational and environmental carcinogens, African-American race, high fat/high cholesterol diet, obesity, chronic pancreatitis, and diabetes mellitus. This retrospective cross-sectional, case-only analysis includes cases of FPC (n = 569) and SPC (n = 689) from the Johns Hopkins National Familial Pancreas Tumor Registry (NFPTR) enrolled between 1994 and 2005. FPC smokers with environmental tobacco smoke (ETS) exposure were diagnosed at a significantly younger mean age (63.7 years) as compared to FPC non-smokers without ETS exposure (66.6 years; p = 0.05). Non-smoker ETS-exposed cases were diagnosed with PC at a significantly younger mean age (64.0 years) compared to non-smoker non-ETS-exposed cases (66.5 years) (p < 0.0004). The mean age at diagnosis for Ashkenazi Jewish SPC subjects was significantly younger (by 2.1 years) than Ashkenazi Jewish FPC cases (p = 0.05). In addition, Ashkenazi Jewish FPC subjects who smoked were diagnosed 5.9 years earlier than Ashkenazi Jewish FPC non-smokers (p = 0.05). The median length of survival for unresected FPC cases was significantly shorter (168 days) as compared to unresected SPC cases (200 days) (p = 0.04). Survival was improved in resected cases, 713 days for FPC cases and 727 days for SPC cases, but was not significantly different between the groups (p = 0.4). Mild to moderate multiplicative interaction was found between a family history of PC and exposure to asbestos, environmental radon, and environmental tobacco smoke (ETS), as evidenced by odds ratios >1.0. These are the first data to show that occupational and environmental exposures may act synergistically with inherited or acquired genetic polymorphisms, resulting in earlier occurrence of PC. Exposure to cigarette smoking and ETS exposure in non-smokers when younger than 21 years of age are associated with a younger mean age of diagnosis in FPC and SPC cases and Ashkenazi Jewish smokers, when compared to non-exposed cases. Risk prediction models which take into account environmental exposures as well as family history may more accurately predict the risk of PC. High-risk individuals will likely benefit from early identification of pre-malignant lesions and molecular profiling, as methods of early detection, prevention, and personalized therapy.


Tympanic Membrane Haematoma in a RivaroxabanTreated Patient: A Case Report.
New generation oral anticoagulants - rivaroxaban, apixaban and edoxaban - represent an important medical achievement. Their therapeutic effectiveness and ease of use make them essential in the management of thromboembolic conditions. However, as warfarin, they have known haemorrhagic risks. This paper reports the case of a 50-year-old female who presented with ear pain and spontaneous blood discharge in her right ear, after a two-week treatment with rivaroxaban. The physical examination revealed a spontaneous tympanic haematoma in the inferior quadrants, adjacent to the umbus. She denied any manipulation of the ear canal. Our goal is to alert for a presumable side effect of this drug in clinical practise.


Metacognitive judgments of repetition and variability effects in natural concept learning: evidence for variability neglect.
In four experiments, we examined the effects of repetitions and variability on the learning of bird families and metacognitive awareness of such effects. Of particular interest was the accuracy of, and bases for, predictions regarding classification of novel bird species, referred to as category learning judgments (CLJs). Participants studied birds in high repetitions and high variability conditions. These conditions differed in the number of presentations of each bird (repetitions) and the number of unique species from each family (variability). After study, participants made CLJs for each family and were then tested. Results from a classification test revealed repetition benefits for studied species and variability benefits for novel species. In contrast with performance, CLJs did not reflect the benefits of variability. Results showed that CLJs were susceptible to accessibility-based metacognitive illusions produced by additional repetitions of studied items.


Recommendations for effective documentation in regional anesthesia: an expert panel Delphi consensus project.
Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia.


Impact of pharmacy care upon adherence to cardiovascular medicines: a feasibility pilot controlled trial.
To investigate the feasibility and potential impact of a pharmacy care intervention, involving motivational interviews among patients with acute coronary syndrome, on adherence to medication and on health outcomes. This article reports a prospective, interventional, controlled feasibility/pilot study. Seventy one patients discharged from a London Heart Attack Centre following acute treatment for a coronary event were enrolled and followed up for 6 months. Thirty two pharmacies from six London boroughs were allocated into intervention or control sites. The intervention was delivered by community pharmacists face-to-face in the pharmacy, or by telephone. Consultations were delivered as part of the New Medicine Service or a Medication Usage Review. They involved a 15-20 min motivational interview aimed at improving protective cardiovascular medicine taking. At 3 months, there was a statistically significant difference in adherence between the intervention group (M=7.7, SD=0.56) and the control group (M=7.0, SD=1.85), p=0.026. At 6 months, the equivalent figures were for the intervention group M=7.5, SD=1.47 and for the controls M=6.1, SD=2.09 (p=0.004). In addition, there was a statistically significant relationship between the level of adherence at 3 months and beliefs regarding medicines (p=0.028). Patients who reported better adherence expressed positive beliefs regarding the necessity of taking their medicines. However, given the small sample size, no statistically significant outcome difference in terms of recorded blood pressure and low density lipoprotein-cholesterol was observed over the 6 months of the study. The feasibility, acceptability and potentially positive clinical outcome of the intervention were demonstrated, long with a high level of patient acceptability. It had a significant impact on cardiovascular medicine taking adherence. But these findings must be interpreted with caution. The intervention should be tested in a larger trial to ascertain its full clinical utility. ClinicalTrials.gov identifier: NCT01920009.


Systemic contact dermatitis and allergy to biomedical devices.
Systemic contact dermatitis (SCD) refers to a skin condition where an individual who is cutaneously sensitized to an allergen will subsequently react to that same allergen or a cross-reacting allergen via the systemic route. It occurs to allergens including metals, medications, and foods. There has been recent interest in metal allergy as it relates to the implantation of devices such as orthopedic, dental, cardiac, and gynecologic implants. This review will briefly address all causes of systemic contact dermatitis with a special and expanded focus on metal implant allergy. We present literature on SCD to various metal biomedical devices, patch testing for diagnosis of metal allergy pre and post implantation and treatment.


Lung volume reduction with endobronchial coils for patients with emphysema.
The lung volume reduction coil treatment is a minimally invasive bronchoscopic treatment option for emphysema patients who suffer from severe hyperinflation. The treatment is aimed at a large group of patients where lung volume reduction surgery and bronchoscopic lung volume reduction using endobronchial valves are no option, or alternatively, can be offered as a bridge to lung transplantation. The nitinol coil exhibits a shape memory effect and is biologically inert. The lung volume reduction coil procedure is performed in two separate treatment sessions, targeting one lobe per session, with the contralateral lobe being treated 4 to 8 weeks after the first session. In one treatment session, around 10 to 14 coils, thereby treating an entire lobe, are being placed. Selecting optimally treated, symptomatic chronic obstructive pulmonary disease (COPD) patients with emphysema and severe hyperinflation, while avoiding significant airway disease such as asthma, chronic bronchitis and bronchiectasis, is key to achieve treatment success. Three randomized clinical trials investigating lung volume reduction coil treatment have been published until now, reporting the results of 452 treated patients up to 12 months after coil treatment. Lung volume reduction coil treatment results in significant improvement of pulmonary function outcomes and quality of life in patients with severe hyperinflation. The most common complications of lung volume reduction coil treatment are: COPD exacerbations, pneumonia, Coil Associated Opacity and an increased risk of pneumothorax. The purpose of this article is to describe the coil technique and review the available literature regarding effect, safety and future perspectives of lung volume reduction with coils for emphysema patients.


The burden of pneumococcal disease among Latin American and Caribbean children: review of the evidence.
To conduct a comprehensive review of data on pneumococcal disease incidence in Latin America and the Caribbean and project the annual number of pneumococcal disease episodes and deaths among children < 5 years of age in the region. We carried out a systematic review (1990 to 2006) on the burden of pneumococcal disease in children < 5 years of age in the region. We summarized annual incidence rates and case fatality ratios using medians and interquartile ranges for invasive pneumococcal disease (IPD) (including all-IPD and separately abstracting pneumococcal meningitis, pneumonia, bacteremia, and sepsis data), pneumonia (all cause and radiologically confirmed), and acute otitis media by age group: < 1 year, < 2 years, and < 5 years. We modeled age-specific cumulative incidence of disease obtained from standard Kaplan-Meier analysis and projected data to obtain regional estimates of disease burden. We adjusted burden estimates by serotype coverage, vaccination coverage, and vaccine efficacy to estimate the number of cases and deaths averted. Of 5 998 citations identified, 26 papers from 10 countries were included. The estimated annual burden of pneumonia, meningitis, and acute otitis media caused by pneumococcus in children < 5 years of age ranged from 980 000 to 1 500 000, 2 600 to 6 800, and 980 000 to 1 500 000, respectively. An estimated 12 000 to 28 000 deaths due to pneumococcal disease occur in the region annually. Pneumococcal conjugate vaccine could save 1 life per 1 100 and prevent 1 case per 13 children vaccinated. A substantial burden of pneumococcal disease in the region is potentially preventable with pneumococcal conjugate vaccines and should be considered in regional vaccine decision making. Results are limited by the very few studies, conducted in selected settings, included in this review.


Brain neoplasms and coagulation-lessons from heterogeneity.
The coagulation system constitutes an important facet of the unique vascular microenvironment in which primary and metastatic brain tumors evolve and progress. While brain tumor cells express tissue factor (TF) and other effectors of the coagulation system (coagulome), their propensity to induce local and peripheral thrombosis is highly diverse, most dramatic in the case of glioblastoma multiforme (GBM), and less obvious in pediatric tumors. While the immediate medical needs often frame the discussion on current clinical challenges, the coagulation pathway may contribute to brain tumor progression through subtle, context-dependent, and non-coagulant effects, such as induction of inflammation, angiogenesis, or by responding to iatrogenic insults (e.g. surgery). In this regard, the emerging molecular diversity of brain tumor suptypes (e.g. in glioma and medulloblastoma) highlights the link between oncogenic pathways and the tumor repertoire of coagulation system regulators (coagulome). This relationship may influence the mechanisms of spontaneous and therapeutically provoked tumor cell interactions with the coagulation system as a whole. Indeed, oncogenes (EGFR, MET) and tumor suppressors (PTEN, TP53) may alter the expression, activity, and vesicular release of tissue factor (TF), and cause other changes. Conversely, the coagulant microenvironment may also influence the molecular evolution of brain tumor cells through selective and instructive cues. We suggest that effective targeting of the coagulation system in brain tumors should be explored through molecular stratification, stage-specific analysis, and more personalized approaches including thromboprophylaxis and adjuvant treatment aimed at improvement of patient survival.


Geometric constraints and optimization in externally driven propulsion.
Micro/nanomachines capable of propulsion through fluidic environments provide diverse opportunities in important biomedical applications. In this paper, we present a theoretical study on micromotors steered through liquid by an external rotating magnetic field. A purely geometric tight upper bound on the propulsion speed normalized with field frequency, known as propulsion efficiency, δ, for an arbitrarily shaped object is derived. Using this bound, we estimate the maximum propulsion efficiency of previously reported random magnetic aggregates. We introduce a complementary definition of the propulsion efficiency, δ*, that ranks propellers according to their maximal speed in body lengths per unit time and that appears to be preferable over the standard definition in a search for fastest machines. Using a bead-based hydrodynamic model combined with genetic algorithms, we determine that δ*-optimal propeller deviates strongly from the bioinspired slim helix and has a surprising chubby skew-symmetric shape. It is also shown that optimized propellers with preprogrammed shape are substantially more efficient than random magnetic aggregates. We anticipate that the results of the present study will provide guidance toward prospective experimental design of more efficient magnetic micro/nanomachines.


Our Healthier Nation: are general practitioners willing and able to deliver? A survey of attitudes to and involvement in health promotion and lifestyle counselling.
The recent Green Paper, Our Healthier Nation, identifies professional advice on healthier living as a key component of its national contract for health. General practitioners (GPs) are ideally placed for this work. However, previous research has reported a discrepancy between patients' expectations of lifestyle advice from GPs and their receipt of such advice. To describe GPs' current attitudes to and involvement in health promotion and lifestyle counselling, and to track changes in these areas over recent years. A postal questionnaire survey of a random sample of 430 GPs, one per practice, from all general practices in Leicestershire, Derbyshire, and Nottinghamshire. GPs who had not responded after two weeks received a reminder telephone call plus two follow-up questionnaires. Four hundred and eleven GPs were eligible for the survey, which yielded a response rate of 68% (n = 279). GPs reported spending an average 16% of practice time on prevention and 79% reported educating patients about lifestyle risk 'most' or 'all of the time'. Solo GPs spent more time on prevention than GPs from group practices. Most enquiries and interventions related to smoking behaviour. GPs felt most effective in changing patients' use of prescription drugs, and the largest reported difference between current and potential effectiveness in helping patient change lifestyle behaviour, after information and training, related to reducing alcohol consumption. Despite an increasing workload, GPs remain positive about health promotion and lifestyle counselling. Over the past 10 years, there has been an increase in routine enquiries about lifestyle behaviour, but confidence about effectiveness in helping patients changes lifestyle behaviour remains low. More training and support concerning lifestyle intervention is required by GPs in order for them to contribute effectively to the Government's health promotion programme.


Assessment of quality of life and activities of daily living in Turkish patients with heart failure.
Heart failure is an entire clinical syndrome affecting many aspects of life, rather than merely a usual disease. This cross-sectional study was designed to assess heart failure patients' quality of life and activities of daily living (ADL). Seventy-five patients who applied to the cardiology department were included in the study. The data were obtained using the left ventricular dysfunction scale (LVD-36) and ADL scale. A statistically significant relationship was found between LVD-36 and ADL scores and New York Heart Association (NYHA) functional class, previous hospitalization, daily medication, age and education (P < 0.05). It was found that LVD-36 and ADL scores increase as the level of education increases and as the NYHA functional class, previous hospitalization, number of drugs taken daily and age decrease. The study found a statistically significantly negative relationship between quality of life and ADL (P < 0.05). In patients with heart failure, age, NYHA functional class, number of drugs taken daily independently affected the ADL scores. Additionally, in these patients, education, NYHA functional class, number of drugs taken daily and previous hospitalizations independently affected the quality of life. As the functional situation deteriorates and becomes severe, individual care, training, social support and consultation services for the patient and their family should be increased.


Incidence of antibiotics resistance among uropathogens in Omani children presenting with a single episode of urinary tract infection.
Urinary tract infection (UTI) is one of the most common community-acquired infections. Different organisms can be the cause of UTI in children, with resistance to antibiotics becoming a significant problem in the choice of treatment. Worldwide studies have documented the prevalence of uropathogens in different countries. However, there is no previous study documenting the incidence of different uropathogens in Oman. We aim to report the most common uropathogens and their antibiotic sensitivity patterns in children presenting with documented, single episode UTI at a tertiary hospital in Oman. A retrospective analysis of all Omani children below 14 years who presented with a case of first documented UTI to SQUH between September 2008 and August 2012 was conducted. Data were obtained from the patients' electronic records in the hospital information system. Data were then analyzed using SSPS (Statistical Package for Social Sciences program, Version 20, IBM, Chicago, IL, USA). In the retrospective review of all urine cultures, 438 positive urine cultures were identified. Out of those, 208 (47.5%) belonged to children with their first episode of UTI. Thirty-three patients were excluded and 75 patients were included in the final analysis. Escherichia coli was the most frequently encountered uropathogen in our cohort (69%), followed by Klebsiella pneumoniae infection (17%). Nearly half (46.6%) of these two common organism were resistant to Cotrimoxazole, while 31% of them were resistant to Augmentin. Twenty-four percent of the E. coli and K. pneumoniae strains were resistant to Cefuroxime, and only 10% were resistant to nitrofurantoin. Both Augmentin and Cotrimoxazole should not be the first line antibiotics to treat UTI.


A multicentre prospective cohort study of the accuracy of conventional landmark technique for cricoid localisation using ultrasound scanning.
Cricoid pressure is employed during rapid sequence induction to reduce the risk of pulmonary aspiration. Correct application of cricoid pressure depends on knowledge of neck anatomy and precise identification of surface landmarks. Inaccurate localisation of the cricoid cartilage during rapid sequence induction risks incomplete oesophageal occlusion, with potential for pulmonary aspiration of gastric contents. It may also compromise the laryngeal view for the anaesthetist. Accurate localisation of the cricoid cartilage therefore has relevance for the safe conduct of rapid sequence induction. We conducted a multicentre, prospective cohort study to determine the accuracy of cricoid cartilage identification in 100 patients. The cranio-caudal midpoint of the cricoid cartilage was identified by a qualified anaesthetic assistant using the conventional landmark technique and marked. While maintaining the patient in the same position, a second mark was made by identifying the midpoint of the cricoid cartilage using ultrasound scanning. The mean (SD) distance between the two marks was 2.07 (8.49) mm. In 41% of patients the midpoint was incorrectly identified by a margin greater than 5 mm. This error was uniformly distributed both above and below the midpoint of the cricoid cartilage. The Pearson correlation coefficient of this error with respect to body mass index was 0.062 (p = 0.539) and with age was -0.020 (p = 0.843). There were also no significant differences in error between male and female patients. Identification of cricoid position using a landmark technique has a high degree of variability and has little correlation with age, sex or body mass index. These findings have significant implications for the safe application of cricoid pressure in the context of rapid sequence induction.


When and why portal vein thrombosis matters in liver transplantation: a critical audit of 174 cases.
To identify complications associated with different techniques utilized to treat portal vein thrombosis (PVT) during primary liver transplantation and their impact on survival. PVT remains an intricate problem in liver transplantation, and the long-term outcomes of patients with PVT who undergo transplantation are not well defined. We performed a retrospective cohort analysis of all consecutive adult patients who underwent primary isolated liver transplantation from 1998 to 2009 (median follow-up period, 89 months). The outcomes of patients with PVT were compared with those without PVT. Among 1379 recipients, 174 (12.6%) had PVT at the time of transplantation [83 (48%) complete and 91 (52%) partial]. Among PVT patients with reestablished physiological portal inflow (PVT: physiological group; n = 149), 123 underwent thrombectomies, 16 received interpositional vein grafts, and 10 received mesoportal jump grafts. In 25 patients, physiological portomesenteric venous circulation was not reconstituted (PVT: nonphysiological group; 18 underwent cavoportal hemitranspositions, 6 renoportal anastomoses, and 1 arterialization). The PVT: nonphysiological group suffered a significantly increased incidence of rethrombosis of the portomesenteric veins and gastrointestinal bleeding, with a marginal 10-year overall survival rate of 42% (no PVT, 61%; P = 0.002 and PVT: physiological, 55%; P = 0.043). The PVT: physiological and no PVT groups exhibited comparable survival rates (P = 0.13). No significant differences in survival were observed between complete and partial PVT as long as physiological portal flow was reestablished. The subset of PVT patients requiring nonphysiological portal vein reconstruction was associated with higher complication rates and suffered diminished long-term prognoses. For the most severe PVT cases, a comprehensive approach is critical to further improve outcomes.


Sleep, dreams, and memory consolidation: the role of the stress hormone cortisol.
We discuss the relationship between sleep, dreams, and memory, proposing that the content of dreams reflects aspects of memory consolidation taking place during the different stages of sleep. Although we acknowledge the likely involvement of various neuromodulators in these phenomena, we focus on the hormone cortisol, which is known to exert influence on many of the brain systems involved in memory. The concentration of cortisol escalates over the course of the night's sleep, in ways that we propose can help explain the changing nature of dreams across the sleep cycle.


Perception of risk of HIV and sexual risk behaviours among students in the United States, Turkey and South Africa.
The aim of this study was to examine HIV sexual risk behaviours and perception of HIV risk among 1 095 students from the United States of America (US), Turkey and South Africa. Randomly selected students who were enrolled in general education courses completed a structured questionnaire. Results revealed statistically significant differences in specific HIV-related sexual behaviours among students from the three countries and among male and female students in each country. A higher percentage of US and South African students engage in HIV risky sexual behaviours compared with their Turkish counterparts, and a higher percentage of female students in the US and South Africa engage in HIV sexual risk behaviours compared with their male colleagues. A higher proportion of Turkish male students engaged in sexual risk behaviours compared with their female counterparts. The perception of HIV risk was low among US and Turkish students, and high among South African students. There was no agreement between engaging in risky sexual behaviour and self-perception of HIV risk among South African female students, while agreement was poor for US male and female students, Turkish male and female students, and South African male students. The observed optimistic bias needs to be considered in the design and implementation of HIV prevention programmes for these populations.


Pulse of the pandemic: Iterative topic filtering for clinical information extraction from social media.
The rapid evolution of the COVID-19 pandemic has underscored the need to quickly disseminate the latest clinical knowledge during a public-health emergency. One surprisingly effective platform for healthcare professionals (HCPs) to share knowledge and experiences from the front lines has been social media (for example, the "#medtwitter" community on Twitter). However, identifying clinically-relevant content in social media without manual labeling is a challenge because of the sheer volume of irrelevant data. We present an unsupervised, iterative approach to mine clinically relevant information from social media data, which begins by heuristically filtering for HCP-authored texts and incorporates topic modeling and concept extraction with MetaMap. This approach identifies granular topics and tweets with high clinical relevance from a set of about 52 million COVID-19-related tweets from January to mid-June 2020. We also show that because the technique does not require manual labeling, it can be used to identify emerging topics on a week-to-week basis. Our method can aid in future public-health emergencies by facilitating knowledge transfer among healthcare workers in a rapidly-changing information environment, and by providing an efficient and unsupervised way of highlighting potential areas for clinical research.


Interplay wellbeing framework: a collaborative methodology 'bringing together stories and numbers' to quantify Aboriginal cultural values in remote Australia.
Wellbeing has been difficult to understand, measure and strengthen for Aboriginal people in remote Australia. Part of the challenge has been genuinely involving community members and incorporating their values and priorities into assessment and policy. Taking a 'shared space' collaborative approach between remote Aboriginal communities, governments and scientists, we merged Aboriginal knowledge with western science - by bringing together stories and numbers. This research aims to statistically validate the holistic Interplay Wellbeing Framework and Survey that bring together Aboriginal-identified priorities of culture, empowerment and community with government priorities including education, employment and health. Quantitative survey data were collected from a cohort of 842 Aboriginal people aged 15-34 years, recruited from four different Aboriginal communities in remote Australia. Aboriginal community researchers designed and administered the survey. Structural equation modeling showed good fit statistics (χ/df = 2.69, CFI = 0.95 and RMSEA = 0.045) confirming the holistic nature of the Interplay Wellbeing Framework. The strongest direct impacts on wellbeing were 'social and emotional wellbeing' (r = 0.23; p < 0.001), 'English literacy and numeracy' (r = 0.15; p < 0.001), 'Aboriginal literacy' (r = 0.14; p < 0.001), 'substances' (lack thereof; r = 0.13; p = 0.003), 'work' (r = 0.12; p = 0.02) and 'community' (r = 0.08; p = 0.05). Correlation analyses suggested cultural factors have indirect impacts on wellbeing, such as through Aboriginal literacy. All cultural variables correlated highly with each other, and with empowerment and community. Empowerment also correlated highly with all education and work variables. 'Substances' (lack thereof) was linked with positive outcomes across culture, education and work. Specific interrelationships will be explored in detail separately. The Interplay Wellbeing Framework and Survey were statistically validated as a collaborative approach to assessing wellbeing that is inclusive of other cultural worldviews, values and practices. New community-derived social and cultural indicators were established, contributing valuable insight to psychometric assessment across cultures. These analyses confirm that culture, empowerment and community play key roles in the interplay with education, employment and health, as part of a holistic and quantifiable system of wellbeing. This research supports the holistic concept of wellbeing confirming that everything is interrelated and needs to be considered at the 'whole of system' level in policy approaches.


Central nervous system toxicity of local anesthetic mixtures in the rat.
Local anesthetics are often administered as mixtures during regional anesthesia. This study investigated whether a synergistic or antagonistic interaction between amide/amide or amide/ester local anesthetic combinations is present with respect to central nervous system toxicity. For surgical preparation, rats were anesthetized with 0.8% halothane in 30% O2/balance N2O and mechanically ventilated. Mean arterial blood pressure and the electroencephalogram were continuously monitored. After surgery, the halothane was discontinued for 15 min. An intravenous infusion of solutions containing lidocaine alone, bupivacaine alone, or any of three mixtures of the two drugs was then begun and continued at a fixed rate until seizure activity was observed on the electroencephalogram. Total administered doses of both drugs were compared by isobolographic analysis. After a similar protocol, a second experiment was performed evaluating lidocaine, tetracaine, or any of three mixtures of those two drugs. In both experiments, normocapnia, normoxia, and normothermia were maintained for all rats. For mixtures of lidocaine/bupivacaine (P = 0.40) and lidocaine/tetracaine (P = 0.24), there was no evidence that a significant degree of either synergism or antagonism was present. At the onset of seizures, mean arterial pressure was lowest in the lidocaine-alone groups in both experiments. Increasing doses of either bupivacaine or tetracaine (with correspondingly decreasing doses of lidocaine) were associated with greater mean arterial pressure values at onset of seizures. We conclude that central nervous system toxic effects of amide/amide or amide/ester anesthetic combinations, such as might occur during accidental intravascular injection, are no more than when the drugs are administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)


Anti-cancer effect of a novel 2,3-didithiocarbamate-substituted naphthoquinone as a tumor metabolic suppressor in vitro and in vivo.
Tumor cells reprogram their cellular metabolism by switching from oxidative phosphorylation to aerobic glycolysis to support aberrant cell proliferation. Suppressing tumor cell metabolism has become an attractive strategy for treating cancer patients. In this study, we identified a 2,3-didithiocarbamate-substituted naphthoquinone 3i that inhibited the proliferation of tumor cells by disturbing their metabolism. Compound 3i reduced cancer cell viability with IC50 values from 50 nM to 150 nM against HCT116, MCF7, MDA-MB231, HeLa, H1299 and B16 cells. Further, compound 3i was found to suppress ATP production in cultured cancer cells, inhibit the M2 isoform of pyruvate kinase (PKM2) which is a rate-limiting enzyme in the glycolytic pathway and block the subsequent transcription of the downstream genes GLUT1, LDH and CCND1. In addition, exposure to compound 3i significantly suppressed tumor growth in a B16 melanoma transplantation mouse model and a spontaneous breast carcinoma mouse model in vivo. The identification of compound 3i as a tumor metabolic suppressor not only offers a candidate compound for cancer therapy, but also provides a tool for an in-depth study of tumor metabolism.


Droplet digital PCR improves urinary exosomal miRNA detection compared to real-time PCR.
Quantification of urinary miRNAs can be challenging especially for low abundance miRNAs. We aimed to optimize the quantification of urinary exosomal miRNAs and compare the performance efficiency between droplet digital PCR (ddPCR) and real-time quantitative PCR (qPCR). We optimized a number of parameters for ddPCR such as annealing temperatures, annealing time and PCR cycle number. We also compared the performance of ddPCR and qPCR. By comparing the fluorescence amplification separation, the optimal annealing temperature was 59 °C, optimal annealing time was 60s and optimal cycle number was 45 for measuring urinary exosomal miRNAs. ddPCR had much higher technical sensitivity compared to qPCR. The minimal detectable concentration of miR-29a was <50 copies/μL by ddPCR compared to 6473 copies/μL for qPCR. Also, ddPCR generated more consistent results for serially diluted samples compared to qPCR. ddPCR generated smaller within-run variations than qPCR though this did not reach statistical significance. It also resulted in better reproducibility with smaller between-run variations. Optimization of urinary exosomal miRNA ddPCR assay is dependent on assessing key variables including experimental annealing temperature and time as well as the number of PCR cycles. ddPCR has a higher sensitivity, reproducibility, and accuracy in comparison to qPCR.


HIV antibodies. Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies.
Some HIV-infected individuals develop broadly neutralizing antibodies (bNAbs), whereas most develop antibodies that neutralize only a narrow range of viruses (nNAbs). bNAbs, but not nNAbs, protect animals from experimental infection and are likely a key component of an effective vaccine. nNAbs and bNAbs target the same regions of the viral envelope glycoprotein (Env), but for reasons that remain unclear only nNAbs are elicited by Env immunization. We show that in contrast to germline-reverted (gl) bNAbs, glnNAbs recognized diverse recombinant Envs. Moreover, owing to binding affinity differences, nNAb B cell progenitors had an advantage in becoming activated and internalizing Env compared with bNAb B cell progenitors. We then identified an Env modification strategy that minimized the activation of nNAb B cells targeting epitopes that overlap those of bNAbs.


Indirect hemagglutination assay in patients with melioidosis in northern Australia.
Melioidosis is caused by the saprophytic organism Burkholderia pseudomallei. The use of the indirect hemagglutination assay (IHA) has found widespread use in areas endemic for this disease. Using this assay, we explored the serologic profile of 275 patients with culture-confirmed melioidosis in the Northern Territory of Australia. Based on a threshold titer of 1:40, the sensitivity of the IHA on admission was 56%. Female patients, those with positive blood cultures, and those with pneumonia independently predicted a negative IHA result. Most patients (68%) with negative admission IHA titers subsequently seroconverted. Most patients (92%) with positive admission IHA titers had persistently positive IHA titers. Relapses were not observed in 36 patients who had a negative IHA at least 1 month after admission, irrespective of initial admission IHA. The IHA has limited utility as a diagnostic test for acute disease, and most patients subsequently have persistently positive titers after recovery from illness.


Surgical debulking of podoconiosis nodules and its impact on quality of life in Ethiopia.
In Ethiopia, severe lymphedema and acute dermato-lymphangio-adenitis (ADLA) of the legs as a consequence of podoconiosis affects approximately 1.5 million people. In some this condition may lead to woody-hard fibrotic nodules, which are resistant to conventional treatment. We present a series of patients who underwent surgical nodulectomy in a resource-limited setting and their outcome. In two teaching hospitals, we offered surgical nodulectomies under local anaesthesia to patients with persisting significant fibrotic nodules due to podoconiosis. Excisions after nodulectomy were left to heal by secondary intention with compression bandaging. As outcome, we recorded time to re-epithelialization after surgery, change in number of ADLA episodes, change in quality of life measured with the Dermatology Quality of Live Index (DQLI) questionnaire, and recurrence rate one year after surgery. 37nodulectomy operations were performed on 21 patients. All wounds re-reepithelialised within 21 days (range 17-42). 4 patients developed clinically relevant wound infections. The DLQI values were significantly better six months after surgery than before surgery (P<0.0001). Also the number of ADLA episodes per three months was significantly lower six months after surgery than before surgery (P<0.0001). Nodulectomy in podoconiosis patients leads to a significant improvement in the quality of life with no serious complications, and we recommend this to be a standard procedure in resource-poor settings.


Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice.
Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol's effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking initiation and nicotine addiction.


Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation.
Steroid hormones are synthesized from cholesterol primarily in the adrenal gland and the gonads and play vital roles in normal physiology, the control of development, differentiation, metabolic homeostasis, and reproduction. The actions of these small lipophilic molecules are mediated by intracellular receptor proteins. It is just over 25 yr since the first cDNA for steroid receptors were cloned, a development that led to the birth of a superfamily of ligand-activated transcription factors: the nuclear receptors. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains but possess distinct N-terminal domains and hinge regions that are intrinsically disordered. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action, and biology of this important class of ligand-activated transcription factors. In recent years, there has been interest in the structural plasticity and function of the N-terminal domain of steroid hormone receptors and in the allosteric regulation of protein folding and function in response to hormone, DNA response element architecture, and coregulatory protein binding partners. The N-terminal domain can exist as an ensemble of conformers, having more or less structure, which prime this region of the receptor to rapidly respond to changes in the intracellular environment through hormone binding and posttranslation modifications. In this review, we address the question of receptor structure and function dynamics with particular emphasis on the structurally flexible N-terminal domain, intra- and interdomain communications, and the allosteric regulation of receptor action.


Mesophilic Sporeformers Identified in Whey Powder by Using Shotgun Metagenomic Sequencing.
Spoilage and pathogenic spore-forming bacteria are a major cause of concern for producers of dairy products. Traditional agar-based detection methods employed by the dairy industry have limitations with respect to their sensitivity and specificity. The aim of this study was to identify low-abundance sporeformers in samples of a powdered dairy product, whey powder, produced monthly over 1 year, using novel culture-independent shotgun metagenomics-based approaches. Although mesophilic sporeformers were the main target of this study, in one instance thermophilic sporeformers were also targeted using this culture-independent approach. For comparative purposes, mesophilic and thermophilic sporeformers were also tested for within the same sample using culture-based approaches. Ultimately, the approaches taken highlighted differences in the taxa identified due to treatment and isolation methods. Despite this, low levels of transient, mesophilic, and in some cases potentially pathogenic sporeformers were consistently detected in powder samples. Although the specific sporeformers changed from one month to the next, it was apparent that 3 groups of mesophilic sporeformers, namely, Bacillus cereus, Bacillus licheniformis/Bacillusparalicheniformis, and a third, more heterogeneous group containing Brevibacillus brevis, dominated across the 12 samples. Total thermophilic sporeformer taxonomy was considerably different from mesophilic taxonomy, as well as from the culturable thermophilic taxonomy, in the one sample analyzed by all four approaches. Ultimately, through the application of shotgun metagenomic sequencing to dairy powders, the potential for this technology to facilitate the detection of undesirable bacteria present in these food ingredients is highlighted.IMPORTANCE The ability of sporeformers to remain dormant in a desiccated state is of concern from a safety and spoilage perspective in dairy powder. Traditional culturing techniques are slow and provide little information without further investigation. We describe the identification of mesophilic sporeformers present in powders produced over 1 year, using novel shotgun metagenomic sequencing. This method allows detection and identification of possible pathogens and spoilage bacteria in parallel. Strain-level analysis and functional gene analysis, such as identification of toxin genes, were also performed. This approach has the potential to be of great value with respect to the detection of spore-forming bacteria and could allow a processor to make an informed decision surrounding process changes to reduce the risk of spore contamination.


Integrating petrography, mineralogy and hydrochemistry to constrain the influence and distribution of groundwater contributions to baseflow in poorly productive aquifers: insights from Gortinlieve catchment, Co. Donegal, NW Ireland.
Identifying groundwater contributions to baseflow forms an essential part of surface water body characterisation. The Gortinlieve catchment (5 km(2)) comprises a headwater stream network of the Carrigans River, itself a tributary of the River Foyle, NW Ireland. The bedrock comprises poorly productive metasediments that are characterised by fracture porosity. We present the findings of a multi-disciplinary study that integrates new hydrochemical and mineralogical investigations with existing hydraulic, geophysical and structural data to identify the scales of groundwater flow and the nature of groundwater/bedrock interaction (chemical denudation). At the catchment scale, the development of deep weathering profiles is controlled by NE-SW regional scale fracture zones associated with mountain building during the Grampian orogeny. In-situ chemical denudation of mineral phases is controlled by micro- to meso-scale fractures related to Alpine compression during Palaeocene to Oligocene times. The alteration of primary muscovite, chlorite (clinochlore) and albite along the surfaces of these small-scale fractures has resulted in the precipitation of illite, montmorillonite and illite-montmorillonite clay admixtures. The interconnected but discontinuous nature of these small-scale structures highlights the role of larger scale faults and fissures in the supply and transportation of weathering solutions to/from the sites of mineral weathering. The dissolution of primarily mineral phases releases the major ions Mg, Ca and HCO3 that are shown to subsequently form the chemical makeup of groundwaters. Borehole groundwater and stream baseflow hydrochemical data are used to constrain the depths of groundwater flow pathways influencing the chemistry of surface waters throughout the stream profile. The results show that it is predominantly the lower part of the catchment, which receives inputs from catchment/regional scale groundwater flow, that is found to contribute to the maintenance of annual baseflow levels. This study identifies the importance of deep groundwater in maintaining annual baseflow levels in poorly productive bedrock systems.


[Hypnosis: logic and cybernetics].
Fundamental notions concerning cybernetics, as derived from the systematic application of logic to questions of communication and control, are illustrated. Particular attention is given to the concepts of "system" "structure" and "dynamics" and it is shown that these concepts ensure that better and more exact understanding and forecasting of reactions in organised beings can be obtained. Turing to hypnosis, it is made clear that a trance is the execution of a momentarily proposed programme; it is not the result of a generalised mechanical action, but is preordained and geared to various situations. The difficulty that the hypnotised subject finds in aciting against his own interests, or against moral priniciples, can be seen, for example, as a consequence of pre-programming. Another result is given moment and a given type of person. Since cybernetis has proved useful in psychology, the hope is expressed that it can be included as a teaching subject for those who learn, practise and teach hypnotism.


Heat preconditioning attenuates renal injury in ischemic ARF in rats: role of heat-shock protein 70 on NF-kappaB-mediated inflammation and on tubular cell injury.
Although heat preconditioning has been known to be protective in various types of injury, the precise molecular mechanism for this is unclear. Recent observations that indicate that previous heat shock has an anti-inflammatory, antiapoptotic effect led to this investigation of the in vivo effect of heat preconditioning on NF-kappaB activation and inflammation and also on tubular cell injury in ischemic acute renal failure (ARF). Heat preconditioning provided marked functional protection and also reduced histologic evidence of tubular necrosis. Ischemia/reperfusion-induced NF-kappaB activation was suppressed by heat preconditioning with a subsequent decrease in monocyte chemoattractant protein-1 expression and inflammatory cell infiltration. Heat preconditioning also suppressed the accumulation of phosphorylated inhibitory kappaBalpha (IkappaBalpha) with a resultant depletion of cytoplasmic IkappaBalpha, indicating that heat preconditioning blocked the activation of the IkappaB kinase complex. Tubular cell apoptosis, determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, also was decreased by heat preconditioning, and this was accompanied by decreased caspase 3 activation. Among several heat-shock proteins (HSP), HSP-70 was induced primarily by heat preconditioning. Inhibition of HSP-70 by quercetin almost completely reversed the functional protection that was provided by heat preconditioning. These data provide evidence that HSP-70 affords protection via inhibition of NF-kappaB-mediated inflammation and also inhibition of the cell death pathway in ischemic ARF. Further elucidation of the cytoprotective mechanism of stress proteins could facilitate new target or drug development in the treatment of ARF.


Local Pulmonary Immunological Biomarkers in Tuberculosis.
Regardless of the eventual site of disease, the point of entry for Mycobacterium tuberculosis (M.tb) is via the respiratory tract and tuberculosis (TB) remains primarily a disease of the lungs. Immunological biomarkers detected from the respiratory compartment may be of particular interest in understanding the complex immune response to M.tb infection and may more accurately reflect disease activity than those seen in peripheral samples. Studies in humans and a variety of animal models have shown that biomarkers detected in response to mycobacterial challenge are highly localized, with signals seen in respiratory samples that are absent from the peripheral blood. Increased understanding of the role of pulmonary specific biomarkers may prove particularly valuable in the field of TB vaccines. Here, development of vaccine candidates is hampered by the lack of defined correlates of protection (COPs). Assessing vaccine immunogenicity in humans has primarily focussed on detecting these potential markers of protection in peripheral blood. However, further understanding of the importance of local pulmonary immune responses suggests alternative approaches may be necessary. For example, non-circulating tissue resident memory T cells (TRM) play a key role in host mycobacterial defenses and detecting their associated biomarkers can only be achieved by interrogating respiratory samples such as bronchoalveolar lavage fluid or tissue biopsies. Here, we review what is known about pulmonary specific immunological biomarkers and discuss potential applications and further research needs.