Dynamics of freshwater snails and Schistosoma infection prevalence in schoolchildren during the construction and operation of a multipurpose dam in central Côte d'Ivoire.
The construction and operation of small multipurpose dams in Africa have a history of altering the transmission of water-based diseases, including schistosomiasis. The current study was designed to investigate the abundance and dynamics of schistosomiasis intermediate host snails and Schistosoma infections in humans during the construction and the first years of operation of a small multipurpose dam in Côte d'Ivoire. The study was carried out in Raffierkro and four neighbouring villages in central Côte d'Ivoire between 2007 and 2012. Snails were collected by two experienced investigators using scoops and forceps for 15 min at each site. Snails were identified at genera and, whenever possible, species level, and subjected to testing for cercarial shedding. Schoolchildren aged 6-15 years were examined once every year for Schistosoma haematobium and S. mansoni infection, using urine filtration and duplication Kato-Katz thick smears, respectively. Additionally, 551 adults were examined for Schistosoma infection before (June 2007) and 359 individuals 2 years after dam construction (June 2009). Overall, 1 700 snails belonging to nine different genera were collected from 19 sampling sites. Bulinus (potential intermediate host snails of S. haematobium) and Pila were the most common genera, whereas Biomphalaria (potential intermediate host snail of S. mansoni), Lymnaea, Physa and Melanoides were found in two villages. During the first-year sampling period, 65 snails were collected, of which 13 (20%) were schistosomiasis intermediate hosts. In subsequent years, out of 1 635 snails collected, 1 079 (66%) were identified as potential intermediate host for schistosomiasis, but none were shedding cercariae. The prevalence of S. mansoni among adults in the study area was low (0.4% in 2007 and 0.3% in 2009), whereas the prevalence of S. haematobium declined from 13.9% to 2.9% in this two-year period. The low prevalence of schistosomiasis in humans and the absence of infected intermediate host snails during the construction and early phase of operation of a small multipurpose dam suggest that there was no or only very little local transmission. However, the considerable increase in the number of intermediate host snails and their dispersion in irrigation canals call for rigorous surveillance, so that adequate public health measures can be taken in case of early signs of an outbreak.


Nitric oxide dioxygenation reaction in DevS and the initial response to nitric oxide in Mycobacterium tuberculosis.
DevS and DosT from Mycobacterium tuberculosis (MTB) are paralogous heme-based sensor kinases that respond to hypoxia and to low concentrations of nitric oxide (NO). Both proteins work with the response regulator DevR as a two-component regulatory system to induce the dormancy regulon in MTB. While DevS and DosT are inactive when dioxygen is bound to the heme Fe(II) at their sensor domain, autokinase activity is observed in their heme Fe(II)-NO counterparts. To date, the conversion between active and inactive states and the reactivity of the heme-oxy complex toward NO have not been investigated. Here, we use stopped-flow UV-vis spectroscopy and rapid freeze quench resonance Raman spectroscopy to probe these reactions in DevS. Our data reveal that the heme-O(2) complex of DevS reacts efficiently with NO to produce nitrate and the oxidized Fe(III) heme through an NO dioxygenation reaction that parallels the catalytic reactions of bacterial flavohemoglobin and truncated hemoglobins. Autophosphorylation activity assays show that the Fe(III) heme state of DevS remains inactive but exhibits a high affinity for NO and forms an Fe(III)-NO complex that is readily reduced by ascorbate, a mild reducing agent. On the basis of these results, we conclude that upon exposure to low NO concentrations, the inactive oxy-heme complex of DevS is rapidly converted to the Fe(II)-NO complex in the reducing environment of living cells and triggers the initiation of dormancy.


Nitrogen exchanges: testing the hypothesis of a country without agricultural production.
Today, finding data on agricultural nitrogen balances is quite easy. Calculations of such balances are carried out by most of the European countries as an indicator of environmental pollution attributable to the agricultural sector. In France, average values of agricultural nitrogen balances show an excess of 1.5 to 2 million tons of nitrogen. This excess is enormous. What would the balance of a country be if agricultural activity were stopped? In the following article, a country (France is used as an example) without agriculture is studied in order to assess its nitrogen balance. Using a previously published model describing nitrogen input and output of a given country, nitrogen flows are identified. Inputs include deposition, fixation, and products not intended for agricultural use. Outputs are reduced to zero if agriculture disappears (in France, agriculture is the only sector exporting products containing nitrogen). All flows are calculated considering the hypothesis of disappearance of agriculture. Nitrogen requirements to feed people and pets in France are estimated based on medical and veterinary data (recommended daily amounts for proteins and/or usual average consumption). Indeed, most of the food that nourishes the French population is produced nationally. If agriculture stops, it will be necessary to import food from foreign countries. Results show an unexpectedly high excess (for a country without agriculture having a structure similar to France: number of human beings and pets) of 1.5 million tons of nitrogen. An attempt to calculate an agricultural balance with the same data gives a result close to 3 million tons. Differences in French agricultural balances found in the literature can mainly be explained by values taken into account for deposition and fixation (values used here are at least 300,000 tons higher than values used by the Organisation for Economic Co-operation and Development). In conclusion, nitrogen excess in agriculture is partly due to social demand; agriculture does not only produce food but also includes many other functions (landscape management, employment, and preservation of culture, for example). As a consequence, efforts that do not involve suppressing agriculture should be made to figure out alternative ways of production.


The anatomy of choice: active inference and agency.
This paper considers agency in the setting of embodied or active inference. In brief, we associate a sense of agency with prior beliefs about action and ask what sorts of beliefs underlie optimal behavior. In particular, we consider prior beliefs that action minimizes the Kullback-Leibler (KL) divergence between desired states and attainable states in the future. This allows one to formulate bounded rationality as approximate Bayesian inference that optimizes a free energy bound on model evidence. We show that constructs like expected utility, exploration bonuses, softmax choice rules and optimism bias emerge as natural consequences of this formulation. Previous accounts of active inference have focused on predictive coding and Bayesian filtering schemes for minimizing free energy. Here, we consider variational Bayes as an alternative scheme that provides formal constraints on the computational anatomy of inference and action-constraints that are remarkably consistent with neuroanatomy. Furthermore, this scheme contextualizes optimal decision theory and economic (utilitarian) formulations as pure inference problems. For example, expected utility theory emerges as a special case of free energy minimization, where the sensitivity or inverse temperature (of softmax functions and quantal response equilibria) has a unique and Bayes-optimal solution-that minimizes free energy. This sensitivity corresponds to the precision of beliefs about behavior, such that attainable goals are afforded a higher precision or confidence. In turn, this means that optimal behavior entails a representation of confidence about outcomes that are under an agent's control.


Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.
Patients with pseudohypoparathyroidism type Ib (PHP-Ib) have hypocalcemia and hyperphosphatemia due to renal parathyroid hormone (PTH) resistance, but lack physical features of Albright hereditary osteodystrophy. PHP-Ib is thus distinct from PHP-Ia, which is caused by mutations in the GNAS exons encoding the G protein alpha subunit. However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS. Furthermore, loss of methylation at a differentially methylated region (DMR) of this locus, exon A/B, has been observed thus far in all investigated sporadic PHP-Ib cases and the affected members of multiple AD-PHP-Ib kindreds. We now report that affected members and obligate gene carriers of 12 unrelated AD-PHP-Ib kindreds and four apparently sporadic PHP-Ib patients, but not healthy controls, have a heterozygous approximately 3-kb microdeletion located approximately 220 kb centromeric of GNAS exon A/B. The deleted region, which is flanked by two direct repeats, includes three exons of STX16, the gene encoding syntaxin-16, for which no evidence of imprinting could be found. Affected individuals carrying the microdeletion show loss of exon A/B methylation but no epigenetic abnormalities at other GNAS DMRs. We therefore postulate that this microdeletion disrupts a putative cis-acting element required for methylation at exon A/B, and that this genetic defect underlies the renal PTH resistance in AD-PHP-Ib.


The "false negative" treadmill exercise test and left ventricular dysfunction.
One hundred and fifteen consecutive symptomatic patients undergoing graded exercise testing, selective coronary angiography and left ventriculography were retrospectively evaluated. The sensitivity, specificity, and false negative response rates of the exercise tests were 79%, 81%, and 21%, respectively. Although the magnitude of a positive ST-segment response was related to more extensive vascular disease, the frequency of false negative responses was nearly identical in patients with single, double, or triple vessel disease (22%, 21%, 19%). Analysis of the false negative group demonstrated significant ventriculographic and hemodynamic abnormalities when compared to the true positive responders. Five out of six patients with the most serious motion disorders in the study fell into the false negative group. There were no significant differences in the extent, distribution and severity of vascular involvement, or in the development of collateral circulation in the two groups. However, occluded vessels supplied abnormal ventricular segments more frequently in the false negative group (88% vs 38%); the absence of an "ischemic response" and the presence of segments of abnormal myocardium may be related. Left ventricular dysfunction appears to be an important reason for a false negative response to exercise.


Constitutive Modeling of Anisotropic Finite-Deformation Hyperelastic Behaviors of Soft Materials Reinforced by Tortuous Fibers.
Many biological materials are composites composed of a soft matrix reinforced with stiffer fibers. These stiffer fibers may have a tortuous shape and wind through the soft matrix. At small material deformation, these fibers deform in a bending mode and contribute little to the material stiffness; at large material deformation, these fibers deform in a stretching mode and induce a stiffening effect in the material behavior. The transition from bending mode deformation to stretching mode deformation yields a characteristic J-shape stress-strain curve. In addition, the spatial distribution of these fibers may render the composite an anisotropic behavior. In this paper, we present an anisotropic finite-deformation hyperelastic constitutive model for such materials. Here, the matrix is modeled as an isotropic neo-Hookean material. "The behaviors of single tortuous fiber are represented by a crimped fiber model". The anisotropic behavior is introduced by a structure tensor representing the effective orientation distribution of crimped fibers. Parametric studies show the effect of fiber tortuosity and fiber orientation distribution on the overall stress-strain behaviors of the materials.


New clinical diagnostic procedures for cystic fibrosis in Europe.
In the majority of cases, there is no difficulty in diagnosing Cystic Fibrosis (CF). However, there may be wide variation in signs and symptoms between individuals which encourage the scientific community to constantly improve the diagnostic tests available and develop better methods to come to a final diagnosis in patients with milder phenotypes. This paper is the result of discussions held at meetings of the European Cystic Fibrosis Society Diagnostic Network supported by EuroCareCF. CFTR bioassays in the nasal epithelium (nasal potential difference measurements) and the rectal mucosa (intestinal current measurements) are discussed in detail including efforts to standardize the techniques across Europe. New approaches to evaluate the sweat gland, future of genetic testing and methods on the horizon like CFTR expression in human leucocytes and erythrocytes are discussed briefly.


A Comparison of Alkaline Water and Mediterranean Diet vs Proton Pump Inhibition for Treatment of Laryngopharyngeal Reflux.
Laryngopharyngeal reflux (LPR) is a common disorder with protean manifestations in the head and neck. In this retrospective study, we report the efficacy of a wholly dietary approach using alkaline water, a plant-based, Mediterranean-style diet, and standard reflux precautions compared with that of the traditional treatment approach of proton pump inhibition (PPI) and standard reflux precautions. To determine whether treatment with a diet-based approach with standard reflux precautions alone can improve symptoms of LPR compared with treatment with PPI and standard reflux precautions. This was a retrospective medical chart review of 2 treatment cohorts. From 2010 to 2012, 85 patients with LPR that were treated with PPI and standard reflux precautions (PS) were identified. From 2013 to 2015, 99 patients treated with alkaline water (pH >8.0), 90% plant-based, Mediterranean-style diet, and standard reflux precautions (AMS) were identified. The outcome was based on change in Reflux Symptom Index (RSI). Recorded change in the RSI after 6 weeks of treatment. Of the 184 patients identified in the PS and AMS cohorts, the median age of participants in each cohort was 60 years (95% CI, 18-82) and 57 years (95% CI, 18-93), respectively (47 [56.3%] and 61 [61.7%] were women, respectively). The percentage of patients achieving a clinically meaningful (≥6 points) reduction in RSI was 54.1% in PS-treated patients and 62.6% in AMS-treated patients (difference between the groups, 8.05; 95% CI, -5.74 to 22.76). The mean reduction in RSI was 27.2% for the PS group and 39.8% in the AMS group (difference, 12.10; 95% CI, 1.53 to 22.68). Our data suggest that the effect of PPI on the RSI based on proportion reaching a 6-point reduction in RSI is not significantly better than that of alkaline water, a plant-based, Mediterranean-style diet, and standard reflux precautions, although the difference in the 2 treatments could be clinically meaningful in favor of the dietary approach. The percent reduction in RSI was significantly greater with the dietary approach. Because the relationship between percent change and response to treatment has not been studied, the clinical significance of this difference requires further study. Nevertheless, this study suggests that a plant-based diet and alkaline water should be considered in the treatment of LPR. This approach may effectively improve symptoms and could avoid the costs and adverse effects of pharmacological intervention as well as afford the additional health benefits associated with a healthy, plant-based diet.


Vitreal Concentrations of Vascular Endothelial Growth Factor in Patients with Rhegmatogenous Retinal Detachment.
The purpose of this study is to evaluate the concentration of vascular endothelial growth factor (VEGF) in the vitreous humor of patients with primary rhegmatogenous retinal detachment (RRD). This is a prospective case control study. Eighteen patients with primary RRD without proliferative vitreoretinopathy C (PVR C) were enrolled as cases, and twenty-two non-diabetic retinopathy patients who were candidates for complete pars plana vitrectomy due to Macular Hole or Epiretinal Membrane were included as the control group. Undiluted vitreal samples were collected during the initiation of Pars Plana Vitrectomy (PPV) prior to any infusion into the posterior cavity. Vitreous samples were also collected from 21 fresh cadaveric globes. The vitreous concentration of VEGF was measured by enzyme-linked immunosorbent assay (ELISA) technique and compared between these two groups. The vitreal concentration of VEGF was 0.643 ± 0.088 ng/mL in the RRD group. Measured concentrations of VEGF in controls were 0.043 ± 0.104 ng/mL, and in cadaveric eyes they were 0.033 ± 0.058 ng/mL. The mean VEGF concentration in the RRD group was statistically higher than in the control group (p < 0.0001) and cadaveric eyes (p < 0.0001). Our study shows that vitreal VEGF concentrations significantly increase in patients with RRD.


Husbands' reproductive health knowledge, attitudes, and behavior in Uttar Pradesh, India.
To enhance the reproductive health status of couples in developing countries, the knowledge, attitudes, and behavior of both women and men must be investigated, especially where women depend on men for the decision to seek care. This study analyzes data from a survey of 6,727 husbands from five districts in the northern state of Uttar Pradesh, India. Data are presented on men's knowledge of women's health and on their own sexual behavior outside the context of marriage, on their perceptions of sexual morbidity and their attempts at treatment for specific conditions, and on their opinions concerning the social role of wives. Findings indicate that men know little about maternal morbidity or sexual morbidity conditions. Few husbands reported that they had had sexual experience outside of marriage and the majority of these few said they had had such a relationship with more than one partner. Of men who said they had had reproductive morbidity symptoms, many said they had not sought treatment. Men's views concerning the role of wives indicate a low level of women's autonomy in this region of India. Results indicate a pressing need for reproductive health education that targets both women and men in Uttar Pradesh.


The effect of maternal intake of sucrose or high-fructose corn syrup (HFCS)-55 during gestation and lactation on lipogenic gene expression in rat offspring at 3 and 12 weeks of age.
Perinatal exposure to sucrose or high-fructose corn syrup-55 (HFCS-55) in rats has previously been associated with altered hepatic fat content and composition post-weaning, although the effects on hepatic metabolism are unknown. The current study aimed to determine the sex-specific effects of maternal consumption of sucrose or HFCS-55 on the expression of hepatic lipogenic genes in the offspring. Liver samples were collected from offspring of albino Wistar rats provided with ad libitum access to either water (control), 10% sucrose or 10% HFCS-55 solution during pregnancy and lactation at 3 weeks (control n=16, sucrose n=22, HFCS-55 n=16) and 12 weeks (control n=16, sucrose n=10, HFCS-55 n=16) of age. Hepatic expression of the transcription factors such as carbohydrate response element-binding protein, sterol regulatory element-binding protein-1c and downstream genes was determined by quantitative real-time PCR. Sucrose-exposed offspring had higher hepatic SREBP-1c messenger RNA expression compared with control and HFCS-55 groups at both 3 weeks (P=0.01) and 12 weeks (P=0.03) of age. There were no differences in the expression of other hepatic lipogenic genes between groups at either 3 or 12 weeks. Thus, perinatal exposure to sucrose may be more detrimental to offspring hepatic metabolism compared with HFCS-55, independent of sex, and it will be important to evaluate the longer-term effects of perinatal sucrose exposure in future studies.


Pancreatic Cancer in Pregnancy Presenting with Thromboembolic Events: Case Report and Review of the Literature.
Stroke and hepatic vein thrombosis are highly associated with neoplasia but are extremely rare events in young, pregnant women. Rare and recurrent thrombotic events in pregnancy increase the suspicion for occult malignancy. We describe the case of a healthy 31-year-old G2P1 who presented with visual changes and dysarthria during pregnancy. Imaging showed cerebral infarcts. Her thrombophilia evaluation was negative. During delivery, she was diagnosed with fulminant Budd-Chiari Syndrome. Hepatic ultrasound suggested malignancy or metastasis, and postpartum CT scan and biopsy confirmed the diagnosis of Stage IV pancreatic cancer. Although rare in pregnancy, a new diagnosis of malignancy should be considered in patients with recurrent unexplained hypercoagulable complications. We propose an evidence-based algorithm for evaluation of occult malignancy in pregnancy based upon this case and review of the literature.


Reduced bacterial skin infections in HIV-infected African children randomized to long-term cotrimoxazole prophylaxis.
To evaluate whether cotrimoxazole prophylaxis prevents common skin conditions in HIV-infected children. Open-label randomized controlled trial of continuing versus stopping daily cotrimoxazole (post-hoc analysis). Three sites in Uganda and one in Zimbabwe. A total of 758 children aged more than 3 years receiving antiretroviral therapy (ART) for more than 96 weeks in the ARROW trial were randomized to stop (n = 382) or continue (n = 376) cotrimoxazole after median (interquartile range) 2.1(1.8, 2.2) years on ART. Continuing versus stopping daily cotrimoxazole. Nurses screened for signs/symptoms at 6-week visits. This was a secondary analysis of ARROW trial data, with skin complaints categorized blind to randomization as bacterial, fungal, or viral infections; dermatitis; pruritic papular eruptions (PPEs); or others (blisters, desquamation, ulcers, and urticaria). Proportions ever reporting each skin complaint were compared across randomized groups using logistic regression. At randomization, median (interquartile range) age was 7 (4, 11) years and CD4 was 33% (26, 39); 73% had WHO stage 3/4 disease. Fewer children continuing cotrimoxazole reported bacterial skin infections over median 2 years follow-up (15 versus 33%, respectively; P < 0.001), with similar trends for PPE (P = 0.06) and other skin complaints (P = 0.11), but not for fungal (P = 0.45) or viral (P = 0.23) infections or dermatitis (P = 1.0). Bacterial skin infections were also reported at significantly fewer clinic visits (1.2 versus 3.0%, P < 0.001). Independent of cotrimoxazole, bacterial skin infections were more common in children aged 6-8 years, with current CD4 cell count less than 500 cells/μl, WHO stage 3/4, less time on ART, and lower socio-economic status. Long-term cotrimoxazole prophylaxis reduces common skin complaints, highlighting an additional benefit for long-term prophylaxis in sub-Saharan Africa.


Novel experimental design for high pressure-high temperature electrical resistance measurements in a "Paris-Edinburgh" large volume press.
We present a novel experimental design for high sensitivity measurements of the electrical resistance of samples at high pressures (0-6 GPa) and high temperatures (300-1000 K) in a "Paris-Edinburgh" type large volume press. Uniquely, the electrical measurements are carried out directly on a small sample, thus greatly increasing the sensitivity of the measurement. The sensitivity to even minor changes in electrical resistance can be used to clearly identify phase transitions in material samples. Electrical resistance measurements are relatively simple and rapid to execute and the efficacy of the present experimental design is demonstrated by measuring the electrical resistance of Pb, Sn, and Bi across a wide domain of temperature-pressure phase space and employing it to identify the loci of phase transitions. Based on these results, the phase diagrams of these elements are reconstructed to high accuracy and found to be in excellent agreement with previous studies. In particular, by mapping the locations of several well-studied reference points in the phase diagram of Sn and Bi, it is demonstrated that a standard calibration exists for the temperature and pressure, thus eliminating the need for direct or indirect temperature and pressure measurements. The present technique will allow simple and accurate mapping of phase diagrams under extreme conditions and may be of particular importance in advancing studies of liquid state anomalies.


Technical-economical evaluation of the operation of oxidation ditches.
The optimisation of the economic performance is a central aspect in the management of wastewater treatment plants. A model-based procedure was developed that could provide a clearly enunciated and concise way of reporting to the stakeholders on how well the assets are performing and can perform, separating the firm inefficiency from the effect of the treatment. The applied modelling method is conventional considering current modelling research practice, but very good from practical point of view in that it is applicable utilising existing plant data, i.e. without the use of additional measuring campaigns. This paper illustrates the validity of the developed procedures through the evaluation of the performance of oxidation ditches.


Optically stitched arbitrary fan-sectors with selective polarization states for dynamic manipulation of surface plasmon polaritons.
Novel hybrid-polarized vector beams with radial and azimuthal polarization states in arbitrary fan-sectors are generated and studied for manipulating surface plasmon polaritons (SPPs). The method has high energy conversion efficiency based on an interferometric arrangement with a Dammann vortex phase grating. The polarization states of generated beams are measured by a linear polarizer and show excellent agreement with theoretical predictions. The manipulation properties of the hybrid-polarized beams on SPPs excitation and distribution are demonstrated by both experiments and simulations. The results show that focusing or standing wave patterns of SPPs can be obtained depending on the polarization of the beams.


Consequences of alcohol consumption on host defence.
This communication reviews recent literature and summarizes current views on the immunomodulatory effects of acute and chronic alcohol consumption. Chronic and even acute, moderate alcohol use can increase host susceptibility to infections caused by bacterial and viral pathogens. Impaired host defence after alcohol exposure appears to be linked to a combination of decreased inflammatory response, altered cytokine production, and abnormal reactive oxygen intermediate generation. Furthermore, cellular immunity, particularly antigen-specific immune response, is impaired by both acute and chronic alcohol use. Although T lymphocyte functions can be directly affected by ethanol, decreased antigen presenting cell function appears to be a key element in the ethanol-induced decrease in cell-mediated immunity. In addition, a preferential induction of Th2 vs Th1 immune response has been suggested, based on the increased immunoglobulin levels seen in chronic alcoholics. The effects of chronic and acute alcohol consumption in humans, animal models and in vitro systems on host defence and immunity are discussed in the context of the functional abnormalities of T and B lymphocytes, natural killer cells and monocytes/macrophages resulting in the altered immune response seen after alcohol use.


New animal model of shigellosis in the Guinea pig: its usefulness for protective efficacy studies.
It has been difficult to evaluate the protective efficacy of vaccine candidates against shigellosis, a major form of bacillary dysentery caused by Shigella spp. infection, because of the lack of suitable animal models. To develop a proper animal model representing human bacillary dysentery, guinea pigs were challenged with virulent Shigella flexneri serotype 2a (strains 2457T or YSH6000) or S. flexneri 5a (strain M90T) by the intrarectal (i.r.) route. Interestingly, all guinea pigs administered these Shigella strains developed severe and acute rectocolitis. They lost approximately 20% of their body weight and developed tenesmus by 24 h after Shigella infection. Shigella invasion and colonization of the distal colon were seen at 24 h but disappeared by 48 h following i.r. infection. Histopathological approaches demonstrated significant damage and destruction of mucosal and submucosal layers, thickened intestinal wall, edema, erosion, infiltration of neutrophils, and depletion of goblet cells in the distal colon. Furthermore, robust expression of IL-8, IL-1beta, and inducible NO synthase mRNA was detected in the colon from 6 to 24 h following Shigella infection. Most importantly, in our new shigellosis model, guinea pigs vaccinated with an attenuated S. flexneri 2a SC602 strain possessing high levels of mucosal IgA Abs showed milder symptoms of bacillary dysentery than did animals receiving PBS alone after Shigella infection. In the guinea pig, administration of Shigella by i.r. route induces acute inflammation, making this animal model useful for assessing the protective efficacy of Shigella vaccine candidates.


Morphometry of hepatic neoplasms and altered foci in the mummichog, Fundulus heteroclitus.
The goal of this study was to intensively sample a small number of livers from a population of mummichog exposed to PAH-contaminated sediments and evaluate them for lesion pathology, distribution, shape, and volume, and the number of histological sections needed to adequately describe the extent of various lesions. Volumetric data for each lesion type from each step section was derived from digitized section images. The total number of hepatic alterations ranged from 10-125 per fish. Alterations included: eosinophilic, basophilic, and clear cell foci; hepatocellular carcinomas; hemangiopericytomas; and cholangiomas. Lesion volumes ranged from 0.00012-64 mm3 and represented 0.21%-67% of total liver volume. There was a tendency for the lesions to be more dorsal-ventrally compressed than spherical or ropelike when observed from longitudinal sections. Periodic subsampling of the data indicated that. on average, 6 evenly spaced, longitudinal histological sections were required to accurately estimate lesion volume and extent in our model population. These data provide a formulation for histological sampling techniques and methodological support for piscine and other cancer study models that observe lesion volume changes over time. Further, this study fosters the development of early quantitative endpoints. rather than using a large number of animals and waiting for tumor progression or death to occur.


An evaluation of video playback using Xiphophorus helleri.
Video playback is being increasingly used as a technique for behavioural research. The importance of critically evaluating the effectiveness of video playback is clear, as available video technology is not designed for nonhuman visual systems. We discuss several aspects concerning the perception of video images that could lead to inconclusive or erroneous results. Researchers should verify that behaviour observed in response to video playback is comparable to behaviour observed in response to live animals. We conducted such a verification using live and video playback methods to measure female response to swords of varying lengths in the green swordtail, Xiphophorus helleri. Using both methods, female response appeared to be an increasing function of male sword length. Females did not differ in their response to live and video versions of noncourting, noninteractive males, however, females tended to prefer video playbacks of males with longer swords, a result that has also been found in experiments using live males. These results suggest that females express the same qualitative mating preference, but not necessarily the same quantitative preference, for sword length when viewing video stimuli. Several methodological factors that may contribute to an apparent difference in the strength of the preference are discussed. Despite these differences, both methods produced comparable results; female response to sworded males tended to increase as sword length increased. These experiments demonstrate that video playback is an effective method to measure female preferences accurately in X. helleri and provide an example of how video playback can be evaluated in other species. Copyright 2000 The Association for the Study of Animal Behaviour.


Remodeling of carotid arteries detected with MR imaging: atherosclerosis risk in communities carotid MRI study.
To determine the extent of thickening of the carotid arterial walls that may be accommodated by outward remodeling. Institutional review board approval was obtained at each participating site, and informed consent was obtained from each participant. All study sites conducted this study in compliance with HIPAA requirements. A total of 2066 participants (age range, 60-85 years) from the Atherosclerosis Risk in Communities (ARIC) study were enrolled in the ARIC Carotid MRI Study. Maximum wall thickness and luminal area were measured with gadolinium-enhanced magnetic resonance (MR) imaging in both common carotid arteries (CCAs) and in one internal carotid artery (ICA) 2 mm above the flow divider. Complete data were available for 1064 ICAs and 3348 CCAs. The association of maximum wall thickness with lumen area was evaluated with linear regression, and adjustments were made for participant age, sex, race, height, and height squared. In the ICA, lumen area was relatively constant across patients with a wall thickness of 1.38 mm or less. In patients with a wall thickness of more than 1.38 mm, however, lumen area decreased linearly as wall thickness increased. Wall area represented a median of 61.9% of the area circumscribed by the vessel at a maximum wall thickness of 1.50 mm +/- 0.05 (standard deviation) and 75.4% at a maximum wall thickness of 4.0 mm +/- 0.10. In the CCA, lumen area was preserved across wall thicknesses less than 2.06 mm, representing 99% of vessels. Atherosclerotic thickening in the ICA appears to be accommodated for vessels with a maximum wall thickness of less than 1.5 mm. Beyond this threshold, greater thickness is associated with a smaller lumen. The CCA appears to accommodate a wall thickness of less than 2.0 mm. These estimates indicate that the carotid arteries are able to compensate for a greater degree of thickening than are the coronary arteries.


Oceans and Human Health (OHH): a European perspective from the Marine Board of the European Science Foundation (Marine Board-ESF).
The oceans and coastal seas provide mankind with many benefits including food for around a third of the global population, the air that we breathe and our climate system which enables habitation of much of the planet. However, the converse is that generation of natural events (such as hurricanes, severe storms and tsunamis) can have devastating impacts on coastal populations, while pollution of the seas by pathogens and toxic waste can cause illness and death in humans and animals. Harmful effects from biogenic toxins produced by algal blooms (HABs) and from the pathogens associated with microbial pollution are also a health hazard in seafood and from direct contact with water. The overall global burden of human disease caused by sewage pollution of coastal waters has been estimated at 4 million lost person-years annually. Finally, the impacts of all of these issues will be exacerbated by climate change. A holistic systems approach is needed. It must consider whole ecosystems, and their sustainability, such as integrated coastal zone management, is necessary to address the highly interconnected scientific challenges of increased human population pressure, pollution and over-exploitation of food (and other) resources as drivers of adverse ecological, social and economic impacts. There is also an urgent and critical requirement for effective and integrated public health solutions to be developed through the formulation of politically and environmentally meaningful policies. The research community required to address "Oceans & Human Health" in Europe is currently very fragmented, and recognition by policy makers of some of the problems, outlined in the list of challenges above, is limited. Nevertheless, relevant key policy issues for governments worldwide include the reduction of the burden of disease (including the early detection of emerging pathogens and other threats) and improving the quality of the global environment. Failure to effectively address these issues will impact adversely on efforts to alleviate poverty, sustain the availability of environmental goods and services and improve health and social and economic stability; and thus, will impinge on many policy decisions, both nationally and internationally. Knowledge exchange (KE) will be a key element of any ensuing research. KE will facilitate the integration of biological, medical, epidemiological, social and economic disciplines, as well as the emergence of synergies between seemingly unconnected areas of science and socio-economic issues, and will help to leverage knowledge transfer across the European Union (EU) and beyond. An integrated interdisciplinary systems approach is an effective way to bring together the appropriate groups of scientists, social scientists, economists, industry and other stakeholders with the policy formulators in order to address the complexities of interfacial problems in the area of environment and human health. The Marine Board of the European Science Foundation Working Group on "Oceans and Human Health" has been charged with developing a position paper on this topic with a view to identifying the scientific, social and economic challenges and making recommendations to the EU on policy-relevant research and development activities in this arena. This paper includes the background to health-related issues linked to the coastal environment and highlights the main arguments for an ecosystem-based whole systems approach.


Altered donor P2X7 activity in human leukocytes correlates with P2RX7 genotype but does not affect the development of graft-versus-host disease in humanised mice.
Graft-versus-host disease (GVHD) is a life-threatening consequence of allogeneic haematopoietic stem cell transplantation, a curative therapy for haematological malignancies. The ATP-gated P2X7 receptor channel is implicated in the development of GVHD. P2X7 activity on human leukocytes can be influenced by gain-of-function (GOF) and loss-of-function (LOF) single nucleotide polymorphisms (SNPs) in the P2RX7 gene. In this study, the P2RX7 gene was sequenced in 25 human donors and the P2X7 activity on subsets of peripheral blood T cells, natural killer (NK) cells and monocytes was measured using an ATP-induced dye uptake assay. GOF and LOF SNPs representing 10 of the 17 known P2RX7 haplotypes were identified, and correlated with P2X7 activity on all leukocyte subsets investigated. Notably, invariant (i) NK T cells displayed the highest P2X7 activity amongst all cell types studied. To determine if donor P2X7 activity influenced the development of GVHD, immunodeficient NOD-SCID-IL2Rγnull (NSG) mice were injected with human peripheral blood mononuclear cells isolated from donors of either GOF (hP2X7GOF mice) or LOF (hP2X7LOF mice) P2RX7 genotype. Both hP2X7GOF and hP2X7LOF mice demonstrated similar human leukocyte engraftment, and showed comparable weight loss, GVHD clinical score and overall survival. Donor P2X7 activity did not affect human leukocyte infiltration or GVHD-mediated tissue damage, or the relative expression of human P2X7 or human interferon-γ (hIFNγ) in tissues. Finally, hP2X7GOF and hP2X7LOF mice demonstrated similar concentrations of serum hIFNγ. This study demonstrates that P2X7 activity correlates with donor P2RX7 genotype on human leukocyte subsets important in GVHD development, but does not affect GVHD development in a humanised mouse model of this disease.


Unbiased tensor-based morphometry: improved robustness and sample size estimates for Alzheimer's disease clinical trials.
Various neuroimaging measures are being evaluated for tracking Alzheimer's disease (AD) progression in therapeutic trials, including measures of structural brain change based on repeated scanning of patients with magnetic resonance imaging (MRI). Methods to compute brain change must be robust to scan quality. Biases may arise if any scans are thrown out, as this can lead to the true changes being overestimated or underestimated. Here we analyzed the full MRI dataset from the first phase of Alzheimer's Disease Neuroimaging Initiative (ADNI-1) from the first phase of Alzheimer's Disease Neuroimaging Initiative (ADNI-1) and assessed several sources of bias that can arise when tracking brain changes with structural brain imaging methods, as part of a pipeline for tensor-based morphometry (TBM). In all healthy subjects who completed MRI scanning at screening, 6, 12, and 24months, brain atrophy was essentially linear with no detectable bias in longitudinal measures. In power analyses for clinical trials based on these change measures, only 39AD patients and 95 mild cognitive impairment (MCI) subjects were needed for a 24-month trial to detect a 25% reduction in the average rate of change using a two-sided test (α=0.05, power=80%). Further sample size reductions were achieved by stratifying the data into Apolipoprotein E (ApoE) ε4 carriers versus non-carriers. We show how selective data exclusion affects sample size estimates, motivating an objective comparison of different analysis techniques based on statistical power and robustness. TBM is an unbiased, robust, high-throughput imaging surrogate marker for large, multi-site neuroimaging studies and clinical trials of AD and MCI.


Healthcare reform: maternity service provision in Ireland.
The objective of this article is to explore recent and proposed future developments in maternity service provision in Ireland in the context of health policy reform. Ireland is experiencing an unprecedented demand for maternity services with in excess of 75,000 births in 2009, the highest since the 1970s when Ireland experienced a 'baby boom'. A further 10% rise is projected for 2010. This demographic change has placed increased demands on an already over-stretched maternity service. Despite more than a decade of economic success the health service has remained in constant crisis with many commentators arguing it has worsened rather than improved since the reform process was instigated in 2001 [1]. Reform of maternity services has begun and this article presents two case studies to demonstrate the regional variations in maternity provision in a country which has a national health service and a national Maternity and Infant Care Scheme. It shows what developments have occurred and what direction maternity services are likely to go in the next decade. The two regions under scrutiny are the North East Health Services Executive (NEHSE) and the Greater Dublin Area (GDA). The former illustrates important developments which have occurred in the NEHSE as a result of the Maternity Services Task Force (2002-2010) and argues that there are important learning outcomes not only for the GDA which is the subject of the latter case study but also for the development of maternity services nationally.


Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children.
Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10-07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.


Knowledge-based segmentation of SAR data with learned priors.
An approach for the segmentation of still and video synthetic aperture radar (SAR) images is described. A priori knowledge about the objects present in the image, e.g., target, shadow and background terrain, is introduced via Bayes' rule. Posterior probabilities obtained in this way are then anisotropically smoothed, and the image segmentation is obtained via MAP classifications of the smoothed data. When segmenting sequences of images, the smoothed posterior probabilities of past frames are used to learn the prior distributions in the succeeding frame. We show with examples from public data sets that this method provides an efficient and fast technique for addressing the segmentation of SAR data.


Enhancement of the pulmonary vasoconstriction reaction to alveolar hypoxia in systemic high blood pressure.
1. In systemic hypertension the pulmonary vessels show an excessive tone at rest and hyper-react to adrenoceptor stimulation. Alterations in Ca2+ handling by the vascular smooth muscle cells seem to underlie these disorders. Alveolar hypoxia also constricts pulmonary arteries, increasing the intracellular Ca2+ availability for smooth muscle contraction. This suggests the hypothesis that hypoxic pulmonary vasoconstriction depends on similar biochemical disorders, and that the response to the hypoxic stimulus may be emphasized in high blood pressure. 2. In 21 hypertensive and 10 normotensive men, pulmonary arterial pressure and arteriolar resistance have been evaluated during air respiration and after 15 min of breathing 17, 15 and 12% oxygen in nitrogen. Curves relating changes in pulmonary arterial pressure and arteriolar resistance to the oxygen content of inspired gas had a similar configuration in the two populations, but in hypertension were steeper and significantly shifted to the left of those in normotension, reflecting a lower threshold and an enhanced vasoconstrictor reactivity. 3. This pattern was not related to differences in severity of the hypoxic stimulus, degree of hypocapnia and respiratory alkalosis induced by hypoxia, and plasma catecholamines. 4. The association of high blood pressure with enhanced pulmonary vasoreactivity to alveolar hypoxia could have clinical implications in patients who are chronically hypoxic and have systemic hypertension.


Regulating, fostering and preserving: the production of sexual normates through cognitive ableism and cognitive othering.
People with cognitive disabilities are commonly positioned as risky sexual subjects. This article discusses the discursive production of sexual normates in the form of desirable and normative able-minded sexual subjects, in scientific research on the sexuality and cognitive disabilities of younger and older individuals (in particular those with dementia). We identify three interrelated discourses: regulating sexuality; fostering sexuality; and preserving sexuality. The first of these, regulation, pathologises sexuality of people with cognitive disabilities as faulty and in need of restriction. The second discourse, fostering, is more affirmative and argues for educating for a 'healthy' sexuality of people with cognitive disabilities, to mitigate risks of abuse. This discourse is more salient with younger people. The third discourse, preservation, in contrast, is more visible with older people with dementia and affirms sexuality so long as it is consistent with a 'genuine' or 'authentic' sexuality of the past. In conclusion, scientific research reinforces the cultural ideal of the rational and autonomous individual (and as such the mature/adult) capable of making independent decisions and engaging in healthy, good sex, based on stable sexual identities. Findings demonstrate how age intersects with cognitive ableism to intensify the cultural anxiety that exists around the sexualities of people with cognitive disabilities.


Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis.
Accumulation of M2 macrophages in the liver, within the context of a strong Th2 response, is a hallmark of infection with the parasitic helminth, Schistosoma mansoni, but the origin of these cells is unclear. To explore this, we examined the relatedness of macrophages to monocytes in this setting. Our data show that both monocyte-derived and resident macrophages are engaged in the response to infection. Infection caused CCR2-dependent increases in numbers of Ly6Chi monocytes in blood and liver and of CX3CR1+ macrophages in diseased liver. Ly6Chi monocytes recovered from liver had the potential to differentiate into macrophages when cultured with M-CSF. Using pulse chase BrdU labeling, we found that most hepatic macrophages in infected mice arose from monocytes. Consistent with this, deletion of monocytes led to the loss of a subpopulation of hepatic CD11chi macrophages that was present in infected but not naïve mice. This was accompanied by a reduction in the size of egg-associated granulomas and significantly exacerbated disease. In addition to the involvement of monocytes and monocyte-derived macrophages in hepatic inflammation due to infection, we observed increased incorporation of BrdU and expression of Ki67 and MHC II in resident macrophages, indicating that these cells are participating in the response. Expression of both M2 and M1 marker genes was increased in liver from infected vs. naive mice. The M2 fingerprint in the liver was not accounted for by a single cell type, but rather reflected expression of M2 genes by various cells including macrophages, neutrophils, eosinophils and monocytes. Our data point to monocyte recruitment as the dominant process for increasing macrophage cell numbers in the liver during schistosomiasis.


Pumpkin (Cucurbita maxima and C. pepo), a new host of Beet pseudo yellows virus in California.
In the summer of 2002, pumpkin plants (Cucurbita pepo L. and C. maxima Duchesne) with extensive leaf chlorosis similar to those observed in crinivirus infections were found in fields at two locations in Monterey County, California. Leaves of diseased plants were observed to have large populations of the greenhouse whitefly (Trialeurodes vaporariorum) present. Double-stranded RNA was extracted from symptomatic leaves of these plants and tested by northern hybridization for numerous criniviruses. A positive signal was identified exclusively with probes against the HSP70h gene of Beet pseudo yellows virus (BPYV) and confirmed by reverse transcription-polymerase chain reaction (RT-PCR) amplification of a 335-nucleotide section of the BPYV minor coat protein (CPm) gene (3). Similar symptoms were observed in additional fields in 2003, and BPYV was again confirmed. In addition, the CPm RT-PCR product was cloned into a TOPO pCR2 vector (Invitrogen, Carlsbad, CA) and sequenced. BLAST analysis of the cloned CPm RT-PCR product sequence corresponded to the published sequence of the CPm gene of BPYV (98%) (3) and Cucumber yellows virus (CuYV), a recently sequenced crinivirus considered to be a strain of BPYV (97%) (2). Incidence of BPYV in pumpkin appears to be variable and probably corresponds to the incidence of viruliferous whiteflies. On the basis of foliar symptoms, BPYV incidence varied from less than 50% in these fields in 2002 to nearly 100% infection of a large commercial field in 2003. BPYV is transmitted semipersistently by the greenhouse whitefly and has an extensive host range (1). The virus causes economic losses worldwide for greenhouse vegetable production and is becoming an increasing problem for field crops in areas of high greenhouse whitefly incidence (3). The impact of BPYV on pumpkin production remains to be determined; however, grower data suggests an increased incidence of fruit abortion and a substantial decrease in fruit weight. To our knowledge, this is the first report of BPYV infecting pumpkin. References: (1) J. E. Duffus. Phytopathology 55:450, 1965. (2) S. Hartono et al. J. Gen. Virol. 84:1007, 2003. (3) I. E. Tzanetakis et al. Plant Dis. 87:1398, 2003.


[Histological typing of lung tumors. Second edition, 1981 (author's transl)].
The WHO Histological Classification of Lung Tumours, published in 1967, has been revised. The main features are as follows: Squamous cell carcinoma (epidermoid carcinoma) has the same definition as in the original version, i.e., the identification of keratin and/or intercellular bridges by light microscopy. Three degrees of histological differentiation are described. Dysplasia and carcinoma in situ are discussed. Small cell carcinoma is divided into oat-cell carcinoma, and intermediate cell type and a category for oat-cell carcinomas combined with other major types. Adenocarcinoma includes the acinar, papillary and bronchiolo-alveolar forms and the solid carcinomas with mucus formation (previously part of the large cell carcinoma group). Mesothelial tumours are divided into fibrous, epithelial and biphasic subtypes. A number of less common tumours and tumour-like lesions are defined.


Systematic review and practice policy statements on urinary tract infection prevention in adults with spina bifida.
Urinary tract infection (UTI) is a source of morbidity and healthcare costs in adults with spina bifida (ASB). UTI prevention strategies are often recommended, but the evidence of various approaches remains unclear. We performed a systematic review to inform a best practice policy statement for UTI prevention in ASB. On behalf of the Neurogenic Bladder Research Group (NBRG.org), we developed an a priori protocol and searched the published English literature for 30 outcomes questions addressing UTI prevention in ASB. The questions spanned the categories of antibiotics, oral supplements, bladder management factors and social support. Where there was little literature in ASB, we included literature from similar populations with neurogenic bladder (NB). Data was abstracted and then reviewed with recommendations made by consensus of all authors. Level of Evidence (LoE) and Grade of Recommendation (GoR) were according to the Oxford grading system. Of 6,433 articles identified by our search, we included 99 publications. There was sufficient evidence to support use of the following: saline bladder irrigation (LoE 1, GoR B), gentamicin bladder instillation (LoE 3, GoR C), single-use intermittent catheterization (IC) (LoE 2, GoR B), hydrophilic catheters for IC (LoE 2, GoR C), intradetrusor onabotulinumtoxinA injection (LoE 3, GoR C), hyaluronic acid (HA) instillation (LoE 1, GoR B), and care coordination (LoE 3, GoR C). There was sufficient evidence to recommend against use of the following: sterile IC (LoE 1, GoR B), oral antibiotic prophylaxis (LoE 2, GoR B), treatment of asymptomatic bacteriuria (LoE 2, GoR B), cranberry (LoE 2, GoR B), methenamine salts (LoE 1, GoR B), and ascorbic acid (LoE1, GoR B). There was insufficient evidence to make a recommendation for other outcomes. Overall, there are few studies in UTI prevention in the specific population of ASB. Research in populations similar to ASB helps to guide recommendations for UTI prevention in the challenging patient group of ASB. Future studies in UTI prevention specific to ASB are needed and should focus on areas shown to be of benefit in similar populations.


An exploration of community partnerships, safety-net hospitals, and readmission rates.
To compare hospital-community partnerships among safety-net hospitals relative to non-safety-net hospitals, and explore whether hospital-community partnerships are associated with reductions in readmission rates. Data from four nationwide hospital-level datasets for 2015-2016, including American Hospital Association (AHA) annual survey, Hospital Inpatient Prospective Payment System (IPPS) data, CMS Hospital Compare, and County Health Rankings National (CHRN) data. We first examined how safety-net hospitals partner with nine different community providers, and how the overall and individual partnership patterns differ from those in non-safety-net hospitals. We then explored their association with 30-day readmission rates by diagnosis and hospital wide. We included 1979 hospitals across 50 US states. Safety-net hospitals were more engaged in hospital-community partnerships, especially with local public health, local governments, social services, nonprofits, and insurance companies, relative to their non-safety-net peers. However, we found that such partnerships were not significantly related to reductions in readmission rates. The findings indicated that merely partnering with various community organizations may not be associated with readmission rate reduction. Before promoting partnerships with various community organizations for its own sake, further prospective, longitudinal, and evidence-based guidance derived from the study of hospital-community partnerships is needed to make meaningful recommendations aimed at readmission rate reduction in safety-net hospitals.


Oceanic warming of western Europe.
In the northern North Atlantic off Europe, deep convection flushes buoyancy and heat out of the upper ocean each winter. It is replaced by horizontal advection during the remainder of the year. Absolute geostrophic currents can be computed from an application of the heat conservation equation. A remarkable spiral with depth emerges as a key feature in the process. The computed field of flow appears to be consistent with several buoyancy and heat flux requirements, with the independent physical information of locally vanishing curl of the wind-stress, and with its implications through the Sverdrup relation.


Health-related quality of life: a primer for gastroenterologists.
The evolution of health care has required physicians to evaluate more critically the impact of interventions on their patients' well-being. Prior clinical interventions focused primarily on biochemical and histological endpoints. These outcomes frequently were tenuously linked to patient benefit. Recently there has been a movement toward patient-oriented outcomes, including health-related quality of life (HRQL). The medical literature now frequently describes the effects of therapies on HRQL. Gastroenterologists need to understand the concepts behind HRQL and the use and utility of the various instruments employed to measure this outcome. The purpose of this article is: 1) to define the concept of health-related quality of life (HRQL); 2) to assess when measurement of HRQL can guide clinical decision-making; 3) to describe the desired properties of an HRQL instrument; and 4) to distinguish types of HRQL instruments. We discuss the varied definitions of HRQL and the clinical scenarios in which they are important. The psychometric properties of HRQL instruments, including validity, reliability, responsiveness, sensitivity, and coverage are defined and discussed. The types of instruments such as health profile, time trade-off, and standard gamble are contrasted. Finally, we compare generic and disease-specific instruments regarding their uses, strengths, and weaknesses. HRQL reflects patients' perceptions of disease and its impact on health status. It is becoming an increasingly important endpoint in therapeutic trials. By understanding its components and how it can meaningfully be measured, gastroenterologists may be better able to optimize the benefit patients receive from their medical interventions.


Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse.
Annexin 7 (ANX7) acts as a tumor suppressor gene in prostate cancer, where loss of heterozygosity and reduction of ANX7 protein expression is associated with aggressive metastatic tumors. To investigate the mechanism by which this gene controls tumor development, we have developed an Anx7(+/-) knockout mouse. As hypothesized, the Anx7(+/-) mouse has a cancer-prone phenotype. The emerging tumors express low levels of Anx7 protein. Nonetheless, the wild-type Anx7 allele is detectable in laser-capture microdissection-derived tumor tissue cells. Genome array analysis of hepatocellular carcinoma tissue indicates that the Anx7(+/-) genotype is accompanied by profound reductions of expression of several other tumor suppressor genes, DNA repair genes, and apoptosis-related genes. In situ analysis by tissue imprinting from chromosomes in the primary tumor and spectral karyotyping analysis of derived cell lines identify chromosomal instability and clonal chromosomal aberrations. Furthermore, whereas 23% of the mutant mice develop spontaneous neoplasms, all mice exhibit growth anomalies, including gender-specific gigantism and organomegaly. We conclude that haploinsufficiency of Anx7 expression appears to drive disease progression to cancer because of genomic instability through a discrete signaling pathway involving other tumor suppressor genes, DNA-repair genes, and apoptosis-related genes.


Two CD34+ stem cells from umbilical cord blood enrichment methods.
The authors describe the relation between clamping time and blood volume collected, and two enrichment systems of CD34+ stem cells from umbilical cord blood, to determine an excellent recovery with high proliferate ability and bone marrow reconstitution. After an obstetrician-based cord blood collection, the purification of stem cells was performed either with a combination of monoclonal antibodies (negative selections) using the Stem Sep method, or with a positive cells selection thanks to their surface CD34 antigens, using the Mini Macs system. An excellent recovery of hematopoietic progenitors, burst-forming unit erythroid, colony-forming unit granulocyte and macrophage, and colony-forming unit granulocyte, erythroid, monocyte, and macrophage, inversely related to the rising of clamping time, was performed with the Mini Macs system (54% of colonies, with a 90% purity), while with Stem Sep method, hematopoietic progenitor recovery was 35% (with an 80% purity). By applying early clamping of the umbilical cord blood a greater number of CD34+ cells was obtained and their clonogenic activity increased with enrichment. This is particularly useful, considering that the number of CD34+ stem cells contained in a unit of placental blood is enough for transplanting to a child, but not for an adult engraftment. Thus, using this method, a larger number of CD34+ stem cells can be obtained, which increases the possibility to reduce graft versus host disease also in adult patients, producing survival rates similar to the ones obtained with transplantation of bone marrow from unrelated donors.


The plant host Brassica napus induces in the pathogen Verticillium longisporum the expression of functional catalase peroxidase which is required for the late phase of disease.
The devastating soilborne fungal pathogen Verticillium longisporum is host specific to members of the family Brassicaceae, including oilseed rape (Brassica napus) as the economically most important crop. The fungus infects through the roots and causes stunting and early senescence of susceptible host plants and a marked decrease in crop yield. We show here that V. longisporum reacts to the presence of B. napus xylem sap with the production of six distinct upregulated and eight downregulated proteins visualized by two-dimensional gel electrophoresis. Identification of 10 proteins by mass spectrometry revealed that all upregulated proteins are involved in oxidative stress response. The V. longisporum catalase peroxidase (VlCPEA) was the most upregulated protein and is encoded by two isogenes, VlcpeA-1 and VlcpeA-2. Both genes are 98% identical, corroborating the diploid or "amphihaploid" status of the fungus. Knock downs of both VlcpeA genes reduced protein expression by 80% and resulted in sensitivity against reactive oxygen species. Whereas saprophytic growth and the initial phase of the plant infection were phenotypically unaffected, the mutants were not able to perform the late phases of disease. We propose that the catalase peroxidase plays a role in protecting the fungus from the oxidative stress generated by the host plant at an advanced phase of the disease.


Improved artefact removal from EEG using Canonical Correlation Analysis and spectral slope.
Contamination of scalp measurement by tonic muscle artefacts, even in resting positions, is an unavoidable issue in EEG recording. These artefacts add significant energy to the recorded signals, particularly at high frequencies. To enable reliable interpretation of subcortical brain activity, it is necessary to detect and discard this contamination. We introduce a new automatic muscle-removal approach based on the traditional Blind Source Separation-Canonical Correlation Analysis (BSS-CCA) method and the spectral slope of its components. We show that CCA-based muscle-removal methods can discriminate between signals with high correlation coefficients (brain, mains artefact) and signals with low correlation coefficients (white noise, muscle). We also show that typical BSS-CCA components are not purely from one source, but are mixtures from multiple sources, limiting the performance of BSS-CCA in artefact removal. We demonstrate, using our paralysis dataset, improved performance using BSS-CCA followed by spectral-slope rejection. This muscle removal approach can reduce high-frequency muscle contamination of EEG, especially at peripheral channels, while preserving steady-state brain responses in cognitive tasks. This approach is automatic and can be applied on any sample of data easily. The results show its performance is comparable with the ICA method in removing muscle contamination and has significantly lower computational complexity. We identify limitations of the traditional BSS-CCA approach to artefact removal in EEG, propose and test an extension based on spectral slope that makes it automatic and improves its performance, and results in performance comparable to competitors such as ICA-based artefact removal.


Loss of lipid synthesis as an evolutionary consequence of a parasitic lifestyle.
Evolutionary loss of traits can result from negative selection on a specific phenotype, or if the trait is selectively neutral, because the phenotype associated with the trait has become redundant. Even essential traits may be lost, however, if the resulting phenotypic deficiencies can be compensated for by the environment or a symbiotic partner. Here we demonstrate that loss of an essential me-tabolic trait in parasitic wasps has evolved through environmental compensation. We tested 24 species for the ability to synthesize lipids de novo and collected additional data from the literature. We found the majority of adult parasitoid species to be incapable of synthesizing lipids, and phylogenetic analyses showed that the evolution of lack of lipogenesis is concurrent with that of parasitism in insects. Exploitive host manipulation, in which the host is forced to synthesize lipids to the benefit of the parasitoid, presumably facilitates loss of lipogenesis through environmental compensation. Lipogenesis re-evolved in a small number of parasitoid species, particularly host generalists. The wide range of host species in which generalists are able to develop may impede effective host manipulation and could have resulted in regaining of lipogenic ability in generalist parasitoids. As trait loss through environmental compensation is unnoticed at the phenotypic level, it may be more common than currently anticipated, especially in species involved in intricate symbiotic relationships with other species.


Dietary patterns and clinical outcomes in hemodialysis patients in Japan: a cohort study.
Little is known about actual dietary patterns and their associations with clinical outcomes in hemodialysis patients. We identified dietary patterns in hemodialysis patients in Japan and examined associations between dietary patterns and clinical outcomes. We used data from 3,080 general-population participants in the Hisayama study (year 2007), and data from 1,355 hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study (JDOPPS: years 2005-2007). Food intake was measured using a brief self-administered diet-history questionnaire (BDHQ). To identify food groups with the Hisayama population data, we used principal components analysis with Promax rotation. We adjusted the resulting food groups for total daily energy intake, and then we used those adjusted food-group scores to identify dietary patterns in the JDOPPS patients by cluster analysis (Ward's method). We then used Cox regression to examine the association between dietary patterns and a composite of adverse clinical outcomes: hospitalization due to cardiovascular disease or death due to any cause. We identified three food groups: meat, fish, and vegetables. Using those groups we then identified three dietary patterns: well-balanced, unbalanced, and other. After adjusting for potential confounders, we found an association between an unbalanced diet and important clinical events (hazard ratio 1.90, 95% C.I. 1.19-3.04). Hemodialysis patients whose diet was unbalanced were more likely to have adverse clinical outcomes. Thus hemodialysis patients might benefit not only from portion control, but also from a diet that is well-balanced diet with regard to the food groups identified here as meat, fish, and vegetables.


Professional identities and interprofessional relations: evaluation of collaborative community schemes.
Despite the widespread support for integrated community care in the U.K., interdisciplinary working between health and social service staff remains complex and tentative. This paper represents the findings of an evaluative research study of two collaborative community nursing schemes at differing stages of project development within West Yorkshire, England. The studies set out to explore in depth the ways social and health care professionals construe their identity and relationships within the changing context of collaborative projects. The research adopted a constructivist phenomenological approach, conducting focus groups with social workers and district nurses; supplemented by in-depth individual interviews. Using template analysis enabled the researchers to explore themes and issues generated from the groups and individuals. A number of areas associated with professional identity and the development of roles in response to changing situations were identified as pertinent including; role ambiguity, role erosion and extension. In cases where joint working required a reconstructing of professional identity, individuals were constrained by their personal meanings, organizational arrangements and public perceptions. Implications for research and practice are discussed.


A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits.
Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and diabetes.


Sleep loss and change detection in simulated driving.
Driver sleepiness is a leading contributor to road crashes. Sleep-related crashes are more likely to involve collision with a stationary object than non-sleep-related crashes. The mechanism underpinning this is unknown; one potential explanation may be an increased propensity for change blindness. Twenty-four drivers with at least one year of independent driving experience completed two simulated drives: one following a normal night of sleep (7-8 h) and one following sleep restriction (5 h). The drive consisted of 5 laps of an 11.3 km circuit, taking approximately 45 min. Each lap comprised half urban and half rural driving environments. Twenty times during the drive the visual screen was blanked for 500 ms, and when it reappeared participants were asked whether there were any changes. Twelve times a change occurred, and eight times no change occurred. Additionally, four unexpected changes occurred; for example, the language of the road signs was changed from English to German. At the end of each drive, participants were asked if anything unusual occurred. Sleep loss resulted in significantly increased subjective sleepiness and subjective workload. Driving in an urban environment did not increase alertness; subjective sleepiness ratings did not significantly differ between urban and rural environments. Change detection accuracy for both cued and unexpected changes was not significantly affected by sleep loss. In line with previous research, accuracy was greater for changes with high safety relevance and those occurring in rural environments. Collectively the findings of the study suggest that increase change blindness is probably not a contributor to sleep-related road crashes; however, future on-road research and with greater levels of sleep loss is needed to confirm findings.


Longitudinal biobanks-based study on the joint effects of infections, nutrition and hormones on risk of prostate cancer.
Background To evaluate the individual and combined effects of enterolactone, vitamin D, free testosterone, Chlamydia trachomatis and HPV-18 on the risk of prostate cancer in a large population-based biochemical material that combined three Nordic serum sample banks. Material and methods A joint cohort of 209 000 healthy men was followed using cancer registry linkages. From this cohort altogether 699 incident cases of prostate cancer were identified. Four controls were selected by incidence density sampling and matching for country, age and date of the blood sampling. Complete data for all investigated exposures was available for 483 eligible cases and 1055 eligible controls. Multivariate regression analyses were performed to investigate the solitary and combined effects. Results The solitary effects were small. Significantly increased risk [rate ratio 1.6 (95% CI 1.0-2.5)] was found in those seronegative for C. trachomatis infection. The joint effect in risk levels of enterolactone and vitamin D was antagonistic [observed rate ratio (RR) 1.4 (1.0-2.1), expected RR 2.0 (1.0-4.1)] as well as that of HPV-18 and C. trachomatis [observed RR 1.9 (0.8-4.5), expected RR 9.9 (1.1-87.0)]. Conclusion A large follow-up study combining data from several previously investigated exposures to investigate joint effects found no evidence that exposure to two risk factors would increase the risk of prostate cancer from that expected on basis of exposure to one risk factor. If anything, the results were consistent with antagonistic interactions.


Metabolic associations of reduced proliferation and oxidative stress in advanced breast cancer.
Aberrant metabolism is a hallmark of cancer, but whole metabolomic flux measurements remain scarce. To bridge this gap, we developed a novel metabolic phenotypic analysis (MPA) method that infers metabolic phenotypes based on the integration of transcriptomics or proteomics data within a human genome-scale metabolic model. MPA was applied to conduct the first genome-scale study of breast cancer metabolism based on the gene expression of a large cohort of clinical samples. The modeling correctly predicted cell lines' growth rates, tumor lipid levels, and amino acid biomarkers, outperforming extant metabolic modeling methods. Experimental validation was obtained in vitro. The analysis revealed a subtype-independent "go or grow" dichotomy in breast cancer, where proliferation rates decrease as tumors evolve metastatic capability. MPA also identified a stoichiometric tradeoff that links the observed reduction in proliferation rates to the growing need to detoxify reactive oxygen species. Finally, a fundamental stoichiometric tradeoff between serine and glutamine metabolism was found, presenting a novel hallmark of estrogen receptor (ER)(+) versus ER(-) tumor metabolism. Together, our findings greatly extend insights into core metabolic aberrations and their impact in breast cancer.


A Prospective Study of Humoral and Cellular Immune Responses to Hepatitis B Vaccination in Habitual Marijuana Smokers.
Exposure to Δ9-tetrahydrocannabinol (THC) in vitro and in animal models can significantly impair the differentiation, activation and function of dendritic cells, T cells and B cells. However, studies directly assessing the impact of marijuana smoking on human immunity are lacking. A prospective study of immune responses to a standard hepatitis B vaccination was therefore carried out in a matched cohort of 9 marijuana smokers (MS) and 9 nonsmokers (NS). In addition to their regular marijuana use, MS smoked four marijuana cigarettes in a monitored setting on the day of each vaccination. Blood samples were collected over time to assess the development of hepatitis B-specific immunity. The majority of subjects from both the NS (8) and MS (6) groups developed positive hepatitis B surface antibody titers (>10 IU/L) and of these 6 NS and 5 MS were classified as high antibody (good) responders (>100 IU/L). The development of a good response correlated with the presence of hepatitis B-specific T cell proliferation and cytokine production, resulting in a clear distinction regarding the immune status of good responders versus non-responders. However, even though there were slighter more non-responders in the MS cohort, there were no significant differences between MS and NS with respect to peripheral blood cell phenotypes or vaccination-related changes in hepatitis B responses. While a larger cohort may be required to rule out a small suppressive effect, our findings do not suggest that habitual marijuana smoking exerts a major impact on the development of systemic immunity to hepatitis B vaccination.


Intracranial Stereotactic Radiation Therapy With a Jawless Ring Gantry Linear Accelerator Equipped With New Dual Layer Multileaf Collimator.
To test the feasibility of a simplified, robust, workflow for intracranial stereotactic radiation therapy (SRT) using a ring gantry linear accelerator (RGLA) equipped with a dual-layer stacked, staggered, and interdigitating multileaf collimator. Twenty recent clinical SRT cases treated using a radiosurgery c-arm linear accelerator were anonymized. From these data sets, a new planning workflow was developed and used to replan these cases, which then were compared to their clinical counterparts. Population-based dose-volume histograms were analyzed for target coverage and sparing of healthy brain. All plans underwent plan review and quality assurance and were delivered on an end-to-end verification phantom using image guidance to simulate treatment. The RGLA plans were able to meet departmental standards for target coverage and organ-at-risk sparing and showed plan quality similar to the clinical plans. RGLA plans showed increases in the 50% isodose in the axial plane but decreases in the sagittal and coronal planes. There were no statistically significant differences in the homogeneity index or number of monitor units between the 2 systems. There were statistically significant increases in conformity and gradient indices, with median values of 1.09 versus 1.11 and 2.82 versus 3.13, respectively, for the c-arm versus RGLA plans. These differences were not believed to be clinically significant because they met clinical goals. The population-based dose-volume histograms showed target coverage and organ-at-risk sparing similar to that of the clinical plans. All plans were able to meet the departmental quality assurance requirements and were delivered under image guidance on an end-to-end phantom with measurements agreeing within 3% of the expected value. RGLA plans showed a median reduction in delivery time of ≈50%. This work describes a simplified and efficient workflow that could reduce treatment times and expand access to SRT to centers using an RGLA.


Validation of the Revised Illness Perception Questionnaire (IPQ-R) in a sample of persons recovering from myocardial infarction--the Swedish version.
When people's health is threatened, they generally develop illness perceptions to make sense of their illness. The Illness Perception Questionnaire (IPQ-R), developed by Moss-Morris et al (2002), has been widely used in many countries to measure such representations. However, since studies in this crucial research area are lacking in Sweden a Swedish version of IPQ-R was validated with a focus on the seven subscales: timeline acute/chronic, timeline cyclical, consequences, personal control, treatment control, illness coherence and emotional representations. Using confirmatory factor analysis, the aim of the present study was to validate the internal structure of the Swedish version in a sample of 202 persons (144 men and 58 women) who had been diagnosed with myocardial infarction four months earlier. Additionally, inter-correlations among the seven subscales and external concurrent validity were also investigated. The results of confirmatory factor analysis revealed that, in line with the English version of the IPQ-R, the specified seven-factor model had a satisfactory fit. One item was however not considered reliable and was therefore excluded from the instrument. The internal consistency (Cronbach's alpha coefficients) and the inter-factor correlations were relatively similar to those reported in the validation study of the original English IPQ-R. In tests of concurrent validity, the seven IPQ-R subscales were, as hypothesized, mainly associated with external variables. To conclude, the Swedish version of the IPQ-R's seven dimensions, with one item removed, (total 37 items) was found to be a reliable and valid measure of illness perception.


Prevalence and correlates of tobacco use in bipolar disorder: data from the first 2000 participants in the Systematic Treatment Enhancement Program.
Only a few small descriptive studies have examined the prevalence and correlates of tobacco use among bipolar patients. We predicted that poorly controlled manic, depressed and mixed states, and the presence of psychotic symptoms, would be associated with a greater prevalence of smoking among patients with bipolar disorder. We examined the prevalence of smoking in a cross-sectional sample of 1904 patients with bipolar disorder enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) database. We also examined the relationship between smoking and other factors including: bipolar subtype, current clinical status, illness severity (e.g., number of prior mood episodes), age of bipolar onset, gender, education, socioeconomic status, and concurrent substance use. At STEP-BD program entry, 31.2% of patients reported that they were smokers. Patients who were male, less educated, and/or had lower income were more likely to be smokers (P<.01). Additionally, patients with rapid cycling, comorbid psychiatric disorders, and/or substance abuse, and those experiencing a current episode of illness were more likely to be smokers (P<.0001). More lifetime depressive and manic episodes as well as greater severity of depressive and manic symptoms were associated with smoking (P<.001). Use of atypical antipsychotic medications was more prevalent among smokers (P=.04). Clinical and demographic variables are associated with smoking in this sample of bipolar patients. Longitudinal analyses are needed to determine how mood and bipolar symptoms interact with smoking over the episodic course of bipolar disorder. Additional studies should focus on whether controlling bipolar symptoms is associated with cessation of smoking.


Dissociable effect of acute varenicline on tonic versus cue-provoked craving in non-treatment-motivated heavy smokers.
The effectiveness of varenicline for smoking cessation has been established, but little is known about the psychological processes that mediate this clinical outcome. This study evaluated the effect of a single dose of varenicline on tonic and cue-provoked changes in craving, withdrawal, and affect using a randomized, double-blind, placebo-controlled, cross-over design. Following overnight abstinence, 38 non-treatment-motivated smokers received either varenicline 2mg or matched placebo, then tonic measures of craving, withdrawal, and positive and negative affect were obtained at 30-min intervals. At 4-h post-administration, a cue exposure session obtained the same subjective measures at three time-points following the physical handling of a lit cigarette versus the sharpening and handling of a pencil. At 4-h post-administration, varenicline reduced tonic craving as well as craving across the smoking and neutral cue conditions, relative to placebo. By contrast, the capacity of the smoking cue to enhance craving relative to the neutral cue was unaffected by varenicline. Measures of withdrawal and positive and negative affect produced mixed results. Acute varenicline selectively attenuates tonic but not cue-provoked craving. This dissociation provides insight into the specific psychological processes that might mediate the effectiveness of varenicline, and highlights cue-provoked craving as a discrete target for advancing smoking cessation pharmacotherapy.


Mental health and behaviour of students of public health and their correlation with social support: a cross-sectional study.
Future public health professionals are especially important among students partly because their credibility in light of their professional messages and activities will be tested daily by their clients; and partly because health professionals' own lifestyle habits influence their attitudes and professional activities. A better understanding of public health students' health and its determinants is necessary for improving counselling services and tailoring them to demand. Our aim was to survey public health students' health status and behaviour with a focus on mental health. A cross-sectional study was carried out among public health students at 1-5-years (N = 194) with a self-administered questionnaire that included standardized items on demographic data, mental wellbeing characterized by sense of coherence (SoC) and psychological morbidity, as well as health behaviour and social support. Correlations between social support and the variables for mental health, health status and health behaviour were characterized by pairwise correlation. The response rate was 75% and represented students by study year, sex and age in the Faculty. Nearly half of the students were non-smokers, more than one quarter smoked daily. Almost one-fifth of the students suffered from notable psychological distress. The proportion of these students decreased from year 1 to 5. The mean score for SoC was 60.1 and showed an increasing trend during the academic years. 29% of the students lacked social support from their student peers. Significant positive correlation was revealed between social support and variables for mental health. Psychological distress was greater among female public health students than in the same age female group of the general population; whereas the lack of social support was a more prevalent problem among male students. Health status and behaviour of public health students is similar to their non-students peers except for their worse mental health. Future public health professionals should be better prepared for coping with the challenges they face during their studies. Universities must facilitate this process by providing helping services targeted at those with highest risk, and developing training to improve coping skills. Social support is also a potentially amenable determinant of mental health during higher education.


Effects of Blackcurrant Anthocyanin on Endothelial Function and Peripheral Temperature in Young Smokers.
Blackcurrant anthocyanin (BCA) is expected to repair endothelial dysfunction, but it remains unclear whether beneficial effects are present in young healthy persons. This study examines whether supplements containing blackcurrant anthocyanin improve endothelial function and peripheral temperature in young smokers. Young, healthy male nonsmokers (N group: n = 11; mean age 22 ± 2 years) and smokers (S group: n = 13; mean age 21 ± 1 years) were enrolled. A randomized and double-blind trial was designed to compare the effects of no supplement, a supplement containing 50 mg of blackcurrant anthocyanin (supplement A), and a supplement containing 50 mg of blackcurrant anthocyanin plus vitamin E (supplement B) on flow-mediated dilatation (FMD) and skin temperature. Under no supplement, FMD was unchanged during the 2 h period after smoking in the N group, whereas it was decreased during the 2 h period after smoking in the S group. Under the A supplement, FMD was decreased 1 h after smoking and returned to the baseline level 2 h after smoking in the S group. The skin temperature in the area of the foot dorsum was decreased in the S group after smoking compared with that in the N group, who did not smoke, whereas under A and B supplements, it was higher in the S group compared with that in the N group. BCA could attenuate the smoking-induced acute endothelial dysfunction and improve peripheral temperature in young smokers.


Associations between commute mode and cardiovascular disease, cancer, and all-cause mortality, and cancer incidence, using linked Census data over 25 years in England and Wales: a cohort study.
Active travel is increasingly recognised as an important source of physical activity. We aimed to describe associations between commute mode and cardiovascular disease, cancer, and all-cause mortality. We analysed data from the Office for National Statistics Longitudinal Study of England and Wales (ONS-LS), which linked data from the Census of England and Wales (henceforth referred to as the Census) for 1991, 2001, and 2011 to mortality and cancer registrations. The cohort included individuals traced in the ONS-LS who were economically active (ie, aged ≥16 years, not retired from work, and not a full-time carer). Commuting by private motorised transport, public transport, walking, and cycling were compared in terms of all-cause mortality, cancer mortality, cardiovascular disease mortality, and cancer incidence, using Cox proportional-hazards models with time-varying covariates. Models were adjusted for age, sex, housing tenure, marital status, ethnicity, university education, car access, population density, socioeconomic classification, Carstairs index quintile, long-term illness, and year entered the study, and were additionally stratified by socioeconomic group. Between the 1991 Census and the 2011 Census, 784 677 individuals contributed data for at least one Census, of whom 394 746 were included in the ONS-LS and were considered to be economically active working-age individuals. 13 983 people died, 3172 from cardiovascular disease and 6509 from cancer, and there were 20 980 incident cancer cases. In adjusted models, compared with commuting by private motorised vehicle, bicycle commuting was associated with a 20% reduced rate of all-cause mortality (hazard ratio [HR] 0·80, 95% CI 0·73-0·89), a 24% decreased rate of cardiovascular disease mortality (0·76, 0·61-0·93), a 16% lower rate of cancer mortality (0·84, 0·73-0·98), and an 11% reduced rate of incident cancer (0·89, 0·82-0·97). Compared with commuting by private motorised vehicle, rail commuters had a 10% lower rate of all-cause mortality (HR 0·90, 95% CI 0·83-0·97) and a 21% decreased rate of cardiovascular disease mortality (0·79, 0·67-0·94), in addition to a 12% reduced rate of incident cancer (0·88, 0·83-0·94). Walk commuting was associated with 7% lower cancer incidence (HR 0·93, 95% CI 0·89-0·97) Stratified analyses did not indicate differences in associations between socioeconomic groups. Our findings augment existing evidence for the beneficial health effects of physically active commute modes, particularly cycling and train use, and suggest that all socioeconomic groups could benefit. National Institute for Health Research.


Modeling analysis of the global and microscopic distribution of immunoglobulin G, F(ab')2, and Fab in tumors.
In order to understand the pharmacology of monoclonal antibodies and their conjugates, one must consider both global and microscopic aspects of antibody distribution. Here we present an analysis of antibody distribution in tumors based on the following factors: (a) molecular weight and valence of the antibody; (b) global pharmacokinetic profile following i.v. bolus injection; (c) penetration through the vascular wall; (d) diffusive and convective transport through interstitial space in the tumor; (e) antigen-antibody interaction; (f) antibody metabolism. Partial differential equations were developed to incorporate these factors and then solved numerically using parameter values from animal experiments, from clinical protocols at our institution, from studies of antibody binding characteristics in vitro, and from the literature. Salient findings from this model are that (a) antigen-antibody interaction in the tumor can retard antibody percolation away from blood capillaries, thus constituting a "binding site barrier"; (b) high antibody affinity tends to decrease antibody penetration and result in a more heterogeneous distribution; (c) high molecular weight [IgG greater than F(ab')2 greater than Fab] slows percolation and results in less uniform spatial distribution; (d) the average antibody concentration in the tumor does not increase linearly with antibody dose; (e) raising the rate of antibody metabolism results in low concentration and poor percolation; (f) perhaps most interesting, there is predicted to be a range of antibody dose and affinity within which the specificity ratio and average concentration could be kept high while limiting the heterogeneity of distribution. PERC, the computer program package developed for these analyses, provides a convenient and flexible way to assess the impact of global and microscopic parameters on the distribution of immunoglobulin in tumors. For calculations presented here, the input data were obtained from experimental sources, and qualitative features of the output proved consistent with the few interpretable observations available. However, detailed validation would require much more data than are currently at hand. The mathematical findings should therefore be considered as aids to concept development and as a set of null hypotheses with which to guide experimentation. Experiments and simulations will continue in tandem. It should be noted that the PERC package (and also the general principles delineated here) can be applied as well to biological ligands other than antibodies.