Drug discrimination assessment of agonist-antagonist opioids in humans: a three-choice saline-hydromorphone-butorphanol procedure.
To assess the discriminative stimulus properties of mixed agonist-antagonist opioids in humans, postaddict volunteers were trained in a three-choice drug discrimination procedure to discriminate among the effects of saline (4 ml i.m.), hydromorphone (3 mg i.m.) and butorphanol (6 mg i.m.). Subjects earned monetary reinforcement by correctly identifying the training drugs by letter code. Other subjective, behavioral and physiological measures were concurrently collected. After training, generalization curves for hydromorphone, butorphanol, pentazocine, nalbuphine and buprenorphine were determined. In generalization testing, both hydromorphone and butorphanol produced dose-related increases in hydromorphone-appropriate and butorphanol-appropriate responses, respectively, and other characteristic subjective effect measures. Nalbuphine produced dose-related increases in discrimination as butorphanol and in those subjective effect measures increased by butorphanol. Buprenorphine produced dose-related increases in discrimination as hydromorphone and in those subjective effect measures increased by hydromorphone. Pentazocine was not consistently discriminated as either butorphanol or hydromorphone. These results differ from those of previous discrimination studies using similar methods but different training drugs. Compared to a previous study in which pentazocine served as the kappa-like training drug, the use as a training drug of the more pharmacologically specific kappa-like drug butorphanol permitted greater differentiation among test drugs and yielded discrimination results more consistent with other pharmacological evidence (buprenorphine being mu-like and nalbuphine being kappa-like). There was a close relationship between results of the discrimination measures and the subjective effect measures.


Physical insight into light scattering by photoreceptor cell nuclei.
A recent study showed that the rod photoreceptor cell nuclei in the retina of nocturnal and diurnal mammals differ considerably in architecture: the location of euchromatin and heterochromatin in the nucleus is interchanged. This inversion has significant implications for the refractive index distribution and the light scattering properties of the nucleus. Here, we extend previous two-dimensional analysis to three dimensions (3D) by using both a numerical finite-difference time-domain and an analytic Mie theory approach. We find that the specific arrangement of the chromatin phases in the nuclear core-shell models employed have little impact on the far-field scattering cross section. However, scattering in the near field, which is the relevant regime inside the retina, shows a significant difference between the two architectures. The "inverted" photoreceptor cell nuclei of nocturnal mammals act as collection lenses, with the lensing effect being much more pronounced in 3D than in two dimensions. This lensing helps to deliver light efficiently to the light-sensing outer segments of the rod photoreceptor cells and thereby improve night vision.


A meta-analysis of the effect of chromium supplementation on anthropometric indices of subjects with overweight or obesity.
The role of chromium as a weight loss agent remains questionable, and although previous meta-analyses findings have reported small reductions in body weight in individuals with overweight/obesity following chromium supplementation, there have been significant limitations with these findings. The objective of this meta-analysis was to evaluate the current evidence for the efficacy of oral chromium supplementation in individuals with overweight/obesity from randomized controlled trials. Studies were identified by a search of electronic databases from inception to November 2018 and combined and stratified analyses were used. Twenty-one trials from 19 studies were identified which met all inclusion criteria which were suitable for statistical pooling, and data from 1316 participants were included. Pooled analysis showed significant reductions in anthropometric indices associated with body composition; for weight loss (weighted mean difference [WMD]: -0.75 kg, 95% confidence interval [CI], -1.04, -0.45, P < 0.001), body mass index (WMD: -0.40, 95% CI, -0.66, -0.13, P = 0.003 and body fat percentage (WMD: -0.68%, 95% CI, -1.32, -0.03, P = 0.04) in individuals with overweight/obesity. No changes were detected in controls. Subgroup analysis showed significant improvements in weight loss and body fat percentage, particularly for study durations ≤12 weeks and doses ≤400 μg/d. Chromium supplementation was associated with some improvements in body composition in subjects with obesity/overweight. The effect size was medium and the clinical relevance of chromium as a weight loss aid remains uncertain. Further investigation from larger and well-designed randomized controlled studies, especially in patients with diabetes, is warranted.


The Zur of Xanthomonas campestris functions as a repressor and an activator of putative zinc homeostasis genes via recognizing two distinct sequences within its target promoters.
It has been long considered that zinc homeostasis in bacteria is maintained by export systems and uptake systems, which are separately controlled by their own regulators and the uptake systems are negatively regulated by Zur which binds to an about 30-bp AT-rich sequence known as Zur-box present in its target promoters to block the entry of RNA polymerase. Here, we demonstrated in vivo and in vitro that in addition to act as a repressor of putative Zn(2+)-uptake systems, the Zur of the bacterial phytopathogen Xanthomonas campestris pathovar campestris (Xcc) acts as an activator of a Zn(2+) efflux pump. The Xcc Zur binds to a similar Zur-box with approximately 30-bp AT-rich sequence in the promoters of the genes encoding putative Zn(2+)-uptake systems but a 59-bp GC-rich sequence with a 20-bp inverted repeat overlapping the promoter's -35 to -10 sequence of the gene encoding a Zn(2+)-export system. Mutagenesis of the inverted repeat sequence resulted in abolishment of the in vitro binding and the in vivo and in vitro activation of the export gene's promoter by Zur. These results reveal that the Xcc Zur functions as a repressor and an activator of putative zinc homeostasis genes via recognizing two distinct sequences within its target promoters.


Sustained hemodynamic effects of the selective dopamine-1 agonist, fenoldopam, during 48-hour infusions in hypertensive patients: a dose-tolerability study.
Eight patients with stage I-II hypertension received a continuous IV infusion of the selective dopamine-1 agonist, fenoldopam, for up to 48 hours at rates from 0.4 to 1.9 micrograms/kg/min. Hemodynamics and clinical symptoms during infusion were compared to the same parameters in the 24-hour periods before and after infusion. Fenoldopam lowered blood pressure and increased heart rate. Greatest changes occurred during the first 12 hours of infusion and gradually returned toward preinfusion values throughout the remaining 36 hours in the six patients who completed 48 hours of infusion. Fenoldopam was discontinued within 2 hours of starting the infusion in two patients who received drug rates of 0.9 microgram/kg/min and 1.9 micrograms/kg/min because of precipitous bradycardia. Clinical symptoms noted at fenoldopam doses higher than 0.8 microgram/kg/min were headache, dizziness, diaphoresis, nausea and vomiting, and restlessness. In this pilot study, fenoldopam effectively reduced blood pressure in patients with stage I-II hypertension for up to 48 hours, but fixed-dose infusion rates above 0.8 microgram/kg/min were associated with a high frequency of clinically significant and often intolerable adverse effects.


Phagocytosis of the Lyme disease spirochete, Borrelia burgdorferi, by cells from the ticks, Ixodes scapularis and Dermacentor andersoni, infected with an endosymbiont, Rickettsia peacockii.
Tick cell lines were used to model the effects of endosymbiont infection on phagocytic immune responses. The lines tested for their ability to phagocytose the Lyme disease spirochete, Borrelia burgdorferi (Spirochaetales: Spirochaetaceae), were ISE6 and IDE12 from the black-legged tick, Ixodes scapularis Say (Acari: Ixodidae) and DAE15 from the Rocky Mountain wood tick, Dermacentor andersoni Stiles. Rickettsia peacockii (Rickettsiales: Rickettsiaceae), an endosymbiont of D. andersoni, was used as a representative tick endosymbiont. 70-80% of uninfected or R. peacocciz-infected IDE12 and DAE15 cells phagocytosed heat-killed borreliae and 80-90% of IDE12 and DAE15 cells phagocytosed viable spirochetes. ISE6 cells were permissive of spirochetes; less than 1% of these cells phagocytosed borreliae, and spirochetes remained adherent to the cells seven days after inoculation. Cytochalasin B blocked phagocytosis of killed and viable borreliae by IDE12 cells, and prevented phagocytosis of killed spirochetes by DAE15 cells, whereas viable spirochetes successfully invaded cytochalasin-treated DAE15. IDE12 and DAE15 cells degraded borreliae within phagolysosome-like compartments. Time-lapse microscopy showed that DAE15 cells phagocytosed borreliae more rapidly than IDE12 cells. IDE12 and DAE15 cells eliminated most adherent spirochetes within 7 days of inoculation. Thus, endosymbiont infection does not significantly interfere with the phagocytic activity of immunocompetent tick cells.


Are protective behavioral strategies associated with fewer negative consequences on high-intensity drinking days? Results from a measurement-burst design.
Heavy episodic drinking (HED) is prevalent among college students and associated with harms. However, many students engage in "high-intensity drinking" (HID) by drinking at thresholds beyond HED. HID relative to HED-only is associated with elevated risk for acute and severe negative consequences. When used, protective behavioral strategies (PBS) are shown to help drinkers limit their drinking and lower their odds of experiencing consequences. This study assessed whether PBS use was associated with reduced consequences on occasions college students engaged in HID relative to HED-only. Data were from a longitudinal measurement-burst design (14-day bursts across 4 semesters) from 256 college students who engaged in HID on at least 1 reported day, yielding 2,352 daily drinking reports. Participants reported the number of standard drinks consumed on each day and, on days with 1+ drinks, whether they used PBS and experienced a variety of negative drinking-related consequences. Three-level multilevel models revealed that on days when students used manner of drinking PBS there was a weaker association between HID and passing out from drinking. On days students used serious harm reduction PBS there was a weaker association of HID with having no one sober enough to drive and experiencing regretted sexual behaviors. Use of some PBS may help college students reduce harms on HID occasions relative to HED-only occasions. Interventions should promote use of planning strategies to minimize harm, especially on HID occasions. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Calcareous Bio-Concretions in the Northern Adriatic Sea: Habitat Types, Environmental Factors that Influence Habitat Distributions, and Predictive Modeling.
Habitat classifications provide guidelines for mapping and comparing marine resources across geographic regions. Calcareous bio-concretions and their associated biota have not been exhaustively categorized. Furthermore, for management and conservation purposes, species and habitat mapping is critical. Recently, several developments have occurred in the field of predictive habitat modeling, and multiple methods are available. In this study, we defined the habitats constituting northern Adriatic biogenic reefs and created a predictive habitat distribution model. We used an updated dataset of the epibenthic assemblages to define the habitats, which we verified using the fuzzy k-means (FKM) clustering method. Redundancy analysis was employed to model the relationships between the environmental descriptors and the FKM membership grades. Predictive modelling was carried out to map habitats across the basin. Habitat A (opportunistic macroalgae, encrusting Porifera, bioeroders) characterizes reefs closest to the coastline, which are affected by coastal currents and river inputs. Habitat B is distinguished by massive Porifera, erect Tunicata, and non-calcareous encrusting algae (Peyssonnelia spp.). Habitat C (non-articulated coralline, Polycitor adriaticus) is predicted in deeper areas. The onshore-offshore gradient explains the variability of the assemblages because of the influence of coastal freshwater, which is the main driver of nutrient dynamics. This model supports the interpretation of Habitat A and C as the extremes of a gradient that characterizes the epibenthic assemblages, while Habitat B demonstrates intermediate characteristics. Areas of transition are a natural feature of the marine environment and may include a mixture of habitats and species. The habitats proposed are easy to identify in the field, are related to different environmental features, and may be suitable for application in studies focused on other geographic areas. The habitat model outputs provide insight into the environmental drivers that control the distribution of the habitat and can be used to guide future research efforts and cost-effective management and conservation plans.


A model for assessing the gap between physician residency demand and present status.
The medical workforce shortage worldwide varies for different residencies. To determine future gaps in medical specialties in Israel by means of a model and to identify trends and considerations among medical students when they choose their residencies. The gap (Gi) assessment model was based upon current demand (Di) and existing (Ei) status for each residency, using the formula [Gi = (Di-Ei)/Ei]. Ei represented the proportion of specific residencies in 2006-2010 out of all Israeli residency graduates and Di was based on questionnaires filled out by medical students at Sackler and Hadassah medical schools in Tel Aviv and Jerusalem, respectively (N = 909). The largest relative shortages (Gi ranges from -1 to 1) were in Pathology (G = -1), Rehabilitation Medicine (-0.9), Radiology (-0.8), Family Medicine (-0.8) and Anesthesiology (-0.8). The highest relative demands were in Surgical subspecialties (2.9) and Obstetrics/Gynecology (OB/GYN) (1.6). More females than males chose residencies in OB/GYN (19.5% vs. 7.1%, P < 0.001) and Pediatrics (28.1% vs. 15.4%, P < 0.001). Surgery subspecialties (9% vs. 23.7%, P < 0.001) were male-predominant. The workload consideration was rated higher among females, while income was rated higher among males. Among students in clinical years, compared to pre-clinical, there was a decline in the selection of some professions, including Surgical subspecialties (9.7% vs. 19.5%, P < 0.001). The suggested model, based on a survey of demand and current or projected future needs, can be used to assess gaps and plan early interventions. Programs at the level of medical school may affect residency preferences. The decline in selection of surgical professions and the increasing workload as a consideration for residency choice should be given attention.


Diagnosis of Cushing's syndrome: re-evaluation of midnight plasma cortisol vs urinary free cortisol and low-dose dexamethasone suppression test in a large patient group.
We studied plasma cortisol levels at 00:00 h and 08:00 h in 103 patients with Cushing's syndrome and 144 patients in whom this diagnosis had been excluded. These patients were hospitalized in our department from 1975 to 1996. Additionally, we measured these parameters in 20 healthy volunteers and in 5 patients with nonendocrine disease. Corresponding data of urinary free cortisol and low-dose dexamethasone suppression testing were included in the evaluation. Values (mean+/-SD) from patients with Cushing's syndrome: 510+/-232 nmol/l (range 165-1488) for plasma cortisol 00:00 h, 574+/-242 nmol/l (range 236-1612) for plasma cortisol 08:00 h, 991+/-885 nmol/24 h (range 154-4866) for urinary free cortisol and 479+/-304 nmol/l (range 34 - 1,393) for plasma cortisol after 1.5 mg dexamethasone. Values from the patients excluded from Cushing's syndrome: 99+/-76 nmol/l (range 5-371) for plasma cortisol 00:00 h, 393+/-136 nmol/l (range 119-812) for plasma cortisol 08:00 h, 126+/-84 nmol/24 h (range 30-485) for urinary free cortisol, and 64+/-82 nmol/l (range 5-395) for plasma cortisol after 1.5 mg dexamethasone. Values of the healthy volunteers respectively patients with non-endocrine disease: 59+/-30 nmol/l (range 25-130) respectively 127+/-80 nmol/l (range 62-265) for plasma cortisol 00:00 h and 388+/-144 nmol/l (range 157-651) respectively 498+/-113 nmol/l (range 302-581) for plasma cortisol 08:00 h. None of the Cushing patients exhibited a 00:00 h plasma cortisol below 140 nmol/l and only one had a urinary free cortisol below 200 nmol/24 h, whereas 4 were complete dexamethasone suppressors. The diagnostic value of these parameters was examined based on various cutoffs. We recommend determination of midnight plasma cortisol as an efficient and simple additional procedure for the diagnosis of Cushing's syndrome. The sensitivity and specificity of this procedure is similar to urinary free cortisol and slightly above the low-dose dexamethasone suppression testing in our hospitalized patients.


Relative Biological Effectiveness and Non-Poissonian Distribution of Dicentric Chromosome Aberrations after Californium-252 Neutron Exposures of Human Peripheral Blood Lymphocytes.
Cells exposed to fast neutrons often exhibit a non-Poisson distribution of chromosome aberrations due to the high ionization density of the secondary reaction products. However, it is unknown whether lymphocytes exposed to californium-252 (252Cf) spectrum neutrons, of mean energy 2.1 MeV, demonstrate this same dispersion effect at low doses. Furthermore, there is no consensus regarding the relative biological effectiveness (RBE) of 252Cf neutrons. Dicentric and ring chromosome formation was assessed in human peripheral blood lymphocytes irradiated at doses of 12-135 mGy. The number of aberrations observed were tested for adherence to a Poisson distribution and the maximum low-dose relative biological effectiveness (RBEM) was also assessed. When 252Cf-irradiated lymphocytes were examined along with previously published cesium-137 (137Cs) data, RBEM values of 15.0 ± 2.2 and 25.7 ± 3.8 were found for the neutron-plus-photon and neutron-only dose components, respectively. Four of the five dose points were found to exhibit the expected, or close to the expected non-Poisson over-dispersion of aberrations. Thus, even at low doses of 252Cf fast neutrons, when enough lymphocyte nuclei are scored, chromosome aberration clustering can be observed.


Synergistic effect of hydrotrope and surfactant on solubility and dissolution of atorvastatin calcium: screening factorial design followed by ratio optimization.
The present study was aimed at investigating the effect of hydrotrope and surfactant on poor solubility of atorvastatin calcium. Excipients screening followed by factorial design was performed to study effect of excipients and manufacturing methods on solubility of drug. Three independent factors (carrier, surfactant and manufacturing method) were evaluated at two levels using solubility as a dependant variable. Solid-state characterisation was performed using Fourier transform infrared spectroscopy and differential scanning calorimetry. Optimised complex were incorporated into orally disintegrating micro tablets and in vitro dissolution test was performed. Nicotinamide, Plasdone and sodium dodecyl sulphate were emerged as promising excipients from excipient screening. General regression analysis revealed only the type of carrier has significantly enhanced (P<0.05) the solubility of drug while other factors were found to be nonsignificant. Ratio optimisation trial revealed that drug to nicotinamide ratio is more critical in enhancing the solubility of drug (40 fold increases in solubility compared to pure drug) in comparison to drug-surfactant ratio; however the presence of surfactant deemed essential. Significantly higher rate and extent of dissolution was observed from solid dispersion complex and tablets compared to dissolution of pure drug (P<0.05). Study revealed hydrotrope and surfactant have synergistic effect on solubility and dissolution of atorvastatin calcium and this can be explored further.


Algae-produced Pfs25 elicits antibodies that inhibit malaria transmission.
Subunit vaccines are significantly more expensive to produce than traditional vaccines because they are based primarily on recombinant proteins that must be purified from the expression system. Despite the increased cost, subunit vaccines are being developed because they are safe, effective, and can elicit antibodies that confer protection against diseases that are not currently vaccine-preventable. Algae are an attractive platform for producing subunit vaccines because they are relatively inexpensive to grow, genetically tractable, easily scaled to large volumes, have a short generation time, and are devoid of inflammatory, viral, or prion contaminants often present in other systems. We tested whether algal chloroplasts can produce malaria transmission blocking vaccine candidates, Plasmodium falciparum surface protein 25 (Pfs25) and 28 (Pfs28). Antibodies that recognize Pfs25 and Pfs28 disrupt the sexual development of parasites within the mosquito midgut, thus preventing transmission of malaria from one human host to the next. These proteins have been difficult to produce in traditional recombinant systems because they contain tandem repeats of structurally complex epidermal growth factor-like domains, which cannot be produced in bacterial systems, and because they are not glycosylated, so they must be modified for production in eukaryotic systems. Production in algal chloroplasts avoids these issues because chloroplasts can fold complex eukaryotic proteins and do not glycosylate proteins. Here we demonstrate that algae are the first recombinant system to successfully produce an unmodified and aglycosylated version of Pfs25 or Pfs28. These antigens are structurally similar to the native proteins and antibodies raised to these recombinant proteins recognize Pfs25 and Pfs28 from P. falciparum. Furthermore, antibodies to algae-produced Pfs25 bind the surface of in-vitro cultured P. falciparum sexual stage parasites and exhibit transmission blocking activity. Thus, algae are promising organisms for producing cysteine-disulfide-containing malaria transmission blocking vaccine candidate proteins.


GABA mediates presynaptic inhibition at glycinergic synapses in a rat auditory brainstem nucleus.
Many inhibitory nerve terminals in the mammalian anteroventral cochlear nucleus (AVCN) contain both glycine and GABA, but the reason for the co-localization of these two inhibitory neurotransmitters in the AVCN is unknown. We have investigated the roles of glycine and GABA at synapses on bushy cells in the rat AVCN, using receptor immunohistochemistry and electrophysiology. Our immunohistochemical results show prominent punctate labelling of postsynaptic clusters of glycine receptors and of the receptor clustering protein gephyrin over the surface of bushy cells. In contrast, weak diffuse membrane immunolabelling of GABAA receptors was observed. Whole-cell recordings from bushy cells in AVCN slices demonstrated that evoked inhibitory postsynaptic currents (IPSCs) were predominantly (81 %) glycinergic, based on the decrease in amplitude of the IPSCs in bicuculline (10 microM). This observation was supported by the effect of strychnine (1 microM), which was to decrease the evoked IPSC (to 10 % of control IPSC amplitude) and to produce a greater than 90 % block of spontaneous miniature IPSCs. These results suggest a minor role for postsynaptic GABAA receptors in bushy cells, despite a high proportion of GABA-containing terminals on these cells. Therefore, a role for metabotropic GABAB receptors was investigated. Activation of GABAB receptors with baclofen revealed a significant attenuation of evoked glycinergic IPSCs. The effect of baclofen was presynaptic, as indicated by a lack of change in the mean amplitude of spontaneous IPSCs. Significantly, the decrease in the amplitude of evoked glycinergic IPSCs observed following repetitive nerve stimulation was reduced in the presence of the GABAB antagonist, CGP 35348. This indicates that synaptically released GABA can activate presynaptic GABAB receptors to reduce transmitter release at glycinergic synapses. Our results suggest specific pre- versus postsynaptic physiological roles for GABA and glycine in the AVCN.


Effects of physical properties of feed on microbial ecology and survival of Salmonella enterica serovar Typhimurium in the pig gastrointestinal tract.
A two-by-two factorial experiment with pigs was conducted to study the effect of feed grinding (fine and coarse) and feed processing (pelleted and nonpelleted) on physicochemical properties, microbial populations, and survival of Salmonella enterica serovar Typhimurium DT12 in the gastrointestinal tracts of pigs. Results demonstrated a strong effect of diet on parameters measured in the stomachs of the pigs, whereas the effect was less in the other parts of the gastrointestinal tract. Pigs fed the coarse nonpelleted (C-NP) diet showed more solid gastric content with higher dry matter content than pigs fed the fine nonpelleted (F-NP), coarse pelleted (C-P), or fine pelleted (F-P) diet. Pigs fed the C-NP diet also showed significantly increased number of anaerobic bacteria (P < 0.05), increased concentrations of organic acids, and reduced pH in the stomach. In addition, pigs fed the C-NP diet showed increased in vitro death rate of S. enterica serovar Typhimurium DT12 in content from the stomach (P < 0.001). Pigs fed the C-NP diet had a significantly higher concentration of undissociated lactic acid in gastric content than pigs fed the other diets (P < 0.001). A strong correlation between the concentration of undissociated lactic acid and the death rate of S. enterica serovar Typhimurium DT12 was found. In the distal small intestine, cecum, and midcolon, significantly lower numbers of coliform bacteria were observed in pigs fed the coarse diets than in pigs fed the fine diets (P < 0.01). Pigs fed the C-NP diet showed the lowest number of coliform bacteria in these segments of the gastrointestinal tract. Pigs fed the coarse diets showed increased concentration of butyric acid in the cecum (P < 0.05) and colon (P < 0.10) compared with pigs fed the fine diets. It was concluded that feeding a coarsely ground meal feed to pigs changes the physicochemical and microbial properties of content in the stomach, which decreases the survival of Salmonella during passage through the stomach. In this way the stomach acts as a barrier preventing harmful bacteria from entering and proliferating in the lower part of the gastrointestinal tract.


Different mixtures of sodium hyaluronate and their ability to create submucosal fluid cushions for endoscopic mucosal resection.
Sodium hyaluronate (SH) is a promising submucosal injection solution during endoscopic mucosal resection, but its high cost is an obstacle to more widespread use. The aim of this study was to identify an appropriate low-cost SH solution by varying the molecular weight of SH and mixing various solutions with it. The viscoelasticity of various SH solutions was first measured. The concentrations of two 1 % SH preparations with different molecular weights (800 kDa and 1900 kDa) were adjusted to 0.5 %, 0.25 %, and 0.125 %, using 0.9 %/3.75 % normal saline (NS), 5 %/20 % dextrose water (DW), and a glycerin solution (Glyceol): 10 % glycerin with 0.9 % normal saline plus 5 % fructose. The ability of these SH solutions to create submucosal fluid cushions (SFCs) was then investigated in the stomachs of two live minipigs. The 0.25 % 1900 kDa SH/NS solution and the 0.125 % 1900 kDa SH/20 % DW solution created a similar viscoelasticity to that of the 0.5 % 800 kDa SH/NS solution. The ability of these solutions to create SFCs was also similar. In addition, the 0.125 % 1900 kDa SH/Glyceol solution created similar SFCs, with a synergistic effect of increased viscoelasticity and the hypertonic nature of glycerin. A mixture of higher molecular weight sodium hyaluronate with a sugar solution (particularly 20 % dextrose), with or without glycerin, should be regarded as a cost-effective option for creating SFCs instead of the conventional SH solution made with the same amount of a 1 % 800 kDa SH preparation and normal saline.


Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR).
The optimal management of blood pressure (BP) in acute stroke remains unclear. For ischemic stroke treated with intravenous thrombolysis, current guidelines suggest pharmacological intervention if systolic BP exceeds 180 mm Hg. We determined retrospectively the association of BP and antihypertensive therapy with clinical outcomes after stroke thrombolysis. The SITS thrombolysis register prospectively recorded 11 080 treatments from 2002 to 2006. BP values were recorded at baseline, 2 hours, and 24 hours after thrombolysis. Outcomes were symptomatic (National Institutes of Health Stroke Scale score deterioration >or=4) intracerebral hemorrhage Type 2, mortality, and independence at (modified Rankin Score 0 to 2) 3 months. Patients were categorized by history of hypertension and antihypertensive therapy within 7 days after thrombolysis: Group 1, hypertensive treated with antihypertensives (n=5612); Group 2, hypertensive withholding antihypertensives (n=1573); Group 3, without history of hypertension treated with antihypertensives (n=995); and Group 4, without history of hypertension not treated with antihypertensives (n=2632). For 268 (2.4%) patients, these data were missing. Average systolic BP 2 to 24 hours after thrombolysis was categorized by 10-mm Hg intervals with 100 to 140 used as a reference. In multivariable analysis, high systolic BP 2 to 24 hours after thrombolysis as a continuous variable was associated with worse outcome (P<0.001) and as a categorical variable had a linear association with symptomatic hemorrhage and a U-shaped association with mortality and independence with systolic BP 141 to 150 mm Hg associated with most favorable outcomes. OR (95% CI) from multivariable analysis showed no difference in symptomatic hemorrhage (1.09 [0.83 to 1.51]; P=0.58) and independence (1.03 [0.93 to 1.10]; P=0.80) but lower mortality (0.82 [0.73 to 0.92]; P=0.0007) for Group 1 compared with Group 4. Group 2 had a higher symptomatic hemorrhage (1.86 [1.34 to 2.68]; P=0.0004) and mortality (1.62 [1.41 to 1.85]; P<0.0001) and lower independence (0.89 [0.80 to 0.99]; P=0.04) compared with Group 4. Group 3 had similar results as Group 1. There is a strong association of high systolic BP after thrombolysis with poor outcome. Withholding antihypertensive therapy up to 7 days in patients with a history of hypertension was associated with worse outcome, whereas initiation of antihypertensive therapy in newly recognized moderate hypertension was associated with a favorable outcome.


Modeling the effect of school closures in a pandemic scenario: exploring two different contact matrices.
School closures may delay the epidemic peak of the next influenza pandemic, but whether school closure can delay the peak until pandemic vaccine is ready to be deployed is uncertain. To study the effect of school closures on the timing of epidemic peaks, we built a deterministic susceptible-infected-recovered model of influenza transmission. We stratified the U.S. population into 4 age groups (0-4, 5-19, 20-64, and ≥ 65 years), and used contact matrices to model the average number of potentially disease transmitting, nonphysical contacts. For every week of school closure at day 5 of introduction and a 30% clinical attack rate scenario, epidemic peak would be delayed by approximately 5 days. For a 15% clinical attack rate scenario, 1 week closure would delay the peak by 9 days. Closing schools for less than 84 days (12 weeks) would not, however, reduce the estimated total number of cases. Unless vaccine is available early, school closure alone may not be able to delay the peak until vaccine is ready to be deployed. Conversely, if vaccination begins quickly, school closure may be helpful in providing the time to vaccinate school-aged children before the pandemic peaks.


Adherence to surveillance guidelines after radical cystectomy: a population-based analysis.
Surveillance after radical cystectomy is recommended to detect tumor recurrence and treatment complications. We evaluated adherence to National Comprehensive Cancer Network (NCCN) guidelines using a large population-based database. The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients aged ≥66 years diagnosed with nonmetastatic bladder cancer who had undergone radical cystectomy between 2000 and 2007. Medicare claims information identified recommended surveillance tests for 2 years after cystectomy as outlined in the NCCN guidelines. Adherence was defined as receipt of urine cytology and imaging of the chest, abdomen, and pelvis in each year. We evaluated the effect of patient and provider characteristics on adherence, controlling for demographic and disease characteristics. Of 3,757 patients who had undergone radical cystectomy, 2,990 (80%) were alive after 2 years. Adherence to all recommended investigations was 17% for the first and the second years following surgery. Among patients surviving 2 years, only 9% had complete surveillance in both years. In either year, adherence was less likely in patients with advanced pathologic stage (III/IV) (adjusted odds ratio [AOR] = 0.74, 95% CI: 0.60-0.91) and unmarried patients (AOR = 0.82, 95% CI: 0.68-0.99). Adherence was more likely in patients treated by high-volume surgeons (AOR = 2.00, 95% CI: 1.70-2.36) and those who saw a medical oncologist (AOR = 1.52, 95% CI: 1.27-1.82). We also observed significant geographic variability in adherence. Patterns of surveillance after radical cystectomy deviate considerably from NCCN recommendations. Despite increased utilization of radiographic imaging investigations, the omission of urine cytology significantly contributed to the low rate of overall adherence to surveillance guidelines. Uniform adherence to surveillance guidelines was observed in patients treated by high-volume surgeons. This suggests an important opportunity for quality improvement in bladder cancer care.


Epidemiology of impaction colic in donkeys in the UK.
Colic (abdominal pain) is a clinical condition of serious concern affecting the welfare and survival of donkeys at the Donkey Sanctuary in the UK. One of the most commonly reported causes is due to impacted ingesta in the large intestine ("impaction colic"). However little is known about the incidence of, or risk factors for, this condition. Here we describe the epidemiology of colic in donkeys, specifically impaction colic. We focus on temporal aspects of the disease and we identify environmental and management related risk factors for impaction colic in UK donkeys. There were 807 colic episodes in the population of 4596 donkeys between January 1st 2000 and March 31st 2005. The majority (54.8%) of episodes were due to a suspected or confirmed diagnosis of impaction of the gastrointestinal tract. The mortality risk for all colics (51.1%) was higher than reported in other equids. The incidence rate of all colics (5.9 episodes per 100 donkeys per year) and of impaction colic (3.2 episodes) was similar to that in horses. A retrospective matched case-control study of all impaction colics from January 2003 (193) indicated that older donkeys, those fed extra rations and those that previously suffered colic were at increased risk of impaction. Lighter body weight, musculo-skeletal problems, farm and dental disease were also significantly associated with a diagnosis of impaction colic. To our knowledge this is the first study to estimate the incidence rate of colic in a large population of donkeys in the UK. In contrast to other equids, impaction was the most commonly reported cause of colic. We identified several risk factors for impaction colic. Increasing age, extra rations and previous colic are known risk factors for colic in other equids. Results support the hypothesis that dental disease is associated with impaction colic. Musculo-skeletal problems may be associated with colic for various reasons including change in amount of exercise or time at pasture. Other associated factors (weight and farm) are the subject of further research. Identification of risk factors for impaction colic may highlight high risk donkeys and may allow intervention strategies to be introduced to reduce the incidence of the disease.


Cyclic AMP-dependent phosphorylation of a neuronal acetylcholine receptor alpha-type subunit.
Chick ciliary ganglion neurons have nicotinic acetylcholine receptors (AChRs) that mediate synaptic transmission through the ganglion. A cAMP-dependent process has previously been shown to enhance the ACh response of the neurons 2- to 3-fold without requiring the synthesis of new receptors. We show here that the receptors can be phosphorylated in situ by a cAMP-dependent process. The phosphorylation occurs predominantly on components of 50 and 58 kDa. Both derive from putative ligand-binding alpha 3 subunits, with the smaller phosphorylated species probably representing a degradation product of the larger. The increase in receptor phosphorylation caused by incubating the neurons with a cAMP analog parallels the increase observed in the ACh response, with respect to both time course and relative extent. The phosphorylation of ciliary ganglion AChRs differs from that reported for electric organ AChRs, which occurs primarily on the non-ligand-binding gamma and delta subunits and increases the rate of agonist-induced receptor desensitization.


Comparison of gastrointestinal responses to CCK-8 and associated with vomiting.
The gastrointestinal motor and myoelectric responses associated with vomiting induced by apomorphine (APO) and activated by cholecystokinin octapeptide (CCK-8) were compared as well as the mechanisms of initiation of these responses. Twelve dogs were surgically implanted with strain-gauge force transducers or bipolar electrodes for chronic recording of contractile or electrical activity. The responses to CCK-8 were determined in the fasted state and compared with the gastrointestinal motor and myoelectric correlates of vomiting activated by APO. After recording control responses, the effects of the following agents on these responses were determined: atropine, domperidone, and proglumide. In addition, the effects of supradiaphragmatic vagotomy or splanchnicectomy were determined. We found that CCK-8 activated contractile and myoelectric responses in the absence of vomiting, which were similar in most respects to those found in association with vomiting. These responses included 1) the retrograde giant contraction (RGC) and 2) the post-RGC phasic contractions. These RGCs were similar with respect to their activation in an all-or-none fashion, magnitude, duration, and position in the small intestine. The myoelectric correlates of these motor responses were similar qualitatively and quantitatively. The responses activated by APO and CCK-8 differed with respect to their coordination at different levels of the gastrointestinal tract. Whether activated by CCK-8 or APO, atropine blocked the RGC but not the post-RGC contractions. Domperidone blocked all responses to APO but not to CCK-8, and splanchnicectomy did not affect responses to either agent. Vagotomy blocked all gastrointestinal responses to APO but not to CCK-8. These results indicated that CCK-8 activates the gastrointestinal motor and myoelectric correlates of vomiting by a peripheral mechanism that does not include dopamine receptors.


Towards a generalization of information theory for hierarchical partitions.
Complex systems often exhibit multiple levels of organization covering a wide range of physical scales, so the study of the hierarchical decomposition of their structure and function is frequently convenient. To better understand this phenomenon, we introduce a generalization of information theory that works with hierarchical partitions. We begin revisiting the recently introduced hierarchical mutual information (HMI), and show that it can be written as a level by level summation of classical conditional mutual information terms. Then, we prove that the HMI is bounded from above by the corresponding hierarchical joint entropy. In this way, in analogy to the classical case, we derive hierarchical generalizations of many other classical information-theoretic quantities. In particular, we prove that, as opposed to its classical counterpart, the hierarchical generalization of the variation of information is not a metric distance, but it admits a transformation into one. Moreover, focusing on potential applications of the existing developments of the theory, we show how to adjust by chance the HMI. We also corroborate and analyze all the presented theoretical results with exhaustive numerical computations, and include an illustrative application example of the introduced formalism. Finally, we mention some open problems that should be eventually addressed for the proposed generalization of information theory to reach maturity.


The Association of Parental Self-Efficacy and Parent-Youth Connectedness With Youth Smoking Intentions.
Little attention has been paid to understanding how parents of differing race/ethnicity perceive their effectiveness in exercising anti-smoking parenting practices and how these behaviors affect youth's smoking intentions. We explored the association of parent-youth connectedness and parental self-efficacy and youths' smoking intentions in a group of African American and Caucasian never-smokers. Based on Social Bonding Theory and Social Learning Theory, a questionnaire was administered to nonsmoking, 9-16-year-old youth and parent dyads, assessing youth smoking intentions and parental measures of connectedness and self-efficacy. Youth risk factors for intending to smoke were increased parent-youth conflict and protective factors were increased parental monitoring, increased parental rule setting, and higher parental self-efficacy. Parent-youth connectedness and parental self-efficacy did not differ by parental smoking status or by race/ethnicity. Our findings underscore the importance of strong parenting practices and parental self-efficacy in protecting against youth intention to smoke and these may be important to target in future interventions.


Structural profiling of lipopolysaccharide glycoforms expressed by non-typeable Haemophilus influenzae: phenotypic similarities between NTHi strain 162 and the genome strain Rd.
Non-typeable Haemophilus influenzae (NTHi) is a significant cause of otitis media in children. We have employed single and multiple step electrospray ionization mass spectrometry (ESIMS) and NMR spectroscopy to profile and elucidate lipopolysaccharide (LPS) structural types expressed by NTHi strain 162, a strain obtained from an epidemiological study in Finland. ESIMS on O-deacylated LPS (LPS-OH) and core oligosaccharide (OS) samples of LPS provided information on the composition and relative abundance of glycoforms differing in the number of hexoses linked to the conserved inner-core element, L-alpha-D-Hepp-(1-->2)-[PEtn-->6]-L-alpha-D-Hepp-(1-->3)-L-alpha-D-Hepp-(1-->5)-[PPEtn-->4]-alpha-Kdop-(2-->6)-Lipid A of H. influenzae LPS. The strain examined was found to elaborate Hex2 to Hex5 LPS glycoform populations having structures identical to those observed for H. influenzae strain Rd [Risberg, A.; Masoud, H.; Martin, A.; Richards, J.C.; Moxon, E.R.; Schweda, E.K.H. Eur. J. Biochem. 1999, 261, 171-180], the strain for which the complete genome has been sequenced. In addition, sialyllactose-containing glycoforms previously identified in strain Rd as well as several NTHi strains, were identified as minor components. Multiple step tandem ESIMS (MS(n)) on dephosphorylated and permethylated OS provided information on the arrangement of glycoses within the major population of glycoforms and on the existence of additional isomeric glycoforms. Minor Hex1 and Hex6 glycoforms were detected and characterized where the Hex6 glycoform was comprised of a dihexosamine-containing pentasaccharide chain attached at the proximal heptose residue of the inner-core unit. LPS structural motifs present in the NTHi strain 162 are expressed by a genetically diverse set of disease causing isolates, providing the basis for a vaccine strategy against NTHi otitis media.


Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review.
Over the past several decades, complementary and alternative medications have increasingly become a part of everyday treatment. With the rising cost of prescription medications and their production of unwanted side effects, patients are exploring herbal and other natural remedies for the management and treatment of psychological conditions. Psychological disorders are one of the most frequent conditions seen by clinicians, and often require a long-term regimen of prescription medications. Approximately 6.8 million Americans suffer from generalized anxiety disorder. Many also suffer from the spectrum of behavioural and physical side effects that often accompany its treatment. It is not surprising that there is universal interest in finding effective natural anxiolytic (anti-anxiety) treatments with a lower risk of adverse effects or withdrawal. An electronic and manual search was performed through MEDLINE/PubMed and EBSCO. Articles were not discriminated by date of publication. Available clinical studies published in English that used human participants and examined the anxiolytic potential of dietary and herbal supplements were included. Data were extracted and compiled into tables that included the study design, sample population, intervention, control, length of treatment, outcomes, direction of evidence, and reported adverse events. A total of 24 studies that investigated five different CAM monotherapies and eight different combination treatments and involved 2619 participants met the inclusion criteria and were analyzed. There were 21 randomized controlled trials and three open-label, uncontrolled observational studies. Most studies involved patients who had been diagnosed with either an anxiety disorder or depression (n = 1786). However, eight studies used healthy volunteers (n = 877) who had normal levels of anxiety, were undergoing surgery, tested at the upper limit of the normal range of a trait anxiety scale, had adverse premenstrual symptoms or were peri-menopausal, reported anxiety and insomnia, or had one month or more of elevated generalized anxiety. Heterogeneity and the small number of studies for each supplement or combination therapy prevented a formal meta-analysis. Of the randomized controlled trials reviewed, 71% (15 out of 21) showed a positive direction of evidence. Any reported side effects were mild to moderate. Based on the available evidence, it appears that nutritional and herbal supplementation is an effective method for treating anxiety and anxiety-related conditions without the risk of serious side effects. There is the possibility that any positive effects seen could be due to a placebo effect, which may have a significant psychological impact on participants with mental disorders. However, based on this systematic review, strong evidence exists for the use of herbal supplements containing extracts of passionflower or kava and combinations of L-lysine and L-arginine as treatments for anxiety symptoms and disorders. Magnesium-containing supplements and other herbal combinations may hold promise, but more research is needed before these products can be recommended to patients. St. John's wort monotherapy has insufficient evidence for use as an effective anxiolytic treatment.


Risk factors for progression of cervical intraepithelial neoplasm grade III to invasive cervical cancer.
Data from four case-control studies on invasive cervical cancer and on cervical intraepithelial neoplasia grade III (CIN III) that were concurrently conducted in Spain and Colombia were used to look for factors that might favor the progression from CIN III to the invasive stage. These studies were compared in two ways; a case-case comparison and an estimation of the ratio of odds ratios with the use of of special logistic regression model that took into account the different design of each study and possible confounding factors. Variables studied were human papillomavirus status, viral load, viral types, sexual behavior, sexually transmitted diseases, reproductive patterns, oral contraceptives, and smoking. Both CIN III and invasive cervical cancer have a very similar profile of risk factors and none of them was different in a consistent way to suggest a role in the progression from CIN III to invasive cervical cancer. Some methodological problems such as cohort-specific differences and some selection biases could be adjusted for with a careful statistical analysis. Other problems derived from the cross-sectional nature of the design are unavoidable and should be considered in the interpretation of the results.


Spatial distribution of U.S. household carbon footprints reveals suburbanization undermines greenhouse gas benefits of urban population density.
Which municipalities and locations within the United States contribute the most to household greenhouse gas emissions, and what is the effect of population density and suburbanization on emissions? Using national household surveys, we developed econometric models of demand for energy, transportation, food, goods, and services that were used to derive average household carbon footprints (HCF) for U.S. zip codes, cities, counties, and metropolitan areas. We find consistently lower HCF in urban core cities (∼ 40 tCO2e) and higher carbon footprints in outlying suburbs (∼ 50 tCO2e), with a range from ∼ 25 to >80 tCO2e in the 50 largest metropolitan areas. Population density exhibits a weak but positive correlation with HCF until a density threshold is met, after which range, mean, and standard deviation of HCF decline. While population density contributes to relatively low HCF in the central cities of large metropolitan areas, the more extensive suburbanization in these regions contributes to an overall net increase in HCF compared to smaller metropolitan areas. Suburbs alone account for ∼ 50% of total U.S. HCF. Differences in the size, composition, and location of household carbon footprints suggest the need for tailoring of greenhouse gas mitigation efforts to different populations.


Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets.
Alzheimer's disease (AD), the most common form of dementia, is recognized as a heterogeneous disease with diverse pathophysiologic mechanisms. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. We identify three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways, such as susceptibility to tau-mediated neurodegeneration, amyloid-β neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Multiscale network analysis reveals subtype-specific drivers such as GABRB2, LRP10, MSN, PLP1, and ATP6V1A We further demonstrate that variations between existing AD mouse models recapitulate a certain degree of subtype heterogeneity, which may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalized human trials across all AD subtypes. Therefore, subtyping patients with AD is a critical step toward precision medicine for this devastating disease.


Analysis of a pitfall in congenital adrenal hyperplasia newborn screening: evidence of maternal use of corticoids detected on dried blood spot.
Neonatal screening for congenital adrenal hyperplasia (CAH) faces many specific challenges. It must be done using a performant analytical approach that combines sensitivity and specificity to capture the potential causes of mortality during the first week of life, such as salt wasting and glucocorticoid deficiency. Here, we confirm that maternal inhaled corticosteroid intake during pregnancy is a possible cause of missed CAH diagnosis. Thanks to liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, we were able to quantify endogenous steroid metabolites and also detect the presence of exogenous steroids in the dried blood spot of a newborn. Adding LC-MS/MS analysis as second-tier test, especially one that includes both 17-hydroxyprogesterone and 21-deoxycortisol measurements, would probably improve CAH diagnosis. In familial neonatal screening one could also look for maternal corticosteroid therapies that are hidden to prevent false-negative tests.


Men with a susceptibility to prostate cancer and the role of genetic based screening.
Prostate cancer is the second most common malignancy affecting men worldwide, and the commonest affecting men of African descent. Significant diagnostic and therapeutic advances have been made in the past decade. Improvements in the accuracy of prostate cancer diagnosis include the uptake of multi-parametric MRI and a shift towards targeted biopsy. We also now have more life-prolonging systemic and hormonal therapies for men with advanced disease at our disposal than ever before. However, the development of robust screening tools and targeted screening programs has not followed at the same pace. Evidence to support population-based screening remains unclear, with the use of PSA as a screening test limiting our ability to discriminate between clinically significant and insignificant disease. Prostate cancer has a large heritable component. Given that most men without risk factors have a low lifetime risk of developing lethal prostate cancer, much work is being done to further our knowledge of how we can best screen men in higher risk categories, such as those with a family history (FH) of the disease or those of African ancestry. These men have been reported to carry upwards of a two-fold increased risk of developing the disease at an earlier age, with evidence suggesting poorer survival outcomes. In men with a FH of prostate cancer, this is felt to be due to rare, high-penetrance mutations and the presence of multiple, common low penetrance alleles, with men carrying specific germline mutations in the BRCA and other DNA repair genes at particularly high risk. To date, large scale genome-wide association studies (GWAS) have led to the discovery of approximately 170 single nucleotide polymorphisms (SNPs) associated with prostate cancer risk, allowing over 30% of prostate cancer risk to be explained. Genomic tests, utilising somatic (prostate biopsy) tissue can also predict the risk of unfavourable pathology, biochemical recurrence and the likelihood of metastatic disease using gene expression. Targeted screening studies are currently under way in men with DNA repair mutations, men with a FH and those of Afro-Caribbean ethnicity which will greater inform our understanding of disease incidence and behaviour in these men, treatment outcomes and developing the most appropriate screening regime for such men. Incorporating a patient's genetic mutation status into risk algorithms allows us an opportunity to develop targeted screening programs for men in whom early cancer detection and treatment will positively influence survival, and in the process offer male family members of affected men the chance to be counselled and screened accordingly.


Target weight gain for moderately wasted children during supplementation interventions--a population-based approach.
In malnourished populations, the weight-for-height Z-score (WHZ) distribution is shifted to the left. The aim of nutrition interventions should be to restore a normal WHZ distribution for the whole population. The present paper examines the WHZ change needed by each individual to achieve this objective. We developed a mathematical model of required individual change in WHZ as a function of characteristics of the initial population to restore a normal distribution. This model was then tested by simulating WHZ change needed to restore a normal WHZ distribution in a test population. A rural area of Democratic Republic of the Congo with a high prevalence of undernutrition. Children under 5 years of age. To restore a normal distribution for the whole population, the WHZ of all children should be shifted. The desired WHZ change of each individual should be higher when the individual's initial WHZ is low, when the mean WHZ of the whole population is low and, for the most wasted individual, when the variance of WHZ and WHZ change in the population are high. Using the suggested model in a simulation on the test population resulted in a WHZ distribution close to the growth standard. To restore a normal WHZ distribution in wasted populations, nutritional programmes should cover the whole population with a higher weight gain in areas where mean WHZ is low.


Bragatston study protocol: a multicentre cohort study on automated quantification of cardiovascular calcifications on radiotherapy planning CT scans for cardiovascular risk prediction in patients with breast cancer.
Cardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Some breast cancer treatments including anthracyclines, trastuzumab and radiotherapy can increase the risk of CVD, especially for patients with pre-existing CVD risk factors. Early identification of patients at increased CVD risk may allow switching to less cardiotoxic treatments, active surveillance or treatment of CVD risk factors. One of the strongest independent CVD risk factors is the presence and extent of coronary artery calcifications (CAC). In clinical practice, CAC are generally quantified on ECG-triggered cardiac CT scans. Patients with breast cancer treated with radiotherapy routinely undergo radiotherapy planning CT scans of the chest, and those scans could provide the opportunity to routinely assess CAC before a potentially cardiotoxic treatment. The Bragatston study aims to investigate the association between calcifications in the coronary arteries, aorta and heart valves (hereinafter called 'cardiovascular calcifications') measured automatically on planning CT scans of patients with breast cancer and CVD risk. In a first step, we will optimise and validate a deep learning algorithm for automated quantification of cardiovascular calcifications on planning CT scans of patients with breast cancer. Then, in a multicentre cohort study (University Medical Center Utrecht, Utrecht, Erasmus MC Cancer Institute, Rotterdam and Radboudumc, Nijmegen, The Netherlands), the association between cardiovascular calcifications measured on planning CT scans of patients with breast cancer (n≈16 000) and incident (non-)fatal CVD events will be evaluated. To assess the added predictive value of these calcifications over traditional CVD risk factors and treatment characteristics, a case-cohort analysis will be performed among all cohort members diagnosed with a CVD event during follow-up (n≈200) and a random sample of the baseline cohort (n≈600). The Institutional Review Boards of the participating hospitals decided that the Medical Research Involving Human Subjects Act does not apply. Findings will be published in peer-reviewed journals and presented at conferences. NCT03206333.


Acquired sociopathy and frontotemporal dementia.
It is not understood why some patients with frontotemporal dementia (FTD) manifest sociopathic behavior. To examine the prevalence and characteristics of sociopathic behavior in FTD patients as compared to those with Alzheimer's disease (AD). We surveyed a group of FTD patients and a group of AD patients for sociopathic behavior, evaluated the characteristics surrounding their acts, and compared the groups on neuropsychological tests and functional neuroimaging. Twenty-eight outpatients with FTD (15 men, 13 women; 61.9+/-7.1 years; Mini-Mental State Examination score 23.6+/-8.1) were compared with 28 patients with clinically probable AD (13 men, 15 women; 66.1+/-9.2 years; Mini-Mental State Examination score 21.3 +/- 5.3). Main outcome measures included: (a) the prevalence of sociopathic acts; (b) a structured interview; (c) neuropsychological tests including the Frontal Assessment Battery, and (d) clinically obtained positron emission tomography or single photon emission tomography scans. Sixteen (57%) of the FTD patients had sociopathic behavior compared to two (7%) of the AD patients (chi(2)=13.84, p<0.001). Sociopathic acts among FTD patients included unsolicited sexual acts, traffic violations, physical assaults, and other unacceptable behaviors. On interview, the FTD patients with sociopathic acts were aware of their behavior and knew that it was wrong but could not prevent themselves from acting impulsively. They claimed subsequent remorse, but they did not act on it or show concern for the consequences. Among FTD patients with sociopathy, neuropsychological assessment showed impaired motor inhibition, and functional neuroimaging showed right frontotemporal involvement. The results suggest that sociopathy in FTD results from a combination of diminished emotional concern for the consequences of their acts and disinhibition consequent to right frontotemporal dysfunction. In many jurisdictions, FTD patients with sociopathy would not pass legal criteria for 'not guilty by reason of insanity'.


Immunogenicity, reactogenicity, and immune memory after primary vaccination with a novel Haemophilus influenzae-Neisseria meningitidis serogroup C conjugate vaccine.
We evaluated two formulations of a new combined Haemophilus influenzae type b (Hib)-meningococcal serogroup C (MenC)-tetanus toxoid (TT) conjugated vaccine and two formulations of a new MenC-TT vaccine (trials 711202/001 and 711202/008; clinical trial register numbers NCT00135486 and NCT00135564 [www.ClinicalTrials.gov]). A total of 520 healthy infants were randomized to receive primary vaccination (at 2, 3, and 4 months) with either MenC-TT plus diphtheria-tetanus-acellular pertussis (DTPa)-hepatitis B virus (HBV)-inactivated poliovirus (IPV)/Hib, Hib-MenC-TT plus DTPa-HBV-IPV, or MenC-CRM(197) plus DTPa-HBV-IPV/Hib (control). At 12 to 15 months, subjects received a polysaccharide challenge with meningococcal polysaccharide C plus a DTPa-HBV-IPV/Hib booster. Immune responses were assessed 1 month after dose 2, 1 month after dose 3, and prior to and 1 month after the booster. After primary vaccination, there was no difference between groups in seroprotection rates as measured by titers of serum bactericidal antibody (SBA) to MenC (> or = 1:8) or concentrations of anti-polyribosyl ribitol phosphate (PRP) antibody (> or = 0.15 microg/ml). Prior to the booster, there was no difference between groups in SBA seroprotection rates, whereas anti-PRP seroprotection rates were significantly higher after priming with Hib-MenC-TT. Booster doses induced large increases in SBA and anti-PRP antibodies in primed groups, indicating successful priming with induction of immune memory. Reactogenicity and safety were similar in all groups during the primary and booster phases. A novel combined Hib-MenC-TT conjugate vaccine induced MenC and Hib responses comparable to those induced by licensed monovalent vaccines. A Hib-MenC-TT conjugate vaccine provides vaccination against two major pathogens in a single injection and is a suitable candidate for use in primary or booster vaccination schedules.


Modeling the emergence of migratory corridors and foraging hot spots of the green sea turtle.
Environmental factors shape the spatial distribution and dynamics of populations. Understanding how these factors interact with movement behavior is critical for efficient conservation, in particular for migratory species. Adult female green sea turtles, Chelonia mydas, migrate between foraging and nesting sites that are generally separated by thousands of kilometers. As an emblematic endangered species, green turtles have been intensively studied, with a focus on nesting, migration, and foraging. Nevertheless, few attempts integrated these behaviors and their trade-offs by considering the spatial configurations of foraging and nesting grounds as well as environmental heterogeneity like oceanic currents and food distribution. We developed an individual-based model to investigate the impact of local environmental conditions on emerging migratory corridors and reproductive output and to thereby identify conservation priority sites. The model integrates movement, nesting, and foraging behavior. Despite being largely conceptual, the model captured realistic movement patterns which confirm field studies. The spatial distribution of migratory corridors and foraging hot spots was mostly constrained by features of the regional landscape, such as nesting site locations, distribution of feeding patches, and oceanic currents. These constraints also explained the mixing patterns in regional forager communities. By implementing alternative decision strategies of the turtles, we found that foraging site fidelity and nesting investment, two characteristics of green turtles' biology, are favorable strategies under unpredictable environmental conditions affecting their habitats. Based on our results, we propose specific guidelines for the regional conservation of green turtles as well as future research suggestions advancing spatial ecology of sea turtles. Being implemented in an easy to learn open-source software, our model can coevolve with the collection and analysis of new data on energy budget and movement into a generic tool for sea turtle research and conservation. Our modeling approach could also be useful for supporting the conservation of other migratory marine animals.


Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1.
Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition of mTORC1 activation. Among mTORC1 regulatory binding partners, the role of Proline Rich AKT Substrate of 40 kDa (PRAS40) in controlling mTORC1 activity and cellular growth in response to pathological and physiological stress in the heart has never been addressed. This report shows PRAS40 is regulated by AKT in cardiomyocytes and that AKT-driven phosphorylation relieves the inhibitory function of PRAS40. PRAS40 overexpression in vitro blocks mTORC1 in cardiomyocytes and decreases pathological growth. Cardiomyocyte-specific overexpression in vivo blunts pathological remodeling after pressure overload and preserves cardiac function. Inhibition of mTORC1 by PRAS40 preferentially promotes protective mTORC2 signaling in chronic diseased myocardium. In contrast, strong PRAS40 phosphorylation by AKT allows for physiological hypertrophy both in vitro and in vivo, whereas cardiomyocyte-specific overexpression of a PRAS40 mutant lacking capacity for AKT-phosphorylation inhibits physiological growth in vivo, demonstrating that AKT-mediated PRAS40 phosphorylation is necessary for induction of physiological hypertrophy. Therefore, PRAS40 phosphorylation acts as a molecular switch allowing mTORC1 activation during physiological growth, opening up unique possibilities for therapeutic regulation of the mTORC1 complex to mitigate pathologic myocardial hypertrophy by PRAS40.


The rapid disintegration of projections: the West Antarctic Ice Sheet and the intergovernmental panel on climate change.
How and why did the scientific consensus about sea level rise due to the disintegration of the West Antarctic Ice Sheet (WAIS), expressed in the third Intergovernmental Panel on Climate Change (IPCC) assessment, disintegrate on the road to the fourth? Using ethnographic interviews and analysis of IPCC documents, we trace the abrupt disintegration of the WAIS consensus. First, we provide a brief historical overview of scientific assessments of the WAIS. Second, we provide a detailed case study of the decision not to provide a WAIS prediction in the Fourth Assessment Report. Third, we discuss the implications of this outcome for the general issue of scientists and policymakers working in assessment organizations to make projections. IPCC authors were less certain about potential WAIS futures than in previous assessment reports in part because of new information, but also because of the outcome of cultural processes within the IPCC, including how people were selected for and worked together within their writing groups. It became too difficult for IPCC assessors to project the range of possible futures for WAIS due to shifts in scientific knowledge as well as in the institutions that facilitated the interpretations of this knowledge.


Localizing age-related changes in brain structure between childhood and adolescence using statistical parametric mapping.
Volumetric studies have consistently shown reductions in cerebral gray matter volume between childhood and adolescence, with the most dramatic changes occurring in the more dorsal cortices of the frontal and parietal lobes. The purpose of this study was to examine the spatial location of these changes employing methods typical of functional imaging studies. T1-weighted structural MRI data (1.2 mm) were analyzed for nine normally developing children and nine normal adolescents. Validity and reliability of the tissue segmentation protocol were assessed as part of several preprocessing analyses prior to statistical parametric mapping (SPM). Using SPM96, a simple contrast of average gray matter differences between the two age groups revealed 57 significant clusters (SPM[Z] height threshold, P<0.001, extent threshold 50, uncorrected). The pattern and distribution of differences were consistent with earlier findings from the volumetric assessment of the same subjects. Specifically, more differences were observed in dorsal frontal and parietal regions with relatively few differences observed in cortices of the temporal and occipital lobes. Permutation tests were conducted to assess the overall significance of the gray matter differences and validity of the parametric maps. Twenty SPMs were created with subjects randomly assigned to groups. None of the random SPMs approached the number of significant clusters observed in the age difference SPM (mean number of significant clusters = 5.8). The age effects observed appear to result from regions that consistently segment as gray matter in the younger group and consistently segment as white matter in the older group. The utility of these methods for localizing relatively subtle structural changes that occur between childhood and adolescence has not previously been examined.


Genetic studies of human apolipoproteins. XVIII. Apolipoprotein polymorphisms in Australian Aborigines.
A tribal aboriginal community, the Mowanjum, from the Kimberley region in Western Australia has been screened to determine the extent of genetic variation in the products of genes coding for apolipoproteins, which are intimately involved in lipid metabolism. Of the seven systems tested, APOE and APOH revealed common structural variations, but their distribution patterns are significantly different from those found in European populations. Australian Aborigines were found to be unique because they have no APOE*2 and APOH*3 alleles and have strikingly high frequencies of the APOE*4 (26%) and APOH*1 (13%) alleles. The contrast in variation observed at these apolipoprotein loci between Australian Aborigines and Europeans not only makes these loci useful genetic markers in biologic anthropology studies but also provides a unique opportunity to investigate the role of genetic-environment interaction in determining interpopulation differences in cardiovascular disease risk factors.


Why we should, in fact, pay for egg donation.
In this perspective, I shall argue that women who donate eggs solely for human embryonic stem cell research ought to be compensated. My argument rests on three inter-related principles. First, it is important to recruit the healthiest possible egg donors to minimize the risks of donation. This would relieve pressure to donate on those suffering from diseases that might be treatable with stem cell-based therapies, who are likely to be at greater risk from donation. Second, I believe that it is crucial to be pro-active in building representative stem cell banks, especially in stem cell initiatives paid for, in part, by the public/government. The right of all groups to participate in and benefit from equitable and safe research must be developed for egg donors as for other kinds of research participants. Particular attention should be paid to the opinions and desires of women from historically underserved populations as to how to conduct donations and guide research so as to serve all members of society. Third, reasonable payment would undermine tendencies for domestic and international black and grey egg markets for stem cell research to develop. I then suggest replacing the question of compensation with the question of harm mitigation as the central donor protection issue.


EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury.
Neointima formation after vascular injury is strongly associated with inflammation. Rapamycin inhibits human neointima formation and reduces expression of the proinflammatory cytokine endothelial-monocyte activating peptide II (EMAP-II) in vitro. Here we investigated the interplay between EMAP-II and rapamycin after vascular injury in vivo. In a mouse model of vascular injury, mice were either not treated, given everolimus, a rapamycin derivate, or subjected to simultaneous challenge with everolimus and EMAP-II. EMAP-II expression was measured in coronary artery smooth muscle cells (CASMC) and monocytic cells in vitro and in patients after percutaneous coronary intervention (PCI). After vascular injury, rapamycin reduced neointima formation and adventitial thickening. Immunohistochemistry revealed reduced EMAP-II protein expression and suppressed recruitment of inflammatory cells. Simultaneous challenge with EMAP-II counteracted these effects of rapamycin. Expression of EMAP-II and its inhibition by rapamycin was confirmed in CASMC and monocytic cells. In patients, EMAP-II upregulation was confined to PCI of distal coronary artery segments and profoundly suppressed by oral rapamycin treatment. These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.


Fetectomy alters maternal pituitary-adrenal function in pregnant rhesus macaques.
The interplay between the fetus and mother may play a key role in the regulation of primate pregnancy and parturition. This study was designed to test the hypothesis that fetectomy alters maternal pituitary-adrenal function. Between 117 and 122 days of gestation (term = 167 days), six rhesus macaques underwent surgery for catheter implantation. At surgery the fetuses were removed while the membranes and placenta were left in situ. Six additional intact catheterized pregnant animals served as controls. Animals were maintained under a 12L:12D cycle with lights-on from 0700 to 1900 h. Beginning at least 1 wk after surgery, maternal arterial blood samples were collected at 3-h intervals for 24 h for hormone and catecholamine analysis. This sampling protocol was repeated at weekly intervals until cesarean delivery at 151-157 days of gestation. Following fetectomy, plasma ACTH, dehydroepiandrosterone sulfate (DHEAS), and cortisol levels were significantly lower (36%, 35%, and 44%, respectively) compared with control animals (P;lt 0.05). Despite a significant reduction in overall levels, the rhythm in maternal plasma cortisol was maintained following fetectomy. Plasma dopamine and norepinephrine were also depressed (P;lt 0.05), whereas epinephrine remained unaffected. Our data clearly demonstrate the role of the fetus in the regulation of the maternal pituitary-adrenal axis during gestation. This interaction plays a significant role in the regulation of maternal endocrine function that may influence the initiation of labor.


High current density electrodeposition of silver from silver-containing liquid metal salts with pyridine-N-oxide ligands.
New cationic silver-containing ionic liquids were synthesized and used as non-aqueous electrolytes for the electrodeposition of silver layers. In the liquid state of these ionic liquids, a silver (i) cation is coordinated by pyridine-N-oxide (py-O) ligands in a 1 : 3 metal-to-ligand ratio, although in some cases a different stoichiometry of the silver center crystallized out. As anions, bis(trifluoromethanesulfonyl)imide (Tf2N), trifluoromethanesulfonate (OTf), methanesulfonate (OMs) and nitrate were used, yielding compounds with the formulae [Ag(py-O)3][Tf2N], [Ag(py-O)3][OTf], [Ag(py-O)3][OMs] and [Ag(py-O)3][NO3], respectively. The compounds were characterized by CHN analysis, FTIR, NMR, DSC, TGA and the electrodeposition of silver was investigated by cyclic voltammetry, linear potential scans, scanning electron microscopy (SEM) and energy-dispersive X-ray spectrometry (EDX). With the exception of [Ag(py-O)3][Tf2N], which melts at 108 °C, all the silver(i) compounds have a melting point below 80 °C and were tested as electrolytes for silver electrodeposition. Interestingly, very high current densities were observed at a potential of -0.5 V vs. Ag/Ag(+) for the compounds with fluorine-free anions, i.e. [Ag(py-O)3][NO3] (current density of -10 A dm(-2)) and [Ag(py-O)3][OMs] (-6.5 A dm(-2)). The maximum current density of the compound with the fluorinated anion trifluoromethanesulfonate, [Ag(py-O)3][OTf], was much lower: -2.5 A dm(-2) at -0.5 V vs. Ag/Ag(+). Addition of an excess of ligand to [Ag(py-O)3][OTf] resulted in the formation of the room-temperature ionic liquid [Ag(py-O)6][OTf]. A current density of -5 A dm(-2) was observed at -0.5 V vs. Ag/Ag(+) for this low viscous silver salt. The crystal structures of several silver complexes could be determined by X-ray diffraction, and it was found that several of them had a stoichiometry different from the 1 : 3 metal-to-ligand ratio used in their synthesis. This indicates that the compounds form crystals with a composition different from that of the molten state. The electrochemical properties were measured in the liquid state, where the metal-to-ligand ratio was 1 : 3. Single crystal X-ray diffraction measurements showed that silver(i) is six coordinate in [Ag(py-O)3][Tf2N] and [Ag(py-O)3][OTf], while it is five coordinate in the other complexes. In [Ag3(py-O)8][OTf]3, there are two different coordination environments for silver ions: six coordinate central silver ions and five coordinate for the outer silver ions. In some of the silver(i) complexes, silver-silver interactions were observed in the solid state.


Acute chest pain - a prospective population based study of contacts to Norwegian emergency medical communication centres.
Acute chest pain is a frequently occurring symptom in patients with medical emergencies and imposes potentially life threatening situations outside hospitals. Little is known about the epidemiology of patients with acute chest pain in a primary care setting in Norway, and we aimed to obtain more representative data on such patients using data from emergency medical communication centres (EMCCs). Data were collected prospectively during three months in 2007 from three EMCCs, covering 816 000 inhabitants. The EMCCs gathered information on every situation that was triaged as a red response (defined as an "acute" response, with the highest priority), according to the Norwegian Index of Medical Emergencies. Records from ambulances and primary care doctors were subsequently collected. International Classification of Primary Care - 2 symptom codes and The National Committee on Aeronautics (NACA) System scores were assigned retrospectively. Only chest pain patients were included in the study. 5 180 patients were involved in red response situations, of which 21% had chest pain. Estimated rate was 5.4 chest pain cases per 1000 inhabitants per year. NACA-scores indicated that 26% of the patients were in a life-threatening medical situation. Median prehospital response time was 13 minutes; an ambulance reached the patient in less than 10 minutes in 30% of the cases. Seventy-six per cent of the patients with chest pain were admitted to a hospital for further investigation, 14% received final treatment at a casualty clinic, while 10% had no further investigation by a doctor ("left at the scene"). The majority of patients with acute chest pain were admitted to a hospital for further investigation, but only a quarter of the patients were assessed prehospitally to have a severe illness. This sheds light on the challenges for the EMCCs in deciding the appropriate level of response in patients with acute chest pain. Overtriage is to some extent both expected and desirable to intercept all patients in need of immediate help, but it is also well known that overtriage is resource demanding. Further research is needed to elucidate the challenges in the diagnosis and management of chest pain outside hospitals.


The portion size effect: Women demonstrate an awareness of eating more than intended when served larger than normal portions.
Large portion sizes lead to increased intake. Some studies suggest that individuals are unaware that they consume more when served larger portions. In a between-subjects design we asked female participants (N = 48) how much pasta and tomato sauce they intended to consume for lunch prior to eating. We then provided a smaller or a larger portion of the same food and invited participants to self-serve a portion into a second bowl (same size in both conditions). After eating until comfortably full, participants were shown an image of the amount they had selected at the beginning of the meal. They were then asked whether they perceived having eaten more or less than this amount, and by how much more or less they had eaten. In total 46 responses were analysed. Of the participants who received the large portion and who ate more than intended, 77% (p = .029) correctly identified eating more. However, when participants were asked to indicate by how much they had eaten above or below their intended amount, those who ate more after receiving a larger portion underestimated their intake by 25% (p = .003). These findings suggest that greater intake from a larger portion is associated with an awareness of having eaten a large quantity combined with a failure to register the actual amount consumed (in the direction of underestimation). The latter might be attributed to an error associated with the visual estimation of volume.


Performance of a Multispectral Optoacoustic Tomography (MSOT) System equipped with 2D vs. 3D Handheld Probes for Potential Clinical Translation.
A handheld approach to optoacoustic imaging is essential for the clinical translation. The first 2- and 3-dimensional handheld multispectral optoacoustic tomography (MSOT) probes featuring real-time unmixing have recently been developed. Imaging performance of both probes was determined in vitro and in a brain melanoma metastasis mouse model in vivo. T1-weighted MR images were acquired for anatomical reference. The limit of detection of melanoma cells in vitro was significantly lower using the 2D than the 3D probe. The signal decrease was more profound in relation to depth with the 3D versus the 2D probe. Both approaches were capable of imaging the melanoma tumors qualitatively at all time points. Quantitatively, the 2D approach enabled closer anatomical resemblance of the tumor compared to the 3D probe, particularly at depths beyond 3 mm. The 3D probe was shown to be superior for rapid 3D imaging and, thus, holds promise for more superficial target structures.


Zinc stannate nanostructures: hydrothermal synthesis.
Nanostructured binary semiconducting metal oxides have received much attention in the last decade owing to their unique properties rendering them suitable for a wide range of applications. In the quest to further improve the physical and chemical properties, an interest in ternary complex oxides has become noticeable in recent times. Zinc stannate or zinc tin oxide (ZTO) is a class of ternary oxides that are known for their stable properties under extreme conditions, higher electron mobility compared to its binary counterparts and other interesting optical properties. The material is thus ideal for applications from solar cells and sensors to photocatalysts. Among the different methods of synthesizing ZTO nanostructures, the hydrothermal method is an attractive green process that is carried out at low temperatures. In this review, we summarize the conditions leading to the growth of different ZTO nanostructures using the hydrothermal method and delve into a few of its applications reported in the literature.


Effect of acid infusion into various levels of the intestine on gastric and pancreatic secretion in the cat.
Intraduodenal infusion of increasing amounts of hydrochloric acid solution results in a stepwise increase in the volume of pancreatic secretion and output of bicarbonate, reaching about 90% of amounts attained with exogenous secretin infused intravenously in increasing doses. Acid infusion into the different regions of the intestine stimulates pancreatic secretion only from the duodenum and upper jejunum, suggesting that the area of endogenous release of secretin by acid is confined to the upper part of the small bowel in the cat. Gastric acid secretion induced by pentagastrin, but not by histamine, is inhibited by acid perfusion of the duodenum. The acidification of other parts of the small intestine does not result in any change in gastric acid secretion induced either by pentagastrin or by histamine.


Effect of GPi DBS on functional imaging of the brain in dystonia.
Five patients with idiopathic dystonic conditions, treated successfully with deep brain stimulation (DBS) of the globus pallidus internus (GPi), were studied using single-photon emission tomography (SPET) in order to evaluate brain perfusion in the presence and absence of DBS. Comparison was made between the "on" and "off" DBS scans on an individual basis and also as part of a group analysis. Whilst the individual data suggested great regional variation in cerebral perfusion between individuals, the results of the group analysis revealed several topographically similar areas of the brain where relative hyperperfusion in the absence of DBS was common to all patients. Based on these results we postulate on possible mechanisms for this phenomenon.


Physico-chemical characterization of liposomes and drug substance-liposome interactions in pharmaceutics using capillary electrophoresis and electrokinetic chromatography.
Liposomes are self-assembled phospholipid vesicles and have numerous research and therapeutic applications. In the pharmaceutical and biomedical sciences liposomes find use as models of biological membranes, partitioning medium and as drug carriers. The present review addresses the use of capillary electrophoresis and liposome electrokinetic chromatography for the characterization of liposomes in a pharmaceutical context. Capillary electrophoretic techniques have been used for the measurement of electrophoretic mobility, which provides information on liposome surface charge, size and membrane permeability of liposomes. The use of liposome electrokinetic chromatography and capillary electrophoresis for determination of liposome/water partitioning and characterization of drug-liposome interactions is reviewed. A number of studies indicate that capillary electrophoresis may have a role in the characterization of liposome drug delivery systems, e.g., for the investigation of encapsulation efficiency and drug leakage. The well-known characteristics of capillary electrophoresis, i.e., low sample volume requirement, high separation efficiency in aqueous media without a stationary phase, minimal sample preparation, and a high degree of automation, makes it an attractive approach in liposome research.


Why are we not screening for anal cancer routinely - HIV physicians' perspectives on anal cancer and its screening in HIV-positive men who have sex with men: a qualitative study.
Anal cancer is a priority health issue in HIV positive men who have sex with men. Anal cancer screening may be aimed at either detecting the precursor lesion (high grade anal intraepithelial neoplasia(HGAIN)) or early anal cancer. To date no qualitative study has explored the views of HIV physicians regarding anal cancer and its screening. We conducted indepth interviews with 20 HIV physicians (Infectious diseases, Immunology, Sexual health, General practice) in different settings (hospital, sexual health centres, general practice) from around Australia. Framework analysis was used to identify themes. HIV physicians viewed anal cancer as a significant health issue and all agreed on the importance of anal cancer screening amongst HIV positive MSM if a valid screening method was available. Barriers for utilizing anal cytology was based primarily on the theme of insufficient evidence (e.g. no studies demonstrating reduction in mortality following screening or effective treatments for HGAIN). Barriers for utilizing DARE for early cancer detection were based on systemic factors (e.g. lack of opportunity, lack of priority, differences in HIV care practices); health provider factors (lack of evidence, difficulty discussing with patients, lack of confidence in DARE) and patient factors (perceived discomfort of DARE for patients, low anal cancer risk awareness). Physicians were willing to consider the idea of patient self-examination and partner-examination although concerns were raised regarding its reliability and issues surrounding partner dynamics. HIV physicians remain ambivalent regarding the most effective means to screen for anal cancer. More research is needed to address the physicians' concerns before anal cancer screening can be implemented into routine HIV care.


Regulation of intracellular Zn homeostasis in two intestinal epithelial cell models at various maturation time points.
After weaning, piglets are often fed diets supplemented with high concentrations of zinc (Zn) to decrease post-weaning diarrhea. The aim of this study was to elucidate the regulation of Zn homeostasis within intestinal epithelial cells during excessive Zn exposure. High Zn concentrations elevated the intracellular Zn level in IPEC-J2 and Caco-2 cells which was influenced by differentiation status and time of exposure. With increasing Zn concentrations, mRNA and protein levels of metallothionein (MT) and zinc transporter 1 (ZnT1) were upregulated, whereas zinc transporter 4 (ZIP4) expression was downregulated. Metal-regulatory transcription factor-1 (MTF1) mRNA expression was upregulated at high Zn concentrations in IPEC-J2 cells, which corresponded to higher intracellular Zn concentrations. Based on these results, we suggest that intestinal epithelial cells adapt the expression of these genes to the amount of extracellular Zn available in order to maintain Zn homeostasis. Cell line-dependent differences in the regulation of Zn homeostasis were detected.


T cell-based tracking of multidrug resistant tuberculosis infection after brief exposure.
Molecular epidemiology indicates significant transmission of Mycobacterium tuberculosis after casual contact with infectious tuberculosis cases. We investigated M. tuberculosis transmission after brief exposure using a T cell-based assay, the enzyme-linked-immunospot (ELISPOT) for IFN-gamma. After childbirth, a mother was diagnosed with sputum smear-positive multidrug-resistant tuberculosis. Forty-one neonates and 47 adults were present during her admission on the maternity unit; 11 weeks later, all underwent tuberculin skin testing (TST) and ELISPOT. We correlated test results with markers of exposure to the index case. The participants, who were asymptomatic and predominantly had no prior tuberculosis exposure, had 6.05 hours mean exposure (range: 0-65 hours) to the index case. Seventeen individuals, including two newborns, were ELISPOT-positive, and ELISPOT results correlated significantly with three of four predefined measures of tuberculosis exposure. For each hour sharing room air with the index case, the odds of a positive ELISPOT result increased by 1.05 (95% CI: 1.02-1.09, p = 0.003). Only four adults were TST-positive and TST results did not correlate with exposure. Thus, ELISPOT, but not TST, suggested quite extensive nosocomial transmission of multidrug-resistant M. tuberculosis after brief exposure. These results help to explain the apparent importance of casual contact for tuberculosis transmission, and may have implications for prevention.


An 11-Year Retrospective Research Study of the Predictive Factors of Peri-Implantitis and Implant Failure: Analytic-Multicentric Study of 1279 Implants in Peru.
To analyze the risk factors by logistic regression and perform the analysis of the survival rate of osseointegrated dental implants placed in public and private institutions. An analytic-multicentric study was carried out, where 1279 dental implants that were placed by specialists from January 2006 to October 2017 in public and private institutions (UPCH-SI, HCFAP, CMNAVAL, UPCH-SM, and UPSJB) were evaluated. The variables sex (X1), location (X2), hypertension (X3), antibiotic prophylaxis (X4), diabetes (X5), osteoporosis (X6), bisphosphonates (X7), history of periodontitis (X8), hypercholesterolemia (X9), bone quality (X10), bone quantity (X11), design (X12), smoker (X13), connection (X14), edentulism type (X15), staging (X16), 3D guided surgery (X17), load (X18), bone graft (X19), peri-implantitis (X20), mucositis (X21), and GBR (X22) were collected and analyzed by the Kaplan-Meier survival analysis. The logit analysis was performed among all the variables to choose the best statistical model that explains the true risk factors. The analysis was performed by multivariate logistic regression and the Kaplan-Meier test, at a level of statistical significance of p < 0.05. It was found that the failure rate of the 1279 implants evaluated was 17.98% corresponding to only 23 implants lost as they have good longevity over time. When establishing the best multivariate logistic regression model, it was found that the variables that remained stable in relation to their statistically significant value and more stable confidence intervals were age, osteoporosis, bisphosphonates, history of periodontitis, bone quality, bone graft, connection, number of implants, GBR (guided bone regeneration), and follow-up. Dental implants placed by specialists in public and private institutions had a failure rate similar to that in studies previously published in other countries.


Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats.
Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.


Substrate Temperature to Control Moduli and Water Uptake in Thin Films of Vapor Deposited N,N'-Di(1-naphthyl)-N,N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine (NPD).
Ultrastable glasses are generated by vapor deposition on substrates heated near the glass transition temperature (Tg), but it is unclear if the remarkable properties of such glasses are present in ultrathin (<100 nm) films. Here, we demonstrate that the moduli of 50 nm thick N,N'-di(1-naphthyl)-N,N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine (NPD) film can be increased from 1.5 to 2.5 GPa by simply increasing the temperature of the substrate during deposition with a maximum in modulus found at T/Tg = 0.94. This maximum in modulus is the same modulus obtained for very thin (<15 nm) NPD films deposited at 295 K (T/Tg = 0.80). However, the modulus of films deposited at this lower temperature abruptly decreases to approximately 1.5 GPa for thicker films; the modulus from deposition at T/Tg = 0.94 is thickness independent. In addition to the thin film modulus, the substrate temperature significantly impacts the water uptake in NPD films. From QCM, the volume fraction of water at equilibrium with nearly saturated water vapor decreases from nearly 4% to less than 1% as the substrate temperature increases from T/Tg = 0.82 to T/Tg = 0.93. The substrate temperature provides a simple route to control mechanical properties and water uptake into vapor-deposited NPD, and these concepts are likely extendable to other organic electronic materials; the increased moduli and decreased water uptake could enable improved performance and lifetime of small molecule glasses for a variety of organic electronic applications.