Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice.
Neonatal hyperoxia impairs vascular and alveolar growth in mice and decreases endothelial progenitor cells. To determine the role of bone marrow-derived cells in restoration of neonatal lung structure after injury, we studied a novel bone marrow myeloid progenitor cell population from Tie2-green fluorescent protein (GFP) transgenic mice (bone marrow-derived angiogenic cells; BMDAC). We hypothesized that treatment with BMDAC would restore normal lung structure in infant mice during recovery from neonatal hyperoxia. Neonatal mice (1-day-old) were exposed to 80% oxygen for 10 days. BMDACs (1 x 10(5)), embryonic endothelial progenitor cells, mouse embryonic fibroblasts (control), or saline were then injected into the pulmonary circulation. At 21 days of age, saline-treated mice had enlarged alveoli, reduced septation, and a reduction in vascular density. In contrast, mice treated with BMDAC had complete restoration of lung structure that was indistinguishable from room air controls. BMDAC comprised 12% of distal lung cells localized to pulmonary vessels or alveolar type II (AT2) cells and persist (8.8%) for 8 wk postinjection. Coculture of AT2 cells or lung endothelial cells (luEC) with BMDAC augmented AT2 and luEC cell growth in vitro. We conclude that treatment with BMDAC after neonatal hyperoxia restores lung structure in this model of bronchopulmonary dysplasia.


Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.
There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. clinicaltrials.gov Identifier: NCT00449865.


Impact of enhanced external counterpulsation on peripheral circulation.
Enhanced external counterpulsation (EECP) is a noninvasive counterpulsation technique that reduces angina and improves exercise capacity in patients with coronary artery disease. Diastolic coronary perfusion is augmented by pneumatic compression of 3 sets of cuffs wrapped around the lower extremities. Although central hemodynamic changes are well investigated, almost no data exist about the changes of peripheral circulation during EECP. In this study, 12 patients with angina and angiographic evidence of coronary artery disease were treated for 1 hour with EECP. In these patients, peripheral artery disease was excluded by duplex sonography. The patients rested 1 hour before EECP in supine position, and they remained in that position for 1 hour after the procedure. Changes of flow volumes and flow pattern of the posterior tibial artery and the brachial artery were measured by sonography at the end of all 3 periods. Furthermore, we measured the concentration of circulating prostanoids at these 3 time points. Averaged flow volume of the posterior tibial artery decreased to 69% +/- 23% (P < .05) during EECP and increased to 133% +/- 34% (P < .05) of baseline 1 hour after the procedure. In contrast, the averaged flow volume of the brachial artery increased by 9% +/- 4% (P < .05) during EECP and returned to baseline values after EECP. The flow pattern of the posterior tibial artery showed a second early diastolic antegrade flow caused by the cuff inflation and a reverse end-diastolic flow after the deflation of the cuffs. These flow changes caused an increase of the pulsatility index by Gosling (397% during EECP), returning to baseline values in the recovery period. Plasma concentrations of circulating prostanoids showed no significant change during EECP. Thus, pedal flow volume decreased to approximately two thirds of baseline during EECP followed by reactive hyperemia even 1 hour after the procedure; however, this decreased perfusion triggered no change of the prostacyclin/thromboxane ratio and was well tolerated by all investigated patients. The observed 4-fold increase of the peripheral pulsatility index supports the thesis of increase of shear-stress-related improvement of endothelial function during EECP.


Physical and psychosocial work factors as explanations for social inequalities in self-rated health.
We investigated the contribution of physical and psychosocial work factors to social inequalities in self-rated health (SRH) in a sample of Danish 40 and 50 years old occupationally active women and men. In this longitudinal study, the study population consisted of 3338 Danish women and men. Data were collected by postal questionnaires in 2000 (baseline) and 2006 (follow-up). The independent variable, socioeconomic position (SEP), was assessed by the highest achieved educational level at baseline. We conducted gender-stratified parallel multiple mediation analyses. In the mediation analyses, SEP was categorised as SEP I, II, III, VI and V among men. Among women, SEP was dichotomised into SEP I-IV and V. The outcome, SRH, was assessed at baseline and follow-up. A wide range of physical and psychosocial work factors were included as potential mediators. We found a social gradient in SRH across all levels of SEP among men. Among women, we only found a poorer SRH among those with the lowest SEP. Mediation analyses showed that work factors together accounted for 56% of the social inequalities in SRH among men and 44% among women. In both genders, ergonomic exposures and job insecurity seemed to play the major role for social inequalities in SRH. For women only, we also found noise to contribute to the social inequalities in SRH. Physical and psychosocial work factors partially explained social inequalities in SRH among both genders. Improvement of the working environment can potentially contribute to the reduction of social inequalities in health.


Speeding up parallel GROMACS on high-latency networks.
We investigate the parallel scaling of the GROMACS molecular dynamics code on Ethernet Beowulf clusters and what prerequisites are necessary for decent scaling even on such clusters with only limited bandwidth and high latency. GROMACS 3.3 scales well on supercomputers like the IBM p690 (Regatta) and on Linux clusters with a special interconnect like Myrinet or Infiniband. Because of the high single-node performance of GROMACS, however, on the widely used Ethernet switched clusters, the scaling typically breaks down when more than two computer nodes are involved, limiting the absolute speedup that can be gained to about 3 relative to a single-CPU run. With the LAM MPI implementation, the main scaling bottleneck is here identified to be the all-to-all communication which is required every time step. During such an all-to-all communication step, a huge amount of messages floods the network, and as a result many TCP packets are lost. We show that Ethernet flow control prevents network congestion and leads to substantial scaling improvements. For 16 CPUs, e.g., a speedup of 11 has been achieved. However, for more nodes this mechanism also fails. Having optimized an all-to-all routine, which sends the data in an ordered fashion, we show that it is possible to completely prevent packet loss for any number of multi-CPU nodes. Thus, the GROMACS scaling dramatically improves, even for switches that lack flow control. In addition, for the common HP ProCurve 2848 switch we find that for optimum all-to-all performance it is essential how the nodes are connected to the switch's ports. This is also demonstrated for the example of the Car-Parinello MD code.


Bioelectrochemical production of hydrogen in an innovative pressure-retarded osmosis/microbial electrolysis cell system: experiments and modeling.
While microbial electrolysis cells (MECs) can simultaneously produce bioelectrochemical hydrogen and treat wastewater, they consume considerable energy to overcome the unfavorable thermodynamics, which is not sustainable and economically feasible in practical applications. This study presents a proof-of-concept system in which hydrogen can be produced in an MEC powered by theoretically predicated energy from pressure-retarded osmosis (PRO). The system consists of a PRO unit that extracts high-quality water and generates electricity from water osmosis, and an MEC for organic removal and hydrogen production. The feasibility of the system was demonstrated using simulated PRO performance (in terms of energy production and effluent quality) and experimental MEC results (e.g., hydrogen production and organic removal). The PRO and MEC models were proven to be valid. The model predicted that the PRO unit could produce 485 mL of clean water and 579 J of energy with 600 mL of draw solution (0.8 M of NaCl). The amount of the predicated energy was applied to the MEC by a power supply, which drove the MEC to remove 93.7 % of the organic compounds and produce 32.8 mL of H2 experimentally. Increasing the PRO influent volume and draw concentration could produce more energy for the MEC operation, and correspondingly increase the MEC hydraulic retention time (HRT) and total hydrogen production. The models predicted that at an external voltage of 0.9 V, the MEC energy consumption reached the maximum PRO energy production. With a higher external voltage, the MEC energy consumption would exceed the PRO energy production, leading to negative effects on both organic removal and hydrogen production. The PRO-MEC system holds great promise in addressing water-energy nexus through organic removal, hydrogen production, and water recovery: (1) the PRO unit can reduce the volume of wastewater and extract clean water; (2) the PRO effluents can be further treated by the MEC; and (3) the osmotic energy harvested from the PRO unit can be applied to the MEC for sustainable bioelectrochemical hydrogen production.


Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhoea without constipation.
Clinical studies suggest that the Ayurvedic plant Boswellia serrata may be effective in reducing diarrhoea in patients with inflammatory bowel disease. In the present study, we evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhoea in rodents. BSE depressed electrically-, acetylcholine-, and barium chloride-induced contractions in the isolated guinea-pig ileum, being more potent in inhibiting the contractions induced by acetylcholine and barium chloride. The inhibitory effect of BSE on acetylcholine-induced contractions was reduced by the L-type Ca(2+) channel blockers verapamil and nifedipine, but not by the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid, by the phosphodiesterase type IV inhibitor rolipram or by the lipoxygenase inhibitor zileuton. 3-acetyl-11-keto-beta-boswellic acid, one of the main active ingredients of B. serrata, inhibited acetylcholine-induced contractions. BSE inhibited upper gastrointestinal transit in croton oil-treated mice as well as castor oil-induced diarrhoea. However, BSE did not affect intestinal motility in control mice, both in the small and in the large intestine. It is concluded that BSE directly inhibits intestinal motility with a mechanism involving L-type Ca(2+) channels. BSE prevents diarrhoea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results could explain, at least in part, the clinical efficacy of this Ayurvedic remedy in reducing diarrhoea in patients with inflammatory bowel disease.


Mutual confounding and interactive effects between hepatitis C and hepatitis B viral infections in hepatocellular carcinogenesis: a population-based case-control study in Taiwan.
A population-based case-control study was conducted in Taiwan to determine the hepatitis C virus (HCV)-associated risk of hepatocellular carcinoma (HCC) in a hyperendemic area for hepatitis B virus (HBV) infection. A total of 58 recently diagnosed HCC patients and 225 matched community controls, who participated in a community-based liver cancer screening program, were recruited between March 1991 and March 1994. Control subjects were matched to HCC patients by age (+/- 5 years), sex, residence, and date of serum sample collection (+/- 3 months). Serum samples from all study subjects were tested for hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCVs) by enzyme immunoassays, as well as HCV RNA by reverse transcription-PCR assays. Accordingly, patients with HCC were more likely than were controls to be positive for HBsAg (82.8% versus 12.9%, with an odds ratio (OR) of 22.9), anti-HCVs (13.8% versus 4.4%, with an OR of 3.9), and HCV RNA (13.8% versus 5.8%, with an OR of 2.7). After adjustment for anti-HCVs and HCV RNA positivities, the matched ORs associated with HBsAg increased to 27.6 and 28.1, respectively, whereas the corresponding adjusted ORs for anti-HCVs and HCV RNA after controlling for HBsAg status were increased to 8.8 and 6.2, respectively. In the meantime, interactive effects between HCV and HBV on risk were also observed. Compared with those who were negative for both anti-HCVs and HBsAg, the matched ORs associated with the sole positivity of anti-HCVs and HBsAg were 4.0 (95% confidence interval = 0.7-24.0) and 24.6 (95% confidence interval = 9.5-64.1), respectively, whereas 6 HCC cases but none of control subjects were positive for both anti-HCVs and HBsAg. These results indicate that there are mutual confounding and interactive effects between HCV and HBV with respect to their links to HCC in this endemic area of chronic HBV infections.


Effect of grafting density on conformation of poly(acrylic acid) in solution by dielectric spectroscopy.
The effect of grafting density of poly(ethylene oxide) and dodecyl groups on the conformation of poly(acrylic acid) in solution was clarified by dielectric relaxation spectroscopy over a frequency range from 40 Hz to 110 MHz. Two distinct dielectric relaxations were found after the elimination of electrode polarization, and valuable information about the conformations and interfacial electrokinetic properties of molecules was obtained by analyzing the dielectric spectra based on a refined double-layer polarization model. The critical aggregation concentration was determined by the concentration dependency of dielectric parameters. The results based on zeta potential suggested that the ionization performance and behavior of counterion condensation were strongly influenced by the grafting density of poly(ethylene oxide) and dodecyl groups. The concentration dependency of correlation length, ratio of zeta potential, ratio of linear density of counterions, and the Debye length showed that the chain length and degree of intermolecular aggregation were also strongly influenced by the grafting density. We revealed the role of grafting density with respect to electrostatic interaction in determining the chain conformation of polyelectrolytes in solution.


Seroprevalence of and Risk Factors Associated with Exposure to Brucella Spp. in Dairy Cattle in Three Different Agroecological Zones in Rwanda.
Livestock production is a key element for poverty alleviation, food security, and economic growth in Rwanda. In 2017, the national average milk production per cow was about 2.5 L per day; in 2020-2021, it is projected to increase to 3.5 L per day if improvement interventions including those designed to reduce the burden of brucellosis in cattle are implemented. The objective of the study reported here was to estimate the seroprevalence of and identify risk factors associated with dairy farms and cattle classified as seropositive to Brucella spp. in three different agroecological zones in Rwanda. Most study farms (40/85 or 47%) had one head of cattle only. Using the Rose Bengal test, the seroprevalence of brucellosis was 28/85 or 33% (95% CI = 24%, 43%) at the farm level and 63/465 or 14% (95% CI = 11%, 17%) at the animal level. Using logistic regression, at the farm level, the presence of seropositive cattle was associated with herd size (2-45 cattle, odds ratio = 21.2; 95% CI = 2.4, 184.5) (46-220 cattle, OR = 288.5; 95% CI = 24.3, 3,423.1) compared to farms with one animal, after controlling for main breed (local breeds, crossbreeds) on the farm. In addition, the odds of testing seropositive were 10.7 (95% CI = 2.3, 49.1) and 149.5 (95% CI = 19.3, 1,158.7) times higher in farms in Nyabihu district and Nyagatare district, respectively, than in farms in Muhanga district, after controlling for main breed on the farm. The odds of seropositivity to Brucella spp. were 2.8 times higher in farms with mostly local breeds, than in those with mostly crossbreeds; but the association was confounded by herd size and geographic location. At the animal level, the odds of seropositivity to Brucella spp. were 2.6 times higher in adult cattle than in young cattle (95% CI = 1.1, 6.3). Finally, we observed a high frequency of adult cattle (86%) and a high seroprevalence of brucellosis in adult cattle (25%) in Nyagatare; an indication that, in the absence of culling and other control measures, Brucella spp. infection pressure can be relatively constant and a steady source of disease transmission in pastoral systems in that district.


DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity.
Specific antibody therapy, including mAbs and bispecific T cell engagers (BiTEs), are important new tools for cancer immunotherapy. However, these approaches are slow to develop and may be limited in their production, thus restricting the patients who can access these treatments. BiTEs exhibit a particularly short half-life and difficult production. The development of an approach allowing simplified development, delivery, and in vivo production would be an important advance. Here we describe the development of a designed synthetic DNA plasmid, which we optimized to permit high expression of an anti-HER2 antibody (HER2dMAb) and delivered it into animals through adaptive electroporation. HER2dMAb was efficiently expressed in vitro and in vivo, reaching levels of 50 μg/ml in mouse sera. Mechanistically, HER2dMAb blocked HER2 signaling and induced antibody-dependent cytotoxicity. HER2dMAb delayed tumor progression for HER2-expressing ovarian and breast cancer models. We next used the HER2dMAb single-chain variable fragment portion to engineer a DNA-encoded BiTE (DBiTE). This HER2DBiTE was expressed in vivo for approximately 4 months after a single administration. The HER2DBiTE was highly cytolytic and delayed cancer progression in mice. These studies illustrate an approach to generate DBiTEs in vivo, which represent promising immunotherapies for HER2+ tumors, including ovarian and potentially other cancers.


Characterization of steroid interactions with gamma-aminobutyric acid receptor-gated chloride ion channels: evidence for multiple steroid recognition sites.
The potentiation of gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several of these steroids, including 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC), increase the potency of muscimol to stimulate 36Cl- uptake in a concentration-dependent and stereospecific manner. Concentration-response curves for 3 alpha-OH-DHP, THDOC, 3 alpha-hydroxy-pregn-4-en-20-one, and pentobarbital enhancement of muscimol-stimulated 36Cl- uptake are biphasic, with Hill coefficients significantly less than 1.0. Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s). In contrast, the concentration-response curve for THDOC 21-mesylate is monophasic, with a smaller maximal response, and yields a Hill coefficients of 1.0. In addition to modulating GABA receptor-mediated 36Cl- uptake, THDOC enhanced the ability of the benzodiazepine clonazepam to potentiate muscimol-stimulated 36Cl- uptake. The central benzodiazepine antagonist Ro15-1788 failed to inhibit THDOC-induced potentiation of muscimol-stimulated 36Cl- uptake, although it has been previously reported to inhibit some of the behavioral actions of THDOC. In contrast to the A ring-reduced metabolites and analogues of progesterone and deoxycorticosterone, glucocorticoids had no effect on muscimol-stimulated 36Cl- uptake in cerebral cortical synaptoneurosomes at concentrations between 20 nM and 5 microM.


Management of the post-cardiac arrest syndrome.
Recent advances in resuscitation science have revolutionized care of the cardiac arrest patient. Dramatic departures from time-honored advanced cardiac life support therapies, such as cardiocerebral resuscitation and bundled post-arrest care, have given rise to a new paradigm of resuscitation practices, which has boosted the rate of neurologically intact survival. This article reviews the pathophysiology of the post-cardiac arrest syndrome, the collective pathophysiology after return of spontaneous circulation, and presents management pearls specifically for the emergency physician. This growing area of scientific inquiry must be managed appropriately to sustain improved outcomes. The emergency physician must understand this pathophysiology, manage resuscitated patients according to the latest evidence, and coordinate with appropriate inpatient resources. The new approach to cardiac arrest care is predicated on a chain of survival that spans the spectrum of care from the prehospital arena through the emergency, intensive, and inpatient settings. The emergency physician is a crucial link in this chain.


19F NMR studies of vaccinia type IB topoisomerase. Conformational dynamics of the bound DNA substrate.
The site-specific DNA cleavage and religation activities of the vaccinia virus type IB topoisomerase at (C/T)CCTT(+1)X(-1) sites in duplex DNA have allowed detailed investigations of the chemical and conformational steps on the reaction pathway of this enzyme (see accompanying article (Kwon, K., and Stivers, J. T. (2002) J. Biol. Chem. 277, 345-352)). To extend these studies to the DNA substrate, we have performed 19F NMR experiments using substrates in which the +1 T has been replaced with the NMR-sensitive thymidine base analogue 5-fluoro-2'-deoxyuridine (5-F-dUrd). Substitution of 5-F-dUrd has little effect on the binding affinity of topoisomerase I for DNA, results in small changes in the cleavage and religation rate constants, and produces a net 3-fold decrease in the cleavage equilibrium constant as compared with the CCCTT consensus DNA. One-dimensional 19F NMR experiments show that the +1 5-F-dUrd is in a dynamic equilibrium between a stacked and unstacked state in both the noncovalent complex and the covalent phosphotyrosine complex. These NMR observations are supported by the selective sensitivity of the +1 T and +1 5-F-dUrd to KMnO4 oxidation. A role for localized DNA distortion in the topoisomerase I mechanism is suggested.


Going with the Grain of Cognition: Applying Insights from Psychology to Build Support for Childhood Vaccination.
Childhood vaccination is widely considered to be one of the most successful public health interventions. Yet, the effective delivery of vaccination depends upon public willingness to vaccinate. Recently, many countries have faced problems with vaccine hesitancy, where a growing number of parents perceive vaccination to be unsafe or unnecessary, leading some to delay or refuse vaccines for their children. Effective intervention strategies for countering this problem are currently sorely lacking, however. Here, we propose that this may be because existing strategies are grounded more in intuition than insights from psychology. Consequently, such strategies are sometimes at variance with basic psychological principles and assumptions. By going against the grain of cognition, such strategies potentially run the risk of undermining persuasive efforts to reduce vaccine hesitancy. We demonstrate this by drawing on key insights from cognitive and social psychology to show how various known features of human psychology can lead many intuitively appealing intervention strategies to backfire, yielding unintended and undesirable repercussions. We conclude with a summary of potential avenues of investigation that may be more effective in addressing vaccine hesitancy. Our key message is that intervention strategies must be crafted that go with the grain of cognition by incorporating key insights from the psychological sciences.


Masked primes evoke partial responses.
Backward-masked primes presented outside conscious awareness can affect responses to subsequently presented target stimuli. Differences in response times have been used to infer a pattern of sub-threshold activation and subsequent inhibition of motor plans associated with the primes. However, it is unclear whether competition between alternative responses is fully resolved in the brain or whether activated responses can begin being executed before the final decision to act has been made. Here, we investigate the dynamics of responses evoked by masked primes using a continuous measure - voltage change in force-sensing resistors simultaneously in both hands. Masked primes produced the predicted pattern of motor activation and subsequent inhibition of the primed response. There is no evidence that the effects of masked primes interact with spatial compatibility (e.g., Simon) effects, suggesting separate mechanisms underpinning these effects. Moreover, masked primes evoked partial motor decisions - measurable at the effectors as small amounts of erroneous response - which were usually rapidly corrected. Together, these errors and fast corrections question the 'sub-threshold' nature of responses evoked by masked primes and provide important constraints on models of decision-making.


Life-time risk of mortality due to different levels of alcohol consumption in seven European countries: implications for low-risk drinking guidelines.
Low-risk alcohol drinking guidelines require a scientific basis that extends beyond individual or group judgements of risk. Life-time mortality risks, judged against established thresholds for acceptable risk, may provide such a basis for guidelines. Therefore, the aim of this study was to estimate alcohol mortality risks for seven European countries based on different average daily alcohol consumption amounts. The maximum acceptable voluntary premature mortality risk was determined to be one in 1000, with sensitivity analyses of one in 100. Life-time mortality risks for different alcohol consumption levels were estimated by combining disease-specific relative risk and mortality data for seven European countries with different drinking patterns (Estonia, Finland, Germany, Hungary, Ireland, Italy and Poland). Alcohol consumption data were obtained from the Global Information System on Alcohol and Health, relative risk data from meta-analyses and mortality information from the World Health Organization. The variation in the life-time mortality risk at drinking levels relevant for setting guidelines was less than that observed at high drinking levels. In Europe, the percentage of adults consuming above a risk threshold of one in 1000 ranged from 20.6 to 32.9% for women and from 35.4 to 54.0% for men. Life-time risk of premature mortality under current guideline maximums ranged from 2.5 to 44.8 deaths per 1000 women in Finland and Estonia, respectively, and from 2.9 to 35.8 deaths per 1000 men in Finland and Estonia, respectively. If based upon an acceptable risk of one in 1000, guideline maximums for Europe should be 8-10 g/day for women and 15-20 g/day for men. If low-risk alcohol guidelines were based on an acceptable risk of one in 1000 premature deaths, then maximums for Europe should be 8-10 g/day for women and 15-20 g/day for men, and some of the current European guidelines would require downward revision.


Minimally invasive mitral valve surgery via submammary hidden incision.
With the recent advancement in minimally invasive cardiac surgery based on the needs of decreasing costs, hospital stay, recovery time and improving cosmetic appearance, minimally invasive mitral valve surgery (MIMS) is being actively pursued. The objective of this study was to compare our submammary hidden incision method to two other more proven methods of MIMS with respect to length of operation, clinical outcome and cosmetic satisfaction. From July, 1996 to June, 1998, a total of 14 patients underwent MIMS in our hospital. Three different approaches were used: the limited right-side thoracotomy approach, the parasternal incision approach and our submammary hidden incision approach, of which, this is the first report. All relevant clinical results are reported, including general characteristics of the operations, morbidity and mortality, length of hospitalization, pain relief and patient satisfaction. Five patients underwent MIMS via limited thoracotomy, four via parasternotomy and five with our submammary hidden incision method. There were six mitral valves repaired and eight replaced. Conversion to traditional sternotomy was not necessary in any of the three groups. The results from the three different approaches did not differ significantly across the different parameters measured. Nonetheless, the submammary hidden incision approach showed promise in the areas of length of stay for both intensive care patients (36.3 +/- 5.0 hours) and total hospitalization (10.7 +/- 0.6 days), pain relief and patient satisfaction. The submammary hidden incision method does not result in any significant disadvantage in clinical outcome. The method resulted in more satisfied patients due to less pain, shorter hospital stay, and most importantly, cosmetic appearance of the resulting surgical scar. We will make the submammary hidden incision approach the MIMS approach of choice at our institution and continue to monitor the long-term results.


Synthesis of substituted pyrenes by indirect methods.
The pyrene nucleus is a valuable component for materials, supramolecular and biological chemistry, due to its photophysical/electronic properties and extended rigid structure. However, its exploitation is hindered by the limited range of methods and outcomes for the direct substitution of pyrene itself. In response to this problem, a variety of indirect methods have been developed for preparing pyrenes with less usual substitution patterns. Herein we review these approaches, covering methods which involve reduced pyrenes, transannular ring closures and cyclisations of biphenyl intermediates. We also showcase the diverse range of substituted pyrenes which have been reported in the literature, and can serve as building blocks for new molecular architectures.


Damage and partitioned mortality of teleosts discarded from two Australian penaeid fishing gears.
Six field experiments were perfromed to (1) quantify the scale loss and partitioned (immediate and short-term) mortality of key teleosts discarded from a penaeid seiner and trawler operating in 2 estuaries in southeastern Australia, and (2) assess the utility of modified operational and/or onboard handling procedures for maximising survival. For both gears, several non-target species were caught, handled and discarded according to 2 general categories of treatment ('mild' and 'extreme') representing the plausible limits of severity of commercial operations. The mild treatments involved the shortest conventional deployments of the gears followed by the immediate sorting of catches in water-filled trays, while the extreme treatments comprised the longest conventional deployments and sorting in dry trays. Discards were examined for immediate mortalities and scale loss before sorting onboard, while live individuals of key species, along with appropriate numbers of controls, were released into sea cages and monitored for mortalities up to 5 d. For both gears, there was a trend of higher percentages of immediate mortalities in the extreme treatments, and more scale loss from dead than live seined and trawled silver biddy Gerres subfasciatus, seined tarwhine Rhabdosargus sarba and trawled yellowfin bream Acanthopagrus australis. Despite considerable interspecific variabilities, few intraspecific differences were detected between treatments for the short-term mortalities of live discards; however, for all species, these deaths were greater than those incurred by the controls (most of which survived). The partitioned mortality estimates were combined to provide a range of total mortalities for seined (95.97 and 99.07%, respectively) and trawled (71.74 and 97.64%) G. subfasciatus, seined R. sarba (23.95 and 100%) and trawled southern herring Herklotsichthys castelnaui (100%) and A. australis (3.40 and 35.01%). Because most deaths occurred irrespective of onboard handling procedures, we conclude that simply reducing the duration of gear deployments would provide a first step toward mitigating discard mortality in these fisheries.


Mutations in a small region of the exportin Crm1p disrupt the daughter cell-specific nuclear localization of the transcription factor Ace2p in Saccharomyces cerevisiae.
The CBK1 gene of Saccharomyces cerevisiae encodes a protein kinase that is a member of the NDR (nuclear Dbf2-related) family of protein kinases, which are involved in morphogenesis and cell proliferation. Previous studies have shown that deletion of CBK1 leads to a loss of polarity and the formation of large aggregates of cells. This aggregation phenotype is due to the loss of the daughter cell-specific accumulation of the transcription factor Ace2p, which is responsible for the transcription of genes whose products are necessary for the final separation of the mother and the daughter at the end of cell division. We show that the daughter cell-specific localization of Ace2p does not occur via a specific localization of the ACE2 mRNA and that, in vivo, the transcription of CTS1, one of the principal targets of Ace2p, is daughter cell-specific. We have shown that extragenic suppressors of the Deltacbk1 aggregation phenotype are located in the nuclear exportin CRM1 and ACE2. These mutations disrupt the interaction of Ace2p and Crm1p, thus impairing Ace2p export and resulting in the accumulation of the protein in both mother and daughter cell nuclei. We propose that in the daughter cell nucleus Cbk1p phosphorylates the Ace2p nuclear export signal, and that this phosphorylation blocks the export of Ace2p via Crm1p, thus promoting the daughter cell-specific nuclear accumulation of Ace2p.


Functional Characterization of Atrophy Patterns Related to Cognitive Impairment.
Introduction: Mild cognitive impairment (MCI) is a heterogenous syndrome considered as a risk factor for developing dementia. Previous work examining morphological brain changes in MCI has identified a temporo-parietal atrophy pattern that suggests a common neuroanatomical denominator of cognitive impairment. Using functional connectivity analyses of structurally affected regions in MCI, we aimed to investigate and characterize functional networks formed by these regions that appear to be particularly vulnerable to disease-related disruptions. Methods: Areas of convergent atrophy in MCI were derived from a quantitative meta-analysis and encompassed left and right medial temporal (i.e., hippocampus, amygdala), as well as parietal regions (precuneus), which were defined as seed regions for connectivity analyses. Both task-based meta-analytical connectivity modeling (MACM) based on the BrainMap database and task-free resting-state functional MRI in a large cohort of older adults from the 1000BRAINS study were applied. We additionally assessed behavioral characteristics associated with the seed regions using BrainMap meta-data and investigated correlations of resting-state connectivity with age. Results: The left temporal seed showed stronger associations with a fronto-temporal network, whereas the right temporal atrophy cluster was more linked to cortico-striatal regions. In accordance with this, behavioral analysis indicated an emphasis of the left temporal seed on language generation, and the right temporal seed was associated with the domains of emotion and attention. Task-independent co-activation was more pronounced in the parietal seed, which demonstrated stronger connectivity with a frontoparietal network and associations with introspection and social cognition. Correlation analysis revealed both decreasing and increasing functional connectivity with higher age that may add to pathological processes but also indicates compensatory mechanisms of functional reorganization with increasing age. Conclusion: Our findings provide an important pathophysiological link between morphological changes and the clinical relevance of major structural damage in MCI. Multimodal analysis of functional networks related to areas of MCI-typical atrophy may help to explain cognitive decline and behavioral alterations not tractable by a mere anatomical interpretation and therefore contribute to prognostic evaluations.


Free anterolateral thigh flap in pediatric patients.
The anterolateral thigh (ALT) flap represents a workhorse flap in reconstructive surgery. We describe our clinical experience with this flap in the pediatric population. A total of 20 patients with an average age of 9.5 years underwent a free ALT flap reconstruction. All flaps were commonly raised on 2 perforators. About 5 flaps were employed for head and neck reconstruction, 7 for upper and 8 for lower limb reconstruction. Traumatic defects and congenital malformations represented the predominant etiology. Sizable perforators were found in all patients. The caliber was smaller compared to adults, and the course of the perforator was shorter. There were no complete flap losses and no significant donor-site morbidity. Donor-site closure required closure with split-thickness skin grafts in 6 cases. Hypertrophic scars developed in 4 patients. Secondary procedures included flap debulking (5) and Z-plasties (2). In conclusion, children have well-developed perforators supplying the ALT flap. With proper technique, this flap can be harvested and employed safely and reliably for reconstruction of varied defects in children.


Effectiveness of a pediatric verbal lead exposure screening protocol in emergency department patients.
The population demographics found in many urban emergency departments (EDs) often mirrors those of children at risk for elevated serum lead levels. We evaluated the effectiveness of a verbal lead screening program for screening high-risk children presenting to the ED. A prospective observational cohort study was conducted of children aged 9 months to 6 years, living in 2 target counties and presenting to an urban, academic, Midwestern ED. Those with a prior lead level, enrolled in a program requiring lead testing, or with an unstable medical condition were excluded. A 6-question validated verbal survey was administered to all parents of eligible children, and the results recorded in the patient's electronic medical record. Children who screened positive were referred to their local health department for blood lead testing. Health department records were reviewed for follow-up visits and blood lead levels. During the study period, 3513 children were eligible (mean age, 2.6 years; 53.3% male), with 815 patients screened and 209 (25.6%) screening positive. Most positively screened patients (71.8%) documented only 1 affirmative question, most often indicating they lived in a home built before 1978. Of those children who screened positive, 14.8% (31/209) had a blood lead level performed within 6 months. Of those tested, 4 children had an elevated lead level (>10 µg/dL). Use of an ED verbal lead exposure screening tool identified children requiring additional follow-up testing. However, health department-referred children had poor follow-up, and few children were ultimately documented with elevated lead levels.


The role of tone and segmental information in visual-word recognition in Thai.
Tone languages represent a large proportion of the spoken languages of the world and yet lexical tone is understudied. Thai offers a unique opportunity to investigate the role of lexical tone processing during visual-word recognition, as tone is explicitly expressed in its script. We used colour words and their orthographic neighbours as stimuli to investigate facilitation (Experiment 1) and interference (Experiment 2) Stroop effects. Five experimental conditions were created: (a) the colour word (e.g., ขาว /khã:w/ [white]), (b) tone different word (e.g., ข่าว /khà:w/[news]), (c) initial consonant phonologically same word (e.g., คาว /kha:w/ [fishy]), where the initial consonant of the word was phonologically the same but orthographically different, (d) initial consonant different, tone same word (e.g., หาว /hã:w/ yawn), where the initial consonant was orthographically different but the tone of the word was the same, and (e) initial consonant different, tone different word (e.g., กาว /ka:w/ glue), where the initial consonant was orthographically different, and the tone was different. In order to examine whether tone information per se had a facilitative effect, we also included a colour congruent word condition where the segmental (S) information was different but the tone (T) matched the colour word (S-T+) in Experiment 2. Facilitation/interference effects were found for all five conditions when compared with a neutral control word. Results of the critical comparisons revealed that tone information comes into play at a later stage in lexical processing, and orthographic information contributes more than phonological information.


Phyllanthus Suppresses Prostate Cancer Cell, PC-3, Proliferation and Induces Apoptosis through Multiple Signalling Pathways (MAPKs, PI3K/Akt, NFκB, and Hypoxia).
Phyllanthus is a traditional medicinal plant that has been found to have antihepatitis, antibacterial, and anticancer properties. The present studies were to investigate the in vitro molecular mechanisms of anticancer effects of Phyllanthus (P. amarus, P. niruri, P. urinaria, and P. watsonii) plant extracts in human prostate adenocarcinoma. The cancer ten-pathway reporter array was performed and revealed that the expression of six pathway reporters were significantly decreased (Wnt, NFκB, Myc/Max, hypoxia, MAPK/ERK, and MAPK/JNK) in PC-3 cells after treatment with Phyllanthus extracts. Western blot was conducted and identified several signalling molecules that were affected in the signalling pathways including pan-Ras, c-Raf, RSK, Elk1, c-Jun, JNK1/2, p38 MAPK, c-myc, DSH, β-catenin, Akt, HIF-1α, GSK3β, NFκB p50 and p52, Bcl-2, Bax, and VEGF, in treated PC-3 cells. A proteomics-based approach, 2D gel electrophoresis, was performed, and mass spectrometry (MS/MS) results revealed that there were 72 differentially expressed proteins identified in treated PC-3 cells and were involved in tumour cell adhesion, apoptosis, glycogenesis and glycolysis, metastasis, angiogenesis, and protein synthesis and energy metabolism. Overall, these findings suggest that Phyllanthus can interfere with multiple signalling cascades involved in tumorigenesis and be used as a potential therapeutic candidate for treatment of cancer.


Comparative study of methyl-CpG-binding domain proteins.
Methylation at CpG dinucleotides in genomic DNA is a fundamental epigenetic mechanism of gene expression control in vertebrates. Proteins with a methyl-CpG-binding domain (MBD) can bind to single methylated CpGs and most of them are involved in transcription control. So far, five vertebrate MBD proteins have been described as MBD family members: MBD1, MBD2, MBD3, MBD4 and MECP2. We performed database searches for new proteins containing an MBD and identified six amino acid sequences which are different from the previously described ones. Here we present a comparison of their MBD sequences, additional protein motifs and the expression of the encoding genes. A calculated unrooted dendrogram indicates the existence of at least four different groups of MBDs within these proteins. Two of these polypeptides, KIAA1461 and KIAA1887, were only present as predicted amino acid sequences based on a partial human cDNA. We investigated their expression by Northern blot analysis and found transcripts of ~8 kb and ~5 kb respectively, in all eight normal tissues studied. Eleven polypeptides with a MBD could be identified in mouse and man. The analysis of protein domains suggests a role in transcriptional regulation for most of them. The knowledge of additional existing MBD proteins and their expression pattern is important in the context of Rett syndrome.


Alveolar soft-part sarcoma: can MRI help discriminating from other soft-tissue tumors? A study of the French sarcoma group.
To investigate the imaging features of alveolar soft-part sarcomas (ASPS) on pre-treatment MRI in order to identify relevant criteria to distinguish ASPS from other soft-tissue tumors. A series of 25 patients (mean age, 18.5 years old) with histologically proven ASPS from five French comprehensive cancer centers was compared to a control cohort of 292 patients with various histologically proven benign and malignant soft-tissue tumors representative of the 10-year long activity of one center. All had a baseline MRI with contrast-agent administration. Two radiologists independently reviewed the MRIs. Features assessing location, size, signal, architecture, periphery, and vascularization were reported. Their association with the histological diagnosis of ASPS was evaluated with chi-square or Fisher's test. Their prevalence, sensitivity, specificity, odds ratio, and reproducibility were calculated. Eight MRI features were significantly associated with ASPS: deep location (p < 0.001), high signal intensities on T1-weighted imaging (p < 0.001), central area of necrosis (p = 0.001), absence of fibrotic component (p = 0.003), infiltrative growth pattern (p = 0.003), absence of tail sign (p = 0.001), presence of intra- and peritumoral flow-voids (p < 0.001), and number of flow-voids ≥ 5 (p < 0.001). Twenty out of the 25 (80%) ASPS showed at least 7 of these 8 features compared to only four out of 292 (1.4%) tumors of the control cohort (1 benign vascular tumor, 1 solitary fibrous tumor, 2 high-grade soft-tissue sarcomas). The five ASPS with less than 7 out of 8 features measured less than 40 mm. The striking histological uniformity of ASPS translates into imaging. However, ASPS may be misdiagnosed as benign tumors or pseudo-tumors, notably intramuscular benign vascular tumors or vascular malformations. • ASPS are rare aggressive mesenchymal tumors displaying recurrent MRI features highly reminiscent of the diagnosis. • Deep-seated tumors presenting with mainly high signal intensity on T1-weighted imaging, an absence of fibrotic component, ill-defined margins without aponeurotic extension, and more than five central and peripheral flow-voids are very likely to be ASPS. • ASPS may be misdiagnosed as intramuscular benign vascular tumor or vascular malformation, which occur in the same age group.


Interleukin-17 is not required for classical macrophage activation in a pulmonary mouse model of Cryptococcus neoformans infection.
Cryptococcus neoformans is an opportunistic fungal pathogen that causes disease in individuals with suppressed cell-mediated immunity. Recent studies in our laboratory have shown that increases in pulmonary Th1-type and interleukin-17A (IL-17A) cytokine production, classical macrophage activation, and sterilizing immunity are elicited in response to infection with a gamma interferon (IFN-γ)-producing C. neoformans strain, H99γ. IL-17A-treated macrophages, compared to IL-4-treated macrophages, have been demonstrated to exhibit increased microbicidal activity in vitro, a characteristic consistent with classical macrophage activation. The purpose of these studies is to determine the role of IL-17A in the induction of classically activated macrophages following infection with C. neoformans. Immunohistochemistry and real-time PCR were used to characterize the macrophage activation phenotype in lung tissues of mice treated with isotype control or anti-IL-17A antibodies and given an experimental pulmonary infection with C. neoformans strain H99γ. The pulmonary fungal burden was resolved, albeit more slowly, in mice depleted of IL-17A compared to the fungal burden in isotype control-treated mice. Nonetheless, no difference in classical macrophage activation was observed in IL-17A-depleted mice. Similarly, classical macrophage activation was evident in mice deficient in IL-17A or the IL-17 receptor A, which mediates IL-17A signaling, following pulmonary infection with wild-type C. neoformans strain H99 or H99γ. These studies suggest that IL-17A may play a role in the early immune response to C. neoformans but is not required for classical macrophage activation in mice experimentally infected with C. neoformans.


Inverse Association Between the Skin and Oral Microbiota in Atopic Dermatitis.
Previous studies have shown independently that the skin and gut microbiota are closely associated with atopic dermatitis (AD); however, the microbiota across different habitats of AD patients as an integrated community has not been characterized. In the present study, we comparatively analyzed the structure and function of the microbial communities in the skin, oral cavity, and gut of 172 AD patients and 120 healthy controls through 16S ribosomal RNA gene amplicon sequencing. The skin and oral cavity, but not the gut, of AD patients demonstrated differential reduction in the microbial diversity, and these were distinctly correlated with disease severity. Different degrees of shifts in the community structure were found among different habitats, and the lineage distance between the skin and oral microbiota of AD patients was closer than that observed in the controls. The different habitats of AD patients exhibited site-specific alterations at the genus level, and many oral-specific microbes of AD showed opposing directions of enrichment in the skin and oral cavity. Most interestingly, an inverse association in the functional pathways was found between the skin and oral microbiota of AD patients. Additionally, the alterations of the microbiota in different body sites of AD patients were differentially affected by age.


Genetic regulation of MUC1 alternative splicing in human tissues.
The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5' end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms ofMUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5' exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, over-representation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well.


Why do people postpone parenthood? Reasons and social policy incentives.
Never before have parents in most Western societies had their first children as late as in recent decades. What are the central reasons for postponement? What is known about the link between the delay of childbearing and social policy incentives to counter these trends? This review engages in a systematic analysis of existing evidence to extract the maximum amount of knowledge about the reasons for birth postponement and the effectiveness of social policy incentives. The review followed the PRISMA procedure, with literature searches conducted in relevant demographic, social science and medical science databases (SocINDEX, Econlit, PopLine, Medline) and located via other sources. The search focused on subjects related to childbearing behaviour, postponement and family policies. National, international and individual-level data sources were also used to present summary statistics. There is clear empirical evidence of the postponement of the first child. Central reasons are the rise of effective contraception, increases in women's education and labour market participation, value changes, gender equity, partnership changes, housing conditions, economic uncertainty and the absence of supportive family policies. Evidence shows that some social policies can be effective in countering postponement. The postponement of first births has implications on the ability of women to conceive and parents to produce additional offspring. Massive postponement is attributed to the clash between the optimal biological period for women to have children with obtaining additional education and building a career. A growing body of literature shows that female employment and childrearing can be combined when the reduction in work-family conflict is facilitated by policy intervention.


Influence of Ambient Air Pollution on Rheumatoid Arthritis Disease Activity Score Index.
Rheumatoid arthritis (RA) is a chronic autoimmune of an unknown etiology. Air pollution has been proposed as one of the possible risk factors associated with disease activity, although has not been extensively studied. In this study, we measured the relationship between exposure to air pollutants and RA activity. Data on RA patients were extracted from the Kuwait Registry for Rheumatic Diseases (KRRD). Disease activity was measured using disease activity score with 28 examined joints (DAS-28) and the Clinical Disease Activity Index (CDAI) during their hospital visits from 2013 to 2017. Air pollution was assessed using air pollution components (PM 10 , NO 2 , SO 2 , O 3 , and CO). Air pollution data were obtained from Kuwait Environmental Public Authority (K-EPA) from six different air quality-monitoring stations during the same period. Multiple imputations by the chained equations (MICE) algorithm were applied to estimate missing air pollution data. Patients data were linked with air pollution data according to date and patient governorate address. Descriptive statistics, correlation analysis, and linear regression techniques were employed using STATA software. In total, 1651 RA patients with 9875 follow-up visits were studied. We detected an increased risk of RA using DAS-28 in participants exposed to SO 2 and NO 2 with β = 0 . 003 (95% CI: 0.0004-0.005, p < 0 . 01 ) and β = 0 . 003 (95% CI: 0.002-0.005, p < 0 . 01 ), respectively, but not to PM 10 , O 3 , and CO concentrations. Conclusively, we observed a strong association between air pollution with RA disease activity. This study suggests air pollution as a risk factor for RA and recommends further measures to be taken by the authorities to control this health problem.


Laser absorption spectroscopy of water vapor confined in nanoporous alumina: wall collision line broadening and gas diffusion dynamics.
We demonstrate high-resolution tunable diode laser absorption spectroscopy (TDLAS) of water vapor confined in nanoporous alumina. Strong multiple light scattering results in long photon pathlengths (1 m through a 6 mm sample). We report on strong line broadening due to frequent wall collisions (gas-surface interactions). For the water vapor line at 935.685 nm, the HWHM of confined molecules are about 4.3 GHz as compared to 2.9 GHz for free molecules (atmospheric pressure). Gas diffusion is also investigated, and in contrast to molecular oxygen (that moves rapidly in and out of the alumina), the exchange of water vapor is found very slow.


Biofeedback dialysis for hypotension and hypervolemia: a systematic review and meta-analysis.
Intradialytic hypotension (IDH) is associated with morbidity and mortality. We conducted a systematic review to determine whether biofeedback hemodialysis (HD) can improve IDH and other outcomes, compared with HD without biofeedback. Data sources included the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and ISI Web of Science. We included randomized trials that enrolled adult patients (>18 years) with IDH or extracellular fluid expansion and that used biofeedback to guide ultrafiltration and/or dialysate conductivity. Two authors assessed trial quality and independently extracted data in duplicate. We assessed heterogeneity using I(2). We applied the GRADE framework for rating the quality of evidence. We found two parallel-arm randomized controlled clinical trials and six randomized crossover trials meeting inclusion criteria. All trials were open-label and at least four were industry-sponsored. Studies were small (median n = 27). No study evaluated hospitalization and the evidence for effect on mortality was of very low quality. Three studies assessed quality of life (QoL); none demonstrated benefit or harm, and quality of evidence was very low. Biofeedback significantly reduced IDH (risk ratio 0.61, 95% confidence interval 0.44-0.86; I(2)= 0%). Quality of evidence for this outcome was low due to risk of bias and potential publication bias. Biofeedback dialysis significantly reduces the frequency of IDH. Large and well-designed randomized trials are needed to assess the effects on survival, hospitalization and QoL.


Avoidant/restrictive food intake disorder: a new eating disorder diagnosis in the diagnostic and statistical manual 5.
Avoidant/restrictive food intake disorder (ARFID) is a new eating disorder diagnosis in the 5th edition of the diagnostic and statistical manual (DSM-5), published in 2013. The purpose of this review is to describe the creation of ARFID as a diagnostic category, and to explain the DSM-5 diagnostic criteria; to demonstrate what is known thus far about the prevalence of ARFID and characteristics of patients with this disorder; to provide guidance to the pediatrician and other providers on making a diagnosis of ARFID; and to discuss evolving treatment approaches. Several studies have been published recently on the prevalence and characteristics of patients with ARFID. Research has just begun to focus on new assessment measures, approaches to treatment based on established therapies for other eating/psychiatric disorders, and short-term outcomes. Robust treatment studies are in development. The addition of ARFID to the DSM-5 has captured a category of patients with clinically significant restrictive eating, but without weight and shape concerns, who were poorly classified in the past. Future research is needed to further elucidate the presentation, characteristics, diagnostic instruments, and effective management.


CT colonography: a systematic review of standard of reporting for studies of computer-aided detection.
To determine objectively the current standard of reporting for studies of computer-aided detection (CAD) for computed tomographic (CT) colonography by systematically reviewing published articles. MEDLINE was searched to identify study articles meeting the inclusion criteria for describing CAD for CT colonography in human subjects. Data were extracted from eligible articles, grouped into five domains: technical description of CAD algorithm, description of subjects, acquisition of data, evaluation strategy used, and presentation of results. Primary studies were scored for each domain and overall findings plotted as star plots. Although 21 (91%) of the 23 studies included presented technical details of the CAD algorithm, methodologic details used for model development and validity were generally poor. Investigators in six (26%) studies described the evaluation data set sufficiently for replication; investigators in eight (35%) studies described age and sex demographics for subjects in whom CAD was tested. Investigators in 11 (48%) studies presented polyps per subject. Investigators in 12 (52%) studies described the reference standard against which CAD was judged; 11 (48%) studies explicitly distinguished between development and evaluation data. In nine (39%) studies, the evaluation strategy used to test CAD could not be deduced at all. Description of subjects included for CAD development and evaluation was most poorly reported, with an average score per study of 33% in this domain. The reporting quality for studies of CAD for CT colonography is highly variable; key methodologic details needed for informed assessment of the generalizability of results are frequently omitted, for which a minimum data set based on the observations is proposed.


Unexpected non-HIV causes of death in children born to HIV-infected mothers. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group.
A high incidence of sudden, unexplained deaths in infants born to HIV-infected mothers has been noted in several epidemiologic studies. During the course of a prospective study of heart and lung disease in children born to HIV-infected mothers, we noted that of 5 unexpected non-HIV-related deaths, 4 were attributed to traumatic events. The Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2) study is a multicenter, prospective investigation of the incidence of heart and lung disease in HIV-infected children. A total of 805 children were enrolled and followed for 5 to 7 years with serial immunologic, pulmonary and cardiac function studies. During the study, a multidisciplinary committee was formed to review the cause of death for those patients who died. The committee used results of pulmonary, cardiac, and laboratory tests, hospital summaries, as well as autopsy and coroners' reports. The committee formed a consensus about the underlying and contributing causes of death for each subject using the definitions from the 1989 US Standard Certificate of Death. A total of 121 deaths occurred during the course of the P2C2 study. Of the 121 deaths, 5 were traumatic or sudden and unexpected and judged by the Mortality Review Committee to be unrelated to HIV infection. The median age at the time of death was 1.3 months and ranged from 1.2 to 37.8 months. Two infants died of trauma: a skull fracture and subdural hematoma in 1 infant and multiple skeletal fractures consistent with battered child syndrome in the other infant. The third infant died of accidental suffocation at home at 1.2 months of age. The fourth infant died suddenly and unexpectedly at home at 1.3 months of age. The autopsy showed no sign of HIV or other infection and was consistent with sudden unexpected death or SIDS. One non-HIV-related death occurred when a 38-month-old child died together with the mother in an unwitnessed drowning. The cumulative mortality rate attributable to trauma and sudden death at 4 months of age was 0.95% (95% CI: 0.02-1. 87%) and the infant mortality rate was 9.5/1000 live births. Three children were born prematurely at 30, 33, and 36 weeks' gestational age, respectively, and 3 mothers admitted using recreational drugs before or during pregnancy. These traumatic and sudden non-HIV-related deaths accounted for 4.1% (5/121) of the deaths during the entire P2C2 study period and for 20% (4/20) of the deaths in the first year of life. Four deaths were attributable to accidental and nonaccidental trauma rather than to other common causes of infant death. One death was a sudden unexpected death, similar to SIDS, a leading cause of infant death in the United States. The majority of previously reported non-HIV-related deaths in infants born to HIV-infected mothers have been attributed to SIDS or to unexplained sudden death. In contrast with other reports, 4 of the 5 children in our series died of accidental or nonaccidental trauma and only 1 was a sudden unexplained death. It is unlikely that HIV exposure is related directly to the deaths described in this report; however, maternal HIV infection may be a marker for factors that place the child at risk for sudden or traumatic death. This report suggests that children born to HIV-infected mothers may be at increased risk for traumatic or sudden, unexplained, non-HIV-related death. These children seem to be at risk regardless of their own HIV infection status. Furthermore, 4 of the deaths in our study occurred within the first few months of life, suggesting that this is a period of increased vulnerability. Studies to identify associated risk factors for non-HIV-related deaths are needed to identify these high-risk infants. Children born to HIV-infected mothers may be more vulnerable than was recognized previously and may be in need of increased social services, especially in early infancy.


High-dose regimen of interleukin-2 and interferon-alpha in combination with lymphokine-activated killer cells in patients with metastatic renal cell cancer.
Seventy-two patients with metastatic renal cell cancer were treated with the combination of high-dose interleukin-2 (IL2), interferon-alpha (IFN alpha), and lymphokine-activated killer cells (LAK). Seventeen patients were entered in a feasibility part of the study (protocol 1) and 55 in an efficacy part (protocol 2). Protocol 2 differed from protocol 1 in the addition of IFN alpha to the first 5 days of IL2 infusion. Each patient was planned to receive two induction cycles. IL2, 18 MIU/m2/day, was administered continuously i.v. on days 1-5, and IFN alpha, 5 MIU/m2/day (protocol 2), was administered i.m. on days 1-5, followed by three daily lymphaphereses on days 7-9. On day 12, treatment was resumed with IL2 and IFN alpha on days 12-15 and LAK reinfusions on days 12-14. In protocol 1, three complete (CR) and one partial (PR) responses were achieved (response rate 24%). The median duration of response and the median survival were 18.1 and 13.9 months, respectively. The 3-year survival was 35%. Of the 51 evaluable patients in protocol 2, 6 achieved a CR and 13 a PR (response rate 37%). The median duration of response was 11.1 months. The median survival was 16.9 months. The 3-year survival was 35%. There were three treatment-related deaths. Other severe toxicities included hypotension, cardiotoxicity, pulmonary edema, renal toxicity, and infectious complications. In the two induction cycles, only 54 and 42% of the planned doses could be administered. We conclude that the use of high-dose regimens of IL2 and IFN alpha is not warranted, unless we can define more accurately which patients may experience long-term survival as a result of treatment.


The influence of trial order on learning from reward vs. punishment in a probabilistic categorization task: experimental and computational analyses.
Previous research has shown that trial ordering affects cognitive performance, but this has not been tested using category-learning tasks that differentiate learning from reward and punishment. Here, we tested two groups of healthy young adults using a probabilistic category learning task of reward and punishment in which there are two types of trials (reward, punishment) and three possible outcomes: (1) positive feedback for correct responses in reward trials; (2) negative feedback for incorrect responses in punishment trials; and (3) no feedback for incorrect answers in reward trials and correct answers in punishment trials. Hence, trials without feedback are ambiguous, and may represent either successful avoidance of punishment or failure to obtain reward. In Experiment 1, the first group of subjects received an intermixed task in which reward and punishment trials were presented in the same block, as a standard baseline task. In Experiment 2, a second group completed the separated task, in which reward and punishment trials were presented in separate blocks. Additionally, in order to understand the mechanisms underlying performance in the experimental conditions, we fit individual data using a Q-learning model. Results from Experiment 1 show that subjects who completed the intermixed task paradoxically valued the no-feedback outcome as a reinforcer when it occurred on reinforcement-based trials, and as a punisher when it occurred on punishment-based trials. This is supported by patterns of empirical responding, where subjects showed more win-stay behavior following an explicit reward than following an omission of punishment, and more lose-shift behavior following an explicit punisher than following an omission of reward. In Experiment 2, results showed similar performance whether subjects received reward-based or punishment-based trials first. However, when the Q-learning model was applied to these data, there were differences between subjects in the reward-first and punishment-first conditions on the relative weighting of neutral feedback. Specifically, early training on reward-based trials led to omission of reward being treated as similar to punishment, but prior training on punishment-based trials led to omission of reward being treated more neutrally. This suggests that early training on one type of trials, specifically reward-based trials, can create a bias in how neutral feedback is processed, relative to those receiving early punishment-based training or training that mixes positive and negative outcomes.


A perivascular origin for mesenchymal stem cells in multiple human organs.
Mesenchymal stem cells (MSCs), the archetypal multipotent progenitor cells derived in cultures of developed organs, are of unknown identity and native distribution. We have prospectively identified perivascular cells, principally pericytes, in multiple human organs including skeletal muscle, pancreas, adipose tissue, and placenta, on CD146, NG2, and PDGF-Rbeta expression and absence of hematopoietic, endothelial, and myogenic cell markers. Perivascular cells purified from skeletal muscle or nonmuscle tissues were myogenic in culture and in vivo. Irrespective of their tissue origin, long-term cultured perivascular cells retained myogenicity; exhibited at the clonal level osteogenic, chondrogenic, and adipogenic potentials; expressed MSC markers; and migrated in a culture model of chemotaxis. Expression of MSC markers was also detected at the surface of native, noncultured perivascular cells. Thus, blood vessel walls harbor a reserve of progenitor cells that may be integral to the origin of the elusive MSCs and other related adult stem cells.


Transforming RNA-Seq data to improve the performance of prognostic gene signatures.
Gene expression measurements have successfully been used for building prognostic signatures, i.e for identifying a short list of important genes that can predict patient outcome. Mostly microarray measurements have been considered, and there is little advice available for building multivariable risk prediction models from RNA-Seq data. We specifically consider penalized regression techniques, such as the lasso and componentwise boosting, which can simultaneously consider all measurements and provide both, multivariable regression models for prediction and automated variable selection. However, they might be affected by the typical skewness, mean-variance-dependency or extreme values of RNA-Seq covariates and therefore could benefit from transformations of the latter. In an analytical part, we highlight preferential selection of covariates with large variances, which is problematic due to the mean-variance dependency of RNA-Seq data. In a simulation study, we compare different transformations of RNA-Seq data for potentially improving detection of important genes. Specifically, we consider standardization, the log transformation, a variance-stabilizing transformation, the Box-Cox transformation, and rank-based transformations. In addition, the prediction performance for real data from patients with kidney cancer and acute myeloid leukemia is considered. We show that signature size, identification performance, and prediction performance critically depend on the choice of a suitable transformation. Rank-based transformations perform well in all scenarios and can even outperform complex variance-stabilizing approaches. Generally, the results illustrate that the distribution and potential transformations of RNA-Seq data need to be considered as a critical step when building risk prediction models by penalized regression techniques.


Eco-evolutionary feedback and the invasion of cooperation in prisoner's dilemma games.
Unveiling the origin and forms of cooperation in nature poses profound challenges in evolutionary ecology. The prisoner's dilemma game is an important metaphor for studying the evolution of cooperation. We here classified potential mechanisms for cooperation evolution into schemes of frequency- and density-dependent selection, and focused on the density-dependent selection in the ecological prisoner's dilemma games. We found that, although assortative encounter is still the necessary condition in ecological games for cooperation evolution, a harsh environment, indicated by a high mortality, can foster the invasion of cooperation. The Hamilton rule provides a fundamental condition for the evolution of cooperation by ensuring an enhanced relatedness between players in low-density populations. Incorporating ecological dynamics into evolutionary games opens up a much wider window for the evolution of cooperation, and exhibits a variety of complex behaviors of dynamics, such as limit and heteroclinic cycles. An alternative evolutionary, or rather succession, sequence was proposed that cooperation first appears in harsh environments, followed by the invasion of defection, which leads to a common catastrophe. The rise of cooperation (and altruism), thus, could be much easier in the density-dependent ecological games than in the classic frequency-dependent evolutionary games.


SEN virus infection in patients on peritoneal dialysis.
Many reports have demonstrated SEN virus (SEN-V) infection rates in hemodialysis patients, but the SEN-V infection rate in peritoneal dialysis (PD) patients has never been reported. In this study, we determined the prevalence rate of SEN-V viremia in a PD population. Serum samples from 47 PD patients and a control group of 43 subjects from the general population at their health examination were assayed for SEN-V-D and -H viremia using polymerase chain reaction. The proportions of female gender (p = 0.001), previous transfusion (p < 0.0001), and higher mean serum AST level (p = 0.012) were significantly higher in PD patients. The prevalence rates of SEN-V-D and/or -H viremia were not significantly different between PD patients and controls (27.7% vs 32.6%). SEN-V-D(+) patients had lower mean duration of PD than SEN-V(-) patients. Mean ALT level was significantly lower in SEN-V-H(+) than in SEN-V(-) patients (12.8 +/- 5.8 vs 19.6 +/- 12.1 (IU/L), p = 0.025). None of the SEN-V-infected PD patients had overt clinical or biochemical signs of liver disease. There were no statistically significant differences in prevalence of SEN-V-D and/or -H viremia between automated PD (APD) patients and continuous ambulatory PD (CAPD) patients. These results indicate that the SEN-V infection rate is not different between healthy individuals and PD patients. Infection with SEN-V is not associated with evident liver disease in PD patients and SEN-V infection rate is not different between APD patients and CAPD patients.


Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma.
Neoadjuvant pemetrexed plus cisplatin was administered, followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT), to assess the feasibility and efficacy of trimodality therapy in stage I to III malignant pleural mesothelioma. Requirements included stage T1-3 N0-2 disease, no prior surgical resection, adequate organ function (including predicted postoperative forced expiratory volume in 1 second > or = 35%), and performance status 0 to 1. Patients received pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) for four cycles. Patients without disease progression underwent EPP followed by RT (54 Gy). The primary end point was pathologic complete response (pCR) rate. Seventy-seven patients received chemotherapy. All four cycles were administered to 83% of patients. The radiologic response rate was 32.5% (95% CI, 22.2 to 44.1). Fifty-seven patients proceeded to EPP, which was completed in 54 patients. Three pCRs were observed (5% of EPP). Forty of 44 patients completed irradiation. Median survival in the overall population was 16.8 months (95% CI, 13.6 to 23.2 months; censorship, 33.8%). Patients completing all therapy had a median survival of 29.1 months and a 2-year survival rate of 61.2%. Radiologic response of complete or partial response was associated with a median survival of 26.0 months compared with 13.9 months for patients with stable disease or progressive disease (P = .05). This multicenter trial showed that trimodality therapy with neoadjuvant pemetrexed plus cisplatin is feasible with a reasonable long-term survival rate, particularly for patients who completed all therapy. Radiologic response to chemotherapy, but not sex, histology, disease stage, or nodal status, was associated with improved survival.


Inhibition of clot formation in deterministic lateral displacement arrays for processing large volumes of blood for rare cell capture.
Microfluidic deterministic lateral displacement (DLD) arrays have been applied for fractionation and analysis of cells in quantities of ~100 μL of blood, with processing of larger quantities limited by clogging in the chip. In this paper, we (i) demonstrate that this clogging phenomenon is due to conventional platelet-driven clot formation, (ii) identify and inhibit the two dominant biological mechanisms driving this process, and (iii) characterize how further reductions in clot formation can be achieved through higher flow rates and blood dilution. Following from these three advances, we demonstrate processing of 14 mL equivalent volume of undiluted whole blood through a single DLD array in 38 minutes to harvest PC3 cancer cells with ~86% yield. It is possible to fit more than 10 such DLD arrays on a single chip, which would then provide the capability to process well over 100 mL of undiluted whole blood on a single chip in less than one hour.


Attitude of dental professionals toward cast partial denture: A questionnaire survey in India.
The use of cast partial dentures (CPDs) has been decreased and its importance has been declined in the teaching curriculum. The purpose of this survey was to evaluate the attitudes of dental professionals toward conditions using CPDs in private practice in India. Descriptive survey. This survey consists of eight close-ended questions concerning the use of CPD by dental professionals practicing in India. The URLs of the questionnaire were shared via E-mail to dentists practicing throughout India, to obtain a response of 384 which is a predetermined sample size. Statistical analysis was done using counts and percentages and the results were further analyzed statistically by the Chi-square test. Nearly 42.79% of general dental practitioners (GDPs), 47.26% of prosthodontists, and 9.95% of other specialist dentists responded to the questionnaire. GDPs mostly preferred removable partial dentures (RPDs) (71.87%) and fixed partial dentures (57.22%), whereas prosthodontists preferred mostly implant (60.91%). GDPs mostly preferred flexible dentures (62.42%), whereas prosthodontists preferred CPDs 62.84%. Almost 52.50% of the GDPs mostly raised a cost issue and 63.11% of the prosthodontists had difficulty in adjustment with CPDs. Nearly 63.46% of the dentists told that implant-supported restorations are better options compared to CPDs; still, majority of the dentists (53.23%) were in favor that more importance for teaching CPDs in graduation curriculum should be given. This survey shows that in India a significant proportion of GDPs (71.87%) preferred RPDs, mostly flexible dentures (62.42%) due to their low cost compared to CPDs. Prosthodontists mostly preferred implants (60.91%) because they are more confident and better trained in these. It is recommended that more importance be given in teaching implants along with CPDs in graduation curriculum so that practitioners can better educate their patients about implants and their advantages over flexible dentures and their utilization in cases where patients are not willing for CPDs.


TcGPXII, a glutathione-dependent Trypanosoma cruzi peroxidase with substrate specificity restricted to fatty acid and phospholipid hydroperoxides, is localized to the endoplasmic reticulum.
Until recently, it had been thought that trypanosomes lack glutathione peroxidase activity. Here we report the subcellular localization and biochemical properties of a second glutathione-dependent peroxidase from Trypanosoma cruzi (TcGPXII). TcGPXII is a single-copy gene which encodes a 16 kDa protein that appears to be specifically dependent on glutathione as the source of reducing equivalents. Recombinant TcGPXII was purified and shown to have peroxidase activity towards a narrow substrate range, restricted to hydroperoxides of fatty acids and phospholipids. Analysis of the pathway revealed that TcGPXII activity could be readily saturated by glutathione and that the peroxidase functioned by a Ping Pong mechanism. Enzyme reduction was shown to be the rate-limiting step in this pathway. Using immunofluorescence, TcGPXII was shown to co-localize with a homologue of immunoglobulin heavy-chain binding protein (BiP), a protein restricted to the endoplasmic reticulum and Golgi. As the smooth endoplasmic reticulum is the site of phospholipid and fatty acid biosynthesis, this suggests that TcGPXII may play a specific role in the T. cruzi oxidative defence system by protecting newly synthesized lipids from peroxidation.


Are increasing 5-year survival rates evidence of success against cancer?
Increased 5-year survival for cancer patients is generally inferred to mean that cancer treatment has improved and that fewer patients die of cancer. Increased 5-year survival, however, may also reflect changes in diagnosis: finding more people with early-stage cancer, including some who would never have become symptomatic from their cancer. To determine the relationship over time between 5-year cancer survival and 2 other measures of cancer burden, mortality and incidence. Using population-based statistics reported by the National Cancer Institute Surveillance, Epidemiology, and End Results Program, we calculated the change in 5-year survival from 1950 to 1995 for the 20 most common solid tumor types. Using the tumor as the unit of analysis, we correlated changes in 5-year survival with changes in mortality and incidence. The association between changes in 5-year survival and changes in mortality and incidence measured using simple correlation coefficients (Pearson and Spearman). From 1950 to 1995, there was an increase in 5-year survival for each of the 20 tumor types. The absolute increase in 5-year survival ranged from 3% (pancreatic cancer) to 50% (prostate cancer). During the same period, mortality rates declined for 12 types of cancer and increased for the remaining 8 types. There was little correlation between the change in 5-year survival for a specific tumor and the change in tumor-related mortality (Pearson r=.00; Spearman r=-.07). On the other hand, the change in 5-year survival was positively correlated with the change in the tumor incidence rate (Pearson r=+. 49; Spearman r=+.37). Although 5-year survival is a valid measure for comparing cancer therapies in a randomized trial, our analysis shows that changes in 5-year survival over time bear little relationship to changes in cancer mortality. Instead, they appear primarily related to changing patterns of diagnosis. JAMA. 2000.


Gene-gene interaction associated with neural reward sensitivity.
Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.


Environmental Suitability of Vibrio Infections in a Warming Climate: An Early Warning System.
Some Vibrio spp. are pathogenic and ubiquitous in marine waters with low to moderate salinity and thrive with elevated sea surface temperature (SST). Our objective was to monitor and project the suitability of marine conditions for Vibrio infections under climate change scenarios. The European Centre for Disease Prevention and Control (ECDC) developed a platform (the ECDC Vibrio Map Viewer) to monitor the environmental suitability of coastal waters for Vibrio spp. using remotely sensed SST and salinity. A case-crossover study of Swedish cases was conducted to ascertain the relationship between SST and Vibrio infection through a conditional logistic regression. Climate change projections for Vibrio infections were developed for Representative Concentration Pathway (RCP) 4.5 and RCP 8.5. The ECDC Vibrio Map Viewer detected environmentally suitable areas for Vibrio spp. in the Baltic Sea in July 2014 that were accompanied by a spike in cases and one death in Sweden. The estimated exposure-response relationship for Vibrio infections at a threshold of 16°C revealed a relative risk (RR)=1.14 (95% CI: 1.02, 1.27; p=0.024) for a lag of 2 wk; the estimated risk increased successively beyond this SST threshold. Climate change projections for SST under the RCP 4.5 and RCP 8.5 scenarios indicate a marked upward trend during the summer months and an increase in the relative risk of these infections in the coming decades. This platform can serve as an early warning system as the risk of further Vibrio infections increases in the 21st century due to climate change. https://doi.org/10.1289/EHP2198.


Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages.
The plasminogen activator (PA) produced by freshly purified human monocytes-macrophages and histiocytic, lymphoma-derived U 937 cells was analyzed by zymography after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and found to migrate with an apparent Mr of 55,000, identical to that of urokinase (Uk). By immunoprecipitation with antibodies specific for the two different types of PA, the enzyme was shown to be immunologically related to urokinase, and not to tissue PA. Urokinase was secreted in the form of the inactive Mr 55,000 zymogen prourokinase , and could be converted to the active Mr 55,000 enzyme by limited proteolysis with plasmin. Conditioned media from cultures of U 937 cells and monocytes-macrophages inhibited the fibrinolytic activity of exogenously added urokinase. Using [125I]-labeled urokinase we observed the formation of an enzyme-ligand complex, which was not dissociated by boiling in SDS and migrated with an apparent Mr 40,000 daltons higher than the free enzyme; since complexed urokinase was functionally inactivated as a PA, the ligand is an inhibitor of urokinase. This inhibitor is different from fibroblast-produced protease- nexin , in that it did not interact with thrombin. These results suggest that plasminogen activation by mononuclear phagocytes can be modulated through the secretion of both (pro)enzyme and a specific inhibitor.


Mechanism of enhanced cold tolerance by an ephedrine-caffeine mixture in humans.
The influence of a thermogenic mixture of ephedrine- (1 mg/kg) caffeine (2.5 mg/kg) on cold tolerance was investigated in nine healthy young male subjects during two seminude exposures to cold air (3 h at 10 degrees C). The drug ingestion reduced the total drop in core, mean skin, and mean body temperatures (P less than 0.01), thus producing significantly warmer final core, mean skin, and mean body temperatures compared with the placebo ingestion. The drug ingestion increased the total 3-h energy expenditure by 18.6% compared with that of the placebo ingestion in the cold (P less than 0.01). By means of the nonprotein respiratory exchange ratio to calculate the rates of substrate oxidation, it was found that the drug ingestion increased carbohydrate oxidation by as much as 41.7% above that of the placebo (P less than 0.05). In contrast, the drug mixture had no significant influence on lipid or protein metabolism. The results demonstrate that the ingestion of an ephedrine-caffeine mixture improves cold tolerance in humans by significantly increasing body temperatures in the cold. These improvements were not caused by an increased conservation of heat but by a greater energy expenditure, which appears to be dependent on an enhanced carbohydrate utilization.


Spatial interactions in the superior colliculus predict saccade behavior in a neural field model.
During natural vision, eye movements are dynamically controlled by the combinations of goal-related top-down (TD) and stimulus-related bottom-up (BU) neural signals that map onto objects or locations of interest in the visual world. In primates, both BU and TD signals converge in many areas of the brain, including the intermediate layers of the superior colliculus (SCi), a midbrain structure that contains a retinotopically coded map for saccades. How TD and BU signals combine or interact within the SCi map to influence saccades remains poorly understood and actively debated. It has been proposed that winner-take-all competition between these signals occurs dynamically within this map to determine the next location for gaze. Here, we examine how TD and BU signals interact spatially within an artificial two-dimensional dynamic winner-take-all neural field model of the SCi to influence saccadic RT (SRT). We measured point images (spatially organized population activity on the SC map) physiologically to inform the TD and BU model parameters. In this model, TD and BU signals interacted nonlinearly within the SCi map to influence SRT via changes to the (1) spatial size or extent of individual signals, (2) peak magnitude of individual signals, (3) total number of competing signals, and (4) the total spatial separation between signals in the visual field. This model reproduced previous behavioral studies of TD and BU influences on SRT and accounted for multiple inconsistencies between them. This is achieved by demonstrating how, under different experimental conditions, the spatial interactions of TD and BU signals can lead to either increases or decreases in SRT. Our results suggest that dynamic winner-take-all modeling with local excitation and distal inhibition in two dimensions accurately reflects both the physiological activity within the SCi map and the behavioral changes in SRT that result from BU and TD manipulations.


Africa in transition: growth trends in children and implications for nutrition.
The aims of this paper were to: (1) review the literature and examine contemporary child growth in terms of stunting prevalence across Africa; (2) discuss child stunting within the context of economic growth and adult obesity, and (3) elucidate the implications for child nutrition. It is evident that stunting in under-5-year-old children still plagues Africa and has not decreased as expected in line with the concomitant improvement in economic development over the past decade. Persisting and possibly widening inequality ensures that not all segments of the population, in particular the most vulnerable, benefit equally from economic growth. Of concern is the association between the increasing economic progress across Africa and the rising adult obesity, especially amongst females. More and more African countries are now afflicted with a double burden of malnutrition. The implication for child nutrition is that African countries need not only apply a multisectoral approach to accelerate the reduction in stunting levels, but also to arrest and prevent obesity.


Sensitive and controversial ethical issues subject of groundbreaking Toronto exhibit.
Medical research and practice have always posed many ethical dilemmas for scientists and physicians, but technologic advances mean that the questions are becoming even more difficult. That is why an exhibit, A Question of Truth, that is being prepared at Toronto's Ontario Science Centre is so timely. It examines the biases and political climates in which science operates, as well as the relative subjectivity of truth, knowledge and reality.


Effect of heavy load carriage on cardiorespiratory responses with varying gradients and modes of carriage.
The present study was undertaken to determine the effect of different uphill and downhill gradients on cardiorespiratory and metabolic responses of soldiers while carrying heavy military loads in two different modes. Eight physically fit male soldiers with a mean age 32.0 ± 2.0 years, a mean height of 169.5 ± 4.9 cm, and a mean weight of 63.8 ± 8.4 kg volunteered for this study. Each volunteer completed treadmill walking trials at a speed of 3.5 km/h while carrying no external load, 31.4 kg load in a distributed mode (existing load carriage ensembles) and compact mode (new back pack) over 5 different downhill and uphill gradients (- 5, - 10%, 0, 5, 10%) for 6 min at each gradient. During the walking trials, heart rate (HR), oxygen uptake (VO2), respiratory frequency (RF) and energy expenditure (EE) were determined by the process of breath-by-breath gas analysis using a K4b2 system. The average of the last 2 min data from each 6 min walking trial for each individual was subjected to statistical analysis. All parameters (HR, VO2, RF, and EE) gradually increased with the change in gradient from downhill to level to uphill. The distributed mode showed higher values compared to compact mode for all gradients, e.g., for VO2, there was a 10.7, 7.4, 5.1, 28.2 and 18.7% increase in the distributed mode across the 5 different gradients. It can be concluded from the present study that the compact mode of load carriage is more beneficial than the distributed mode in terms of cardiorespiratory responses while walking on downhill and uphill surfaces with a 31.4 kg load.


Lidar fluorosensing of mineral oil spills on the sea surface.
Airborne fluorosensor measurements over maritime oil spills show that this method enables a sensitive classification and quantification of surface films having a thickness in the 1-microm range. However, significant changes of the optical signature of oil occur in the presence of submicrometer films which are not yet fully understood. Possible reasons for this effect are discussed and the limitations of laser fluorosensing of small oil discharges are outlined.