Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins.

Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress. Tsa1 counteracted the accumulation of ubiquitinated aggregates during aging and the reduction of hyperoxidized Tsa1 by sulfiredoxin facilitated clearance of H2O2-generated aggregates. The data reveal a conceptually new role for H2O2 signaling in proteostasis and lifespan control and shed new light on the selective benefits endowed to eukaryotic peroxiredoxins by their reversible hyperoxidation.

Reining in H(2)O(2) for safe signaling.

Mammalian cells use hydrogen peroxide (H(2)O(2)) not only to kill invading pathogens, but also as a signaling modulator. Woo et al. (2010) now show that the local inactivation of a H(2)O(2)-degrading enzyme ensures that the production of this oxidant is restricted to the signaling site.

Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip.

In the endoplasmic reticulum (ER), Ero1 catalyzes disulfide bond formation and promotes glutathione (GSH) oxidation to GSSG. Since GSSG cannot be reduced in the ER, maintenance of the ER glutathione redox state and levels likely depends on ER glutathione import and GSSG export. We used quantitative GSH and GSSG biosensors to monitor glutathione import into the ER of yeast cells. We found that glutathione enters the ER by facilitated diffusion through the Sec61 protein-conducting channel, while oxidized Bip (Kar2) inhibits transport. Increased ER glutathione import triggers H2O2-dependent Bip oxidation through Ero1 reductive activation, which inhibits glutathione import in a negative regulatory loop. During ER stress, transport is activated by UPR-dependent Ero1 induction, and cytosolic glutathione levels increase. Thus, the ER redox poise is tuned by reciprocal control of glutathione import and Ero1 activation. The ER protein-conducting channel is permeable to small molecules, provided the driving force of a concentration gradient.

Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study.

RATIONALE & OBJECTIVE: In this pilot study, we hypothesized that autosomal dominant polycystic kidney disease (ADPKD) is characterized by impaired kidney oxidative metabolism that associates with kidney size and cyst burden. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Twenty adults with ADPKD (age, 31±6 years; 65% women; body mass index [BMI], 26.8 [22.7-30.4] kg/m2; estimated glomerular filtration rate [eGFR, 2021 CKD-EPI creatinine], 103±18mL/min/1.73m2; height-adjusted total kidney volume [HTKV], 731±370mL/m; Mayo classifications 1B [5%], 1C [42%], 1D [21%], and 1E [32%]) and 11 controls in normal weight category (NWC) (age, 25±3 years; 45% women; BMI, 22.5 [21.7-24.2] kg/m2; eGFR, 113±15mL/min/1.73m2; HTKV, 159±31mL/m) at the University of Colorado Anschutz Medical Campus. PREDICTORS: ADPKD status (yes/no) and severity (Mayo classifications). OUTCOME: HTKV and cyst burden by magnetic resonance imaging, kidney oxidative metabolism, and perfusion by 11C-acetate positron emission tomography/computed tomography, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]). ANALYTICAL APPROACH: For categorical variables, χ2/Fisher's exact tests, and for continuous variables t tests/Mann-Whitney U tests. Pearson correlation was used to estimate the relationships between variables. RESULTS: Compared with NWC individuals, the participants with ADPKD exhibited lower mean±SD M/I ratio (0.586±0.205 vs 0.424±0.171 [mg/kg lean/min]/(µIU/mL), P=0.04), lower median cortical perfusion (1.93 [IQR, 1.80-2.09] vs 0.68 [IQR, 0.47-1.04] mL/min/g, P<0.001) and lower median total kidney oxidative metabolism (0.17 [IQR, 0.16-0.19] vs. 0.14 [IQR, 0.12-0.15] min-1, P=0.001) in voxel-wise models excluding cysts. HTKV correlated inversely with cortical perfusion (r: -0.83, P < 0.001), total kidney oxidative metabolism (r: -0.61, P<0.001) and M/I (r: -0.41, P = 0.03). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSIONS: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements. FUNDING: Grants from government (National Institutes of Health, Centers for Disease Control and Prevention) and not-for-profit (JDRF) entities. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study numbers NCT04407481 and NCT04074668. PLAIN-LANGUAGE SUMMARY: In our study, we explored how a common genetic kidney condition, autosomal dominant polycystic kidney disease (ADPKD), relates to kidney metabolism. ADPKD leads to the growth of numerous cysts in the kidneys, which can impact their ability to work properly. We wanted to understand the kidneys' ability to process oxygen and blood flow in ADPKD. Our approach involved using advanced imaging techniques to observe kidney metabolism and blood flow in people with ADPKD compared with healthy individuals. We discovered that those with ADPKD had significant changes in kidney oxygen metabolism even when their kidney function was still normal. These findings are crucial as they provide deeper insights into ADPKD, potentially guiding future treatments to target these changes.

Keeping Oxidative Metabolism on Time: Mitochondria as an Autonomous Redox Pacemaker Animated by H2O2 and Peroxiredoxin.

In this issue of Molecular Cell, Kil et al. (2015) provide evidence for self-sustained circadian oscillations of the hyperoxidation of the mitochondrial Peroxiredoxin, PrxIII, and cytosolic release of mitochondrial H2O2, which might constitute one biochemical output coupling metabolic changes and transcriptional-based core clocks.

Exploring changes in violence across two waves of the COVID-19 pandemic in Richmond, VA.

The first wave of the COVID-19 pandemic carried with it an increase in violence in the United States and abroad. The proportion of violence cases involving firearms also increased during this time, yet little research has examined these effects using data from the second wave of COVID infections. Explanations for these documented increases in gun violence put forward by scholars include increased firearm purchases, alcohol consumption, unemployment, and organized crime activity. The current work examined these trends in Richmond, VA. We collected data on patients (N = 1744) presenting with violent injuries from 2018 to 2022 from the emergency department of a Level-1 Trauma Center in Richmond, VA. Data were coded on the basis of whether they presented before the pandemic, during the first wave, or during the second wave. Logistic binomial regressions revealed that the risk of gunshot wounds increased by 32% during the first wave and 44% during the second wave, relative to the pre-COVID period, but that the increase between the first and second wave was not significant. These findings held after controlling for victim age, race, sex, and injury severity. Further analyses revealed that these effects were specific to violent injury, as we found no increase in firearm use among self-injury cases. The heightened violence reported during the COVID-19 pandemic was also observed in Richmond, VA. Gun violence in particular increased over time as other forms of violence (i.e., assaults, stabbings, and self-harm) decreased.

Iron Insertion at the Assembly Site of the ISCU Scaffold Protein Is a Conserved Process Initiating Fe-S Cluster Biosynthesis.

Iron-sulfur (Fe-S) clusters are prosthetic groups of proteins biosynthesized on scaffold proteins by highly conserved multi-protein machineries. Biosynthesis of Fe-S clusters into the ISCU scaffold protein is initiated by ferrous iron insertion, followed by sulfur acquisition, via a still elusive mechanism. Notably, whether iron initially binds to the ISCU cysteine-rich assembly site or to a cysteine-less auxiliary site via N/O ligands remains unclear. We show here by SEC, circular dichroism (CD), and Mössbauer spectroscopies that iron binds to the assembly site of the monomeric form of prokaryotic and eukaryotic ISCU proteins via either one or two cysteines, referred to the 1-Cys and 2-Cys forms, respectively. The latter predominated at pH 8.0 and correlated with the Fe-S cluster assembly activity, whereas the former increased at a more acidic pH, together with free iron, suggesting that it constitutes an intermediate of the iron insertion process. Iron not binding to the assembly site was non-specifically bound to the aggregated ISCU, ruling out the existence of a structurally defined auxiliary site in ISCU. Characterization of the 2-Cys form by site-directed mutagenesis, CD, NMR, X-ray absorption, Mössbauer, and electron paramagnetic resonance spectroscopies showed that the iron center is coordinated by four strictly conserved amino acids of the assembly site, Cys35, Asp37, Cys61, and His103, in a tetrahedral geometry. The sulfur receptor Cys104 was at a very close distance and apparently bound to the iron center when His103 was missing, which may enable iron-dependent sulfur acquisition. Altogether, these data provide the structural basis to elucidate the Fe-S cluster assembly process and establish that the initiation of Fe-S cluster biosynthesis by insertion of a ferrous iron in the assembly site of ISCU is a conserved mechanism.

Valvular regurgitation flow jet assessment using in vitro 4D flow MRI: Implication for mitral regurgitation.

PURPOSE: The purpose of this study was to evaluate the accuracy of four-dimensional (4D) flow MRI for direct assessment of peak velocity, flow volume, and momentum of a mitral regurgitation (MR) flow jets using an in vitro pulsatile jet flow phantom. We systematically investigated the impact of spatial resolution and quantification location along the jet on flow quantities with Doppler ultrasound as a reference for peak velocity. METHODS: Four-dimensional flow MRI data of a pulsatile jet through a circular, elliptical, and 3D-printed patient-specific MR orifice model was acquired with varying spatial resolution (1.5-5 mm isotropic voxel). Flow rate and momentum of the jet were quantified at various axial distances (x = 0-50 mm) and integrated over time to calculate Voljet and MTIjet . In vivo assessment of Voljet and MTIjet was performed on 3 MR patients. RESULTS: Peak velocities were comparable to Doppler ultrasound (3% error, 1.5 mm voxel), but underestimated with decreasing spatial resolution (-40% error, 5 mm voxel). Voljet was similar to regurgitant volume (RVol) within 5 mm, and then increased linearly with the axial distance (19%/cm) because of flow entrainment. MTIjet remained steady throughout the jet (2%/cm) as theoretically predicted. Four and 9 voxels across the jet were required to measure flow volume and momentum-time-integral within 10% error, respectively. CONCLUSION: Four-dimensional flow MRI detected accurate peak velocity, flow rate, and momentum for in vitro MR-mimicking flow jets. Spatial resolution significantly impacted flow quantitation, which otherwise followed predictions of flow entrainment and momentum conservation. This study provides important preliminary information for accurate in vivo MR assessment using 4D flow MRI.

Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. STUDY DESIGN: Prospective randomized controlled double-blind clinical trial. SETTING & PARTICIPANTS: 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. EXPOSURE: Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. OUTCOME: Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. RESULTS: The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. LIMITATIONS: Short study duration. CONCLUSIONS: We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. FUNDING: Government and philanthropic grants (NIDDK and the Zell Foundation). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02903511.

Extrinsic Point Defects in Low-Positive Thermal Expansion Al2W3O12 and Their Effects on Thermal and Optical Properties.

A2M3O12-type ceramics are potentially useful in a variety of applications due to their peculiar thermal and mechanical properties. In addition, their intrinsic coefficients of thermal expansion can be finely tuned through different mechanisms. Despite the great influence of extrinsic point defects on physical properties, only a few reports have dealt with their relationship to thermal expansion and thermal conductivity. Extrinsic oxygen vacancies in orthorhombic Al2W3O12, in different concentrations, were formed through heat treatments in argon or hydrogen atmospheres. X-ray powder diffraction, diffuse reflectance spectroscopy, and Raman and electron paramagnetic resonance spectroscopies were used to study the as-formed vacancies, and X-ray photoelectron spectroscopy was employed to propose a charge compensation mechanism. It was found that the intrinsic coefficient of thermal expansion of orthorhombic Al2W3O12 was severely affected by extrinsic oxygen vacancies. Thermal expansion was decreased up to 40% (from 25 to 400 °C) with respect to the extrinsic-point-defect-free counterpart. Unit-cell volumes of defective orthorhombic Al2W3O12 were larger, while their W-O bonds were weaker, likely leading to higher lattice flexibility and enhanced low-energy transverse acoustic modes. Extrinsic oxygen vacancies could be an additional mechanism for fine-tuning the intrinsic coefficients of thermal expansion in A2M3O12-type ceramics and in other framework structures built through two or threefold linkages.

Trends in Adoption of Twitter by Health Sciences Librarians.

There is substantial research on librarians' engagement with various social media platforms as part of their professional obligations. We were interested in examining librarians' use of Twitter outside of the context of a job-related, but still professional, context. To find out more, we invited health sciences librarians via Twitter to discuss the impact that the platform has had on their professional lives, offering this column as an opportunity to share their experiences. The case reports support the premise that Twitter can be an impactful communications tool and can benefit librarians in meaningful ways, both professionally and personally.

[Anticholinergic scales: Use in psychiatry and update of the anticholinergic impregnation scale]. / Les échelles anticholinergiques : usage en psychiatrie et mise à jour de l'échelle d'imprégnation anticholinergique.

Anticholinergic properties are well known to prescribers, notably in mental health, as a therapeutic strategy for i.e. extrapyramidal syndrome but also as a source of numerous adverse side effects. Herein, we propose a narrative literature review describing: (i) cholinergic pharmacology and anticholinergic properties; (ii) the importance of anticholinergic therapeutic properties in psychiatry; (iii) the existing anticholinergic drug scales and their usage limitations in Psychiatry and; last (iv) an update to the anticholinergic drug impregnation scale, designed for the French psychiatry practice. The anticholinergic side effects can appear both in the peripheral level (dry mouth, constipation, etc.) and in the central level (especially as cognitive deficits). Many of the so called « anticholinergic ¼ drugs are in fact entirely or mostly antimuscarinic and act essentially as parasympathetic system antagonists. Overall, anticholinergic/antimuscarinic side effects are usually attributed to psychotropic medications: to certain antipsychotics, notably classical neuroleptics such as phenothiazine and also to tricyclic antidepressants. In practice, the impact of anticholinergic toxicity treatments is often highlighted due to their excessively prolonged use in patients on antipsychotics. Interestingly, these antipsychotic treatments are better known for their anticholinergic side effects, especially cognitive ones, with an early onset specially in elder patients and/or in the case of polymedication. In order to evaluate anticholinergic side effects, metrics known as anticholinergic burden scales were created in the last few decades. Nowadays, 13 different scales are documented and accepted by the international academic community, but only three of them are commonly used: the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS) and the Anticholinergic Burden Scale (ACB). All of them are based on a similar principle, consisting of grading treatments individually, and they are normally scored from 0 - no presence of side effects - to 3 - anticholinergic effects considered to be strong or very strong. Using these scales enables the calculation of the so-called "anticholinergic burden", which corresponds to the cumulative effect of using multiple medications with anticholinergic properties simultaneously. The application of anticholinergic scales to patients with psychiatric disorders has revealed that schizophrenic patients seem to be especially sensitive to anticholinergic cognitive side effects, while elder and depressed patients were more likely to show symptoms of dementia when exposed to higher anticholinergic burden. Unfortunately, these tools appear to have a low parallel reliability, and so they might induce large differences when assessing side effects predictability. In addition, the capacity of these scales to predict central adverse effects is limited due to the fact they poorly or do not differentiate, the ability of treatments to cross the blood-brain barrier. Finally, one last limitation on the validity of these scales is prescription posology is not accounted for side effects considered to be dose dependent. Recently, the MARANTE (Muscarinic Acetylcholine Receptor ANTagonist Exposure) scale has incorporated an anticholinergic burden weighting by posology. Nevertheless, this new model can be criticized, due to the limited number of medications included and due to testing a limited number of potency ranges and dosages for each treatment. Herein, we propose an update to the Anticholinergic Impregnation Scale, developed specifically for the French Psychiatry practice. The scale validation was based on an evaluation of the prescriptions correcting anticholinergic peripheral side effects (constipation, xerostomia and xeropthalmia). This indirect evaluation allowed us to show patients with an anticholinergic impregnation score higher than 5 received significantly more treatments for constipation and xerostomia. This strategy bypasses the bias of a cognitive evaluation in patients with severe mental health disorders. Moreover, the relevance of a tool developed specifically for French psychiatry is justified by the fact that some highly prescribed treatments for mental illness in France (cyamemazine and tropatemine) are strong anticholinergics, and also by the fact they are rarely included in the existing anticholinergic scales. This update of the original scale, published in 2017, includes information whether prescribed drugs cross the blood-brain barrier and thus makes possible a more accurate assessment when evaluating anticholinergic central side effects. Finally, the anticholinergic impregnation scale will soon be integrated into a prescription help software, which is currently being developed to take into consideration dose dependent adverse effects.

Reaching the Challenging Diagnosis of Complicated Liver Hydatid Disease: A Single Institution's Experience from an Endemic Area.

Background and Objectives: Hydatid disease (HD) remains a significant public health issue causing morbidity and mortality in many Mediterranean countries. Material and Methods: The present cohort study included 50 consecutive patients with liver hydatid disease who underwent surgery in a tertiary University Hospital. A total of 18 patients (36%) had a case of complicated HD, including simple communication of the cyst with the biliary tree (6 cases), rupture of the cyst into the biliary tree (6 cases), presence of a bronco-biliary fistula (2 cases), rupture of the cyst in the peritoneal cavity (2 cases), and rupture of the cyst and formation of a hepatic abscess (2 cases). Endoscopic retrograde cholangiopancreatography (ERCP) was pre-operatively performed on six patients. Results: The main clinical symptom presented was right upper quadrant pain in 16 patients (88%), which was associated with high fever (>39 °C) in 14 patients (78%). C-reactive protein (CRP) was the primary indicator of a complicated HD (p = 0.003); however, it was only elevated in 67% of cases. CRP was a more sensitive indicator of a rupture in the biliary tree cyst (p = 0.02). Computer tomography (CT) detected more cases (44%) of a complicated HD than ultrasonography (US) (25%); however, the difference was not statistically significant. Conclusions: For prevention and control of HD, a high suspicion of the disease leading to early referral to specialized centers, mainly in endemic areas, is required. Prior to surgical or percutaneous intervention, a combination of imaging and laboratory findings are essential in diagnosing a complicated case and avoiding unnecessary interventions.

The importance of naturally attenuated SARS-CoV-2in the fight against COVID-19.

The current SARS-CoV-2 pandemic is wreaking havoc throughout the world and has rapidly become a global health emergency. A central question concerning COVID-19 is why some individuals become sick and others not. Many have pointed already at variation in risk factors between individuals. However, the variable outcome of SARS-CoV-2 infections may, at least in part, be due also to differences between the viral subspecies with which individuals are infected. A more pertinent question is how we are to overcome the current pandemic. A vaccine against SARS-CoV-2 would offer significant relief, although vaccine developers have warned that design, testing and production of vaccines may take a year if not longer. Vaccines are based on a handful of different designs (i), but the earliest vaccines were based on the live, attenuated virus. As has been the case for other viruses during earlier pandemics, SARS-CoV-2 will mutate and may naturally attenuate over time (ii). What makes the current pandemic unique is that, thanks to state-of-the-art nucleic acid sequencing technologies, we can follow in detail how SARS-CoV-2 evolves while it spreads. We argue that knowledge of naturally emerging attenuated SARS-CoV-2 variants across the globe should be of key interest in our fight against the pandemic.

Diagnostic accuracy of ultrasound-guided core biopsy of peripheral nerve sheath tumors.

PURPOSE: To retrospectively evaluate the diagnostic accuracy of and complications from ultrasound-guided core needle biopsy (UGCNB) of suspected peripheral nerve sheath tumors (PNSTs). METHODS: Patients undergoing UGCNB from January 2004 to December 2016, based on the suspicion of PNST, were included in the study. Age, gender, anatomical location, dates of relevant events, and histopathological reports of the UGCNB cores and the resected tumors were retrieved from the patients' medical records. RESULTS: A total of 154 UGCNBs were identified. One hundred and forty (90.9%) of these resulted in a conclusive histopathological report, while 14 were unsuited for histopathological analysis due to insufficient amount of tissue and/or nonrepresentative tissue. The overall diagnostic accuracy of UGCNB with respect to discriminate malignant from benign tumors was 99.3%, while correct specific UGCNB diagnoses were confirmed in 95.1% of the cases. Sensitivity and specificity were 90.9% (95% CI: 58.7-99.8%) and 100% (95% CI: 97.2-100%), respectively. The positive predictive value was 100%, and the negative predictive value was 99.2%. Except for one patient, who reported mild dysesthesia, which resolved 2 days after the UGCNB, no complications were reported. CONCLUSION: This study suggests that UGCNB is accurate and safe in patients suspected for PNST.

A scaffold protein that chaperones a cysteine-sulfenic acid in H2O2 signaling.

In Saccharomyces cerevisiae, Yap1 regulates an H2O2-inducible transcriptional response that controls cellular H2O2 homeostasis. H2O2 activates Yap1 by oxidation through the intermediary of the thiol peroxidase Orp1. Upon reacting with H2O2, Orp1 catalytic cysteine oxidizes to a sulfenic acid, which then engages into either an intermolecular disulfide with Yap1, leading to Yap1 activation, or an intramolecular disulfide that commits the enzyme into its peroxidatic cycle. How the first of these two competing reactions, which is kinetically unfavorable, occurs was previously unknown. We show that the Yap1-binding protein Ybp1 brings together Orp1 and Yap1 into a ternary complex that selectively activates condensation of the Orp1 sulfenylated cysteine with one of the six Yap1 cysteines while inhibiting Orp1 intramolecular disulfide formation. We propose that Ybp1 operates as a scaffold protein and as a sulfenic acid chaperone to provide specificity in the transfer of oxidizing equivalents by a reactive sulfenic acid species.

The Behavioral Economics of Alcohol Demand in French and American University Students.

BACKGROUND: Behavioral economic approaches have revealed several characteristics of alcohol demand (e.g., intensity, elasticity, and essential value) in university students; however, these approaches have not yet examined alcohol demand among students outside of the United States. The current study examined alcohol demand among student samples in the United States and France using a hypothetical alcohol purchase task (APT) and a novel APT Choice task, in which nonalcoholic beverages were concurrently available at a fixed low price. METHODS: Participants at each site (United States, n = 132; France, n = 132) were asked to complete an Internet-based survey including the APT, APT Choice, Alcohol Use Disorders Identification Test, Daily Drinking Questionnaire, and Drinking Motives Questionnaire-Revised Short Form. Group demand functions were produced for each of the 2 samples in both country-specific and standardized drink units, and the exponential demand equation was fitted to each of the APT and APT Choice demand curves. Slope analyses were performed on the Non-Alcoholic Cross-Price demand to assess substitutability. RESULTS: APT data revealed that in both samples, alcohol price and consumption were inversely related and demand measures were significantly associated with other alcohol measures. In addition, the availability of a nonalcoholic alternative reduced alcohol demand in both samples, with evidence of substitutability revealed by increases in cross-price consumption. CONCLUSIONS: Low-cost alcohol is associated with increased alcohol consumption in both French and U.S. university students, and concurrent availability of a nonalcoholic beverage within the APT both reduces alcohol demand and demonstrates behavioral economic substitutability. These findings will inform future studies investigating behavioral and environmental factors underlying transcultural differences and specific prevention efforts.

ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.

Reactive oxygen species (ROS) have been shown to be toxic but also function as signalling molecules. This biological paradox underlies mechanisms that are important for the integrity and fitness of living organisms and their ageing. The pathways that regulate ROS homeostasis are crucial for mitigating the toxicity of ROS and provide strong evidence about specificity in ROS signalling. By taking advantage of the chemistry of ROS, highly specific mechanisms have evolved that form the basis of oxidant scavenging and ROS signalling systems.

Life span extension and H(2)O(2) resistance elicited by caloric restriction require the peroxiredoxin Tsa1 in Saccharomyces cerevisiae.

Caloric restriction (CR) extends the life span of organisms ranging from yeast to primates. Here, we show that the thiol-dependent peroxiredoxin Tsa1 and its partner sulfiredoxin, Srx1, are required for CR to extend the replicative life span of yeast cells. Tsa1 becomes hyperoxidized/inactive during aging, and CR mitigates such oxidation by elevating the levels of Srx1, which is required to reduce/reactivate hyperoxidized Tsa1. CR, by lowering cAMP-PKA activity, enhances Gcn2-dependent SRX1 translation, resulting in increased resistance to H(2)O(2) and life span extension. Moreover, an extra copy of the SRX1 gene is sufficient to extend the life span of cells grown in high glucose concentrations by 20% in a Tsa1-dependent and Sir2-independent manner. The data demonstrate that Tsa1 is required to ensure yeast longevity and that CR extends yeast life span, in part, by counteracting age-induced hyperoxidation of this peroxiredoxin.

Suggestion for new 4.4 mm pubo-femoral distance cut-off value for hip instability in lateral position during DDH screening.

Background and purpose - Current selective screening algorithms for developmental dysplasia of the hip (DDH) are insufficient. Universal screening programs have been proposed but so far have been deemed too expensive and time consuming. The pubo-femoral distance may solve this problem as a quick, low-cost, highly sensitive, and specific sonographic measurement for DDH, but this has only been validated in the supine position. Therefore we validated pubo-femoral distance (PFD) in the lateral position as an indicator for instability of the hip. Methods - All participants had undergone ultrasonographic diagnostics using the modified Graf technique. In addition, PFD measurements in lateral position were performed. Results were compared between 25 infants who had been treated for DDH because of dysplastic appearance on ultrasound combined with clinical instability and a control group consisting of 100 untreated infants screened for DDH. Sensitivity, specificity, and cut-off points were determined using Receiver operating characteristics (ROC) analysis. Results - We found a mean PFD of 6.8 mm (6.2-7.4) in the treated group with a control group PFD of 3.4 mm (3.3-3.6) (p < 0.005). A PFD value above a threshold of 4.4 mm yielded a sensitivity of 100% and a specificity of 93% for detecting unstable DDH. Interpretation - PFD measured in lateral position was statistically significantly increased in hips of children treated for DDH with Denis Browne hip brace compared with healthy children with unaffected stable hips. Furthermore, the PFD measurement had a high level of sensitivity and specificity at a cut-off value of 4.4 mm. A cut-off value of 6.00 mm has previously been reported as the gold standard in supine position. We suggest that 4.4 mm is used in lateral position.