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This article is the second of a series of two articles. In the first article of the series, a new K v distribution model and an experimental methodology to measure the K v distribution were introduced. In this second part, the K v distribution is integrated into a lyo-simulation tool, to more accurately predict the variability of the product temperature, primary drying time, total sublimation mass flow and Pirani signal. The K v distribution is also integrated into the graphical design space. The impact of incorporating the R p distribution is briefly discussed. The comparison of the simulation tool with actual product temperature monitoring, Pirani signal or overall sublimation flow shows very good agreement in the case studies presented. Overall, the lyo-simulation incorporating the K v distribution is a very useful tool to support industrial development, i.e. process optimization, scale assessment, technology transfer, and troubleshooting of the lyophilization process., Competing Interests: Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All the authors worked for Sanofi at the time where the research work was done, except one working for Astek - IT&M STATS (contracting company for Sanofi). All the work was Sanofi financed., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

A commonly encountered challenge with freeze-dried drug products is glass vial fogging. Fogging is characterized by a thin layer of product deposited upon the inner surface of the vial above the lyophilized cake. While considered to be a routine cosmetic defect in many instances, fogging around the shoulder and neck of the vial may potentially impact container closure integrity and reject rates during inspection. In this work, the influence of processing conditions i.e. vial pre-treatment, lyophilization cycle modifications and filling conditions on fogging was evaluated. A battery of analytical techniques was employed to investigate factors affecting glass vial fogging. A fogging score was used to quantify its severity in freeze-dried products. Additionally, a dye-based method was used to study solution upcreep (Marangoni flow) following product filling. Our lab-scale results indicate measurable improvement in fogging following the addition of an annealing step in the lyophilization cycle. Pre-freeze isothermal holding of the vials (at 5°C on the lyophilizer shelf) for an extended duration indicated a reduction in fogging whereas an increase in the freezing time exhibited no effect on fogging. Vial pre-treatment conditions were critical determinants of fogging for Type 1 vials whereas they had no impact on fogging in TopLyo® vials. The headspace relative humidity (RH) investigation also indicated sufficient increase in the water vapor pressure inside the vial to be conducive to the formulation of a hydration film - the precursor to Marangoni flow., Competing Interests: Declaration of competing interest All authors were employees of Sanofi during the work described in this manuscript and may hold shares and/or stock options in the company. The authors declare no other conflicts of interest., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

In the current radiation protection system, preventive measures and occupational exposure limits for controlling occupational exposure to ionizing radiation are based on the linear no-threshold extrapolation model. However, currently an increasing body of evidence indicates that this paradigm predicts very poorly biological responses in the low-dose exposure region. In addition, several in vitro and in vivo studies demonstrated the presence of hormetic dose response curves correlated to ionizing radiation low exposure. In this regard, it is noteworthy that also the findings of different epidemiological studies, conducted in different categories of occupationally exposed workers (e.g., healthcare, nuclear industrial and aircrew workers), observed lower rates of mortality and/or morbidity from cancer and/or other diseases in exposed workers than in unexposed ones or in the general population, then suggesting the possible occurrence of hormesis. Nevertheless, these results should be considered with caution since the identification of hormetic response in epidemiological studies is rather challenging because of a number of major limitations. In this regard, some of the most remarkable shortcomings found in epidemiological studies performed in workers exposed to ionizing radiation are represented by lack or inadequate definition of exposure doses, use of surrogates of exposure, narrow dose ranges, lack of proper control groups and poor evaluation of confounding factors. Therefore, considering the valuable role and contribution that epidemiological studies might provide to the complex risk assessment and management process, there is a clear and urgent need to overcome the aforementioned limits in order to achieve an adequate, useful and more real-life risk assessment that should also include the key concept of hormesis. Thus, in the present conceptual article we also discuss and provide possible approaches to improve the capacity of epidemiological studies to identify/define the hormetic response and consequently improve the complex process of risk assessment of ionizing radiation at low exposure doses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Measurement of heat transfer coefficients (K v ) is an important part of freeze-dryers characterization and as well a necessary step for executing any modelling. In most cases only an average value of K v is calculated, or an average value of center and edge vials is provided. Our aim is to go a step further and to describe the overall K v distribution various vial/ freeze drier combinations, whatever the pressure. From an experimental point of view, in this article we propose three methods to calculate the K v value for individual vials based on the ice sublimation gravimetric method. The first method we use is the most usual one, where the K v value is calculated based on the mass of sublimated ice and the product temperature measured in selected vias. In the second method, the average product temperature is estimated for each vial, based on the mass difference before and after sublimation and the K v value is calculated accordingly. In the third method, the K v is estimated by comparison to sublimation results from a simulation. Results from methods 2 and 3 are very similar results and are slightly different from those of method 1. Method 1 was shown to exhibit a systematic bias due to the fact that it is based on the temperature of recording of selected vials only, which are not representative for all positions. Once the individual values of K v have been calculated, it is possible to establish a distribution for each method. It was observed that an overlay of two normal distributions describing the center and the edge vials provides a good representation of the empirical distribution. Furthermore, we propose a holistic model aiming to calculate the K v distribution for any specified pressure., Competing Interests: Declaration of Competing Interest All the authors worked for Sanofi at the time where the research work was done. All the work was Sanofi financed., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Raman scattering shows promise as a powerful routine tool, to determine both secondary and the smaller tertiary structural changes that precede aggregation in both solutions and solids. A method was developed utilizing principal component analysis (PCA) of Raman spectra for detection of small, but meaningful, pH induced changes in tertiary protein structure linked to aggregate formation using α-lactalbumin solutions as a model. The sample preparation and spectral parameters, were optimized for a bulk Raman probe. Analysis of large regions (600-1850 cm -1 ) yielded principal component (PC) scores useful for semi-quantitative comparison of protein conformation between formulations. PC loadings corresponded to specific structural peaks known to change with solution pH. PCA of circular dichroism (CD) spectra of dilute solutions yielded similar results. Sucrose is a common formulation excipient with a Raman spectrum that overlaps many protein peaks. With sucrose in the protein solution, the ability of PCA to discern protein structural changes from the Raman spectra was somewhat reduced. Analysis of a more limited spectral region (1530-1780 cm -1 ) with negligible sucrose spectral contribution improved the discrimination of protein conformational states. The new Raman method accurately distinguished differences in protein structure in concentrated solutions. The long-term goal is to explore Raman characterization as a routine monitoring tool of protein stability in both solution and solid states., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Objective: To describe 5-year postoperative outcomes of a small series of Fuchs' endothelial dystrophy (FED) patients who underwent Descemet stripping only (DSO) with a scraping technique., Methods: DSO technique and early clinical outcomes of 5 patients with mild central FED were previously reported. In the same cohort of patients, corrected distance visual acuity, central corneal ultrasound pachymetry, refractive spherical equivalent, endothelial cell count, slit-lamp photography, and corneal Scheimpflug tomography were obtained at baseline, 6 months, and 1 and 5 years postoperatively. No patient used topical Rho-kinase inhibitors at any point in time., Results: One patient (20%) failed to clear the early postoperative edema and 1 patient (20%) developed corneal decompensation 1 year after DSO. Both patients underwent successful Descemet stripping automated endothelial keratoplasty. The remaining 3 patients had stable corrected distance visual acuity, progressive reduction of corneal ultrasound pachymetry, and mild myopic shift of the refractive spherical equivalent over the follow-up time. An improvement in posterior stromal opacities and irregular astigmatism was observed, whereas posterior elevation at Scheimpflug tomography remained unchanged., Conclusion: At 5 years postoperatively, DSO with a scraping technique and without Rho-kinase inhibitors resulted in sustained clinical amelioration of 3 of 5 patients (60%) with mild FED., (Copyright © 2021 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

The environmental contamination of antibiotics caused by their over or inappropriate use is a major issue for environmental and human health since it can adversely impact the ecosystems and promote the antimicrobial resistance. Indeed, considering that in the environmental matrices these drugs are present at low levels, the possibility that bacteria exhibit a hormetic response to increase their resilience when exposed to antibiotic subinhibitory concentrations might represent a serious threat. Information reported in this review showed that exposure to different types of antibiotics, either administered individually or in mixtures, is capable of exerting hormetic effects on bacteria at environmentally relevant concentrations. These responses have been reported regardless of the type of bacterium or antibiotic, thus suggesting that hormesis would be a generalized adaptive mechanism implemented by bacteria to strengthen their resistance to antibiotics. Hormetic effects included growth, bioluminescence and motility of bacteria, their ability to produce biofilm, but also the frequency of mutation and plasmid conjugative transfer. The evaluation of quantitative features of antibiotic-induced hormesis showed that these responses have both maximum stimulation and dose width characteristics similar to those already reported in the literature for other stressors. Notably, mixtures comprising individual antibiotic inducing stimulatory responses might have distinct combined effects based on antagonistic, synergistic or additive interactions between components. Regarding the molecular mechanisms of action underlying the aforementioned effects, we put forward the hypothesis that the adoption of adaptive/defensive responses would be driven by the ability of antibiotic low doses to modulate the transcriptional activity of bacteria. Overall, our findings suggest that hormesis plays a pivotal role in affecting the bacterial behavior in order to acquire a survival advantage. Therefore, a proactive and effective risk assessment should necessarily take due account of the hormesis concept to adequately evaluate the risks to ecosystems and human health posed by antibiotic environmental contamination., Competing Interests: Declaration of competing interest E.J.C. is Guest Editor and E.A. is the Managing Guest Editor of the Virtual Special Issue in which this paper is included. However, none of the authors has been involved in the peer review process of this paper. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to investigate the inflammatory response, lipid peroxidation and muscle damage in men and women athletes subjected to an acute resistance exercise., Methods: Twenty college athletes (10 men and 10 women) performed a half-squat exercise consisting of five incremental intensities: 20%, 40%, 60%, 80% and 100% of the one-repetition maximum. Blood samples were collected at rest, 15 min and 24 h post-test. The concentration of lipid peroxidation markers and the activities of a skeletal muscle damage marker and a cardiac muscle damage marker were determined in serum. Serum α-actin was measured as a marker of sarcomere damage. Serum levels of interleukin-6, interleukin-10, and tumor necrosis factor alpha were determined to assess the inflammatory response., Results: Interleukin-6 levels were higher at 24 h post-test than at rest and 15 min post-test in men (p < 0.05). Moreover, men showed significantly higher hydroperoxide levels in response to resistance exercise at 24 h post-test than at 15 min post-test (p < 0.05). No differences were found in muscle damage parameters regardless of sex or the time point of the test. No differences regarding the studied variables were found when comparing among different time points in women., Conclusion: Our results show a larger influence of half-squat exercises on the release of IL6 and on lipid peroxidation in men than in women at equivalent workloads., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Stroke is one of the main causes of death, neurological dysfunctions or disability in elderly. Neuroprotective drugs have been proposed to improve long-term recovery after stroke, but failed to reach clinical effectiveness. Hence, recent studies suggested that restorative therapies should combine neuroprotection and remyelination. Montelukast, an anti-asthmatic drug, was shown to exert neuroprotection in animal models of CNS injuries, but its ability to affect oligodendrocytes, restoring fiber connectivity, remains to be determined. In this study, we evaluated whether montelukast induces long-term repair by promoting fiber connectivity up to 8 weeks after middle cerebral artery occlusion (MCAo), using different experimental approaches such as in vivo diffusion magnetic resonance imaging (MRI), electrophysiological techniques, ex vivo diffusion tensor imaging (DTI)-based fiber tracking and immunohistochemistry. We found that, in parallel with a reduced evolution of ischemic lesion and atrophy, montelukast increased the DTI-derived axial diffusivity and number of myelin fibers, the density of myelin binding protein (MBP) and the number of GSTpi + mature oligodendrocytes. Together with the rescue of MCAo-induced impairments of local field potentials in ischemic cortex, the data suggest that montelukast may improve fibers reorganization. Thus, to ascertain whether this effect involved changes of oligodendrocyte precursor cells (OPCs) activation and maturation, we used the reporter GPR17iCreERT2:CAG-eGreen florescent protein (GFP) mice that allowed us to trace the fate of OPCs throughout animal's life. Our results showed that montelukast enhanced the OPC recruitment and proliferation at acute phase, and increased their differentiation to mature oligodendrocytes at chronic phase after MCAo. Considering the crosstalk between OPCs and microglia has been widely reported in the context of demyelinating insults, we also assessed microglia activation. We observed that montelukast influenced the phenotype of microglial cells, increasing the number of M2 polarized microglia/macrophages, over the M1 phenotype, at acute phase after MCAo. In conclusion, we demonstrated that montelukast improves fiber re-organization and long-term functional recovery after brain ischemia, enhancing recruitment and maturation of OPCs. The present data suggest that montelukast, an already approved drug, could be "repositioned "as a protective drug in stroke acting also on fiber re-organization., (Copyright © 2019. Published by Elsevier Ltd.)

Moisture-induced flow variabilities in pharmaceutical blends lead to multiple impediments during manufacturing of solid dosage formulations. Processing and storage humidity conditions both govern the moisture contents of the pharmaceutical mixtures and bear significant impact on the final product quality. In this study, experimentally validated discrete element method-based computational models along with statistical formalism have been implemented to develop a predictive tool for moisture-induced cohesion in binary and tertiary mixtures. V-blending was applied to prepare the pharmaceutical blends, and mixing characterization was performed using a Raman PhAT probe. Optimum fill volume was established for the mixing conditions to minimize static charging due to blender wall interactions on the pharmaceutical powders. A simplex-centroid (augmented) design for 3-component system was implemented to predict and quantify the nonlinear behavior of moisture-induced cohesion between the pharmaceutical powders based on their systematic hopper discharge studies (experiments and simulations). A methodical implementation of these quantification tools was hence performed to validate a design space that enables an approach to the appropriate selection of blend concentrations that achieve minimum mixture flow variability across different humidity conditions., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Exposure assessment is a key stage in the risk assessment/management of engineered nanomaterials. Although different sampling strategies and instruments have been used to define the occupational exposure to nano-scale materials, currently there is no international consensus regarding measurement strategy, metrics and limit values. In fact, the assessment of individual exposure to engineered nanomaterials remains a critical issue despite recent innovative developments in personal monitors and samplers. Hence, we used several of these instruments to evaluate the workers' personal exposure in a large research laboratory where engineered nanomaterials are produced, handled, and characterized in order to provide input data for nanomaterial exposure assessment strategies and future epidemiological studies. The results obtained using personal monitors showed that the workplace concentrations of engineered nanomaterials (lung deposited surface area and particle number concentrations) were quite low in all the different workplaces monitored, with short spikes during the execution of some specific job tasks. The sampling strategy was been adopted on the basis of an Organisation for Economic Cooperation and Development (OECD) suggestion for a tiered approach and was found to be suitable for determining the individual exposure and for identifying possible sources of emission, even those with very low emission rates. The use of these instruments may lead to a significant improvement not only in the exposure assessment stage but, more generally, in the entire risk assessment and management process., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Lagoons in the southeast coast of Brazil have experienced eutrophication due to the exponential increase of human population and sewage discharges. Living benthic foraminifera have demonstrated to be good bioindicators of such impacts. This study aims to evaluate the organic matter accumulation effects on the foraminiferal distribution in the Itaipu lagoon (Brazil). On the basis of the biotic and abiotic analyses, three sectors are identified. The Sector I, an inner area, is characterized by high dissolved oxygen values and foraminiferal species with preference for marine conditions, demonstrating the sea influence. The Sector II, in the mangrove margins, is associated to sandy sediment and biopolymers and mainly represented by euryhaline species. The Sector III is marked by low density or absence of living foraminifera and corresponds to a low quality organic matter enriched area (North, Southwest and Centre)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Myotonic Dystrophy type 2 (DM2) is a multisystemic disorder associated with an expanded [CCTG]n repeat in intron 1 of the CNBP gene. Epigenetic modifications have been reported in many repeat expansion disorders, including myotonic dystrophy type 1 (DM1), either as a mechanism to explain somatic repeat instability or transcriptional alterations in disease genes. The purpose of our work was to determine the effect of DM2 mutation on the methylation status of CpG islands localized in the 5' promoter region and in the 3' end of the [CCTG]n expansion of the CNBP gene. By bisulfite pyrosequencing, we characterized the methylation profile of two different CpG islands within these regions, either in whole blood and skeletal muscle tissues of DM2 patients (n=72 and n=7, respectively) and controls (n=50 and n=7, respectively). Moreover, we compared the relative mRNA transcript levels of CNBP gene in leukocytes and in skeletal muscle tissues from controls and DM2 patients. We found that CpG sites located in the promoter region showed hypomethylation, whereas CpG sites at 3' end of the CCTG array are hypermethylated. Statistical analyses did not demonstrate any significant differences in the methylation profile between DM2 patients and controls in both tissues analyzed. According to the methylation analysis, CNBP gene expression levels are not significantly altered in DM2 patients. These results show that [CCTG]n repeat expansion, differently from the DM1 mutation, does not influence the methylation status of the CNBP gene and suggest that other molecular mechanisms are involved in the pathogenesis of DM2., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Several studies have suggested that higher consumption of dietary fiber is beneficial for a variety of health outcomes. However, many results have been inconclusive and, to our knowledge, there has been no attempt to systematically capture the breadth of outcomes associated with dietary fiber intake or to systematically assess the quality and the strength of the evidence on the associations of dietary fiber intake and different health outcomes or medical conditions., Objective: The aim of this study was to describe the diverse health outcomes convincingly associated with dietary fiber consumption., Design: This was an umbrella review of systematic reviews with meta-analysis of observational studies. For each association, random-effects summary effect size, 95% CIs, and 95% prediction intervals were estimated. We also assessed heterogeneity, evidence for small-study effect, and evidence for excess significance bias. We used these metrics to evaluate the credibility of the identified evidence., Results: Our literature search identified 1351 abstracts. Of these, 18 meta-analyses including a total of 298 prospective observational studies and 21 outcomes were included. Outcomes studied included cancer and precancer lesions (n = 12), cardiovascular diseases (CVDs; n = 3), all-cause and specific-cause mortality (n = 4), type 2 diabetes (n = 1), and Crohn disease (n = 1). Overall, 6 (29%) of the 21 eligible outcomes reported highly significant summary results (P < 1 × 10-6); these included CVD and CVD mortality, coronary artery disease, pancreatic cancer, and gastric cancer. Overall, 3 of 21 (14%) outcomes presented convincing evidence (pancreatic cancer, CVD mortality, and all-cause mortality), but only CVD and all-cause mortality were based on prospective studies. Two other outcomes (10%), CVD and coronary artery disease, presented highly suggestive evidence based on prospective studies., Conclusion: Our results support dietary recommendations that promote higher fiber intake as part of a healthy diet.

Exposure to airborne agents needs to be assessed in the personal breathing zone by the use of personal measurement equipment. Specific measurement devices for assessing personal exposure to airborne nanomaterials have only become available in the recent years. They can be differentiated into direct-reading personal monitors and personal samplers that collect the airborne nanomaterials for subsequent analyses. This article presents a review of the available personal monitors and samplers and summarizes the available literature regarding their accuracy, comparability and field applicability. Due to the novelty of the instruments, the number of published studies is still relatively low. Where applicable, literature data is therefore complemented with published and unpublished results from the recently finished nanoIndEx project. The presented data show that the samplers and monitors are robust and ready for field use with sufficient accuracy and comparability. However, several limitations apply, e.g. regarding the particle size range of the personal monitors and their in general lower accuracy and comparability compared with their stationary counterparts. The decision whether a personal monitor or a personal sampler shall be preferred depends strongly on the question to tackle. In many cases, a combination of a personal monitor and a personal sampler may be the best choice to obtain conclusive results., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The role of polyphenol intake on cardiovascular risk factors is little explored, particularly in people with diabetes., Aim: To evaluate the association between the intake of total polyphenols and polyphenol classes with the major cardiovascular risk factors in a population with type 2 diabetes., Methods: Dietary habits were investigated in 2573 males and females participants of the TOSCA.IT study. The European Prospective Investigation on Cancer and Nutrition (EPIC) questionnaire was used to assess dietary habits. In all participants, among others, we assessed anthropometry, plasma lipids, blood pressure, C-reactive protein and HbA1c following a standard protocol. The USDA and Phenol-Explorer databases were used to estimate the polyphenol content of the habitual diet., Results: Average intake of polyphenols was 683.3 ± 5.8 mg/day. Flavonoids and phenolic acids were the predominant classes (47.5% and 47.4%, respectively). After adjusting for potential confounders, people with the highest intake of energy-adjusted polyphenols (upper tertile) had a more favorable cardiovascular risk factors profile as compared to people with the lowest intake (lower tertile) (BMI was 30.7 vs 29.9 kg/m 2 , HDL-cholesterol was 45.1 vs 46.9 mg/dl, LDL-cholesterol was 103.2 vs 102.1 mg/dl, triglycerides were 153.4 vs 148.0 mg/dl, systolic and diastolic blood pressure were respectively 135.3 vs 134.3 and 80.5 vs 79.6 mm/Hg, HbA1c was 7.70 vs 7.67%, and C-reactive Protein was 1.29 vs 1.25 mg/dl, p < .001 for all). The findings were very similar when the analysis was conducted separately for flavonoids or phenolic acids, the two main classes of polyphenols consumed in this population., Conclusions: Polyphenol intake is associated with a more favorable cardiovascular risk factors profile, independent of major confounders. These findings support the consumption of foods and beverages rich in different classes of polyphenols particularly in people with diabetes., Clinical Trial: http://www.clinicaltrials.gov; Study ID number: NCT00700856., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: To assess the ability of swept-source (SS) optical coherence tomography (OCT) of the anterior segment (AS) to measure anterior chamber (AC) inflammation (both flare and cells) objectively. To compare OCT-derived inflammatory indices with standard techniques., Design: Prospective evaluation of a diagnostic test., Participants: Patients diagnosed with anterior uveitis (active or inactive) and controls., Methods: Participants underwent an AC inflammation evaluation including: clinical cell and flare grading and laser flare photometry (LFP). Uveitis patients were divided into active or inactive uveitis status according to clinical grading. Anterior segment SS-OCT scans were obtained for each participant. Tomographic images were analyzed to count the AC cells, and to calculate to absolute measurements of aqueous signal intensity. The absolute values were compared with the signal measured by the scan outside the eye, generating an optical density ratio (aqueous-to-air relative intensity [ARI] index). Correlations between OCT-derived AC inflammatory indexes and LFP, clinical grading, participant category (active or inactive uveitis, control), age, gender, and central corneal thickness (CCT) were assessed., Main Outcome Measures: Correlation between OCT-derived AC inflammatory indexes (ARI index and AC cells on OCT) and standard clinical techniques (LFP, clinical cell grading)., Results: Two hundred thirty-seven eyes (70 active uveitis, 97 inactive uveitis, and 70 controls) were included. Anterior chamber cells count on OCT did not differ between inactive uveitis and controls, but was significantly higher in active uveitis compared to the other categories (both P < 0.0001). All groups had different LFP (all P < 0.0001). Active uveitis had significantly higher ARI index compared with inactive uveitis and controls (both P < 0.0001). Interobserver agreement (intraclass correlation coefficient) for ARI index was 0.78. The ARI index correlated positively with age (P = 0.043) and negatively with CCT (P = 0.006). The ARI index correlated with LFP in the active uveitis group (P < 0.0001), but not in the others. Anterior chamber cells on OCT increased among all cell clinical grades (P < 0.0001). The ARI index increased among all flare clinical grades (P < 0.005)., Conclusions: Anterior segment SS-OCT could be used for a comprehensive assessment of AC inflammation, providing objective measurements of inflammatory cells and aqueous flare., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future., Competing Interests: Author disclosures: PM, DMB, SP, CA, AA, FB, RC, EF, LF, RAG, RG, GHG, JPAI, ASJ, DMK, MM, BM, AM, CJP, GR, HJS, RS, NZ, and AP, no conflicts of interest., (© 2017 American Society for Nutrition.)

Introduction: Intrauterine growth restriction (IUGR) and preeclampsia (PE) are pregnancy disorders characterized by placental insufficiency with oxygen/nutrient restriction and oxidative stress, all influencing mitochondria functionality and number. Moreover, IUGR and PE fetuses are predisposed to diseases later in life, and this might occur through epigenetic alterations. Here we analyze content and methylation of mitochondrial DNA (mtDNA), for the first time in IUGR and PE singleton fetuses, to identify possible alterations in mtDNA levels and/or epigenetic control of mitochondrial loci relevant to replication (D-loop) and functionality (mt-TF/RNR1: protein synthesis, mt-CO1: respiratory chain complex)., Methods: We studied 35 term and 8 preterm control, 31 IUGR, 17 PE/IUGR and 17 PE human singleton pregnancies with elective cesarean delivery. Fetal cord blood was collected and evaluated for biochemical parameters. Extracted DNA was subjected to Real-time PCR to assess mtDNA content and analyzed for D-loop, mt-TF/RNR1 and mt-CO1 methylation by bisulfite conversion and pyrosequencing., Results: mtDNA levels were increased in all pathologic groups compared to controls. Mitochondrial loci showed very low methylation levels in all samples; D-loop methylation was further decreased in the most severe cases and associated to umbilical vein pO 2 . mt-CO1 methylation levels inversely correlated to mtDNA content., Discussion: Increased mtDNA levels in IUGR, PE/IUGR and PE cord blood may denote a fetal response to placental insufficiency. Hypomethylation of D-loop, mt-TF/RNR1 and mt-CO1 loci confirms their relevance in pregnancy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Few studies have assessed the association between potato consumption and mortality. Objective: We investigated whether potato consumption (including fried and unfried potatoes) is associated with increased premature mortality risk in a North American cohort. Design: A longitudinal analysis included 4440 participants aged 45-79 y at baseline with an 8-y follow-up from the Osteoarthritis Initiative cohort study. Potato consumption (including fried and unfried potatoes) was analyzed by using a Block Brief 2000 food-frequency questionnaire and categorized as ≤1 time/mo, 2-3 times/mo, 1 time/wk, 2 times/wk, or ≥3 times/wk. Mortality was ascertained through validated cases of death. To investigate the association between potato consumption and mortality, Cox regression models were constructed to estimate HRs with 95% CIs, with adjustment for potential confounders. Results: Of the 4400 participants, 2551 (57.9%) were women with a mean ± SD age of 61.3 ± 9.2 y. During the 8-y follow-up, 236 participants died. After adjustment for 14 potential baseline confounders, and taking those with the lowest consumption of potatoes as the reference group, participants with the highest consumption of potatoes did not show an increased risk of overall mortality (HR: 1.11; 95% CI: 0.65, 1.91). However, subgroup analyses indicated that participants who consumed fried potatoes 2-3 times/wk (HR: 1.95; 95% CI: 1.11, 3.41) and ≥3 times/wk (HR: 2.26; 95% CI: 1.15, 4.47) were at an increased risk of mortality. The consumption of unfried potatoes was not associated with an increased mortality risk. Conclusions: The frequent consumption of fried potatoes appears to be associated with an increased mortality risk. Additional studies in larger sample sizes should be performed to confirm if overall potato consumption is associated with higher mortality risk. This trial was registered at clinicaltrials.gov as NCT00080171., (© 2017 American Society for Nutrition.)

Background: Calorie restriction (CR) retards aging and increases longevity in many animal models. However, it is unclear whether CR can be implemented in humans without adverse effects on body composition. Objective: We evaluated the effect of a 2-y CR regimen on body composition including the influence of sex and body mass index (BMI; in kg/m 2 ) among participants enrolled in CALERIE-2 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a multicenter, randomized controlled trial. Design: Participants were 218 nonobese (BMI: 21.9-28.0) adults aged 21-51 y who were randomly assigned to 25% CR (CR, n = 143) or ad libitum control (AL, n = 75) in a 2:1 ratio. Measures at baseline and 12 and 24 mo included body weight, waist circumference, fat mass (FM), fat-free mass (FFM), and appendicular mass by dual-energy X-ray absorptiometry; activity-related energy expenditure (AREE) by doubly labeled water; and dietary protein intake by self-report. Values are expressed as means ± SDs. Results: The CR group achieved 11.9% ± 0.7% CR over 2-y and had significant decreases in weight (-7.6 ± 0.3 compared with 0.4 ± 0.5 kg), waist circumference (-6.2 ± 0.4 compared with 0.9 ± 0.5 cm), FM (-5.4 ± 0.3 compared with 0.5 ± 0.4 kg), and FFM (-2.0 ± 0.2 compared with -0.0 ± 0.2 kg) at 24 mo relative to the AL group (all between-group P < 0.001). Moreover, FFM as a percentage of body weight at 24 mo was higher, and percentage of FM was lower in the CR group than in the AL. AREE, but not protein intake, predicted preservation of FFM during CR ( P < 0.01). Men in the CR group lost significantly more trunk fat ( P = 0.03) and FFM expressed as a percentage of weight loss ( P < 0.001) than women in the CR group. Conclusions: Two years of CR had broadly favorable effects on both whole-body and regional adiposity that could facilitate health span in humans. The decrements in FFM were commensurate with the reduced body mass; although men in the CR group lost more FFM than the women did, the percentage of FFM in the men in the CR group was higher than at baseline. CALERIE was registered at clinicaltrials.gov as NCT00427193., (© 2017 American Society for Nutrition.)

Objective: Ten to thirty percent of lung cancer is thought to be of occupational origin. Lung cancer is under-declared as an occupational disease in Europe, and most declarations of occupational disease concern asbestos. The purpose of this study was to design and validate a short, sensitive self-administered questionnaire, as an aid for physicians in detecting occupational exposure to asbestos and other lung carcinogens in order to remedy occupational lung cancer under-declaration., Study Design: Cross-sectional study., Methods: A short (30-question) self-administered questionnaire was drawn up by oncologist-pneumologists and occupational physicians, covering situations of exposure to proven and probable lung carcinogens. Understanding and acceptability were assessed on 15 lung cancer patients. Validity and reliability were assessed on 70 lung cancer patients by comparison against a semi-directive questionnaire considered as gold standard. Sensitivity and specificity were assessed by comparing responses to items on the two questionnaires. Reliability was assessed by analysing the kappa concordance coefficient for items on the two questionnaires., Results: Sensitivity was 0.85 and specificity 0.875. Concordance between responses on the two questionnaires was 85.7%, with a kappa coefficient of 0.695 [0.52-0.87]. Mean self-administration time was 3.1 min (versus 8.12 min to administer the gold-standard questionnaire). In 16 patients, the self-administered questionnaire detected lung carcinogen exposure meeting the criteria for occupational disease., Conclusion: The present short, easy-to-use self-administered questionnaire should facilitate detection of occupational exposure to lung carcinogens. It could be used in occupational lung cancer screening and increase the presently low rate of application for recognition of lung cancer as an occupational disease., (Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate whether frailty is associated with an increased risk of incident type 2 diabetes mellitus (T2DM) in a prospective cohort of community-dwelling older people., Design: Longitudinal study, mean follow-up of 4.4 years., Setting: Progetto Veneto Anziani (Pro.V.A.) study that involved older community-dwellers., Participants: 1754 men and women older than 65 years without T2DM at baseline., Measurements: Frailty status was defined according to Fried criteria and categorized as frailty (≥3 criteria), prefrailty (1-2 criteria), or no frailty (0 criterion). Incident T2DM was defined as fasting plasma glucose (FPG) ≥7.0 mmol/L, or glycosylated hemoglobin ≥6.5%, the use of glucose-lowering drugs, or FPG ≥11.1 mmol/L on a 2-hour oral glucose tolerance test during the follow-up. All T2DM diagnoses were confirmed by endocrinologists., Results: At baseline, frail participants (n = 174) were significantly (a) more obese and had higher waist circumference, (b) experienced a higher rate of cardiovascular disease (including hypertension), and (c) presented with higher, but not pathologic, values of glycosylated hemoglobin and FPG than prefrail (n = 830) and nonfrail participants (n = 750). Over a 4.4-year follow-up, 265 individuals developed T2DM. In a logistic regression analysis, adjusted for potential baseline confounders, frailty [odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.31-2.13, P < .0001] and prefrailty (OR = 1.60, 95% CI = 1.27-2.00, P < .0001) were associated with a significantly higher incidence of T2DM than in nonfrail individuals., Conclusion: Among community-dwelling older people, frailty and prefrailty were significant and independent predictors of T2DM, which is a major and potentially preventable risk factor for multiple comorbidities., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes., Methods and Results: We studied 2573 people, aged 50-75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire. Women had a more adverse plasma lipid profile than men. Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 ± 2.4 vs 11.5 ± 2.5 and 3.4 ± 3.2 vs 2.3 ± 3.2, P < 0.04), and a higher intake of fiber (11.2 ± 2.8 vs 10.4 ± 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women., Conclusions: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Gold nanoparticles (AuNPs) represent an effective choice for topical drug delivery systems thanks to their small size, general non-toxicity, ease of functionalization and high surface to volume ratio. Even if systemic, methotrexate still plays an important role in psoriasis treatment: its topical use shows insufficient percutaneus penetration owing to limited passive diffusion, high molecular weight and dissociation at physiological pH. The aim of our study was to design a new drug delivery nanocarrier for Methotrexate and to improve its solubility, stability and biodistribution. AuNPs were on purpose prepared with a hydrophilic stabilizing layer, in order to improve the colloidal stability in water. Water-soluble gold nanoparticles functionalized by sodium 3-mercapto-1-propansulfonate (Au-3MPS) were prepared and loaded with methotrexate (MTX). The loading efficiency of MTX on Au-3MPS was assessed in the range 70-80%, with a fast release (80% in one hour). The release was studied up to 24h reaching the value of 95%. The Au-3MPS@MTX conjugate was fully characterized by spectroscopic techniques (UV-vis, FTIR) and DLS. Preliminary toxicity tests in the presence of keratinocytes monolayers allowed to assess that the used Au-3MPS are not toxic. The conjugate was then topically used on C57BL/6 mouse normal skin in order to trace the absorption behavior. STEM images clearly revealed the distribution of gold nanoparticles inside the cells. In vitro studies showed that Methotrexate conjugated with Au-3MPS is much more efficient than Methotrexate alone. Moreover, DL50, based on MTT analysis, is 20 folds reduced at 48 h, by the presence of nanoparticles conjugation. UV-vis spectra for in vivo tracing of the conjugate on bare mouse skin after 24h of application, show increased delivery of Methotrexate in the epidermis and dermis using Au-3MPS@MTX conjugate, compared to MTX alone. Moreover we observed absence of the Au-3MPS in the dermis and in the epidermis, suggesting that these layers of the skin do not retain the nanoparticles. Based on our data, we found that the novel Au-3MPS@MTX conjugate is an effective non-toxic carrier for the satisfactory percutaneous absorption of Methotrexate and could help in possible topical treatment of psoriasis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Core-shell gold nanoparticles [AuNPs], stabilized with a hydrophilic polymer, poly(3-dimethylammonium-1-propyne hydrochloride) [PDMPAHCl], have been used for the immobilization of bovine serum amine oxidase [BSAO]. The functionalized surface of the hybrid nanoparticles is pH responsive, due to the presence of aminic groups that carry out a double role: on one hand they act as ligands for the gold nanoparticle surface, allowing the colloidal stabilization and, on the other hand, they give a hydrophilic characteristic to the whole colloidal suspension. The core-shell nanoparticles [Au@PDMPAHCl] have been characterized by using UV-vis and X-ray photoelectron spectroscopy, DLS, ζ-potential measurements and by FE-TEM microscopy. BSAO enzyme can be loaded by non-covalent immobilization onto Au@PDMPAHCl nanoparticles up to 70% in weight, depending on the pH values of the environmental medium. Activity tests on Au@PDMPAHCl-BSAO bioconjugates confirm an enzymatic activity up to 40%, with respect to the free enzyme activity. Moreover, our results show that loading and enzymatic activity are rather interrelated characteristics and that, under appropriate polymer concentration and pH conditions, a satisfactory compromise can be reached. These results, as a whole, indicate that Au@PDMPAHCl-BSAO bioconjugate systems are promising for future biomedical applications., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In this work, a simple and versatile methodology to obtain two different bioconjugated systems has been developed by the immobilization of Candida rugosa lipase (CRL) on hydrophilic gold nanoparticles functionalized with 2-diethylaminoethanethiol hydrochloride (DEA) or with sodium 3-mercapto-1-propanesulfonate (3MPS), namely Au-DEA@CRL and Au-3MPS@CRL. Both spectroscopic and morphological properties of metal nanoparticles have been deeply investigated. The enzyme loading and lipolytic activity of AuNPs@CRL bioconjugates have been studied with respect to different surface functionalization and compared with the free enzyme. Some physical and chemical parameters had a strong effect on enzyme activity and stability, that were improved in the case of the Au-DEA@CRL bioconjugate, which showed a remarkable biocatalytic performance (95% of residual lipolytic activity compared with free CRL) and stability in experimental conditions concerning pH (range 5-8) and temperature (range 20-60°C), as often required for the industrial scale up of catalytic systems., (Copyright © 2015 Elsevier B.V. All rights reserved.)

MARK4 is a serine-threonine kinase that phosphorylates MAP proteins, increasing microtubule dynamics. MARK4 differs from the other members of the MARK family for encoding two isoforms (MARK4L and MARK4S), differentially expressed in the nervous system, and for the peculiar localisation at the centrosome and the midbody. By cytofluorimetric analysis we showed that MARK4 is expressed throughout the cell cycle and preferentially activated during mitosis. Depletion of MARK4S affected the morphology and proliferation of fibroblasts and glioma cells, as the percentages of cells in S and G2/M phases were reduced and the percentage of cells in G1 was increased. In MARK4S silenced cells, centrosomes were duplicated and positioned apically to the nucleus, indicating that the centrosome cycle was altered and the cells arrested in G1 phase. Overexpression of MARK4L or MARK4S reduced the density of the microtubule network, confirming microtubules as the main target of MARK4, and revealed a novel co-localisation of MARK4 and vimentin. Taken together, our data confirm that MARK4 is a key component in the regulation of microtubule dynamics and highlight its major role in cell cycle progression, particularly at the G1/S transition. The co-localisation of vimentin and MARK4L suggests that MARK4 has a wide-ranging influence on cytoskeleton., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

While exposure to nanoparticles is a growing concern, research into their toxicological impact and possible hazard for human health is limited. There remains a lack of information concerning the nature of the dose-response relationship especially at low level exposures. The present paper assesses the occurrence of hormetic-like biphasic dose responses within the nanotoxicology literature. The findings indicate that nanoparticles may induce hormetic-like biphasic dose responses in a wide range of biological cell types, and that these responses can be highly dependent upon the physical and chemical properties of the agent. While the mechanistic foundations of hormetic dose responses induced by chemicals and pharmaceuticals have markedly advanced over the past decade, this remains an important data need for nanotoxicology., (Copyright © 2014. Published by Elsevier B.V.)

Background: The energy intake necessary to maintain weight and body composition is called the energy requirement for weight maintenance and can be determined by using the doubly labeled water (DLW) method., Objective: The objective was to determine the energy requirements of nonobese men and women in the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy 2 study., Design: Energy requirements were determined for 217 healthy, weight-stable men and women [aged >21 to <50 y; 70% female, 77% white; body mass index (BMI; in kg/m(2)) 22 to <28; 52% overweight] over 28 d with 2 consecutive 14-d DLW assessments in addition to serial measures of body weight and fat-free mass and fat mass by dual-energy X-ray absorptiometry. Energy intake and physical activity were also estimated by self-report over ≥6 consecutive d in each DLW period., Results: Total daily energy expenditure (TDEE) was consistent between the 2 DLW studies (TDEE1: 2422 ± 404 kcal/d; TDEE2: 2465 ± 408 kcal/d; intraclass correlation coefficient = 0.90) with a mean TDEE of 2443 ± 397 kcal/d that was, on average, 20% (580 kcal/d) higher in men than in women (P < 0.0001). The regression equation relating mean TDEE to demographics and weight was as follows: TDEE (kcal/d) = 1279 + 18.3 (weight, kg) + 2.3 (age, y) - 338 (sex: 1 = female, 0 = male); R(2) = 0.57. When body composition was included, TDEE (kcal/d) = 454 + 38.7 (fat-free mass, kg) - 5.4 (fat mass, kg) + 4.7 (age in y) + 103 (sex: 1 = female, 0 = male); R(2) = 0.65. Individuals significantly underreported energy intake (350 kcal/d; 15%), and underreporting by overweight individuals (~400 kcal/d; 16%) was greater (P < 0.001) than that of normal-weight individuals (~270 kcal/d; 12%). Estimates of TDEE from a 7-d physical activity recall and measured resting metabolic rate also suggested that individuals significantly underreported physical activity (~400 kcal/d; 17%; P < 0.0001)., Conclusion: These new equations derived over 1 mo during weight stability can be used to estimate the free-living caloric requirements of nonobese adults. This trial was registered at clinicaltrials.gov as NCT00427193.

Aims: The aim of this consensus paper is to review the available evidence on the association between moderate alcohol use, health and disease and to provide a working document to the scientific and health professional communities., Data Synthesis: In healthy adults and in the elderly, spontaneous consumption of alcoholic beverages within 30 g ethanol/d for men and 15 g/d for women is to be considered acceptable and do not deserve intervention by the primary care physician or the health professional in charge. Patients with increased risk for specific diseases, for example, women with familiar history of breast cancer, or subjects with familiar history of early cardiovascular disease, or cardiovascular patients should discuss with their physician their drinking habits. No abstainer should be advised to drink for health reasons. Alcohol use must be discouraged in specific physiological or personal situations or in selected age classes (children and adolescents, pregnant and lactating women and recovering alcoholics). Moreover, the possible interactions between alcohol and acute or chronic drug use must be discussed with the primary care physician., Conclusions: The choice to consume alcohol should be based on individual considerations, taking into account the influence on health and diet, the risk of alcoholism and abuse, the effect on behaviour and other factors that may vary with age and lifestyle. Moderation in drinking and development of an associated lifestyle culture should be fostered., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Despite the widespread use of iridium (Ir) in catalytic converters for improved capacity for reducing carbon monoxide (CO), hydrocarbon (HC) and nitrogen oxide (NO(x)) emissions, there is a lack of studies that have assessed possible toxicological hazards of exposure to Ir. The present investigation indicates that female Wistar rats exposed to Ir in the drinking water for 90 days displayed renal toxicity based on the elevated urinary retinol binding protein (RBP) and albumin. The RBP was more sensitive to albumin, showing significant increases at 0.01 mg/L., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Age-related reductions in serum dehydroepiandrosterone (DHEA) concentrations may be involved in bone mineral density (BMD) losses., Objective: The objective was to determine whether DHEA supplementation in older adults improves BMD when co-administered with vitamin D and calcium., Design: In year 1, a randomized trial was conducted in which men (n = 55) and women (n = 58) aged 65-75 y took 50 mg/d oral DHEA supplements or placebo. In year 2, all participants took open-label DHEA (50 mg/d). During both years, all participants received vitamin D (16 microg/d) and calcium (700 mg/d) supplements. BMD was measured by using dual-energy X-ray absorptiometry. Concentrations of hormones and bone turnover markers were measured in serum., Results: In men, no difference between groups occurred in any BMD measures or in bone turnover markers during year 1 or year 2. The free testosterone index and estradiol increased in the DHEA group only. In women, spine BMD increased by 1.7 +/- 0.6% (P = 0.0003) during year 1 and by 3.6 +/- 0.7% after 2 y of supplementation in the DHEA group; however, in the placebo group, spine BMD was unchanged during year 1 but increased to 2.6 +/- 0.9% above baseline during year 2 after the crossover to DHEA. Hip BMD did not change. Testosterone, estradiol, and insulin-like growth factor 1 increased in the DHEA group only. In both groups, serum concentrations of bone turnover markers decreased during year 1 and remained low during year 2, but did not differ between groups., Conclusion: DHEA supplementation in older women, but not in men, improves spine BMD when co-administered with vitamin D and calcium. This trial was registered at clinicaltrials.gov as NCT00182975.

Colorectal cancer (CRC) is among the most prevalent cancers worldwide and represents a major public health challenge in the developed world. From the perspective of translational investigation, scientists have enormous opportunity to elucidate the molecular genetic mechanisms that contribute to CRC pathogenesis because most cancers develop from adenomatous precursor lesions. The process of adenoma growth and transformation is accompanied by cumulative mutations in dominant genetic pathways that confer a growth advantage. Although this developmental process permits interrogation of informative pathways before the development of cancer, only a few adenomas progress to CRC. Accordingly, a major challenge for clinical translational investigators is to identify the molecular signatures that indicate increased likelihood for adenoma progression. By corollary, these molecular signatures include mutations in high penetrance alleles, which include the Adenomatous Polyposis Coli (APC) gene as well as other alleles in the Wnt/beta-catenin signaling pathway that specify increased genetic susceptibility to CRC. Interactions between these high penetrance alleles and other modifier genes as well as with environmental factors are of particular importance to understand the complex network of events that lead to CRC. This brief review will highlight 3 areas where important questions concerning genetic and environmental risk factors have fueled translational investigation into possible pathways that lead to CRC.

Purpose: Among other etiologic factors involved in first carpometacarpal (CMC) osteoarthritis (OA), occupational factors have been postulated as influencing the occurrence of this condition. Very few epidemiologic studies, however, have evaluated this topic. Determining the occupational risk factors is important in proposing preventive measures at the workplace. This case-control study was undertaken to explore whether there was a history of greater exposure to some occupational factors (eg, occupations, hand postures, tasks involving the CMC joint) in women requiring surgery for CMC OA compared with women with no CMC OA noted by history and physical examination., Methods: The case subjects were 61 women surgically treated for primary CMC OA and the control subjects were 120 aged matched women without history or features of CMC OA. A detailed structured interview was developed to elicit information about age, smoking habits, medical history, lifestyle history, and occupational factors. Occupational factors were based on a detailed history of jobs, coded according to the International Standard Classification of Occupations. For the main occupation/job held for the longest duration and during an average working day, subjects were asked about hand posture or tasks involving requirements presumed to cause a strain or a high load to the CMC joint and about certain work conditions., Results: Of the 61 case and 120 control subjects, 5 and 14, respectively, had never worked. There was no difference between the average number of jobs through the working lifetime of the group of case subjects compared with the group of control subjects. Logistic regression analysis showed that after adjustment for age, smoking status, obesity, CMC OA family history, hysterectomy history, parity, and occasional job, the following occupational factors were risk factors for CMC OA: occupations presumed to be associated with increased risk for CMC OA, occupations involving repetitive thumb use, and jobs perceived by the subject having not enough rest breaks during a day. The group of case subjects had a higher prevalence of hysterectomy history and family CMC OA history compared with the group of control subjects., Conclusions: Although previous studies have reported that work and exposure history may lack precision as risk factors, our results give further evidence to support the role of certain occupational factors in the occurrence of CMC OA in women., Type of Study/level of Evidence: Therapeutic II.

Background: Western diets, obesity, and sedentary lifestyles are associated with increased cancer risk. The mechanisms responsible for this increased risk, however, are not clear., Objective: We hypothesized that long-term low protein, low calorie intake and endurance exercise are associated with low concentrations of plasma growth factors and hormones that are linked to an increased risk of cancer., Design: Plasma growth factors and hormones were evaluated in 21 sedentary subjects, who had been eating a low-protein, low-calorie diet for 4.4 +/- 2.8 y (x +/- SD age: 53.0 +/- 11 y); 21 endurance runners matched by body mass index (BMI; in kg/m2); and 21 age- and sex-matched sedentary subjects eating Western diets., Results: BMI was lower in the low-protein, low-calorie diet (21.3 +/- 3.1) and runner (21.6 +/- 1.6) groups than in the Western diet (26.5 +/- 2.7; P < 0.005) group. Plasma concentrations of insulin, free sex hormones, leptin, and C-reactive protein were lower and sex hormone-binding globulin was higher in the low-protein, low-calorie diet and runner groups than in the sedentary Western diet group (all P < 0.05). Plasma insulin-like growth factor I (IGF-I) and the concentration ratio of IGF-I to IGF binding protein 3 were lower in the low-protein, low-calorie diet group (139 +/- 37 ng/mL and 0.033 +/- 0.01, respectively) than in the runner (177 +/- 37 ng/mL and 0.044 +/- 0.01, respectively) and sedentary Western (201 +/- 42 ng/mL and 0.046 +/- 0.01, respectively) diet groups (P < 0.005)., Conclusions: Exercise training, decreased adiposity, and long-term consumption of a low-protein, low-calorie diet are associated with low plasma growth factors and hormones that are linked to an increased risk of cancer. Low protein intake may have additional protective effects because it is associated with a decrease in circulating IGF-I independent of body fat mass.

Background: Coronary heart disease (CHD) risk factors increase with age and body mass index (BMI; in kg/m2). However, whether lifestyle intervention ameliorates metabolic CHD risk factors in obese older adults is unknown., Objective: The objective was to determine whether lifestyle intervention improves metabolic CHD risk factors in obese older adults., Design: A 6-mo outpatient randomized controlled trial was conducted in obese (BMI >or= 30) older (>or=65 y) adults randomly assigned to diet and exercise therapy (treatment group; n = 17) or no therapy (control group; n = 10). The main outcomes were CHD risk factors., Results: Body weight decreased by 8.4% (8.2 kg) in the treatment group; weight did not change significantly (0.7 kg) in the control group (P < 0.001 between groups). Changes between the control and treatment groups, respectively, in waist circumference (1 and -10 cm), plasma glucose (4 and -4 mg/dL), serum triacylglycerols (0 and -45 mg/dL), and systolic (-2 and -10 mm Hg) and diastolic (0 and -8 mm Hg) blood pressure were different (P < 0.05 for all). The number of subjects with the metabolic syndrome decreased by 59% in the treatment group but did not change significantly in the control group (P < 0.05). Serum free fatty acids increased by 10 micromol/L in the control group and decreased by 99 micromol/L in the treatment group (P < 0.05). Changes between the control and treatment groups, respectively, in C-reactive protein (0.8 and -2.5 mg/L) and interleukin 6 (1.6 and -2.4 pg/mL) were different (P < 0.05 for both)., Conclusions: Lifestyle intervention decreases multiple metabolic CHD risk factors simultaneously in obese older adults.

Background: Weight loss, through calorie restriction or increases in energy expenditure via exercise, improves glucose tolerance and insulin action. However, exercise-induced energy expenditure may further improve glucoregulation through mechanisms independent of weight loss., Objective: The objective was to assess the hypothesis that weight loss through exercise-induced energy expenditure improves glucoregulation and circulating factors involved in insulin action to a greater extent than does similar weight loss through calorie restriction., Design: Sedentary men and women aged 50-60 y with a body mass index (kg/m(2)) of 23.5-29.9 were randomly assigned to 1 of 2 weight-loss interventions [12 mo of exercise training (EX group; n = 18) or calorie restriction (CR group; n = 18)] or to a healthy lifestyle (HL) control group (n = 10). The insulin sensitivity index and areas under the curve for glucose and insulin were assessed with an oral-glucose-tolerance test. Adiponectin and tumor necrosis factor alpha concentrations were measured in fasting serum. Fat mass was measured by dual-energy X-ray absorptiometry., Results: Yearlong energy deficits were not significantly different between the EX and CR groups, as evidenced by body weight and fat mass changes. The insulin sensitivity index increased and the glucose and insulin areas under the curve decreased in the EX and CR groups, remained unchanged in the HL group, and did not differ significantly between the EX and CR groups. Marginally significant increases in adiponectin and decreases in the ratio of tumor necrosis factor alpha to adiponectin occurred in the EX and CR groups but not in the HL group., Conclusions: Weight loss induced by exercise training or calorie restriction improves glucose tolerance and insulin action in nonobese, healthy, middle-aged men and women. However, it does not appear that exercise training-induced weight loss results in greater improvements than those that result from calorie restriction alone.

Latent transforming growth factor (TGF)-beta binding proteins (LTBPs) modulate the secretion and activation of latent TGF-beta. To explore LTBP function in vivo, we created an Ltbp-3(-/-) mouse that has developmental emphysema with decreased septation in terminal alveoli. Differences in distal airspace enlargement were obvious at day 6 after birth. Secondary septation was inhibited, so by days 21 to 28 the mean linear intercept was approximately twofold greater in mutant versus control lungs. There were no differences in lung collagen and elastin, visualized by immunohistochemistry, or in myofibroblast numbers, determined by alpha-smooth muscle actin-positive cells, between mutant or wild-type lungs as the animals aged, other than differences associated with altered lung structure in mutant animals. However, from day 10 there was twice the number of alveolar type II cells in mutant alveoli compared to controls. At days 6 and 10, a transient enhancement in cell proliferation in the mutant lungs was observed by both 5-bromo-2'-deoxy-uridine and proliferating cell nuclear antigen labeling, accompanied by enhanced numbers of terminal dUTP nick-end labeling-positive cells at days 4, 6, and 10. Finally, there was a transient decrease in TGF-beta signaling at days 4 to 6 in Ltbp-3(-/-) lungs. These results indicate that in the absence of Ltbp-3, a temporary decrease in TGF-beta signaling in the lungs at days 4 to 6 alters cell proliferation, correlating with inhibition of septation and developmental emphysema.

Objective: As in other countries, Moroccan health-care workers are exposed to occupational blood exposure (OBE) hazards. The purpose of this study was to estimate the occupational safety and hygiene conditions determining the OBE risk for health-care workers. WORKERS AND METHODS: In March 2000, a multicentric study was carried out in Morocco on 420 health-care workers, with an anonymous questionnaire. The study included health-care workers in the Taza and Temara hospitals and health centers, as well as in a Rabat public medical analysis laboratory., Results: The participation rate was 67.8% (285/420). The population was mainly female (61%) with a mean age of 41.4 years (+/-7 years). Health-care workers answered that: occupational hygiene and safety were inadequate (55.1%); wearing single-use gloves was rare (34.5%); resheathing used needles was frequent (74.5%); safe containers were often missing (67%). In 1999, the annual average incidence of OBE was 1.5 (+/-4.3) per capita. If we consider the whole career of health-care workers, the incidence reached about 14.3+/-28.1 per capita. The absence of post-exposure chemoprophylaxis was the rule., Conclusion: The study shows that there is a need to improve occupational hygiene and safety conditions for Moroccan health-care workers in order to reduce OBE hazards.

Latent TGF-beta binding proteins are multidomain proteins with a common, highly repetitive structural organization and partially overlapping expression patterns. Latent TGF-beta binding protein-1, -3 and -4 bind latent TGF-beta. TGF-betas are normally secreted as latent complexes, consisting of the mature TGF-beta dimer non-covalently bound to its processed propeptide dimer plus a latent TGF-beta binding protein. The latent TGF-beta binding protein is covalently bound to the propeptide. These binding proteins may perform at least two functions: structural, as components of the matrix, and regulatory, as modulators of TGF-beta availability.

Exogenous nucleotides (NT) have been reported to exert a reparative role in animal models of intestinal and hepatic damage. Thus, the administration of NT in the diet of rats with thioacetamide-induced liver cirrhosis normalized many of the histological and biochemical alterations produced by this hepatotoxin. We are currently studying the mechanism by which NT exert this effect using cell culture models. The aim of this work was to investigate whether exogenous nucleosides (NS) modulate the proliferation of hepatocytes. We used fetal rat hepatocytes, which, unlike adult hepatocytes, are proliferative cells. Fetal rat primary hepatocytes were incubated with mixtures of NS, and cell proliferation was studied. NS added to the medium of fetal hepatocytes were taken up in a selective fashion by the cells. Cell proliferation was enhanced, as demonstrated by the induction of c-myc and h-ras gene expression as well as by the higher percentage of cells in S phase, and exogenous NS increased the expression of alpha-fetoprotein. These results suggest that exogenous NS may in fact stimulate proliferation of hepatic cells and help preserve the undifferentiated state of fetal rat hepatocytes.

Background & Aims: We have previously reported the antifibrotic effect of dietary nucleotides in cirrhotic rats. In this work, we used primary rat hepatocytes, a liver stellate cell line (CFSC-2G) and co-cultures of both cell types to investigate the effects of exogenous nucleosides on the gene expression of various extracellular matrix components and on markers of liver function, and to ascertain whether the effects found in vivo are due to CFSC-2G, hepatocytes, or are the consequence of cell-cell interactions., Results: Nucleosides enhanced fibronectin, laminin, and alpha1(I) procollagen levels in CFSC-2G and hepatocytes, as well as collagen synthesis and secretion in CFSC-2G. In contrast, nucleosides lowered fibronectin, laminin and alpha1(I) procollagen levels, and decreased collagen synthesis in co-cultures. Matrix metalloproteinase-13 content and collagen secretion increased in co-cultures incubated with nucleosides. Albumin increased in hepatocytes and co-cultures incubated in the presence of nucleosides., Conclusions: Nucleosides modulate the production of extracellular matrix in single cultures of hepatocytes and of CFSC-2G, and in co-cultures. This effect seems to be regulated at the translational level. The opposite behavior of single cultures and co-cultures is probably due to the fact that the latter model reproduces many of the physical and functional relationships observed in vivo between hepatocytes and stellate cells.