Search

Sickle cell disease (SCD) is a life-threatening blood disorder affecting >500 000 infants annually, mostly in sub-Saharan Africa. Most infants do not have access to an early diagnosis and die early from treatable complications of SCD. Universal newborn screening (NBS) is not yet available in any African country for a variety of reasons, including lack of laboratory capacity, difficulty in tracking affected infants, and the relatively short stay of mothers and newborns at maternity hospitals. Several point-of-care (POC) tests for SCD have been recently developed and validated, but the 2 most well-established tests (Sickle SCAN and HemoTypeSC) have not been rigorously compared with one another. In this study, we aimed to evaluate and compare these 2 POC tests to screen infants aged ≤6 months in Luanda, Angola. Challenging the traditional NBS paradigm, we performed testing not only at maternity centers, but also at vaccination centers across Luanda. We enrolled 2000 babies and performed 1000 tests with each POC test. Both tests demonstrated diagnostic accuracy, with 98.3% of Sickle SCAN results and 95.3% of HemoTypeSC results aligning with the gold standard isoelectric focusing hemoglobin pattern. When the result was provided at the POC, 92% of infants were linked to SCD care compared with 56% in the pilot Angolan NBS program, which used centralized laboratory testing. This study demonstrates the real-world feasibility and accuracy of POC tests to screen infants for SCD in Angola. This study also suggests that including vaccination centers may improve the capture rate for early infant SCD screening programs., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

To inform women of the Navajo Nation of safety measures implemented to minimize COVID-19 virus exposure during screening and treatment procedures at Navajo Nation based health care facilities, the Navajo Nation Breast and Cervical Cancer Prevention Program (NNBCCPP) and the University-based Partnership for Native American Cancer Prevention Program (NACP) collaborated to develop a podcast to describe the continued availability of services. During the COVID-19 pandemic, women of all ages and ethnicities in the US needing breast and cervical cancer prevention screenings and treatment, have been hesitant to seek services given the advice to avoid crowded spaces and maintain physical distancing. Epidemiological trends indicate that proactive, intensive strategies are needed in Native American communities for early detection and treatment to support early cancer diagnosis and improve cancer survival. The NNBCCPP and Northern Arizona University (NAU) through the National Institute of Health's National Cancer Institute funded NACP had a nascent partnership prior to the onset of COVID-19 pandemic. This partnership relied on face-to-face interaction to allow for informal social interaction, facilitate clear communication and support continued trust building. To adhere to federal, state and tribal recommendations to minimize gatherings and to stay in-place to minimize the spread of the virus, the Navajo Nation and NAU restricted, and in most cases would not approve employee travel for partnership meetings. The plans to develop a podcast necessitated bringing additional members into the collaboration who were unfamiliar to the original partners and due to travel restrictions, required all interactions to be remote. This expanded group met virtually to develop a script, record and edit the podcast. More importantly, group members had to build and maintain trust over months of communicating via a teleconference video platform. This collaborative addressed challenges related to unstable Internet connections and periodic stay-at-home policies; thus, these emerging partners had to modify social and professional communication to respect and accommodate the stress and uncertain circumstances created by the pandemic on the citizens and employees of Navajo Nation. This case study describes strategies used to maintain and respect all members of the partnership., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Teufel-Shone, Goldtooth-Begay, Begay, Lazaro, Yellowhair, Todecheenie, Begay, Singer and Briscoe.)

Introduction: Improved teamwork and communication have been associated with improved quality of care. Early Warning Scores (EWS) and rapid response algorithms are a way of identifying deteriorating patients and providing a common framework for communication and response between physicians and nurses. The impact of EWS implementation on interprofessional collaboration (IPC) has been minimally studied, especially in resource-limited settings., Methods: The study took place in the Pediatric Department of the main academic referral hospital in Rwanda between April 2019 and January 2020. Pediatric nurses and residents were trained on the use of the Pediatric Warning Score for Resource-Limited Settings (PEWS-RL) and a rapid response algorithm. Training included vital sign collection, PEWS-RL calculation, IPC and rapid response algorithm implementation. Prior to training, participants completed surveys on IPC with Likert scale responses (from "strongly disagree" to "strongly agree"). Follow-up surveys were then administered nine months later and also included an open-response question on the impact of the PEWS-RL implementation on IPC., Results: Sixty-five (96%) nurses were trained and completed the pre-survey and thirty-seven (54%) of the trained nurses completed the post-survey. Twenty-two (59%) pediatric residents were trained in the workshop and completed the pre-survey and twenty-four physicians (4 pediatricians (40%) and 20 pediatric residents (53%)) completed the post-implementation survey. There was a statistically significant increase in the percent of nurses indicating strong agreement across all domains of communication and collaboration from the pre- to the post-survey. Although the percent of physicians indicating strong agreement increased in the post-survey for all items, only the "share information" item was statistically significant., Conclusion: Training and implementation of a PEWS-RL and a rapid response algorithm at a tertiary hospital in Rwanda resulted in significant improvement of nurse and physician ratings of IPC nine months later., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: This study was funded by a grant from the Boston Children’s Hospital Global Health Program. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Couple therapy and related literature has problematized men's emotional inexpressiveness as constraining for men and as contributing to men's privileged and dominating position vis-à-vis women. Fostering men's emotionality in and outside of therapy has been proposed as a way to improve men's well-being and relationships and promote gender equality. Critical masculinity scholars have noted that many men now enact vulnerable ("softer") and emotional forms of masculinity. Yet, there is lack of insight into how such enactment may intersect with gender inequality. This article presents a critical thematic analysis of 30 transcribed videotaped couple therapy sessions focusing on the performance of men's affective masculinities and the political dimensions of men's increasing emotionality within couple therapy. The study shows that vulnerable masculinities, although argued as bearing the potential to foster relational and social change, may also obscure continuing commitment to dominant masculinity norms. Implications for practice are discussed., (© 2021 American Association for Marriage and Family Therapy.)

The 2019 13 th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA on 1-5 April 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on the 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy. Part 1 (Innovation in small molecules and oligonucleotides and mass spectrometry method development strategies for large molecules bioanalysis) and Part 3 (New insights in biomarker assay validation, current and effective strategies for critical reagent management, flow cytometry validation in drug discovery and development and CLSI H62, interpretation of the 2019 FDA immunogenicity guidance and gene therapy bioanalytical challenges) are published in volume 10 of Bioanalysis , issues 22 and 24 (2019), respectively.

The 13 th GCC Closed Forum for Bioanalysis was held in New Orleans, Louisiana, USA on April 5 th , 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants from eight countries representing 44 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the ICH M10 Bioanalytical Method Validation Draft Guideline and to build unified comments to be provided to the ICH.

The 12th GCC Closed Forum was held in Philadelphia, PA, USA, on 9 April 2018. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: critical reagents; oligonucleotides; certificates of analysis; method transfer; high resolution mass spectrometry; flow cytometry; recent regulatory findings and case studies involving stability and nonclinical immunogenicity. Conclusions and consensus from discussions of these topics are included in this article.

Over the last decade, the use of biomarker data has become integral to drug development. Biomarkers are not only utilized for internal decision-making by sponsors; they are increasingly utilized to make critical decisions for drug safety and efficacy. As the regulatory agencies are routinely making decisions based on biomarker data, there has been significant scrutiny on the validation of biomarker methods. Contract research organizations regularly use commercially available immunoassay kits to validate biomarker methods. However, adaptation of such kits in a regulated environment presents significant challenges and was one of the key topics discussed during the 12th Global Contract Research Organization Council for Bioanalysis (GCC) meeting. This White Paper reports the GCC members' opinion on the challenges facing the industry and the GCC recommendations on the classification of commercial kits that can be a win-win for commercial kit vendors and end users.

Parents and children with high negative emotionality may be more likely to provide and receive non-supportive contingencies, respectively. However, no study has examined child and parent negative emotionality in the same study and explored whether the link between child and parent negative emotionality may exist in part because of parental emotion socialization. The present study was designed to explore the link between the negative emotionality of mothers and their adolescent children and the potential mechanisms for this similarity. Maternal emotion socialization was explored as a mediator between maternal and adolescent negative emotionality, and between maternal negative emotionality and adolescent internalizing symptoms. Participants were mothers (M age = 30.47) with their children at two time points: preschool (Time 1; M age = 4.55 years old) and adolescence (Time 2; M = 13.73), with 81 boys and 94 girls. Negative emotionality was measured using a questionnaire, with mothers reporting for herself and her child. Maternal emotion socialization was measured by mothers' self-report of their contingencies to their adolescent child's negative emotions: 1) Punish; 2) magnify; 3) ignore; 4) override; and 5) support. The results revealed that the maternal punishing of the adolescent's negative emotions was a mediator between concurrent mother negative emotionality and adolescent negative emotionality, such that higher mother negative emotionality was associated with more punishing, and more punishing was associated with higher adolescent negative emotionality, controlling for previous levels of maternal and child negative emotionality. Furthermore, being supportive of a child's negative emotions was negatively associated with concurrent levels of adolescent internalizing symptoms, while magnifying a child's emotions held a marginal positive association, controlling for previous levels of internalizing symptoms. The results highlight the importance of considering maternal emotion socialization strategies, even into adolescence, for a more comprehensive understanding of children's emotional well-being. The findings have implications for developing and implementing emotion-based parenting interventions.

The 11th Global CRO Council Closed Forum was held in Universal City, CA, USA on 3 April 2017. Representatives from international CRO members offering bioanalytical services were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The second CRO-Pharma Scientific Interchange Meeting was held on 7 April 2017, which included Pharma representatives' sharing perspectives on the topics discussed earlier in the week with the CRO members. The issues discussed at the meetings included cumulative stability evaluations, matrix stability evaluations, the 2016 US FDA Immunogenicity Guidance and recent and unexpected FDA Form 483s on immunogenicity assays, the bioanalytical laboratory's role in writing PK sample collection instructions, biosimilars, CRO perspectives on the use of chiral versus achiral methods, hybrid LBA/LCMS assays, applications of fit-for-purpose validation and, at the Global CRO Council Closed Forum only, the status and trend of current regulated bioanalytical practice in China under CFDA's new BMV policy. Conclusions from discussions of these topics at both meetings are included in this report.

The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California from 3 April 2017 to 7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis, Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS and ligand-binding assay (LBA) approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for Small Molecules, Peptides and Small Molecule Biomarkers using LCMS. Part 2 (Biotherapeutics, Biomarkers and Immunogenicity Assays using Hybrid LBA/LCMS and Regulatory Agencies' Inputs) and Part 3 (LBA: Immunogenicity, Biomarkers and PK Assays) are published in volume 9 of Bioanalysis, issues 23 and 24 (2017), respectively.

The 10th Global CRO Council (GCC) Closed Forum was held in Orlando, FL, USA on 18 April 2016. In attendance were decision makers from international CRO member companies offering bioanalytical services. The objective of this meeting was for GCC members to meet and discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at this closed forum included reporting data from failed method validation runs, GCP for clinical sample bioanalysis, extracted sample stability, biomarker assay validation, processed batch acceptance criteria, electronic laboratory notebooks and data integrity, Health Canada's Notice regarding replicates in matrix stability evaluations, critical reagents and regulatory approaches to counteract fraud. In order to obtain the pharma perspectives on some of these topics, the first joint CRO-Pharma Scientific Interchange Meeting was held on 12 November 2016, in Denver, Colorado, USA. The five topics discussed at this Interchange meeting were reporting data from failed method validation runs, GCP for clinical sample bioanalysis, extracted sample stability, processed batch acceptance criteria and electronic laboratory notebooks and data integrity. The conclusions from the discussions of these topics at both meetings are included in this report.

The 2016 10 th Workshop on Recent Issues in Bioanalysis (10 th WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis including Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This white paper is published in 3 parts due to length. This part (Part 1) discusses the recommendations for small molecules, peptides and small molecule biomarkers by LCMS. Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in the Bioanalysis journal, issue 23.

Bioanalysis invited a selection of leading researchers to express their views on increasing and maintaining productivity in the bioanalytical laboratory. The topics discussed include the challenges of maintaining productivity when integrating new innovations into existing processes, the impact of automation on productivity, and how they effectively manage productivity in their own bioanalytical laboratories. Their enlightening responses provide a valuable insight into current methods of increasing productivity and the future of the constantly evolving bioanalytical laboratory.

Behaviour change communication is vital for increasing the enactment of particular behaviours known to promote health and growth. The techniques used to change behaviour are important for determining how successful the intervention is. In order to integrate findings from different interventions, we need to define and organize the techniques previously used and connect them to effectiveness data. This paper reviews 24 interventions and programs implemented to change four health behaviours related to child health in developing countries: the use of bed nets, hand washing, face washing and complementary feeding. The techniques employed are organized under six categories: information, performance, problem solving, social support, materials, and media. The most successful interventions use three or even four categories of techniques, engaging participants at the behavioural, social, sensory, and cognitive levels. We discuss the link between techniques and theories. We propose that program development would be more systematic if researchers considered a menu of technique categories appropriate for the targeted behaviour and audience when designing their studies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Cyclosporine inhalation solution (CIS) delivered via nebulization is under evaluation for the prevention of chronic rejection post-lung transplant. A 300-patient randomized, controlled clinical trial (CYCLIST) is expected to be completed late in 2011. In support of this trial, a chronic inhalation toxicology study in dogs has been completed., Methods: To mimic the clinical setting, animals (four/sex/dose plus two/sex/dose in the control and high dose recovery groups) were exposed to aerosolized CIS, via nose-only exposure, three times per week for 9 months at targeted inhaled doses of 0 (air), 4, 12, and 24 mg/kg. In addition, the potential for persistence or reversibility of any toxic effects were assessed after a 6-week recovery period. The toxicological endpoints included clinical observations, body-weight, food consumption, toxicokinetics, clinical chemistry, and histopathology., Results: All dogs receiving CIS completed the study with the only consistent observations being excessive salivation and changes in minute ventilation. There was no limiting lung or systemic toxicity associated with exposure to CIS, and the only possible drug-related effect was an observation of benign fibroadenoma tissue in the mammary glands of the high-dose female recovery group. Toxicokinetic data showed that cyclosporine is initially absorbed rapidly with little drug remaining in lung tissue or blood 24 h after the end of dosing., Conclusion: The study supports the pulmonary and systemic safety of aerosolized CIS at expected lung dose levels/kg of up to 12 times greater than the average dose patients are receiving in the CYCLIST trial.

Epithelial cell lines were established from the transition and peripheral zones of human prostate by transduction with cdk4 and hTERT. The properties of these lines were investigated using immunocytochemical markers, ability to generate anchorage-independent colonies and by spectral karyotyping (SKY). Cells were exposed to fractionated doses of gamma irradiation to investigate their ability to transform. Cell lines were established from the transition and peripheral zones of human prostate. The expression of CD133, CK5, CK14, CK18, p16, PSCA, p63 and c-myc varied between the lines from the two regions. The line derived from the peripheral zone exhibited properties of a tumour line. A similar pattern was observed in two separate transductions. It was thus unlikely to be an in vitro transformation event, which is very rarely observed with human cells in vitro, and thus more likely to be derived from the immortalisation of a quiescent tumour clone. Fractionated irradiation of the transition zone cell line resulted in forming of transformed colonies. The transformed and tumour line had marked chromosomal rearrangements as demonstrated by SKY analysis. Cell lines have been derived from different zones of human prostate for studies on radiation carcinogenesis. The unirradiated cell line derived from the peripheral zone exhibited chromosomal rearrangements similar to those observed in prostate carcinoma. The cell line derived from the transitional zone exhibited a near diploid karyotype and could be transformed following exposure to fractionated doses of gamma irradiation.

Unlabelled: We previously demonstrated that male mice display significantly reduced pain behavior on the acetic acid abdominal constriction test when confined in close proximity to a stranger male mouse. We show here the testosterone-dependence (via castration and testosterone propionate replacement) of this phenomenon, likely a form of (social) stress-induced analgesia. However, when similar male dyads are separated by vertical metal bars, allowing only partial physical contact, we find that the mice exhibit hyperalgesia, not analgesia, in response to both acetic acid injection and noxious radiant heat, relative to testing in isolation. This finding is specific to same-sex male dyads, and no change in nociceptive sensitivity is observed when males are tested in the presence of a female conspecific. We propose that pain sensitivity varies with respect to the severity of the social threat: mild social threat produces hyperalgesia and more severe social threat produces analgesia., Perspective: This work highlights the importance of social threat in modulating pain behavior in a sex-specific manner. The findings add to a growing body of evidence that social factors affect pain behavior in mice, thus allowing the study of the mechanistic underpinnings of social modulation of pain in humans., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Chromosomal copy number alterations and chromosomal rearrangements are frequent mutations in human cancer. Unlike copy number alterations, little is known about the role and occurrence of chromosomal rearrangements in breast cancer. This may be due to the fact that chromosome-based breakpoint analysis is widely restricted to cultured cells. In order to identify gene rearrangements in breast cancer, we studied the chromosomal breakpoints in radiation-transformed epithelial breast cell lines using a high-resolution array-based approach using 1 Mb bacterial artificial chromosome (BAC) arrays. The breakpoints were further narrowed down by fluorescence in situ hybridisation (FISH) with clones from the 32 k BAC library. The analysis of the cell lines B42-11 and B42-16 revealed rearrangements of chromosomes 7, 8, 10 and 12. We identified the genes Has2, Grid1, Ret, Cpm, Tbx3, Tbx5, Tuba1a, Wnt1 and Arf3 within the breakpoint regions. Quantitative RT-PCR showed a deregulated expression of all of these candidate genes except for Tbx5 and Tbx3. This is the first study demonstrating gene rearrangements and their deregulated mRNA expression in radiation-transformed breast cells. Since the gene rearrangements occurred in the transformed and tumourigenic cell lines only, it is likely that these were generated in conjunction with malignant transformation of the epithelial breast cells and therefore might reflect early molecular events in breast carcinogenesis. Initial studies indicate that these gene alterations are also found in sporadic breast cancers.

We investigate the nature of randomness in disordered packings of frictional spheres. We calculate the entropy of 3D packings through the force and volume ensemble of jammed matter, a mesoscopic ensemble and numerical simulations using volume fluctuation analysis and graph theoretical methods. Equations of state are obtained relating entropy, volume fraction and compactivity characterizing the different states of jammed matter. At the mesoscopic level the entropy vanishes at random close packing, while the microscopic states contribute to a finite entropy. The entropy of the jammed system reveals that the random loose packings are more disordered than random close packings, allowing for an unambiguous interpretation of both limits.

Introduction: Many substances that form methemoglobin (MHb) effectively counter cyanide (CN) toxicity. Although MHb formers are generally applied as treatments for CN poisoning, it has been proposed that a stable, long-acting MHb former could serve as a CN pretreatment. Using this rationale, the 8-aminoquinoline WR242511, a potent long-lasting MHb former in rodents and beagle dogs, was studied in the rhesus monkey for advanced development as a potential CN pretreatment., Methods: In this study, WR242511 was administered intravenously (IV) in 2 female and 4 male rhesus monkeys in doses of 3.5 and/or 7.0 mg/kg; a single male also received WR242511 orally (PO) at 7.0 mg/kg. Health status and MHb levels were monitored following exposure., Results: The selected doses of WR242511, which produced significant methemoglobinemia in beagle dogs in earlier studies conducted elsewhere, produced very little MHb (mean < 2.0%) in the rhesus monkey. Furthermore, transient hemoglobinuria was noted approximately 60 minutes postinjection of WR242511 (3.5 or 7.0 mg/kg), and 2 lethalities occurred (one IV and one PO) following the 7.0 mg/kg dose. Myoglobinuria was also observed following the 7.0 mg/kg dose. Histopathology analyses in the 2 animals that died revealed liver and kidney toxicity, with greater severity in the orally-treated animal., Conclusions: These data demonstrate direct and/or indirect drug-induced toxicity. It is concluded that WR242511 should not be pursued as a pretreatment for CN poisoning unless the anti-CN characteristics of this compound can be successfully dissociated from those producing undesirable toxicity.

We report experimental measurements of particle dynamics on slowly sheared granular matter in a three-dimensional Couette cell. A closely packed ensemble of transparent spherical beads is confined by an external pressure and filled with fluid to match both the density and refractive index of the beads. This allows us to track tracer particles embedded in the system and obtain three-dimensional trajectories [r(t),theta(t),z(t)] as a function of time. We study the probability distribution function of the vertical and radial displacements, finding Gaussian and exponential distributions, respectively. For slow shear rates, the mean-square fluctuations in all three directions are found to be dependent only on the angular displacement of the Couette cell, Delta theta e, (Delta z 2) approximately Delta theta e, (Delta r2) approximately Delta theta e alpha, Delta theta 2 approximately Delta theta e beta, where alpha and beta are constants. With Delta theta e proportional to the time between measurements, the values of the constants, alpha and beta , are found to be subdiffusive and superdiffusive, respectively. ThFe linear relation between (Delta z 2) and angular displacement implies a diffusive process, from which we can calculate an "effective temperature," T eff, in the vertical direction, through a fluctuation-dissipation relation. It is of interest to determine whether these systems can be described by analogous equilibrium statistical mechanics concepts such as "effective temperature" and "compactivity." By studying the dynamics of tracer particles, we find the effective temperature defined by the Stokes-Einstein relation to be independent of the tracer particle characteristic features, such as density and size, and dependent only on the packing density of the system. For slow shear rate, both the diffusivity and mobility of tracer particles are proportional to the shear rate, giving rise to a constant effective temperature, characteristic of the jammed system. We finally discuss the significance of the existence of T eff for a statistical mechanics formulation of granular matter.

Background: Atrioventricular (AV) optimization of cardiac resynchronization therapy (CRT) is typically calculated at rest. However, patients often become symptomatic during exercise., Objective: In this study, we use acute noninvasive hemodynamics to optimize the AV delay of CRT during exercise and investigate whether this exercise optimum can be predicted from a three-phase resting model., Methods: In 20 patients with CRT, we adjusted the sensed AV delay while the patient exercised on a treadmill up to a heart rate of 100 bpm to identify the hemodynamically optimal value. Separately, at rest, by pacing with three different configurations and calculating the sensed-paced difference, we calculated an "expected" value for the exercise optimum., Results: It was possible to perform AV delay optimization while a patient exercised. The resting three-phase model correlated well with the actual exercise optimal AV delay (r = 0.85, mean difference +/- standard deviation [SD] = 3.7 +/- 17 ms). Simply using measurements made at rest during atrial-sensed pacing showed a poorer correlation with exercise (r = 0.64, mean difference +/- SD = 2.2 +/- 24 ms). The three-phase resting model allows improved exercise hemodynamics to be achieved. Programming according to the three-phase resting model yields an exercise blood pressure of only 0.5 mmHg (+/-1.4 mmHg; P = NS) less than the true exercise optimum, whereas programming the resting sensed optimum yields an exercise blood pressure of 1.4 mmHg (+/-2.2 mmHg, P = .02) less than the true optimum., Conclusions: Using acute noninvasive hemodynamics and a protocol of alternations, it is possible to optimize the AV delay of cardiac resynchronization devices even while a patient exercises. In clinical practice, the exercise optimum AV delay could be determined from three phases of resting measurements, without performing exercise.

Incisional hernias occur in up to 11 per cent of patients undergoing abdominal surgery. Up to 50 per cent of these patients with hernias will require repeat operative procedures. Management of these hernias have focused primarily on tensile strength of the mesh material, have not addressed currently used materials, and have not compared the strength of these repairs with each other. Forty-nine adult Sprague-Dawley rats had an incisional hernia created by removing a portion of their abdominal wall that was then repaired primarily, using either a composite mesh, Dual mesh (Gore-Tex), or polypropylene mesh. Six weeks after the repair, the rats were euthanized. Hydrostatic distension of the abdominal cavity was performed to compare bursting strength of each repair. Wound tensile strength was assessed and compared. Tissue samples were also taken to compare repair types for incorporation of prosthetic materials. The gross weight of the animals subjected to hydrostatic distention was equivalent between groups, as was the volume required prior to failure of the repair. There was a trend toward improved tensile strength of the Prolene mesh repair, which had a lower average inflammatory and fibrosis score on histology. Overall, the type of mesh used for repair does not seem to impact significantly the strength of the repair when assessed 6 weeks postoperatively. Choice of prosthetic material to repair the hernia should be made based on economics and handling characteristics alone. Prolene mesh has satisfactory strength with the least amount of inflammation and fibrosis.

Jammed matter is by definition impenetrable to light, such that little is known about the geometry of jammed systems. Using confocal microscopy to image an emulsion in 3D, we first explain the origin of the enhanced fluorescence at the droplet contacts and then determine the contact network inside the model frictionless system. This enables the experimental determination of the average coordination number which agrees with the isostatic predicted value of approximately 6. Furthermore, we calculate the entropy of the packing from the network of contacts.

Objective: To examine concordance between treatment effects in animal experiments and clinical trials. Study design Systematic review., Data Sources: Medline, Embase, SIGLE, NTIS, Science Citation Index, CAB, BIOSIS., Study Selection: Animal studies for interventions with unambiguous evidence of a treatment effect (benefit or harm) in clinical trials: head injury, antifibrinolytics in haemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroids to prevent neonatal respiratory distress syndrome, and bisphosphonates to treat osteoporosis. Review methods Data were extracted on study design, allocation concealment, number of randomised animals, type of model, intervention, and outcome., Results: Corticosteroids did not show any benefit in clinical trials of treatment for head injury but did show a benefit in animal models (pooled odds ratio for adverse functional outcome 0.58, 95% confidence interval 0.41 to 0.83). Antifibrinolytics reduced bleeding in clinical trials but the data were inconclusive in animal models. Thrombolysis improved outcome in patients with ischaemic stroke. In animal models, tissue plasminogen activator reduced infarct volume by 24% (95% confidence interval 20% to 28%) and improved neurobehavioural scores by 23% (17% to 29%). Tirilazad was associated with a worse outcome in patients with ischaemic stroke. In animal models, tirilazad reduced infarct volume by 29% (21% to 37%) and improved neurobehavioural scores by 48% (29% to 67%). Antenatal corticosteroids reduced respiratory distress and mortality in neonates whereas in animal models respiratory distress was reduced but the effect on mortality was inconclusive (odds ratio 4.2, 95% confidence interval 0.85 to 20.9). Bisphosphonates increased bone mineral density in patients with osteoporosis. In animal models the bisphosphonate alendronate increased bone mineral density compared with placebo by 11.0% (95% confidence interval 9.2% to 12.9%) in the combined results for the hip region. The corresponding treatment effect in the lumbar spine was 8.5% (5.8% to 11.2%) and in the combined results for the forearms (baboons only) was 1.7% (-1.4% to 4.7%)., Conclusions: Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately.

Recent deorphanization efforts have paired the G-protein-coupled receptors GPR40, GPR41 and GPR43 with fatty acids as endogenous ligands. While carboxylic acids have been historically known to serve as fuel sources and biomarkers of disease, these studies demonstrate that fatty acids can act as signalling molecules at the cell-surface level. This receptor subfamily shares approx. 30% identity among members, with some limited cross-over between ligand activities. Generalized expression patterns within the pancreatic beta-cell, adipose depots and the gastrointestinal tract infer involvement in energy source recognition, absorption, storage and/or metabolism. GPR40, activated by medium and long-chain fatty acids, has been shown to potentiate insulin secretion at the beta-cell, and has been hypothesized to participate in the detrimental effects of chronic fatty acid exposure on beta-cell function. GPR41 and GPR43 have been reported to stimulate leptin release and adipogenesis respectively via activation by short-chain fatty acids. These common themes implicate GPR40, GPR41 and GPR43 in playing significant roles in metabolic diseases, such as diabetes, obesity and the metabolic syndrome.

Evidence from clinical and laboratory studies suggests that angiogenesis is important in the progression of solid tumours and hematologic malignancies. We have shown that the naturally occurring tetrapeptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a potent angiogenic factor normally present at nanomolar concentrations in the blood. A murine leukemia model was used to assess whether there was a correlation between levels of endogenous AcSDKP and the development of disease. Levels of AcSDKP in the plasma and bone marrow (BM) cells from mice bearing an acute myeloid leukemia (AML) were five- to ten-fold greater than those in non-leukemic mice. Furthermore, a strong correlation between the concentration of endogenous AcSDKP and the progression of AML was demonstrated. These results are consistent with the marked increase in BM vascularity observed in leukemic mice. The physiologic relevance of these findings awaits further studies and the contribution of AcSDKP to the pathogenesis of leukemia is under investigation.

Bisphosphonates are extremely hydrophilic and structurally similar to many endogenous phosphorylated compounds, making their selective extraction from serum or urine very challenging. Many bisphosphonates lack strong chromophores for sensitive UV or fluorescence detection. We report here the first general approach to enable sensitive and selective quantitation of N-containing bisphosphonates by liquid chromatography/tandem mass spectrometry (LC/MS/MS) following derivatization with diazomethane. The novelty of the strategy lies in performing the derivatization on silica-based anion-exchange sorbents as an integrated step in the sample purification by solid-phase extraction (SPE). The 'on-cartridge' reaction with diazomethane not only led to higher efficiency of derivatization, but also enabled a more discriminatory recovery of the drug's derivatives. The derivatized bisphosphonates demonstrated improved chromatographic separation and increased sensitivity of the detection. The general applicability of the approach was demonstrated by validation of bioanalytical methods for risedronate and alendronate in human serum and urine. Sensitivity was achieved at the pg/mL level with merely 100-200 microL of sample., (Copyright 2006 John Wiley & Sons, Ltd.)