Uterine fibroids and risk of hypertensive disorders of pregnancy - results from a racially diverse high-risk cohort.

Study Question: What is the impact of the presence of uterine fibroids on the risk of developing hypertensive disorders of pregnancy (HDP) in a predominantly urban, low-income, Black, and Hispanic population of women with ultrasound or clinically diagnosed uterine fibroids with rich phenotypic data to carefully control for potential confounders? Summary answers: The odds of HDP were 39% higher in women with uterine fibroids compared to those without when controlled for age at delivery, race, prepregnancy BMI, education, parity, and smoking status; neither fibroid location or size modified this risk. What is known already: Studies are conflicting regarding the impact of uterine fibroids on risk of HDP; limitations of prior studies include primarily Western European populations and lack of measurement of potential confounders. Study design size and duration: A total of 7030 women from the Boston Birth Cohort (a racially diverse cohort recruited from 1998 to 2018) that had clinical and ultrasound data regarding uterine fibroid status were included in this analysis. Participants/materials setting and methods: Four hundred eighty-nine women with uterine fibroids and 6541 women without were included. Hypertensive disorders of pregnancy were ascertained from medical records. Logistic regression was performed to assess the risk of HDP in women with and without uterine fibroids. Covariates adjusted for included age at delivery, race, pre-pregnancy BMI, education, parity, and smoking status during pregnancy. Sub-analyses were performed to assess the impact of specific fibroid location and overall fibroid volume burden. Main results and the role of chance: The incidence of uterine fibroids in the cohort was 7% (N=489). Twelve percent of women without uterine fibroids and 17% of women with fibroids developed HDP; in multivariate analyses adjusted for the potential confounders above, the odds of HDP were 39% higher in women with uterine fibroids compared to those without (p=0.03). Women with a uterine fibroid diagnosis based on ICD code (n=297) versus asymptomatic incidental ultrasound diagnosis (n=192) had a significantly greater chance of developing HDP (20 vs 15%, p=0.006). There did not appear to be an association between number of fibroids or total fibroid volume and the risk of developing HDP. Limitations, reasons for caution: This study has a relatively small sample size. While post-hoc power calculation determined that there was adequate power to detect a 4.6% difference in the incidence of development of HDP between participants with uterine fibroids and those without, the sub-analyses based on fibroid size, location, and method of diagnosis were underpowered to determine a similar level of difference. Wider implications of the findings: In a racially diverse cohort, presence of uterine fibroids was a significant risk factor for developing HDP, regardless of uterine fibroid size or location. This may have implications for additional monitoring and risk stratification in women with uterine fibroids. Study funding/competing interests: KC supported by WRHR NIH NICHD Award # K12 HD103036, PI Andrew Satin, RD James Segars. The Boston Birth Cohort (the parent study) was supported in part by the National Institutes of Health (NIH) grants (2R01HD041702, R01HD098232, R01ES031272, R01ES031521, and U01 ES034983); and the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) (UT7MC45949). This information or content and conclusions are those of the authors and should not be construed as the official position or policy of, nor should any endorsements be inferred by any funding agencies. Trial registration number: The BBC is registered under clinicaltrials.gov NCT03228875 .

"I have failed to separate my HIV from this pain": the challenge of managing chronic pain among people with HIV.

Pain is a highly prevalent and burdensome symptom among people with HIV (PWH). This study aims to identify how the experience of living with HIV and chronic pain influences pain beliefs, health-seeking and pain management. Thirty-nine purposively sampled PWH with chronic pain (sample characteristics = 61% women, 79% Black, Asian and minority ethnic groups, 18% men who have sex with men, 45-54 median age category) participated in focus groups in London. Focus groups were co-facilitated with community members. Transcripts wereanalysed using a thematic approach. Findings revealed that HIV stigma, fractured care pathways, and general practitioners' lack of HIV training are barriers to supported pain management. Unaddressed pain results in poorer mental health and reduced quality of life, which has important clinical implications for HIV treatment adherence. Creating HIV-specific pain resources, activating social networks, and pain self-management techniques are potential solutions. Person-centred assessment and HIV training is needed to help clinicians identify PWH with chronic pain. Clear guidelines need to be developed to identify which health service providers are responsible for chronic pain management in PWH. This study generated a refined version of the Fear Avoidance Model that introduces a dimension of HIV-specific behaviours that impact PWHs seeking chronic pain management.

The Global Task Force for Chronic Pain in People with HIV (PWH): Developing a research agenda in an emerging field.

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward.

Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study.

BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. PATIENTS AND METHODS: Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. RESULTS: Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. CONCLUSIONS: In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.

The Oldest Highlands of Mars May Be Massive Dust Fallout Deposits.

The oldest terrains of Mars are cratered landscapes, in which extensive valleys and basins are covered by ubiquitous fluvial plains. One current paradigm maintains that an impact-generated megaregolith underlies these sediments. This megaregolith was likely largely generated during the Early Noachian (~4.1 to ~3.94 Ga) when most Martian impact basins formed. We examined the geologic records of NW Hellas and NW Isidis, which include this epoch's most extensive circum-basin outcrops. Here, we show that these regions include widespread, wind-eroded landscapes, crater rims eroded down by several hundred meters, pitted plains, and inverted fluvial and crater landforms. These surfaces exhibit few fresh craters, indicating geologically recent wind erosion. The deep erosion, topographic inversions, and an absence of dunes on or near talus across these regions suggest that sediments finer than sand compose most of these highland materials. We propose that basin-impact-generated hurricane-force winds created sediment-laden atmospheric conditions, and that muddy rains rapidly settled suspended sediments to construct extensive Early Noachian highlands. The implied high abundance of fine-grained sediments before these impacts suggests large-scale glacial silt production and supports the previously proposed Noachian "icy highlands" hypothesis. We suggest that subglacial meltwater interactions with the sedimentary highlands could have promoted habitability, particularly in clay strata.

The 1997 Mars Pathfinder Spacecraft Landing Site: Spillover Deposits from an Early Mars Inland Sea.

The Martian outflow channels comprise some of the largest known channels in the Solar System. Remote-sensing investigations indicate that cataclysmic floods likely excavated the channels ~3.4 Ga. Previous studies show that, in the southern circum-Chryse region, their flooding pathways include hundreds of kilometers of channel floors with upward gradients. However, the impact of the reversed channel-floor topography on the cataclysmic floods remains uncertain. Here, we show that these channel floors occur within a vast basin, which separates the downstream reaches of numerous outflow channels from the northern plains. Consequently, floods propagating through these channels must have ponded, producing an inland sea, before reaching the northern plains as enormous spillover discharges. The resulting paleohydrological reconstruction reinterprets the 1997 Pathfinder landing site as part of a marine spillway, which connected the inland sea to a hypothesized northern plains ocean. Our flood simulation shows that the presence of the sea would have permitted the propagation of low-depth floods beyond the areas of reversed channel-floor topography. These results explain the formation at the landing site of possible fluvial features indicative of flow depths at least an order of magnitude lower than those apparent from the analyses of orbital remote-sensing observations.

Safety and efficacy of paramedic treatment of regular supraventricular tachycardia: a randomised controlled trial.

INTRODUCTION: Supraventricular tachycardias (SVTs) are a common cause of acute hospital presentations. Adenosine is an effective treatment. To date, no studies have directly compared paramedic-with hospital-delivered treatment of acute SVT with adenosine. METHOD: Randomised controlled trial comparing the treatment of SVT and discharge by paramedics with conventional emergency department (ED)-based care. Patients were excluded if they had structural heart disease or contraindication to adenosine. Discharge time, follow-up management, costs and patient satisfaction were compared. RESULTS: Eighty-six patients were enrolled: 44 were randomised to paramedic-delivered adenosine (PARA) and 42 to conventional care (ED). Of the 37 patients in the PARA group given adenosine, the tachycardia was successfully terminated in 81%. There was a 98% correlation between the paramedics' ECG diagnosis and that of two electrophysiologists. No patients had any documented adverse events in either group. The discharge time was lower in the PARA group than in the ED group (125 min (range 55-9513) vs 222 min (range 72-26 153); p=0.01), and this treatment strategy was more cost-effective (£282 vs £423; p=0.01). The majority of patients preferred this management approach. Being treated and discharged by paramedics did not result in the patients being less likely to receive ongoing management of their arrhythmia and cardiology follow-up. CONCLUSIONS: Patients with SVT can effectively and safely be treated with adenosine delivered by trained paramedics. Implementation of paramedic-delivered acute SVT care has the potential to reduce healthcare costs without compromising patient care. TRIAL REGISTRATION NUMBER: NCT02216240.

Telomere shortening and telomerase activity in ischaemic cardiomyopathy patients - Potential markers of ventricular arrhythmia.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) reduce mortality in patients with ischaemic cardiomyopathy at high risk of ventricular arrhythmias (VA). However, the current indication for ICD prescription needs improvement. Telomere and telomerase in leucocytes have been shown to associate with biological ageing and pathogenesis of cardiovascular diseases. We hypothesised that leucocyte telomere length, load-of-short telomeres and/or telomerase activity are associated with VA occurrence in ischaemic cardiomyopathy patients. METHODS AND RESULTS: 90 ischaemic cardiomyopathy patients with primary prevention ICDs were recruited. 35 had received appropriate therapy from the ICD for potentially-fatal VA while the remaining 55 patients had not. No significant differences in baseline demographic data relevant to telomere biology were seen between the two groups. There was no significant difference in the age and sex adjusted mean telomere length analysed by qPCR between the groups (p=0.88). In contrast, the load-of-short telomeres assessed by Universal-STELA method and telomerase activity by TRAP assay were both higher in patients who had appropriate ICD therapy and were significantly associated with incidence of ICD therapy (p=0.02, p=0.02). ROC analyses demonstrated that the sensitivity and specificity of these telomere dynamics in predicting potentially-fatal VA was higher than the current gold-standard - left ventricular ejection fraction (AUC 0.82 versus 0.47). CONCLUSION: The load-of-short telomeres and telomerase activity had a significant association with ICD therapy (for VA) in ischaemic cardiomyopathy patients. These biomarkers should be tested in prospective studies to assess their clinical utility in predicting VA after myocardial infarction and guiding primary prevention ICD prescription.

Serum biomarker levels for musculoskeletal disease in two- and three-year-old racing Thoroughbred horses: A prospective study of 130 horses.

REASON FOR PERFORMING STUDY: Biomarkers have shown some in vivo promise for the detection of musculoskeletal injuries, but further study to assess biomarker levels in clinical orthopaedic disease is required. OBJECTIVE: To assess 7 serum biomarkers for the detection of musculoskeletal injuries. METHODS: Two- and 3-year-old racehorses were entered into the study (n = 238). Exit criteria were lack of training for >30 days, or completion of 10 study months. Data from horses with solitary musculoskeletal injuries and completion of >2 months were analysed. Musculoskeletal injury was considered intra-articular fragmentation (IAF), tendon or ligamentous injury (TL), stress fractures (SF) and dorsal metacarpal disease (DMD). Monthly lameness examination and serum collection were performed. Serum was analysed for glycosaminoglycan (GAG), type I and II collagen degradation (C1, 2C), type II collagen synthesis (CPII), type II collagen degradation (Col CEQ), aggrecan synthesis (CS846), osteocalcin (OC) as a marker of bone formation and (C-terminal telopeptide of type I collagen) CTX as a marker of bone degradation. RESULTS: Of the 238 horses 59 injured and 71 uninjured control horses met the analysis criteria. Based on injury no significant differences in the proportions were observed for age, gender or lesion type, although a higher proportion of injuries occurred at the beginning of the study. Of injured horses, 16 (27%) sustained an IAF, 17 (29%) a TL injury, 7 (12%) SF and 19 (32%) were diagnosed with DMD. There were significant changes seen in biomarkers based on the injury incurred when longitudinal samples were assessed. Furthermore, based on the serum biomarkers collected prior to injury, horses could be correctly classified as injured or uninjured 73.8% of the time. CONCLUSIONS: A unique biomarker pattern occurred before each injury and this was beneficial in classifying horses as injured or uninjured. POTENTIAL RELEVANCE: Biomarkers have the potential to be used as a screening aid prior to musculoskeletal injury.

Long-term efficacy of catheter ablation for atrial fibrillation: impact of additional targeting of fractionated electrograms.

OBJECTIVES: To investigate long-term efficacy of catheter ablation for atrial fibrillation (AF) and the impact of ablating complex or fractionated electrograms (CFEs) in addition to pulmonary vein isolation and linear lesions in persistent AF (PeAF). METHODS: Consecutive cases from 2002-2007 were analysed. All the patients underwent a wide-area circumferential ablation with confirmation of electrical isolation. For PeAF, linear lesions were added, with additional targeting of CFE from 2005. Data were collected in a prospective database. Attempts were made to contact all patients for follow-up. RESULTS: 285 patients underwent 530 procedures. The mean (SD) age was 57 (11) years, 75% were male, 20% had structural heart disease and 53% had paroxysmal AF (PAF). The mean number of procedures was 1.9 per patient (1.7 for PAF and 2.0 for PeAF). Procedural complications included stroke or transient ischemic attack in 0.6% and pericardial effusion requiring drainage in 1.7%. During 2.7 years (0.2 to 7.4 years) of follow-up from the last procedure, there were seven deaths (unrelated to their ablation or AF) and three strokes or transient ischemic attack (0.3% per year). Freedom from AF/atrial tachyarrhythmia was 86% for PAF and 68% for PeAF. Late recurrence was 3 per 100 years of follow-up after >3 years. The Kaplan-Meier analysis showed that CFE ablation improved the outcome for PeAF after the first cluster of procedures (p=0.049), with a trend towards improved final outcome (p=0.130). CONCLUSIONS: Long-term freedom from AF is achievable in most patients with PAF and PeAF with low rates of late recurrence. Additional targeting of CFE improves outcome for PeAF. Late adverse events including stroke are few.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) plasma concentrations in residents of Paritutu, New Zealand: evidence of historical exposure.

An assessment of community exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was undertaken in Paritutu, New Zealand. The suburb lies adjacent to an agrichemical facility that produced 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), between 1962 and 1987. Soil TCDD measurements from 73 nearby addresses demonstrated a pattern of TCDD deposition consistent with an aerial plume following the prevailing local wind patterns and the agrichemical plant as the point source. Blood samples were taken from 52 volunteers having lived for three or more years in Paritutu between 1962 and 1987. Candidate selection focused primarily on individuals who were most likely to show elevated TCDD blood lipid levels when compared to age and gender stratified national average blood concentrations, and secondarily on individuals that provided additional information about specific exposure periods, potential exposures of younger age groups, and specific dietary patterns. A multipathway exposure model was used to estimate serum TCDD levels in each participant. Age and gender-specific TCDD elimination kinetics were also considered. Historical TCDD environmental concentrations were back-calculated from soil concentrations at each residence assuming TCDD releases occurred pre-dominantly between 1962 and 1975. Serum was analysed for chlorinated dibenzodioxins and dibenzofurans, and a subset was analysed for dioxin-like polychlorinated biphenyls. TCDD in serum lipid exceeded two standard deviations above national background levels for 14 participants, and 3 standard deviations for 10 participants. The highest TCDD lipid concentration was 33.3 ng/kg-lipid, or 11 times higher than the comparative 1997 national average. Elevated TCDD concentrations were observed primarily, but not exclusively, in the older study participants who had been in residence in Paritutu before 1968. The study demonstrated TCDD exposure in this community, occurring most likely through the aerial route, and most probably from fugitive emissions during manufacture.

An investigation into the relationship between input-output nonlinearities and rate-induced nonlinearities of click-evoked otoacoustic emissions recorded using maximum length sequences.

The maximum length sequence (MLS) technique allows otoacoustic emissions (OAEs) to be recorded using clicks presented at very high presentation rates. It has previously been found that increasing the click presentation rate leads to increasing suppression (termed "rate-suppression") of the MLS evoked OAE (Hine, J.E., Thornton, A.R.D., 1997. Transient evoked otoacoustic emissions recorded using maximum length sequences as a function of stimulus rate and level. Ear Hear. 18, 121-128). It has been suggested that the source of rate-suppression arises from the same nonlinear processes that give rise to the well-known nonlinear growth of OAEs. Based on this assumption, a simple model of rate-suppression (Kapadia, S., Lutman, M.E., 2001. Static input-output nonlinearity as the source of nonlinear effects in maximum length sequence click-evoked OAEs. Br. J. Audiol. 35, 103-112) predicts that both input-output (I/O) nonlinearity and rate-suppression can be unified by characterising the stimulus in terms of its acoustic power which, at high rates, is proportional to the click presentation rate. The objective of this study was to test this simple model by recording MLS OAEs from a group of normally hearing adults over a range of stimulus rates from 40 to 5000 clicks/s, and of stimulus levels from 45 to 70dB peSPL. The results are broadly in agreement with the predictions from the model, though there appears to be some tendency for the model to slightly overestimate the degree of rate-suppression for a given degree of I/O nonlinearity. It is also suggested that the model may break down more significantly in the presence of spontaneous OAEs.

Nonlinear properties of otoacoustic emissions in normal and impaired hearing.

Click-evoked otoacoustic emissions (CEOAEs) exhibit nonlinearities in amplitude and time domains. The first objective of this study was to investigate whether there is any correlation between the temporal and amplitude nonlinearities of CEOAEs in normals. Additionally there is evidence that pathology affects the normal cochlear nonlinearity. The second objective was to investigate whether pathology affects the temporal nonlinear components. Conventional and maximum length sequence (MLS) CEOAEs were recorded in normal subjects and in patients with mild hearing loss. The slope of the input-output (I/O) function of the conventional CEOAE measured the amplitude nonlinearity. Two measures of temporal nonlinearity were the magnitude of the suppression that occurs with increase in stimulus rate and the amplitudes of the second and third order temporal interaction components (Volterra slices). The amplitude nonlinearity is well correlated with both the magnitude of the rate suppression and the amplitudes of the Volterra slices. The 'linear' CEOAE amplitude showed no differences between the normal and patient groups but the differences in the Volterra slices were substantial. This suggests that the first sign of damage to the cochlea is that the system becomes more linear. Hence the Volterra slices may provide a sensitive measure of cochlear damage.

Inhibition of paclitaxel-induced apoptosis by the specific COX-2 inhibitor, NS398, in epithelial ovarian cancer cells.

OBJECTIVE: In vitro studies have revealed that treatment of various human cancer cell lines with specific cyclo-oxygenase 2 (COX-2) inhibitors induces apoptotic cell death. It is currently proposed that the combination of COX-2 inhibitors with chemotherapeutic agents improves the efficacy of cancer treatment. MATERIALS AND METHODS: In this study we sought to determine the effects of combining paclitaxel and the COX-2 inhibitor NS398 on apoptosis of epithelial ovarian cancer (EOC) cells. Two EOC cell lines, SKOV3 and MDAH2774, were exposed to increasing concentrations of paclitaxel (0.1, 10, and 100 microM) and NS398 (10, 100 microM) as well as a combination of both drugs. Apoptosis was evaluated by the Tunel assay. The fluorescein-labeled DNA was visualized directly by fluorescence microscopy and quantitated by flow cytometry. RESULTS: While NS398 did not significantly alter apoptosis of either EOC cell lines after 24 h of continuous exposure, treatment of both cell lines with paclitaxel resulted in a significant increase in the rate of apoptosis (60-70%). Concomitant treatment of both SKOV3 and MDAH2774 cells with paclitaxel and NS398 resulted in marked impairment of paclitaxel-induced apoptosis. Similarly, sequential treatment during which both cell lines were treated with NS398 for 4 h, triple-washed, and then exposed to paclitaxel for 24 h resulted in a significant inhibition of paclitaxel-induced apoptosis. Similar inhibition was seen when NS398 was replaced by aspirin. CONCLUSIONS: Combining COX-2 inhibitors and paclitaxel does not have an additive or synergistic tumoricidal effect. On the contrary, NS398 treatment markedly inhibited the apoptotic effects of paclitaxel in each of these two EOC cell lines.

Methods of in vitro toxicology.

In vitro methods are common and widely used for screening and ranking chemicals, and have also been taken into account sporadically for risk assessment purposes in the case of food additives. However, the range of food-associated compounds amenable to in vitro toxicology is considered much broader, comprising not only natural ingredients, including those from food preparation, but also compounds formed endogenously after exposure, permissible/authorised chemicals including additives, residues, supplements, chemicals from processing and packaging and contaminants. A major promise of in vitro systems is to obtain mechanism-derived information that is considered pivotal for adequate risk assessment. This paper critically reviews the entire process of risk assessment by in vitro toxicology, encompassing ongoing and future developments, with major emphasis on cytotoxicity, cellular responses, toxicokinetics, modelling, metabolism, cancer-related endpoints, developmental toxicity, prediction of allergenicity, and finally, development and application of biomarkers. It describes in depth the use of in vitro methods in strategies for characterising and predicting hazards to the human. Major weaknesses and strengths of these assay systems are addressed, together with some key issues concerning major research priorities to improve hazard identification and characterisation of food-associated chemicals.

Enhancing recall of information from a patient education booklet: a trial using cardiomyopathy patients.

A quasi-experimental trial was conducted to compare the effect on information recall of: (a) the use of adjunct questions (AQ) in printed materials; and (b) a procedure (the 5Rs) for integrating printed patient education materials into face-to-face teaching. A total of 51 patients with severe left ventricular failure (cardiomyopathy) was assigned to one of three groups (n=17). Each group worked with a purpose-prepared booklet, the first in association with the 5Rs procedure; the second group with a version of the booklet containing adjunct questions; and the third with a text only version of the booklet. Recall of information from the booklet was measured using a checklist scored on the basis of responses secured in a standardised interview. Improved recall was associated with both the adjunct questions and the 5Rs procedure, with the latter achieving a substantially superior outcome. The practical implications of these findings are presented and directions for further research indicated.

Genetic variability and linkage disequilibrium within the HLA-DP region: analysis of 15 different populations.

In order to understand the forces governing the evolution of the genetic diversity in the HLA-DP molecule, polymerase chain reaction (PCR)-based methods were used to characterize genetic variation at the DPA1 and DPB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including individuals of African, Asian, Amerindian, Indian and European origin. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger, presumably admixed populations. Ten DPA1 and 39 DPB1 alleles were identified and observed on 87 distinct DP haplotypes, 34 of which were found to be in significant positive linkage disequilibrium in at least one population. Some haplotypes were found in all ethnic groups while others were confined to a single ethnic group or population. Strong positive global linkage disequilibrium (Wn) between DPA1 and DPB1 was present in all 15 populations. The African populations displayed the lowest values of Wn whereas the Amerindian populations displayed near absolute disequilibrium. Analysis of the distribution of haplotypes using the normalized deviate of the Ewens-Watterson homozygosity statistic, F, suggests that DP haplotypes encoding the functional heterodimer are subject to much lower degrees of balancing selection than other loci within the HLA region. Finally, neighbor joining tree analyses demonstrate the power of haplotype diversity for inferring the relationships between the different populations.

Gene expression analysis of EpiDerm following exposure to SLS using cDNA microarrays.

There is a need to investigate the mechanistic basis of the human skin irritation response if relevant in vitro test systems for the predictive identification of skin irritation hazards are to be developed. Recent progress in genomics technologies mean that tools for the identification and investigation of important biochemical events in the processes of skin irritation are now available. The aim of this work was to identify genes (for further mechanistic investigation) which may be regulated in response to skin irritation, following exposure of the EpiDerm skin model to the known skin irritant sodium lauryl sulphate (SLS). EpiDerm cultures were treated in triplicate with a non-cytotoxic dose of SLS (0.1 mg/ml, as determined by the MTT assay and histological examination) for 15 min, 30 min, 1 h, 2 h, 3 h, 4 h and 24 h. Total RNA was extracted from the pooled EpiDerm cultures and used to probe Atlas human arrays (Clontech) covering approximately 3600 genes. Preliminary data indicated an up-regulation at early time points (15-30 min) of a number of genes involved in transportation (e.g. the sodium and chloride dependent taurine transporter) and receptors (e.g. ZAP70 and protocadherin 42 precursor). The gene encoding the UV excision repair protein and other DNA repair genes (e.g. DNA-directed RNA polymerase II) were up-regulated after 1-3 h, along with TGF beta 3 and other tumour suppressors, which play a role in cellular development and wound healing. At the later time points of 4-24 h, genes involved in protein translation (e.g. Cathepsin D receptor) and metabolism (e.g. CYP27A) were up-regulated. In addition, a number of genes were down-regulated in response to treatment with SLS, although these followed less of a time dependent pattern. These results indicate the differential regulation of a number of genes in response to treatment with SLS, some of which may provide additional clues to the molecular events underpinning the irritation response to this particular surfactant and possibly to other chemical irritants.