The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

Objectives:

Visceral adipose tissue (VAT) is an independent risk factor in cardiometabolic diseases and is commonly measured by computed tomography (CT). It is measured clinically by waist circumference (WC). The L4/5 intervertebral space VAT (L4/5 VAT) is traditionally used to represent total VAT volume. We set out to determine (1) the level of intervertebral space on CT that best approximates the total VAT volume; (2) compare the association between WC and VAT in Singaporean Chinese and Indian; and (3) examine the correlation between VAT and cardiometabolic risk factors.

Subjects:

A total of 60 Chinese and 60 Asian Indian men older than 60 years were recruited. Their medical history was taken and anthropometry was measured. Fasting glucose, insulin, lipids, adipokines and inflammatory markers were measured. Insulin resistance was evaluated by homeostasis model assessment-insulin resistance. VAT was determined by CT. Total VAT volume was calculated in 22 patients from VAT areas at seven intervertebral levels. The optimal VAT area most representative of total VAT volume was determined and used for all patients to approximate total VAT volume.

Results:

The VAT area at L2/3 intervertebral space (L2/3 VAT) correlated almost perfectly with VAT volume (R2=0.974 and 0.946 for Chinese and Indians, respectively). Subjects from the two races had similar height, weight, body mass index (BMI), WC and L2/3 VAT but more Indian men had hypertension, hyperlipidemia and type 2 diabetes mellitus. WC was correlated with the L2/3 VAT area in both Chinese (r=0.484, P<0.001) and Indian subjects (r=0.366, P=0.004) without racial difference (P=0.2 for interaction term). L2/3 VAT also correlated better with cardiometabolic risk factors, adipokines and C-reactive protein than WC, BMI or L4/5 VAT.

Conclusion:

The L2-L3 intervertebral space was the best anatomic level for a single-slice CT cross-sectional area measurement of VAT to approximate total body visceral adipose volume in this population of Chinese and Asian Indian men older than 60 years. L2/3 VAT was better correlated with multiple cardiovascular risk factors, adipokines and inflammatory marker than either L4/5 VAT, WC or BMI.

Even though myelodysplastic syndromes are characterized by ineffective hematopoiesis, the molecular alterations that lead to marrow failure have not been well elucidated. We have previously shown that the myelosuppressive TGF-β pathway is constitutively activated in MDS progenitors. Since there is conflicting data about upregulation of extracellular TGF-b levels in MDS, we wanted to determine the molecular basis of TGF-β pathway overactivation and consequent hematopoietic suppression in this disease. We observed that SMAD7, a negative regulator of TGF-β receptor I (TBRI) kinase is markedly decreased in a large meta-analysis of gene expression studies from MDS marrow derived CD34+ cells. SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in a bone marrow tissue microarray. Reduced expression of SMAD7 in hematopoietic cells led to increased TGF-β mediated gene transcription and enhanced sensitivity to TGF-β mediated suppressive effects. The increased TGF-β signaling due to SMAD7 reduction could be effectively inhibited by a novel clinically relevant TBRI (ALK5 kinase) inhibitor, LY-2157299. LY-2157299 could inhibit TGF-β mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells. Furthermore, in vivo administration of LY-2157299 ameliorated anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure. Most importantly, treatment with LY-2157199 stimulated hematopoiesis from primary MDS bone marrow specimens. These studies demonstrate that reduction in SMAD7 is a novel molecular alteration in MDS that leads to ineffective hematopoiesis by activating of TGF-β signaling in hematopoietic cells. These studies also illustrate the therapeutic potential of TBRI inhibitors in MDS.

Background:

Intra-tumour genetic heterogeneity has been reported in both leukaemias and solid tumours and is implicated in the development of drug resistance in CML and AML. The role of genetic heterogeneity in drug response in solid tumours is unknown.

Methods:

To investigate intra-tumour genetic heterogeneity and chemoradiation response in advanced cervical cancer, we analysed 10 cases treated on the CTCR-CE01 clinical study. Core biopsies for molecular profiling were taken from four quadrants of the cervix pre-treatment, and weeks 2 and 5 of treatment. Biopsies were scored for cellularity and profiled using Agilent 180k human whole genome CGH arrays. We compared genomic profiles from 69 cores from 10 patients to test for genetic heterogeneity and treatment effects at weeks 0, 2 and 5 of treatment.

Results:

Three patients had two or more distinct genetic subpopulations pre-treatment. Subpopulations within each tumour showed differential responses to chemoradiotherapy. In two cases, there was selection for a single intrinsically resistant subpopulation that persisted at detectable levels after 5 weeks of chemoradiotherapy. Phylogenetic analysis reconstructed the order in which genomic rearrangements occurred in the carcinogenesis of these tumours and confirmed gain of 3q and loss of 11q as early events in cervical cancer progression.

Conclusion:

Selection effects from chemoradiotherapy cause dynamic changes in genetic subpopulations in advanced cervical cancers, which may explain disease persistence and subsequent relapse. Significant genetic heterogeneity in advanced cervical cancers may therefore be predictive of poor outcome.

Summary

MTH1203, a β-CASP metallo-β-lactamase family nuclease from the archaeon Methanothermobacter thermautotrophicus, was identified as a putative nuclease that might contribute to RNA processing. The crystal structure of MTH1203 reveals that, in addition to the metallo-β-lactamase nuclease and the β-CASP domains, it contains two contiguous KH domains that are unique to MTH1203 and its orthologs. RNA-binding experiments indicate that MTH1203 preferentially binds U-rich sequences with a dissociation constant in the micromolar range. In vitro nuclease activity assays demonstrated that MTH1203 is a zinc-dependent nuclease. MTH1203 is also shown to be a dimer and, significantly, this dimerization enhances the nuclease activity. Transcription termination in archaea produces mRNA transcripts with U-rich 3′ ends that could be degraded by MTH1203 considering its RNA-binding specificity. We hypothesize that this nuclease degrades mRNAs of proteins targeted for degradation and so regulates archaeal RNA turnover, possibly in concert with the exosome.

Graphical Abstract

Highlights

► MTH1203 combines RNA-processing and binding domains, unique to archaea ► MTH1203 is a Zn-dependent β-CASP RNase that functions as a dimer ► The MBL domain of MTH1203 binds U-rich sequences with a Kd in the micromolar range ► We propose MTH1203 acts with the proteasome degrading mRNAs of aberrant proteins

Background

Information on arthritis and other musculoskeletal disorders among Aboriginal people is sparse. Survey data show that arthritis and rheumatism are among the most commonly reported chronic conditions and their prevalence is higher than among non-Aboriginal people.

Objective

To describe the burden of arthritis among Aboriginal people in northern Canada and demonstrate the public health significance and social impact of the disease.

Methods

Using cross-sectional data from more than 29 000 Aboriginal people aged 15 years and over who participated in the Aboriginal Peoples Survey 2006, we assessed regional differences in the prevalence of arthritis and its association with other risk factors, co-morbidity and health care use.

Results

The prevalence of arthritis in the three northern territories ("North") is 12.7% compared to 20.1% in the provinces ("South") and is higher among females than males in both the North and South. The prevalence among Inuit is lower than among other Aboriginal groups. Individuals with arthritis are more likely to smoke, be obese, have concurrent chronic diseases, and are less likely to be employed. Aboriginal people with arthritis utilized the health care system more often than those without the disease.

Conclusion:

Aboriginal-specific findings on arthritis and other chronic diseases as well as recognition of regional differences between North and South will enhance program planning and help identify new priorities in health promotion.

Keywords

arthritis, Aboriginal people, Northern Canada, Inuit, First Nations, Métis, North American Indians, Aboriginal Peoples Survey

PURPOSE

We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biologic effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor (PDGFR) and VEGFR2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib.

EXPERIMENTAL DESIGN

A standard 3+3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth).

RESULTS

Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1–2 rash, hyperglycemia and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg po qam/200 mg po qpm and tipifarnib po 100 mg BID. Despite the low doses of tipifarnib, one-quarter of patients had ≥50% reduction in farnesyltransferase (FTase) levels. Interestingly, 6 of 8 patients with medullary thyroid cancer (MTC) had durable stable disease (N=3) or partial remissions (N=3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (≥ 6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (N=4; 18+ to 27+ months); adrenocortical cancer (N=2; 7 and 11 months); and one each of melanoma (PDGFR mutation-positive) (14 months), renal (6 months) and pancreatic cancer (6 months).

CONCLUSION

Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations.

Background. Irritable bowel syndrome (IBS) is a chronic, difficult to treat condition. The efficacy of Aloe vera in treating IBS symptoms is not yet proven. The purpose of this study was to determine if Aloe vera is effective in improving quality of life. Methods. A multicentre, randomised, double-blind, cross-over placebo controlled study design. Patients were randomised to Aloe vera, wash-out, placebo or placebo, washout, Aloe vera. Each preparation (60 mL) was taken orally twice a day. Patient quality of life was measured using the Gastrointestinal Symptoms Rating Score, Irritable Bowel Syndrome Quality of Life, EuroQol and the Short-Form-12 at baseline and treatment periods 1 and 2. Results. A total of 110 patients were randomised, but only 47 completed all questionnaires and both study arms. Statistical analysis showed no difference between the placebo and Aloe vera treatment in quality of life. Discussion. This study was unable to show that Aloe vera was superior to placebo in improving quality of life. Drop outs and other confounding factors may have impacted on the power of the study to detect a clinically important difference. Conclusion. This study failed to find Aloe vera superior to placebo in improving quality of life proven Irritable Bowel Syndrome patients.

Introduction

Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO2) in patients with inflammatory arthritis with macroscopic/microscopic inflammation and local levels of proinflammatory mediators.

Methods

Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO2 under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor α (TNFα), interleukin 1β (IL1β), interferon γ (IFNγ), IL6, macrophage inflammatory protein 3α (MIP3α) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA.

Results

The tPO2 was 22.5 (range 3.2–54.1) mm Hg and correlated inversely with macroscopic synovitis (r=−0.421, p=0.02), sublining CD3 cells (−0.611, p<0.01) and sublining CD68 cells (r=−0.615, p<0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO2 in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor α (TNFα), IL1β, IFNγ and MIP3α in patients with tPO2 <20 mm Hg (all p values <0.05).

Conclusions

This is the first study to show a direct in vivo correlation between synovial tPO2, inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Background

Defects in the human Shwachman-Bodian-Diamond syndrome (SBDS) protein-coding gene lead to the autosomal recessive disorder characterised by bone marrow dysfunction, exocrine pancreatic insufficiency and skeletal abnormalities. This protein is highly conserved in eukaryotes and archaea but is not found in bacteria. Although genomic and biophysical studies have suggested involvement of this protein in RNA metabolism and in ribosome biogenesis, its interacting partners remain largely unknown.

Results

We determined the crystal structure of the SBDS orthologue from Methanothermobacter thermautotrophicus (mthSBDS). This structure shows that SBDS proteins are highly flexible, with the N-terminal FYSH domain and the C-terminal ferredoxin-like domain capable of undergoing substantial rotational adjustments with respect to the central domain. Affinity chromatography identified several proteins from the large ribosomal subunit as possible interacting partners of mthSBDS. Moreover, SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments, combined with electrophoretic mobility shift assays (EMSA) suggest that mthSBDS does not interact with RNA molecules in a sequence specific manner.

Conclusion

It is suggested that functional interactions of SBDS proteins with their partners could be facilitated by rotational adjustments of the N-terminal and the C-terminal domains with respect to the central domain. Examination of the SBDS protein structure and domain movements together with its possible interaction with large ribosomal subunit proteins suggest that these proteins could participate in ribosome function.

Over the past decade, video assisted thoracic surgery (VATS) has changed the way spontaneous pneumothorax (SP) is managed. Benefits of VATS include less postoperative pain, shorter hospital stay, and attenuated postoperative inflammatory response are evident compared with open thoracic procedures. Furthermore, the increasing acceptance by patients and referring physicians is testament to its success. Recent studies and the authors decade of experience in management of SP by VATS show that it is quick, safe, and effective, with recurrence rates generally comparable to open procedures, with some exceptions. However, selecting the correct procedure and patient, as well as knowing the limitations of the surgeons and techniques are paramount for success. Even to this day, there are considerable variations in the treatment of SP and large scale controlled studies are needed to better define timing of surgery and the role of the different procedures in the treatment and prevention of SP.

Förster resonance energy transfer (FRET) detected via fluorescence lifetime imaging microscopy (FLIM) and global analysis provide a way in which protein–protein interactions may be spatially localized and quantified within biological cells. The FRET efficiency and proportion of interacting molecules have been determined using bi-exponential fitting to time-domain FLIM data from a multiphoton time-correlated single-photon counting microscope system. The analysis has been made more robust to noise and significantly faster using global fitting, allowing higher spatial resolutions and/or lower acquisition times. Data have been simulated, as well as acquired from cell experiments, and the accuracy of a modified Levenberg–Marquardt fitting technique has been explored. Multi-image global analysis has been used to follow the epidermal growth factor-induced activation of Cdc42 in a short-image-interval time-lapse FLIM/FRET experiment. Our implementation offers practical analysis and time-resolved-image manipulation, which have been targeted towards providing fast execution, robustness to low photon counts, quantitative results and amenability to automation and batch processing.

Aim

To study the prevalence rate of uncorrected refractive error and associated risk factors among Singapore schoolchildren aged 12–16 years (grade 7).

Methods

A cross sectional study of 628 participants (participation rate 99.8%) was conducted in two schools. An interviewer led questionnaire asking about sociodemographic variables and risk factors was administered. Refractive errors were measured using a table mounted autorefractor. Participants with habitual visual acuity (VA) of 0.2 logMAR or worse underwent subjective refraction. Uncorrected refractive error was defined as improvement of at least 0.2 logMAR in best corrected visual acuity after subjective refraction.

Results

The prevalence rate of uncorrected refractive error was 22.3% (95% confidence interval (CI) 19.0% to 25.5%). The multivariate adjusted odds ratio of uncorrected refractive error in students with the lowest academic ability was 2.24 (95% CI 1.34 to 3.73). Increasing time interval since the last visit to an eye care provider increased the risk of uncorrected refractive error (trend p = 0.001).

Conclusion

Uncorrected refractive error was a significant problem among Singapore students aged 12–16 years (grade 7). Uncorrected refractive error was more common among students with low academic ability or those who had not visited an eye care provider for a long time.

Background

We have previously reported that tolerance to class I disparate lung allografts in miniature swine could be induced using an intensive 12-day course of tacrolimus and that pre-transplant sensitization with immunogenic MHC class I allopeptides failed to block the induction of tolerance. We also have previously reported the importance of the presence of the thymus in the induction of tolerance to isolated heart, kidney, and combined heart-kidney transplants. In this study, we examined the impact of thymectomy on tolerance induction.

Methods

Orthotopic left lung transplantation was performed using MHC class I-disparate donors. The recipients received a 12-day course of high-dose tacrolimus (n = 6). Total thymectomies were performed in three of the swine, 21 days prior to transplantation. Lung grafts were monitored by chest radiography and serial open lung biopsy.

Results

All euthymic recipients maintained their grafts over one year. None of the thymectomized recipients has shown graft loss in the six to ten months following transplantation. Although isolated lesions of obliterative bronchiolitis (OB) were occasionally seen in one thymectomized animal on biopsy, donor-specific unresponsiveness has been observed on assays of cell-mediated lymphocytotoxicity (CML) in all recipients. Moreover, co-culture CML assays have shown that recipient lymphocytes can strongly inhibit the normally robust response of naïve recipient-matched lymphocytes to donor antigen. This inhibition was not seen when using stimulators primed with third-party antigens against appropriate targets.

Conclusions

These data suggest that thymus-independent peripheral regulatory mechanisms may be sufficient to induce and maintain long-term acceptance of the lung allografts.

Background

Considerable evidence suggests that indirect recognition of MHC allopeptides plays an important role in solid-organ rejection. Here, we examine whether immunization with class I or class II allopeptides accelerates rejection in a fully MHC-mismatched lung transplant model in miniature swine.

Methods

Recipients were immunized with either donor-derived class I or class II peptides. Sensitization to the peptides was confirmed by DTH testing and in vitro proliferation assays. Non-immunized control (n=6), class I peptide-immunized (n=3) and class II peptide-immunized (n=3) swine were transplanted with fully mismatched lungs using only a 12-day course of tacrolimus.

Results

One control animal rejected its graft on POD 103, while the others maintained their grafts over one year. In the class I peptide-immunized group, two recipients rejected their grafts (POD 14 and 52). The third animal has not rejected the graft (POD120, experiment is ongoing). In contrast, in the class II-peptide immunized group, only one animal rejected its graft on POD52, while the others maintained their grafts over one year. Both anti-donor IgM and IgG antibodies were detectable in all acute rejectors, although no alloantibody was detectable in long-term acceptors. Regardless of the fate of the graft, all animals have maintained their proliferative responses to the peptides. However, only acceptors maintained donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity and mixed lymphocyte reaction assays.

Conclusions

Pre-transplant sensitization of lung allograft recipients to donor allopeptides accelerates graft rejection. This appears particularly true for class I-derived allopeptides, suggesting that class II molecules may be less antigenic when presented indirectly.

Objectives: To examine the effects of running and swimming exercises on the functional performance and mechanical strength of a recovering Achilles tendon.

Methods: 30 Sprague-Dawley rats had surgical transection of their right medial Achilles tendon. The rats were divided into running (n = 11), swimming (n = 10), and control (n = 9) groups. The running and swimming groups were given daily exercise training, starting from the fifth day after the injury; the control group did not exercise throughout the period of the experiment. An Achilles functional index (AFI) was recorded before the operation and on the third, 10th, and 30th days after the operation. On the 30th day, the rats were killed and their Achilles tendons harvested for biomechanical testing of load relaxation properties, stiffness, and ultimate tensile strength (UTS). The AFI data were analysed by two way analysis of variance; load relaxation, stiffness, and UTS data were analysed by multivariate analysis, with α at 0.05.

Results: The UTS of the running group was higher than in the control group (p = 0.015), while there was no significant difference between the swimming and control groups (p = 0.228). Differences in stiffness and load relaxation were non-significant (p = 0.823 and 0.633, respectively). The AFI results did not differ among the three groups (p = 0.242).

Conclusions: Running exercises can improve the strength of partially ruptured Achilles tendons at 30 days after injury.

Background: The long term physiological and radiological outcomes of SARS survivors and their possible determinants are uncertain.

Methods: SARS survivors in a follow up clinic in a regional hospital underwent high resolution computed tomography (HRCT) of the thorax and lung function tests 6 months after admission to hospital. The associations between the clinical and demographic data of the patients and the physiological and radiological outcomes were examined.

Results: Fifty seven patients took part in the study. Lung function abnormalities were detected in 43 patients (75.4%), with restrictive defects (n = 16) being most common (28.1%). Radiological abnormalities of any degree were detected in 43 patients (75.4%). Only the use of pulse corticosteroids was associated with the presence of CT abnormalities (p = 0.043, OR 6.65, 95% CI 1.06 to 41.73).

Conclusions: Physiological and radiological abnormalities are still present in a considerable proportion of SARS survivors at 6 months.

Background: Severe acute respiratory syndrome (SARS) was diagnosed in Hong Kong in over 1700 patients between March and early June 2003.

Methods: 115 patients diagnosed with SARS were admitted to Queen Elizabeth Hospital, a large regional hospital in Hong Kong, from March 2003, of whom 100 were either discharged or were dead at 31 May. The patients were prospectively studied after admission to assess their short term outcomes and the risk factors associated with adverse outcomes, defined as death or the need for mechanical ventilation

Results: At the time of writing 18 patients had died, with a crude mortality rate of 15.7% and a 21 day mortality of 10% (standard error 3%). Thirty nine patients (34%) were admitted to the intensive care unit, 30 of whom (26%) required mechanical ventilation. Multivariate analysis showed that age above 60 (hazards ratio (HR) 3.5, 95% CI 1.2 to 10.2; p=0.02), presence of diabetes mellitus or heart disease (HR 9.1, 95% CI 2.8 to 29.1; p<0.001), and the presence of other comorbid conditions (HR 5.2, 95% CI 1.4 to 19.7; p=0.01) were independently associated with mortality. However, only the presence of diabetes mellitus and/or cardiac disease (HR 7.3, 95% CI 3.1 to 17.4; p<0.001) was associated with adverse outcomes as a whole.

Conclusion: SARS is a new disease entity that carries significant morbidity and mortality. Specific clinical and laboratory parameters predicting unfavourable outcomes have been identified.

Background: Liver dysfunction in pregnancy has serious consequences. Its frequency and characteristics have not been systematically documented in Britain. We have prospectively determined incidence, causes, and outcome of liver dysfunction in pregnancy in an obstetric unit in Southwest Wales, UK.

Methods: A central laboratory identified all abnormal liver tests (bilirubin >25 μmol/l, aspartate transaminase >40 U/l, or γ glutamyl transpeptidase >35 U/l) from patients in antenatal clinics and wards of an obstetric unit serving a population of 250 000. Patients with abnormal liver tests were assessed and followed through after pregnancy. Medical advice was provided to obstetric teams.

Findings: There were 4377 deliveries during the 15 month study. A total of 142 patients had abnormal liver tests. There were 206 contributing diagnoses, the great majority being pregnancy specific. Among the most important were pre-eclampsia (68), HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome (30), obstetric cholestasis (23), hyperemesis gravidarum (11), acute fatty liver of pregnancy (five), and hepatic infarct (one). Sepsis, postoperative factors, and placental pathology (51) were not uncommonly responsible but incidental or pre-existing hepatobiliary disease was infrequent (17). Sixty five patients were delivered early by induction or caesarean section because of liver dysfunction. Despite substantial liver related morbidity, there were no maternal deaths and only two intrauterine deaths.

Conclusions: Liver dysfunction was seen in 3% of deliveries during a 15 month prospective study and was usually directly related to pregnancy with spontaneous recovery in the puerperium. Incidence of the most serious conditions, acute fatty liver of pregnancy and HELLP syndrome, was much greater than previously reported. Profound effects on maternal and infant health were observed but close medical and obstetric collaboration ensured low mortality.

Background: Cows' milk sensitive reflux oesophagitis is an emerging clinical entity in children, normally indistinguishable from primary gastro-oesophageal reflux (GOR) apart from the response to dietary antigen exclusion. It is conjectural whether a tendency towards mucosal eosinophilia distinguishes this group from primary GOR.

Aims: To determine whether there may be differences in the mucosal lesion within the oesophagus in those children with reflux in association with cows' milk induced small bowel pathology, particularly in relation to the eosinophil chemokine eotaxin.

Methods: A total of 29 children underwent endoscopic assessment, including nine with cows' milk sensitive enteropathy (CMSE) and associated GOR, seven histologically normal controls, six with primary GOR, and seven disease controls. Oesophageal biopsy specimens were examined immunohistochemically for the chemokines eotaxin and MCP-2, and T cell lineage and activation markers.

Results: Strong upregulation of eotaxin expression, limited to basal and papillary epithelium, occurred in all CMSE patients. By contrast, weak expression was seen in a minority of controls and in 50% of primary GOR patients. Infiltration of CD3, CD4, and CD8 lymphocytes occurred in similar distribution in CMSE patients, significantly increased above controls. Significant upregulation of activation markers (CD25, HLA-DR) was also seen in the CMSE group within basal and papillary epithelium compared to controls and primary GOR.

Conclusion: Basal and papillary epithelial eotaxin expression, with focal lymphocyte activation, was seen in infants with CMSE associated GOR. This preliminary study provides early evidence to suggest a pathogenesis distinct from primary GOR, in which specific recruitment of T cells and eosinophils may contribute to oesophageal dysmotility.