Glycated haemoglobin and the risk of postoperative complications in people without diabetes: a prospective population-based study in UK Biobank.

The aim of our study was to clarify the association between glycated haemoglobin (HbA1c ) and postoperative outcomes in people without an existing diagnosis of diabetes. Half a million adults were recruited into the UK Biobank prospective cohort study between March 2006 and October 2010. We divided participants into three groups: no diagnosis of diabetes and HbA1c < 42 mmol.mol-1 ; no diagnosis of diabetes and elevated HbA1c (≥ 42 mmol.mol-1 with no upper limit); and prevalent diabetes (regardless of HbA1c concentration) at recruitment. We followed up participants by linkage with routinely collected hospital data to determine any surgical procedures undertaken after recruitment and the associated postoperative outcomes. Our main outcome measure was a composite primary outcome of 30-day major postoperative complications and 90-day all-cause mortality. We used logistic regression to estimate the odds of the primary outcome by group. We limited analyses to those who underwent surgery within one year of recruitment (n = 26,653). In a combined effects logistic regression model, participants not known to have diabetes with HbA1c ≥ 42 mmol.mol-1 had increased odds of the primary outcome (OR [95% CI] 1.43 [1.02-2.02]; p = 0.04), when compared with those without diabetes and HbA1c < 42 mmol.mol-1 . This effect was attenuated and no longer statistically significant in a direct effects model with adjustment for hyperglycaemia-related comorbidity (OR [95% CI] 1.37 [0.97-1.93]; p = 0.07). Elevated pre-operative HbA1c in people without diabetes may be associated with an increased risk of complications, but the association is likely confounded by end-organ comorbidity. In contrast to previous evidence, our findings suggest that to prevent adverse postoperative outcomes, optimisation of pre-existing morbidity should take precedence over reducing HbA1c in people without diabetes.

The effect of statin therapy on disease-related outcomes in idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive disease and antifibrotic therapies do not reverse existing fibrosis. There has been emerging evidence of potential role for statins in idiopathic pulmonary fibrosis. The aim of this review is to synthesise the evidence on the efficacy of statins in idiopathic pulmonary fibrosis, focusing on associations with all-cause mortality, disease-specific mortality and change in pulmonary function. METHODS: Medline and Embase were reviewed to identify relevant publications. Studies were selected if they examined disease-related outcomes including mortality, pulmonary function and adverse events in people with idiopathic pulmonary fibrosis receiving statin therapy. RESULTS: Five studies with a total of 3407 people with IPF were selected and analysed. The overall risk of bias of five included studies was moderate to serious. In the fixed effect meta-analysis, statin use was associated with a reduction in mortality (RR 0.8; 95% CI 0.72-0.99). However, in the random effects model, there was no longer any significant association between statin use and all-cause mortality (RR 0.87; 95% CI 0.68-1.12). There was no statistically significant association between statin use and decline in FVC % predicted. CONCLUSION: There is currently insufficient evidence to conclude the effect of statin therapy on disease-related outcomes in idiopathic pulmonary fibrosis. Considering the limitations of available literature, we would recommend a prospective cohort study with capture of dosage and preparation of statin, statin adherence and use of concurrent antifibrotic treatment. PROSPERO REGISTRATION NUMBER: CRD42019122745.

Adjuvant statin therapy for oesophageal adenocarcinoma: the STAT-ROC feasibility study.

BACKGROUND: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT. METHODS: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival. RESULTS: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise. CONCLUSION: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com).

ANTECEDENTES: Las estatinas inhiben las señalizaciones proliferativas en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC) y su uso se asocia con mejor supervivencia en estudios observacionales. El presente estudio se llevó a cabo para examinar la viabilidad de evaluar el tratamiento adyuvante con estatinas en pacientes con OAC operable en un ensayo aleatorizado y controlado de fase III. MÉTODOS: En este ensayo de viabilidad controlado por placebo, aleatorizado, de grupos paralelos, doble ciego y multicéntrico, los pacientes adultos con OAC (incluyendo lesiones Siewert I/II) que fueron sometidos a esofaguectomía se asignaron de forma centralizada (1:1) a tratamiento con simvastatina 40 mg o placebo equivalente mediante aleatorización en bloques, estratificados por centro. Los participantes, los clínicos y los investigadores desconocían la asignación del tratamiento. Los pacientes recibieron el tratamiento hasta un año. Los resultados de viabilidad fueron reclutamiento, retención, absorción del fármaco, adherencia, seguridad, calidad de vida, generalización, y supervivencia. RESULTADOS: Un total de 120 pacientes fueron evaluados para elegibilidad en 4 centros, de los cuales 32 (26,7%) fueron aleatorizados, 16 en cada grupo. Siete pacientes abandonaron el ensayo. Los pacientes asignados a tratamiento con simvastatina tenían niveles de colesterol LDL más bajos a los 3 meses (diferencia media ajustada, −0,83 mmol/L, i.c. del 95% −1,4 a −0,22, P = 0,009). La mediana de la adherencia a la medicación fue mayor del 90% entre los 3-12 meses de seguimiento. Los eventos adversos fueron similares entre los grupos. Los datos de calidad de vida estaban completos en el 98,3% de las preguntas del cuestionario. Enfermedad cardiovascular, diabetes y uso de aspirina eran más prevalentes en el grupo no aleatorizado, mientras que la localización del tumor, el estadio y el grado fueron similares entre los grupos. Las estimaciones de supervivencia fueron imprecisas. CONCLUSIÓN: Este RCT apoya la realización e informa de las consideraciones de diseño para un futuro ensayo de fase III de tratamiento adyuvante con estatinas en pacientes con OAC.

Habitual chocolate consumption and the risk of incident heart failure among healthy men and women.

BACKGROUND: We aimed to examine the association between chocolate intake and the risk of incident heart failure in a UK general population. We conducted a systematic review and meta-analysis to quantify this association. METHODS AND RESULTS: We used data from a prospective population-based study, the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Chocolate intake was quantified based on a food frequency questionnaire obtained at baseline (1993-1997) and incident heart failure was ascertained up to March 2009. We supplemented the primary data with a systematic review and meta-analysis of studies which evaluated risk of incident heart failure with chocolate consumption. A total of 20,922 participants (53% women; mean age 58 ± 9 years) were included of whom 1101 developed heart failure during the follow up (mean 12.5 ± 2.7 years, total person years 262,291 years). After adjusting for lifestyle and dietary factors, we found 19% relative reduction in heart failure incidence in the top (up to 100 g/d) compared to the bottom quintile of chocolate consumption (HR 0.81 95%CI 0.66-0.98) but the results were no longer significant after controlling for comorbidities (HR 0.87 95%CI 0.71-1.06). Additional adjustment for potential mediators did not attenuate the results further. We identified five relevant studies including the current study (N = 75,408). The pooled results showed non-significant 19% relative risk reduction of heart failure incidence with higher chocolate consumption (HR 0.81 95%CI 0.66-1.01). CONCLUSIONS: Our results suggest that higher chocolate intake is not associated with subsequent incident heart failure.

Outcomes in idiopathic pulmonary fibrosis: a meta-analysis from placebo controlled trials.

BACKGROUND: Most data on outcomes in Idiopathic Pulmonary Fibrosis (IPF) pre-dates current guidelines. Data on rates of infection is sparse; the effect of low-dose corticosteroids and disease severity is unknown. METHODS: We identified randomised-controlled trials of IPF and analysed rates of mortality, lower respiratory tract infections (LRTIs), IPF progression and acute exacerbations from the placebo arms. We standardised event rates and compared differences using incidence rate ratios (IRRs) between subgroups according to disease severity or use of low-dose immunosuppression. RESULTS: Mortality was lower in trials that recruited patients with mild-moderate disease severities only, as compared to trials where patients with severe disease were allowed (188.6 vs 78.6 deaths per 1000 patient/years, IRR 0.30-0.59, p < 0.0001). No statistical difference was seen between trials permitting and excluding low-dose prednisolone use. LRTIs were found to be commoner in trials allowing low dose prednisolone use compared with those that did not (227.1 vs 63.4 infections per 1000 patient/years. IRR 2.56-5.13, p < 0.0001), and were less frequent in trials excluding patients with severe disease (153.9 vs 257.8 infections per 1000 patient/years, IRR 0.45-0.81, p = 0.0003). Acute exacerbations occurred less frequently in trials excluding severe disease (28.2 vs 122.9 exacerbations per 1000 patient/years, IRR 0.11-0.55, p < 0.0001). There was no difference between groups in rates of IPF progression. CONCLUSION: Mortality is heterogeneous and dependent on entry criteria. Infection rates were high, both with and without immunosuppression, and were higher in severe disease. Consideration should be given to alternative outcomes to mortality in future IPF trials if severe disease is excluded.

Prednisolone combined with adjunctive immunosuppression is not superior to prednisolone alone in terms of efficacy and safety in giant cell arteritis: meta-analysis.

To conduct a meta-analysis of published data of the effectiveness of drug treatment in giant cell arteritis (GCA) to provide evidence to support the optimal use of glucocorticoids (GCs) and adjunct therapy. MEDLINE, CENTRAL and EMBASE searches were used to identify randomised control trials on the treatment of GCA. Studies included were trials in which: (1) the participants were classified as having GCA by the 1990 ACR criteria or biopsy proven disease; (2) parallel-group randomised control of at least 16 weeks duration had been conducted with at least 20 participants; (3) the design included either alternative adjunct immunosuppressant regimens, alternative GCs dosing or routes of administration; and (4) outcome data was included on either relapse rates or rates of infection. One thousand eight hundred thirty-six articles were retrieved, of which only 37 met the primary inclusion criteria. Sixteen of these studies reported some information about the GCs or adjuvant regimen used. Only ten studies were of sufficient quality to be included in the meta-analysis. Together these comprised 638 participants of which 72 % were female. Three studies compared various GCs regimens, with two comparing IV GCs, the latter showing a marginal benefit with respect to relapse (risk ratio (RR) = 0.78, 95 % CI = 0.54 to 1.12) but a greater risk of infection (RR = 1.58, 95 % CI = 0.90 to 2.78). Another three used methotrexate as an adjunctive agent and showed marginal benefit with respect to relapse (RR = 0.85, 95 % CI = 0.66 to 1.11). The remaining four trials compared prednisolone to dapsone, infliximab, adalimumab and hydroxychloroquine, respectively. There are various clinical trials of varying quality. The results from this meta-analysis show that the use of adjunct agents is not associated with improved outcome.

Systematic review evaluating cardiovascular events of the 5-alpha reductase inhibitor - Dutasteride.

WHAT IS KNOWN AND OBJECTIVES: A recently published large, long-term randomized controlled trial (RCT) brought into question the safety of dutasteride after a significantly increased risk of 'cardiac failure' was noted in the dutasteride arm of the trial compared with placebo. Our objective was to perform a meta-analysis to assess the risk of cardiovascular adverse events with the use of dutasteride for the prevention or treatment of prostatic disease. METHODS: We searched MEDLINE and EMBASE, unpublished articles identified through FDA/EMEA websites, study registers of pharmaceutical companies and reference lists of articles. Parallel-group, randomized controlled trials where men received dutasteride for the prevention of prostate cancer or treatment of prostatic hyperplasia against any comparator intervention were included. Heart failure was the primary outcome of interest but we also looked at myocardial infarction and stroke. Fixed-effect meta-analysis of pooled relative risk (RR) ratios of adverse effect outcomes was conducted. RESULTS AND DISCUSSION: In all, 12 RCTs were included in the meta-analysis after detailed screening of 564 citations. The total number of participants was 18,802, and study duration ranged from 6 to 208 weeks. Only two trials provided details on adequate allocation concealment, whereas all the trials stated they were double blind in nature. Dutasteride was not associated with a statistically significant increased risk of heart failure (RR 1·05; 95% confidence interval [CI], 0·71-1·57, I(2) = 20%), myocardial infarction (RR 1·00; 95% CI 0·77-1·30, I(2) = 0%) and stroke (RR, 1·20; 95% CI 0·88-1·64, I(2) = 0%) as compared to controls. WHAT IS NEW AND CONCLUSION: We did not find consistent evidence of a significant association between dutasteride therapy and the risk of cardiovascular adverse events.

Measures used to treat contrast-induced nephropathy: overview of reviews.

OBJECTIVES: Despite many interventions that have been tried, controversy remains regarding the efficacy of interventions for contrast-induced nephropathy (CIN), so we aimed to evaluate the best evidence from recent meta-analyses. METHODS: We searched MEDLINE, EMBASE and the Cochrane library for interventions which have been used for CIN. We included only the most recent meta-analysis of each intervention. We extracted data on the methodology, quality and results of each meta-analysis. We performed narrative synthesis and adjusted indirect comparison of interventions that were shown to be statistically significant compared with a placebo. RESULTS: We included 7 systematic reviews and meta-analyses involving 9 different interventions for CIN, with a total of 15 976 participants. A significantly decreased risk of CIN was reported in meta-analysis of the following interventions: N-acetylcysteine [odds ratio (OR) 0.65, 95% confidence interval (CI) 0.48-0.88, I(2)=64%], theophylline [relative risk (RR) 0.48, 95% CI 0.26-0.89, I(2)=44%], statins (RR 0.51, 95% CI 0.34-0.77, I(2)=0%) and sodium bicarbonate (RR 0.62, 95% CI 0.45-0.86, I(2)=49%). Furosemide was shown to increase the risk of CIN (RR 3.27, 95% CI 1.48-7.26, I(2)=0%). Other interventions such as renal replacement therapy, angiotensin-converting enzyme inhibitors, dopamine and fenoldapam failed to show any significant difference from the control group. CONCLUSION: Although there is some evidence to suggest that N-acetylcysteine, theophylline, sodium bicarbonate and statins may reduce incidence of CIN, limitations in the study quality and heterogeneity preclude any firm recommendations. ADVANCES IN KNOWLEDGE: N-acetylcysteine, theophylline, sodium bicarbonate and statins show some promise as potentially efficacious agents for preventing CIN, but more high-quality studies are needed before they can be recommended for use in routine practice.

Meta-analysis: risk of esophageal adenocarcinoma with medications which relax the lower esophageal sphincter.

Reasons for the rising annual incidence of esophageal adenocarcinoma (EAC) remain uncertain. Previous studies have given conflicting results, but some have suggested that drugs which relax the lower esophageal sphincter (LES) may increase the risk of EAC. This study is to determine systematically the risk of EAC associated with individual medications which relax the LES and compare risks with esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). Relevant published studies were identified by systematic searching PubMed for case-control studies reporting on risk of EAC, ESCC or GCA with use of medications known to reduce LES pressure. Pooled odds ratios (ORs) were calculated for each malignancy. Data were analyzed from four case-control studies involving 9,412 participants. EAC was significantly associated with theophylline use (OR 1.55, 95% confidence interval [CI] 1.05-2.28; P= 0.03, I(2) = 0%) and anticholinergic medications (OR 1.66, 95% CI 1.13-2.44; P= 0.01, I(2) = 84%). This effect was not observed in cases of ESCC or GCA. Other drug groups including calcium channel modulators and nitrates did not increase the risk of EAC. An inverse relationship was observed between ESCC and nitrates and between GCA and benzodiazepines. The lack of increased EAC risk with many commonly used medications is reassuring. However, a significant correlation was found between EAC and the use of anticholinergics and theophyllines. This may reflect common causality between obstructive lung disease and EAC, and further studies to explore these relationships are warranted.

Dabigatran and rivaroxaban for prevention of venous thromboembolism--systematic review and adjusted indirect comparison.

WHAT IS KNOWN AND OBJECTIVE: Dabigatran and rivaroxaban are new oral anticoagulants for thromboprophylaxis after elective orthopaedic surgery. We aimed to systematically compare their relative benefits and harms through meta-analysis, and adjusted indirect comparison. METHODS: We searched PubMed, EMBASE, trial registries and regulatory documents through May 2009 for randomized controlled trials (RCTs) of dabigatran (150 and 220 mg daily) and rivaroxaban (10 mg daily) compared with enoxaparin (40-60 mg daily) in elective orthopaedic surgery. We used random effects meta-analysis to calculate pooled relative risks (RRs) and 95% confidence intervals (95% CI) for the outcomes of total venous thromboembolism, VTE (deep venous thrombosis, non-fatal pulmonary embolism and all-cause mortality), and haemorrhagic adverse events (major and clinically relevant non-major bleeds). Adjusted indirect comparison was used for the pooled RRs of dabigatran and rivaroxaban with enoxaparin as the common control. RESULTS: Rivaroxaban was superior to enoxaparin for the prevention of venous thromoboembolism (RR 0.56, 95% CI 0.43-0.73, P<0.0001), with a trend for increased haemorrhage (RR 1.26, 95% CI 0.94-1.69, P=0.13). Dabigatran was not superior to enoxaparin for prevention of VTE (RR 1.12, 95% 0.97-1.29, P=0.12), and did not reduce haemorrhage risk (RR 1.10, 95% 0.90-1.35, P=0.32). Adjusted indirect comparison showed that rivaroxaban was superior to dabigatran in preventing VTE, RR 0.50 (95% CI 0.37-0.68), but with a slight trend towards increased haemorrhage RR 1.14 (95% CI 0.80-1.64). WHAT IS NEW AND CONCLUSION: Rivaroxaban may be more effective than dabigatran for prevention of VTE after elective orthopaedic surgery but might also slightly increase the risk of haemorrhage.

Homocysteine and peripheral arterial disease: systematic review and meta-analysis.

OBJECTIVE: To evaluate homocysteine (Hcy) levels in patients with peripheral arterial disease (PAD) as compared to unaffected controls, and to review the clinical effects of therapy aimed at lowering homocysteine in PAD patients. METHODS: MEDLINE, EMBASE and Cochrane databases were searched from 1950 to December 2007. We selected observational studies and trials that evaluated Hcy levels in patients with PAD compared to unaffected controls. We also included trials on the effect of Hcy-lowering therapy (folate supplementation) in PAD patients. Continuous outcomes were pooled in a random effects meta-analysis of the weighted mean difference between comparator groups. RESULTS: We retrieved 33 potentially suitable articles from our search. Meta-analysis of 14 relevant studies showed that Hcy was significantly elevated (pooled mean difference +4.31micromoll; 95% C.I. 1.71, 6.31, p<0.0001 with significant heterogeneity) in patients with PAD compared to controls. As all 14 studies consistently demonstrated raised plasma Hcy levels in PAD patients, the significant heterogeneity in this meta-analysis probably arises from differences in the degree of Hcy elevation. The effect of folate supplementation on PAD was tested in eight clinical trials but clinically important end points were inconsistently reported. CONCLUSION: Patients with PAD have significantly higher Hcy levels than unaffected controls. However, we did not find any robust evidence on clinically beneficial effects of folate supplementation in PAD.

Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells.

Angiogenesis is essential for endometrial growth and repair, and disruption of this process may lead to common disorders of women, including menorrhagia and endometriosis. In pregnancy, failure of the endometrial spiral arterioles to undergo remodeling leads to preeclampsia. Here we report that in addition to vascular endothelial growth factor A (VEGF-A), human endometrium expresses messenger ribonucleic acids (mRNAs) encoding VEGF-C, placenta growth factor (PlGF), the angiopoietins, angiopoietin 1 (Ang1) and Ang2, and the receptors VEGFR-3 (Flt-4), Tie 1, and Tie 2. Levels of VEGF-C, PlGF, and Tie 2 changed during the menstrual cycle. Intense hybridization for VEGF-C and PlGF mRNAs was found in uterine nature killer cells in secretory phase endometrium and for Ang2 mRNA in the same cells in the late secretory phase. Interleukin-2 (IL-2) and IL-15 up-regulated VEGF-C, but not PlGF or Ang2, mRNA levels in isolated NK cells. Conditioned medium from decidual NK cells did not induce human umbilical vein endothelial cell apoptosis. These results indicate that human endometrium expresses a wide range of angiogenic growth factors and that uterine nature killer cells may play an important role in the abnormal endometrial angiogenesis that underlies a range of disorders affecting women.

HLA-G expression by tumors.

PROBLEM: It has been proposed that the expression of the non-classical MHC class I antigen, HLA-G, by trophoblast is one mechanism by which the placenta evades attack by maternal uterine NK cells. A similar mechanism is thought to be operative in the escape from immunosurveillance by tumor cells. However, data on the expression of HLA-G by tumor cells are highly conflicting. METHOD OF STUDY: In the present study, we have examined tissue sections from a wide variety of tumors by immunohistology and also several cell lines by flow cytometry and RT-PCR. Whilst very faint bands were detected in three cell lines (hepG2, Mead, CaSki) by RT-PCR, no tumors or cell lines were observed to express HLA-G protein. Furthermore, we found that tumor deposits are not usually infiltrated by NK cells. CONCLUSION: Our observations, therefore, do not support the proposal that tumor cells express HLA-G in order to evade host NK cell cytolysis.

Melanomas and melanoma cell lines do not express HLA-G, and the expression cannot be induced by gammaIFN treatment.

HLA-G is an effective ligand of natural killer (NK) inhibitory receptors, HLA-G transcripts have been detected in several human tumors, and cytokines like gamma interferon (IFN) enable HLA-G molecules to be expressed. These findings are particularly upsetting in case of melanomas: IFN treatment is frequently included in melanoma therapeutic protocols, and downregulation of classical class I molecules occurs in nearly half of these tumors. Therefore, a melanoma cell downregulating classical class I and de novo expressing HLA-G, either constitutively or upon IFN treatment, is probably a stealthy target for the immune system, having inhibited both the cytotoxic T lymphocyte (CTL) and the NK activity. To elucidate this point we have investigated the expression of HLA-G molecules in 45 melanoma cell lines before and after gammaIFN treatment. Analysis was performed by immunofluorescence and flow cytometry, using the anti-HLA-G MoAbs 87G and G233, by Western blot, using the anti-HLA-G MEM/G1 MoAb and PAG1 antiserum, and by RT-PCR analysis. In addition, 8 melanoma tissues from patients free from therapy and 6 nevi were studied by immunohistochemistry using the 87G MoAb. No evidence was gathered of HLA-G expression, neither constitutive nor, in cell lines, after gammaIFN treatment. We therefore conclude that HLA-G expression is an uncommon event in melanomas, and that a therapy including IFNs cannot harm the patient by inducing the de novo expression of HLA-G molecules at least in its G1 isoform.

Immunological aspects of human implantation.

The immunological relationship between the mammalian fetus and its mother during pregnancy has been considered similar to that between a transplanted allograft and its recipient. Hence, it has been assumed that implantation of the fetal placenta in the uterus would be controlled in a similar way by a maternal immune response mediated by T cells recognizing paternally derived alloantigens expressed by the placenta. However, recent evidence indicates that implantation might involve predominantly a novel allogeneic recognition system based on natural killer cells rather than T cells. The cellular and molecular basis of this local immune interaction between the fetal placenta and maternal uterus is the focus of intense research interest. As aberrant implantation can cause a variety of clinical problems including miscarriage, intrauterine growth retardation and pre-eclampsia, an understanding of the immunological mechanism by which this process is controlled could lead to the development of regimens to improve fetal growth and development.

HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells.

Non-classical MHC class I molecule HLA-E is the ligand for CD94/NKG2 NK cell receptors. Surface expression of HLA-E requires binding of specific HLA class I leader sequences. The uterine mucosa in early pregnancy (decidua) is infiltrated by large numbers of NK cells, which are closely associated with placental trophoblast cells. In this study we demonstrate that trophoblast cells express HLA-E on their cell surface in addition to the previously reported expression of HLA-G and HLA-C. Furthermore, we show that the vast majority of decidual NK cells bind to HLA-E tetrameric complexes and this binding is inhibited by mAb to CD94. Thus, recognition of fetal HLA-E by decidual NK cells may play a key role in regulation of placentation. The functional consequences of decidual NK cell interaction were investigated in cytotoxicity assays using polyclonal decidual NK cells. The overall effect of CD94/NKG2 interaction with HLA-E is inhibition of cytotoxicity by decidual NK cells. However, since decidual NK cells are unable to kill trophoblast even in the presence of mAb to MHC class I molecules and NK cell receptors, HLA-E interaction with CD94/NKG2 receptors may regulate other functions besides cytolysis during implantation.

Surface expression of HLA-C antigen by human extravillous trophoblast.

In this paper definitive evidence that the classical class I product, HLA-C, is expressed on the surface of normal trophoblast cells is provided. HLA-C transcripts were sequenced from cDNA isolated from first trimester trophoblast cells obtained by flow cytometric sorting. Both paternal and maternal alleles were transcribed. HLA-C proteins were demonstrated by biochemical analysis and found on the cell surface in association with beta(2)-microglobulin. Upregulation of cell surface HLA-C but not HLA-G expression after interferon (IFN)-gamma treatment was demonstrated by flow cytometric analysis. Immunohistology has confirmed HLA-C is expressed by all extravillous subpopulations in vivo. The question of whether trophoblast HLA-C molecules interact with decidual NK cells expressing killer Ig-like receptors (KIR) has also been addressed. Our results demonstrate that extravillous trophoblast expresses at least two HLA class I molecules, HLA-G and HLA-C on the cell surface.

Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15.

The natural killer (NK) cells that are present in the uterine mucosa (decidua) during early pregnancy have a distinctive phenotype, CD56(bright) CD16(-). These cells have previously been shown to proliferate and be activated by interleukin (IL)-2. However, IL-2 is absent from the decidua and placenta, and we have therefore investigated whether IL-15 is present in the uterus and can act on decidual NK cells. Both IL-15 mRNA and protein were found in a variety of cells but particularly in decidual macrophages. IL-15 induced a proliferative response in decidual NK cells that was blocked by anti-IL-15 and was augmented by stem cell factor. The cytolytic activity of decidual NK cells against K562 was augmented. Interestingly, in contrast to IL-2, although activation with IL-15 resulted in some killing of JEG-3 choriocarcinoma cells, normal trophoblast cells remained resistant to lysis. These findings suggest that IL-15 is a candidate cytokine responsible for NK cell proliferation in vivo in the progesterone-dominated secretory endometrium and early decidua.

Cutting edge: KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties.

Transmembrane adapter proteins are a class of molecules that mediate signals from an extracellular receptor to the cytoplasm of the cell. We have cloned a novel transmembrane adapter protein called KAP10, a approximately 10-kDa protein that is encoded within 100 bp of the DAP12 locus on human chromosome 19. KAP10 is predominantly expressed in immune cells, including NK cells, T cells, and monocytes. We show that KAP10, unlike other transmembrane adapter proteins, binds phosphatidylinositol-3 kinase following phosphorylation of a cytoplasmic YINM motif, which results in activation of Akt. In addition, we identify KAP10 as being able to bind the adapter protein Grb2. Based on our data, we suggest that this molecule is involved in stimulation and costimulation in cells of both myeloid and lymphoid origin.

HLA-G in the human thymus: a subpopulation of medullary epithelial but not CD83(+) dendritic cells expresses HLA-G as a membrane-bound and soluble protein.

The human MHC class Ib gene HLA-G is transcribed and translated in different placental cell subpopulations during pregnancy. In addition to this restricted tissue distribution, HLA-G proteins were also recently detected in the thymus of HLA-G transgenic mice, as well as in some human thymic epithelial cells (TEC). There was a need to further define the phenotype of the HLA-G-expressing cells in the human thymus as well as the type of translated forms that they produce. Using several HLA-G-specific mAb and immunohistochemistry performed on cryosections of human thymi at different ages, we found that the HLA-G-expressing cells are present on medullary cells exhibiting the epithelial morphological type 6. Co-localization experiments performed by double or triple immunofluorescence staining demonstrate that these HLA-G-expressing cells express various cytokeratins, epithelial cell markers but not the CD83 dendritic cell marker. We further show by ELISA measurements that a subset of primary cultured human TEC also expresses soluble HLA-G. Therefore, HLA-G protein tissue distribution is not restricted solely to placental cells. A subpopulation of medullary TEC also expresses HLA-G both at their cell surface and in secreted form, raising the question of the functional significance of such MHC class Ib molecules. Whether thymic soluble and/or membrane-bound HLA-G contribute to inhibit NK cells or to a negative selection of autoreactive T cells which could be harmful in case of pregnancy and/or to a positive selection of viral peptides/HLA-G-restricted CD8(+) T cells remains to be demonstrated.