Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors: modeling the function of an inactivating receptor mutation.

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.

Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63-0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.

Lifetime Measurements of Excited States in

Lifetimes of the first excited 2^{+} and 4^{+} states in the extremely neutron-deficient nuclide ^{172}Pt have been measured for the first time using the recoil-distance Doppler shift and recoil-decay tagging techniques. An unusually low value of the ratio B(E2:4_{1}^{+}→2_{1}^{+})/B(E2:2_{1}^{+}→0_{gs}^{+})=0.55(19) was found, similar to a handful of other such anomalous cases observed in the entire Segré chart. The observation adds to a cluster of a few extremely neutron-deficient nuclides of the heavy transition metals with neutron numbers N≈90-94 featuring the effect. No theoretical model calculations reported to date have been able to explain the anomalously low B(E2:4_{1}^{+}→2_{1}^{+})/B(E2:2_{1}^{+}→0_{gs}^{+}) ratios observed in these cases. Such low values cannot, e.g., be explained within the framework of the geometrical collective model or by algebraic approaches within the interacting boson model framework. It is proposed that the group of B(E2:4_{1}^{+}→2_{1}^{+})/B(E2:2_{1}^{+}→0_{gs}^{+}) ratios in the extremely neutron-deficient even-even W, Os, and Pt nuclei around neutron numbers N≈90-94 reveal a quantum phase transition from a seniority-conserving structure to a collective regime as a function of neutron number. Although a system governed by seniority symmetry is the only theoretical framework for which such an effect may naturally occur, the phenomenon is highly unexpected for these nuclei that are not situated near closed shells.

Conflicting HLA assignment by three different typing methods due to the apparent loss of heterozygosity in the MHC region.

Loss of heterozygosity (LOH) has been reported to cause false human leukocyte antigen (HLA) homozygous typing results in pre-transplant patients suffering from haematological malignancies, who in fact are HLA heterozygous. This poses a challenge for histocompatibility testing, as a stem cell graft from a genuinely HLA homozygous donor to a mistyped patient may lead to acute life-threatening graft-vs-host disease. LOH in the HLA region on chromosome 6 is known to be quite common in solid tumours, helping malignant cells to escape T-cell surveillance, but the incidence in haematological malignancies is less well known and the estimates vary. Here we report LOH in the HLA region of five patients with haematological malignancy. We found considerable differences in sensitivity between the three different HLA typing methods used in our laboratory: SSP was clearly the most sensitive method for detecting the lost haplotype, followed by rSSO, while SBT was the least sensitive technique. A subsequent, retrospective genotyping of 65 HLA homozygous haematological patients by SSP method showed no mistyped LOH cases in our laboratory in the past 10 years. The frequency of HLA homozygosity was found to be similar between haematological patients and control groups. It is important for an HLA laboratory to be aware of the differences in various HLA typing techniques' sensitivity for detecting an under-represented haplotype between HLA typing techniques when genotyping patients with haematological diseases. It is advisable for HLA laboratories to have at least two different methods with different sensitivities in their repertoire to be able to retype samples when a false homozygous result is suspected.

Minor histocompatibility antigens as determinants for graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Minor histocompatibility antigens (minor H antigens) are genetically polymorphic peptides that have been shown to elicit immune response when mismatched between donor and recipient of haematopoietic stem cell transplantation (HSCT). Depending on the expression profiles, mismatches in these genes may either lead to harmful graft-versus-host (GvH) reaction or desired graft-versus-leukaemia (GvL) effect. We analysed retrospectively the effect of HLA-restricted matching 11 established autosomal minor H antigens on the risk of graft-versus-host disease and relapse in 311 HLA-matched sibling HSCT of a single centre. Increased incidence of chronic GvH disease was shown to be associated with mismatches in the HA-8 and ACC-1. The mRNA expression profiles in a large set of healthy and malignant tissue samples of minor H antigen genes demonstrated in silico that the expression profiles of HA-8 and ACC-1 were surprisingly different: HA-8 gene was expressed in practically all tissues, whereas ACC-1 gene had a restricted profile. The results demonstrated that mismatches in minor H antigens HA-8 and ACC-1 predisposed to chronic graft-versus-host disease (GvHD).

Molecular regulation of GABAergic neuron differentiation and diversity in the developing midbrain.

The midbrain GABAergic neurones control several aspects of behaviour, play important roles in psychiatric disease and are targets of medical treatments as well as drugs of abuse. However, their molecular diversity and regulation of development are only beginning to be understood. In this review, we briefly introduce distinct subpopulations of the midbrain GABAergic neurones and discuss knowledge on their development, including the developmental origins of midbrain GABAergic neurones as well as transcriptional regulatory mechanisms guiding their differentiation and identity. Important GABAergic neuron subpopulations are found within the dopaminergic (DA) nuclei in the ventral midbrain. GABAergic substantia nigra pars reticulata is the main output pathway of the basal ganglia system regulating voluntary movements. Recent studies have also highlighted importance of the GABAergic neurones associated with the ventral tegmental area for the control of DA neuron activity and motivated behaviours. Interestingly, the development of the GABAergic neurones associated with the DA nuclei is very different from the rest of the midbrain. Knowledge on developmental regulation can lead to insights into the molecular, structural and functional diversity of the midbrain GABAergic neurones and their subpopulations, cell groups of great physiological and medical interest.

Gliadin antibodies in older population and neurological and psychiatric disorders.

OBJECTIVES: A variety of neurological and psychiatric disorders have recently been linked to coeliac disease and gluten sensitivity. We here explored whether persistently positive gliadin antibodies (AGA) and coeliac-type HLA increase the risk of gluten sensitivity-related neurological and psychiatric manifestations. The study was carried out in an older population who had consumed gluten for decades but who had no previous coeliac disease diagnosis. MATERIALS AND METHODS: The original study population comprised 4272 randomly selected older individuals, of whom 2089 had AGA and transglutaminase 2 antibodies (antiTG2) measured twice within a 3-year interval. Forty-nine persistently AGA-positive but antiTG2-negative subjects with coeliac-type HLA and 52 randomly selected persistently AGA- and antiTG2-negative age- and sex-matched controls were clinically examined for neurological disorders. The Psychological General Well-Being (PGWB) questionnaire, the SF-36 health survey questionnaire and the Depression Scale (DEPS) were employed to evaluate psychological well-being. The medical files of all the study subjects were analysed for previous illnesses. RESULTS: Persistently AGA-positive but antiTG2-negative older subjects carrying coeliac disease-type HLA did not evince significantly more neurological symptoms or diseases than AGA-negative control subjects (P = 0.682, P = 0.233). There were no statistically significant differences between AGA-positive and AGA-negative groups in psychological well-being and quality of life when measured by PGWB (P = 0.426), SF-36 questionnaires (P = 0.120) and DEPS (P = 0.683). CONCLUSIONS: At population level, persistent AGA positivity did not indicate gluten sensitivity-related neurological and psychiatric disorders.

Association study of FUT2 (rs601338) with celiac disease and inflammatory bowel disease in the Finnish population.

Homozygosity for a nonsense mutation in the fucosyltransferase 2 (FUT2) gene (rs601338G>A) leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. As the secretor status has been shown to be a major determinant for the gut microbial spectrum, assumed to be important in the gut immune homeostasis, we studied the association of rs601338-FUT2 with celiac disease (CelD) and inflammatory bowel disease (IBD) in the Finnish population. Rs601338 was genotyped in CelD (n = 909), dermatitis herpetiformis (DH) (n = 116), ulcerative colitis (UC) (n = 496) and Crohn's disease (CD) (n = 280) patients and healthy controls (n = 2738). CelD showed significant genotypic [P = 0.0074, odds ratio (OR): 1.28] and recessive (P = 0.015, OR: 1.28) association with the rs601338-AA genotype. This was also found in the combined CelD+DH dataset (genotype association: P = 0.0060, OR: 1.28; recessive association: P < 0.011, OR: 1.28). The A allele of rs601338 showed nominal association with dominant protection from UC (P = 0.044, OR: 0.82) and UC+CD (P = 0.035, OR: 0.84). The frequency of non-secretors (rs601338-GG) in controls, CelD, DH, UC and CD datasets was 14.7%, 18%, 18.1%, 14.3% and 16.1%, respectively. No association was evident in the DH or CD datasets alone. In conclusion, FUT2 non-secretor status is associated with CelD susceptibility and FUT2 secretor status may also play a role in IBD in the Finnish population.

Toll-like receptor gene polymorphisms confer susceptibility to graft-versus-host disease in allogenic hematopoietic stem cell transplantation.

Graft-versus-host disease (GvHD) is a major complication in hematopoietic stem cell transplantation (HSCT). The immune response against gut microbes is thought to be an important factor in the beginning of GvHD. Toll-like receptors (TLR) recognize molecular structures of microbes and viruses and play central part in the innate immunity. We studied whether genetic variation in the TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 genes confers susceptibility to GvHD in 305 human leucocyte antigen-identical sibling donor HSCT's performed in a single Finnish centre. The results showed that the genetic markers rs4833079 (P = 0.035) in TLR1, rs4837656 (P = 0.032) and rs17582214 (P = 0.029) in TLR4, rs10737416 (P = 0.048) in TLR5, rs6531656 (P = 0.035) in TLR6, and rs337629 (P = 0.005) in TLR10 were associated with the occurrence of acute GvHD. Interestingly, two markers in the TLR5 gene, rs2800230 (P = 0.010) and rs2800237 (P = 0.017), were associated with chronic GvHD. These results indicate that many genes of the TLR system are involved in the overall genetic risk for GvHD and emphasize the role of innate immunity in GvHD.

Combination of radiograph-based trabecular and geometrical parameters can discriminate cervical hip fractures from controls in individuals with BMD in non-osteoporotic range.

Majority of hip fractures occur in individuals with bone mineral density (BMD) in non-osteoporotic range. This suggests that factors other than BMD are associated with increased fracture risk in these individuals. The aim of this study was to investigate the combined ability of radiograph-based trabecular and geometrical parameters to discriminate cervical hip fractures from controls in individuals with non-osteoporotic BMD. A total of 39 postmenopausal females with non-pathologic cervical hip fracture were recruited to the study. Nineteen of the fracture patients (48.7%) had non-osteoporotic BMD and they constituted the fracture group. The control group consisted of 35 BMD-matched non-osteoporotic females. Several geometrical and trabecular parameters were extracted from plain pelvic radiographs, and their combined ability to discriminate fracture patients from controls was studied using a receiver operating characteristics (ROC) analysis. Significant differences in several radiograph-based geometrical and trabecular parameters were found between the fracture patients and controls, whereas no statistically significant difference in BMD was observed (p=0.92) between the groups. Area under the ROC curve was 0.993 (95% CI 0.977-1.008) for the combined multiple regression model, which included both trabecular and geometrical parameters as explanatory factors. Here, the sensitivity of 100% was achieved with the specificity of 94%. In a cross-validation of the model, 94.4% of the fracture patients, and 94.1% of the controls were classified correctly. The combination of radiograph-based trabecular and geometrical parameters was able to discriminate the cervical hip fracture cases from controls with similar BMD, showing that the method can provide additional information on bone structure and fracture risk beyond BMD.

BMD T-score discriminates trochanteric fractures from unfractured controls, whereas geometry discriminates cervical fracture cases from unfractured controls of similar BMD.

UNLABELLED: The ability of bone mineral density (BMD) to discriminate cervical and trochanteric hip fractures was studied. Since the majority of fractures occur among people who are not diagnosed as having osteoporosis, we also examined this population to elucidate whether geometrical risk factors can yield additional information on hip fracture risk beside BMD. The study showed that the T-score criterion was able to discriminate fracture patients from controls in the cases of trochanteric fractures, whereas geometrical measures may discriminate cervical fracture cases in patients with T-score >-2.5. INTRODUCTION: Low bone mineral density (BMD) is a well-established risk factor for hip fracture. However, majority of fractures occur among people not diagnosed as having osteoporosis. We studied the ability of BMD to discriminate cervical and trochanteric hip fractures. Furthermore, we examined whether geometrical measures can yield additional information on the assessment of hip fracture risk in the fracture cases in subjects with T-score >-2.5. METHODS: Study group consisted of postmenopausal females with non-pathologic cervical (n = 39) or trochanteric (n = 18) hip fracture (mean age 74.2 years) and 40 age-matched controls. BMD was measured at femoral neck, and femoral neck axis length, femoral neck and shaft cortex thicknesses (FNC and FSC), and femoral neck-shaft angle (NSA) were measured from radiographs. RESULTS: BMD T-score threshold of -2.5 was able to discriminate trochanteric fractures from controls (p < 0.001). Seventeen out of 18 trochanteric fractures occurred in individuals with T-score -2.5. Within these non-osteoporotic cervical fracture patients (N = 19) and non-osteoporotic controls (N = 35), 83.3% were classified correctly based on a model including NSA and FNC (p < 0.001), area under the receiver operating characteristics curve being 0.85 for the model, while it was only 0.56 for BMD alone. CONCLUSIONS: The study suggests that the risk of trochanteric fractures could be discriminated based on a BMD T-score <-2.5 criterion, whereas cervical fracture cases would remain under-diagnosed if solely using this criterion. Instead, geometrical risk factors are able to discriminate cervical fracture cases even among individuals with T-score >-2.5. For cervical and trochanteric fractures combined, BMD and geometric measures independently contributed to hip fracture discrimination. Our data support changing from T-score <-2.5 to a more comprehensive assessment of hip fracture etiology, in which fracture type is also taken into account. The findings need to be confirmed with a larger sample, preferably in a prospective study.

Domestic and foreign donor candidates result in differential probability of matching minor histocompatibility antigens--relevance of selection for hematopoietic stem cell transplantation.

Mismatches between patient and donor at minor histocompatibility antigens (minor H antigens) account for most of the genetic component of histocompatibility problems in human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantations (HSCTs). There are usually more genetic differences outside the matched HLA region between unrelated donors and patients than in transplantations between related individuals. Also, foreign unrelated donors may differ from domestic donors at several loci as allele frequencies vary between populations. To unravel differences in minor H antigen matching when using unrelated donors from various registries worldwide, we genotyped 10 minor H antigen loci for 143 consecutive Finnish patients and 424 unrelated donor candidates. We observed that probability of matching specific minor H antigens was different for domestic and foreign donor candidates. HA-2 and HA-3 minor H antigens were significantly more often mismatched with Finnish donor candidates (P = 0.0003 for HA-2 and P= 0.004 for HA-3), whereas ACC1 and ACC2 minor H antigens were significantly more often mismatched with foreign donor candidates (P = 0.04 for ACC1 and P = 0.03 for ACC2). This observation is of clinical importance when specific minor H antigens are intended to match or mismatch in the future to minimize the risk for graft-vs-host disease or to maximize the graft-vs-malignancy effect in HLA-matched HSCT from an unrelated donor.

Hippocampal sclerosis in refractory temporal lobe epilepsy is associated with gluten sensitivity.

BACKGROUND: Previous studies have associated coeliac disease (CD) and gluten sensitivity (defined as the presence of anti-gliadin antibodies and positive immunogenetics) with cerebellar degeneration and epilepsy with occipital calcifications. Hippocampal sclerosis (HS) in temporal lobe epilepsy (TLE) is a potentially progressive disorder with unknown aetiology; however, autoimmunity has been implicated as one of the possible mechanisms leading to HS. The purpose of this study is to analyze CD-associated antibodies and gluten sensitivity in a well-characterised group of patients with refractory focal epilepsy. METHODS: We measured anti-gliadin, anti-tissue-transglutaminase and anti-endomysium antibodies, and coeliac-type human leukocyte antigen (DQ2 and DQ8), in 48 consecutive patients with therapy-resistant, localisation-related epilepsy. The patients were categorised into the following three groups on the basis of ictal electro-clinical characteristics and the findings of high resolution MRI: TLE with HS (n = 16), TLE without HS (n = 16) and extratemporal epilepsy (n = 16). Patients with suspected CD or gluten sensitivity underwent duodenal biopsies. RESULTS: Seven patients in total were gluten sensitive; all of these patients fell in the TLE with HS group. On the other hand, none of the TLE without HS patients or those with extratemporal epilepsy were gluten sensitive (p<0.0002). The results of duodenal biopsies showed that three of the seven gluten-sensitive patients had histological evidence of CD and four had inflammatory changes consistent with early CD without villous atrophy. Four of the patients with gluten sensitivity had evidence of dual pathology (HS+another brain lesion), whereas none of the remaining patients did (p<0.0002). CONCLUSIONS: The present study demonstrates a previously unrecognised link between gluten sensitivity and TLE with HS. This association was very robust in this well-characterised group of patients; thus gluten sensitivity should be added to the list of potential mechanisms leading to intractable epilepsy and HS.

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency.

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14-18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.

Myosin IXB gene region and gluten intolerance: linkage to coeliac disease and a putative dermatitis herpetiformis association.

BACKGROUND: Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in the skin as dermatitis herpetiformis. Recently, a novel candidate gene, myosin IXB on chromosome 19p13, was shown to be associated with coeliac disease in the Dutch and Spanish populations. The same gene has previously been associated with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis risk, making myosin IXB a potential shared risk factor in these inflammatory disorders. METHODS: In this study, previously reported myosin IXB variants were tested for genetic linkage and association with coeliac disease in 495 Hungarian and Finnish families and in an additional 270 patients and controls. RESULTS AND CONCLUSION: The results show significant linkage (logarithm of odds (LOD) 3.76, p = 0.00002) to 19p13 which supports the presence of a genuine risk factor for coeliac disease in this locus. Myosin IXB variants were not associated with coeliac disease in this study; however, weak evidence of association with dermatitis herpetiformis was found. The association could not explain the strong linkage seen in both phenotypes, indicating that the role of other neighbouring genes in the region cannot be excluded. Therefore, more detailed genetic and functional studies are required to characterise the role of the myosin IXB gene in both coeliac disease and dermatitis herpetiformis.

Performance of a new rapid whole blood coeliac test in adult patients with low prevalence of endomysial antibodies.

BACKGROUND: In coeliac disease endomysial and transglutaminase autoantibodies are directed against the human autoantigen, transglutaminase. The conventional coeliac antibody tests are performed from serum samples in centralized laboratories. AIMS: To evaluate a rapid and easy immunoglobulin A-class whole blood point-of-care test and its commercial application, the Biocard test, in coeliac autoantibody detection. METHODS: In the whole blood point-of-care test transglutaminase is liberated from the red blood cells by haemolysis. Transglutaminase antibodies, if present, complex with the liberated antigen, and are visualized. Altogether 51 biopsy-proven untreated coeliac adult patients, 48 of the same patients after treatment, and 36 controls were tested. The point-of-care test results were compared with serum endomysial and transglutaminase antibody and Biocard test results and histology. RESULTS: The whole blood point-of-care test was as sensitive (82%) as the serum endomysium test (80%) in detecting untreated coeliac disease while the serum transglutaminase antibody test was superior (88%). The tests had 100% specificity. A positive point-of-care test result seroconverted or the test reaction weakened in 90% of the treated coeliac patients. Biocard test-positive were 22 of the 24 tested untreated coeliac patients. Biocard test-negative were 15 of 19 controls. CONCLUSIONS: The whole blood rapid tests are as reliable as the conventional serological tests in detecting untreated coeliac disease and in coeliac disease diet monitoring.

Heme oxygenase 1 gene polymorphisms and outcome of renal transplantation.

Heme oxygenase isoenzyme HO-1 has been linked to several cytoprotective functions with a potentially beneficial role in transplantation. In the present study, the effect of genetic variation in HO-1 on renal allograft outcome was investigated. Six hundred and eighty patients subject to renal transplantation in a single transplant unit and their cadaveric kidney donors were included in this study. Four single-nucleotide polymorphisms and one microsatellite marker in the HO-1 gene region were analysed. Some statistically nominally significant associations were observed in preliminary analyses between polymorphisms studied and clinical outcomes, but after correction for multiple comparisons none remained significant. Our data suggest that the HO-1 gene polymorphisms studied have no significant role on outcome of kidney transplantation in the Finnish population.

Killer-cell immunoglobulin-like receptor ligand compatibility in the outcome of Finnish unrelated donor hematopoietic stem cell transplantation.

Incompatibility in killer-cell immunoglobulin-like receptor (KIR) ligand between recipient and donor of hematopoietic stem cell transplantation has been reported to lead to natural killer (NK) cell activation. This activation may result in better transplantation outcome through reduced risk of graft-versus-host (GvH) disease, relapse and mortality. In the present study the effect of KIR ligand incompatibility was investigated retrospectively in 186 unrelated stem cell transplantations performed in Finland during years 1993-2004. No clear evidence for a better outcome in cases with KIR ligand incompatibility was obtained. Transplantation-related mortality was 64% in Kaplan-Meier analysis in the GvH direction KIR ligand-mismatched group and 33% in the KIR ligand-matched group. This difference was statistically non-significant. Consequently, no support could be obtained for a beneficial effect of KIR ligand incompatibility in the present set of unrelated donor transplantations.

Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease.

BACKGROUND: Refractory sprue with malabsorption carries a risk of lymphoma. AIM: To examine whether a good clinical but poor histological response during a strict gluten-free diet predicts a poor outcome. METHODS: The study involved all coeliac patients who showed no histological recovery within 2 years on a strict gluten-free diet. Small intestinal biopsy and bone mineral density were investigated in 2001 and clinical features were followed up until 2005. The results were compared to those in 18 coeliac patients with a good histological recovery. RESULTS: Thirteen coeliac patients had persistent small intestinal villous atrophy despite maintaining gluten-free diet. All had demonstrated a good clinical response. Osteoporosis was found in 58% and 22% of the non-responders and responders, respectively (P = 0.04). In 2005, two of the non-responders had developed symptomatic refractory sprue, one died of lymphoma and one of carcinoid tumour, and one gastric adenocarcinoma was operated. None of the 18 controls had developed refractory sprue or malignancy. The frequency of histological non-responsive disease was 1.9%. CONCLUSIONS: Persistent villous atrophy in adult coeliac disease, even in the absence of symptoms, carries a risk of subsequent severe complications. The follow-up biopsy is important in detecting these individuals.