Are patient educational resources effective at deterring stroke survivors from considering experimental stem cell treatments? A randomized controlled trial.

OBJECTIVE: To evaluate whether online resources developed to educate people about the risks associated with experimental stem cell (SC) treatments influence stroke survivors' attitudes about the safety and effectiveness of these treatments. METHODS: Adult stroke survivors who had not previously received SC treatments (N = 112) were recruited from international stroke advocacy/support groups for a prospective, parallel-group randomized controlled trial. Participants indicated whether they were considering SC treatments (yes/no) prior to, immediately following, and 30-days after reading/viewing the International Society for Stem Cell Research booklet or Stem Cell Network video. Participant attitudes regarding the safety, effectiveness, accessibility and affordability of SC treatments were examined on each occasion, and compared to those of a waitlist control group. RESULTS: Significantly fewer participants were considering SC treatments immediately after reading the SC research booklet (p =.031), although neither intervention had any impact after 30-days (p >.05). Waitlist and intervention groups reported positive attitudes toward SC treatments at each assessment. CONCLUSIONS: Stroke survivor attitudes toward SC treatments were initially influenced by the patient booklet, however these changes were not maintained. PRACTICAL IMPLICATIONS: Clinicians are encouraged to initiate discussions about experimental SC treatments during inpatient rehabilitation and to reinforce the risks throughout subsequent care.

The high prevalence of autoantibodies to tissue transglutaminase in first-degree relatives of patients with type 1 diabetes is not associated with islet autoimmunity.

OBJECTIVE: To determine the extent of celiac autoimmunity in type 1 diabetic patients and the overlap between islet and celiac autoimmunity in their nondiabetic relatives. RESEARCH DESIGN AND METHODS: IgA antibodies to tissue transglutaminase were determined in serum taken from 433 type 1 diabetic patients and 1,442 nondiabetic first-degree relatives. Samples with transglutaminase antibodies above the 97.5th percentile of 347 schoolchildren were also assayed for IgA anti-endomysial antibodies (EMAs). Markers of islet autoimmunity (islet cell antibodies and autoantibodies to insulin, glutamate decarboxylase. and protein tyrosine phosphatase IA-2) had previously been measured in all relatives. RESULTS: In the absence of known celiac disease, the prevalence of transglutaminase antibody levels above the 97.5th percentile of the schoolchildren was 13.4% in diabetic patients and 7.0% in nondiabetic relatives. ENMAs were found in addition to transglutaminase antibodies in 2.6% of probands and in 1.9% of first-degree relatives, but none of the schoolchildren. Transglutaminase antibodies were found to persist in 10 of 30 patients and in 30 of 59 relatives with follow-up samples taken at least 2 years after the initial sample. Of 186 nondiabetic relatives with islet autoantibodies, only 10 also had transglutaminase antibodies. CONCLUSIONS: We found a high prevalence of celiac autoimmunity in patients and first-degree relatives of children with type 1 diabetes, but we found limited overlap between islet and celiac autoimmunity in nondiabetic relatives. The high prevalence of celiac autoimmunity may be explained by shared genetic susceptibility and identifies a population within which screening for the disease may be justified.

Laboratory clues to immunodeficiency; missed chances for early diagnosis?

Primary immunodeficiency is seen in an estimated one in 1200 people, and secondary immunodeficiency is increasingly common, particularly with the use of immunosuppresion, cancer therapies and the newer biological therapies such as rituximab. Delays in the diagnosis of immunodeficiency predictably lead to preventable organ damage. Examples of abnormal pathology tests that suggest immunodeficiency from all laboratory specialities are given, where vigilant interpretation of abnormal results may prompt earlier diagnosis. If immunodeficiency is suspected, suggested directed testing could include measuring immunoglobulins, a lymphocyte count and T-cell and B-cell subsets.

Binding of wheat gliadin in vitro to reticulum in normal and dermatitis herpetiformis skin.

We have demonstrated by indirect immunofluorescence that wheat gliadin binds in vitro to reticulin-like fibrils present in cryostat sections of human skin, and rat liver, kidney and stomach. Gliadin was seen to bind to fibrils throughout the dermis of both normal and dermatitis herpetiformis skin, and this was particularly striking in the dermal papillae. Serum from 2 dermatitis herpetiformis patients who did not have antireticulin antibody gave reticulin staining when retested by immunofluorescence on cryostat sections of rat tissue pretreated with gliadin. Gliadin treated sections may prove useful in screening patients with gluten sensitive enteropathy for anti-gliadin antibody. Binding of gliadin to skin sites in dermatitis herpetiformis patients and subsequent deposition of antigliadin antibody at these sites may be involved in the development of skin lesions.

Evaluation of a high-throughput second antibody radiobinding assay for measuring IgA antibodies to human tissue transglutaminase.

We describe a novel high-throughput radiobinding assay for IgA antibodies to tissue transglutaminase (TG) which uses second antibody precipitation to isolate immune complexes. Using this assay, 24 of 25 patients with untreated coeliac disease (96%) and nine of 526 healthy blood donors (2%) had TG antibody levels above a threshold defined by the 97.5th centile of 347 schoolchildren. All patients and five of the nine blood donors with transglutaminase antibodies above this threshold were endomysial antibody (EMA) positive. Using this threshold, 410/445 (92%) routine clinical samples were concordant for TG antibodies and EMA, including 72 of 75 with EMA. TG antibodies above the 97.5th centile were found in 32 of 370 EMA negative samples, 15 of whom had anti-gliadin antibodies (AGA), histologically proven coeliac disease or partial villous atrophy. We conclude that this assay achieves a sensitivity and a specificity at least equivalent to those of EMA. It is technically simple and suitable for coeliac disease screening.

Antibodies to extractable nuclear antigens. Has technological drift affected clinical interpretation?

Precipitating antibodies to extractable nuclear antigens are important in the diagnosis of connective tissue diseases. Disease associations are defined using gel based techniques. Alternative technologies have been introduced, including passive haemagglutination, enzyme linked immunosorbent assay, and western blotting. This leader contains a review of the literature on the clinical usefulness of these assays, together with knowledge gained from personal experience. Using the example of systemic lupus erythematosus, the sensitivity, specificity, and positive predictive value of the assays for disease is discussed, as is their differences in performance. The conclusion drawn is that disease specificity is method dependent. Validation and audit of performance of the method selected by the investigation laboratory is essential.

The immunopathogenesis of meningococcal disease.

This review describes the mechanisms of the immune response to meningococcal disease, examining the extent to which individual variation of the immune response can determine susceptibility. It concludes by summarising the difficulties encountered by recent efforts to develop new immunomodulatory treatments.

Type 1 diabetes mellitus masking primary antibody deficiency.

A patient with a history of recurrent cutaneous and pulmonary infections, nephrotic syndrome, and an established diagnosis of type 1 diabetes was found to have unsuspected and unrecognised primary immunodeficiency. On review of the case, previous investigations pointed to the correct diagnosis over 10 years earlier. This combination of diagnoses has not previously been reported. The patient is now well on replacement intravenous immunoglobulin therapy, urinary loss of IgG having been specifically excluded before treatment. This case highlights how antibody deficiency can easily be missed despite an obvious infection history unless results are interpreted carefully and in context.

IgA anti-tissue transglutaminase as a diagnostic marker of gluten sensitive enteropathy.

AIMS: To compare and contrast the sensitivity, specificity, and positive predictive values of IgA antibodies to guinea pig tissue transglutaminase (ELISA), endomysium, and reticulin (immunofluorescence), and gliadin (ELISA), and IgG antibodies to gliadin and tissue transglutaminase. METHODS: Sera from 27 newly diagnosed patients with coeliac disease, 65 biopsied gastrointestinal disease controls, and 50 consecutive blood donors were tested. All cases were adults. RESULTS: IgA anti-tissue transglutaminase showed a sensitivity of 85% (23/27 coeliac disease cases seropositive), specificity 97% (2/65 controls and one blood donor showing low titre positivity), and a positive predictive value of 92%. High titre anti-tissue transglutaminase was only seen in coeliac disease. Disease controls with mucosal damage unrelated to gluten enteropathy were IgA anti-tissue transglutaminase negative. Sensitivity, specificity, and positive predictive values for IgA anti-endomysial antibody (monkey oesophagus) were 100%, 100%, and 100%, respectively, and for IgA anti-gliadin, 93%, 95%, and 89%, respectively. CONCLUSIONS: Tissue transglutaminase is a major autoantigen in coeliac disease. IgA (but not IgG) anti-tissue transglutaminase, especially when in high titre, is closely associated with coeliac disease, but low titres may not be disease specific. In this small pilot study, the established IgA anti-endomysial assay was the superior test.

Pneumocystis carinii, cytomegalovirus, and severe transient immunodeficiency.

Pneumocystis carinii infection is rare in infants, and raises strong concerns of immune deficiency. This report describes the unusual case of a male infant with concurrent chest infections caused by P carinii and cytomegalovirus. Investigation was complicated by the strong suspicion of non-accidental injury, including subdural haematomas. The case illustrates how to investigate for possible immunodeficiency. Low immune function tests at presentation slowly improved and have remained normal on longterm follow up. Possible explanations for the transient severe clinical immunodeficiency in this case are discussed.

Gliadins bind to reticulin in a lectin-like manner.

It has previously been reported that gliadins bind to reticulin in tissue sections. Three lines of evidence are reported in this study which indicate that the gliadins bind to reticulins because they are lectins which bind to sugars expressed on glycoproteins in reticulin and other sites. First, immunofluorescence studies on tissue sections showed that although gliadin binding is largely confined to areas rich in reticulin, it is, nonetheless, also seen in one or two other sites devoid of reticulin. Second, by using fluorescein-labelled lectins of known specificity, it has been shown that the areas to which gliadins bind in tissue sections (including those sites devoid of reticulin) are rich in particular sugars. Third, it has been shown that one of these sugars, alpha-D-mannose, partially inhibited gliadin binding to tissue sections.

Immunoglobulins and immunoglobulin subclasses in the elderly.

BACKGROUND: Published data imply that adult concentrations are achieved for all Ig isotypes and plateau by 15-18 years of age. Recent data, however, suggest that these results are not applicable in the elderly. There are no equivalent data for IgG subclasses. We present reference range data for an elderly UK patient population, for IgG, IgA, IgM and IgG subclasses. METHODS: Serum immunoglobulins were reviewed on samples from 1146 patients > 60 years of age and 925 patients aged 18-60 years. Serum IgG subclasses were reviewed on samples from 498 patients >60 years and 484 patients aged 18-60 years. All Igs and subclasses were measured by nephelometry. Reference ranges were derived by probability plotting. RESULTS: Serum median IgG and IgM concentrations are reduced in the elderly (IgG female P < 0.001, IgG male P < 0.03; IgM female P < 0.001, IgM male P < 0.001). Serum IgA concentrations are maintained. Indeed, men showed a slight increase in serum IgA with age (P = 0.03). Few differences dependent on gender were seen. Median IgM was lower in men in the younger age groups (18-60 years P < 0.001; 61-70 years P = 0.017). IgG(2) is reduced in elderly men (P = 0.002) and IgG, reduced in elderly women (P = 0.009). CONCLUSIONS: We advocate that centres offering these investigations provide local, method-dependent reference ranges, and suggest an approach as to how this might be achieved.

Antiendomysial and antigliadin antibody tests and diagnosis of celiac disease.

Celiac disease and the related condition dermatitis herpetiformis are caused by ingestion of wheat gluten (gliadin being the active moiety) and certain other cereal proteins.

Coeliac disease, anaemia and pregnancy.

We have investigated the prevalence of positive serology for coeliac disease in pregnant women, using the IgA anti-endomysium antibody test. Five of 216 pregnant women with a haemoglobin less than 11 g/dl were positive, compared to 0/350 with haemoglobin > or = 11 g/dl. Four of these five had low plasma ferritin levels, indicative of iron deficiency anaemia; the fifth was borderline normal. We found no association between positive coeliac disease serology and folate deficiency. None of thirty mothers of children born with neural tube defects were IgA anti-endomysium antibody positive. This study has identified a very high prevalence of occult coeliac disease in pregnancy and a strong association with anaemia. We advise that in cases with a haemoglobin of less than 11 g/dl in pregnancy, coeliac disease should be excluded.

Immunoglobulin A deficiency on serological coeliac screening: an opportunity for early diagnosis of hypogammaglobulinaemia.

We present a serendipitous case of clinically significant pan-hypogammaglobulinaemia, diagnosed after routine serological testing for possible coeliac disease led first to identification of IgA deficiency (discovered as a low background in IgA-based routine serological screening), and subsequently to confirmed pan-hypogammaglobulinaemia (antibody immunodeficiency). Hypogammaglobulinaemia is a relatively rare diagnosis (estimated at 1 in 36,000), in which delayed diagnosis and treatment are associated with chronic organ damage including bronchiectasis. Routine serological testing for coeliac disease using the IgA anti-tissue transglutaminase (IgA TTG) test is in widespread use and provides an opportunity for early diagnosis of hypogammaglobulinaemia. Routine serological screening for coeliac disease may uncover IgA deficiency, and we suggest that all IgA-deficient cases identified should also be checked for antibody deficiency by quantifying the other immunoglobulins (IgG, IgM).

Unscrambling Egg Allergy: The Diagnostic Value of Specific IgE Concentrations and Skin Prick Tests for Ovomucoid and Egg White in the Management of Children with Hen's Egg Allergy.

Resolution of egg allergy occurs in the majority of egg allergic children. Positive specific IgE antibodies to ovomucoid (OVM) have been suggested to be of greater predictive value for persistent egg allergy than specific IgE to egg white. The performance of OVM-specific IgE antibody levels in a cohort of children referred for a routine egg challenge was compared with egg white specific IgE levels in predicting a positive egg challenge. 24/47 subjects had persistent egg allergy. Receiver operating characteristic analysis showed that OVM-specific IgE testing was the most useful test for the diagnosis of persistent egg allergy. The optimal decision points for the prediction of persistent egg allergy were >0.35 kUA/L for specific IgE levels to both EW and OVM, and ≥3 mm for SPT. Children with specific IgE levels suggestive of persistent egg allergy need not be subject to an egg provocation challenge, reducing both costs and risks to the child.

HLA and kidney transplantation.

This article focuses on the immunogenetics, immunology, rejection and immunosuppression in kidney transplantation. HLA matching still affects outcome data, and HLA matching improves graft survival. Graft sources and related outcomes are discussed.