No increase in adverse events with lateral extra-articular tenodesis augmentation of anterior cruciate ligament reconstruction - Results from the stability randomized trial.

OBJECTIVES: Results from the Stability Study suggest that adding a lateral extra-articular tenodesis (LET) to a hamstring tendon autograft reduces the rate of anterior cruciate ligament reconstruction (ACLR) failure in high-risk patients. The purpose of this study is to report adverse events over the 2-year follow-up period and compare groups (ACLR alone vs. ACLR + LET). METHODS: Stability is a randomized clinical trial comparing hamstring tendon ACLR with and without LET. Patients aged 14-25 years with an ACL deficient knee were included. Patients were followed and adverse events documented (type, actions taken, resolution) with visits at 3, 6, 12, and 24 months postoperatively. Adverse events were categorized as none, minor medical, minor surgical, contralateral ACL rupture, or graft rupture. Patient reported outcome measures (PROMs) collected at each visit included the Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee Score (IKDC), and ACL Quality of Life Questionnaire (ACL-QOL). RESULTS: In total, 618 patients were randomized (mean age 18.9 years, 302 (49%) male). Forty-five patients (7%) suffered graft rupture; 34 (11%) in the ACLR group compared to 11 (4%) in the ACLR + LET group (RRR = 0.67, 95% CI 0.36 to 0.83, p < 0.001). There were no differences in effusion or infection rates between groups. The ACLR + LET group experienced an increased number of hardware removals (10 vs. 4). Overall, the rate of minor medical events (11%), minor surgical events (7%), and ipsilateral or contralateral ACL tears (10%) were low considering the high-risk patient profile. Increasing severity of adverse events was associated with lower PROMs at 24 months post-operative. Patients in the ACLR + LET group reported greater degree of pain at 3 months only. There were no clinically significant differences in range of motion between groups. CONCLUSIONS: The addition of LET to hamstring tendon autograft ACLR in young patients at high risk of re-injury resulted in a statistically significant reduction in graft rupture. While the addition of LET may increase rates of hardware irritation, there was no significant increase in overall rates of minor medical adverse events, minor surgical events, or overall re-operation rates. The concerns regarding complications associated with a LET did not materialize in this study. LEVEL OF EVIDENCE: Level I.

Prediction of reparability of meniscal tears in athletes using magnetic resonance.

Meniscal tears account for approximately 15% of all knee injuries and almost 25% of them require surgical procedures. Magnetic Resonance Imaging (MRI) is widely used for noninvasive assessment of the knee joint and is considered reliable and a powerful tool for the detection of soft tissue injuries of the knee. The aim of the study was to evaluate the sensitivity, specificity, and accuracy of magnetic resonance imaging (MRI) to predict the meniscal tears repair in sports practitioners. 104 incoming consecutive patients who underwent knee joint ligament reconstruction and/or arthroscopy for the treatment of meniscal injury at knee joint were imaged using a 1.5-T MRI scanner prior to arthroscopy. MRI images were evaluated for anterior cruciate ligament (ACL), articular cartilage, and meniscal injury. Images were correlated with arthroscopic findings, used as the gold standard. The sensitivity, specificity, and accuracy of MRI in predicting meniscal repair were 61.1%, 65.94%, and 64.58%, respectively. The agreement between MRI and arthroscopy yielded a kappa index of 0.236, indicating fair agreement. When the menisci were evaluated separately, 65.85% sensitivity, 45.45% specificity, and 54.16% accuracy were found for the medial meniscus, while 46.15%, 79.51%, and 75.0% for the lateral meniscus, respectively. The accuracy was 62.09% in whose patients that arthroscopy was performed up to 3 months after MRI and 67.18% in those that this time frame was more than 3 months before surgery. The 54 meniscal injuries occurred more frequently in the posterior horn; most injuries had a longitudinal pattern and were located in the red-red (vascular) zone. We suggest that magnetic resonance imaging is only moderately accurate for the prediction of meniscus reparability.

Early functional rehabilitation or cast immobilisation for the postoperative management of acute Achilles tendon rupture? A systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To determine which postoperative rehabilitation regime is superior following surgical repair of acute Achilles tendon rupture. The primary outcomes were patient safety and satisfaction. DESIGN: Intervention meta-analysis. DATA SOURCES: The MEDLINE and CINAHL electronic databases were searched from their date of inception until June 2015 using keywords related to acute Achilles tendon rupture, surgical repair and rehabilitation. The electronic database search was supplemented with forward citation tracking using the Web of Science. ELIGIBILITY CRITERIA: Randomised controlled trials comparing clinical and/or patient-reported outcomes between patients receiving early functional postoperative ankle motion and weight bearing (bracing group), and traditional ankle immobilisation with a non-weight bearing rigid cast (cast group) were eligible for inclusion. Fourteen articles were identified as potentially eligible; 10 sufficient-quality randomised controlled trials involving 570 patients were included for meta-analysis. MAIN RESULTS: A high proportion of patients were able to return to prior employment and sporting activity in both groups. Five of the six trials measuring the time interval showed a faster return to prior sporting level in the bracing group. Subjective patient outcomes were significantly better in the bracing group (for good and excellent results, p=0.01; OR, 3.13; 95% CI 1.30 to 7.53). There was no difference in major complications between the two groups (p=0.21; RD, -0.03; 95% CI -0.06 to 0.01). Dynamometry and anthropometry measurements favoured functional rehabilitation at 6-12 weeks postoperation; however, by 6 months postoperative, the differences were negligible. CONCLUSIONS: Compared to traditional ankle immobilisation, with a non-weight bearing cast following surgical repair of acute Achilles tendon rupture, early dynamic functional rehabilitation is as safe with higher patient satisfaction.

Effect of opening-wedge high tibial osteotomy on the three-dimensional kinematics of the knee.

Although it is clear that opening-wedge high tibial osteotomy (HTO) changes alignment in the coronal plane, which is its objective, it is not clear how this procedure affects knee kinematics throughout the range of joint movement and in other planes. Our research question was: how does opening-wedge HTO change three-dimensional tibiofemoral and patellofemoral kinematics in loaded flexion in patients with varus deformity?Three-dimensional kinematics were assessed over 0° to 60° of loaded flexion using an MRI method before and after opening-wedge HTO in a cohort of 13 men (14 knees). Results obtained from an iterative statistical model found that at six and 12 months after operation, opening-wedge HTO caused increased anterior translation of the tibia (mean 2.6 mm, p < 0.001), decreased proximal translation of the patella (mean -2.2 mm, p < 0.001), decreased patellar spin (mean -1.4°, p < 0.05), increased patellar tilt (mean 2.2°, p < 0.05) and changed three other parameters. The mean Western Ontario and McMaster Universities Arthritis Index improved significantly (p < 0.001) from 49.6 (standard deviation (sd) 16.4) pre-operatively to a mean of 28.2 (sd 16.6) at six months and a mean of 22.5 (sd 14.4) at 12 months. The three-dimensional kinematic changes found may be important in explaining inconsistency in clinical outcomes, and suggest that measures in addition to coronal plane alignment should be considered.

Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a 'purely' psychotic illness without overt neurological symptoms. METHOD: We conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis. RESULTS: Seven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69-9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94-2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used. CONCLUSIONS: A minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.

First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.

BACKGROUND: Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). TREATMENT: gefitinib 250 mg day(-1) until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. RESULTS: Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7). CONCLUSION: First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable.

A multicentre, prospective, randomised comparison of the sliding hip screw with the Medoff sliding screw and side plate for unstable intertrochanteric hip fractures.

OBJECTIVE: This study aimed to compare the dynamic hip screw (DHS) and Medoff sliding plate (MSP) for unstable intertrochanteric hip fractures. DESIGN: A randomised, prospective trial design was used. SETTING: The study was undertaken in two level-1 trauma centres and one community hospital. PATIENTS/PARTICIPANTS: A total of 163 patients with unstable intertrochanteric hip fractures (Orthopaedic Trauma Association (OTA) 31-A2) were randomised to DHS or MSP. Inclusion and exclusion criteria were designed to focus on isolated unstable intertrochanteric hip fractures in ambulatory patients. INTERVENTION: Randomisation was performed intra-operatively, after placement of a 135° guide wire. Follow-up assessments were performed at regular intervals for a minimum of 6 months. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was re-operation rate. The secondary outcome was patient function, evaluated using a validated outcome measure, the Hip Fracture Functional Recovery Score. Tertiary outcomes included: mortality, hospital stay, quality of reduction and malunion rate. RESULTS: A total of 86 patients were randomised to DHS and 77 to MSP. The groups had similar patient demographics, pre-fracture status and in-hospital course. The quality of reduction was the same for each group, but the operative time was longer in the MSP group (61.6 vs. 50.1min, P=0.01). The rate of re-operation was low (3/86 in DHS and 2/77 in MSP) with no statistically significant difference. The functional outcomes were the same for both groups, with functional recovery scores at 6 months of 51.0% in the DHS arm and 49.7% in the MSP arm. CONCLUSIONS: The two techniques produced similar results for the clinically important outcomes of the need for further surgery and functional status of the patients at 6 months' follow-up.

Perforin-2 restricts growth of Chlamydia trachomatis in macrophages.

Chlamydia trachomatis is a Gram-negative obligate intracellular bacterium that preferentially infects epithelial cells. Professional phagocytes provide C. trachomatis only a limited ability to survive and are proficient killers of chlamydiae. We present evidence herein that identifies a novel host defense protein, perforin-2, that plays a significant role in the eradication of C. trachomatis during the infection of macrophages. Knockdown of perforin-2 in macrophages did not alter the invasion of host cells but did result in chlamydial growth that closely mirrored that detected in HeLa cells. C trachomatis L2, serovar B, and serovar D and C. muridarum were all equally susceptible to perforin-2-mediated killing. Interestingly, induction of perforin-2 expression in epithelial cells is blocked during productive chlamydial growth, thereby protecting chlamydiae from bactericidal attack. Ectopic expression of perforin-2 in HeLa cells, however, does result in killing. Overall, our data implicate a new innate resistance protein in the control of chlamydial infection and may help explain why the macrophage environment is hostile to chlamydial growth.

An evaluation study of EGFR mutation tests utilized for non-small-cell lung cancer in the diagnostic setting.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation is predictive for the efficacy of EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC) treatment. We evaluated the performance, sensitivity, and concordance between five EGFR tests. MATERIALS AND METHODS: DNA admixtures (n = 34; 1%-50% mutant plasmid DNA) and samples from NSCLC patients [116 formalin-fixed paraffin-embedded (FFPE) tissue, 29 matched bronchofiberscopic brushing (BB) cytology, and 20 additional pleural effusion (PE) cytology samples] were analyzed. EGFR mutation tests were PCR-Invader, peptide nucleic acid-locked nucleic acid PCR clamp, direct sequencing, Cycleave, and Scorpion Amplification Refractory Mutation System (ARMS). Analysis success, mutation status, and concordance rates were assessed. RESULTS: All tests except direct sequencing detected four mutation types at ≥1% mutant DNA. Analysis success rates were 91.4%-100% (FFPE) and 100% (BB and PE cytology), respectively. Inter-assay concordance rates of successfully analyzed samples were 94.3%-100% (FFPE; kappa coefficients: 0.88-1.00), 93.1%-100% (BB cytology; 0.86-1.00), and 85.0%-100% (PE cytology; 0.70-1.00), and 93.1%-96.6% (0.86-0.93) between BB cytology and matched FFPE. CONCLUSIONS: All EGFR assays carried out comparably in the analysis of FFPE and cytology samples. Cytology-derived DNA is a viable alternative to FFPE samples for analyzing EGFR mutations.

Liaison neurologists facilitate accurate neurological diagnosis and management, resulting in substantial savings in the cost of inpatient care.

BACKGROUND: Despite understaffing of neurology services in Ireland, the demand for liaison neurologist input into the care of hospital inpatients is increasing. This aspect of the workload of the neurologist is often under recognised. AIMS/METHODS: We prospectively recorded data on referral and service delivery patterns to a liaison neurology service, the neurological conditions encountered, and the impact of neurology input on patient care. RESULTS: Over a 13-month period, 669 consults were audited. Of these, 79% of patients were seen within 48 h and 86% of patients were assessed by a consultant neurologist before discharge. Management was changed in 69% cases, and discharge from hospital expedited in 50%. If adequate resources for neurological assessment had been available, 28% could have been seen as outpatients, with projected savings of 857 bed days. CONCLUSIONS: Investment in neurology services would facilitate early accurate diagnosis, efficient patient and bed management, with substantial savings.

The uptake and use of the Monospot test in patients with tonsillitis.

The objective of the study was to ascertain the uptake of the Monospot test in St. James's hospital in Dublin over the five years 2002-2006 and to determine the percentage of Monospot tests which had a positive result. Using the HIPE, Electronic Patient Record (EPR) and Patient Access System (PAS) databases in St. James's Hospital, a cohort of 593 patients with a diagnosis of tonsillitis or infectious mononucleosis was identified. Fourteen patients met the exclusion criteria as outlined below leaving a valid pool of 579 patients. It was ascertained whether each patient had a Monospot performed and if so, whether the result was positive or negative. In total, 249 (43.0%) of the included patients had a Monospot test. Of these, 197 (79.1%) were negative and 29 (11.6%) were positive. In 23 (9.2%) cases, no result was available. The uptake of the Monospot increased over the five years studied. A positive Monospot impacts on treatment and follow up. We therefore recommend that one is carried out in all patients presenting with acute tonsillitis.

Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment.

The purpose of this study was to determine whether primary breast cancer patients showed evidence of circulating tumour cells (CTCs) during follow-up as an alternative to monitoring disseminated bone marrow tumour cells (DTCs) by immunocytochemistry and reverse transcriptase (RT)-PCR for the detection of micrometastases. We planned to compare CTC and DTC frequency in low-risk and high-risk patients. We identified two cohorts of primary breast cancer patients who were at low (group II, T(1)N(0), n=18) or high (group III, >3 nodes positive (with one exception, a patient with two positive nodes) n=33) risk of relapse who were being followed up after primary treatment. We tested each cohort for CTCs using the CellSearch system on 1-7 occasions and for DTCs by immunocytochemistry and RT-PCR on 1-2 occasions over a period of 2 years. We also examined patients with confirmed metastatic disease (group IV, n=12) and 21 control healthy volunteers for CTCs (group I). All group I samples were negative for CTCs. In contrast, 7 out of 18 (39%) group II primary patients and 23 out of 33 (70%) group III patients were positive for CTCs (P=0.042). If we count only samples with >1 cell as positive: 2 out of 18 (11%) group II patients were positive compared with 10 out of 33 (30%) in group III (P=0.174). In the case of DTCs, 1 out of 13 (8%) group II patients were positive compared with 19 out of 27 (70%) in group III (P<0.001). Only 10 out of 33 (30%) patients in group III showed no evidence of CTCs in all tests over the period of testing, compared with 11 out of 18 (61%) in group II (P=0.033). A significant proportion of poor prognosis primary breast cancer patients (group III) have evidence of CTCs on follow-up. Many also have evidence of DTCs, which are more often found in patients who were lymph node positive. As repeat sampling of peripheral blood is more acceptable to patients, the measurement of CTCs warrants further investigation because it enables blood samples to be taken more frequently, thus possibly enabling clinicians to have prior warning of impending overt metastatic disease.

Antepartum bleeding of unknown origin in the second half of pregnancy and pregnancy outcomes.

OBJECTIVE: The purpose of our investigation was to evaluate factor(s) associated with unexplained antepartum bleeding of unknown origin (ABUO) after 24 weeks of pregnancy and correlate unexplained haemorrhage with maternal and perinatal outcomes. DESIGN: This is a retrospective observational study. SETTING: King Edward Memorial Hospital (KEMH), Subiaco, Western Australia. POPULATION: Singleton pregnancies delivering at KEMH between January 1998 and December 2004. METHODS: ABUO was defined as bleeding after 20 weeks of gestation but before the onset of labour with no cause detected on vaginal examination or abdominal ultrasound. Outcomes of these pregnancies were collated and compared with those of pregnancies without ABUO. MAIN OUTCOME MEASURES: Antepartum complications assessed included pre-eclampsia/eclampsia, gestational diabetes and preterm birth. Intrapartum evaluations included labour inductions, mode of delivery and gestational age at delivery. Neonatal outcomes evaluated included birthweight, Apgar scores, newborn intensive care unit (NICU) admission, neonatal complications and risk of perinatal/neonatal death. RESULTS: Between January 1998 and December 2004, there were 26 583 deliveries without ABUO and 1431 with ABUO. Multivariable analyses of the ABUO effects revealed that ABUO was a simultaneously significant risk factor for term labour inductions (OR = 2.00, 95% CI: 1.72-2.32, P < 0.001), preterm delivery (OR = 4.31, 95% CI: 3.84-4.84, P < 0.001), NICU admission (OR = 1.23, 95% CI: 1.01-1.51, P = 0.042), hyperbilirubinaemia (OR = 1.29, 95% CI: 1.01-1.63, P = 0.041) and reduced birthweight (26 g, 95% CI: 3-50, P = 0.026). CONCLUSION: Women with ABUO are at greater risk of preterm delivery, term labour induction and their neonates are at greater risk for NICU admissions, hyperbilirubinaemia and a reduced birthweight.

Persistence of Mycoplasma bovis infection in the mammary glands of lactating cows inoculated experimentally.

To study the course of clinical mycoplasma mastitis and investigate its potential for persistence, 10(8) colony-forming units (cfu) of an Irish isolate of Mycoplasma bovis was inoculated aseptically into the right fore teat canal of three lactating cows. M bovis rapidly colonised the infected quarters and grew exponentially to more than 10(10) cfu/ml within the first three days, and spread to other quarters of each of the three cows within five to 10 days. After periods of between 24 and 72 hours the infected quarters became distended and sensitive to touch, and their secretions changed from containing visible particles, to a seropurulent exudate, to an aqueous suspension of fine particles which formed a sediment after a sample was collected. M bovis-specific antibody levels increased to varying degrees in all three cows. Subsequently, the concentrations of mycoplasma decreased to less than 10(7) cfu/ml in two of the cows, but remained at more than 10(8) cfu/ml to the end of the lactation of the other cow. Apparently normal milk was secreted by one of the cows within a month of the challenge, and by the other two cows at the start of their next lactation. However, in two of the cows subclinical M bovis infection persisted through the dry periods and into their next lactations.

Complications following management of displaced intra-articular calcaneal fractures: a prospective randomized trial comparing open reduction internal fixation with nonoperative management.

OBJECTIVE: To report on all complications experienced by patients with displaced intra-articular calcaneal fractures (DIACFs) following nonoperative management or open reduction internal fixation (ORIF). DESIGN: Prospective, randomized, multicenter study. SETTING: Four level I trauma centers. PATIENTS: The patient population consisted of consecutive patients, age 17 to 65 at the time of injury, presenting to 1 of the centers with DIACFs between April 1991 and December 1998. INTERVENTIONS: Patients were randomized to the nonoperative treatment group or to operative reduction using a lateral approach to the calcaneus. MAIN OUTCOME MEASUREMENTS: Follow-up for patients was at 2 weeks, 6 weeks, 3 months, 12 months, 24 months, and once greater than 24 months following injury. At each follow-up interval, patients were assessed for the development of major and minor complications. After a minimum of 2-year follow-up, patients were asked to fill out a validated visual analogue scale questionnaire (VAS) and a general health review (SF-36). RESULTS: There were 226 DIACFs (206 patients) in the ORIF group with 57 of 226 (25%) fractures (57 of 206 patients [28%]) having at least 1 major complication. Of 233 fractures (218 patients) nonoperatively managed, 42 (18%) (42 of 218 patients [19%]) developed at least 1 major complication (indirectly resulting in surgery). CONCLUSION: Complications occur regardless of the management strategy chosen for DIACFs and despite management by experienced surgeons. Complications are a cause of significant morbidity for patients. Outcome scores in this study tend to support ORIF for calcaneal fractures. However, ORIF patients are more likely to develop complications. Certain patient populations (WCB and Sanders type IV) developed a high incidence of complications regardless of the management strategy chosen.

The IL12B 3' untranslated region DNA polymorphism is not associated with early-onset type 1 diabetes.

A recent study employing Australian and UK type 1 diabetes families has demonstrated significant transmission bias to affected offspring of a polymorphism (1188A allele; termed allele 1) in the 3' untranslated region (3'UTR) of the interleukin 12B (IL12B) gene which encodes the IL-12p40 subunit of the pro-inflammatory cytokine IL-12. However, results from replication studies in other populations have been controversial. We performed both case-control (n=120 cases; n=330 controls) and family-based (n=307 families) association studies, using the transmission disequilibrium test, to investigate if allele 1 is associated with early-onset type 1 diabetes in Northern Ireland. No association was observed between allele 1 and type 1 diabetes in either case-control (80.8% vs 80.8%; P=0.98) or family-based (49.7% transmissions; P=0.94) studies. Our results do not support earlier reports of an association between allele 1 in the 3'UTR of the IL12B gene and type 1 diabetes.

Possible association between CTLA4 DNA polymorphisms and early onset type 1 diabetes in a UK population.

Linkage and association has been reported between CTLA4 DNA markers and susceptibility to type 1 diabetes in some populations, but not others. We performed case-control and family-based association studies to assess if the CTLA4 A49G and intron 1 C/T polymorphisms were associated with development of early onset type 1 diabetes in the Northern Ireland population. The distribution of A49G and C/T alleles in cases (n = 144) was similar to those observed in controls (n = 307). In contrast, significant distortions in allele transmissions from informative parents to probands were observed for both the A49G (P = 0.02) and C/T (P = 0.01) polymorphisms employing 297 nuclear families. Our results suggest that the CTLA4 gene may play a minor role in the overall genetic predisposition to type 1 diabetes in this UK population.