Risk factors associated with progression to referable retinopathy: a type 2 diabetes mellitus cohort study in the Republic of Ireland.

AIM: To determine factors associated with progression to referable diabetic retinopathy in people with type 2 diabetes in the Republic of Ireland. RESEARCH DESIGN AND METHODS: The study was conducted in a dynamic cohort of 2770 people with type 2 diabetes, recruited between April 2005 and July 2013. Systemic factors (systolic and diastolic blood pressure, HbA1c , lipid levels, BMI) and baseline diabetic retinopathy grading results were evaluated at 4-monthly and yearly intervals, respectively. Associations between risk factors (most recently recorded value, and rate of change in value between pairs of consecutive systemic evaluations) and development of referable diabetic retinopathy were estimated using Cox proportional hazards models. RESULTS: There was a fourfold increased risk of progression to referral when retinopathy was present at baseline vs no retinopathy at baseline (hazard ratio 4.02, 95% CI 2.80-5.78; P<0.001). Higher current values of HbA1c (hazard ratio 1.22, 95% CI 1.11-1.34; P<0.001), systolic blood pressure (hazard ratio 1.29, 95% CI 1.15-1.45; P<0.001) and triglycerides (hazard ratio 1.10, 95% CI 1.03-1.18; P=0.004) were associated with increased risk of referral. Higher current BMI (hazard ratio 0.83, 95% CI 0.73-0.95; P=0.007) and diastolic blood pressure (hazard ratio 0.91, 95% CI 0.85-0.97; P=0.006) were associated with reduced risk of referral. CONCLUSIONS: Presence of retinopathy at baseline was strongly associated with increased risk of referral. Modest associations between systemic factors and risk of progression to referable retinopathy were detected.

An analysis of effects of heterozygosity in dairy cattle for bovine tuberculosis resistance.

Genetic selection of cattle more resistant to bovine tuberculosis (bTB) may offer a complementary control strategy. Hypothesising underlying non-additive genetic variation, we present an approach using genome-wide high density markers to identify genomic loci with dominance effects on bTB resistance and to test previously published regions with heterozygote advantage in bTB. Our data comprised 1151 Holstein-Friesian cows from Northern Ireland, confirmed bTB cases and controls, genotyped with the 700K Illumina BeadChip. Genome-wide markers were tested for associations between heterozygosity and bTB status using marker-based relationships. Results were tested for robustness against genetic structure, and the genotypic frequencies of a significant locus were tested for departures from Hardy-Weinberg equilibrium. Genomic regions identified in our study and in previous publications were tested for dominance effects. Genotypic effects were estimated through ASReml mixed models. A SNP (rs43032684) on chromosome 6 was significant at the chromosome-wide level, explaining 1.7% of the phenotypic variance. In the controls, there were fewer heterozygotes for rs43032684 (P < 0.01) with the genotypic values suggesting that heterozygosity confers a heterozygote disadvantage. The region surrounding rs43032684 had a significant dominance effect (P < 0.01). SNP rs43032684 resides within a pseudogene with a parental gene involved in macrophage response to infection and within a copy-number-variation region previously associated with nematode resistance. No dominance effect was found for the region on chromosome 11, as indicated by a previous candidate region bTB study. These findings require further validation with large-scale data.

Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis.

Tuberculosis (TB) caused by Mycobacterium bovis is a re-emerging disease of livestock that is of major economic importance worldwide, as well as being a zoonotic risk. There is significant heritability for host resistance to bovine TB (bTB) in dairy cattle. To identify resistance loci for bTB, we undertook a genome-wide association study in female Holstein-Friesian cattle with 592 cases and 559 age-matched controls from case herds. Cases and controls were categorised into distinct phenotypes: skin test and lesion positive vs skin test negative on multiple occasions, respectively. These animals were genotyped with the Illumina BovineHD 700K BeadChip. Genome-wide rapid association using linear and logistic mixed models and regression (GRAMMAR), regional heritability mapping (RHM) and haplotype-sharing analysis identified two novel resistance loci that attained chromosome-wise significance, protein tyrosine phosphatase receptor T (PTPRT; P=4.8 × 10(-7)) and myosin IIIB (MYO3B; P=5.4 × 10(-6)). We estimated that 21% of the phenotypic variance in TB resistance could be explained by all of the informative single-nucleotide polymorphisms, of which the region encompassing the PTPRT gene accounted for 6.2% of the variance and a further 3.6% was associated with a putative copy number variant in MYO3B. The results from this study add to our understanding of variation in host control of infection and suggest that genetic marker-based selection for resistance to bTB has the potential to make a significant contribution to bTB control.

Buried or unburied K-wires for lateral condyle elbow fractures.

INTRODUCTION: Lateral humeral condyle fractures typically require a longer period of internal fixation than other distal humeral fractures due to the increased risk of non-union. K-wires can be buried and left in situ until union or they can be left unburied and require removal after four weeks, with plaster immobilisation until union. There is no consensus as to whether wire burial is preferable or not. The aim of this study was to determine whether K-wire burial is associated with more complications than non-buried wires in treating lateral condyle fractures of the elbow. METHODS: All patients with lateral humeral condyle fractures treated with K-wire fixation at our institution from May 2008 to August 2011 were included in the study. Fracture configuration, mode of reduction, wire burial and complications were assessed. RESULTS: Sixty-seven patients (19 girls and 48 boys, mean age: 6.5 years, range: 1-17 years) were included in the study. All had closed injuries and were treated with open reduction and K-wire fixation. K-wires were buried in 55 patients. Thirteen cases of buried wires eroded through skin and were removed on average 45 days (range: 30-58 days) post-operatively. Of the wire erosion cases, three developed microbiologically proven infections, one of which was a deep infection. There were a further three superficial wound infections in the absence of wire erosion through the skin. There were complications in 2 of the 12 cases in the unburied wires group: 1 microbiologically proven superficial wire site infection and 1 wire backed out after 11 days, requiring refixation. CONCLUSIONS: Wire erosion through the skin is the most common complication of K-wire burial. This may be due to the decrease in swelling after fracture fixation, making the wires more prominent under the skin. Skin integrity should be monitored closely if wires are buried.

Current practice in bowel preparation for colorectal surgery: a survey of the members of the Association of Coloproctology of GB & Ireland.

AIM: Recent meta-analyses have suggested that mechanical bowel preparation is not beneficial in patients undergoing colorectal resection. This study aimed to assess current surgical practice in the UK. METHOD: Three hundred and ninety-eight members of the Association of Coloproctology of GB & Ireland were invited to complete an online survey to ascertain their current practice for bowel preparation. RESULTS: One hundred and ninety-nine surgeons completed the survey, of whom 95 (48%) routinely performed laparoscopic resection. The proportions using full bowel preparation for open vs laparoscopic surgery were, respectively, 9.5%vs 16.8% for right hemicolectomy, 43.4%vs 40.2% for left hemicolectomy, 20.5%vs 22.5% for an abdominoperineal resection and 72.2%vs 63.6% for low anterior resection. Among the surgeons who participated, 13.6% changed their practice between doing the same procedure open and laparoscopically, 76% of surgeons routinely defunctioned a low anterior resection. Of these, 22% did not feel that full bowel preparation was necessary before formation of an ileostomy. CONCLUSION: The study demonstrates that a large proportion of patients still receive full bowel preparation despite recent advice to the contrary.

Hydroxyapatite nano and microparticles: correlation of particle properties with cytotoxicity and biostability.

Synthetic colloid and gel hydroxyapatite (HA) nanoparticles (NPs) were spray dried to form microparticles (MPs). These are intended for use as slow release vaccine vectors. The physico-chemical properties of gel and colloid NPs and MPs were compared to those of HA obtained commercially. Their cytotoxicity to human monocytes'-derived macrophages (HMMs) was assessed in vitro using a range of techniques. These included the MTT assay, LDH leakage and a confocal based live-dead cell assay. Cytotoxicity differed significantly between preparations, with the suspended gel preparation being the most toxic (31-500 microg/ml). Other preparations were also toxic but only at higher concentrations (>250 microg/ml). Transmission electron microscopy (TEM) and stereology showed variable cellular uptake and subsequent dissolution of the various forms of HA. We have demonstrated that HA particle toxicity varied considerably and that it was related to their physico-chemical properties. Cell death correlated strongly with particle load. The intracellular dissolution of particles as a function of time in HMM suggests that increased cytoplasmic calcium load is likely to be the cause of cell death. Some HA NPs eluded the phagocytic pathway and a few were even seen to enter the nuclei through nuclear pores.

Chemotherapy induced carcinoma-adenoma regression in the caecum.

The case of a male patient with synchronous oesophago-gastric junction (OGJ) and caecal adenocarcinomas is reported. His management is described, particularly the administration of neoadjuvant chemotherapy targeting his upper gastrointestinal cancer. Synchronous gastrectomy and hemicolectomy were performed. Histopathological examination of the surgical specimen confirmed the OGJ cancer but only identified a caecal adenoma. This is believed to be the first description of chemotherapy induced reversal of the adenoma-carcinoma sequence.

Defunctioning stomas in patients with locally advanced rectal cancer prior to preoperative chemoradiotherapy.

OBJECTIVE: A literature search did not produce any evidence-based objective criteria to determine which patients with locally advanced rectal cancer would benefit from a defunctioning stoma prior to neoadjuvant chemoradiotherapy. Our criteria for formation of a defunctioning stoma are: faecal incontinence and inability to cannulate the tumour at colonoscopy. The aim of this study was to examine whether these current criteria are appropriate. METHOD: Forty-nine consecutive locally advanced rectal cancer patients treated from February 2003 to November 2006 were identified from our colorectal database. All received long-course chemoradiotherapy (Bossett regimen) and definitive surgery was performed 6-8 weeks later. RESULTS: Of the 49 patients, 31 presented with diarrhoea and two with faecal incontinence; nine patients were defunctioned by trephine stoma prior to treatment [cannulation impossible at colonoscopy (n = 8); faecal incontinence (n = 1)]. One patient with faecal incontinence refused early defunctioning stoma. Median hospital stay was 12 days (interquartile range: 7-30), and complications included pneumonia (n = 1) and peristomal cellulitis (n = 2). Of the 40 patients who went directly to neoadjuvant chemoradiotherapy, two subsequently required a defunctioning stoma for severe diarrhoeal symptoms during therapy. Eight patients had worsening diarrhoeal symptoms but tolerated treatment. Three patients, who had stoma formation, did not proceed to definitive surgery following neoadjuvant therapy: poor operative fitness (n = 2) and disease progression (n = 1). CONCLUSION: Stenosis causing inability to cannulate the tumour at colonoscopy and faecal incontinence were the only objective indications for an early defunctioning stoma. Worsening diarrhoea during therapy (unless severe) did not appear to be a good indication for a defunctioning stoma.

The use of orthopaedic POSSUM as an audit tool for fractured neck of femur.

In this prospective study, 230 patients who were operated on for a fractured neck of femur were evaluated using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM). We observed 25 deaths (10.9%) and 95 patients had a post-operative complication (41.3%). The orthopaedic POSSUM equations yielded an overall predicted mortality of 21 patients and morbidity in 106 patients. This gave observed to expected (O:E) ratios of 1.19 and 0.95 respectively meaning that POSSUM agreed well with the observed mortality and morbidity. We concluded that POSSUM accurately predicts mortality and morbidity in patients with femoral neck fractures and when used as an audit tool would provide a fairer system of comparison and would allow an unbiased interpretation of results when changes in patient management are made.

Spontaneous vacuum phenomenon in the lateral compartment of the knee associated with a lateral tibial plateau fracture.

A case of spontaneous vacuum phenomenon in the lateral compartment of the knee is presented in an 83-year-old woman who attended the Accident and Emergency department two weeks after a twisting injury to the left knee. At the time of examination she still had a marked effusion in the knee with lateral joint line tenderness. X-rays showed a lateral tibial plateau fracture involving the entire lateral condyle and extending into the opposite compartment beneath the intercondylar eminence. The X-rays also demonstrated the presence of gas in the lateral joint line. This is the first reported case of vacuum phenomenon occurring on the same side as a lateral tibial plateau fracture. It is also demonstrated that the phenomenon may occur in the presence of an effusion.

A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial.

OBJECTIVE: To compare two new generation antimuscarinics at their recommended doses for treatment of overactive bladder syndrome (OAB). METHODS: A prospective, double blind, double-dummy, two-arm, parallel-group, 12-week study was conducted to compare the efficacy and safety of solifenacin 5 or 10 mg and tolterodine extended release (ER) 4 mg once daily in OAB patients. After 4 weeks of treatment patients had the option to request a dose increase but were dummied throughout as approved product labelling only allowed an increase for those on solifenacin. RESULTS: Solifenacin, with a flexible dosing regimen, showed greater efficacy to tolterodine in decreasing urgency episodes, incontinence, urge incontinence and pad usage and increasing the volume voided per micturition. More solifenacin treated patients became continent and reported improvements in perception of bladder condition assessments. The majority of side effects were mild to moderate in nature, and discontinuations were comparable and low in both groups. CONCLUSIONS: Solifenacin, with a flexible dosing regimen, was found to be superior to tolterodine ER with respect to the majority of the efficacy variables.

Carcinogenic potential of commonly used hernia repair prostheses in an experimental model.

BACKGROUND: The purpose of this study was to assess the carcinogenic potential of commonly used hernia repair prostheses in an animal model. METHODS: Three types of prosthetic material (monofilament polypropylene, multifilament polypropylene and expanded polytetrafluoroethylene) were implanted in CBA/H mice. Flat (1 cm(2)) and rolled pieces of the same material were placed subcutaneously in either flank, and a further flat piece was placed in the preperitoneal space. Owing to a high incidence of mesh extrusion in the polypropylene groups, the study protocol was modified to allow only preperitoneal placement of the material. A fourth, control, group had the pockets for the prostheses created but no material implanted. After modification of the protocol there were approximately 60 mice in each group. The mice were followed for 2 years, then killed and assessed histologically for tumour development. RESULTS: No sarcoma developed at the site of mesh implantation in any of the groups. CONCLUSION: This study indicates that the risk of sarcoma formation at the site of hernia repair prostheses is very low.

Role of Ca(2+) for the mechanical properties of fibrillin.

Fibrillin-rich microfibrils are important structural elements widespread throughout connective tissues. Genetic defects identified in the Ca(2+) binding sites of fibrillin have severe effects and in addition Ca(2+) has a marked effect on the microfibrillar structure. We have studied the role of Ca(2+) on the mechanical behavior of fibrillin-rich microfibrils using the micro-needle technique. We find that Ca(2+)-depletion results in a 50% decrease in rest length and reduces the stiffness of fibrillin-rich microfibrils. At high strain, irreversible damage occurs. This behavior is consistent with Ca(2+) stabilization of interactions between consecutive EGF-like domains and breakdown in the quaternary structure upon over-extension.

Evading detection on the MMPI-2: does caution produce more realistic patterns of responding?

Studies on MMPI and MMPI-2 malingering indexes often sacrifice generalizability in an attempt to control internal validity. This study improves external validity while still maintaining internal validity by providing graduate student participants with a realistic context for malingering on the MMPI-2 (n=94) and MMPI (n=30). Contextual parameters include a realistic life predicament, psychological knowledge, an incentive, the presence versus absence of a specific diagnosis, and a caution to be realistic. This study found that cautioning participants not to overexaggerate their responses significantly improves their ability to evade detection on the MMPI-2 and MMPI. Standard malingering indexes (Infrequency, F; Back Side, F, Fb; F-Correction, F-K; and Infrequency-Psychopathology, F(p)) were insufficiently sensitive in identifying simulators using common cutoff scores for these cautious simulators.

Case series: amantadine open-label treatment of impulsive and aggressive behavior in hospitalized children with developmental disabilities.

OBJECTIVE: A growing body of literature implicates interactions between glutamatergic and neostriatal dopaminergic neurotransmitter systems in the development and expression of impulsivity, hyperactivity, and stereotypy. Amantadine hydrochloride, a drug used in young children for influenza prophylaxis, acts both as an indirect dopamine agonist as well as an N-methyl-D-aspartate (NMDA) receptor antagonist. Thus an open clinical trial of this medication for the treatment of symptoms of impulse control disorders in children was performed. METHOD: A total of eight children (seven with neurodevelopmental disorders and all inpatients) with target behaviors refractory to other treatments were selected after parental informed consent. All patients were male and ranged in age from 4 to 12 years. Outcome was based on subjective consensus clinical ratings by the multidisciplinary treatment team. RESULTS: For four of the children, amantadine was associated with marked clinical improvement. In the remainder, improvement was also observed. Amantadine was well tolerated. CONCLUSIONS: On the basis of this experience, it appears that amantadine hydrochloride or related NMDA antagonists may warrant additional study in this and related populations.

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder.

OBJECTIVE: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.