Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that, in addition to motor, sensory, and cognitive symptoms, also causes constipation, which is poorly understood. Here, we characterize gastrointestinal (GI) dysmotility in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and evaluate whether autoantibodies target the enteric nervous system (ENS) and cause dysmotility. METHODS: EAE was induced in male SJL and B6 mice. GI motility was assessed in vivo and ex vivo in wild type (WT) and B cell-deficient mice. MS and EAE serum was used to survey potential targets in the ENS and changes in the ENS structure were characterized using immunohistochemistry. KEY RESULTS: EAE mice developed accelerated gastric emptying and delayed whole GI transit with reduced colonic motility. Fecal water content was reduced, and colonic migrating myoelectrical complexes (CMMC) and slow waves were less frequent. Colons from EAE mice exhibited decreased GFAP levels in glia. Sera from MS patients and from EAE mice targeted ENS neurons and glia. B-cell deficiency in EAE protected against colonic dysmotility. CONCLUSIONS & INFERENCES: Consistent with symptoms experienced in MS, we demonstrate that EAE mice widely exhibit features of GI dysmotility that persisted in the absence of extrinsic innervation, suggesting direct involvement of ENS neurocircuitry. The absence of GI dysmotility in B cell-deficient mice with EAE together with EAE and MS serum immunoreactivity against ENS targets suggests that MS could be classified among other diseases known to induce autoimmune GI dysmotility.

In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines.

Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 µM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 µM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 µM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 µM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection.

A new synthetic route to in-chain metallopolymers via copper(i) catalyzed azide-platinum-acetylide iClick.

The first example of an in-chain metallo-poly(triazolate) synthesized by CuAAC is reported. Azido-platinum-acetylide (A-M-B) monomers are catalytically polymerized with copper(i) acetate to yield 1,2,3-triazolate linked Pt(ii) units. The metallopolymers are characterized by multinuclear NMR, IR, UV/Vis, GPC, and MS.

A decision tool for whole-body CT in major trauma that safely reduces unnecessary scanning and associated radiation risks: An initial exploratory analysis.

BACKGROUND: Whole-body CT (WBCT) has become routine practice in the assessment of major trauma patients. Whilst this may be associated with increased survival, several studies report high rates of negative scans. As no national guideline exists, selection criteria for WBCT vary widely. This study aims to (1) produce a scoring system that improves patient selection for WBCT (2) quantify patient radiation doses and their concomitant risk of malignancy. METHODS: Clinical notes were reviewed for all patients undergoing a WBCT for trauma over a 21-month period at a UK major trauma centre. Clinical and radiological findings were categorised according to body region. Univariate analysis was performed using Chi-squared testing, followed by multivariable logistic regression. Secondary regression analysis of patients with significant injuries that the model did not identify was performed. The model was optimised and used to develop a scoring system. Sensitivity and specificity were calculated using the same dataset as was used to derive the models. Radiation exposure was determined and the excess lifetime risk of malignancy calculated. RESULTS: 255 patients were included, with a mean age of 45 years. 16% of scans were positive for polytrauma, 42% demonstrated some injury and 42% showed no injury. The regression model identified independent predictors of polytrauma to be (1) clinical signs in more than one body region, (2) reduced Glasgow Coma Score, (3) haemodynamic abnormality, (4) respiratory abnormality, (5) mechanism of injury. The final model had a sensitivity of 95% (95% CI 86-99%) and specificity of 59% (95% CI 52-66%) for significant CT findings. Mean radiation exposure was 31.8 mSv, conferring a median excess malignancy risk of 1 in 474. CONCLUSION: After including neurological deficit, our scoring system had a sensitivity of 97% (95% CI 88-99%) and specificity of 56% (95% CI 49-64%) for significant injury. We propose this is used to stratify the use of trauma radiographs, focused CT and WBCT for major trauma patients. Although not intended to replace clinical judgement, our scoring system adds an objective component to decision-making. We believe this will safely reduce the number of unnecessary CT scans performed on a relatively young cohort of patients.

A comparison of interview methods to ascertain fluoroquinolone exposure before tuberculosis diagnosis.

SUMMARY Fluoroquinolone use before tuberculosis (TB) diagnosis delays the time to diagnosis and treatment, and increases the risk of fluoroquinolone-resistant TB and death. Ascertainment of fluoroquinolone exposure could identify such high-risk patients. We compared four methods of ascertaining fluoroquinolone exposure in the 6 months prior to TB diagnosis in culture-confirmed TB patients in Tennessee from January 2007 to December 2009. The four methods included a simple questionnaire administered to all TB suspects by health department personnel (FQ-Form), an in-home interview conducted by research staff, outpatient and inpatient medical record review, and TennCare pharmacy database review. Of 177 TB patients included, 72 (41%) received fluoroquinolones during the 6 months before TB diagnosis. Fluoroquinolone exposure determined by review of inpatient and outpatient medical records was considered the gold standard for comparison. The FQ-Form had 61% [95% confidence interval (CI) 48-73] sensitivity and 93% (95% CI 85-98) specificity (agreement 79%, kappa = 0.56) while the in-home interview had 28% (95% CI 18-40) sensitivity and 99% (94-100%) specificity (agreement 68%, kappa = 0.29). A simple questionnaire administered by health department personnel identified fluoroquinolone exposure before TB diagnosis with moderate reliability.

Litigation relating to conditions affecting the shoulder and elbow: an analysis of claims against the National Health Service.

We present a review of claims made to the NHS Litigation Authority (NHSLA) by patients with conditions affecting the shoulder and elbow, and identify areas of dissatisfaction and potential improvement. Between 1995 and 2012, the NHSLA recorded 811 claims related to the shoulder and elbow, 581 of which were settled. This comprised 364 shoulder (64%), and 217 elbow (36%) claims. A total of £18.2 million was paid out in settled claims. Overall diagnosis, mismanagement and intra-operative nerve injury were the most common reasons for litigation. The highest cost paid out resulted from claims dealing with incorrect, missed or delayed diagnosis, with just under £6 million paid out overall. Fractures and dislocations around the shoulder and elbow were common injuries in this category. All 11 claims following wrong-site surgery that were settled led to successful payouts. This study highlights the diagnoses and procedures that need to be treated with particular vigilance. Having an awareness of the areas that lead to litigation in shoulder and elbow surgery will help to reduce inadvertent risks to patients and prevent dissatisfaction and possible litigation.

Public Health England survey of eye lens doses in the UK medical sector.

The ICRP has recently recommended that the occupational exposure limit for the lens of the eye be reduced to 20 mSv in a year, averaged over defined periods of 5 years, with no single year exceeding 50 mSv. There has been concern amongst some groups of individuals, particularly interventional cardiologists and radiologists as well as relevant professional bodies, that implementation of these recommendations into UK law will adversely affect working patterns. However, despite a number of informative European studies, there is currently little UK dosimetry data available upon which judgements can effectively be based. In order to address this knowledge gap, Public Health England has carried out a small, targeted survey of UK lens doses to medical staff undertaking procedures likely to involve the highest levels of radiation exposure. Two out of a total of 61 individuals surveyed had projected annual doses which could be close to 20 mSv, measured outside lead glasses. Use of protective equipment was generally good; however, lead glasses were only used by 9 participants. The results of this survey suggest that compliance with the ICRP recommendations is likely to be possible for most individuals in the UK medical sector.

A cross-sectional study of mental health in UK veterinary undergraduates.

Wellbeing (positive mental health) and mental ill-health of veterinary students from a single UK school were quantified using validated psychological scales. Attitudes towards mental ill-health and suicide were also assessed. Results were compared with published data from the UK general population and veterinary profession. Of the total student population (N=1068), 509 (48 per cent) completed a questionnaire. Just over half (54 per cent) of the respondents had ever experienced mental ill-health, with the majority reporting a first occurrence before veterinary school. Student wellbeing was significantly poorer (p<0.0001) than general population estimates, but not significantly different (p=0.2) from veterinary profession estimates. Degree of mental distress in students was significantly higher than in the general population (p<0.0001). Despite the majority (94 per cent) agreeing that 'Anyone can suffer from mental health problems', students were significantly more likely than members of the general population to agree that 'If I were suffering from mental health problems, I wouldn't want people knowing about it' (p<0.0001). Students were more likely to have thought about suicide, but less likely to have made an attempt (p<0.001; p=0.005), than members of the general population. The possibility of non-response bias must be considered when interpreting findings. However, strong similarities between results from this study population and the UK veterinary profession, as well as other veterinary student populations internationally, suggest no substantial school-level bias.

Fluoroquinolone exposure prior to tuberculosis diagnosis is associated with an increased risk of death.

SETTING: Fluoroquinolone (FQ) exposure before tuberculosis (TB) diagnosis is common, but its effect on outcomes, including mortality, is unclear. DESIGN: Among TB patients reported to the Tennessee Department of Health from 2007 to 2009, we assessed FQ exposure within 6 months before TB diagnosis. The primary outcome was the combined endpoint of death at the time of TB diagnosis and during anti-tuberculosis treatment. RESULTS: Among 609 TB cases, 214 (35%) received FQs within 6 months before TB diagnosis. A total of 71 (12%) persons died; 10 (2%) were dead at TB diagnosis and 61 (10%) died during anti-tuberculosis treatment. In multivariable logistic regression analysis, factors independently associated with death were older age (OR 1.05 per year, 95%CI 1.04-1.07), human immunodeficiency virus infection (OR 8.08, 95%CI 3.83-17.06), US birth (OR 3.03, 95%CI 1.03-9.09), and any FQ exposure before TB diagnosis (OR 1.82, 95%CI 1.05-3.15). Persons with FQ exposure before TB diagnosis were more likely to have culture- and smear-positive disease than unexposed persons. CONCLUSIONS: Among this patient population, FQ exposure before TB diagnosis was associated with an increased risk of death. These findings underscore the need for cautious use of FQs in persons with possible TB.

Associated comorbidities in psoriasis and inflammatory bowel disease.

BACKGROUND: The association between psoriasis and inflammatory bowel disease (IBD) has been previously reported although a great deal remains unknown about associated comorbidities. OBJECTIVES: The aim of this study was to examine comorbidities in individuals diagnosed with both psoriasis and IBD, and to compare those with individuals diagnosed with psoriasis-only. We also looked at differences within the IBD group by clearly defining that cohort. METHODS: We included 146 patients diagnosed with both psoriasis and IBD and 146 controls diagnosed of psoriasis-only without previous records of IBD, matched by gender, ethnicity and age (±5 years). Patients were obtained from the research patient data repository of Brigham and Women's Hospital (BWH) and Massachusetts General Hospital. Controls were obtained from the psoriatic arthritis and psoriasis follow-up study (PAFS) at BWH. The comparison between the two groups included socio-demographics, comorbidities and laboratory inflammation parameters. RESULTS: Compared to individuals with psoriasis-only, patients with both psoriasis and IBD had significantly higher rates of autoimmune thyroiditis (2.1% vs. 6.8%), hepatitis (0.7 vs. 6.2%) and diabetes (11.0% vs. 26.7%). In addition, of the 146 patients with psoriasis and IBD, 60 (41.1%) were diagnosed with seronegative arthritis. The average C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) of the last visits in our clinics were significantly elevated compared to the individuals with psoriasis-only (ESR, 33.5 vs. 4.0 mm/h; CRP, 9.1 vs. 2.3 mg/L; both P-values <0.0001). CONCLUSIONS: We found that patients with both, psoriasis and IBD have a number of further associated comorbidities, some at significantly higher levels than individuals with psoriasis-only. Common inflammatory pathways and genetic predispositions for specific patterns in the immune response may play an important role in the evolution of associated conditions.

Polymyositis following Vogt-Koyanagi-Harada-like syndrome in a Jack Russell terrier.

A male Jack Russell terrier developed bilateral uveitis and glaucoma at 1 year of age. Since the ocular disease was painful and unresponsive to treatment, both globes were enucleated. Microscopical evaluation of one enucleated globe revealed panuveitis, with pigment dispersion and phagocytosis consistent with the ocular lesions of canine Vogt-Koyanagi-Harada (VKH)-like syndrome. Three years later the dog was represented with severe muscle disease and skin lesions. Due to rapid clinical deterioration the dog was humanely destroyed. Necropsy examination revealed lichenoid interface inflammation in the skin and mucous membranes, with pigmentary incontinence consistent with VKH-like syndrome and lymphocytic and histiocytic polymyositis with marked muscle atrophy. Canine VKH-like syndrome is an autoimmune disease that targets melanocyte antigens. Some human patients with VKH disease develop additional autoimmune diseases. To our knowledge this is the first reported case of polymyositis subsequent to VKH-like disease in a dog. In addition, VKH-like disease has not been previously reported in a Jack Russell terrier.

Development and pilot-testing of a psoriasis screening tool.

BACKGROUND: There is a need to validate psoriasis self-reports in epidemiological studies, where individuals may not be seeing dermatologists or other health care providers. OBJECTIVES: To develop and pilot test the Psoriasis Screening Tool (PST) in an ambulatory setting. PATIENTS AND METHODS: The PST was designed with eight closed-ended questions requiring a 'yes' or 'no' response. Typical images of skin, nail and scalp changes in psoriasis were included with respective questions. We administered the PST to 222 consecutive individuals being seen at a dermatology clinic. All English-speaking subjects completed the PST without assistance. A board-certified dermatologist established the diagnosis of psoriasis or excluded psoriasis in all participants. RESULTS: A total of 222 completed PST questionnaires were included for analysis. There were 111 individuals in the psoriasis group and 111 individuals in the nonpsoriasis group. A combination of three questions resulted in a sensitivity of 96.4% [95% confidence interval (CI) 93.2-98.0] and specificity of 97.3% (95% CI 94.1-98.9) for psoriasis. Adding a pictorial question increased the sensitivity of the screening tool to 98.2% (95% CI 95.0-99.5). Of the 111 individuals with psoriasis, 69% answered yes to having plaque-type psoriasis, 50% answered yes to having nail involvement, 66% answered yes to having scalp involvement, and 59% answered yes to having inverse-type psoriasis. CONCLUSIONS: This pilot study suggests that the PST can distinguish individuals with psoriasis from individuals without psoriasis in an English-speaking population being seen at an outpatient dermatology clinic. Furthermore, the PST may be used to identify psoriasis phenotypes. Although the PST may be limited by spectrum bias in this pilot study, we believe it remains a reliable tool to collect information on psoriasis in remote populations.

Chromium, cobalt and titanium metallosis involving a Nottingham shoulder replacement.

Metallosis after shoulder replacement has not previously been described in the literature. We report a patient who developed extensive metallosis after implantation of an uncemented Nottingham shoulder replacement. He underwent a revision procedure. Examination of the retrieved prosthesis showed that the titanium porous coating was separating from the humeral stem and becoming embedded in the ultra-high-molecular-weight polyethylene glenoid component, resulting in abrasive wear of the humeral component. There was metallosis despite exchange of the modular humeral head. Both components had to be exchanged to resolve the problem.

Ogilvie's syndrome: a case report.

OBJECTIVE: Ogilvies syndrome (OS) is a rare condition in obstetrics but occurs most commonly after caesarean section. Mortality rates from OS can be as high as 36-50% when bowel perforation or ischemia develops which highlights the early recognition of this condition. Early diagnosis is therefore essential to prevent serious morbidity and mortality. CONCLUSION: We, therefore report a case of OS after caesarean section in which early detection by senior clinicians resulted in successful management of the condition and an excellent outcome.

The impact of spirometry on pediatric asthma diagnosis and treatment.

Research has shown that spirometry is underutilized in the clinical setting. This study profiles the use of spirometry in an asthma management program at an inner-city community health clinic. Eligible subjects included 56 children who presented with an acute asthma exacerbation. Physicians recorded patient diagnosis before and after viewing spirometry. Bivariate and multivariate analysis was used to determine associations between symptoms and forced expiratory volume in 1 second (FEV1). Physicians changed 30.4% of patients' treatment plans after viewing spirometry results. Wheezing was significantly associated with FEV1 in bivariate analysis; however, multivariate modeling failed to identify significant relationships. The use of spirometry influenced patient diagnosis and treatment.

Tension free vaginal tape: is the intra-operative cough test necessary?

The tension-free vaginal tape (TVT) procedure is recognised as an effective treatment for genuine stress incontinence. It was first described using local anaesthesia, with an intra-operative cough test helping to correctly position the tape. Many patients prefer general anaesthesia and often, patients with genuine stress incontinence do not leak when supine. This aim of this study was to compare the outcome in TVTs performed under general anaesthesia with those performed under spinal anaesthesia. Retrospective analysis of 105 patients, all of whom had urodynamically proven genuine stress incontinence and underwent TVT procedure, was performed: 52 under spinal anaesthesia and 53 under general anaesthesia. The primary and secondary outcome measures were the success or failure of the procedure and the complication rate, respectively. There was no significant difference in outcome or complication rate between the two groups. The type of anaesthetic used does not influence the outcome and we question the necessity of an intra-operative cough test.

Inheritance, biochemical abnormalities, and clinical features of feline mucolipidosis II: the first animal model of human I-cell disease.

Mucolipidosis II (ML II), also called I-cell disease, is a unique lysosomal storage disease caused by deficient activity of the enzyme N-acetylglucosamine-1-phosphotransferase, which leads to a failure to internalize enzymes into lysosomes. We report on a colony of domestic shorthair cats with ML II that was established from a half-sibling male of an affected cat. Ten male and 9 female kittens out of 89 kittens in 26 litters born to clinically normal parents were affected; this is consistent with an autosomal recessive mode of inheritance. The activities of three lysosomal enzymes from affected kittens, compared to normal adult control cats, were high in serum (11-73 times normal) but low in cultured fibroblasts (9-56% of normal range) that contained inclusion bodies (I-cells), reflecting the unique enzyme defect in ML II. Serum lysosomal enzyme activities of adult obligate carriers were intermediate between normal and affected values. Clinical features in affected kittens were observed from birth and included failure to thrive, behavioral dullness, facial dysmorphia, and ataxia. Radiographic lesions included metaphyseal flaring, radial bowing, joint laxity, and vertebral fusion. In contrast to human ML II, diffuse retinal degeneration leading to blindness by 4 months of age was seen in affected kittens. All clinical signs were progressive and euthanasia or death invariably occurred within the first few days to 7 months of life, often due to upper respiratory disease or cardiac failure. The clinical and radiographic features, lysosomal enzyme activities, and mode of inheritance are homologous with ML II in humans. Feline ML II is currently the only animal model in which to study the pathogenesis of and therapeutic interventions for this unique storage disease.