Diazepam induced sleep spindle increase correlates with cognitive recovery in a child with epileptic encephalopathy.

BACKGROUND: Continuous spike and wave of sleep with encephalopathy (CSWS) is a rare and severe developmental electroclinical epileptic encephalopathy characterized by seizures, abundant sleep activated interictal epileptiform discharges, and cognitive regression or deceleration of expected cognitive growth. The cause of the cognitive symptoms is unknown, and efforts to link epileptiform activity to cognitive function have been unrevealing. Converging lines of evidence implicate thalamocortical circuits in these disorders. Sleep spindles are generated and propagated by the same thalamocortical circuits that can generate spikes and, in healthy sleep, support memory consolidation. As such, sleep spindle deficits may provide a physiologically relevant mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies. CASE PRESENTATION: We describe the longitudinal course of a child with CSWS with initial cognitive regression followed by dramatic cognitive improvement after treatment. Using validated automated detection algorithms, we analyzed electroencephalograms for epileptiform discharges and sleep spindles alongside contemporaneous neuropsychological evaluations over the course of the patient's disease. We found that sleep spindles increased dramatically with high-dose diazepam treatment, corresponding with marked improvements in cognitive performance. We also found that the sleep spindle rate was anticorrelated to spike rate, consistent with a competitively shared underlying thalamocortical circuitry. CONCLUSIONS: Epileptic encephalopathies are challenging electroclinical syndromes characterized by combined seizures and a deceleration or regression in cognitive skills over childhood. This report identifies thalamocortical circuit dysfunction in a case of epileptic encephalopathy and motivates future investigations of sleep spindles as a biomarker of cognitive function and a potential therapeutic target in this challenging disease.

Psychotropic medications use and side effects of individuals with intellectual and developmental disabilities.

BACKGROUND: Many people with intellectual and developmental disabilities (IDD) are treated with psychotropic medications, and polypharmacy is common. Although few studies address psychotropic side effects in the population, people with IDD have been found more likely to experience side effects than others who do not have IDD. Because many individuals with IDD may not report side effects reliably, there is risk that side effects may be missed. METHODS: Psychotropic use and side effects of 71 adults with IDD admitted for a 30-day crisis stay to a Systemic, Therapeutic, Assessment, Resources, and Treatment (START) Resource Center were reviewed. START is a specialised behavioural health outreach, training and crisis programme for individuals with IDD. During crisis stays, centre nurses administer the Matson Evaluation of Drug Side Effects screen, a psychometrically established psychotropic medication side effects screen developed for use with people with IDD. Data reviewed were de-identified data used to inform day-to-day practices and assess outcomes for individuals START served. RESULTS: The average age was 28 years, and 56% of the sample was male. All individuals were taking at least one psychotropic, while 79% were taking three or more. The average number of psychotropics used was 3.94. Antipsychotics were the most commonly prescribed medications taken by 85% of the sample; 49% of whom were not reported to have psychosis. Although the overall number of psychotropics did not correlate with Matson Evaluation of Drug Side Effects scores, the average scale scores for all participants was high in contrast to prior studies of people with IDD not taking psychotropics, with central nervous system side effects being the most commonly reported. CONCLUSION: In the present study, data for individuals experiencing a crisis were reviewed and indicated high rates of psychotropic polypharmacy and side effects rates higher than previously reported for people with IDD not taking psychotropics. Prospective study in larger samples is needed to determine if missed or under-appreciated psychotropic side effects may play a role in behavioural health challenges of some people with IDD.

The pursuit of the magic pill: the overuse of psychotropic medications in children with intellectual and developmental disabilities in the USA.

Children with intellectual and developmental disabilities (IDD) are likely to receive high-risk prescribing practices, such as polypharmacy, long-term use of psychotropic medications, and overuse of antipsychotics. Behavioural interventions, such as applied behavioural analysis, are evidence-based practices for children with IDD and should be the first-line treatment. Short-term use of psychotropic medications may be helpful in reducing the severity and frequency of challenging behaviours while evidence-based behavioural interventions are pursued. In this essay, we offer practical guidelines for better care.

Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

The impact of communicating information about air pollution events on public health.

Short-term exposure to air pollution has been associated with exacerbation of asthma and chronic obstructive pulmonary disease (COPD). This study investigated the relationship between emergency hospital admissions for asthma, COPD and episodes of poor air quality in an English city (Southampton) from 2008-2013. The city's council provides a forecasting service for poor air quality to individuals with respiratory disease to reduce preventable admissions to hospital and this has been evaluated. Trends in nitrogen dioxide, ozone and particulate matter concentrations were related to hospital admissions data using regression analysis. The impacts of air quality on emergency admissions were quantified using the relative risks associated with each pollutant. Seasonal and weekly trends were apparent for both air pollution and hospital admissions, although there was a weak relationship between the two. The air quality forecasting service proved ineffective at reducing hospital admissions. Improvements to the health forecasting service are necessary to protect the health of susceptible individuals, as there is likely to be an increasing need for such services in the future.

A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model.

Open fractures are at risk of serious infection and, if infected, require several surgical interventions and courses of systemic antibiotics. We investigated a new injectable formulation that simultaneously hardens in vivo to form a porous scaffold for bone repair and delivers antibiotics at high concentrations to the local site of infection. Duration of antimicrobial activity against Staphylococcus aureus was determined using the serial plate transfer test. Ultimate compressive strength and porosity of the material was measured with and without antibiotics. The material was evaluated in vivo in an ovine medial femoral condyle defect model contaminated with S. aureus. Sheep were sacrificed at either 2 or 13 weeks and the defect and surrounding bone assessed using micro-computed tomography and histology. Antimicrobial activity in vitro persisted for 19-21 days. Sheep with antibiotic-free material and bacteria became infected, while those with antibiotic-containing material and bacteria did not. Similarly, new bone growth was seen in uninoculated animals with plain polymer, and in those with antibiotic polymer with bacteria, but not in sheep with plain polymer and bacteria. The antibiotic-impregnated scaffolds were effective in preventing S. aureus infections whilst supporting bone growth and repair. If translated into clinical practice, this approach might reduce the need for systemic antibiotics.

Is Clostridium difficile associated with the '4C' antibiotics? A retrospective observational study in diabetic foot ulcer patients.

AIMS: Clostridium difficile is an anaerobic cytotoxin-producing bacterium that can cause infectious diarrhoea, pseudomembranous colitis and toxic megacolon. The major risk factors for developing C. difficile infection include recent or current antimicrobial use, diabetes, age over 65, proton pump inhibitor use, immunosuppression and previous infection with C. difficile. Most diabetic foot ulcers are polymicrobial. METHODS: As a result guidelines advise treatment with broad spectrum antibiotics which include the '4C's' (clindamycin, cephalosporins, co-amoxiclav and ciprofloxacin) which are associated with a higher risk of C. difficile infection. Retrospective observational data (June 2008 to January 2012) for the diabetes foot ulcers were gathered from the Diabetes/Podiatry Clinic database in NHS Ayrshire and Arran and cross-matched with the NHS Ayrshire and Arran Microbiology database. There were 111 patients with mean age 59 years (range 24-94 years), 33 type 1 patients, 78 type 2 patients, mean duration of diabetes 16 years (6 months-37 years) and mean HbA1c 67 mmol/mol (54-108 mmol/mol) [8.3% (7.1-12%)]. RESULTS: The total number of days antimicrobials prescribed for all patients was 7938 (mean number of antimicrobial days per patient = 71.5 days). There was one case of C. difficile infection of 111 patients giving an incidence of 1.25 cases per 10,000 patient-days of antibiotics/1 case per 209 foot ulcers. CONCLUSIONS: Large doses, numbers and greater duration of antibiotic therapy all result in a greater degree of normal gut flora depletion. It is possible that the alterations in gut flora in diabetic foot ulcer patients protect them from antibiotic-induced C. difficile overgrowth.

Orbital decompression for Graves' orbitopathy in England.

AIMS: The purpose of this study was to obtain data on orbital decompression procedures performed in England, classed by hospital and locality, to evaluate regional variation in care. METHODS: Data on orbital decompression taking place in England over a 2-year period between 2007 and 2009 were derived from CHKS Ltd and analysed by the hospital and primary care trust. RESULTS AND CONCLUSIONS: In all, 44% of these operations took place in hospitals with an annual workload of 10 or fewer procedures. Analysis of the same data by primary care trust suggests an almost 30-fold variance in the rates of decompression performed per unit population. Expertise available to patients with Graves' orbitopathy and rates of referral for specialist care in England appears to vary significantly by geographic location. These data, along with other outcome measures, will provide a baseline by which progress can be judged.

Mucositis, conjunctivitis but no rash - the "Atypical Stevens - Johnson syndrome".

The Stevens-Johnson syndrome (SJS) classically involves a rash, conjunctivitis and mucositis. We describe the case of a young adult male with isolated mucositis and conjunctivitis . Previous rare reports of severe SJS like syndromes without a rash are confined to children, usually with mycoplasma pnemoniae infection.(1) Terminology for this syndrome includes - "Stevens-Johnson Syndrome without skin lesions", or "Atypical Stevens - Johnson Syndrome".(2) This case highlights the importance of maintaining an open mind when a "full house" of clinical features is absent. It also illustrates the use of a rapid electronic literature review as a clinical tool. The importance of updating records when a drug has been cleared of causing harm is highlighted.

Automated assessment of keratocyte density in clinical confocal microscopy of the corneal stroma.

Cell density in the corneal stroma is typically determined by counting the number of bright objects, presumably keratocyte nuclei, in images from clinical confocal microscopy. We present a program that identifies bright objects and counts those that most likely represent cells. Selection variables were determined from 125 normal corneas with cell densities that had been assessed manually. The program was tested on 17 corneas of patients before and at several intervals to 5 years after laser in situ keratomileusis (LASIK) surgery. In these corneas, which showed a decrease in cell density after surgery, the program identified cells as well as human observers did.

Grain sorghum is a viable feedstock for ethanol production.

Sorghum is a major cereal crop in the USA. However, sorghum has been underutilized as a renewable feedstock for bioenergy. The goal of this research was to improve the bioconversion efficiency for biofuels and biobased products from processed sorghum. The main focus was to understand the relationship among "genetics-structure-function-conversion" and the key factors impacting ethanol production, as well as to develop an energy life cycle analysis model (ELCAM) to quantify and prioritize the saving potential from factors identified in this research. Genetic lines with extremely high and low ethanol fermentation efficiency and some specific attributes that may be manipulated to improve the bioconversion rate of sorghum were identified. In general, ethanol yield increased as starch content increased. However, no linear relationship between starch content and fermentation efficiency was found. Key factors affecting the ethanol fermentation efficiency of sorghum include protein digestibility, level of extractable proteins, protein and starch interaction, mash viscosity, amount of phenolic compounds, ratio of amylose to amylopectin, and formation of amylose-lipid complexes in the mash. A platform ELCAM with a base case showed a positive net energy value (NEV) = 25,500 Btu/gal EtOH. ELCAM cases were used to identify factors that most impact sorghum use. For example, a yield increase of 40 bu/ac resulted in NEV increasing from 7 million to 12 million Btu/ac. An 8% increase in starch provided an incremental 1.2 million Btu/ac.

Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes.

Lymphocyte proliferation is key to the regulation of the immune system. Cyclin D2 is the first cell cycle protein induced following stimulation through the T-cell receptor, the B-cell receptor or cytokines. The promoter of this cyclin integrates a diverse range of signals. Through investigating the regulation of this promoter by interleukin-2 and phosphatidylinositol 3-kinase, we have identified a role for the transcription factor CREB, cAMP response element-binding protein. Mutation of the CREB-binding site reduced cyclin D2 promoter activity 5-10-fold. CREB-1 is phosphorylated at serine 133, a critical site for activity, in both T cells and Epstein-Barr virus immortalized B cells. The introduction of an S133A mutant of CREB-1 reduces IL-2 induction of cyclin D2 promoter activity, demonstrating a role for this phosphorylation site in promoter activity. Two inhibitors of protein kinase A reduce lymphocyte proliferation and CREB-1 phosphorylation. This study demonstrates that the cyclin D2 promoter is capable of being regulated by PI3K and CREB and identifies CREB-1 and protein kinase A as potential targets for altering lymphocyte proliferation.

Photoperiodic effects on body mass, energy balance and hypothalamic gene expression in the bank vole.

We examined the effect of increasing photoperiod, at a constant low temperature, on the body mass and energy budget of the bank vole Clethrionomys glareolus. Simultaneously, we determined the hypothalamic gene expression of neuropeptides and receptors known to be involved in short-term energy balance. Despite an increase in body mass (approximately 10% of initial mass), we found no significant changes in any energetic parameters (food intake, energy assimilation rate, resting metabolic rate and total daily energy expenditure by doubly-labelled water). Apparent energy assimilation efficiency was higher in voles exposed to long-days (LD) compared to short-days (SD). Surprisingly, gene expression of corticotrophin releasing factor (CRF; in the paraventricular nucleus), and the melanocortin-3 receptor (in the arcuate nucleus), both known to be involved in appetite suppression and elevation of energy expenditure in short-term energy balance, were higher in voles kept in LD compared to SD. CRF expression was also elevated in females compared to males. These paradoxical data suggest an alternative mechanism for the control of seasonal body mass changes compared to short-term body mass changes, and between male and female voles. Furthermore, they highlight the need for studies to perform simultaneous measurements at both the molecular and whole animal levels.

Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura.

Matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and -9), play a significant role in tumour invasion and angiogenesis. The expression and activities of MMPs have not been characterised in malignant mesothelioma (MM) tumour samples. In a prospective study, gelatinase activity was evaluated in homogenised supernatants of snap frozen MM (n=35), inflamed pleura (IP, n=12) and uninflammed pleura (UP, n=14) tissue specimens by semiquantitative gelatin zymography. Matrix metalloproteinases were correlated with clinicopathological factors and with survival using Kaplan-Meier and Cox proportional hazard models. In MM, pro- and active MMP-2 levels were significantly greater than for MMP-9 (P=0.006, P<0.001). Active MMP-2 was significantly greater in MM than in UP (P=0.04). MMP-2 activity was equivalent between IP and MM, but both pro- and active MMP-9 activities were greater in IP (P=0.02, P=0.009). While there were trends towards poor survival with increasing total and pro-MMP-2 activity (P=0.08) in univariate analysis, they were both independent poor prognostic factors in multivariate analysis in conjunction with weight loss (pro-MMP-2 P=0.03, total MMP-2 P=0.04). Total and pro-MMP-2 also contributed to the Cancer and Leukemia Group B prognostic groups. MMP-9 activities were not prognostic. Matrix metalloproteinases, and in particular MMP-2, the most abundant gelatinase, may play an important role in MM tumour growth and metastasis. Agents that reduce MMP synthesis and/or activity may have a role to play in the management of MM.

Diagnosis and assessment of systemic vasculitis.

The diagnosis of systemic vasculitis requires clinical evidence with appropriate symptoms and physical signs, supported by histological or radiological confirmation. Earlier recognition of these diseases has been facilitated by a greater awareness of their incidence, and also by the more widespread introduction of the anti-neutrophil cytoplasmic antibody (ANCA) test. Early diagnosis provides a greater potential for effective intervention in the course of disease and this may limit subsequent damage. However, an early diagnosis poses the more difficult challenge in the classification of the vasculitides, since traditional classification systems have depended on the presence of well-established manifestations of the disease. The accurate assessment of disease activity and damage in vasculitis has become necessary as a result of significant improvements in survival with the use of chemotherapy. The disease course however is frequently characterised by relapse as well as the scars of irreversible organ damage from disease and drug toxicity. Clinical methods of assessment are simple to apply, reliable and often more effective than any current laboratory test in evaluating the effects of therapy and determining changes in therapy. The increasing use of surrogate clinical measures of disease should provide a greater opportunity to establish the effectiveness of existing and novel therapies in the management of these complex diseases.

The diagnostic value of anti-neutrophil cytoplasmic antibody testing in a routine clinical setting.

Anti-neutrophil cytoplasmic antibody (ANCA) tests are a routine clinical assay in most UK hospitals. We examined the role of routine ANCA testing in achieving a diagnosis of systemic vasculitis in a routine clinical setting. From April 1996 to March 2000, 2734 samples from five hospital departments were tested for ANCA by indirect immunofluorescence (IIF) at a single laboratory. After April 1999, enzyme-linked immunosorbent assays (ELISAs) were performed on all IIF-positive samples. Clinical diagnosis was determined for all patients with a positive IIF ANCA, and a sample of the ANCA-negative patients. Some 2-18% of patients with suspected ANCA-associated systemic vasculitis (AASV) had positive IIF ANCA. The AASV diagnosis was confirmed in 0-56% of these cases. Analysis by department suggested that 88-100% of patients with a positive IIF ANCA did not have AASV, except in the Rheumatology department. The positive predictive value (PPV) of IIF ANCA for AASV was 59% and the negative predictive value (NPV) was 84%. Of the patients with proven AASV, 41% did not have ANCA on IIF. Combined ANCA testing by IIF/ELISA had a higher sensitivity and PPV but lower specificity than IIF alone for AASV. For the combined IIF/ELISA test, only the Rheumatology department had a sensitivity or PPV >0% for AASV. The PPV of ANCA by IIF/ELISA for AASV was 79% and the NPV was 63%. The ANCA test is being widely applied with very poor return. Guidelines for more effective usage are proposed.

Aminoglycoside ototoxicity in adult CBA, C57BL and BALB mice and the Sprague-Dawley rat.

The availability of genetic information, transgenic and knock-out animals make the mouse a primary model in biomedical research. Aminoglycoside ototoxicity, however, has rarely been studied in mature mice because they are considered highly resistant to the drugs. This study presents models for kanamycin ototoxicity in adult CBA/J, C57BL/6 and BALB/c mouse strains and a comparison to Sprague-Dawley rats. Five-week-old mice were injected subcutaneously twice daily with 400-900 mg kanamycin base/kg body weight for 15 days. Kanamycin induced dose-dependent auditory threshold shifts of up to 70 dB at 24 kHz as measured by auditory brain stem-evoked responses. Vestibular function was also affected in all strains. The functional deficits were accompanied by hair cell loss in both cochlear and vestibular neurosensory epithelia. Concomitant administration of the antioxidant 2,3-dihydroxybenzoate significantly attenuated the kanamycin-induced threshold shifts. In adult male Sprague-Dawley rats, doses of 1 x 500 mg or 2 x 300 mg kanamycin base/kg body weight/day x 14 days induced threshold shifts of approximately 50 dB at 20 kHz. These were accompanied by loss of outer hair cells. The order of susceptibility, BALB>CBA>C57, was not due to differences in the pharmacokinetics of kanamycin. It also did not correlate with the presence of Ahl/Ahl2 genes which predispose C57 and BALB strains, respectively, to accelerated age-related hearing loss. Pigmentation, however, paralleled this rank order suggesting an influence of melanin on cochlear antioxidant status.

Analysis of postoperative glare and intraocular lens design.

PURPOSE: To assess the potential for reflected glare images from commonly used intraocular lens (IOL) materials and designs. SETTING: Mayo Clinic, Rochester, Minnesota, USA. METHODS: The interaction of reflected light rays from 3 commonly used IOLs (Bausch & Lomb LI61U and P359UV; Alcon AcrySof(R) MA60BM) with different optic designs (equi-biconvex: 10.0 and 15.0 mm anterior radius of curvature; unequal biconvex: 32.0 mm anterior radius of curvature) and optic materials (silicone, poly[methyl methacrylate], and acrylic) were examined in an eye model using the Zemax optical design program. The potential of each IOL model to produce subjective glare was determined from the size of the defocused reflected glare image at the retina. RESULTS: The unequal biconvex design concentrated reflected light on a retinal area that was 60-fold smaller than that of the equi-biconvex design. Increasing the refractive index of the IOL material from 1.43 (silicone) to 1.55 (acrylic) increased the amount of reflected light 5-fold. Compared to an equi-biconvex design composed of a lower refractive index material, the unequal biconvex design with a higher refractive index material increased the relative intensity of reflected light at the retina 300-fold, and for eyes with low corneal power the intensity increased 3500-fold. Similarly, for external glare apparent to an outside observer, the intensity of reflected light increased 400-fold and for low corneal power it increased 6000-fold. CONCLUSION: An unequal biconvex IOL design (32.0 mm anterior radius of curvature) composed of a higher refractive index material increased the potential for postoperative glare and external reflections.