Search

Animal models of cystic fibrosis (CF) are essential for investigating disease mechanisms and trialing potential therapeutics. This study generated two CF rat models using clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 gene editing. One rat model carries the common human Phe508del (ΔF508) CF transmembrane conductance regulator (CFTR) mutation, whereas the second is a CFTR knockout model. Phenotype was characterized using a range of functional and histologic assessments, including nasal potential difference to measure electrophysiological function in the upper airways, RNAscope in situ hybridization and quantitative PCR to assess CFTR mRNA expression in the lungs, immunohistochemistry to localize CFTR protein in the airways, and histopathologic assessments in a range of tissues. Both rat models revealed a range of CF manifestations, including reduced survival, intestinal obstruction, bioelectric defects in the nasal epithelium, histopathologic changes in the trachea, large intestine, and pancreas, and abnormalities in the development of the male reproductive tract. The CF rat models presented herein will prove useful for longitudinal assessments of pathophysiology and therapeutics.

BACKGROUND: Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. METHODS: We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (

Background:\ud Pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment.\ud \ud Objective:\ud We sought to estimate the effectiveness of topical therapies in the treatment of patients with PG.\ud \ud Methods:\ud This was a retrospective cohort study of UK secondary care patients with a clinical diagnosis of PG that was suitable for topical treatment (recruited between July 2009 and June 2012). Participants received topical therapy after normal clinical practice (primarily topical corticosteroids [classes I-III] and tacrolimus 0.03% or 0.1%). The primary outcome was speed of healing at 6 weeks. Secondary outcomes included the following: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality of life; treatment failure; and recurrence.\ud \ud Results:\ud Sixty-six patients (22-85 years of age) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28 of 66 (43.8%) ulcers healed by 6 months. The median time to healing was 145 days (95% confidence interval, 96 days to ∞). Initial ulcer size was a significant predictor of time to healing (hazard ratio, 0.94 [95% confidence interval, 0.88-1.00); P = .043). Four patients (15%) had a recurrence.\ud \ud Limitations:\ud Our study did not include a randomized comparator.\ud \ud Conclusion:\ud Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone.

Clinical trials may benefit clinical practice in three ways: firstly, clinicians may change their practice according to the new trial evidence; secondly, clinical processes can improve when working on a trial; and thirdly, research capacity is increased. We held a meeting to present and discuss the results of two large multicentre randomized controlled trials delivered through the U.K. Dermatology Clinical Trials Network. Investigators gave reflections on how the trials had changed their clinical practice. The STOP GAP trial showed that prednisolone and ciclosporin are equally effective as first-line systemic treatment for pyoderma gangrenosum. The final decision of which treatment to use should be based on the different adverse event profiles of the two drugs in relation to comorbidities, along with age, disease severity and patient preference. The BLISTER trial showed that starting people with pemphigoid on doxycycline produces acceptable short-term effectiveness and a superior safety profile to oral corticosteroids. Recruiting to these trials has led to the development of new specialist clinics with improved documentation. It has increased the profile of participating departments and embedded research in the department's activities. Helping to design and run these trials has also allowed trial staff to develop new skills in research design, which has been beneficial for career development. These and other benefits of recruiting to the trials are summarized here. We hope that these reflections will inspire wider involvement in clinical research.

Job opportunities for women have been slender throughout the modem era. The UK isn't alone in having a very small proportion of women in the engineering workforce. Other English speaking countries are almost as bad. Recent statistics show Australia with 9.6 per cent, and the USA and Canada both on 11 per cent. Ireland manages 14.3 per cent. Things are a lot better in some other parts of the EU. Statistics from 2007 give top marks to Latvia, where 30 per cent of engineers are female, closely followed by Bulgaria on 29.3 per cent, Cyprus on 28.6 per cent and Sweden on 25.9 per cent. Interestingly, in modern China women engineers make up 40 per cent of the workforce, whereas in the former USSR the proportion was 58 per cent: more female engineers than male!

The year is 2050, the city is London. The landscape of the capital has changed radically after the decision-making process over the effects of climate change was taken out of the hands of engineers and put into the hands of bureaucrats. The story is fiction, taking some worst-case scenarios and building a tale of one potential future - but is such a thing so very unlikely? Decide for yourself...

Aims: To ascertain the characteristics and short-term outcomes of infants born to illicit drug-using mothers in public hospitals in the state of New South Wales and the Australian Capital Territory during 2004. Methods: Patients were identified retrospectively by hospital records searches using ICD-10 morbidity codes and records of local Drug and Alcohol Services. Records were reviewed on site. All public hospitals (n= 101) with obstetric services were included. Results: A total of 879 (1.4%, 95% confidence interval: 1.3–1.5%) drug-using mothers were identified from 62 682 confinements. Opiates (46.8%), amphetamines (23.0%) and polydrug (16.4%) exposure were most common. There were eight stillbirths. Among these 871 infants, prematurity (23.6%) and low birthweight (27.1%) were common and 51.1% were admitted to nurseries for further care. Two infants died. Major congenital anomalies were detected in 15 infants. Pharmacological treatment for withdrawal was required for 202 (23.2%), and 143 (70.8%) infants were discharged home on medication. Infants who completed inpatient pharmacological treatment were hospitalised longer (median 26.0 vs. 12.0 days) and were more likely to be premature (37.3 vs. 14.0%). Child-at-risk notifications affected 40.6% of the infants, and 7.6% were fostered prior to discharge. A total of 333 (38.2%) infants were breastfed at discharge. Conclusions: Our regional study highlights a substantial prevalence of drug use in pregnancy with considerable adverse perinatal and hospital outcomes in infants born to these mothers. Coordinated health care and resources are needed to support these mother–infant pairs because of their social, medical and mental-health issues.

According to estimates from market researchers YouGov, 1.3 million e-readers found their way under UK Christmas trees last year. An online survey carried out between 28 December 2011 and 3 January 2012 indicates that one in 40 adults received or bought a device over the festive period. The bulk of the sales, more than 90 percent, were down to Amazon, with the Kindle becoming the online retailer's biggest selling product for the second year running.

Importance Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a “diagnosis of exclusion,” a definition not compatible with clinical decision making or inclusion for clinical trials. Objective To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum. Evidence Review Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation. Findings Delphi exercise yielded 1 major criterion—biopsy of ulcer edge demonstrating neutrophilic infiltrate—and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively. Conclusions and Relevance This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.

OBJECTIVE: To determine whether radiochemical purity is affected when 99mTc radiopharmaceuticals are prepared using sodium chloride injection from plastic ampoules that have been exposed to light. METHODS: Sodium chloride injection from plastic ampoules that were either exposed to light for 7 days or protected from light was used in the preparation of nine common 99mTc radiopharmaceuticals: albumin nanocolloid, exametazime, macrosalb, mebrofenin, medronate, pentetate, sestamibi, succimer and tetrofosmin. Five different batches of ampoules (exposed and unexposed) were used for each radiopharmaceutical. Radiochemical purity was measured by established analytical methods (thin-layer chromatography, liquid chromatography and nuclepore filtration) as specified in the European Pharmacopoeia or by the manufacturer. Analysis was performed within 1 h of preparation and at the products' expiries. RESULTS: The radiochemical purity of each 99mTc radiopharmaceutical was satisfactory when unexposed sodium chloride injection was used in its preparation. There was a significant difference between exposed and unexposed results (P < 0.05) for 99mTc exametazime (69.0 ± 9.3% vs. 88.6 ± 0.8%), 99mTc albumin nanocolloid (94.3 ± 1.1% vs. 98.8 ± 0.4%) and 99mTc macrosalb (84.0 ± 4.1% vs. 98.0 ± 2.2%) after preparation. Unsatisfactory radiochemical purity was the result of 99mTc pertechnetate impurity. The radiochemical purities of 99mTc albumin nanocolloid and 99mTc macrosalb increased over time and were satisfactory at their expiries. CONCLUSION: When 99mTc albumin nanocolloid, 99mTc macrosalb and 99mTc exametazime are prepared using sodium chloride injection from plastic ampoules that have been exposed to light, radiochemical purity is adversely affected. The other 99mTc radiopharmaceuticals tested are unaffected.

Background: The European Pharmacopoeia and radiopharmaceutical manufacturers specify Instant Thin-Layer Chromatography Silica Gel impregnated glass fibre (ITLC-SG) as the stationary phase for measuring the radiochemical purity (RCP) of most technetium-99m (99mTc) radiopharmaceuticals. During 2008, The Pall Corporation stopped manufacturing ITLC-SG. A replacement is required. Aim: To evaluate Varian's Glass Microfibre Chromatography Paper impregnated with salicic acid (GMCP-SA) as a replacement. Experimental: Samples of six 99mTc radiopharmaceuticals (albumin nanocolloid, colloidal tin, exametazime, medronate, pentetate and succimer) were prepared containing levels of radiochemical impurities between 0 and 10%. Samples were tested using ITLC-SG and GMCP-SA with the mobile phase specified in the pharmacopoeia or by the manufacturer. Analysis was performed by thin-layer radiochromatogram scanning. Results: For measuring the RCP of albumin nanocolloid, colloidal tin, exametazime and succimer, GMCP-SA is a suitable replacement for ITLC-SG. For medronate, GMCP-SA is suitable for measuring colloidal 99mTc impurity despite producing slightly higher values than ITLC-SG, but unsuitable for measuring 99mTc pertechnetate impurity due to significant over-estimation. For pentetate, GMCP-SA is suitable for measuring colloidal 99mTc impurity but gives slightly higher values for 99mTc pertechnetate impurity than ITLC-SG. Conclusion: GMCP-SA is a suitable alternative to ITLC-SG for analysing some 99mTc radiopharmaceuticals but is not a universal replacement. Copyright © 2009 John Wiley & Sons, Ltd.

Objectives: The aim of the present study was to determine the characteristics and short-term outcomes of mother–infant pairs with comorbid drug dependency and psychiatric disorders. Methods: A population-based retrospective chart review was carried out of 879 drug-dependent mother and infant pairs in New South Wales (NSW) and the Australian Capital Territory (ACT) who delivered between 1 January and 31 December 2004. Results: Psychiatric comorbidity (dual diagnosis, DD) was identified in 396 (45%) of the 879 drug-dependent women. DSM-IV depression (79%), followed by anxiety (20%), was most prevalent. DD women were more likely to use amphetamines (29% vs 18%, p < 0.05), less likely to use opiates (42% vs 51%, p < 0.05) and to have had no antenatal care (24% vs 8%, p < 0.05). They also had more previous pregnancies (4, range = 2–5 vs 3, range = 2–5, p < 0.05) and domestic violence (29% vs 14%, p < 0.05) was more common. DD infants were less likely to be admitted to a nursery (47% vs 55%, p < 0.05). Withdrawal scores were similar (maximum median Finnegan scores = 4 (interquartile range = 3–8) vs 10 (interquartile range = 7–12, p = 0.30) but fewer needed withdrawal medication (19% vs 27%, p < 0.05). Maternal psychotropic agents did not worsen the severity of neonatal withdrawal. Conclusions: Psychiatric comorbidity, especially depression, is common and affects almost half of drug-using mothers. Antenatal care, drug use and social outcomes are worse for DD mothers and their infants. It is recommended that all drug-using women be assessed antenatally for psychosocial disorders so that timely mental health intervention can be offered, if required.

The Tat HIV-1 accessory protein has been found to play a role in both transcriptional initiation and elongation of RNA transcripts and provirus. For historical “safety” reasons, clinical trials using HIV-1 vectors do not generally accept the use of Tat. The aim of this experiment was to compare the efficacy of Tat-dependent and Tat-independent vector systems, to ensure the most effective gene therapy can be achieved.

Aim This study determined the influence of prematurity on the manifestation and treatment of neonatal abstinence syndrome (NAS). Methods This was a medical record review of Australian infants exposed to opiates in 2004 and 2007. Finnegan scores were obtained for 215 of 361 (59%) preterm infants under 37-week gestation and 694 of 1178 (59%) term infants. Results The mean and standard deviation (SD) gestational ages were 34 (3) and 38 (3) weeks for preterm and term infants, respectively. Maternal daily methadone doses were similar for the preterm and term infants with a mean (SD) of 79 mg (39) versus 72 mg (38) (p = 0.06). Maximum Finnegan scores were significantly lower in preterm infants (10 versus 11, p = 0.01), scores were positively correlated with gestation and fewer preterm infants were medicated for NAS (40% versus 48% p = 0.05). Maximum median daily and interquartile range morphine doses were lower for preterm than term infants (0.5 mg/kg/day (0.3–0.6) versus 0.5 mg/kg/day (0.4–0.7), p = 0.02). Conclusion Preterm infants were just as likely to be monitored for withdrawal as term infants, but their Finnegan scores were lower and fewer preterm infants were treated for NAS. Whether this indicates decreased NAS severity or physiological immaturity is uncertain. Other means of evaluating NAS in preterm infants are warranted, especially long-term outcomes.

Basal cell carcinoma (BCC) is the most common form of skin cancer, predominantly affecting the head and neck, and can be diagnosed clinically in most cases. Metastasis of BCC is rare, but localised tissue invasion and destruction can lead to morbidity. Incidence of BCC increases markedly after the age of 40 years, but incidence in younger people is rising, possibly as a result of increased sun exposure.We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions on treatment response/recurrence (within 1 year of therapy) in people with basal cell carcinoma? What are the effects of interventions on long-term recurrence (a minimum of 2 years after treatment) in people with basal cell carcinoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.In this systematic review we present information relating to the effectiveness and safety of the following interventions: cryotherapy/cryosurgery, curettage and cautery/electrodesiccation, fluorouracil, imiquimod 5% cream, photodynamic therapy, and surgery (conventional or Mohs' micrographic surgery).

To determine the short-term outcomes of newborn infants and mothers exposed to antenatal amphetamines in the state of New South Wales and the Australian Capital Territory during 2004.Amphetamine exposure was determined retrospectively using ICD-10 AM morbidity code searches of hospital medical records and from records of local drug and alcohol services. Records were reviewed on site. All public hospitals (n = 101) with obstetric services were included.Amphetamines were used by 200 (22.9%) of the 871 identified drug-using mothers. Most women (182, 91%) injected amphetamines intravenously. Compared with the other 669 drug users, amphetamine-using mothers were significantly more likely to use multiple classes of drugs (45.0% vs 7.8%), be subject to domestic violence (32.1% vs 17.5%), be homeless (14.8% vs 4.9%) and be involved with correctional services (19.8% vs 9.7%). The incidence of comorbid psychiatric illnesses were significantly higher (57.4% vs 41.7%) and their infants were more likely to be preterm (29.5% vs 20.4%), notified as children at risk (67.0% vs 32.8%), fostered before hospital discharge (14.5% vs 5.5%) and less likely to be breastfed (27.0% vs 41.6%).Amphetamine-exposed mothers and infants in public hospitals of NSW and the ACT are at significantly higher risk of adverse social and perinatal outcomes even when compared with mothers and infants exposed to other drugs of dependency. Increased vigilance for amphetamine exposure is recommended due to a high prevalence of use, especially in Australia, as a recreational drug.

Background: The European Pharmacopoeia specifies Instant Thin-Layer Chromatography Silica Gel (ITLC-SG) as the stationary phase for measuring radiochemical impurities in 99mTc Medronate. The Pall Corporation has stopped manufacturing ITLC-SG. Aim: To investigate chromatography papers as alternatives to ITLC-SG. Experimental: The resolution of the main 99mTc Medronate and impurity peaks were compared on five Whatman papers (1CHR, 31ET, 3MM, 4CHR and 54SFC) using the pharmacopoeial mobile phases: methyl ethyl ketone for detecting 99mTc pertechnetate impurity and sodium acetate solution (136 g/l) for detecting hydrolysed reduced and colloidal 99mTc impurities. The effects of three sample spot treatments (wet, hot dried and air dried) on the distribution of the radiochemical impurities were compared. The levels of radiochemical impurities measured in samples of 99mTc Medronate were compared. Results: The highest resolutions were obtained with 1CHR, 4CHR and 54SFC. Sample spot drying resulted in the measurement of artifactually high levels of 99mTc pertechnetate impurity. When analysing 99mTc Medronate, erroneously high levels of colloidal and 99mTc pertechnetate impurities were measured with 1CHR and 4CHR. Conclusions: 54SFC paper is a suitable alternative to ITLC-SG for measuring radiochemical impurities in 99mTc Medronate. The sample spot should be wet when the paper strip is placed in the chromatography tank. Copyright © 2009 John Wiley & Sons, Ltd.