Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion.

An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0-30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50-200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

OBJECTIVE: To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. RESULTS: Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. CONCLUSIONS: Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression. TRAIL REGISTRATION NUMBER: NIHRID6160.

Profilin1 E117G is a moderate risk factor for amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders that share significant clinical, pathological and genetic overlap and are considered to represent different ends of a common disease spectrum. Mutations in Profilin1 have recently been described as a rare cause of familial ALS. The PFN1 E117G missense variant has been described in familial and sporadic cases, and also found in controls, casting doubt on its pathogenicity. Interpretation of such variants represents a significant clinical-genetics challenge. OBJECTIVE AND RESULTS: Here, we combine a screen of a new cohort of 383 ALS patients with multiple-sequence datasets to refine estimates of the ALS and FTD risk associated with PFN1 E117G. Together, our cohorts add up to 5118 ALS and FTD cases and 13 089 controls. We estimate a frequency of E117G of 0.11% in controls and 0.25% in cases. Estimated odds after population stratification is 2.44 (95% CI 1.048 to ∞, Mantel-Haenszel test p=0.036). CONCLUSIONS: Our results show an association between E117G and ALS, with a moderate effect size.

Costs and cost effectiveness of different strategies for chlamydia screening and partner notification: an economic and mathematical modelling study.

OBJECTIVES: To compare the cost, cost effectiveness, and sex equity of different intervention strategies within the English National Chlamydia Screening Programme. To develop a tool for calculating cost effectiveness of chlamydia control programmes at a local, national, or international level. DESIGN: An economic and mathematical modelling study with cost effectiveness analysis. Costs were restricted to those of screening and partner notification from the perspective of the NHS and excluded patient costs, the costs of reinfection, and costs of complications arising from initial infection. SETTING: England. Population Individuals eligible for the National Chlamydia Screening Programme. MAIN OUTCOME MEASURES: Cost effectiveness of National Chlamydia Screening Programme in 2008-9 (as cost per individual tested, cost per positive diagnosis, total cost of screening, number screened, number infected, sex ratio of those tested and treated). Comparison of baseline programme with two different interventions-(i) increased coverage of primary screening in men and (ii) increased efficacy of partner notification. RESULTS: In 2008-9 screening was estimated to cost about £46.3m in total and £506 per infection treated. Provision for partner notification within the screening programme cost between £9 and £27 per index case, excluding treatment and testing. The model results suggest that increasing male screening coverage from 8% (baseline value) to 24% (to match female coverage) would cost an extra £22.9m and increase the cost per infection treated to £528. In contrast, increasing partner notification efficacy from 0.4 (baseline value) to 0.8 partners per index case would cost an extra £3.3m and would reduce the cost per infection diagnosed to £449. Increasing screening coverage to 24% in men would cost over six times as much as increasing partner notification to 0.8 but only treat twice as many additional infections. CONCLUSIONS: In the English National Chlamydia Screening Programme increasing the effectiveness of partner notification is likely to cost less than increasing male coverage but also improve the ratio of women to men diagnosed. Further evaluation of the cost effectiveness of partner notification and screening is urgently needed. The spreadsheet tool developed in this study can be easily modified for use in other settings to evaluate chlamydia control programmes.

Topical tacrolimus ointment combined with 6% salicylic acid gel for plaque psoriasis treatment.

BACKGROUND: While oral tacrolimus is effective for the treatment of psoriasis, tacrolimus ointment has shown only spotty efficacy in the treatment of plaque psoriasis. The efficacy of tacrolimus ointment for the treatment of facial and intertriginous psoriasis suggests that if tacrolimus penetration can be increased, the ointment could be used for effective treatment of plaque psoriasis. OBJECTIVE: To assess whether tacrolimus ointment is an effective psoriasis treatment when used in a combination regimen with the penetration-enhancer salicylic acid. METHODS: A total of 30 adult subjects with generally symmetrical plaque-type psoriasis were randomized to treatment with 6% salicylic acid gel plus vehicle or 6% salicylic acid gel plus 0.1% tacrolimus ointment in a 12-week left-right comparison study. The primary outcome was the difference between tacrolimus- and vehicle-treated target lesions in the change in the sum of erythema, scale, and thickness scores from baseline to end of treatment. RESULTS: A total of 24 subjects completed the trial. Combination treatment with tacrolimus ointment or vehicle plus salicylic acid gel was well tolerated. There was greater improvement of the sum score in the tacrolimus plus salicylic acid-treated target plaques than in the vehicle plus salicylic acid-treated plaques at weeks 1, 2, and 8 (P<.05). The efficacy of this regimen was confirmed by investigator and subject global assessments of plaque severity. CONCLUSIONS: The combination of 0.1% tacrolimus ointment and 6% salicylic acid gel is an effective treatment for psoriasis. Although the results reported herein are from a small exploratory study, the magnitude of the effect was sufficiently large as to be detectable with statistical significance (P<.05).

Tacrolimus ointment in the treatment of eyelid dermatitis.

The safety and efficacy of tacrolimus ointment 0.1% (Protopic) in the treatment of atopic dermatitis of the eyelids were assessed in an open-label clinical trial of 21 patients with moderate to severe eyelid dermatitis. Of those 21 patients, 20 received study drug and were followed. Patients applied tacrolimus ointment 0.1% twice daily for 8 weeks and were followed for 2 additional weeks after the last day of treatment. Complete eye examinations were conducted throughout the study. Efficacy was assessed through the investigator's evaluation of the patients' individual signs and symptoms of eyelid dermatitis and the physician global assessment (PGA) of eyelid clinical response. Improvement in the investigator's evaluation of the signs and symptoms of eyelid dermatitis was observed during the study. A total of 80% of patients (16/20) experienced marked improvement or better in PGA at 8 weeks. Adverse events were limited to local burning and itching after the first few applications of study medication. Of the 20 patients, 12 reported burning (60%), and 5 reported itching (25%). There was no statistically significant increase in intraocular pressure (IOP) during the study compared with baseline. In addition, none of the patients developed cataracts or glaucoma during the study. In summary, tacrolimus ointment 0.1% may be a safe and effective treatment option for patients with moderate to severe eyelid dermatitis.

Effects of an episode of specialist care on the impact of childhood atopic dermatitis on the child's family.

INTRODUCTION: Although some preliminary work has examined the impact of atopic dermatitis (AD) on families, no empirical work has examined changes in the impact on families dealing with AD over time. An exploratory analysis of change in impact on families dealing with AD before and after an episode of medical care in a physician office setting was conducted. METHOD: Baseline and follow-up surveys were completed by 35 parent caregivers before and 1 month after a dermatologist visit for the child at an academic medical center. RESULTS: In the postcare survey, there was a 43% reduction in the Dermatitis Family Impact Questionnaire (DFI) scores (P <.01) compared with baseline. Significant differences were also observed in other parent caregiver-reported characteristics. The significant change in parent caregiver characteristic associated with the decreased DFI score was the increased satisfaction with the medical care related to the child's treatment (P <.01). DISCUSSION: These data reveal that there is a strong decrease in impact on a family associated with an episode of specialist care for children with AD. The importance of pediatric health care professionals in decreasing the impact of AD on families needs further exploration.

The family impact of atopic dermatitis in children: the role of the parent caregiver.

Although some preliminary work exists examining the impact of atopic dermatitis (AD) in children on their families, there is no empirical work examining specific parent caregiver factors that could contribute to the family impact of this condition. We conducted a cross-sectional, exploratory analysis of how parent caregivers are affected by their child's AD, and how certain parent caregiver characteristics and perceptions affect the family impact of this condition. Parent caregivers of children with AD (n = 49) were administered a survey to collect detailed data on socioeconomic status, health perceptions, and caregiving issues. Family impact of the child's AD was measured using a modified AD Family Impact Scale. Multiple regression analyses revealed that three major factors associated with the parent caregiver were correlated with large increases in the family impact scores: 1) perception that the child's condition is severe (13%, p < 0.01), 2) high use of nonmedical services for child's condition (21%, p < 0.01), and 3) financial concern about the child's condition (18%, p < 0.01). These preliminary data indicate distinct characteristics of the parent caregiver that are associated with higher family impact of AD in children. These parent caregiver factors may be important in identifying suitable audiences and areas for education for optimal management of children's AD.