A randomized controlled trial protocol assessing the effectiveness, safety and cost-effectiveness of methotrexate vs. ciclosporin in the treatment of severe atopic eczema in children: the TREatment of severe Atopic eczema Trial (TREAT).

BACKGROUND: Oral systemic immunomodulatory medication is regularly used off-licence in children with severe atopic eczema. However, there is no firm evidence regarding the effectiveness, safety, cost-effectiveness and impact on quality of life from an adequately powered randomized controlled trial (RCT) using systemic medication in children. OBJECTIVES: To assess whether there is a difference in the speed of onset, effectiveness, side-effect profile and reduction in flares post-treatment between ciclosporin (CyA) and methotrexate (MTX), and also the cost-effectiveness of the drugs. Treatment impact on quality of life will also be examined in addition to whether FLG genotype influences treatment response. In addition, the trial studies the immune-metabolic effects of CyA and MTX. METHODS: Multicentre, parallel group, assessor-blind, pragmatic RCT of 36 weeks' duration with a 24-week follow-up period. In total, 102 children aged 2-16 years with moderate-to-severe atopic eczema, unresponsive to topical treatment will be randomized (1 : 1) to receive MTX (0·4 mg kg-1 per week) or CyA (4 mg kg-1 per day). RESULTS: The trial has two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare following treatment cessation. CONCLUSIONS: This trial addresses important therapeutic questions, highlighted in systematic reviews and treatment guidelines for atopic eczema. The trial design is pragmatic to reflect current clinical practice.

Oral propranolol in the treatment of proliferating infantile haemangiomas: British Society for Paediatric Dermatology consensus guidelines.

BACKGROUND: Infantile haemangiomas (IH) are the most common vascular tumours of infancy. Despite their frequency and potential complications, there are currently no unified U.K. guidelines for the treatment of IH with propranolol. There are still uncertainties and diverse opinions regarding indications, pretreatment investigations, its use in PHACES (posterior fossa malformations-haemangiomas-arterial anomalies-cardiac defects-eye abnormalities-sternal cleft and supraumbilical raphe) syndrome and cessation of treatment. OBJECTIVES: To provide unified guidelines for the treatment of IH with propranolol. METHODS: This study used a modified Delphi technique, which involved an international treatment survey, a systematic evidence review of the literature, a face-to-face multidisciplinary panel meeting and anonymous voting. RESULTS: The expert panel achieved consensus on 47 statements in eight categories, including indications and contraindications for starting propranolol, pretreatment investigations, starting and target dose, monitoring of adverse effects, the use of propranolol in PHACES syndrome and how to stop treatment. CONCLUSIONS: These consensus guidelines will help to standardize and simplify the treatment of IH with oral propranolol across the U.K. and assist in clinical decision-making.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Ultraviolet A1 phototherapy: a British Photodermatology Group workshop report.

Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK.

Tackling tuberculosis in sub-Saharan Africa: EDCTP achievements and the road ahead.

The European and Developing Countries Clinical Trials Partnership (EDCTP) was established in 2003 to accelerate the development of medical interventions for tuberculosis (TB), human immunodeficiency virus (HIV) and malaria, with a particular focus on Phase II and III clinical trials. Between 2003 and 2015, the first EDCTP programme committed €65.6 million to research on TB and TB-HIV co-infection. The programme made a significant contribution to the first three elements of the DOTS TB control strategy, which mobilised European and African funding for TB-related research and generated important evidence on TB diagnostics and treatment regimens. As well as informing the development of international policy on TB diagnosis and treatment, the programme also significantly enhanced the capacity of countries in sub-Saharan Africa to undertake clinical trials and associated clinical research. The lessons learned from the first EDCTP programme have informed the development of a second, expanded EDCTP programme, EDCTP2, which was launched in 2014, and is due to run until 2024. One key lesson is the need for continued partnerships to fight the global threat of TB.

Photogenotoxicity of hypericin in HaCaT keratinocytes: implications for St. John's Wort supplements and high dose UVA-1 therapy.

Extract of St. John's Wort (Hypericum perforatum) is commonly used as natural remedy for treatment of mild to moderate depression. However, it contains a powerful photoactive component, hypericin, which can cause a severe photodermatitis when eaten by grazing animals (hypericism). In humans, there is evidence that supplementation with St. John's Wort can reduce the minimal erythemal dose (MED) in patients undergoing high dose UVA-1 phototherapy. This is a recent development in phototherapy where the most erythemogenic parts of the UVA spectrum are filtered out, allowing delivery of higher doses of the longer wavelengths of UVA. Although current published evidence suggests that the plasma levels of hypericin are unlikely to cause clinical phototoxicity, it has been established that photoactive compounds can cause DNA damage at sub-toxic and sub-erythemal doses, the effects of which might not be apparent for many years after the event. The present study used HaCaT keratinocytes to investigate the photoclastogenic ability of hypericin on irradiation with UVA. The results show that although the combination of hypericin and UVA light increased the genotoxic burden, when all factors are taken into account, the risk of significant photogenotoxic damage incurred by the combination of Hypericum extracts and UVA phototherapy may be low in the majority of individuals.

Cloning and sequencing of four structural genes for the Na(+)-translocating NADH-ubiquinone oxidoreductase of Vibrio alginolyticus.

Oligonucleotide probes based on the N-terminal amino acid sequences of the NqrA and NqrC subunits were used to clone genes for the Na(+)-dependent NADH-ubiquinone oxidoreductase complex from Vibrio alginolyticus. Four consecutive ORFs were identified encoding subunit proteins of 48.6, 46.8, 27.7 and 22.6 kDa, respectively (NqrA-D). A further ORF, showing 71% homology to the BolA protein of Escherichia coli, was located upstream. From sequence comparisons, we conclude that the Na(+)-dependent NADH-ubiquinone oxidoreductase complex of V. alginolyticus is clearly distinct from the corresponding H(+)-dependent enzymes of both prokaryotes and eukaryotes.

Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency.

OBJECTIVE: To determine whether dichloroacetate (DCA) treatment can increase pyruvate dehydrogenase (PDH) activity in PDH-deficient cell lines harboring pathogenic mutations in the PDH E1alpha gene. BACKGROUND: PDH deficiency is a nuclear-encoded mitochondrial disorder and a major recognized cause of neonatal encephalomyopathies associated with primary lactic acidosis. Over the last decade, DCA has been used therapeutically, but it has not been clear which patients might benefit. Recent studies suggest that chronic DCA treatment may act by increasing the stability of mutant E1alpha polypeptide. The relative effects of DCA treatment on PDH-deficient cell lines with E1alpha mutations primarily affecting polypeptide stability or catalytic activity were determined and the mechanism of enhancement of residual PDH activity explored. METHODS: The effect of chronic 5-day DCA treatment on PDH activity was assessed in PDH-deficient cell lines containing the R378H, R141Q, K387(FS), and R302C E1alpha mutations. PDH subunit turnover and steady-state E1alpha levels before and after DCA treatment were measured in the R378H mutant line. RESULTS: Chronic DCA treatment resulted in 25% (p = 0.0434), 31% (p = 0.0014) increases in PDH activity in the K387(FS) and R378H cell lines, both of which are associated with decreased mutant polypeptide stability. In the R378H mutant cell line, chronic DCA treatment increased steady-state E1alpha levels and slowed the rate of E1alpha turnover twofold. In contrast, PDH activity did not change in the chronically DCA-treated R302C mutant line, in which the mutant polypeptide has normal stability and reduced catalytic activity. CONCLUSIONS: Chronic DCA treatment can increase PDH activity in PDH-deficient cell lines harboring mutations that affect E1alpha stability, suggesting a biochemical criterion by which DCA-responsive patients might be selected.

Postoperative evaluation for disseminated medulloblastoma involving the spine: contrast-enhanced MR findings, CSF cytologic analysis, timing of disease occurrence, and patient outcomes.

BACKGROUND AND PURPOSE: Postoperative MR imaging is routinely performed for staging of medulloblastoma because of frequent tumor dissemination along CSF pathways. The goals of this study were to: 1) determine the timing of disease occurrence and contrast-enhanced MR imaging features of disseminated medulloblastoma involving the spine and their relationship to patient outcomes; and 2) compare the diagnostic accuracy of MR imaging findings with CSF cytologic analysis. METHODS: Medical records, pathologic reports, and unenhanced and contrast-enhanced postoperative MR images of the spine and head from 112 patients who had resection of medulloblastoma were retrospectively reviewed. MR images of the spine were evaluated for abnormal contrast enhancement in the meninges and vertebral bone marrow. MR images of the head were evaluated for recurrent or residual intracranial tumor. Imaging data were correlated with available CSF cytologic results and patient outcomes. RESULTS: Twelve patients (11%) had tumor within the spinal leptomeninges depicted on MR images at the time of diagnosis. Twenty-five patients (22%) had disseminated disease in the spine (leptomeninges, n = 22; vertebral marrow, n = 1; or both locations, n = 2) on MR images 2 months to 5.5 years (mean, 2 years) after initial surgery and earlier negative imaging examinations. Eleven other patients (10%) had recurrent intracranial medulloblastoma without spinal involvement seen with MR imaging. Spinal MR imaging had a sensitivity of 83% in the detection of disseminated tumor, whereas contemporaneous CSF cytologic analysis had a sensitivity of 60%. The sensitivity of CSF cytologic analysis increased to 78% with acquisition of multiple subsequent samples, although diagnosis would have been delayed by more than 6 months compared with diagnosis by spinal MR imaging in six patients. Spinal MR imaging was found to have greater overall diagnostic accuracy than CSF cytologic analysis in the early detection of disseminated tumor (P = .03). Spinal MR imaging confirmed disseminated tumor when contemporaneous CSF cytologic findings were negative in 13 patients, whereas the opposite situation occurred in only two patients. False-positive results for spinal MR imaging and CSF cytologic analysis occurred when these examinations were obtained earlier than 2 weeks after surgery. The 5-year survival probability for patients with spinal tumor was 0.24 +/- 0.08 versus 0.68 +/- 0.05 for the entire study group. CONCLUSION: Spinal MR imaging was found to have greater diagnostic accuracy than CSF cytologic analysis in the early detection of disseminated medulloblastoma. CSF cytologic analysis infrequently confirmed disseminated tumor when spinal MR imaging results were negative. Delaying spinal MR imaging and CSF cytologic analysis by more than 2 weeks after surgery can reduce false-positive results for both methods. The presence of disseminated medulloblastoma in the spine seen with MR imaging is associated with a poor prognosis.

Associations between patient report of symptoms and anatomic impairment visible on lumbar magnetic resonance imaging.

STUDY DESIGN: A cross-sectional study comparing the relationship of symptoms with anatomic impairment visible on lumbar magnetic resonance imaging in 408 symptomatic subjects. OBJECTIVE: To determine how various anatomic impairments, including the magnitude and location of nerve compression visible on lumbar magnetic resonance imaging, are associated with patient reports of pain, weakness, and dysesthesia. SUMMARY AND BACKGROUND DATA: Anatomic impairments of the intervertebral disc, radicular canal, and associated soft tissues are prevalent in people with and those without low back pain or lower extremity radiculopathy. This has led to confusion in differentiating between symptom generators and benign variation visible on lumbar magnetic resonance imaging. Recent literature has suggested that the presence of nerve compression is an important finding in the prediction of symptoms. However, the threshold for meaningful nerve compression has not been described. METHODS: In this study, 408 participants undergoing a diagnostic workup for low back pain, radiculopathy, and/ or completed a survey and pain drawing. Participants underwent standardized lumbar magnetic resonance imaging using a 1.5-T scanner. Two classification systems describing the spatial distribution of symptoms were developed. An additional system to quantify the magnitude of nerve and thecal sac compression was created. All systems were assessed for reliability, after which comparisons among variables were performed using Chi2 as well as simple and multiple logistic regression analysis. RESULTS: The reliability coefficients for categorizing patients on the basis of pain drawing ranged from 0. 75 to 0.88. The S1-S2 segmental distribution was the most commonly reported location of symptoms, followed by L4-L5. The most common magnetic resonance imaging diagnosis was "unremarkable," followed by "disc impairment without nerve compression." Disc extrusion was present in 10.8% of participants. The reliability of classifying nerve compression visible on magnetic resonance imaging ranged from 0.27 to 1. Nerve compression was present in 37% of participants, and 18% had severe nerve compression. There were no significant associations between segmental distribution of symptoms and the presence of anatomic impairment. However, according to a collapsed classification scale, severe nerve compression and disc extrusion were predictive of pain distal to the knee (odds ratios, 2.72 and 3. 34). The self-report of weakness was associated mildly with severe nerve compression and disc extrusion, but not with other findings. Magnetic resonance imaging findings did not predict self-reports of dysesthesia. CONCLUSIONS: The presence of disc extrusion and/or ipsilateral, severe nerve compression at one or multiple sites is strongly associated with distal leg pain. Mild to moderate nerve compression, disc degeneration or bulging, and central spinal stenosis are not significantly associated with specific pain patterns. Although segmental distributions of pain can be determined reliably from pain drawings, this finding alone is of little use in predicting lumbar impairment. The self-report of lower extremity weakness or dysesthesia is not significantly related to any specific lumbar impairments. [Key words: back pain, diagnosis, magnetic resonance imaging, nerve compression, pain drawing, pathology]

Effect of lordosis on the position of the nucleus pulposus in supine subjects. A study using magnetic resonance imaging.

STUDY DESIGN: Healthy young women (N = 20) underwent magnetic resonance imaging while supine with their hips and knees flexed (flexed position) and supine with a lumbar roll under the low back (extended position). The posterior and anterior margins of the nucleus pulposus (NP) relative to posterior and anterior margins of the adjacent vertebral bodies were calculated from mid-sagittal T2-weighted images to determine the position change of the NP as a function of two supine postures. OBJECTIVES: This study describes the effect of two commonly used supine postures on the position of the NP. SUMMARY OF BACKGROUND DATA: Management of patients with low back pain is often based on theorized positional changes of the NP during spinal extension and flexion. Data describing NP positional changes have not been reported for noninvasive measurements. RESULTS: The distance of the posterior margin of the NP to the posterior margins of the adjacent vertebral bodies was greater in the extended compared with the flexed position. There was no difference in the anterior distance. Eight of the 20 subjects had at least one degenerative disc in the lower lumbar spine. The NPs of the degenerative discs did not move the same as normal discs. CONCLUSIONS: The use of a lumbar roll under the low back when supine causes an increase in the distance from the posterior margin of the NP to the posterior portions of the vertebral bodies in normal discs of healthy young females. Degenerative discs deform differently from nondegenerative discs.

The use of an eclectic approach for the treatment of low back pain: a case study.

The purposes of this case report are (1) to describe an examination approach that relates identification of an impairment to a disability and (2) to describe an eclectic treatment approach for an individual with low back pain (LBP). The individual described in this case report is an intercollegiate athlete who, because of chronic LBP, was unable to perform his sport of pole vaulting. The findings of the physical therapy examination suggested that an impairment of lumbar motion prevented the patient from assuming the spinal position necessary for pole vaulting. The goals of the treatment consisted of increasing the patient's lumbar motion to that required for pole vaulting and to have the patient pole vault without pain or stiffness. The treatment approach that was used combined procedures described by Maitland, McKenzie, and others. The rationale for the use of these procedures and their limitations are discussed.

Biobehavioral factors affecting pain and disability in low back pain: mechanisms and assessment.

Patients with recurrent or persistent low back pain (LBP) and disability represent a formidable challenge to physical therapists. Classic models of disease and pain mechanisms do not adequately explain the commonly observed discrepancies between the extent of pathology and reported pain, or the level of pain and disability. Research over the past decade that considers the interactive role of biological, environmental, and psychological processes in pain and disability has supported the involvement of a number of biobehavioral factors in these conditions. Physical therapists and other health care providers have become more aware of these factors and their impact on the evaluation, treatment, and management of LBP. Despite this recognition, little information is available that translates the implications of this research to direct care within physical therapy practice. The purposes of this article are (1) to provide an operational definition of biobehavioral factors; (2) to review the role of these factors in the clinical presentation of LBP, functional limitation, and disability; (3) to identify commonly used approaches for their recognition and quantification; (4) to illustrate how an understanding of biobehavioral factors can assist the physical therapist in evaluation and treatment of patients with LBP; and (5) to identify certain gaps in current knowledge of the role of biobehavioral factors and their application in physical therapy. Given the central role assumed by many physical therapists in the management of LBP, acknowledging and addressing these factors in clinical practice should assist in the prevention of chronic LBP and disability, as well as potentially improve physical therapy interventions and management.

Magnetic resonance imaging in low back pain: general principles and clinical issues.

The purpose of this article is to provide an overview of the general principles of lumbar magnetic resonance imaging (MRI), including signal generation and image interpretation. Additionally, a discussion of the clinical usefulness as it relates to lumbar MRI is presented using degenerative disk disease as an example. Lumbar MRI provides high-resolution, multiaxial, multiplanar views that have high contrast between soft tissues. Obtaining these images in vivo creates minimal risk for patients and provides examiners with an excellent mechanism to study anatomic detail and the biochemical composition of the lumbar spine. Different tissue characteristics known as T1, T2, and proton density may be accentuated, allowing examiners to detect variations in tissue shape and hydration that may correspond to disease processes. There is strong agreement that lumbar MRI is indicated for the evaluation of patients with risk factors for neoplastic or infectious disorders or in persons with coexisting evidence of neurologic impairment. The utilization of lumbar MRI in patients with low back pain (LBP), however, is controversial. Lumbar MRI has a high technical capacity to detect degenerative disk disease, bulging and herniated disks, and distortions in the thecal sac or nerve roots associated with these conditions. The diagnostic accuracy, however, of most lumbar anatomic impairments related to the symptoms of LBP is low or unknown. Although lumbar MRI remains as an excellent tool to study morphology, findings must be related to data from clinical examinations to provide meaningful judgments.

Reliability of the attraction method for measuring lumbar spine backward bending.

The distraction method is one method used to measure forward bending of the spine. Although this technique, which requires the use of a tape measure held over the spine and the location of anatomical landmarks, appears to be highly practical, previous studies have not examined its use for measuring backward bending. The purpose of our study was to determine the reliability of a similar technique, the attraction method, for measuring backward bending of the lumbar spine and to examine whether subjects with low back pain (LBP) could perform similar motion as subjects without LBP. Two groups composed of 100 subjects each, one with "significant" limiting low back pain (SLBP) and the other without "significant" limiting low back pain (NSLBP), were evaluated twice by a physical therapist to assess intrarater reliability. To assess interrater reliability, 11 subjects from the NSLBP Group were evaluated by a second therapist. For the total sample of 200 subjects, the intraclass correlation coefficient (ICC) for intrarater reliability was .95; for the SLBP Group, the ICC was .93; and for the NSLBP Group, the ICC was .90. For the sample of 11 NSLBP Group subjects examined for interrater reliability, the ICC was .94. Using a Kolmogorov-Smirnov test, we found the distribution for backward bending of the two groups to be significantly different. The attraction method, thus, appears to be a reliable method for measuring backward bending of the lumbar spine.

Validity of derived measurements of leg-length differences obtained by use of a tape measure.

Determining the difference in the length of an individual's legs is often an important component of a musculoskeletal examination. Although measurements are easily obtained with a tape measure, the validity of these measurements is not known. The purpose of this study was to examine the validity of determinations of leg-length differences (LLDs) obtained by use of a specified tape measure method (TMM). Leg-length differences using the TMM and a radiographic technique were determined for 10 subjects who were candidates for clinical leg-length measurements and for 9 healthy control subjects. Validity of the TMM measurements was determined by assessing the degree of agreement between TMM-obtained LLDs and those obtained by the radiographic method. Validity estimates as determined by intraclass correlation coefficients (ICCs) were .770 for patients, .359 for healthy subjects, and .683 for all subjects. When the means of the two values obtained by use of the TMM were compared with the radiographic measurements, the ICCs were .852 for the patient group, .637 for the healthy subjects, and .793 for all subjects. This study suggests that TMM-derived LLD measurements are valid indicators of leg-length inequality and that the estimates of validity are improved by using the average of two determinations rather than a single determination.

Issues in determining treatment effectiveness of manual therapy.

The purpose of this article is to examine issues pertinent to the study of the clinical effectiveness of manual therapy. The need for complete operational definitions of treatment procedures, criteria for altering treatment, and criteria for subject selection is discussed. The need for studies that examine the relationship among impairment, functional limitations, and disability is also discussed. Considerations for selecting relevant outcome measures are presented. The use of a clinical decision-making model to direct the design of clinical studies on manual therapy is described. This article concludes with a discussion of alternative ways for clinicians to contribute to the manual therapy literature.

The frequency and incidence of low back pain/sciatica in an urban population.

The frequency, incidence and severity of low back pain was assessed by a random telephone survey of 314 urban New Zealanders. Relationships between the severity and frequency of low back pain and referred lower extremity pain and other variables such as occupation, recreation, age, sex and predominant working posture was analysed. Point incidence was 17.5%, weekly incidence 33.4%, yearly incidence 63.7% and total incidence 79%. Some 28.3% get frequent minor episodes and 6.4% get frequent severe episodes of low back pain. Nearly 50% suffer the initial episode before the age of 30 years. Of those suffering low back pain within the last seven days, 14.3% experience reference below the knee and the total incidence of below knee pain was 13.7%. Over half (51.6%) have pain that has lasted seven days or less, but a third have had pain for longer than seven weeks. No correlation between the incidence of low back pain and referred pain and occupational posture was found. In conclusion, this telephone survey established that the incidence of low back pain in New Zealand is similar to that reported in overseas studies. The survey could not establish differences in low back pain characteristics across different social groupings, nor could a relationship between occupational posture and low back pain be established.