Transcutaneous sacral neurostimulation for irritative voiding dysfunction

with refractory irritative voiding dysfunction. Following an initial response, patients may successfully apply this treatment themselves to ensure long-term relief. Objective: Patients with irritative voiding dysfunction are often unresponsive to standard clinical treatment. We evaluated the response of such individuals to transcutaneous electrical stimulation of the third sacral nerve. Methods: 32 patients with refractory irritative voiding dysfunction (31 female and 1 male; mean age 47 years) were recruited to the study. Ambulatory transcutaneous electrical neurostimulation was applied bilaterally to the third sacral dermatomes for 1 week. Symptoms of frequency, nocturia, urgency, and bladder pain were scored by each patient throughout and up to 6 months following treatment. Results: The mean daytime frequency was reduced from 11.3 to 7.96 (p = 0.01). Nocturia episodes were reduced from a mean of 2.6 to 1.8 (p = 0.01). Urgency and bladder pain mean symptom scores were reduced from 5.97 to 4.89 and from 1.48 to 0.64, respectively. After stopping therapy, symptoms returned to pretreatment levels within 2 weeks in 40% of the patients and within 6 months in 100%, Three patients who continued with neurostimulation remained satisfied with this treatment modality at 6 months. Conclusions: Transcutaneous third sacral nerve stimulation may be an effective and noninvasive ambulatory technique for the treatment of patients with refractory irritative voiding dysfunction. Following an initial response, patients may successfully apply this treatment themselves to ensure long-term relief.

Treatment of intestinal Behçet's syndrome with chimeric tumour necrosis factor alpha antibody

Few patients with Behçet's syndrome have gastrointestinal ulceration. Such patients are difficult to treat and have a higher mortality. Faced with refractory symptoms in two patients with intestinal Behçet's, we used the tumour necrosis factor alpha (TNF-alpha) monoclonal antibody infliximab to induce remission. Both women (one aged 27 years, the other 30 years) presented with orogenital ulceration, pustular rash, abdominal pain, bloody diarrhoea due to colonic ulceration, weight loss, and synovitis. One had thrombophlebitis, digital vasculitis, perianal fistula, and paracolic abscess; the other had conjunctivitis and an ulcer in the natal cleft. Treatment with prednisolone, methyl prednisolone, and thalidomide in one and prednisolone, colchicine, and cyclosporin in the other was ineffective. After full discussion, infliximab (3 mg/kg, dose reduced because of recent sepsis in one, and 5 mg/kg in the other) was administered. Within 10 days the ulcers healed, with resolution of bloody diarrhoea and all extraintestinal manifestations. A second infusion of infliximab was necessary eight weeks later in one case, followed by sustained (>15 months) remission on low dose thalidomide. Remission was initially sustained for 12 months in the other but thalidomide had to be stopped due to intolerance, and a good response to retreatment lasted only 12 weeks without immunosuppression, before a third infusion. The cause of Behçet's syndrome is unknown but peripheral blood CD45 gammadelta T cells in Behçet's produce >50-fold more TNF-alpha than controls when stimulated with phorbol myristate acetate and anti-CD3. Infliximab could have a role for inducing remission in Behçet's syndrome.

Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34 + cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript andor exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicingprocessing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expressionsplicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34 + cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processespathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

Intermedin and calcitonin gene-related peptide fail to shine in acute coronary syndrome

Aims: To measure levels of intermedin and calcitonin gene-related peptide (CGRP) in acute coronary syndrome (ACS) and to determine if they are elevated. 
Methods and results: 81 patients admitted with suspected ACS were enrolled into the study. 50 were confirmed ACS by ACC (2000) guidelines and 31 were in a control group as non-cardiac chest pain. Intermedin was nonsignificantly elevated 6.14 pg/ml vs 4.84 pg/ml b8 h in the ACS group; sensitivity 68%, specificity 63% on presenting sample. Intermedinwas significantly elevated in those patientswho had an initially negative troponin T (b0.03 ng/ml) on presentation, 6.67 pg/ml vs 4.84 pg/ml, p = 0.03. CGRP was significantly elevated in ACS patients, 8–b16 h after pain onset, 8.67 pg/ml vs 7.08 pg/ml, p= 0.036. However, it didn't aid diagnosis in initially negative troponin patients; sensitivity 61%, specificity 60% on presenting sample. Both intermedin and CGRP were elevated in STEMI patients on a first sample, but only intermedin was significantly elevated; 7.03 pg/ml vs 4.84 pg/ml, p =0.02 and 8.87 pg/ml vs 7.03 pg/ml p = 0.093, respectively. High sensitivity troponin T was significant elevated in the ACS group at b8 h (414.9 vs 17.22, p= 0.006) and at 8–b16 h (3325.27 vs 21.54, p = 0.02). 
Conclusions: Both intermedin and CGRP are detectable in human patients. Levels showa trend to elevation in ACS, with CGRP being significantly raised N8 h after pain onset. The degree of elevation will have limited clinical applicability.

The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis

We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon Lefevre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early,onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T>A/p. V129E, c.935A>G/p.Q312R, and c.1235A>G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 mu moles/mg/min vs. 1,678.7 +/- SD 527.2 mu moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS. (C) 2004 Wiley-Liss, Inc.

Islands of pain in a sea of change: Behaviour analysis and bereavement,

The paper Bereavement: A behavioural process (Dillenburger & Keenan, 1994) was first published within a vacuum of behaviour analytic thinking or research in this field. The paper was meant to be a first step in stimulating others to contribute to the understanding of one of the most complex, yet most universal, human behavioural processes. The only behaviour analyst addressing the issues directly was Calkin (1990). Recently, after reading our original 1994 paper, Beth Sulzer-Azaroff suggested that we should solicit comments directly from the behaviour analytic community. This we did with the help of Erik Arntzen and now the reprint and the commentaries in this edition of the European Journal of Behaviour Analysis (EJBA) fully embrace and extend the contribution of behaviour analysis to the understanding of the behavioural process that is bereavement.

Randomized controlled trial of interferential therapy and manipulative therapy for acute low back pain.

Study Design. A multi-center assessor-blinded randomized clinical trial was conducted. Objectives. To investigate the relative effectiveness of interferential therapy and manipulative therapy for patients with acute low back pain when used as sole treatments and in combination. Summary of Background Data. Both manipulative therapy and interferential therapy are commonly used treatments for low back pain. Evidence for the effectiveness of manipulative therapy is available only for the short term. There is no evidence for interferential therapy and no study has investigated the effectiveness of interferential therapy combined with manipulative therapy. Methods. Consenting subjects (n=240) were randomly assigned to receive a copy of the Back Book and either manipulative therapy (MT; n=80), interferential therapy (IFT; n=80) or combined manipulative therapy and interferential therapy (CT; n=80). Follow-up outcome questionnaires were posted at discharge, 6 and 12 months. Results. The groups were balanced at baseline for low back pain and demographic characteristics. All interventions were found to significantly reduce functional disability and pain and increase quality of life at discharge and to maintain these improvements at 6 and 12 months. No significant differences were found between groups for reported LBP recurrence, work absenteeism, medication consumption, exercise participation and healthcare use at 12 months. Conclusions. For acute low back pain, interferential therapy whether used in isolation or in combination with manipulative therapy was as effective as manipulative therapy alone (in addition to the Back Book).

A descriptive study of the usage of spinal manipulative therapy techniques within a randomised clinical trial in acute low back pain

The majority of randomized clinical trials (RCTs) of spinal manipulative therapy have not adequately de?ned the terms ‘mobilization’ and ‘manipulation’, nor distinguished between these terms in reporting the trial interventions. The purpose of this study was to describe the spinal manipulative therapy techniques utilized within a RCT of manipulative therapy (MT; n=80), interferential therapy (IFT; n=80), and a combination of both (CT; n=80) for people with acute low back pain (LBP). Spinal manipulative therapy was de?ned as any ‘mobilization’ (low velocity manual force without a thrust) or ‘manipulation’ (high velocity
thrust) techniques of the spine described by Maitland and Cyriax.
The 16 physiotherapists, all members of the Society of Orthopaedic Medicine, utilized three spinal manipulative therapy patterns in the RCT: Maitland Mobilization (40.4%, n=59), Maitland Mobilization/Cyriax Manipulation (40.4%, n=59) and Cyriax Manipulation (19.1%, n=28). There was a signi?cant difference between the MT and CT groups in their usage of spinal manipulative therapy techniques (w2=9.178; df=2;P=0.01); subjects randomized to the CT group received three times more Cyriax Manipulation (29.2%, n=21/72) than those randomized to the MT group (9.5%, n=7/74; df=1; P=0.003).
The use of mobilization techniques within the trial was comparable with their usage by the general population of physiotherapists in Britain and Ireland for LBP management. However, the usage of manipulation techniques was considerably higher than reported in physiotherapy surveys and may re?ect the postgraduate training of trial therapists.