Early and intensive Motor Training for people with spinal cord injuries (the SCI-MT Trial): description of the intervention.

STUDY DESIGN: Descriptive. OBJECTIVES: The primary objective is to describe the intervention that will be provided in a large multi-centre randomised controlled trial titled: Early and Intensive Motor Training for people with Spinal Cord Injuries (the SCI-MT Trial). The secondary objective is to describe the strategies that will be used to operationalise and standardise the Motor Training provided to participants while keeping the intervention person-centred. METHODS: The paper focuses on the rationale and principles of Motor Training for people with spinal cord injuries (SCI). The description of the intervention is based on the Template for Intervention Description and Replication (TIDieR) checklist. Specifically, it addresses the following 6 criteria of the TIDieR checklist: why the effectiveness of Motor Training is being examined; what, how, where and when the Motor Training will be administered; and how much Motor Training will be provided. RESULTS: A detailed intervention manual has been developed to help standardise the delivery of the intervention. CONCLUSIONS: This paper describes the details of a complex intervention administered as part of a large randomised controlled trial. It will facilitate the subsequent interpretation of the trial results and enable the intervention to be reproduced in clinical practice and future trials.

Anxiety affects disability and quality of life in patients with painful diabetic neuropathy.

BACKGROUND: Painful diabetic neuropathy (PDN) is known to negatively affect psychosocial functioning as expressed by enhanced levels of anxiety and depression. The aim of this study was to specify diabetes and pain-related fears. METHODS: This questionnaire-based cross-sectional study included 154 patients with PDN (mean age 65.7 ± 6.6 years). Correlation analyses corrected for age, gender, pain intensity, pain duration and insulin treatment were performed to assess the associations of fear of hypoglycaemia (Hypoglycaemia Fear Survey, HFS), kinesiophobia (Tampa Scale of Kinesiophobia, TSK), fear of pain (Pain Anxiety Symptom Scale, PASS-20), fear of falling (Falls Efficacy Scale-I, FES-I), fear of fatigue (Tampa Scale of Fatigue, TSF) and fear of negative evaluation (Brief Fear of Negative Evaluation Scale, BFNE), with quality of life (QoL) (Norfolk Quality of Life Questionnaire, Diabetic Neuropathy Version, QOL-DN) and disability (Pain Disability Index, PDI), respectively. RESULTS: In univariate analyses, all fears were independently associated with QOL-DN and PDI (p < 0.001 for all variables). Linear regression models including all fears and confounders, showed that pain intensity, pain duration and FES-I were significantly associated with QOL-DN (R2  = 0.603). Pain intensity, male gender and FES-I were significantly associated with PDI (R2  = 0.526). CONCLUSIONS: After controlling for confounders, levels of pain intensity, duration of pain and fear of falling were negatively associated with QoL in patients with PDN. Pain intensity, male gender and fear of falling were positively associated with disability. Specifying fears enables us to identify potential targets for behavioural interventions that aim to improve psychosocial well-being in patients with PDN. SIGNIFICANCE: This study shows that patients with PDN suffer from various fears, which should enable us to design a treatment strategy that directly targets these fears, hereby improving physical and psychosocial well-being in these patients.

BclI glucocorticoid receptor polymorphism is associated with greater body fatness: the Hoorn and CODAM studies.

CONTEXT: The BclI polymorphism in the glucocorticoid receptor (GR) gene is associated with enhanced glucocorticoid (GC) sensitivity. OBJECTIVE: Our objective was to investigate the association of the BclI polymorphism with body fatness and insulin resistance. DESIGN AND SETTING: We conducted an observational cohort study, combining data from 2 cohort studies enriched with individuals with impaired glucose metabolism and/or diabetes mellitus type 2 (DM2). PATIENTS AND METHODS: We examined 1228 participants (mean age 64.7 years, 45% women) from the Cohort Study on Diabetes and Atherosclerosis Maastricht (CODAM, n = 543) and the Hoorn Study (n = 685). Body mass index (BMI), waist and hip circumferences, and waist-to-hip ratio (WHR) were obtained; insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA2-IR). RESULTS: We identified 519 noncarriers (CC), 540 heterozygous (CG) carriers, and 169 homozygous (GG) carriers of the G-allele of the BclI polymorphism. Homozygous carriers had a higher BMI (28.9 vs 27.9 kg/m(2)) and waist (99.6 vs 97.2 cm) and hip (105.5 vs 103.2 cm) circumference compared with noncarriers, also after adjustment for age, sex, cohort, glucose tolerance, and lifestyle risk factors: ß = 0.94 kg/m(2) (95% confidence interval, 0.24-1.63), ß = 2.84 cm (0.95;4.73) and ß = 2.38 cm (0.88-3.87), respectively. Similar results were obtained when comparing homozygous carriers with heterozygous carriers: ß = 1.03 kg/m(2) (0.34-1.72), ß = 2.20 cm (0.31-4.08) and ß = 1.99 cm (0.51-3.48), respectively. There were no differences in WHR. Ln-HOMA2-IR was higher in GG carriers compared with CG carriers; 0.29 vs 0.17 [ß = 0.09 (0.01-0.17)], but this effect was attenuated after adjustment for BMI [ß = 0.04 (-0.04 to 0.11)]. CONCLUSION: Homozygous carriers of the BclI polymorphism of the GR gene have significantly greater total body fatness, contributing to higher HOMA2-IR, compared with heterozygous carriers and noncarriers.

Fas ligand gene expression is directly regulated by stress-inducible heat shock transcription factor-1.

Heat shock transcription factor-1 (HSF-1) is the primary stress responsive transcription factor that regulates expression of heat shock proteins (Hsps) in response to elevated temperature. We show that the transcriptional activity of HSF-1 can also directly mediate hyperthermia-induced Fas ligand (FasL) expression in activated T cells. We identify a conserved region within the human FasL promoter spanning from -276 to -236 upstream of the translational start site that contains two 15 bp non-identical adjacent HSF-1-binding sites or heat shock elements (HSEs) separated by 11 bp. Both the distal HSE (HSE1) (extending from -276 to -262) and the proximal HSE (HSE2) (spanning from -250 to -236) consist of two perfect and one imperfect nGAAn pentamers. We show the direct binding of HSF-1 to these elements and that mutation of these sites abrogates the ability of HSF-1 to bind and drive promoter activity. HSF-1 associates with these elements in a cooperative manner to mediate optimal promoter activity. We propose that the ability of HSF-1 to mediate stress-inducible expression of FasL extends its classical function as a regulator of Hsps to encompass a function for this transcription factor in the regulation of immune function and homeostasis.

Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 ligand (CD95L) are potent inducers of apoptosis in various tumour cell types. Death receptors DR4 and DR5 can induce and decoy receptors DcR1 and DcR2 can inhibit TRAIL-mediated apoptosis. The study aim was to investigate whether anticancer agents can modulate similarly TRAIL-receptor and CD95 membrane expression and TRAIL and CD95L sensitivity. Three colon carcinoma cell lines (Caco-2, Colo320 and SW948) were treated with 5-fluorouracil (5-FU), cisplatin or interferon-gamma. TRAIL-receptor and CD95 membrane expression was determined flow cytometrically. Sensitivity to TRAIL or CD95L agonistic anti-CD95 antibody was determined with cytotoxicity and apoptosis assays. SW948 showed highest TRAIL sensitivity. The protein synthesis inhibitor cycloheximide decreased FLICE-like inhibitory protein levels in all cell lines, and the TRAIL-resistant cell lines Caco-2 and Colo320 became sensitive for TRAIL. Exposure of the cell lines to 5-FU, cisplatin and interferon-gamma left TRAIL-receptor membrane expression and TRAIL sensitivity unaffected. CD95 membrane expression and anti-CD95 sensitivity was, however, modulated by the same drugs in all lines. Cisplatin and interferon-gamma raised CD95 membrane levels 6-8-fold, interferon-gamma also increased anti-CD95 sensitivity. These results indicate that the CD95 and TRAIL pathways use different mechanisms to respond to various anticancer agents. Induced CD95 membrane upregulation was associated with increased anti-CD95 sensitivity, whereas no upregulation of TRAIL-receptor membrane expression or TRAIL sensitisation could be established. For optimal use of TRAIL-mediated apoptosis for cancer therapy in certain tumours, downregulation of intracellular inhibiting factors may be required.

Modulation of death receptor pathways in oncology.

Chemotherapeutic efficacy is hampered by occurrence of drug resistance. Several mechanisms cause this phenomenon. A final common factor is the reduced capacity of resistant cells to go into apoptosis following treatment with DNA-damaging agents. It is therefore interesting to search for ways to facilitate this apoptotic process following use of chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), FasL and TNF-related apoptosis-inducing ligand (TRAIL) might be interesting candidates as they are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands potentiate chemotherapeutic drug effects in preclinical models. For the clinical application of TNF, FasL and TRAIL, it is of primary importance that their safety be guaranteed. RhTNF is the only ligand currently used in humans. However, systemic rhTNF has shown low antitumor activity and higher doses induce severe sepsis-like toxicity. Perfusion setting aimed at limb preservation with rhTNF plus melphalan is currently used in sarcoma patients. A number of options have been tested in the preclinical setting that might allow circumvention of TNF toxicity in the clinic. Systemic rhFasL administration in humans is not yet feasible because of observed severe liver toxicity in mice due to Fas-mediated apoptosis of hepatocytes. Measures to circumvent liver toxicity have not yet been exploited. Another option for using FasL in the clinic may be to identify an alternative route of administration. In the animal model, FasL appeared to be less toxic for the liver compared with anti-Fas antibodies when administered intraperitoneally. There are relatively nontoxic modulators of the Fas death pathway, such as interferon and nonsteroidal antiinflammatory drugs (NSAIDs), which might prove interesting in combination with chemotherapy. Finally, it may be possible to produce a modified FasL with a reduced toxicity profile. TRAIL, produced as soluble, zinc-stabilized rhTRAIL seems to be without preclinical toxicity. Agonistic DR4 and DR5 antibodies against their TRAIL death receptor are being studied as another potential clinical option to induce apoptosis. Due to the synergistic effect observed in the preclinical setting between death receptor ligands and other modulators of the death receptor pathways and chemotherapy, it may well be that this approach is especially of value in the clinic when combined with chemotherapy. Ideally, choices for specific (modified) death receptor ligands for the treatment of patients can be rationally made based on tumor characteristics.

Speech perception performance of congenitally deaf patients with a cochlear implant: the effect of age at implantation.

The relation between age at cochlear implantation and long-term open-set speech recognition was studied in a group of nine congenitally deaf children. The age at cochlear implant surgery ranged from 4 to 13 years. The results showed that there was a tendency toward poorer results in the children implanted at a relatively older age. However, the results also indicated that an upper limit for age at implantation cannot yet be defined in these children.

Speech perception performance of children with a cochlear implant compared to that of children with conventional hearing aids. II. Results of prelingually deaf children.

In a previous paper, a method was introduced to transform the results obtained by children with a cochlear implant (CI) on a battery of speech perception tests into an overall value, the "equivalent hearing loss" value. This was achieved by matching the speech perception test scores with those of a reference group of children with conventional hearing aids and hearing loss ranging from 50 to 130 dB hearing level (HL). The equivalent hearing loss values of 16 prelingually deaf children with a CI were plotted as a function of time. There was considerable spread in the rate of progress made by the children in terms of the equivalent hearing loss values. The variables studied, age at onset of deafness/duration of deafness (in the present study, these two factors were indistinguishable) and the communication mode used at the children's school, accounted for 64% of the variance in speech perception performance. A plateau in the performance of the better performers was found which seemed to be caused by the level of hearing (the aided thresholds) with the CI.

Degree of tumour differentiation as a prognostic factor in advanced laryngeal cancer.

Degree of tumour differentiation as a prognostic factor in advanced laryngeal cancer. As part of a retrospective analysis on treatment results in 139 patients with advanced laryngeal squamous cell carcinoma (T3-4) differentiation grade of the tumour was analyzed as a prognostic factor. Univariate analysis differentiation grade was related to tumour size, presence of neck node metastasis and conversion of N-stage during follow-up. For statistical analysis, patients with G1-G2 and G3-G4 were grouped. Prognosis for G3-G4 carcinomas is significantly worse for disease specific survival (p < 0.025), due to significantly more regional recurrence (p = 0.05). At multivariate analysis it turned out that regional control and disease specific survival in patients with no palpable neck nodes were adversely affected by the histological degree of differentiation of the diagnostic biopsy. For this group of patients extensive treatment of neck nodes is recommended.