Splinting for carpal tunnel syndrome: prognostic indicators of success

OBJECTIVES: To identify (combinations of) prognostic indicators for the long term success of splinting in patients with electrophysiologically confirmed idiopathic carpal tunnel syndrome (CTS). METHODS: This study was conducted within the framework of a randomised controlled trial on the efficacy of splinting and surgery for CTS. Patients randomised to splinting received a wrist splint, which they had to wear during the night for at least six weeks. To assess the long term success, patients were asked to indicate whether there was any improvement 12 months after randomisation. Potential prognostic indicators included variables from the history taking and physical examination, self administered questionnaires on severity of symptoms, and electrodiagnostic studies. Multiple logistic regression was used to identify (combinations of) prognostic indicators. RESULTS: Of the 89 patients randomised to splinting, 83 attended the follow up measurement at 12 months, of whom 60 reported improvement. However, 34 patients had received one or more additional types of treatment during the follow up period and were therefore considered as treatment failures for splinting, resulting in a final success rate of 31% for splinting (26 of 83 patients). Only two prognostic indicators could be identified, namely a short duration of CTS complaints (one year or less) and a score of 6 or less for severity of paraesthesia at night at baseline. CONCLUSIONS: For patients to whom both factors applied, the predicted probability of treatment success, according to the model, was 62%. The overall percentage of patients who were correctly classified by the model was 78% (95% CI 69% to 87%).     

A fully human anti-Ep-CAM scFv-beta-glucuronidase fusion protein for selective chemotherapy with a glucuronide prodrug

Monoclonal antibodies against tumour-associated antigens could be useful to deliver enzymes selectively to the site of a tumour for activation of a non-toxic prodrug. A completely human fusion protein may be advantageous for repeated administration, as host immune responses may be avoided. We have constructed a fusion protein consisting of a human single chain Fv antibody, C28, against the epithelial cell adhesion molecule and the human enzyme beta-glucuronidase. The sequences encoding C28 and human enzyme beta-glucuronidase were joined by a sequence encoding a flexible linker, and were preceded by the IgGkappa signal sequence for secretion of the fusion protein. A CHO cell line was engineered to secrete C28-beta-glucuronidase fusion protein. Antibody specificity and enzyme activity were retained in the secreted fusion protein that had an apparent molecular mass of 100 kDa under denaturing conditions. The fusion protein was able to convert a non-toxic prodrug of doxorubicin, N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate to doxorubicin, resulting in cytotoxicity. A bystander effect was demonstrated, as doxorubicin was detected in all cells after N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate administration when only 10% of the cells expressed the fusion protein. This is the first fully human and functional fusion protein consisting of an scFv against epithelial cell adhesion molecule and human enzyme beta-glucuronidase for future use in tumour-specific activation of a non-toxic glucuronide prodrug.     

Secreted and tumour targeted human carboxylesterase for activation of irinotecan

Irinotecan (CPT-11) is an anticancer agent for the treatment of colon cancer. CPT-11 can be considered as a prodrug, since it needs to be activated into the toxic drug SN-38 by the enzyme carboxylesterase. An approach to achieve tumour specific activation of CPT-11 is to transduce the cDNA encoding carboxylesterase into tumour cells. A secreted form of carboxylesterase may diffuse through a tumour mass and may activate CPT-11 extracellularly. This could enhance the antitumour efficacy by exerting a bystander effect on untransduced cells. In addition a secreted tumour-targeted form of carboxylesterase should prevent leakage of the enzyme from the site of the tumour into the circulation. We have constructed a secreted form of human liver carboxylesterase-2 by deletion of the cellular retention signal and by cloning the cDNA downstream of an Ig kappa leader sequence. The protein was secreted by transfected cells and showed both enzyme activity and efficient CPT-11 activation. To obtain a secreted, tumour-targeted form of carboxylesterase-2 the cDNA encoding the human scFv antibody C28 directed against the epithelial cell adhesion molecule EpCAM, was inserted between the leader sequence and carboxylesterase-2. This fusion protein showed CPT-11 activation and specific binding to EpCAM expressing cells. Importantly, in combination with CPT-11 both recombinant carboxylesterase proteins exerted strong antiproliferative effects on human colon cancer cells. They are, therefore, promising new tools for gene directed enzyme prodrug therapy approaches for the treatment of colon carcinoma with CPT-11.     

Conditionally replicative adenovirus expressing p53 exhibits enhanced oncolytic potency

Conditionally replicative adenoviruses (CRAds) hold promise as anticancer agents. Their potency depends on their replication efficiency in cancer cells and their capacity to destroy these cells by oncolysis. In this regard, a critical determinant is the capacity of CRAds to induce cell death at late stages of infection to release their progeny. One of the cell death pathways that are exploited by adenoviruses involves the tumor suppressor protein p53. Unfortunately, many cancer cells have a nonfunctional p53 pathway and thus do not effectively support CRAd-induced cell death. We hypothesized that restoration of the p53-dependent cell death pathway in cancer cells would promote CRAd-induced cell lysis. Exogenous expression of p53 in human cancer cells during adenovirus replication accelerated cell death by several days and augmented early virus progeny release. The p53-enhanced oncolysis occurred independent of E1A binding to pRb and independent of E3 functions. On the basis of these findings, we constructed a new CRAd, AdDelta24-p53. This virus expressed functional p53 while replicating in cancer cells. Most importantly, AdDelta24-p53 exhibited enhanced oncolytic potency on 80% of tested human cancer cell lines of various tissue origins and with different p53 status. CRAd potency was increased up to >100-fold by p53 expression. We conclude that CRAds expressing p53 are promising new agents for more effective treatment of many human cancers.     

A changing paradigm of glioma biology

The past 30 years have witnessed a major paradigm shift in brain tumor research with the development of a wide variety of molecular     

Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study

Aims/hypothesis. Currently, three categories of measures are used to assess cardiovascular autonomic dysfunction: measures of the Ewing-test, measures of heart-rate variability, and measures of baroreflex sensitivity. We studied the determinants of these measures obtained from cardiovascular autonomic function tests in the Hoorn Study. Methods. The study group (n = 631) consisted of a glucose-tolerance-stratified sample from a 50- to 75-year-old group of people. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (a) spontaneous breathing, (b) six deep breaths over one minute, and (c) an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (three Ewing, six heart-rate variability and one baroreflex sensitivity). As possible determinants we considered age, sex, glucose tolerance, cardiovascular disease, use of anti-hypertensive drugs, anthropometric factors, metabolic factors and lifestyle factors. Results. Multivariate analysis showed that eight of ten cardiovascular autonomic function measures were most strongly associated with glucose tolerance. Furthermore, measures were moderately associated with age, sex, waist-to-hip ratio, use of anti-hypertensive drugs, and insulin. The measures were weakly associated with coronary artery disease but not with lipids. The strongest determinants seemed to differ between subjects with and without diabetes: in the non-diabetic subjects the most strongly associated were age and use of anti-hypertensive drugs and in subjects with diabetes, insulin. No consistent differences in association between the three categories of measures were observed. Conclusion/interpretation. The strongest determinants of autonomic function were age, presence of diabetes and use of anti-hypertensive drugs. [Diabetologia (2000) 43: 561–570] Received: 25 October 1999 and in revised form: 3 January 2000     

Ambulatory blood pressure monitoring

Ambulatory blood pressure monitoring (ABPM) in adults is proving to be useful. The aim of this study was to determine if ABPM is accurate in the lower blood pressure range encountered in children and, equally important, whether it is acceptable to children. Thirty one children, between the ages of 6 and 18 years, were assessed using an ambulatory blood pressure monitor that uses an auscultatory method. Blood pressure was measured in the contralateral arm with a mercury sphygmomanometer and an oscillometric device at the beginning and end of the study for comparison. Over a blood pressure range of 90-130 mm Hg systolic and 40-80 mm Hg diastolic, a close agreement was found with the sphygmomanometer; the limits of agreement (+/- 2 SD) were 11.6 mm Hg for systolic blood pressure and 13.6 mm Hg for diastolic blood pressure. The bias was less than 1.0 mm Hg. The ambulatory device was worn by all patients for at least 16 hours with an average of 52 recordings per patient. The majority found the device comfortable to wear and were not woken from sleep.     

Hypercalcaemia in a child with miliary tuberculosis

Hypercalcaemia and hypercalciuria were diagnosed in a 21-week-old boy with miliary tuberculosis. The tuberculosis was treated with isoniazid, rifampin and streptomycin. After 2 months, streptomycin was replaced by ethambutol. The hypercalcaemia was treated initially with prednisone, which decreased the serum 1,25 (OH)₂ cholecalciferol level but the serum calcium level remained unaltered. After calcium and vitamin D restriction, the serum calcium level normalized within 1 day. The patient's tuberculosis was treated and he remains well.