Missense mutations to the TSC1 gene cause tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Here we investigate the effects of putative TSC1 missense mutations identified in individuals with signs and/or symptoms of TSC on TSC1-TSC2 complex formation and mTOR signalling. We show that specific amino-acid substitutions close to the N-terminal of TSC1 reduce steady-state levels of TSC1, resulting in the activation of mTOR signalling and leading to the symptoms of TSC.     

Prevention of glucocorticoid induced osteoporosis with alendronate or alfacalcidol: relations of change in bone mineral density, bone markers, and calcium homeostasis

OBJECTIVE: To explore the relation of changes in measures of bone turnover and changes in bone mineral density (BMD) of the lumbar spine and total hip over 18 months in a double-blinded, randomized trial, comparing the effect of alfacalcidol (101 patients) versus alendronate (100 patients) on BMD in patients who recently started treatment with glucocorticoids for various rheumatic diseases. METHODS: Associations between changes in serum procollagen type I C-propeptide (P1CP), fasting urine N-terminal telopeptide of type I collagen (NTx), serum calcium, parathyroid hormone (PTH), osteocalcin, and change from baseline in BMD over 18 months were explored with regression and correlation analyses. RESULTS: In both treatment groups, there was a statistically significant decrease in NTx. In the alfacalcidol group there was also a significant increase in P1CP and osteocalcin, in contrast to the alendronate group, but BMD in the alfacalcidol decreased versus an increase in the alendronate group (p < 0.001). In neither treatment group were changes in biochemical measures correlated with the change in BMD, with the exception of a negative correlation in the alendronate group between changes in total hip BMD and NTx. Use of alendronate resulted in an increased PTH in 27 patients, but the increase in BMD of these patients was not statistically significantly different compared to patients taking alendronate with normal PTH levels. CONCLUSION: Changes in BMD were not associated with changes in bone measures, with the exception of NTx in the alendronate group. For the patient taking glucocorticoids in clinical practice, the value of serial assessment of bone markers is low; changes in markers are no substitute for changes in BMD. ClinicalTrials.gov number: NCT00138983.     

The presence of persistent high-risk hpv genotypes in dysplastic cervical lesions is associated with progressive disease: Natural history up to 36 months

To evaluate the clinical significance of HPV genotyping for the prediction of progressive cervical intraepithelial neoplasia (CIN) in women with cytomorphologically abnormal smears, a prospective, blind, non-intervention study was performed. A total of 342 patients screened with cytomorphologically abnormal cervical smears were monitored every 3–4 months by cervical cytology, colposcopy and HPV testing using PCR. Women with progressive CIN disease were defined as patients developing lesions with a colposcopic impression of CIN III over more than 2 quadrants or resulting in a cytological smear equivalent to Pap 5. These patients were subsequently treated according to standard procedures. If any doubt arose about the true status of the patients (n = 75) these patients were censored and biop-sied. The mean follow-up time was 16.5 months (range 3–36 months). Nineteen women showed progressive CIN disease and all appeared to be continuously HPV-positive from the start of the study. At biopsy, all these patients were histologically classified as CIN III. Seventeen of these women were positive for high-risk HPV types. Two cases were classified as still unidentified HPV. No progression was seen in the absence of HPV DNA or in the presence of low-risk HPV types. In life-table analysis the cumulative rate of progressive, histologically verified CIN disease was 17% after 36 months. Further analyses showed that other risk factors such as age, sexarche, number of sexual partners or smoking hardly influenced the effect of HPV on progression. The results show that the continuous presence of high-risk HPV types in women with cytomorphologically abnormal smears is a strong marker for progressive CIN disease. © 1995 Wiley Liss. Inc.     

Quantitative evaluation of a beam-matching procedure using one-dimensional gamma analysis

This article provides a quantitative evaluation of Varian Medical Systems' beam matching procedure. A one-dimensional y analysis is employed to investigate the level of agreement of matched beams. A customized concept of one-dimensional gamma evaluation was designed. Our algorithm first performs a "local" fit of the reference and the evaluated datasets. For a particular point on the fitted evaluated curve, the y is derived as the shortest distance between the point and the fitted reference curve. This approach removes variations of the obtained y value related to the discrete character and noise in the original datasets. Criteria of 1 mm distance-to-agreement and 1% dose difference were used to evaluate the level of agreement of according profiles. Relative point and profile measurements were performed for all photon and electron beams of two Varian Clinacs 2100C/D. Matched beams show a good level of agreement. 70% of profiles completely pass the chosen criteria. The analysis of remaining 30% of the profiles demonstrates that measurement error becomes a limiting factor in achieving a better score. The highest obtained y value was 1.70. The quality of beam matching allowed us to treat according beams of both treatment units as "identical" and to use the reference beam data for the new unit. Nevertheless, the vendor's acceptance criteria of beam matching are much more benevolent. It might happen that the acceptance criteria are met, however, resulting quality of beam matching does not allow full interchangeability of beams.     

The Pain Associates' International Network Initiative: A Novel Practical Approach to the Challenge of Chronic Pain Management in Europe

Chronic pain is a debilitating condition with a multidimensional impact on the lives of patients, their families and communities. The public health burden of chronic pain is gathering recognition as a major healthcare problem in its own right and deserves closer attention. The challenge in treating chronic pain is to provide effective clinical management of a complex, multifaceted set of conditions that require a coordinated strategy of care. Epidemiological data and patient surveys have highlighted the areas of pain management that might be improved. These include a need for better understanding and documentation of the symptoms of chronic pain, standardized levels of care, improved communication among clinical personnel and with patients, and an updated education program for clinicians. For these reasons, new strategies aimed at improving the standards of pain management are needed. The Pain Associates' International Network (P.A.I.N.) Initiative was set up to devise practical methods for improving the quality of pain management for patients. These strategies have recently been put into practice through a number of activities: P.A.I.N. Workshops are meetings of international pain management professionals dedicated to discussing current management strategies and producing consensus recommendations for improving standards of care; P.A.I.N. Quality is a unique software program designed to help treating clinicians to document patient data and derive effective treatment plans; P.A.I.N. Online provides a web site forum for discussion of pain management topics; and P.A.I.N. Management is a clinician education program providing up‐to‐date training in pain management.