Rapamycin‐mediated suppression of renal cyst expansion in del34 Pkd1−/− mutant mouse embryos: An investigation of the feasibility of renal cyst prevention in the foetus

Aim: Polycystic kidney disease (PKD) in humans involves kidney cyst expansion beginning in utero. Recessive PKD can result in end‐stage renal disease (ESRD) within the first decade, whereas autosomal dominant PKD (ADPKD), caused by mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade of life. Inhibition of mTOR signalling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in foetal Pkd1 homozygous mutant mice. Methods: Pregnant Pkd1^+/? female mice (mated with Pkd1^+/? male mice) were treated with rapamycin from E14.5 to E17.5. Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2. Results: Numerous cysts were present in Pkd1^?/? kidneys, which were twice the weight of wild‐type kidneys. Cyst size was reduced by a third in rapamycin‐treated Pkd1^?/? kidney sections and kidney mass was reduced to near wild‐type levels. However, total cyst number was not reduced compared with control embryos. Pax2 expression and kidney development were unaltered in rapamycin‐treated mice but some lethality was observed in Pkd1^?/? null embryos. Conclusion: Rapamycin treatment reduces cyst formation in Pkd1^?/? mutant mice; therefore, the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. However, selective rapamycin‐associated lethality limits its usefulness as a treatment in utero.     

ERA SPECIFIC BIOCHEMICAL RECURRENCE-FREE SURVIVAL FOLLOWING RADICAL PROSTATECTOMY FOR CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE: We retrospectively reviewed a large series of men with clinically localized prostate cancer who underwent surgery to define the extent of stage migration and its influence on biochemical recurrence in 3 different eras of prostate cancer management. MATERIALS AND METHODS: A total of 2,370 men were treated with radical prostatectomy from 1982 to 1998. We analyzed the freedom from biochemical (prostate specific antigen) progression after radical prostatectomy. We compared the distribution of pathological stage by the year of surgery. We then compared the biochemical recurrence-free survival rate according to the different eras that reflect a change in prostate cancer management. RESULTS: There was a significant downward stage migration of prostate cancer and an increasing proportion of men who presented with organ confined disease in recent years. The actuarial biochemical recurrence-free rate was significantly different for patients who underwent surgery between 1982 and 1988, compared with those between 1989 and 1998 (p <0.001). These changes may have reflected the benefits of early detection with prostate specific antigen and digital rectal examination, better preoperative selection of patients for surgery as well as the effect of lead time. CONCLUSIONS: Widespread early detection programs for prostate cancer resulted in downward stage migration in men presenting with prostate cancer at our institution during the last 18 years. Also, we have demonstrated a biochemical recurrence-free survival advantage, probably secondary to an improved therapeutic outcome as well as lead time bias, in men who underwent surgery between 1989 and 1998, compared with those between 1982 and 1988. When trying to compare the efficacy of different treatment modalities for prostate cancer, the era in which patients underwent therapy is an important factor to be considered.     

The Importance of Atrial Fibrillation Burden and the Origin of Device‐Tailored Anticoagulation

The current paradigm for anticoagulation in patients with atrial fibrillation is based upon clinical risk factors for stroke without reference to the frequency or duration (i.e., burden) of atrial fibrillation episodes. In the last decade, increasing evidence derived from device‐based surveillance of atrial fibrillation has suggested that in some patients the burden of atrial fibrillation may be associated with thromboembolic risk. The development of rapidly acting oral anticoagulants and devices with remote monitoring capability has allowed the testing of a strategy of tailored or “pill‐in‐the‐pocket” anticoagulation based upon atrial fibrillation burden.     

Book Reviews

Creative Collaboration. Interprofessional Learning Priorities in Primary Health and Community Care Jill Spratley &; Marilyn Pietroni Marylebone Centre Trust, for CCETSW, 59 pp., £7.50 Benbt Sivberg Lund University Press, 1993 160pp., £14.95

Professional Judgement. A Theoretical Model and Multi-Experiments in Nursing Professional Judgement Benbt Sivberg Lund University Press, 1993 160pp., £14.95

Age, Race and Ethnicity: A Comparative Approach K. Blakemore &; M. Boneham Open University Press, 1994 150pp., £13.99 Social Care in a Mixed Economy Gerald Wistow Martin Knapp Brian Hardy &; Caroline Allen Buckingham Open University Press, 1994 166 pp. Hb £40.00, Pb £14.99

Social Care in a Mixed Economy Gerald Wistow, Martin Knapp, Biuan Hardy &; Caroline Allen Buckingham Open University Press, 1994 166 pp. Hb E40.00, Pb £14.99

Total Quality Management in Human Service Organizations L. Martin Sage Publications, 1993 109 pp., £13.50

Reflecting on Research Practice P. Shakespeare, D. Atkinson &; S. French (Eds) Buckingham, Open University Press, 1993 160 PP., HB £37.50, PB £12.99     

What nephrologists need to know about diagnostic test accuracy articles

Systematic reviews of randomized controlled trials are well‐recognized as the best evidence for an intervention and are also becoming more available for diagnostic test evaluation. In the absence of a well‐conducted and well‐reported systematic review clinicians must rely on primary studies to determine how best to interpret and understand diagnostic test information. Diagnostic test studies are abundant in the published literature; however, there are considerable limitations to the information provided in many of these papers and careful appraisal is required before the findings can be applied to individual patients. The current paper provides a framework for determining bias, clinical applicability and erroneous findings within a paper, allowing greater efficiency in selecting studies and deciding on the value of the information reported in them.