[Guidelines on the urological management of the adult patient with spinal dysraphism (spina bifida)]. / Recommandations sur la gestion du risque et la prise en charge urologique du patient adulte atteint de dysraphisme spinal (spina bifida).

INTRODUCTION: Improved life expectancy and prenatal screening have changed the demographics of spina bifida (spinal dysraphism) which has presently become a disease of adulthood. Urinary disorders affect almost all patients with spinal dysraphism and are still the leading cause of mortality in these patients. The aim of this work was to establish recommendations for urological management that take into account the specificities of the spina bifida population. MATERIALS AND METHODS: National Diagnosis and Management Guidelines (PNDS) were drafted within the framework of the French Rare Diseases Plan at the initiative of the Centre de Référence Maladies Rares Spina Bifida - Dysraphismes of Rennes University Hospital. It is a collaborative work involving experts from different specialties, mainly urologists and rehabilitation physicians. We conducted a systematic search of the literature in French and English in the various fields covered by these recommendations in the MEDLINE database. In accordance with the methodology recommended by the authorities (Guide_methodologique_pnds.pdf, 2006), proposed recommendations were drafted on the basis of this literature review and then submitted to a review group until a consensus was reached. RESULTS: Bladder dysfunctions induced by spinal dysraphism are multiple and varied and evolve over time. Management must be individually adapted and take into account all the patient's problems, and is therefore necessarily multi-disciplinary. Self-catheterisation is the appropriate micturition method for more than half of the patients and must sometimes be combined with treatments aimed at suppressing any neurogenic detrusor overactivity (NDO) or compliance alteration (anticholinergics, intra-detrusor botulinum toxin). Resort to surgery is sometimes necessary either after failure of non-invasive treatments (e.g. bladder augmentation in case of NDO resistant to pharmacological treatment), or as a first line treatment in the absence of other non-invasive alternatives (e.g. aponeurotic suburethral tape or artificial urinary sphincter for sphincter insufficiency; urinary diversion by ileal conduit if self-catheterisation is impossible). CONCLUSION: Spinal dysraphism is a complex pathology with multiple neurological, orthopedic, gastrointestinal and urological involvement. The management of bladder and bowel dysfunctions must continue throughout the life of these patients and must be integrated into a multidisciplinary context.

Implementing surgical mentorship in a resource-constrained context: a mixed methods assessment of the experiences of mentees, mentors, and leaders, and lessons learned.

BACKGROUND: A well-qualified workforce is critical to effective functioning of health systems and populations; however, skill gaps present a challenge in low-resource settings. While an emerging body of evidence suggests that mentorship can improve quality, access, and systems in African health settings by building the capacity of health providers, less is known about its implementation in surgery. We studied a novel surgical mentorship intervention as part of a safe surgery intervention (Safe Surgery 2020) in five rural Ethiopian facilities to understand factors affecting implementation of surgical mentorship in resource-constrained settings. METHODS: We designed a convergent mixed-methods study to understand the experiences of mentees, mentors, hospital leaders, and external stakeholders with the mentorship intervention. Quantitative data was collected through a survey (n = 25) and qualitative data through in-depth interviews (n = 26) in 2018 to gather information on (1) intervention characteristics including areas of mentorship, mentee-mentor relationships, and mentor characteristics, (2) organizational context including facilitators and barriers to implementation, (3) perceived impact, and (4) respondent characteristics. We analyzed the quantitative and qualitative data using frequency analysis and the constant comparison method, respectively; we integrated findings to identify themes. RESULTS: All mentees (100%) experienced the intervention as positive. Participants perceived impact as: safer and more frequent surgical procedures, collegial bonds between mentees and mentors, empowerment among mentees, and a culture of continuous learning. Over 70% of all mentees reported their confidence and job satisfaction increased. Supportive intervention characteristics included a systems focus, psychologically safe mentee-mentor relationships, and mentor characteristics including generosity with time and knowledge, understanding of local context, and interpersonal skills. Supportive organizational context included a receptive implementation climate. Intervention challenges included insufficient clinical training, inadequate mentor support, and inadequate dose. Organizational context challenges included resource constraints and a lack of common understanding of the intervention. CONCLUSION: We offer lessons for intervention designers, policy makers, and practitioners about optimizing surgical mentorship interventions in resource-constrained settings. We attribute the intervention's success to its holistic approach, a receptive climate, and effective mentee-mentor relationships. These qualities, along with policy support and adapting the intervention through user feedback are important for successful implementation.

[Autologous fascia pubovaginal slings in women with stress urinary incontinence at high risk of mesh/device-related complications]. / Bandelette aponévrotique pubovaginale pour incontinence urinaire d'effort chez les femmes à risque de complications prothétiques.

INTRODUCTION: Very popular in many parts of the world, autologous fascial pubovaginal sling (AFPVS) remains marginally used in France. However, it may be of particular interest in patients carrying a high risk of mesh-related or device-related related complications. The aim of the present series was to report the outcomes of AFPVS in this high-risk population. MATERIAL AND METHODS: The charts of all female patients who underwent a fascial sling for SUI at a single academic center between April 2019 and May 2021 were reviewed retrospectively. Only patients deemed at high-risk of device/mesh related complications were included in the present analysis: female with a neurological condition who were doing clean intermittent catheterization (CIC), female with SUI after radical cystectomy and ileal neobladder, female with urethral/bladder extrusion of any synthetic material placed for SUI. Success was defined as complete resolution of SUI at 3 months. RESULTS: Sixteen patients were included in this study: 13 rectus fascia slings and 3 fascia lata slings. The success rate was 56.3% (9/16 patients). Four patients were improved but not completely dry (25%). Two patients had major postoperative complications (i.e. Clavien grade 3 or higher, 11.2%). Two patients had a persisting significant post-void residual (PVR) postoperatively, managed by self-catheterization (transition to self-catheterization at 3 months: 2/8, 25%). CONCLUSION: The use of autologous fascia pubovaginal sling is an interesting option in female SUI patients with high risk of device/mesh related complications with satisfactory functional outcomes. LEVEL OF PROOF: 4.

Effects of Moringa oleifera leaves extract, vitamin C, and taurine co-exposures on calcium and metallothionein levels, oxidative stress, and gill histopathological changes in Clarias gariepinus exposed to sub-lethal cadmium.

Cadmium aquatic environmental pollution poses great threats to fish and their would-be consumers. The present work investigated the effects of ethyl acetate extract of Moringa oleifera leaves (EAEMOL), vitamin C, and taurine co-exposures on calcium and metallothionein levels, oxidative stress, and gill histopathological changes in Clarias gariepinus exposed to sub-lethal cadmium (CdCl2) for 28 days. Fish were exposed to CdCl2 only (1.048 mg/L) as well as co-exposed with EAEMOL (20 mg/L), vitamin C (5 mg/L), and taurine (5 mg/L) separately. There was significant (p < 0.05) deterioration in fish water quality with increasing exposure period but no significant (p > 0.05) changes occurred between the exposed groups. However, the co-exposure of EAEMOL, vitamin C, and taurine did not significantly (p > 0.05) improve the CdCl2-induced fish water quality deterioration. Sub-lethal exposure to CdCl2 only caused significant (p < 0.05) increase in the serum malondialdehyde (MDA) and liver metallothionein (MT) levels with significant (p < 0.05) decrease in serum catalase activity only. However, EAEMOL, vitamin C, and taurine co-exposures did not significantly (p > 0.05) improve the MDA, superoxide dismutase, catalase, and glutathione activities, as well as MT and calcium (Ca2+) levels, condition factor (CF), hepatosomatic index (HSI), and gill histopathological changes induced by the CdCl2 exposure. Similarly, none of the present exposures, CdCl2 only or its co-exposures with EAEMOL, vitamin C, and taurine significantly (p > 0.05) altered the normal functioning of the gills despite the observed histopathological changes based on the degree of tissue change protocol. Therefore, EAEMOL, vitamin C, and taurine co-exposures, as administered in the present case, did not considerably alter the physicochemical parameters of the experimental fish water. However, outside significantly (p < 0.05) increasing MDA level, EAEMOL, vitamin C, and taurine co-exposures did not significantly (p > 0.05) improve the CdCl2-induced Ca2+, MT, CF, HSI, and gill histopathological alterations by sub-lethal CdCl2 exposure of C. gariepinus.

Heavy Metals Bioaccumulation and Health Risks with Associated Histopathological Changes in Clarias gariepinus from the Kado Fish Market, Abuja, Nigeria.

BACKGROUND: Aquatic pollution by heavy metals has become a global problem and is of great concern due to the detrimental effects on aquatic ecosystems and possible human uptake. OBJECTIVES: The present study aimed to evaluate tissue bioaccumulations of heavy metals and possible human health risks in addition to associated cellular damages in fish for sale in a fish market in Abuja, Nigeria. METHODS: Clarias gariepinus sold at the Kado Fish Market in Abuja, Nigeria, in March-April 2017 and March-April 2018 were randomly purchased and sampled. The heavy metal contents of the sampled fish were assayed and used to assess the extent of potential health risks to human consumers. The extent of histopathological changes associated with the bioaccumulations in the sampled fish were also evaluated according to standard procedures. RESULTS: Levels of most heavy metals were above permissible limits, except for lower levels of zinc (Zn) in liver and muscle and higher levels of lead (Pb) in muscle in the sampled fish. Similarly, significant (p<0.05) liver bioaccumulation occurred for Zinc (Zn), chromium (Cr), iron (Fe), and copper (Cu) compared to their levels in muscle. The total hazard index (non-cancer risk across all metals) was 0.0415, which is very low and acceptable. The cancer risks ranged between the acceptable values of 1.98 × 10-5 - 3.71 × 10-6. Associated histopathological changes, which occurred in the sampled fish, differed between the various assayed tissues. CONCLUSIONS: Most of the heavy metals were significantly bioaccumulated (p<0.05) and were above the permissible levels, particularly in liver samples. The levels of muscle heavy metal bioaccumulation in the sampled fish posed no apparent cancer or non-cancer health risks to human consumers. However, further efforts are needed to minimize heavy metal aquatic environmental pollution to safeguard the health of aquatic flora and fauna and human consumers because of the tendency of these pollutants to persist and bioaccumulate to toxic levels over time. COMPETING INTERESTS: The authors declare no competing financial interests.

Anti-diarrhea activity of the aqueous root bark extract of Byrsocarpus coccineus on castor oil-induced diarrhea in Wistar rats.

AIM: The use of traditional medicine as an alternative source of cure for many ailments has played an important role in health care delivery in both developing and developed countries. Byrsocarpus coccineus Schum and Thonn (Connaraceae) is used in traditional medicine for treatment of various disease conditions, including diarrhea. The anti-diarrhea activity of the root bark aqueous extract of B. coccineus was investigated in this study. MATERIALS AND METHODS: Acute toxicity evaluation of the aqueous extract of B. coccineus root bark was performed in exposed rats. Diarrhea was induced in exposed rats with castor oil, and the effect of the extract on castor oil-induced gastrointestinal motility and enteropooling was consequently investigated. RESULTS: In the acute toxicity study, the extract caused no death in treated rats nor produced signs of delayed toxicity, even at 5000 mg/kg. The aqueous root bark extract of B. coccineus also decreased the distance travelled by activated charcoal in the gastrointestinal tract of treated rats when compared to control rats. Results of castor oil-induced enteropooling revealed slight reduction in the weight of intestinal contents of treated rats compared to control rats. There was significant (p<0.05) decrease in the frequency of defecation as well as in the number of unformed feces produced by castor oil-induced diarrhea at 100 mg/kg dose with 74.96% inhibition of defecation. CONCLUSION: The study demonstrated the anti-diarrheic property of the aqueous extract of B. coccineus root bark as currently exploited in our traditional herbal therapy.

External radiation dose and cancer mortality among French nuclear workers: considering potential confounding by internal radiation exposure.

OBJECTIVES: French nuclear workers have detailed records of their occupational exposure to external radiation that have been used to examine associations with subsequent cancer mortality. However, some workers were also exposed to internal contamination by radionuclides. This study aims to assess the potential for bias due to confounding by internal contamination of estimates of associations between external radiation exposure and cancer mortality. METHODS: A cohort of 59,004 workers employed for at least 1 year between 1950 and 1994 by CEA (Commissariat à l'Energie Atomique), AREVA NC, or EDF (Electricité de France) and badge-monitored for external radiation exposure were followed through 2004 to assess vital status and cause of death. A flag based on a workstation-exposure matrix defined four levels of potential for internal contamination. Standardized mortality ratios were assessed for each level of the internal contamination indicator. Poisson regression was used to quantify associations between external radiation exposure and cancer mortality, adjusting for potential internal contamination. RESULTS: For solid cancer, the mortality deficit tended to decrease as the levels of potential for internal contamination increased. For solid cancer and leukemia excluding chronic lymphocytic leukemia, adjusting the dose-response analysis on the internal contamination indicator did not markedly change the excess relative risk per Sievert of external radiation dose. CONCLUSIONS: This study suggests that in this cohort, neglecting information on internal dosimetry while studying the association between external dose and cancer mortality does not generate a substantial bias. To investigate more specifically the health effects of internal contamination, an effort is underway to estimate organ doses due to internal contamination.

[Effects of chronic uranium internal exposure on mortality: results of a pilot study among French nuclear workers]. / Effets de la contamination chronique à l'uranium sur la mortalité : bilan d'une étude-pilote chez les travailleurs de l'industrie nucléaire en France.

BACKGROUND: This article presents the mortality data compiled among a cohort of workers at risk of internal uranium exposure and discusses the extent to which this exposure might differentiate them from other nuclear workers. METHODS: The cohort consisted of 2897 Areva-NC-Pierrelatte plant workers, followed from 1st January 1968 through 31st December 2006 (79,892 person-years). Mortality was compared with that of the French population, by calculating Standardized Mortality Ratios (SMR) and 95% confidence intervals (CI95%). External radiation exposure was reconstructed using external dosimetry archives. Internal uranium exposure was assessed using a plant-specific job-exposure-matrix, considering six types of uranium compounds according to their nature (natural and reprocessed uranium [RPU] and solubility [fast-F, moderate-M, and slow-S]). Exposure-effect analyses were performed for causes of death known to be related to external radiation exposure (all cancers and circulatory system diseases) and cancer of uranium target-organs (lung and hematopoietic and lymphatic tissues, HLT). RESULTS: A significant deficit of mortality from all causes (SMR=0.58; CI95% [0.53-0.63]), all cancers (SMR=0.72; CI95% [0.63-0.82]) and smoking related cancers was observed. Non-significant 30%-higher increase of mortality was observed for cancer of pleura (SMR=2.32; CI95 % [0.75-5.41]), rectum and HLT, notably non-Hodgkin's lymphoma (SMR=1.38; CI95 % [0.63-2.61]) and chronic lymphoid leukemia (SMR=2.36; CI95% [0.64-6.03]). No exposure-effect relationship was found with external radiation cumulative dose. A significant exposure-effect relationship was observed for slowly soluble uranium, particularly RPU, which was associated with an increase in mortality risk reaching 8 to 16% per unit of cumulative exposure score and 10 to 15% per year of exposure duration. CONCLUSION: The Areva-NC-Pierrelatte workers cohort presents a non-significant over-mortality from HLT cancers, notably of lymphoid origin, unrelated to external radiation exposure. The pilot study suggests an association between mortality from the HLT and lung cancers and exposure to slowly soluble RPU compounds. The results of this study should be investigated further in more powerful studies, with a dose-response analysis based on individual assessment of uranium absorbed dose to uranium-target organs.

Mortality associated with chronic external radiation exposure in the French combined cohort of nuclear workers.

OBJECTIVE: The long-term effects of protracted low level ionising radiation exposure are investigated in a combined analysis of French nuclear workers employed by the Commissariat à l'Energie Atomique (CEA), AREVA Nuclear Cycle (AREVA NC) and Electricité de France (EDF). Associations between cumulative external radiation dose and mortality due to solid cancers, leukaemia and circulatory disease were examined. METHODS: All workers hired by CEA, AREVA NC and EDF between 1950 and 1994 who were employed for at least 1 year, badge-monitored for radiation exposure and alive on 1 January 1968 were included. Individual data of annual exposure to penetrating photons (X-rays and gamma rays) were reconstructed for each worker. Estimates of radiation dose-mortality associations were obtained using a linear excess relative risk (ERR) Poisson regression model. RESULTS: Among the 59 021 nuclear workers, 2312 died of solid cancer, 78 of leukaemia and 1468 of circulatory diseases during the 1968-2004 period. Approximately 72% of the cohort had a non-zero cumulative radiation dose estimate, with a mean cumulative dose of 22.5 mSv. Positive but non-significant ERR/Sv were observed for all solid cancers, leukaemia excluding chronic lymphocytic leukaemia (CLL), ischaemic heart diseases and cerebrovascular diseases. A significant ERR/Sv was found for myeloid leukaemia. CONCLUSIONS: This is the first combined analysis of major French cohorts of nuclear workers. Results were consistent with risks estimated in other nuclear worker cohorts and illustrate the potential of a further joint international study to yield direct risk estimates in support to radiation protection standards.

Leukemia risk associated with chronic external exposure to ionizing radiation in a French cohort of nuclear workers.

Leukemia is one of the earliest cancer effects observed after acute exposure to relatively high doses of ionizing radiation. Leukemia mortality after external exposure at low doses and low-dose rates has been investigated at the French Atomic Energy Commission (CEA) and Nuclear Fuel Company (AREVA NC) after an additional follow-up of 10 years. The cohort included radiation-monitored workers employed for at least one year during 1950-1994 at CEA or AREVA NC and followed during 1968-2004. Association between external exposure and leukemia mortality was estimated with excess relative risk (ERR) models and time-dependent modifying factors were investigated with time windows. The cohort included 36,769 workers, followed for an average of 28 years, among whom 73 leukemia deaths occurred. Among the workers with a positive recorded dose, the mean cumulative external dose was 21.7 mSv. Results under a 2-year lag assumption suggested that the risk of leukemia (except chronic lymphatic leukemia) increased significantly by 8% per 10 mSv. The magnitude of the association for myeloid leukemia was larger. The higher ERR/Sv for doses received 2-14 years earlier suggest that time since exposure modifies the effect. The ERR/Sv also appeared higher for doses received at exposure rates ≥20 mSv per year. These results are consistent with those found in other studies of nuclear workers. However, confidence intervals are still wide. Further analyses should be conducted in pooled cohorts of nuclear workers.

Solid cancer mortality associated with chronic external radiation exposure at the French atomic energy commission and nuclear fuel company.

Studies of nuclear workers make it possible to directly quantify the risks associated with ionizing radiation exposure at low doses and low dose rates. Studies of the CEA (Commissariat à l'Energie Atomique) and AREVA Nuclear Cycle (AREVA NC) cohort, currently the most informative such group in France, describe the long-term risk to nuclear workers associated with external exposure. Our aim is to assess the risk of mortality from solid cancers among CEA and AREVA NC nuclear workers and its association with external radiation exposure. Standardized mortality ratios (SMRs) were calculated and internal Poisson regressions were conducted, controlling for the main confounding factors [sex, attained age, calendar period, company and socioeconomic status (SES)]. During the period 1968-2004, there were 2,035 solid cancers among the 36,769 CEA-AREVA NC workers. Cumulative external radiation exposure was assessed for the period 1950-2004, and the mean cumulative dose was 12.1 mSv. Mortality rates for all causes and all solid cancers were both significantly lower in this cohort than in the general population. A significant excess of deaths from pleural cancer, not associated with cumulative external dose, was observed, probably due to past asbestos exposure. We observed a significant excess of melanoma, also unassociated with dose. Although cumulative external dose was not associated with mortality from all solid cancers, the central estimated excess relative risk (ERR) per Sv of 0.46 for solid cancer mortality was higher than the 0.26 calculated for male Hiroshima and Nagasaki A-bomb survivors 50 years or older and exposed at the age of 30 years or older. The modification of our results after stratification for SES demonstrates the importance of this characteristic in occupational studies, because it makes it possible to take class-based lifestyle differences into account, at least partly. These results show the great potential of a further joint international study of nuclear workers, which should improve knowledge about the risks associated with chronic low doses and provide useful risk estimates for radiation protection.

Mortality among workers monitored for radiation exposure at the French nuclear fuel company.

A cohort of 9,285 nuclear workers employed at the French company AREVA NC specializing in the nuclear fuel cycle was established. Vital status, causes of death, employment characteristics and annual exposure to ionizing radiation were reconstructed for each individual over the time period 1977-2004. Standardized mortality ratios (SMRs) were computed using national mortality rates as an external reference. Tests for trends in mortality with duration of employment and cumulative external dose were performed. The all-cause and all-cancer mortality was significantly lower than expected from the French population. No significant excess among cancer sites studied was observed. Significant positive trends with cumulative dose were observed for colon and liver cancer and for respiratory diseases. Isolated significant trends should be carefully interpreted and considered in line with the large number of trend tests performed.

Epidemiological studies of leukaemia in children and young adults around nuclear facilities: a critical review.

The existence of an increased risk of childhood leukaemia near nuclear installations is a recurrent issue. A review of the related epidemiological literature is presented here. Results for 198 nuclear sites throughout 10 countries were included in the review. In addition to local studies, 25 multi-site studies have been published for eight countries. A large variability was noticed in the quality of the data as well as in the definition of the study population and in the methods of analysis. Many studies present important limits that make the results difficult to interpret. The review confirms that some clusters of childhood leukaemia cases exist locally. However, results based on multi-site studies around nuclear installations do not indicate an increased risk globally. Many studies were launched to investigate possible origins of the observed clusters around specific sites, but up to now, none of the proposed hypotheses have explained them.

External radiation exposure and mortality in a cohort of French nuclear workers.

OBJECTIVE: To analyse the effect of external radiation exposure on the mortality of French nuclear workers. METHODS: A cohort of 29 204 workers employed between 1950 and 1994 at the French Atomic Energy Commission (Commissariat à l'Energie Atomique (CEA)) or at the General Company of Nuclear Fuel (COmpagnie GEnérale des MAtières nucléaires (Cogema, now Areva NC)) was followed up for an average of 17.8 years. Standardised mortality ratios (SMRs) were computed with reference to French mortality rates. Dose-effect relationship were analysed through trend tests and Poisson regression, with linear and log-linear models. RESULTS: The mean exposure to X and gamma radiation was 8.3 mSv (16.9 mSv for exposed worker population). A total of 1842 deaths occurred between 1968 and 1994. A healthy worker effect was observed, the number of deaths in the cohort being 59% of the number expected from national mortality statistics. Among the 21 main cancer sites studied, a statistically significant excess was observed only for skin melanoma, and an excess of borderline statistical significance was observed for multiple myeloma. A dose-effect relationship was observed for leukaemia after exclusion of chronic lymphoid leukaemia (CLL). The relative risk observed for non-CLL leukaemia, n = 20, was 4.1 per 100 mSv (90% CI 1.4 to 12.2), linear model and 2.2 per 100 mSv (90% CI 1.2 to 3.3), log-linear model. Significant dose-effect relationship were also observed for causes of deaths associated with alcohol consumption: mouth and pharynx cancer, cirrhosis and alcoholic psychosis and external causes of death. CONCLUSION: The risk of leukaemia increases with increasing exposure to external radiation; this is consistent with published results on other nuclear workers cohorts.

Cancer mortality among French Atomic Energy Commission workers.

BACKGROUND: All causes and cancer mortality of 58,320 workers employed at the Commissariat à l'Energie Atomique (CEA) between 1946 and 1994 were compared with that of the general population in a retrospective cohort study. METHODS: Standardized Mortality Ratios (SMR) were computed with reference to the French national population. RESULTS: Between 1968 and 1994, 4,809 deaths occurred. A healthy worker effect is observed for men (SMR = 0.57, CI(90%) = [0.56;0.59]) and for women (SMR = 0.72, CI(90%) = [0.67;0.77]). Nine sites of cancer death were found to be in statistically significant deficit among men, none among women. An excess of pleural cancers is observed among men (SMR = 1.79, CI(90%) = [1.27;2.45]) and of malignant melanoma (SMR = 1.50, CI(90%) = [1.04;2.11]). An excess of breast cancer is observed among women on the borderline of significance (SMR = 1.14, CI(90%) = [0.94;1.37]). CONCLUSIONS: Excesses observed will have to be related to occupational exposures in the on-going cohort study on French nuclear workers which includes a retrospective exposures assessment.

Involvement of minor structural proteins in recombination of polyoma virus DNA.

We have previously observed that a polyoma-mouse chimeric DNA molecule (RmI) in which the murine DNA insert is flanked by directly repeated viral sequences is effectively converted into unit-length polyoma DNA upon transfection of permissive mouse cells. This intramolecular recombination event appears to be dependent on VmP1, a protein encoded by RmI which includes the 328 N-terminal amino acids of polyoma VP1, and nine amino acids of murine origin carrying the C-terminus of the protein. We report here that introducing mutations into the VP2/VP3 coding sequence reduces the ability of RmI to generate polyoma DNA, even though the same mutations seem to exert little or no effect on the ability of polyoma DNA to either replicate or accumulate inside transfected cells. A mutation affecting VP2 alone being as effective as one that affects both VP2 and VP3, VP2 appears to be playing a critical role in recombination.

Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children (Dagher, R., and Helman, L. (1999) Oncologist 4, 34-44), whereas medulloblastoma, a highly malignant tumor of the cerebellum, accounts for 20% of childhood brain tumors (Goodrich, L. V., and Scott, M. P. (1998) Neuron 21, 1243-1257). Both tumors are associated with a deficiency in the tumor suppressor Patched (PTCH) in Gorlin syndrome (Gorlin, R. J. (1987) Medicine (Baltimore) 66, 98-113), and they are present in the corresponding murine models. RMS in Ptch mutant mice consistently contain elevated levels of the tumor growth-promoting insulin-like growth factor 2 (Igf2). We have investigated the mechanism of Igf2 overexpression and its significance in medulloblastoma and RMS tumorigenesis. Here we report that Igf2 is indispensable for the formation of medulloblastoma and RMS in Ptch mutants. Overexpression of Igf2 in RMS in these mice does not involve loss of imprinting, uniparental disomy, amplification of the Igf2 locus, or polyploidy. Since Igf2 is also overexpressed in non-tumor tissue deficient in Ptch, these observations suggest that Ptch regulates Igf2 levels through a transcriptional mechanism. They also identify Igf2 as a potential target for medulloblastoma and RMS.