Additive action of 11beta-HSD1 inhibition and PPAR-gamma agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats.

Both 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibition and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonism reduce liver and plasma lipids in rodents through partly distinct mechanisms. This study aimed to assess their additivity of action on liver and plasma lipids in a model of diet-induced steatosis. Rats were fed an obesogenic diet and were treated either with an 11beta-HSD1 inhibitor (Compound A, 3 mg kg(-1) day(-1)) or rosiglitazone (RSG, 5 mg kg(-1) day(-1)) or both for 6 weeks. Compound A and RSG reduced liver steatosis and triglyceridemia, and did so additively when given in combination. The 11beta-HSD1 inhibitor had no effect on serum adiponectin, but increased liver adiponectin receptor type 2 (Adipo-R2) mRNA levels. Conversely, RSG increased serum adiponectin, a likely mediator of its antisteatotic action, but had no effect per se on the Adipo-R2 expression. mRNA levels of representative genes of fatty acid oxidation tended to be increased by both compounds. The study shows that combined 11beta-HSD1 inhibition and PPAR-gamma agonism additively reduce liver steatosis and triglyceridemia, which may eventually prove therapeutically useful.

Metabolic action of peroxisome proliferator-activated receptor gamma agonism in rats with exogenous hypercorticosteronemia.

OBJECTIVE: The beneficial metabolic actions of peroxisome proliferator-activated receptor gamma (PPARgamma) agonism are associated with modifications in adipose tissue metabolism that include a reduction in local glucocorticoid (GC) production by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This study aimed to assess the contribution of GC attenuation to PPARgamma agonism action on gene expression in visceral adipose tissue and global metabolic profile. DESIGN: Rats were treated (2 weeks) with the PPARgamma agonist rosiglitazone (RSG, 10 mg/kg/day) with concomitant infusion of vehicle (cholesterol implant) or corticosterone (HiCORT, 75 mg/implant/week) to defeat PPARgamma-mediated GC attenuation. MEASUREMENTS: mRNA levels of enzymes involved in lipid uptake (and lipoprotein lipase activity), storage, lipolysis, recycling, and oxidation in retroperitoneal white adipose tissue (RWAT). Serum glucose, insulin and lipids, and lipid content of oxidative tissues. RESULTS: Whereas HiCORT did not alter RWAT mass, RSG increased the latter (+33%) independently of the corticosterone status. Both HiCORT and RSG increased lipoprotein lipase activity, the mRNA levels of the de novo lipogenesis enzyme fatty acid synthase, and that of the fatty acid retention-promoting enzyme acyl-CoA synthase 1, albeit in a nonadditive fashion. Expression level of the lipolysis enzyme adipose triglyceride lipase was increased additively by HiCORT and RSG. PPARgamma agonism increased mRNA of the fatty acid recycling enzymes glycerol kinase and cytosolic phosphoenolpyruvate carboxykinase and those of the fatty acid oxidation enzymes muscle-type carnitine palmitoyltransferase 1 and acyl-CoA oxidase, whereas HiCORT remained without effect. HiCORT resulted in liver steatosis and hyperinsulinemia, which were abrogated by RSG, whereas the HiCORT-induced elevation in serum nonesterified fatty acid levels was only partially prevented. The hypotriglyceridemic action of RSG was maintained in HiCORT rats. CONCLUSION: The GC and PPARgamma pathways exert both congruent and opposite actions on specific aspects of adipose tissue metabolism. Both the modulation of adipose gene expression and the beneficial global metabolic actions of PPARgamma agonism are retained under imposed high ambient GC, and are therefore independent from PPARgamma effects on 11beta-HSD1-mediated GC production.

PPARgamma agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control.

AIMS/HYPOTHESIS: The aim of this study was to investigate the effect and mechanisms of action of in vivo peroxisome proliferator-activated receptor gamma (PPARgamma) activation on white adipose tissue (WAT) lipolysis and NEFA metabolism. MATERIALS AND METHODS: Study rats were treated for 7 days with 15 mg/kg of rosiglitazone per day; control rats were not treated. After a 6-h fast, lipolysis and levels of mRNA for lipases were assessed in explants from various adipose depots. RESULTS: Rosiglitazone markedly increased basal and noradrenaline (norepinephrine)-stimulated glycerol and NEFA release from WAT explants, and amplified their inhibition by insulin. Primary adipocytes isolated from PPARgamma agonist-treated rats were also more responsive to noradrenaline stimulation expressed per cell, ruling out a contribution of an altered number of mature adipocytes in explants. Rosiglitazone concomitantly increased levels of mRNA transcripts for adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) in subcutaneous and visceral WAT, and mRNA for hormone-sensitive lipase (HSL) in subcutaneous WAT. Lipase expression increased within 12 h of in vitro exposure of naïve explants to rosiglitazone, suggesting direct transcriptional activation. In parallel, chronic in vivo treatment with rosiglitazone lowered plasma NEFAs and in WAT its expected stimulatory action on glycerol and NEFA recycling, and on the expression of genes involved in NEFA uptake and retention by WAT, such processes counteracting net NEFA export. CONCLUSIONS/INTERPRETATION: These findings demonstrate that, in the face of its plasma NEFA-lowering action, PPARgamma agonism stimulates WAT lipolysis, an effect that is compensated by lipid-retaining pathways. The results further suggest that PPARgamma agonism stimulates lipolysis by increasing the lipolytic potential, including the expression levels of the genes encoding adipose triglyceride lipase and monoglyceride lipase.

Natural history of renal masses followed expectantly.

PURPOSE: An increasing number of incidental renal masses have been detected with increasing use of ultrasonography, computerized tomography and magnetic resonance imaging. We investigated the natural history of incidentally detected renal masses. MATERIALS AND METHODS: A total of 24 patients were included in this retrospective analysis. Average patient age was 68.3 years (range 29 to 83). The 16 males and 8 females were followed with abdominal imaging for a mean and median followup of 31.6 and 24 months, respectively (range 8 to 86). Patients elected to be observed because of age, poor medical condition or the presence of a mass in a solitary kidney. The majority of patients (22 of 24) were asymptomatic at diagnosis. Two patients were followed with bilateral renal masses, and 2 with T3b tumors. Of the 20 patients with incidental solitary renal masses, 6 were at the upper pole, 9 were mid polar and 5 lower pole. Mean maximum diameter of lesions was 3.3 cm (median 2.7, range 0.9 to 10). Growth rate was calculated based on diameter and tumor volume. RESULTS: Of the 24 patients only 5 demonstrated tumor growth during the surveillance period. No metastasis developed in any patients. Mean tumor growth rate observed in the 5 patients was 0.49 cm per year or 7.3 cc per year. Of the 24 patients 4 underwent surgery after surveillance because of apparent tumor growth or per patient request. Pathology revealed renal cell carcinoma in all 4. CONCLUSIONS: Tumor growth of renal masses is often limited. Most of our patients did not demonstrate significant growth when followed expectantly. Without tumor growth the risk of metastasis seems limited.

[Exposure of French emergency medical personnel to violence]. / Exposition à la violence en Smur.

OBJECTIVES: Evaluate the problem of violence in French EMS system and characterize assaults. STUDY DESIGN: Multicentric, descriptive, open study. PATIENTS AND METHODS: A questionnaire was given to a sample of prehospital care providers in Paris area. People were asked about assaults during their careers, typology of the assaults and consequences. Results are presented in percentage and means. RESULTS: Two hundred seventy-six questionnaires were returned. One or more assaults were recounted by 23% (61/271) of the sample (median of 8 +/- 7 years experience on the job). The injuries were bruises in 40% (17/43), wounds in 9% (4/43) and fractures in 2% (1/43). Only 4% of assaults were followed by sick leave, 15% by a complaint. After the assaults, 4% (2/45) reported having got therapy against post-traumatic stress disorder. Eighty-eight per cent reported verbal threat and 41% physical threat. Thirteen per cent (25/200) were threatened with a knife and 12% (23/200) with a gun. Only 9% (24/270) had a formal training for management of violence. CONCLUSION: Formal training in the management of violent encounters and prevention of post-traumatic stress should be developed.

Testicular seminoma and Down's syndrome.

OBJECTIVE: To review cases of testicular seminoma in Down's syndrome (DS) patients. METHODS: The case of a patient diagnosed and treated at our institution is reported. The literature is reviewed for previous cases, with attention paid to age, stage, treatment and outcome. RESULTS: Nineteen cases were found. The mean age at diagnosis is 32. Seventy three percent are Stage I. At 47, our patient is the oldest reported case. A body of evidence exists for an association between DS and testicular seminoma. An increased rate of cryptorchidism, increased gonadotropin levels and genetic instability are possible pathways. CONCLUSION: The age distribution of seminoma in DS is skewed by the decreased life expectancy of patients with DS. More cases should be seen as this life expectancy increases. The stage at presentation in DS patients is comparable to that seen in the general population. Standard therapy has been successfully delivered in these patients.

The use of participation-oriented education in the rehabilitation of driving skills in older adults.

The driving abilities of adults appear to diminish in conjunction with age-related physical and cognitive changes. In this exploratory study, rehabilitation strategies used with 21 older adults were examined to determine the most effective method of retraining driving skills. Subjects, who met the study's eligibility criteria (aged 55 years or older, held a valid driver's license, drove a minimum of 1000 miles/year, and no participation in an adult re-education program) received driver simulation training, classroom viewing of driver simulation films, or no treatment. Outcome measures included on-road and clinical evaluations, as well as self-report information. A significant difference was found between treatment type and subjects' accuracy scores for on-road evaluation, thus suggesting that driving simulation may result in a significant improvement in older adults' driving performance as compared to other intervention strategies. The study has particular relevance to occupational therapy practitioners, with their growing involvement in driving programs throughout the United States.

A horseshoe kidney harboring large symptomatic renal angiomyolipoma with a false macro-aneurysm.

We report a case of a large angiomyolipoma in a horseshoe kidney associated with a macro-aneurysm bleeding into the retroperitoneum. The patient was successfully treated by embolization of the macro-aneurysm, using thrombogenic cois and Ivalon particles. He remains free of symptoms at 18 months of follow-up. CT scan and renal ultrasound confirm no flow to the previous area of the macro-aneurysm and no change in size of the benign tumor.

Vesico-acetabular fistula.

To our knowledge we report the first case of an isolated prosthetic vesico-acetabular fistula in a woman 12 years after total hip arthroplasty. Etiology, presentation, diagnosis and management are discussed.

Survival after pelvic lymphadenectomy and radical cystectomy in patients with lymph-node metastatic transitional-cell carcinoma of the bladder.

The objective of this study was to determine the clinical outcome of patients with invasive transitional cell carcinoma of the bladder and pelvic lymph node metastases treated by radical cystectomy and bilateral pelvic lymphadenectomy in a single institution. From January 1980 to December 1993, 116 patients with transitional cell carcinoma of the bladder underwent bilateral pelvic lymphadenectomy and radical cystectomy at the Montreal General Hospital. Of these patients, 25 (21.6%) were found to have nodal metastases and form the basis of this retrospective analysis. Extent of nodal disease was as follows: 7 (28%) with N1, 17 (68%) with N2, and 1 (4%) patient with N3 disease. Of the 25 patients, 9 (36%) were alive with no evidence of disease and 1 (4%) died at 42 months from cardiovascular disease without clinical evidence of cancer recurrence. The median follow-up interval for these 10 patients was 26.5 months (mean, 31.4 months; range, 7-104 months). Fourteen (56%) patients died of recurrent bladder cancer and one patient was alive with systemic disease at 14 months. The median survival was estimated at 27 months, with 73% alive at 1 year, 51% alive at 2 years, and 33% alive at 3 years. Our data suggests that long-term survival free of disease can be achieved by radical surgery in some patients with node-positive bladder cancer.

Medical expenditures for disability and disabling comorbidity.

Disability and disabling comorbidity place a disproportionately large burden on the health care system. National Medical Care Utilization and Expenditure Survey data show that medical care expenditures for noninstitutionalized persons amounted to $154 billion ($691 per capita) in 1980. The medical expenditure per capita for people reporting two or more disabling chronic conditions ($2456) was 5 times the amount incurred by those with no limiting conditions ($486) and more than 1.5 times the amount incurred by those with one limiting condition.

The demographics of disability.

In this article, I have attempted to clarify some of the disparate estimates and ways of measuring disability that have been used in different surveys. The definitional issue has implications for the size of the population that will be covered by the ADA. I have reviewed several perspectives, including that of researchers, disability advocates, and individual self-perceptions, which need to be considered in understanding the meaning of disability. Disability involves limitations in actions and activities because of mental and physical impairments. Comparison of these different perspectives reveals that the differences lie in the range of activities that are considered. At least 36 million persons, over 14 percent of the U.S. population, are limited in selected activities. Depending on what are considered to be major life activities, the population covered by the ADA could vastly exceed that figure. Little information is available about the extent to which persons with disabilities, however defined, are affected by discrimination and unequal treatment. Limited data are available from one survey conducted by the International Center for the Disabled, which indicate that as many as 66 percent of persons with activity limitations who are not working would like a job. On the other hand, many persons with activity limitations indicate that their limitations are an important cause of their unemployment. About a quarter of persons with activity limitations due to impairments have experienced discrimination in some form. The impact of the ADA will likely vary by impairment. Because the prevalence of chronic diseases is far greater than the prevalence of physical and sensory impairments, chronic diseases are more frequently the cause of disability. The risk of disability is highest for impairments with low prevalence. Because states and local areas differ in the prevalence of disability, the impact of the ADA will also be likely to vary by geographic area. For some states, the rate of work disability is more than twice the rate of other states. Yet, research indicates that much of the variation is due to socioeconomic characteristics of areas. This reflects, at the macroeconomic level, that persons with disabilities are more likely to be poor and less educated than persons without disabilities. Because of differences in understanding what disability is and insufficient knowledge about the extent of the problem of discrimination toward persons with disabilities, assessment of the potential impact of the ADA is challenging.(ABSTRACT TRUNCATED AT 400 WORDS)

Life expectancy and health status of the aged.

There are several research issues which need further exploration if we are to better understand the implications of what appears to be increased levels of morbidity. Three general areas require additional research: the time of onset of chronic illness, the progression rate of illness, and the overlap and interaction between chronic and non-chronic conditions as well as multiple chronic conditions in a single individual. A major reason for the present uncertainty about morbidity is that information is unavailable regarding the incidence of chronic illness. However, incidence of chronic disease is difficult to measure unless there are either clear clinical indications or functional limitations. Work by survey researchers in defining initial reports of functional limitations associated with chronic illness would be very helpful. Furthermore, an understanding of incidence is necessary to further our understanding of the rate of progression of illness. The concept of a progression rate of illness makes sense only if we can have agreed upon measures of the onset of the illness. Both of these issues clearly require the use of longitudinal data. In fact any serious attempt to predict changes in health status over time as well as to relate changing patterns of mortality with changing patterns of morbidity will require a longitudinal data base. The difficulty in establishing a longitudinal data base is not only the time and expense of follow given set of individuals over a prolonged period of time, but also the problem of having a sample large enough to include individuals with specific chronic conditions of illness. One way to resolve the problem of sufficient sample size may be to do a combined survey which includes both a national probability sample of individuals as well as a sample of individuals with specific chronic diseases. Monitoring a group of individuals known to have specific chronic conditions would provide information about the progression and impact of the disease over time. Including a national probability sample of the entire population would provide information on the impact over time of changing health conditions for the entire population. While screening for specific conditions is an expensive procedure, it is likely to be far cheaper than including a sample size large enough to provide reliable estimates for specific conditions based on a national probability sample. Because the effects of postponed social security benefit eligibility will not be felt for many years, the opportunity for fruitful research is great. For now, we will summarize what we know from current research.

Prophylaxis against radiation injury. The use of elemental diet prior to and during radiotherapy for invasive bladder cancer and in early postoperative feeding following radical cystectomy and ileal conduit.

Previous studies done in animals have shown that significant prophylaxis against radiation injury could be afforded by feeding an elemental diet (ED) for three days before and during radiation. In the present study 20 patients were fed an ED for three days before and for the four days during radiotherapy (five fractions of 400 rad [4 Gy] each) prior to radical cystectomy and ileal conduit for invasive bladder cancer; ED feeding was recommenced 24 hours postoperatively via a feeding jejunostomy. The ED-fed patients exhibited positive nitrogen balance preoperatively and had an early return to positive nitrogen balance postoperatively (3.60 +/- 0.32 days). There was also prompt return of bowel sounds (3.00 +/- 0.32 days). Histologically and ultrastructurally, biopsy specimens of the ileal mucosa showed normal morphologic findings, with maintenance of normal levels of enzyme activity in the brush border. Severe or bloody diarrhea was absent in these patients. These data suggest that ED feeding provides prophylaxis against the acute phase of radiation injury in patients undergoing high-dose, short-course radiotherapy for invasive bladder cancer and that it is a safe and feasible means of postoperative nutritional support, even in the presence of a fresh bowel anastomosis.

Lymphadenectomy for testicular carcinoma.

Since 50% of patients with testicular tumour have retroperitoneal metastases at the time of presentation, there has been little argument that the area of primary drainage requires further treatment following orchiectomy. Patients with nonseminomatous germ cell tumours in stages A and B are candidates for retroperitoneal lymphadenectomy because this procedure is of therapeutic value and allows accurate staging of the disease. The development of extremely effective modern, cyclic, multidrug chemotherapy for extensive nonseminomatous testicular tumour has led to a rethinking of the role of lymphadenectomy in treating testicular cancer. Clinical staging is still not 100% accurate even with modern techniques. Lymphadenectomy, therefore, continues to be an important step in managing patients with nonseminomatous germ cell tumours. These facts are endorsed by the authors' review of 72 cases of nonseminomatous germ cell tumours managed at McGill University teaching hospitals over a 10-year period. The authors also discuss the indications for retroperitoneal dissection.

Results of radical nephrectomy in 178 cases of renal cell adenocarcinoma.

One hundred and seventy-eight patients with renal cell adenocarcinoma were classified by stage and treated by radical nephrectomy. A transabdominal approach was used in 92% of cases and lymphadenectomy was not performed unless ipsilateral hilar nodes were involved. Survival rates are presented in the form of life-table curves. These curves indicate that survival depends on the stage of the disease at the time of initial treatment; about 80% of patients with stage 1 lesions (tumour confined to the kidney) survived for 10 years compared with only 30% to 35% of stage 2 (involvement of perinephric fat) and stage 3 (involvement of renal vein or regional lymph nodes) patients and less than 10% of stage 4 (metastatic spread) patients. Radical nephrectomy appears to be the best method of treatment for patients with stage 1, 2 or 3 lesions. Simple palliative nephrectomy may be indicated in selected patients with stage 4 lesions.

Experience with polytetrafluoroethylene grafts in patients on long-term hemodialysis.

Expanded polytetrafluoroethylene (PTFE) is a new material now being used to create subcutaneous arteriovenous anastomoses for vascular access in hemodialysis. The authors have been impressed with the versatility of grafts made from this material and, where failure occurs, the ease with which surgical revision can be carried out. Two cases are described to illustrate the adaptability of this material to reconstruction. The authors' initial impression based on 22 months' experience is that PTFE grafts have appreciably modified the management with respect to vascular access, of many patients on long-term hemodialysis.

Polytetrafluorethylene (PTFE) grafts for hemodialysis. 18 months' experience.

18 months clinical experience with 6 mm polytetrafluorethylene forearm grafts for hemodialysis access has been described. 35 grafts were implanted, all in patients who had unsuitable vessels for construction of a regular Brescia-Cimino forearm fistula. The overall patency was 71% with mean duration of 10.3 months, and at any one time more than 85% of the grafts at risk were functional. Complications, including undesirable flow rates, edema, thrombosis, aneurysm and cardiac failure have been discussed and rational methods of avoidance described. We believe the polytetrafluorethylene (PTFE) graft represents an important advance in hemodialysis access.