Pathways from weight fluctuations to metabolic diseases: focus on maladaptive thermogenesis during catch-up fat

It has long been known that obesity is a high risk factor for cardiovascular diseases. In more recent years, the analysis of several large epidemiological databases has also revealed that, independently of excess weight, large fluctuations in body weight at some point earlier in life represent an independent risk factor for type 2 diabetes and hypertension-two major contributors to cardiovascular diseases. High cardiovascular morbidity and mortality have indeed been reported in men and women who in young adulthood experienced weight fluctuations (involving the recovery of body weight after weight loss due to disease, famine or voluntary slimming), or when weight fluctuations occurred much earlier in life and involved catch-up growth after fetal or neonatal growth retardation. This paper addresses the pathways from weight fluctuations to chronic metabolic diseases by focusing on the phenomenon of accelerated fat recovery (ie catch-up fat) after weight loss or growth retardation. Arguments are put forward that, during catch-up growth or weight recovery on our modern refined foods, the mechanisms of adaptive thermogenesis that regulate catch-up fat are pushed beyond the limits for which they were meant to operate and turn maladaptive. The consequences are enhanced susceptibilities towards skeletal muscle insulin resistance and overactive sympathetic activity, both of which are major contributors to the pathogenesis of chronic metabolic diseases. Since weight fluctuation earlier in life (independently of excess weight later in life) is an independent risk factor for metabolic diseases, the mechanisms by which body fat is acquired would seem to be at least as important as the consequences of excess fat per se in the pathogenesis of diabetes, hypertension and cardiovascular diseases.     

Endovascular treatment of peripheral artery disease with expanded PTFE-covered nitinol stents: interim analysis from a prospective controlled study

Purpose: Current covered peripheral stent designs have significant drawbacks in terms of stent delivery characteristics and flexibility. The aim of this study was to analyze the technical performance, safety and initial clinical efficacy of expanded polytetrafluoroethylene (PTFE)-covered nitinol stents for arteriosclerotic peripheral artery disease. Methods:Eighty-two patients underwent implantation of PTFE-covered nitinol stents for iliac and/or femoral obstructions. The study was conducted prospectively in seven European centers and one Canadian center. Patients were controlled clinically and by duplex ultrasound follow-up. Data up to discharge were collected in 79 patients. Seventy-four patients have thus far received 1 month follow-up and 32 patients, 6 month follow-up examinations. Results: The average lesion length measured 47 mm for the common and external iliac arteries and 50 mm for the femoral arteries. The mean severity of the stenoses was reduced from 94% to 4% in the iliac arteries and from 98% to 7% in the femoral arteries after stent placement and dilatation. One device deviation (inadvertent stent misplacement) and one puncture-related severe adverse event with formation of a pseudoaneurysm occurred. There were occlusions of the stent in five patients. No infections were noticed. Conclusion: The interim analysis of this trial using PTFE-covered nitinol stents indicates that a strategy using primary implantation of this stent type is technically feasible, has an acceptable safety profile and is effective from a short-term perspective.     

Modulation of IL-1beta,IL-6, TNF-alpha and PGE(2) by pharmacological agents in explants of membranes from failed total hip replacement

Introduction and goal Proinflammatory cytokines and prostaglandin E(2) (PGE(2)) play an important role in the pathophysiology of osteolysis and implant loosening. The aim of this study was to evaluate the role of pharmacological agents in the inhibition of Interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) and PGE(2) in explants of interface membranes from failed total hip replacements (fTHR).Material and methods Membranes from fTHR were retrieved (N=20) and explants were incubated for 72h in the absence or presence of tenidap at three different concentrations (5, 20 or 50 microg/ml) or diclofenac (125 microg/l). IL-1beta, IL-6, TNF-alpha, and PGE(2) levels were measured in the culture medium using ELISA Capture or EIA kits. Statistical analysis was done using the Mann-Whitney U-test.Results A statistically significant inhibition in IL-1beta synthesis was found at tenidap concentrations of 20 microg/ml (71.3%, P< 0.05) and 50 microg/ml (79.3%,P< 0.02). Tenidap reduced IL-6 levels by 90.4% at 20 microg/ml (P< 0.005) and 96.0% (P< 0.05) at 50 microg/ml. Tenidap also reduced the synthesis of TNF-alpha by 66.9% (P< 0.05) and 77.4% at concentrations of 20 microg/ml and 50 microg/ml. Tenidap had a marked suppressive effect of over 90% (P< 0.0001) on PGE(2) synthesis in all three concentrations. Diclofenac (125 microg/l) decreased PGE(2) production by 95% (P< 0.0001), but had no significant effect in IL-1beta, IL-6, and TNF-alpha levels in the culture medium.Conclusion The ability to simultaneously suppress the release of proinflammatory cytokines and PGE(2) may help control osteolysis and prevent aseptic loosening of THR. This effect could increase implant longevity and lead the way to the pharmacological treatment of this pathology.     

Can altered production of interleukin-1beta,interleukin-6, transforming growth factor-beta and prostaglandin E(2) by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients

OBJECTIVE: To determine the capacity of human subchondral osteoarthritic osteoblasts (Ob) to produce interleukin (IL)-1beta, IL-6, transforming growth factor-beta (TGF-beta) and prostaglandin E(2) (PGE(2)), and determine if a relationship exists between IL-1beta, TGF-beta, PGE(2) and IL-6 production. METHODS: We measured the abundance of IL-1beta, IL-6, TGF-beta and PGE(2) using very sensitive ELISA in conditioned-media of human primary subchondral Ob from normal individuals and osteoarthritic patients. Selective inhibition of IL-6 or IL-6 receptor signaling was performed to determine its effect on PGE(2) production whereas the inhibiton of PGE(2) production was performed to determine its effect on IL-6 production. The expression of bone cell markers and urokinase plasminogen activator (uPA) activity was also determined. RESULTS: Osteoarthritic Ob produced all these factors with greater variability than normal cells. Interestingly, the production of IL-6 and PGE(2) by osteoarthritic Ob separated patients into two subgroups, those whose Ob produced levels comparable to normal (low producers) and those whose Ob produced higher levels (high producers). In those cells classified as high osteoarthritic Ob, PGE(2) and IL-6 levels were increased two- to three-fold and five- to six-fold, respectively, compared with normal. In contrast, while using their IL-6 and PGE(2) production to separate osteoarthritic Ob into low and high producers, we found that IL-1beta levels were similar in normal and all osteoarthritic Ob. Using the same criteria, TGF-beta levels were increased in all osteoarthritic Ob compared with normal. Reducing PGE(2) synthesis by Indomethacin [a cyclo-oxygenase (COX) -1 and -2 inhibitor] reduced IL-6 levels in all osteoarthritic Ob, whereas Naproxen (a more selective COX-2 inhbitor) reduced PGE(2) and IL-6 levels only in the high osteoarthritic group. Conversely, PGE(2) addition to osteoarthritic Ob enhanced IL-6 production in both groups. Moreover, the addition of parathyroid hormone also stimulated IL-6 production to similar normal levels in both osteoarthritic groups. In contrast, using an antibody against IL-6 or IL-6 receptors did not reduce PGE(2) levels in either group. The evaluation of alkaline phosphatase activity, osteocalcin release, collagen type I and uPA activity in osteoarthritic Ob failed to show any differences between these cells regardless to which subgroup they were assigned. CONCLUSIONS: These results indicate that IL-6 and PGE(2) production by subchondral Ob can discriminate two subgroups of osteoarthritic patients that cannot otherwise be separated by their expression of cell markers, and that endogenous PGE(2) levels influence IL-6 synthesis in osteoarthritic Ob.     

Prediction of VO(2peak) in wheelchair-dependent athletes from the adapted Léger and Boucher test

PURPOSE: :The purpose of this study was to provide a predictive peak oxygen uptake ([V]O(2) peak) equation in wheelchair-dependent athletes using the Adapted Léger and Boucher test. SUBJECTS AND PROTOCOL: :Fifty-six wheelchair-dependent athletes, 47 males and nine females (30.3+/-4 years), underwent a clinical examination to assess their anthropometric characteristics: height, mass, body mass index (BMI), lean body mass, arm length, and muscular arm volume. They performed a deceleration field test to assess the subject-wheelchair resistance defined as a mechanical variable, and they then performed the Adapted Léger and Boucher test to assess physiological data at maximal exercise ([V]O(2) peak, heart rate max) concomitantly with biomechanical (number of pushes) and performance variables (maximal aerobic velocity Va(max) and maximal distance). The [V]O(2) peak was measured directly using a portable telemetric oxygen analyzer. Subjects were then randomly assigned to an experimental group (n=49) to determine the predictive equation, and a validation group (n=7) to check the external validity of the equation. RESULTS: A stepwise multiple regression with [V]O(2) peak (l min(-1)) as the dependent variable led to the following equation: [V]O(2) peak=0.22 Va(max) - 0.63 log(age)+0.05 BMI 0.25 level+0.52, with r(2)=0.81 and SEE=0.01. Paraplegic subjects with high and low lesion level spinal injuries were attributed the coefficient of 1 and 0, respectively. The external validity of the equation was positive since the predicted [V]O(2) peak values did not significantly differ from directly measured [V]O(2) peak (P>0.05). CONCLUSION: We concluded that [V]O(2) peak in wheelchair-dependent athletes was predictable using the equation of the present study and the described incremental test.     

Use of bacille Calmette-Guérin in superficial bladder cancer

Intravesical bacille Calmette-Guérin (BCG) has been used by urologists for several years after its first reported use as a cancer therapy in the 1930s. Morales in 1976 described the usage of BCG as a once weekly intravesical instillation for six weeks; this is a treatment regimen that still exists today. Its success as a treatment depends on it being used appropriately. It is employed: (1) to treat carcinoma in situ or occasionally residual papillary tumours; (2) to reduce the number and frequency of recurrent high grade superficial tumours; and (3) to prevent disease progression (although this remains a controversial point, on which there is no consensus view). Unfortunately, the more widespread use of BCG is often limited due its high side effect profile. Present research is directed towards reducing its side effect profile, improving its efficacy, and understanding its exact mechanism of action, which is not fully understood.     

High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.     

Implementation of transabdominal ultrasound image guided conformal intensity modulated radiotherapy]

PURPOSE: Optically guided ultrasound imaging has been used in our department since 2003 in order to implement an on line correction scheme in intensity modulated radiation therapy of prostate carcinoma. PATIENTS AND METHODS: The corrections observed during the initial time period of the system (17 patients) are compared to those observed more recently (10 patients). Treatment margins are calculated. RESULTS: Overall systematic errors decreased between 2003 and 2006, and are presently statistically not different from zero. Random errors remain the same (max 4.3 mm). Proposed margins are 7 mm both in lateral and longitudinal direction and 8.4 mm in anteroposterior. CONCLUSION: Ultrasound can be used for on line correction of both positioning and internal organs motion errors and allows reduction of the margins between clinical and planning volume.     

Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors.

BACKGROUND: This investigation evaluates prognostic variables in patients with seminomatous and non-seminomatous extragonadal germ-cell tumors (EGCT) in order to identify relevant factors for long-term outcome following cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients from six countries treated at 11 centers in Europe and the USA from 1975 to 1996 were evaluated retrospectively. Uni- and multivariate analyses of prognostic variables for survival and for response to chemotherapy were performed. RESULTS: Data were available for 635 EGCT patients, 104 with seminomatous and 524 with non-seminomatous EGCT (n = 7 not specified). For non-seminomatous EGCT the following independent adverse factors were identified: presence of either liver, lung or central nervous system metastases, primary mediastinal tumor or elevation of pretreatment beta-human gonadotropin; for extragonadal seminoma (only univariate) adverse factors were: presence of liver metastases, two or greater metastatic sites or International Germ Cell Cancer Collaborative Group (IGCCCG) grouping (intermediate versus good). Integration of these variables produced the following prognostic risk groupings: 'excellent prognosis', all seminomatous EGCT (89% 5-year survival rate); 'intermediate low', 'intermediate high' and 'poor', all non-seminomatous EGCT with a 69, 55 and 17% 5-year survival rate, respectively. The decreased survival among the different groups was due to a lower rate of favorable objective remissions and a higher rate of relapses. Classification and regression tree (CART) modeling confirmed histology and location of primary tumor as the major prognosticators. For the subgroup of patients with mediastinal non-seminoma, the 2-year survival rate ranged from 34 to 84%. Multivariate testing for the probability to respond to chemotherapy revealed non-seminomatous histology, primary mediastinal tumor site, and the presence of liver, lung or CNS metastases as independent adverse factors. CONCLUSIONS: In EGCT, prognostic variables for the outcome and for the response to chemotherapy could be identified, which in part differ from gonadal GCT. The proposed model might help to better understand the specific prognosis of EGCT and to tailor risk-adapted treatment strategies. In addition, CART analysis demonstrated the heterogenous prognosis of patients with mediastinal non-seminoma.