Exercise training restores aerobic capacity and energy transfer systems in heart failure treated with losartan

OBJECTIVE: Clinical and experimental studies demonstrate that exercise training improves aerobic capacity and cardiac function in heart failure, even in patients on optimal treatment with angiotensin inhibitors and beta-blockers, but the cellular mechanisms are incompletely understood. Since myocardial dysfunction is frequently associated with impaired energy status, the aim of this study was to assess the effects of exercise training and losartan on myocardial systems for energy production and transfer in heart failure. METHODS: Maximal oxygen uptake, cardiac function and energy metabolism were assessed in heart failure after a myocardial infarction induced by coronary artery ligation in female Sprague-Dawley rats. Losartan was initiated one week after infarction and exercise training after four weeks, either as single interventions or combined. Animals were sacrificed 12 weeks after surgery. RESULTS: Heart failure, confirmed by left ventricular diastolic pressure >15 mmHg and by >20 mmHg drop in peak systolic pressure, was associated with 40% lower aerobic capacity and significant reductions in enzymes involved in energy metabolism. Combined treatment yielded best improvement of aerobic capacity and ventricular pressure characteristics. Exercise training completely restored aerobic capacity and partly or fully restored creatine and adenylate kinases, whereas losartan alone further reduced these enzymes. In contrast, losartan reduced left ventricle diastolic pressure, whereas exercise training had a neutral effect. CONCLUSION: Exercise training markedly improves aerobic capacity and cardiac function after myocardial infarction, either alone or in combination with angiotensin inhibition. The two interventions appear to act by complementary mechanisms; whereas exercise training restores cardiac energy metabolism, mainly at the level of energy transfer, losartan unloads the heart by lowering filling pressure and afterload.     

Radiotherapy adapted to spatial and temporal variability in tumor hypoxia

PURPOSE: To explore the feasibility and clinical potential of adapting radiotherapy to temporal and spatial variations in tumor oxygenation. METHODS AND MATERIALS: Repeated dynamic contrast enhanced magnetic resonance (DCEMR) images were taken of a canine sarcoma during the course of fractionated radiation therapy. The tumor contrast enhancement was assumed to represent the oxygen distribution. The IMRT plans were retrospectively adapted to the DCEMR images by employing tumor dose redistribution. Optimized nonuniform tumor dose distributions were calculated and compared with a uniform dose distribution delivering the same integral dose to the tumor. Clinical outcome was estimated from tumor control probability (TCP) and normal tissue complication probability (NTCP) modeling. RESULTS: The biologically adapted treatment was found to give a substantial increase in TCP compared with conventional radiotherapy, even when only pretreatment images were used as basis for the treatment planning. The TCP was further increased by repeated replanning during the course of treatment, and replanning twice a week was found to give near optimal TCP. Random errors in patient positioning were found to give a small decrease in TCP, whereas systematic errors were found to reduce TCP substantially. NTCP for the adapted treatment was similar to or lower than for the conventional treatment, both for parallel and serial normal tissue structures. CONCLUSION: Biologically adapted radiotherapy is estimated to improve treatment outcome of tumors having spatial and temporal variations in radiosensitivity.     

Seasonal and geographical variations in lung cancer prognosis in Norway. Does Vitamin D from the sun play a role?

Vitamin D derivatives can modulate proliferation and differentiation of cancer cells. Our main source of Vitamin D is ultraviolet (UV) radiation-induced synthesis in skin following sun exposure. UV measurements show that the ambient annual UV exposures increase by about 50% from north to south in Norway. As judged from the incidence rates of squamous cell carcinoma, the same is true for the average personal UV exposures. Solar ultraviolet B (UVB) (280-320nm) exhibits a strong seasonal variation with a minimum during the winter months. The present work aims at investigating the impact of season of diagnosis and residential region, both influencing the Vitamin D level, on the risk of death from lung cancer in patients diagnosed in Norway. Data on all incident cases of lung cancer between 1964 and 2000 were collected. Risk estimates were calculated as relative risk (RR), with 95% confidence intervals using Cox regression model. The seasonal variation of 25-hydroxyvitamin D was assessed from routine measurements of 15,616 samples performed at The Hormone Laboratory of Aker University Hospital. Our results indicate that season of diagnosis is of prognostic value for lung cancer patients, with a approximately 15% lower case fatality for young male patients diagnosed during autumn versus winter (RR=0.85; 95% CI, -0.73 to 0.99; p=0.04). Residing in a high UV region resulted in a further lowering of the death risk than residing in a low UV region. We propose, in agreement with earlier findings for prostate-, breast- colon cancer and Hodgkins lymphoma, that a high level of sun-induced 25-hydroxyvitamin D can be a prognostic advantage for certain groups of lung cancer patients, notably for young men. Lung cancer has for several decades been the leading cause of cancer-related mortality in men in Norway and during the last two decades, became the second most common cause of cancer-related death in women . There are two main types of lung cancer: small cell lung cancer for which chemotherapy is the primary treatment and non-small cell lung cancer, which in its early stages is treated primarily with surgery. Gender-related differences have been described in the literature with respect to survival after therapy, male gender being a significant independent negative prognostic factor . In Norway the 5 years relative survival for localized tumours is about 30% for females and 20% for males. Calcitriol, which is the most active form of Vitamin D, is involved in key regulatory processes such as proliferation, differentiation and apoptosis in a wide variety of cells . Mechanisms for these actions have been proposed to be the interaction of active Vitamin D derivatives with a specific nuclear receptor (VDR receptor) and/or with membrane targets . In vitro studies, performed with lung cancer cell lines, have shown an inhibitive effect of Vitamin D derivatives on cell-growth and proliferation . Furthermore, animal studies have demonstrated the capability of these compounds to suppress invasion, metastasis and angiogenesis in vivo , suggesting that administration of Vitamin D derivatives may be used as adjuvant therapy for lung cancer. Humans get optimal Vitamin D levels by exposure to sun or artificial ultraviolet B (UVB, 280-320nm) sources , and possibly also by consumption of food rich in this nutrient (fat fish, eggs, margarine, etc.) or of vitamin supplements . Among these sources, solar radiation appears to be the most important one . Thus, the Vitamin D status (assessed by the serum levels of 25-hydroxyvitamin D, calcidiol) exhibits a strong seasonal variation that parallels the seasonal change in the fluence of solar UVB that reaches the ground. During winter, the UVB fluence rate in the Nordic countries (50-71 degrees N) is below the level required for Vitamin D synthesis in skin . The maximal level of calcidiol is reached between the months July and September, and is 20-120% higher than the corresponding winter level . Recently we hypothesised that the seasonal variation of calcidiol might be of prognostic significance for colon-, breast- prostate cancer as well as for Hodgkins lymphoma in Norway. Patients diagnosed during summer and autumn have a better survival after standard treatment than patients diagnosed during the winter season . This might be a consequence of a higher Vitamin D level. An American study investigated the effect of season of surgery and recent Vitamin D intake on the survival of non-small cell lung cancer patients. The authors reported a significant beneficial joint effect of summer season and high Vitamin D intake compared with winter season and low Vitamin D intake while Vitamin D intake alone did not affect prognosis. Similar results were recently reported from a large study in United Kingdom involving over a million cancer patients including over 190,000 patients diagnosed with lung cancer . Norway (58-71 degrees N) has a significant north-south variation in UV fluence. This makes the country suitable for studies relating cancer epidemiology to UV levels . We investigated whether variations in UV, and, consequently, in Vitamin D level, influence the prognosis of lung cancer, using season of diagnosis and residential regions as variables. Survival data obtained for patients diagnosed over a 40 years period were compared with variations in serum Vitamin D levels obtained from routine measurements performed in The Hormone Laboratory of Aker University Hospital during the period 1996-2001. Seasonal and gender variations in Vitamin D level have been estimated from the analyses.     

Transient partial amnesia complicating cardiac and peripheral arteriography with nonionic contrast medium

The aim of this study was to present a case of disruption of the blood-brain barrier during the coronary and lower extremity angiographies with radiological and clinical findings. This condition was secondary to intraarterial use of a nonionic, monomeric contrast medium. A total of 450 cc contrast media was used. Computed tomography examination showed contrast enhancement of the right occipital and frontoparietal cortical regions, which returned to normal one day after. The patient also fully recovered from the neurological symptoms within 24 h. We discussed the possible mechanism for blood-brain barrier disruption in this case.

     

Acromegaly with Normal Growth Hormone Levels: Response to Sandostatin-LAR Treatment

We report a case of acromegaly with relatively low GH secretion in a patient with GH-secreting pituitary macroadenoma. The 44-year-old male patient presented with left temporal hemianopsia and characteristic acromegalic face, but had relatively low baseline and post-glucose GH levels. IGF-1 and IGFBP-1 were elevated. Transsphenoidal surgery did not achieve clinical or biochemiacl remission, and the patient still had elevated IGF-1 levels with low GH. Histological examination of the resected tumor revealed a pituitary adenoma stained weakly for GH. The patient was treated then with monthly injections of Sandostatin-LAR, with clinical improvement and suppression of IGF-I to the normal range. This is a rare case of acromegaly without elevated GH levels, and good response to treatment with somatostatin analog, as expected in classical GH-secreting pituitary adenomas.     

Improved pregnancy outcome with the addition of leuprolide acetate to gonadotropins for in vitro fertilization

In vitro fertilization treatment outcomes were compared prospectively in unselected patients with and without the addition of leuprolide acetate to gonadotropins for ovarian hyperstimulation. While the leuprolide patients required greater quantities of exogenous gonadotropins to achieve ovarian stimulation, significant improvements in the fertilization, implantation, and spontaneous abortion rates were observed compared with patients not receiving leuprolide. The ongoing pregnancy ("take home baby") rates per aspiration with and without leuprolide were 29% and 12%, respectively. Furthermore, the multiple pregnancy rate was markedly increased in the leuprolide group (44% versus 8%), suggesting that the improved pregnancy outcome with pituitary suppression was due primarily to higher oocyte and embryo quality.     

An endogenous colon mitosis inhibitor reduces the increased cell proliferation in colonic epithelium induced by dietary cholic acid and treatment with 1,2-dimethylhydrazine

We have recently purified and identified a tripeptide (pGlu-His-GlyOH)in mouse intestinal extracts which reversibly inhibits normalcolonic epithelial cell renewal in mice. We also found a similarresponse to a single injection of the peptide during bile-acid-inducedhyperproliferation in the colonic epithelium. To investigatethe effect of repeated injections of the same dose of the inhibitorunder various pathological conditions of the colonic mucosawe either fed mice low-calcium cholic acid diet, treated theanimals with a single injection of the colon carcinogen 1,2-dimethyl-hydrazine(DMH), or gave both treatments. The peptide reduced the mitoticrate and the labelling indices in the colonic epithelium duringthe first 5 days of feeding the low-calcium cholic acid diet,and the size of the proliferative compartment was reduced. Proliferatingcells were found significantly closer to the base of the crypisin the peptide-treated animals. The mitotic rate was also reducedby each of repeated peptide injections during the first 72 hin the DMH-treated animals; the labelling indices at 48 and72 h only. By feeding DMH-treated animals low-calcium cholicacid diet, similar results were obtained. However, in all carcinogen-treatedanimals the tripeptide had no effect on the size and localizationof the proliferating cells in the colonic crypts.