Demonstration of coronary artery myogenic vasoconstriction in the awake dog

Summary The aim of this study was to determine whether or not coronary vasoconstriction occurs in response to a transient increase in coronary perfusion pressure. Eleven awake dogs with formalin-induced heart block, chronically instrumented with aortic and left ventricular catheters and left circumflex coronary and aortic electromagnetic flowprobes, were studied at a paced heart rate of 60 beats/min. A transient increase in aortic diastolic pressure of 17.3±1.5% for 330±20 ms and of 33.6±2.2% for 520±20 ms, via the inflation of an intra-aortic balloon, resulted in an increase in diastolic coronary vascular resistance index in the first response beat of 6±1% and 11±1%, respectively. An identical increase in diastolic coronary flow produced by the omission of a single paced beat resulted in no significant change in diastolic coronary vascular resistance index in the first response beat. Thus, the increase in diastolic coronary vascular resistance index following diastolic pressure augmentation is related to the increase in aortic diastolic pressure and not to the increase in diastolic coronary flow. These data are consistent with that of a brief myogenic response.Supported in part by the National Institutes of Health Grant HL 18468 and the Medical Research Service of the Veterans Administration. Dr. Sadick is a recipient of an Overseas Research Fellowship from Australian National Heart Foundation. His current address is Blacktown Hospital, P.O. Box 105, Blacktown, N.S.W. 2148 Australia. Dr. Dube is supported by Multidisciplinary Heart and Vascular Diseases, #HL07101 training grant.     

The effects of five-year growth hormone replacement therapy on muscle strength in elderly hypopituitary patients

OBJECTIVE: Little is known of the long-term effects of GH replacement therapy on muscle strength in elderly adults with adult onset GH deficiency (GHD). In this study, the effects of 5 years of GH replacement therapy on muscle function were determined in adults over 60 years of age with adult onset GHD. DESIGN: A prospective, open-label, single-centre study. Patients Twenty-six (12 male and 14 female) consecutive hypopituitary adults with adult onset GHD, mean age 65.0 (range 61-74) years. MEASUREMENTS: Upper leg muscle strength was measured using a Kin-Com dynamometer. Right and left handgrip strength were measured using an electronic grip force instrument. RESULTS: The mean insulin-like growth factor-I (IGF-I) SD score increased from -1.10 at baseline to 1.21 at end of the study. Body weight was unchanged during the 5-year study. A sustained increase in lean body mass and a sustained reduction of body fat was observed as measured using dual-energy X-ray absorptiometry (DEXA). The GH replacement therapy induced a sustained increase in isometric (60 degrees ) knee flexor strength. After statistical correction for age and sex variables using observed/predicted value ratios, a sustained increase was also observed in concentric knee flexor strength at an angular velocity of 60 degrees /s, concentric knee extensor strength at 60 degrees /s and 180 degrees /s, and peak right handgrip strength. At baseline, knee flexor strength was 90-96% of predicted, knee extensor strength was 85-87% of predicted, and hand-grip strength was 74-80% of predicted values. At study end, knee flexor strength was 98-106% of predicted, knee extensor strength was 90-100% of predicted, and hand-grip strength was 80-87% of predicted values. CONCLUSION: Elderly patients with adult onset GH deficiency had decreased baseline muscle strength also after correction for age and sex. The 5-year GH replacement therapy normalized knee flexor strength and improved, but did not fully normalize, knee extensor strength and handgrip strength.     

Effects of the chemokine MIP-1alpha on anemia and inflammation in rheumatoid arthritis

Macrophage inflammatory protein-1alpha (MIP-1alpha) is an interesting chemokine because in addition to its variety proinflammatory activities including chemotaxis and immunomodulation, it is a potent inhibitor of hematopoetic stem cell proliferation. Inhibition of erythroid progenitor cells due to MIP-1alpha or other cytokines can play a role in the pathogenesis of anemia which is one of the most common extra-articular features of active rheumatoid arthritis (RA). In 84 patients with RA, serological and immunological parameters were assessed to detect inflammatory mechanisms and anemia in relation to the serum concentrations of MIP-1alpha. All patients fulfilled the ACR criteria for the diagnosis of a definite or classic RA. We used a quantitative enzyme immuno assay for the detection of MIP-1alpha as well as for the measurement of the acute phase protein serum amyloid A (SAA), the erythropoiesis inducer erythropoietin (EPO) and the transferrin receptor (TfR). The immune activation marker neopterin was measured radioimmunologically. Half of the patients with RA were anemic with hemoglobin values below 12 g/dl. MIP-1alpha was found to be elevated significantly in serum of patients with active rheumatoid arthritis and in patients with anemia. Most of the anemic patients with markedly elevated acute phase reactions had an anemia with chronic diseases and not a functional iron deficiency alone. TfR correlated with EPO. The results show that enhanced expression of MIP-1alpha is indicative of systemic inflammation in RA. Moreover, besides the regulation of inflammatory processes, this chemokine may influence the pathogenesis of anemia in RA patients.     

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA_257-264 peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.