Citations

Little information is available regarding the optimal timing of exercise in insulin-dependent diabetes mellitus (IDDM) patients. In this study, six IDDM patients receiving ultralente-based intensive insulin therapy were studied during 30 min of exercise (∼60% Vo2max), before breakfast, and at 1600. On two other occasions, they were studied at rest. Plasma glucose increased from 6.7 ± 0.4 to 9.1 ± 0.4 mM during morning exercise (P < 0.01). In contrast, mean plasma glucose did not change during afternoon exercise (≸ = 0.3 ± 0.5 mM, NS); however, there was a 0.3- to 1.0-mM decrease in three subjects. The observed difference in the glycemic response to exercise could not be explained on the basis of changes in plasma glucagon, growth hormone, norepinephrine, or epinephrine. Plasma cortisol was higher (P < 0.02) in the morning than in the afternoon, and plasma free-insulin concentrations were lower (P < 0.05). These data indicate that the risk of exerciseinduced hypoglycemia is lowest before breakfast. The reason for the divergent glycemic responses to exercise is not entirely clear but may be related to the observed differences in free-insulin concentrations. Because of the lower risk of hypoglycemia, our results suggest prebreakfast exercise may be preferable for some IDDM patients receiving intensive insulin therapy. Whether these findings are relevant to patients receiving other types of insulin therapy will require further investigation.

AbstractWaldenström macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Protein kinase Cβ (PKCβ) regulates cell survival and growth in many B-cell malignancies. In this study, we demonstrate up-regulation of PKCβ protein in WM using protein array techniques and immunohistochemistry. Enzastaurin, a PKCβ inhibitor, blocked PKCβ activity and induced a significant decrease of proliferation at 48 hours in WM cell lines (IC50, 2.5-10 μM). Similar effects were demonstrated in primary CD19+ WM cells, without cytotoxicity on peripheral blood mononuclear cells. In addition, enzastaurin overcame tumor cell growth induced by coculture of WM cells with bone marrow stromal cells. Enzastaurin induced dose-dependent apoptosis at 48 hours mediated via induction of caspase-3, caspase-8, caspase-9, and PARP cleavage. Enzastaurin inhibited Akt phosphorylation and Akt kinase activity, as well as downstream p-MARCKS and ribosomal p-S6. Furthermore, enzastaurin demonstrated additive cytotoxicity in combination with bortezomib, and synergistic cytotoxicity in combination with fludarabine. Finally, in an in vivo xenograft model of human WM, significant inhibition of tumor growth was observed in the enzastaurin-treated mice (P = .028). Our studies therefore show that enzastaurin has significant antitumor activity in WM both in vitro and in vivo, providing the framework for clinical trials to improve patient outcome in WM.

Abstract Rationale Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult. Objectives Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers. Methods Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days. Measurements and Main Results Each observer's diagnosis was coded into one of eight categories. A κ statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (κ = 0.55–0.71) than within community centers (κ = 0.32–0.44). Clinically significant disagreement was present between academic and community-based physicians (κ = 0.11–0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians. Conclusions Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.

Abstract Innovations and Challenges in Renal Cancer, chaired by Michael B. Atkins, was held April 28 to 29, 2006 in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, urology, immunology, radiology, and immunotherapy, with the goal of advancing the field of renal cancer treatment by critiquing new data from ongoing clinical trials and stimulating communication among those involved in basic and clinical research. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on important aspects of renal cancer genetics and biology and advances in prognostic classification and treatment.

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 μg/kg for 6 sequential weeks (total dose 12 μg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.

AbstractPhosphatidylcholine acyltransferase (lecithin:cholesterol acyltransferase or LCAT; EC 2.3.1.43) activity was found to be present in pig ovarian follicular fluid (POFF), in addition to pig serum (PS). The cholesterol esterification rate in both POFF and PS is linear with incubation time up to 2 hr. The mean absolute rate of POFF‐cholesterol esterification was 8.1±0.4 nmoles per ml per hr approximately one‐fourth of that in PS. However, the fractional rate (percent of labeled cholesterol esterified per hr) of POFF‐cholesterol esterification was similar to that observed in PS. There was little variation of absolute rate of cholesterol esterification in the fluid obtained from different sizes of follicles. Fatty acid or triacylglycerol did not participate in the reaction of cholesterol esterification in POFF. No appreciable change in enzymatic activity was found from storing POFF at 4 C for periods of time up to 24 hr or at −70 C up to 2 months, but activity was lost thereafter. On the other hand, PS showed a much longer period of stability (5 days at 4 C and 9 months at −70 C). A discrepancy between the fatty acid composition of cholesteryl esters formed by the LCAT reaction and the fatty acid composition at the C‐2 position of phosphatidylcholine led us to propose a two‐step mechanism for the LCAT reaction. It is concluded that the LCAT of POFF, as well as that of plasma, is specific for individual fatty acids rather than for the fatty acid composition of phosphatidylcholine. The fatty acid concentration of lysophosphatidylcholine decreased during prolonged incubation times (6 to 21 hr) suggesting that the increased lysophosphatidylcholine formed as a product of the LCAT reaction may be reused as substrate for the LCAT reaction or for hydrolysis by lysophosphatidylcholine hydrolase.

AbstractThree of six kin were identified, by high performance thin layer chromatography, capillary gas chromatography and mass spectrometry, as having phytanic acid storage disease. Phytanic acid was found in triacylglycerol and, to a lesser degree, in phosphatidylcholine and free fatty acids. An unsaturated analogue of phytanic acid was additionally identified in plasma and erythrocyte triacylglycerols. In plasma, branched chain fatty acids were primarily localized in the low density lipoprotein fraction. The concentration of plasma major fatty acids was not affected by the presence of these branched chain fatty acids. In contrast to plasma, only small amounts of phytanic acid were found in cerebrospinal fluid and biopsied sural nerve. The nerve phytanate was mainly associated with triacylglycerol in epineurial and perineurial tissues. Lack of phytanate accumulation in sural endoneurium, even in cases with severe fiber degeneration, suggests that demyelination in Refsum's disease may not be due to myelin instability resulting from the incorporation of branched chain fatty acids into peripheral nerve membrane.