Altered crossbridge kinetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy

A mutation in the cardiac beta-myosin heavy chain, Arg403Gln (R403Q), causes a severe form of familial hypertrophic cardiomyopathy (FHC) in humans. We used small-amplitude (0.25%) length-perturbation analysis to examine the mechanical properties of skinned left ventricular papillary muscle strips from mouse hearts bearing the R403Q mutation in the alpha-myosin heavy chain (alphaMHC403/+). Myofibrillar disarray with variable penetrance occurred in the left ventricular free wall of the alphaMHC403/+ hearts. In resting strips (pCa 8), dynamic stiffness was approximately 40% greater than in wild-type strips, consistent with elevated diastolic stiffness reported for murine hearts with FHC. At pCa 6 (submaximal activation), strip isometric tension was approximately 3 times higher than for wild-type strips, whereas at pCa 5 (maximal activation), tension was marginally lower. At submaximal calcium activation the characteristic frequencies of the work-producing (b) and work-absorbing (c) steps of the crossbridge were less in alphaMHC403/+ strips than in wild-type strips (b=11+/-1 versus 15+/-1 Hz; c= 58+/-3 versus 66+/-3 Hz; 27 degrees C). At maximal calcium activation, strip oscillatory power was reduced (0. 53+/-0.25 versus 1.03+/-0.18 mW/mm3; 27 degrees C), which is partly attributable to the reduced frequency b, at which crossbridge work is maximum. The results are consistent with the hypothesis that the R403Q mutation reduces the strong binding affinity of myosin for actin. Myosin heads may accumulate in a preforce state that promotes cooperative activation of the thin filament at submaximal calcium but blunts maximal tension and oscillatory power output at maximal calcium. The calcium-dependent effect of the mutation (whether facilitating or debilitating), together with a variable degree of fibrosis and myofibrillar disorder, may contribute to the diversity of clinical symptoms observed in murine FHC.     

Twenty years of gerontological education: a report on the experience of one program.

The Center for Studies in Aging at the University of North Texas has been in existence for over 20 years. Data were collected from 339 of the 493 students who completed its program between 1967 and 1987. Data suggest that: levels of both initial employment and retention in the field of aging are high; gender differences in salaries exist among program concentrations and year of completion; and former students report high levels of involvement in collateral activities.     

Mycobacterium avium-intracellulare induces interleukin-6 from human monocytes and large granular lymphocytes

Mycobacterium avium-intracellulare (MAI) is an opportunistic pathogen commonly found in acquired immunodeficiency syndrome patients, whose immune systems are severely compromised. However, normal responses to this bacterium are apparently sufficient to prevent disseminated infection because disease is rarely found unless an immunocompromised state is present. Because interleukin-6 (IL-6) is an inflammatory cytokine with a multitude of activities, we investigated the potential of MAI to induce IL-6 from normal human leukocytes. Peripheral blood mononuclear cells were fractionated into monocytes (Mo), large granular lymphocytes (LGL), and T cells and stimulated with bacteria. Culture supernatants were collected and assayed for IL-6 activity by bioassay. Mo and LGL, but not T cells, were found to release IL-6 within 12 hours of stimulation, with optimal production occurring by 2 days of culture. Production of IL-6 from human leukocyte subsets was confirmed by Northern blot analysis and by neutralization of biologic function of the culture supernatants with specific antisera. Taken together, these results indicate that production of IL-6 is a key response of Mo and LGL to MAI. The role of IL-6 in MAI infection, therefore, needs to be further investigated.     

Production of granulocyte-macrophage colony-stimulating factor by large granular lymphocytes stimulated with Candida albicans: role in activation of human neutrophil function

In the present study, culture supernatants from larger granular lymphocytes (LGL) that were activated with Candida albicans antigens were shown to stimulate the ability of neutrophils to inhibit fungal growth. Identification of the activation factors showed that granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor, was involved. Human peripheral blood mononuclear cells were fractionated by Percoll density centrifugation and each subpopulation of cells was stimulated with C albicans yeast cells. GM-CSF was produced in those fractions enriched for LGL, but not T lymphocytes or adherent monocytes. Additionally, the phenotype of the GM-CSF-producing cell was found to be CD2+, CD16+, HLA-DR+, and negative for CD4, CD8, and CD15. Kinetic studies demonstrated that GM-CSF appeared in the supernatants within 2 days of culture and continued to be produced up to 7 days. Optimal stimulation of LGL was seen at a ratio of 3 heat-killed C albicans yeast cells per LGL. Thus, LGL play an important role in host defense against this opportunistic pathogen by producing cytokines, including GM-CSF, which in turn activates the fungicidal activity of neutrophils.     

Dynamic calcium requirements for activation of rabbit papillary muscle calculated from tension-independent heat

The heat generated by right ventricular papillary muscles of rabbits was measured after adenosine triphosphate (ATP) splitting by the contractile proteins was chemically inhibited. This tension-independent heat (TIH) (1 mJ/g wet weight) was used to calculate the total calcium (Ca) cycled in a muscle twitch by assuming that 87% of TIH was due to Ca2+ transport by the sarcoplasmic reticulum with a coupling ratio of 2 Ca2+/ATP split; the enthalpy of creatine phosphate hydrolysis buffering ATP was taken as -34 KJ/mol. The estimated Ca turnover per muscle twitch at 21 degrees C, 0.2 Hz pacing rate, and 2.5 mM Ca in the Krebs solution was approximately equal to 50 nmol/g wet weight. There was a tight positive correlation between TIH and mechanical activation during steady-state measurements but no correlation during the sharp increase in mechanical activation (treppe) when stimulation was resumed after a rest period. It is suggested that while total Ca cycling remains unchanged during the initial period of tension treppe, the free Ca2+ transient and mechanical activation increase sharply due to resaturation of high affinity Ca2+ buffers, other than troponin C, depleted of Ca2+ during the rest period.     

Long-term clinical results of coronary surgery. Apropos of 400 patients followed for 5 to 11 years

Between 1976 and 1982 four hundred consecutive patients underwent coronary artery bypass surgery and were operated by the same surgical team: 345 men (88.5%) and 46 women (11.5%). The average age was 56 years (7.5% were over 75 years of age); 86% of patients were infunctional classes III and IV; 46% had triple vessel disease and 9.25% had severe stenosis of the left main stem. Left ventricular ejection fractions were decreased in 26% and very poor in 4.5% of patients. The average number of bypass grafts was 1.72 per patient and the operative mortality was 3.5%. The 10 year survival rate was 81% and 75% of these patients still thought that their condition had been improved by surgery although only 30% were completely asymptomatic and had had no further coronary event. A comparison with a control population of the same age showed better survival in the surgical group in patients surviving operation. Contrary to traditional thinking, the surgical patients suffered relatively few deaths of cardiac causes but as many, if not more, of cancer. The operated patients died of approximately the same diseases as the control population of the same age but in lower proportions for each cause of death (17 cardiovascular deaths in the control population compared with 13 in the operated group; 18 versus 10 deaths of cancer, and 18 versus 8 deaths of other causes in the control and operated patients, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study

BACKGROUND & AIMS: We aimed to discern the relative risk for several chronic inflammatory conditions in patients with ulcerative colitis (UC) and Crohn's disease. METHODS: We used the population-based University of Manitoba IBD Database that includes longitudinal files on all patients from all health system contacts identified by International Classification of Diseases, 9th revision, Clinical Modification codes for visit diagnosis. From the provincial database we extracted a control cohort matching the IBD patients 10:1 by age, sex, and geography. We considered a potential comorbid disease to be present if the patient had 5 or more health system contacts for that diagnosis. The comorbid disease period prevalence was analyzed separately for patients with UC and Crohn's disease and a prevalence ratio was calculated comparing the IBD populations with the matched cohort. RESULTS: There were 8072 cases of IBD from 1984 to 2003, including UC (n = 3879) and Crohn's disease (n = 4193). There was a mean of approximately 16 person-years of coverage for both patients and control patients. Both UC and Crohn's disease patients had a significantly greater likelihood of having arthritis, asthma, bronchitis, psoriasis, and pericarditis than population controls. An increased risk for chronic renal disease and multiple sclerosis was noted in UC but not Crohn's disease patients. The most common nonintestinal comorbidities identified were arthritis and asthma. CONCLUSIONS: The finding of asthma as the most common comorbidity increased in Crohn's disease patients compared with the general population is novel. These may be diseases with common causes or complications of one disease that lead to the presentation with another. Studies such as this should encourage further research into the common triggers in the organ systems that lead to autoimmune diseases.     

Breast-specific gamma imaging is a cost effective and efficacious imaging modality when compared with MRI

Background

Both MRI and breast-specific gamma imaging are tools for surgical planning in newly diagnosed breast cancer. Breast-specific gamma imaging (BSGI) is used less frequently although it is of similar utility and lower cost. We compared the diagnostic and cost efficacy of BSGI with MRI.

Methods

Retrospective review of 1,480 BSGIs was performed in a community breast health center, 539 had a new diagnosis of cancer, 75 patients having both MRI and BSGI performed within 2 months of each other. Institutional charges for BSGI ($850) and MRI ($3,381) were noted.

Results

BSGI had a sensitivity of 92%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 90%. This compared favorably with MRI that had sensitivity of 89%, specificity 54%, positive predictive value 67%, and negative predictive value 83%. The accuracy of BSGI was higher at 82% vs MRI at 72%. Total cost of MRI imaging was $253,575 vs BSGI at $63,750.

Conclusions

BSGI is a cost-effective and accurate imaging study for further evaluation of dense breast tissue and new diagnosis of cancer.