Arterial Wall Stiffening in Caveolin-1 Deficiency-Induced Pulmonary Artery Hypertension in Mice.

BACKGROUND: Pulmonary artery hypertension (PAH) is a complex disorder that can lead to right heart failure. The generation of caveolin-1 deficient mice (CAV-1-/-) has provided an alternative genetic model to study the mechanisms of pulmonary hypertension. However, the vascular adaptations in these mice have not been characterized. OBJECTIVE: To determine the histological and functional changes in the pulmonary and carotid arteries in CAV-1-/- induced PAH. METHODS: Pulmonary and carotid arteries of young (4-6 months old) and mature (9-12 months old) CAV-1-/- mice were tested and compared to normal wild type mice. RESULTS: Artery stiffness increases in CAV-1-/- mice, especially the circumferential stiffness of the pulmonary arteries. Increases in stiffness were quantified by a decrease in circumferential stretch and transition strain, increases in elastic moduli, and an increase in total strain energy at physiologic strains. Changes in mechanical properties for the pulmonary artery correlated with increased collagen content while carotid artery mechanical properties correlated with decreased elastin content. CONCLUSIONS: We demonstrated that an increase in artery stiffness is associated with CAV-1 deficiency-induced pulmonary hypertension. These results improve our understanding of artery remodeling in PAH.

Pulmonary mononuclear cell responses to antigens of Mycobacterium tuberculosis in healthy household contacts of patients with active tuberculosis and healthy controls from the community.

Protective immunity against Mycobacterium tuberculosis requires CD4+ lymphocyte-mediated immune responses and IFN-gamma activity. As the primary portal of entry of M. tuberculosis is the lung, pulmonary immune responses against multiple M. tuberculosis Ags were compared between both M. tuberculosis-exposed tuberculin skin test-positive healthy household contacts (HHC) of patients with active sputum smear and culture-positive tuberculosis and tuberculin skin test-positive healthy control individuals from the community (CC). Frequencies of M. tuberculosis Ag-specific IFN-gamma-producing cells, IFN-gamma concentrations in culture supernatants, and DNA synthesis in bronchoalveolar cells (BAC) and PBMC were studied in HHC (n = 10) and CC (n = 15). Using enzyme-linked immunospot assay we found higher frequencies of IFN-gamma-producing cells with specificity to M. tuberculosis-secreted Ag 85 (Ag 85) in BAC from HHC than in BAC from CC (p < 0.022) and relative to autologous PBMC, indicating compartmentalization of Ag 85-specific cells to the lungs. Further, IFN-gamma-producing cells with specificity to components A and B of Ag 85 were specifically compartmentalized to the lungs in HHC (p < 0. 05). IFN-gamma concentrations in culture supernatants of BAC and Ag-specific DNA synthesis were low and comparable in the two subject groups. Increased immune responses to Ag 85 at the site of repeated exposure to M. tuberculosis (the lung) may represent an important component of protective immunity against M. tuberculosis. Correlates of protective immunity against M. tuberculosis are required for assessment of the efficiency of anti-tuberculous vaccines.

Sentinel lymph node localization in early breast cancer.

METHODS: Thirty-two patients with clinical node-negative breast cancer underwent sentinel node localization study as part of a National Cancer Institute-sponsored multicenter trial. Anatomical and histopathologic characteristics of sentinel lymph node (SLN) and a kinetic analysis of nodal uptake were studied. Patients were injected with 1 mCi/4 ml unfiltered 99mTc-sulfur colloid in four divided doses around the palpable lesion or immediately adjacent to the excision cavity if prior biopsy was performed. SLN biopsy was performed 1.5-6 hr (mean = 3 hr) postinjection. Intraoperative localization was performed using a gamma probe. All patients underwent complete axillary dissection. RESULTS: SLN was identified in 30 of 32 (94%) patients. There were no false-negative SLN biopsies. CONCLUSION: This study supports the clinical validity of SLN biopsy in breast cancer and confirms that, unlike the blue dye technique, the learning curve with unfiltered 99mTc-sulfur colloid and the gamma detection probe is short, and SLN localization is achievable in over 90% of cases by surgeons with modest experience. The use of unfiltered 99mTc-sulfur colloid (larger particle size) with larger injected volume permits effective localization of SLNs.

Absence of human placental lactogen and placental growth hormone (HGH-V) during pregnancy: PCR analysis of the deletion.

Human placental lactogen (HPL) is produced in large amounts in normal pregnancies. We report a pregnancy with complete lack of HPL and the placental variant of the human growth hormone HGH-V. The pregnancy resulted in a severely growth-retarded but otherwise normal male baby. PCR analysis of DNA extracted from the placenta showed that the HPL encoding genes hPL-4 and hPL-3 were deleted along with the human growth hormone variant gene (hGH-V), which is located between these two active hPL genes and also expressed in the normal placenta. Of the five members of this multigene family, hGH-N, which is expressed in the pituitary gland, and hPL-1, a presumed pseudogene, were left intact. The latter (hPL-1) was expressed as RNA transcripts only at very low levels as is usually reported in normal pregnancies. Analysis of the parents' DNA showed that both of them carried a different heterozygous deletion at the 3' end of the hGH/hPL locus.

T lymphocytic and immature macrophage alveolitis in active pulmonary tuberculosis.

The phenotype of bronchoalveolar cells from 11 healthy subjects and from affected and unaffected lungs of 15 patients with pulmonary tuberculosis (PTB) was determined. An immature macrophage alveolitis was found in the affected lung and the unaffected lung versus controls as determined by morphology and peroxidase activity. T lymphocytic alveolitis also was found in the affected but not the unaffected tuberculous lung compared with healthy controls. The majority of alveolar lymphocytes in unaffected and affected PTB lungs were T cells expressing the alpha beta T cell receptor. Alveolar T cells from both unaffected and affected lungs were activated, as determined by increased expression of CD69 and HLA-DR. Interleukin-2 receptor (IL-2R alpha) expression was, however, unchanged on alveolar lymphocytes from affected lung and was decreased in the unaffected lung. Thus, activated T lymphocytes and immature macrophages in the tuberculous lung are basic to the local immunopathogenesis of PTB.

Effect of peroxisomicine and related anthracenones on catalase activity.

Dimeric anthracenones were isolated from toxic plants of the genus Karwinskia (Rhamnaceae). T 514 or peroxisomicine A1 is one of these toxic compounds which produces an irreversible and selective damage on the peroxisomes of yeast cells in vivo. In this paper we now report the inhibitory effect in vitro of peroxisomicine A1 and other structurally related anthracenones on liver catalase activity. The peroxisomicine A1 produces a non-competitive inhibition with respect to H2O2 on bovine, dog, and mouse liver catalases. In the three cases Vmax was decreased whereas Km was unaffected. Other dimeric anthracenones of natural origin were also found to be inhibitors of bovine liver catalase. There is a relationship between structure and degree of inhibition of all anthracenonic compounds tested. Peroxisomicine A1 and peroxisomicine A2 caused the highest degree of inhibition (IC50 = 3.34 and 3.64 microM, respectively).

Mechanical determinants of coronary blood flow during dynamic alterations in myocardial contractility.

Recently it has been proposed that the decrease in coronary blood flow (CBF) resulting from cardiac contraction referred to as systolic flow impediment (SFI) is dependent on the level of left ventricular elastance (Ees). The average rate of LV relaxation (Ravg) has been shown to be major determinant of diastolic flow development (DFD). We tested these hypotheses using the unique hemodynamic condition of pulsus alternans (PA) where end-systolic LV pressure and instantaneous Ees vary on beat-to-beat basis. In six mongrel dogs instrumented with LV and aortic manometers, ultrasonic dimension crystals, and Doppler coronary flow probes we measured phasic CBF and Ees during PA and control conditions. Maximal pressure development over time (dP/dtmax) and SFI were significantly different between weak (WB) and strong beats (SB) as were Ravg and DFD. Minimum CBF (Qmin) was not different between SB and WB; however, Qmin and peak Ees occurred nearly simultaneously in the WB. Qmin occurred much earlier than peak Ees in the strong and control beats. Plots of instantaneous LV elastance and CBF showed that for control beats and for the strong beats of PA CBF was similar during systole and diastole, suggesting elastance is a unique determinant of CBF. This was quantified as CBF at the time in either systole or diastole when elastance was half-maximal for that beat (E50). During the WB of PA, however, CBF at E50 was significantly higher during systole than during diastole. We conclude that while SFI and DFD are highly dependent on the dP/dt and Ravg, Ees is not a unique determinant of CBF under all conditions.