Valve-related complications with the Hancock I porcine bioprosthesis. A twelve- to fourteen-year follow-up study

Valve-related morbidity and mortality after heart valve replacement with the Hancock I porcine bioprosthesis has been retrospectively analyzed. From June 1974 through December 1976, 253 Hancock I bioprostheses (150 mitral and 103 aortic) were inserted in 220 selected patients who survived the operation and had follow-up until June 1989 (mean follow-up 13.5 years, with an accumulative follow-up of 2956.4 patient-years). One hundred seventeen patients had mitral valve replacement, 70 had aortic valve replacement, and 33 had combined mitral and aortic valve replacement. There were 27 thromboembolic events. The probability of being free from thromboembolism at 14 years was 81.0% +/- 7.4% for the mitral valve replacement group, 85.4% +/- 6.7% for the aortic group, and 67.1% +/- 18.4% for the mitral-aortic group. Fifteen episodes of prosthetic valve endocarditis occurred. There were 10 instances of nonstructural dysfunction (paravalvular leaks) in seven mitral valves (4.6%) and in three aortic valves (2.9%). One hundred twenty-two bioprostheses in 106 patients resulted in structural deterioration. The probability of freedom from structural deterioration at 14 years was 37.2% +/- 3.9% for the mitral group, 43.9% +/- 7.1% for the aortic group, and 30.1% +/- 8.9% for the mitral-aortic group. The logistic regression analysis between age at the time of operation and bioprosthetic life (structural deterioration-free period) demonstrates a linear regression curve (r = 0.53). There were 56 late deaths (27 patients died at reoperation). The actuarial survival rate (including hospital mortality) at 14 years was 57.2% +/- 5.4% for the entire series, with no statistically significant difference between groups. The probability of remaining free from valve-related morbidity and mortality at 14 years was 16.7% +/- 4.8% for the mitral group, 20.8% +/- 6.2% for the aortic group, and 14.0% +/- 7.0% for the mitral-aortic group. The long-term results of this series show that the clinical performance of the Hancock I porcine valve appears satisfactory during the first 6 years. The behavior of this bioprosthesis at 14 years' follow-up changes drastically, because only a minor group of patients is free from valve-related complications, justifying the restriction of its use for selected patients.     

Effects of nerve growth factor on cortical and striatal acetylcholine and dopamine release in rats with cortical devascularizing lesions

The effects of intraventricular nerve growth factor (NGF) or saline treatments on extracellular acetylcholine (ACh), dopamine (DA) and adenosine (Ade) levels in the cortex and striatum of rats with unilateral devascularizing cortical lesions were studied in vivo with microdialysis. The devascularizing cortical lesion produced a decrease in extracellular ACh levels in both cortex and striatum as compared to those in normal rats, while the NGF treatment produced a significant increase in ACh levels in both regions. NGF could even increase cortical ACh levels in normal rats. The cortical lesion produced a decrease in extracellular DA in the cortex, while the NGF treatment appeared to reverse this effect. No significant changes in DA were observed in the striatum. The present study gives evidence that a unilateral cortical devascularizing lesion leads to changes in extracellular ACh and DA levels in cortex and striatum and that these changes could be reversed with intraventricular NGF treatment.     

Prevalences, genotypes, and risk factors for HIV transmission in South America

HIV cross-sectional studies were conducted among high-risk populations in 9 countries of South America. Enzyme-linked immunosorbent assay screening and Western blot confirmatory testing were performed, and env heteroduplex mobility assay genotyping and DNA sequencing were performed on a subset of HIV-positive subjects. HIV prevalences were highest among men who have sex with men (MSM; 2.0%-27.8%) and were found to be associated with multiple partners, noninjection drug use (non-IDU), and sexually transmitted infections (STIs). By comparison, much lower prevalences were noted among female commercial sex workers (FCSWs; 0%-6.3%) and were associated mainly with a prior IDU and STI history. Env subtype B predominated among MSM throughout the region (more than 90% of strains), whereas env subtype F predominated among FCSWs in Argentina and male commercial sex workers in Uruguay (more than 50% of strains). A renewed effort in controlling STIs, especially among MSM groups, could significantly lessen the impact of the HIV epidemic in South America.     

Inhibition of experimental autoimmune encephalomyelitis in Lewis rats by nasal administration of encephalitogenic MBP peptides: synergistic effects of MBP 68-86 and 87-99

Induction of mucosal tolerance by inhalation of soluble peptides with defined T cell epitopes is receiving much attention as a means of specifically down-regulating pathogenic T cell reactivities in autoimmune and allergic disorders. Experimental autoimmune encephalomyelitis (EAE) induced in the Lewis rat by immunization with myelin basic protein (MBP) and Freund's adjuvant (CFA) is mediated by CD4+ T cells specific for the MBP amino acid sequences 68-86 and 87-99. To further define the principles of nasal tolerance induction, we generated three different MBP peptides (MBP 68-86, 87-99 and the non- encephalitogenic peptide 110-128), and evaluated whether their nasal administration on day -11, -10, -9, -8 and -7 prior to immunization with guinea pig MBP (gp-MBP) + CFA confers protection to Lewis rat EAE. Protection was achieved with the encephalitogenic peptides MBP 68-86 and 87-99, MBP 68-86 being more potent, but not with MBP 110-128. Neither MBP 68-86 nor 87-99 at doses used conferred complete protection to gp-MBP-induced EAE. In contrast, nasal administration of a mixture of MBP 68-86 and 87-99 completely blocked gp-MBP-induced EAE even at lower dosage compared to that being used for individual peptides. Rats tolerized with MBP 68-86 + 87-99 nasally showed decreased T cell responses to MBP reflected by lymphocyte proliferation and IFN-gamma ELISPOT assays. Rats tolerized with MBP 68-86 + 87-99 also had abrogated MBP-reactive IFN-gamma and tumor necrosis factor-alpha mRNA expression in lymph node cells compared to rats receiving MBP 110-128 nasally, while similar low levels of MBP-reactive transforming growth factor-beta and IL-4 mRNA expressing cells were observed in the two groups. Nasal administration of MBP 68-86 + 87-99 only slightly inhibited guinea pig spinal cord homogenate-induced EAE, and passive transfer of spleen mononuclear cells from MBP 68-86 + 87-99-tolerized rats did not protect naive rats from EAE. Finally, we show that nasal administration of MBP 68-86 + 87-99 can reverse ongoing EAE induced with gp-MBP, although higher doses are required compared to the dosage needed for prevention. In conclusion, nasal administration of encephalitogenic MBP peptides can induce antigen-specific T cell tolerance and confer incomplete protection to gp-MBP-induced EAE, and MBP 68-86 and 87-99 have synergistic effects. Non-regulatory mechanisms are proposed to be responsible for tolerance development after nasal peptide administration.      

NGF prevents further atrophy of cholinergic cells of the nucleus basalis due to cortical infarction in adult post-hypothyroid rats but does not restore cell size compared to euthroid rats

We have tested the hypotheses that nerve growth factor treatment in adult post-hypothyroid rats can: (1) restore cross-sectional area of cholinergic cells of the nucleus basalis and (2) prevent further atrophy of these neurons following cortical infaction. In addition, we assessed the expression of p75^NGFR and p140^trkA mRNAs in the nucleus basalis cells of post-hypothyroid rats. Rats were rendered hypothyroid by the addition of propylthiouracil to their diet beginning on embryonic day 19 until the age of 1 month. At this time both the pups and their dams continued to receive 0.05% propylthiouracil in their diet and the pups were thyroidectomized. At 60 days, propylthiouracil treatment was interrupted and thyroxine levels were restored to normal by daily subcutaneous administration of physiological levels of thyroxine. Morphometric analysis identified atrophied nucleus basalis magnocellularis cholinergic cells at two ages, days 75 and 105, identified by in situ hybridization for p75^NGFR and p140^trkA mRNAs in methylene blue stained cells (day 75) and choline acetyltransferase immunostaining (day 105). The mean number of silver grains (pixels) per μm² (mean±S.E.M.) of cell body cross-sectional area for p75^NGFR mRNA in the nucleus basalis magnocellularis of euthyroid rats was 3.43±0.89, which was not statistically different from post-hypothyroid animals (4.02±1.07). A similar finding was noted for p140^trkA mRNA: mean number of grains in the euthyroid group was 5.54±0.96 and was not statistically different from the post-hypothyroid group (6.32±1.45). Nerve growth factor treatment in adulthood (between days 75 and 82) did not restore cross-sectional area from early thyroid deprivation. However, it prevented further atrophy of nucleus basalis magnocellularis neurons following cortical devascularization inflicted in adulthood (day 75).     

Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.      

Chlamydophila abortus (Chlamydia psittaci serotype 1) clearance is associated with the early recruitment of neutrophils and CD8(+)T cells in a mouse model

The immune mechanisms in response to Chlamydophila abortus (Chlamydia psittaci serotype 1) infection were studied in C57BL/6 and CBA mice. The infection was monitored and the following aspects of the immune response were evaluated: the nature of the leucocyte infiltrate in the liver, the percentages of polymorphonuclear neutrophils (PMNs), macrophages and lymphocytes in the spleen, and the concentrations of cytokines in serum. In addition, the serum concentrations of IgG1 and IgG2a were determined. Both mouse strains showed a Th1-like immune response, with high concentrations of IFN-gamma and minimal levels of IL-4; however, C57 mice differed from CBA mice in showing milder clinical signs and earlier resolution of infection. The greater ability of C57 mice than CBA mice to eliminate chlamydophilae was related to the establishment of an earlier innate immunity, based on a more pronounced PMN response, and on a greater presence of CD8(+)T cells.