Immune reconstitution inflammatory syndrome in association with HIV/AIDS and tuberculosis: Views over hidden possibilities

Background  

CD4+ T lymphocyte (CD4) cell count testing is the standard method for determining eligibility for antiretroviral therapy (ART), but is not widely available in sub-Saharan Africa. Total lymphocyte counts (TLCs) have not proven sufficiently accurate in identifying subjects with low CD4 counts. We developed clinical algorithms using TLCs, hemoglobin (Hb), and body mass index (BMI) to identify patients who require ART.     

A simple and practical technic for detecting cancer cells in urine and urinary bladder washings by flow cytometry

DNA measurement by flow cytometry has been demonstrated to be a potentially useful technic in the diagnosis of bladder cancer by detecting neoplastic cells in bladder washings and urine specimens. The authors' goal was to develop a simple and practical method utilizing the new generation of cytofluorographs designed for use in the clinical laboratory. This method combined direct fixation with cell lysis yielding fixed intact nuclei. Following RNase and pepsin digestion, the nuclei were separated from debris and aggregates on a sucrose barrier, stained with ethidium bromide, and analyzed with an argon laser analytic cytofluorograph. Urines and bladder washings from 14 patients with positive urinary cytology and histologically diagnosed bladder cancers were compared with specimens from patients without urothelial malignancies. DNA histograms clearly delineated aneuploid from diploid populations and often identified S, G2M, and G1 phase nuclei. Aneuploid populations have been detected in all tumor specimens with positive cytologies studied to date.     

Toxoplasma gondii: differentiation and death of bradyzoites

The living parasites inToxoplasma cysts cannot be eradicated by current therapy and maintain latent infections for many years. Relatively little is known about encystedToxoplasma. We therefore undertook studies using mice infected with the avirulent ME 49 strain ofToxoplasma. The bradyzoites in young (12- to 17-day-old) cysts contained the same organelles as did tachyzoites. The bradyzoites of older cysts (4 weeks postinoculation) had differentiated, losing certain organelles and acquiring others. Our major new finding was that in animals inoculated 4 weeks previously, some bradyzoites were totally disrupted, splling their contents (perhaps including lytic substances) into the cyst matrix. Many older bradyzoites in the same cysts lacked internal membranes and their viability was questionable, but there were also occasional parasites resembling viable tachyzoites and mature bradyzoites, organisms that might possibly initiate daughter cyst formation after cyst rupture. The life span of an individual bradyzoite may be shorter than formerly appreciated despite the prolonged course of latent infections.     

Biochemical and clinical characterization of prealbuminCHICAGO: an apparently benign variant of serum prealbumin (transthyretin) discovered with high-resolution two-dimensional electrophoresis

We report identification, biochemical, clinical, and genetic studies of an apparently benign, electrophoretic variant of serum prealbumin (PALB, transthyretin, TTR) in a North American kindred of Swedish ancestry. The variant polypeptide stems from a C to T point mutation in exon 4 which results in methionine instead of threonine at position 119 of the mature molecule. It was discovered incidentally in a girl with classic alpha-1-anti-trypsin (A1AT) deficiency and her father during diagnostic A1AT phenotyping by ISO-DALT high-resolution two-dimensional electrophoresis (2DE). Twelve relatives in the four-generation paternal kindred, including five individuals who were heterozygous for the variant prealbumin, were studied. In each of these five heterozygotes, the variant allele product was equimolar and isoelectric with the normal protein, yet migrated with an apparently lower mass in the SDS-PAGE dimension. The inheritance pattern was consistent with autosomal dominant transmission. Histories and physical examinations showed no evidence of amyloidosis, as has been observed with other variants of prealbumin. Mean values of serum prealbumin and retinol binding protein levels were higher in the carriers as compared to the normal relatives in the family, but the difference was not statistically significant. Thyroid hormone levels and distribution of thyroxine and triiodothyronine among binding proteins in serum were within reference limits. Four members of the lineage had dominant, scalp-restricted keratinaceous cysts, yet only three of these four individuals had the variant. We counseled the family that this is likely a benign variant with regard to amyloidosis-related morbidity or shortened life span, although senile effects cannot be entirely ruled out. The provisional designation assigned to this allele is PALBCHICAGO. The substitution of methionine at position 119, as predicted by the DNA sequence, was confirmed by amino acid sequencing of CNBr and tryptic peptides. This substitution occurs at a CpG dinucleotide that may be a point mutational "hot spot," as has been postulated for the methionine-30 and isoleucine-122 PALB variants. The apparently lower mass of the variant probably results from a more compact conformation in SDS. With the exception of histidine-58, a charge substitution, all other amyloidosis-related prealbumin variant polypeptides had normal mobility in the ISO-DALT 2DE system.     

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.     

Declining immune function in children and adolescents with hemophilia and HIV infection: effects on neuropsychological performance. Hemophilia Growth and Development Study

OBJECTIVE: To determine whether declines in immune functioning are associated with changes in neuropsychological performance in children and adolescents with hemophilia who are infected with the human immunodeficiency virus (HIV). METHODS: Participants were 333 males with hemophilia, ages 6-19 years at entry. A baseline and four annual neuropsychological evaluations were given. A longitudinal growth curves analysis of data was performed to detect changes associated with declining immune function. The cohort was stratified into four groups: (1) HIV- (n = 126); (2) HIV+, average of first two and last two CD4 counts > or = 200, (n = 106; High CD4 group); (3) HIV+, average first two counts > or = 200, average last two counts < 200 (n = 41; CD4 Drop group); and (4) HIV+, average first two and last two counts < 200 (n = 60; Low CD4 group). RESULTS: There were significant differences among the four groups over time in nonverbal intelligence, perceptual/performance skills, nonverbal memory, academic achievement, and language. The Low CD4 group consistently showed the greatest decrement in performance. On measures showing a practice effect for repeated measurements, the Low CD4 group participants' scores remained stable over time, suggesting opposing effects of practice and HIV-related declines. Lowered academic performance relative to IQ was found in all groups. CONCLUSIONS: Declines in neuropsychological functioning are directly related to declines in immune functioning in HIV+ children, adolescents, and young adults with hemophilia. Hemophilia itself may be a risk factor for academic underachievement.     

Comparison of the effects of intravenous and intrasplenic infusions of glucagon on cardiac output and its distribution in the rat

Summary In order to determine whether or not glucagon released from the pancreas might have local vascular effects, the actions upon regional haemodynamics in the anaesthetised rat of two doses of glucagon (2 and 10 g kg^–1 min^–1) infused intrasplenically (and thus into the portal vein) were compared with those of a single dose (2 g kg^–1 min^–1) infused i. v. Infusion of glucagon i. v. produced a significantly increased heart rate (by 6%) and cardiac output (by 23%) in the experimental animals compared to those receiving saline by the same route. Total peripheral resistance fell by 24%. A greater proportion of the cardiac output passed to the coronary and renal vascular beds and blood flow was increased in the spleen, testes, pectoral skeletal muscle, stomach and small intestine as well as the heart and kidneys.The lower dose infused intrasplenically had no significant effect on cardiac output or total peripheral resistance but significantly increased the proportion of cardiac output passing both to the stomach and the small intestine such that the percentage of cardiac output flowing through the portal vein increased from 19.1 ± 1.1% to 23.8 ± 1.7%.Intrasplenic infusion of 10 g kg^–1 min^–1 significantly increased cardiac output (by 29%) but reduced total peripheral resistance by 37%. Greater fractions of the cardiac output were received by the spleen, small intestine and epididymides. Blood flow was increased in these organs and the skin, kidneys, stomach, large intestine and the mesentery.It is concluded that pharmacologically effective amounts of glucagon only passed into the systemic circulation with the higher dose infused intrasplenically. Thus the redistribution of cardiac output in favour of the splanchnic bed with the lower dose of glucagon infused into the portal region is most likely the result of local mechanisms rather than a direct effect of the hormone on the inflow vasculature resulting from recirculation. Send offprint requests to C. R. Hiley at the above address     

Is thrombosis of the infrarenal abdominal aortic aneurysm an acceptable alternative?

Aortic aneurysm thrombosis with extra-anatomic bypass has been proposed for persons with infrarenal aortic aneurysms who are "too debilitated" to undergo standard aortic reconstruction. Thirteen patients (mean age, 75 years) were selected between January 1980 and June 1984 for axillobifemoral bypass with bilateral iliac artery occlusion to manage their infrarenal aortic aneurysms (mean size, 6.3 cm; range, 4.9 to 7.5 cm). Preoperative risk factors were cardiac (angina, compensated congestive heart failure, and significant preoperative arrhythmias), 100% of patients; pulmonary (symptomatic chronic obstructive pulmonary disease with a 1-second forced expiratory volume less than 50% of the predicted value), 46% of patients; renal (creatinine value greater than or equal to 2.0 mg/dl or creatinine clearance less than 20 ml/min), 46% of patients; or nutritional (albumin less than or equal to 3.5 gm/dl or body weight less than 90% of ideal), 46%. Ninety-two percent of the patients had two risk factors whereas 46% had three or more risk factors. The operative mortality rate was 31%; three patients died of multisystem organ failure and another died of thrombin-induced consumptive coagulopathy and hemorrhage. (Our operative mortality rate for conventional graft replacement of abdominal aortic aneurysms is less than 3%.) Morbidity in persons surviving at least 1 month included thrombosis of the extra-anatomic bypass graft requiring thrombectomy (three patients), ischemic colitis (two patients), ischemic neuropathy (one patient), and patients), ischemic colitis (two patients), ischemic neuropathy (one patient), and bilateral above-knee amputations (one patient). Thrombosis of the aneurysm was not achieved in two patients despite use of fluoroscopically controlled embolization of runoff vessels.(ABSTRACT TRUNCATED AT 250 WORDS)