A community randomized controlled clinical trial of mixed carotenoids and micronutrient supplementation of patients with acquired immunodeficiency syndrome.

OBJECTIVE: This clinical trial aims to evaluate if natural mixed carotenoids supplementation can improve the health and survival of acquired immunodeficiency syndrome (AIDS) patients. DESIGN: A placebo-controlled, prospective, randomized, double-blind, multicenter clinical trial. SETTING: Community, tertiary care human immunodeficiency virus (HIV) clinics of the Canadian HIV Trials Network (CTN). PARTICIPANTS: Three hundred and thirty-one adults with advanced AIDS on conventional management were recruited during routine clinic visits. INTERVENTIONS: All participants, including 166 controls, received daily oral specially formulated multivitamins including vitamin A and trace elements; 165 treatment group participants received additional daily oral natural mixed carotenoids, equivalent to 120,000 IU (72 mg) of beta-carotene daily. Follow-up was quarterly at routine clinic visits. RESULTS: Mean (s.d.) follow-up was for 13 (6) months. Thirty-six participants died by 18 months. Serum carotene concentration <1.0 micromol/l was present in 16% participants at baseline. Despite variation in carotene content of the treatment medication, serum carotene concentrations increased significantly to twice the baseline levels to 18 months follow-up in participants who received carotenoids treatment compared with controls (P < 0.0001). Although not statistically significant, mortality was increased in participants who did not receive carotenoids treatment compared with those who did (HR time to death 1.76, 95% CI 0.89, 3.47, P = 0.11). In multivariate analysis, survival was significantly and independently improved in those with higher baseline serum carotene concentrations (P = 0.04) or higher baseline CD4 T-lymphocyte counts (P = 0.005). Adjusted mortality was also significantly and independently increased in those who did not receive carotenoids treatment compared with those who did (HR time to death 3.15, 95% CI 1.10, 8.98, P = 0.03). CONCLUSIONS: Low serum carotene concentration is common in AIDS patients and predicts death. Supplementation with micronutrients and natural mixed carotenoids may improve survival by correction of a micronutrient deficiency. Further studies are needed to corroborate findings and elucidate mechanism of action.

Efficacy and toxicity of D-penicillamine for rheumatoid disease in the elderly.

The efficacy and the toxicity pattern of D-penicillamine were studied in patients with rheumatoid disease followed up between April 1975 and March 1979. The population of patients was divided into an elderly group (greater than or equal to 60 years old, mean = 65 years) and a younger group (less than 60 years old, mean = 41 years). Patients with classic or definite rheumatoid disease not responsive to nonsteroidal drugs were eligible. The mean durations of disease prior to D-penicillamine therapy were five years in the elderly and seven years in the younger group. Overall, the mean follow-up time was 11 months. The average dosages of D-penicillamine were 461 mg/day in the elderly and 520 mg/day in the younger patients. Results indicated that D-penicillamine was efficacious in 75 per cent of the elderly during all time periods after three months, and in 75 per cent of the younger patients after three months until at least two years. Prior gold-salt therapy did not influence efficacy. Toxicity was significantly greater in the elderly for overall skin rash (P less than 0.01), severe skin rash (P less than 0.01), and marked abnormalities in the ability to taste (P less than 0.05). The incidence of hematologic toxicity was not increased in the elderly compared with the younger patients. Toxicity in either group was not influenced by prior gold-salt therapy. It is concluded that D-penicillamine was equally efficacious in both elderly and younger groups, and that the toxicity patterns were similar except for increased tendencies toward rashes and taste abnormalities in the elderly.

Heterogeneity of laboratory test results for antiphospholipid antibodies in patients treated with chlorpromazine and other phenothiazines.

Ninety-seven psychiatric patients who have been treated with the antipsychotic drug chlorpromazine or another phenothiazine have been investigated for the presence of antiphospholipid antibodies. A variety of coagulation studies and specific antiphospholipid immunoassays were performed to define the spectrum of antigen specificity of these antibodies. Coagulation studies showed an increasing sensitivity for the lupus anticoagulant with reagents of differing phospholipid content. Prolonged activated partial thromboplastin times (APTTs) were found in five patients with the use of an insensitive APTT reagent and in 14 patients with a lower phospholipid content reagent. In every case, attempted correction of the clotting time with normal plasma was unsuccessful. Twenty-one patients had abnormal kaolin clotting time profiles. In seven of these patients, test results with both APTT reagents had been normal. Antibody reactivity was tested against three negatively charged phospholipids, phosphatidyl-serine, cardiolipin, and phosphatidylinositol. Only five patients demonstrated reactivity against phosphatidylinositol, whereas high antibody titers were observed in 28 patients against one or both of phosphatidylserine and cardiolipin. Twenty-three of these patients were found to have elevated anticardiolipin-specific IgM antibodies. Overall, 41 of the patients had at least one laboratory abnormality suggestive of antiphospholipid antibody activity. Seven of the 26 patients, taking phenothiazines other than chlorpromazine, had positive test results for antiphospholipid antibodies. No clinical thromboembolic events were recorded in any patient. These findings demonstrate the heterogeneity of antiphospholipid antibody specificity induced in patients treated with various phenothiazine drugs and indicate that none of these patterns of reactivity marks a predisposition for thromboembolism in this population.

The cardiovascular pathology of phospholipid antibodies: An illustrative case and review of the literature.

There is some confusion in the literature regarding the pathology associated with phospholipid antibodies. These antibodies, formed to a number of negatively charged phospholipids, are associated with an increased tendency to both arterial and venous thrombosis and embolism and may be manifest in a primary syndrome, a syndrome secondary to systemic lupus erythematosis, or as an isolated phenomenon, which may or may not be associated with thromboembolism. The pathogenesis of thrombosis in these syndromes has not yet been elucidated. Indeed it is not even clearly established that the antibodies have a pathogenic role, as opposed to existing as an epiphenomenon or arising secondary to some form of vascular damage. Clarification of the reported pathologic literature is needed as a basis for studying the pathogenesis of thrombosis in these syndromes, and therefore we present a review of papers that have reported pathology in association with phospholipid antibodies. In order to illustrate the review, we present a typical case of primary antiphospholipid antibody syndrome.

The detection of autoantibodies with an enzyme bridge method.

The horseradish peroxidase bridge method described by Mason, Phifer, Spicer, Swallow, and Dreskin (1969) has been found to be as sensitive and specific as fluorescence methods for detecting antinuclear factor and gastric parietal cell antibody, and to a lesser extent, antibodies to smooth muscle and mitochondria. However, the method has at least four practical advantages over fluorescence techniques.

Clinicopathological spectrum of late postpartum renal failure; two contrasting cases.

The clinical and renal biopsy findings from two patients in whom renal functional abnormalities developed in the late postpartum period are described. Both biopsies showed fibrin deposition in the renal vasculature, in one case marked and in the other mild. The patient with the more severely damaged kidney subsequently died, and the other is alive but with evidence of slowly progressing renal damage. The clinicopathological spectrum and pathogenesis of late postpartum renal failure are discussed.

Maternal and neonatal implications of congenital complete heart block in the fetus.

The detection of congenital complete heart block (CCHB) in a fetus should alert the obstetrician that the welfare of both the mother and the newborn infant may be in jeopardy. An awareness of this uncommon cause of fetal bradycardia and judicious intrapartum monitoring can avert hasty and unnecessary cesarean section for suspected fetal asphyxia. Neonatal consequences may range from no effect to life-threatening congestive heart failure. The apparently healthy mothers of these infants may be at increased risk for the subsequent development of collagen vascular disease. Three recent case reports demonstrate the spectrum of neonatal and maternal disease that may accompany CCHB. The significance of abnormal serology suggesting a propensity for collagen vascular disease in an otherwise healthy parturient is discussed, and a program for follow-up is proposed.

HIV, hepatitis C and risk behaviour in a Canadian medium-security federal penitentiary. Queen's University HIV Prison Study Group.

In a voluntary anonymous HIV and hepatitis C serology screen in a Canadian male medium security federal penitentiary, 68% of 520 prisoners volunteered a blood sample and 99% of those giving a blood sample completed a risk behaviour questionnaire which was linked numerically to the blood sample. Compared to previous screenings for HIV (4 years earlier), and hepatitis C (3 years earlier) in the same institution, HIV seroprevalence had risen from 1% to 2% and hepatitis C seroprevalence from 28% to 33%. The overwhelming risk association for hepatitis C was with drug use outside prison, although there was a small group of men who had only ever injected drugs inside prison, over half of whom had been infected with hepatitis C. The proportion of prisoners who had injected drugs in prison rose from 12% in 1995 to 24% in 1998. The proportion of surveyed individuals sharing injection equipment at some time in prison was 19%, and while HIV rates in the prison are currently low, HIV prevalence amongst Canadian street i.v. drug users is rising rapidly, underlining the need for urgent preventative measures in prisons.

Lupus anticoagulant, antiphospholipid antibodies and migraine.

The records of fifteen patients referred for neurological assessment and found to have lupus anticoagulant or elevated anticardiolipin antibodies were reviewed. The mean age for females in the group was 29.4 years and for males was 35. A diagnosis of migraine, either as an acute or chronic problem, was made in 10 (66%) of these patients. Seven of the 15 patients had ischemic stroke and two patients had other thrombotic complications associated with lupus anticoagulant. Three of the nine female patients with migraine had histories of spontaneous abortions. All migraine patients experienced transient or more prolonged neurological deficits with their headaches. An association between lupus anticoagulant and migraine can only be suggested. Data on the incidence of migraine in patients with lupus anticoagulant in the general medical population does not exist. Furthermore the prevalence of lupus anticoagulant in migraine sufferers is unknown. Therefore further studies are required to investigate this possible association.

Clinicopathologic correlations of antiphospholipid antibodies. An autopsy study.

The clinicopathologic correlations of antiphospholipid antibodies (aPLs) have so far only been examined in case reports and highly selected series. This study assessed the incidence of aPLs in 156 consecutive, unselected autopsies and correlated the pathological findings with the clinical histories. Elevations of aPLs were found in 20.5% of the autopsy population, compared with 9.6% of age- and sex-matched controls and 2% of healthy normal subjects. There was a higher incidence of thromboembolic disease in patients with elevated aPL levels compared with those without, but the histology of thrombi was similar in both groups, with no evidence of vasculitis in the aPL-positive individuals. Patients with transient ischemic attacks and cardiac valve lesions had a high incidence of aPLs, as reported previously. Five cases that fit the designation of primary antiphospolipid antibody syndrome were noted. The study concludes that aPLs are relatively common in a hospital autopsy population and are commonly associated with thromboembolic events, that the thromboemboli are not associated with vasculitis, and that primary aPL syndrome is more common than generally appreciated.

Interaction of rheumatoid factor with immune complexes in experimental glomerulonephritis--possible role of antiglobulins in chronicity.

Rheumatoid factor (RF) is found in the circulation in several human disorders associated with glomerular immune complex deposition and glomerulonephritis. RF has also been found in the involved glomeruli of several of these diseases. In several experimental systems RF has been shown to bind in situ to glomerular bound complexes and to subsequently act as an immunoabsorbent. The implications of these observations in terms of chronicity of immune complex associated glomerular lesions are discussed.

Glomerular localization of aggregated protein in mice; effect of strain difference and relationship to systemic macrophage function.

Glomerular uptake of aggregated bovine serum albumin has been studied in 3 different mouse strains. Systemic macrophage activity in the same 3 strains has been estimated by measuring the uptake of carbon particles. The amount of aggregated protein taken up by the glomerular mesangium in each strain appears to be inversely related to the systemic macrophage activity. The possible significance of these findings is discussed.

Passive serum sickness in the mouse: effect of interstrain differences on glomerular deposition of immune complexes.

Glomerular uptake of passively administered immune complexes in mice differs in different inbred strains. The amount of immune material deposited in the glomeruli in the strains examined is inversely related to the susceptibility to immune complex induced anaphylaxis. The significance of these findings is discussed.

The effect of manipulation of reticuloendothelial system activity on glomerular deposition of aggregated protein and immune complexes in two different strains of mice.

Glomerular uptake of intravenously administered aggregated albumen or immune complexes in mice appears to be inversely related to the activity of the reticuloendothelial system (RES). Stimulation of RES activity diminishes the amount of material appearing in the glomerulus whereas RES blockade enhances glomerular uptake. The possible relevance of these observations to experimental models of immune complex disease is discussed.

Passive serum sickness in the mouse: the role of vasoactive amines in glomerular deposition of immune complexes.

This paper reports a study of the importance of vasoactive amines in glomerular localization of passively administered immune complexes in the mouse. Two strains of mice were investigated, one sensitive and the other relatively resistant to the anaphylactogenic effect of intravenously administered immune complexes. The effect on glomerular deposition immune complexes in animals of both strains treated with either vasoactive amine depletors or antagonists leads to the conclusion that in this experimental system vasoactive amines do not play a major part in the glomerular localization of immune complexes.

Arthropathies associated with renal disease including dialysis-related amyloid.

In recent years most of the interest in musculoskeletal problems secondary to renal disease has focused on problems occurring in patients with chronic renal failure and specifically in patients on long-term hemodialysis. The musculoskeletal involvement in long-term hemodialysis may involve the joints, soft tissues, or both, and there is presently no good classification to which authors may refer when they report musculoskeletal problems in these patients. There has been intense interest in the past few years in the amyloidosis associated with long-term hemodialysis, and now, apparently, also with peritoneal dialysis. This type of amyloidosis is due to a specific type of amyloid, namely beta 2-microglobulin amyloid. Debate is ongoing about the role of both aluminum toxicity and iron deposition as cofactors affecting the location and extent of amyloid deposits. Debate is also unresolved about the role of specific dialysis membranes in lessening the incidence of dialysis-related amyloid. I review some of these areas as well as interesting new developments in localization of amyloid deposits in patients with chronic renal failure who are on hemodialysis.