Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens.

OBJECTIVES: There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. METHODS: The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. RESULTS: The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95-1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37-2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84-1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90-1.61) and 0.83 (95% CI 0.70-0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47-1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65-1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53-1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76-1.72 for RALvs. CONC). CONCLUSIONS: We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people.

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case-control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

Dissection of the humoral immune response toward an immunodominant epitope of HIV: a model for the analysis of antibody diversity in HIV+ individuals.

Understanding the dynamics of the humoral immune response to HIV epitopes in the presence of genetic drift and antigenic variation of the virus may reveal critical elements of protective immunity against HIV. Analysis of antibody maturation and diversity is difficult to study at the molecular level in humans. We used a combinatorial phage display peptide library to elucidate antibody diversity in HIV-infected individuals to a single immunodominant epitope in gp41. A serum sample derived from an HIV+ individual was used to screen a phage display a 12 mer cysteine-constrained loop peptide library. In doing so, we isolated mimotope-presenting phages corresponding to the immunodominant gp41 epitope CSGKLIC (residues 603-609). The mimotopes and control phages expressing epitope variants were reacted with a panel of 30 HIV+ sera. The patients showed distinct and variable recognition patterns compared with one another. Subfractions of the polyclonal sera were affinity purified and analyzed for epitope specificities. These analyses illustrated that epitope variants can be used to decipher antibody diversity. Elucidation of the plasticity of the humoral response and its polyclonality toward discrete epitopes contributes to our understanding of the antibody maturation process in individuals infected with viruses such as HIV.

Malabsorption syndrome, coccidiosis, combined immune deficiency, and fulminant lymphoproliferative disease.

Coccidia were found in a patient suffering from malabsorption syndrome. In addition, immunologic investigation showed combined humoral and cellular immunodeficiency. Treatment with metronidazole induced the disappearance of coccidia from the stool and clinical remission. Six months later, the patient was seen with acute lymphoproliferative disease and died thereafter. The possible relationship between malabsorption, immunodeficiency, coccidiosis, metronidazole, and malignancy is reviewed.

Acute respiratory distress caused by erythromycin hypersensitivity.

Severe respiratory distress developed in a patient after ingestion of two tablets of erythromycin (Erythrocin) stearate. Complete atelectasis of the left lung was found. The patient was treated intravenously with 200 mg of prednisolone sodium tetrahydrophthalate. On the same day the patient's condition improved dramatically and repeated chest roentgenograms disclosed an almost complete expansion of the atelectatic lung. Using the indirect mast cell degranulation test and the inhibition of direct mast cell degranulation test, we have shown the presence of IgE and non-IgE antibodies (heat stable) against erythromycin. This suggests that an allergic reaction of type 1 and type 3 participated in the course of the clinical picture.

The central nervous system-specific myelin oligodendrocytic basic protein (MOBP) is encephalitogenic and a potential target antigen in multiple sclerosis (MS).

Uncovering primary target antigens in multiple sclerosis (MS) is of major significance for understanding the etiology and pathophysiology of the disease, and for designing immunospecific therapy. In this study, a synthetic peptide representing a predicted T cell epitope on myelin oligodendrocytic basic protein (MOBP) was found to be encephalitogenic in C3H.SW mice, inducing experimental autoimmune encephalomyelitis with an abrupt onset. Two separate preliminary studies with MOBP peptides indicated that autoreactivity to MOBP occurs in MS. These data strongly suggest that MOBP is a highly relevant target in MS and further point to the complexity of antigen specificities in MS.

Autoimmune and inflammatory responses may have an additive effect in postpercutaneous transluminal coronary angioplasty restenosis.

Patients who had an increase in their serum amyloid type A level of > 100% in the first 24 hours after percutaneous transluminal coronary angioplasty (PTCA) and also developed a positive antibody result (antinuclear factor or anticardiolipin), had a relative risk of 10.6 for developing restenosis in the first year after PTCA.

Anti-HIV indeterminate western blot in dialysis patients: a long-term follow-up.

In a group of 520 patients undergoing chronic hemodialysis, 23 (4. 4%) were enzyme immunoassay (EIA) positive for human immunodeficiency virus (HIV) and indeterminate by Western blot (IWB) analysis. The antibodies were mostly directed against p24 and p55 antigens. A comparison between hemodialysis patients with and without IWB showed significant differences between the two groups with respect to number of units of blood transfused, history of renal transplant rejection, and Rh status. No significant differences were observed with respect to ethnic group, nature of renal disease, duration of hemodialysis, associated diseases, and ABO blood group. The HIV IWB phenomenon may represent abnormal immune reactivity as a result of transplantation antigens and/or autoantibody formation. Five-year follow-up of the HIV EIA-positive IWB patients showed that none had seroconverted to HIV-positive status.

Anti-heart antibodies in postpericardiotomy syndrome: cause or epiphenomenon? A prospective, longitudinal pilot study.

OBJECTIVES: To assess the role of anti-heart antibodies (AHA) in postpericardiotomy syndrome (PPS) and the timing of their appearance in relation to the initial manifestations of PPS. DESIGN AND SUBJECTS: Twenty patients who were scheduled to undergo elective coronary artery bypass grafting (CABG) were enrolled in a prospective, longitudinal pilot study. METHODS: Serum was sampled for AHA on the day prior to surgery and at regular intervalsfollowing surgery in all patients. In those who developed PPS, the serum AHA was determined on the day that typical clinical manifestations of PPS appeared and at regular intervals following the onset of PPS. RESULTS: All patients were negative for AHA on the day precedingsurgery. Three(15%) patients developed PPS. Their sera were negative for AHA on the day they were diagnosed as sufferingfrom PPS and the sera became positive for AHA within 14 days from the time of diagnosis. The intensity of immunofluorescence decreased markedly 30 days afterwards and AHA had disappeared within 90days after diagnosis of PPS. The other 17 (85%) patients were negative for AHA prior to surgery and remained so during the six-month postoperative follow-up period. CONCLUSION: The findings of this study suggest that serum AHA may not play a causal role inthe pathogenesis of PPS, but may rather be an epiphenomenon, reflecting an immune response to pericardial and/or myocardial injury.

Lethal occult pulmonary hemorrhage in drug-induced thrombocytopenia.

A patient with drug-induced thrombocytopenia who died because of massive pulmonary hemorrhage is described. The patient had a clinical picture of acute respiratory distress resembling pulmonary edema, but there was no hemoptysis. Chest x-ray films showed granular density in the pulmonary fields, and the electrocardiograms revealed a pattern of acute biatrial enlargement. The diagnosis was confirmed at autopsy.

Lymphomatoid granulomatosis with impaired cellular immunity. Eight year survival without treatment.

Lymphomatoid granulomatosis (LYG), a non-neoplastic lymphoreticular disorder, was diagnosed in a 65-year-old woman. Chest radiographs demonstrated bilateral lower lobe nodular infiltrates. Percutaneous needle biopsy of the lung showed an infiltrate composed of plasma cells, lymphocytes and large histiocytic-like cells. Impairment of cellular immunity was found by in vivo as well as by in vitro tests. The clinical condition of the patient has remained stable for the last eight years without specific treatment.

Hepatic granuloma in polymyalgia rheumatica.

Hepatic granuloma occurs rarely in the polymyalgia rheumatica syndrome. A case was presented of a 62-year-old woman with polymyalgia rheumatica, elevated concentrations of hepatic enzymes, and granuloma of the liver. Low doses of corticosteroids produced a marked improvement in the patient's condition and a return of liver function tests to normal. This is apparently the first case of polymyalgia rheumatica associated with liver granuloma that has been reported in Israel.

Chlorpropamide-induced Syndrome of Inappropriate Antidiuretic Hormone Secretion.

The Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is a rare but serious complication of chlorpropamide therapy. In 2 elderly women who had diabetes mellitus, the SIADH developed two months after the chlorpropamide dosage had been increased to 500 mg daily. The syndrome disappeared after withdrawal of the drug. In one of these patients, re-administration of chlorpropamide resulted in recurrence of the SIADH. A review of the current literature disclosed certain common denominators, i.e., most of the patients are elderly women whose dosage of chlorpropamide was increased shortly before the development of the SIADH.

Demonstration of antispermatozoal antibodies in varicocele-related infertility with an enzyme-linked immunosorbent assay (ELISA).

To assess the existence of a possible immunologic factor in varicocele-associated infertility, we searched for antispermatozoal antibodies in serum, seminal plasma, and bound to spermatozoa in 32 infertile men with varicocele and 22 infertile patients without palpable varicocele, with the use of an enzyme-linked immunosorbent assay. In addition, we performed morphologic and microbiologic analyses of the semen and urethral smears for isolation of Chlamydia trachomatis. Twenty-nine men from the varicocele group (90.6%) demonstrated antispermatozoal antibodies, compared with only 9 men (40.9%) in the control group. The antibodies in both groups, when present, were mainly serum and seminal plasma immunoglobulins IgA and IgM. A significant quantitative difference between the varicocele and control groups was also observed for serum IgA, seminal plasma IgA and IgM, and sperm-bound IgG, IgA, and IgM. Oligozoospermia and asthenozoospermia were significantly more prevalent in the varicocele men. An asymptomatic genital tract infection with C. trachomatis, Ureaplasma urealyticum, and Escherichia coli was traced in 40.6% of the varicocele men and in 45.5% of the control group. No interaction could be demonstrated between the infection and antispermatozoal antibody formation. These data suggest that an immunologic factor may play a role in varicocele-associated infertility; however, its impact on reproduction has yet to be assessed.

Thromboagglutination by anticardiolipin antibody complex in the antiphospholipid syndrome: a possible mechanism of immune-mediated thrombosis.

The tendency for patients with antiphospholipid syndrome (APLS) to thromboembolism and the criteria for its detection are well established, whereas the mechanism of this thrombophilic syndrome is still obscure. Using immunofluorescent techniques and a microscopic spontaneous platelet aggregation test (mSPAT), we have previously demonstrated platelet binding by antibody followed by aggregation in patients with lupus anticoagulant. In the present study, we investigated 18 anticardiolipin antibody-positive (ACLA pos.) patients, comprised of 12 primary APLS and 6 secondary APLS lupus patients. We demonstrated direct platelet microaggregate formation in 16/18 cases, whereas this finding was not present in 20 ACLA-negative (ACLA neg.) subjects (P<.001). Indirect testing revealed 10/12 cases of platelet microaggregation and none in the ACLA neg. subjects. In addition, immunofluorescent studies showed that platelet antibody complex binding occurred in 8/12 cases tested directly and in 11/12 cases in indirect testing, as compared to 1 out of 20 binding in ACLA neg. subjects (P<.001). Antibody complex binding was inhibited in two cases by prior extraction of phospholipids. Platelet aggregation could be demonstrated in two ACLA neg. individuals by the addition of exogenous ACLA to platelets in EDTA-plasma. We therefore propose a mechanism for immune-mediated thrombosis in APLS in which calcium-independent platelet aggregation, or thromboagglutination, is initiated by an ACLA-phospholipid complex present in the patients' plasma. Following the antibody complex-induced platelet agglutination, thrombosis proceeds by release, recruitment, and fibrin formation. The mechanism should have important implications in the diagnosis, management, and monitoring of APLS.

Felty's syndrome without concomitant arthritis: a variant.

A young female patient who had documented seropositive rheumatoid arthritis and was treated consecutively with aspirin, diclofenac, and gold salts was admitted years later for severe neutropenia. On examination she had, in addition, fever, positive rheumatoid factor, reversible swan-neck deformity of the fingers but otherwise normal joint findings. The patient responded to prednisone therapy. This case would appear to be a most unusual variant of Felty's syndrome.

Serum amyloid type A may be a predictor of restenosis.

BACKGROUND: Elevation of acute phase proteins [C-reactive protein (CRP) and serum amyloid type A (SAA)] has been demonstrated in unstable angina with an adverse clinical prognosis. HYPOTHESIS: The study was undertaken to determine the effect of angioplasty on the levels of SAA and the correlation with postangioplasty restenosis. METHODS: In a university-affiliated tertiary medical center, a prospective case study was undertaken in 55 patients who underwent successful percutaneous transluminal coronary angioplasty (PTCA) of a single coronary lesion for angina pectoris. Three groups of patients were clinically characterized according to Braunwald's classification of anginal syndrome: Group A: class III; Group B: class I; Group C: stable angina. Serum amyloid type A was measured by an ELISA method before PTCA and after 24 h, 1, and 3 months. Patients were followed clinically for 12 months. A thallium stress perfusion scan was performed 3 months after PTCA and coronary angiography was repeated in patients with an abnormal thallium perfusion scan. RESULTS: Serum amyloid type A levels > 100 micrograms/ml could identify Group A patients with a high sensitivity and specificity (r = 0.85 and 0.86, respectively). Of the patients studied, 75% increased their SAA level 24 h after angioplasty. An increase of SAA by > 100% was associated with an increased risk of restenosis, with a relative risk of 6.4 (p < 0.05). CONCLUSION: Increased levels of SAA characterize patients with unstable angina pectoris with a high specificity and sensitivity. Levels of SAA that increase > 100% 24 h after angioplasty may serve as a marker of restenosis.

Impairment of cellular immunity in patients with malignant external otitis.

Immunological studies were performed on 4 elderly diabetic patients with Malignant External Otitis caused by Pseudomonas aeruginosa. Impairment of cellular immunity was found. Skin tests for delayed hypersensitivity to PPD, SK-SD and Mumps antigen were negative and stimulation rates of peripheral blood lymphocytes by PHA, Con-A and PWM were depressed in all 4 patients. Serum immunoglobulins and complement levels were normal except in one case in which paraprotein IgG was found. Peripheral blood lymphoid cell markers and the neutrophil nitroblue tetrazolium (NBT) test were within normal limits in the 2 patients tested. These results indicate that cellular immune deficiency predisposes to the development of Malignant External Otitis in elderly diabetic patients.

Bullous eruption in a case of bullous pediculid.

We present a case of a bullous eruption appearing in a patient with pediculosis pubis. The eruption was apparently a reaction to the pediculi, possibly to their salivary secretions. To our knowledge, this is the first report of such a case. We have called this condition "bullous pediculid."