Biomedical subjects
Publications and source records attributed to R Lawrence.
We describe a patient with hypersensitivity vasculitis due to ofloxacin therapy; the vasculitis was associated with elevated transaminase and IgA levels. Cyclophosphamide and intravenous pulse prednisolone resulted in clinical improvement.
The NF-kappa B/Rel family of transcription factors is commonly expressed in non-hematopoietic cells in an inactive form within the cytoplasm, complexed with an inhibitor I kappa B protein. Thus, it was surprising that NF-kappa B element-driven heterologous promoter-reporter gene constructs were active upon transient transfection into vascular smooth muscle cells (VSMCs). Here, we report that VSMCs express a constitutive nuclear NF-kappa B-like activity. In electrophoretic mobility shift assays, nuclear extracts demonstrated binding to a wild type NF-kappa B element but not to those mutated at nucleotides critical for Rel-protein DNA interaction. Binding was abrogated by the presence of I kappa B-alpha. Furthermore, addition of an antibody to the p50 subunit of classical NF-kappa B (but not p65, c-Rel, or RelB) resulted in supershifted complexes. Transactivation of element-driven constructs was negatively affected by co-transfection of a vector expressing a dominant negative p50 subunit, which can dimerize with other Rel subunits but not bind DNA. The long terminal repeat of the human immunodeficiency virus-1, which is driven in part by two NF-kappa B elements, displayed strong activity within VSMCs. This activity was abrogated upon co-transfection of the vector expressing the dominant negative p50 mutant. Taken together, these experiments indicate that VSMCs constitutively express a functional NF-kappa B-like trans-acting factor, which may play a significant role in the regulation of proliferation and viral infection of these cells.
Vascular smooth muscle cells (SMCs) produce the bulk of the connective tissue of major arteries, including collagen types I, III, and V. Recently, we have shown, they also have the capacity to synthesize the alpha 1 chain of type XI, a collagen related to type V (Brown, K., Lawrence, R., and Sonenshein, G. (1991) J. Biol. Chem. 266, 23268-23273). Furthermore, expression of types V and XI collagen were coordinately regulated with respect to serum deprivation and cell density in a fashion distinct from that for types I and III. To begin to determine the factors that influence vascular SMC production of types V/XI collagen, we have examined the effects of transforming growth factor (TGF)-beta 1, a major modulator of connective tissue expression. In serum-deprived confluent cultures of bovine pulmonary artery SMCs, TGF-beta 1 treatment increased the steady-state levels of the mRNAs of collagen types V and XI, as well as of types I and III, elastin and fibronectin. The largest increase was seen for alpha 2(V) procollagen. The increase in alpha 2(V) mRNA was detectable by 12 h after addition of 2 ng/ml TGF-beta 1, and concentrations as little as 0.5 ng/ml were effective. A similar increase in alpha 2(V) mRNA levels was observed with SMCs derived from the aortic arch and carotid artery. Type V collagen protein was found to be elevated by TGF-beta 1 treatment in both the conditioned media and the cell layer associated fraction of pulse-labeled cultures. A slight decrease in SMC proliferation as judged by DNA content, [3H]thymidine incorporation, and steady-state levels of histone H3.2 mRNA resulted from TGF-beta 1 treatment. These results suggest that the elevated levels of TGF-beta 1 in the vessel wall during atherosclerosis may be, in part, responsible for the increase in type V collagen that typifies advanced fibrotic lesions.
The purpose of this study was to determine the prevalence of emergency department-based POISINDEX (Micromedex Inc, Denver, CO) and assess its perceived impact on use of poison control centers. Survey methodology was used. A written questionnaire was distributed to all emergency departments (EDs) in the state of New York. ED directors or their designee (n = 239) were surveyed regarding the presence of POISINDEX in their ED and their perceptions of its impact on ED use of poison control centers. Completed questionnaires were returned from 180 of 239 (75%) EDs. Of the returned questionnaires, 42 of 180 (23%) have their own POISINDEX. In 32 of 42 (76%) of these EDs that have their own POISINDEX, it was perceived that ED-based POISINDEX decreased poison control center use. Use of ED-based POISINDEX may decrease ED use of poison control centers.
To evaluate the efficacy of primary chemoprophylaxis in preventing Pneumocystis carinii pneumonia (PCP) in infants with perinatal human immunodeficiency virus-1 infection during the first year of life, we conducted a retrospective chart review of infants with human immunodeficiency virus-1 infection born at New York University Medical Center-Bellevue Hospital Center, in New York. Between March 1989 and March 1993, 24 infants received primary chemoprophylaxis with trimethoprim-sulfamethoxazole in the first year of life and 24 infants did not receive primary prophylaxis. The CD4+ T-lymphocyte counts in the two groups did not differ during the first year of life. The median age at the time of initiation of prophylaxis was 3 months, and the average duration of prophylaxis was 5.5 months. Among the infants who had not received prophylaxis, five cases of PCP were diagnosed at a median age of 5 months; in contrast, no cases of PCP were observed in the infants receiving prophylaxis (log-rank test, p = 0.017). The probability of surviving after 1 year of age was 92% for the children who received prophylaxis and 74% for those who did not (log-rank test, p = 0.035). These data indicate that chemoprophylaxis is highly effective in preventing primary PCP and improving survival time in infants with human immunodeficiency virus-1 infection.
The purpose of this study was to characterize systemic Streptococcus pneumoniae disease in human immunodeficiency virus type 1 (HIV-1)-infected children. All cases of bacteremia and meningitis caused by S. pneumoniae among children less than 18 years old were collected by review of the Microbiology Laboratory records at the Bellevue Hospital Center during the period August 1, 1978, through July 31, 1993. There were 31 bouts of systemic S. pneumoniae disease in 19 of 235 HIV-1-infected children cared for by the Pediatric Infectious Disease staff and 116 bouts in 113 children not known to be HIV-1-infected. Four of the 19 HIV-1-infected children had multiple episodes of S. pneumoniae bacteremia as compared with 3 of 113 in the general population (P = 0.008). The frequency of serotypes and distribution of infections by season of the year did not differ between the 2 groups. The median ages at the time of the S. pneumoniae infection were 1.8 and 1.1 years for the HIV-1-infected children and the general population of children, respectively, when those children with multiple episodes were included for their initial episode only (P = 0.06). In the HIV-1-infected patients, 10 episodes were associated with pneumonia, 5 with pneumonia and otitis media, 5 with otitis media only, 1 with pneumonia and meningitis, 1 with meningitis only and 1 with periorbital cellulitis; 5 had no apparent focus of infection. One episode of pneumonia was complicated by lung abscess and there were 2 deaths. Most HIV-1-infected patients recovered without significant sequelae, and the clinical course of their systemic infections did not appear to be markedly different than that of healthy children.
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Much of the lung damage that limits the life of young adults with cystic fibrosis is due to proteases and oxygen metabolites generated by neutrophils, which are recruited into the airway by the interaction between Pseudomonas aeruginosa and pulmonary macrophages. Leukotriene B4 (LTB4) has been proposed as a local mediator of this process; its production is susceptible to specific modulation with dietary eicosapentaenoic acid (EPA). We carried out a placebo-controlled trial of EPA (2.7 g daily for 6 weeks) to assess its effects on markers of clinical state, peripheral neutrophil function, and lung inflammation in sixteen patients with cystic fibrosis colonised with P aeruginosa. EPA was well tolerated and resulted in a significant reduction in sputum volume (median change with EPA -10 mL/day, placebo 0; p = 0.015), and improvements in Schwachman score (EPA 5%, placebo 0; p = 0.034), forced expiratory volume in 1 s (EPA 0.25 L, placebo -0.1 L; p = 0.006), and vital capacity (EPA 0.6 L, placebo 0; p = 0.011). Relative chemotaxis of circulating neutrophils to LTB4 increased from a subnormal baseline of 4 (median; range 0-10) microns/30 min before treatment, to a near normal value of 11 (5-18) microns/30 min after EPA. Relative chemotaxis to LTB4 of patients taking placebo did not change: the difference in response was highly significant (p = 0.001). Specific reduction of neutrophil chemotaxis to LTB4 is a sensitive assay of chronic in-vivo exposure to LTB4. Our results suggest that LTB4 has a pathogenetic role in the lung damage of cystic fibrosis. Longer-term clinical trials of EPA are warranted in a larger number of cystic fibrosis patients.
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BACKGROUND: Kaposi's sarcoma (KS) is commonly associated with the acquired immunodeficiency syndrome (AIDS) in adults. Little is known regarding its occurrence in children. OBJECTIVE: Our purpose was to report the clinical and epidemiologic characteristics of KS in three Romanian children with AIDS and to compare them with previously reported AIDS-associated KS in children. METHODS: This was a clinicopathologic study and computer-based literature review. RESULTS: All three Romanian children had skin involvement; two had involvement of lymph nodes and internal organs. All had acquired human immunodeficiency virus (HIV) infection postnatally. Including these children, 33 cases of AIDS-associated KS in children have been reported. Thirteen of 30 evaluable patients had acquired HIV infection postnatally; nine of these children (69%) had cutaneous involvement by KS. A perinatal route of transmission was present in the remaining 17 cases; only two of these children (12%) with KS had cutaneous involvement. No case was noted in which intravenous drug use was the sole parental HIV risk factor. CONCLUSION: The data support the contention that KS is caused by a second infectious agent prevalent only in certain HIV-infected populations. Children of parents in high-risk groups for KS and children who acquire HIV via contaminated blood or blood products are at highest risk for KS. The route of acquisition of HIV infection may also be associated with different clinical manifestations of KS in children.
The ultrasonic appearance of in vitro normal and atherosclerotic arterial wall was investigated with an intravascular ultrasound (IVUS) probe. Fresh cadaver specimens were used: two carotid, two aorta, four iliac and eight superficial femoral arteries. The wall of muscular arteries has a three-layered sonographic appearance. The central hypoechoic layer corresponds to the media, which is primarily composed of smooth muscle. Elastic arteries whose media have a high elastin content appear uniformly echogenic. Calcified plaque is strongly echogenic with acoustic shadowing, fibrous plaque is moderately echogenic, and where there is no cellular matrix the plaque is poorly echogenic. IVUS can provide information about internal plaque architecture. Three-dimensional reconstructions can be generated using a transputer-based workstation coupled to the transducer, providing detailed views of surface contour.
OBJECTIVE: Varicella-zoster virus (VZV) infections can cause severe disease in immunocompromised individuals. To evaluate the spectrum of VZV infections in human immunodeficiency virus (HIV)-infected children, we retrospectively analyzed all the cases of VZV infection in a cohort of children cared for at a hospital for infectious diseases in Bucharest, Romania. METHODS: The records of 391 HIV-infected children admitted to the acquired immunodeficiency syndrome pavilion of Colentina Hospital during the period January 1, 1991, through March 31, 1992, were reviewed for evidence of VZV infection. The diagnosis of varicella or zoster was made clinically and information was collected concerning course of the illness, number of skin lesions, and clinical evidence of complications. Lymphocyte subpopulation typing, as an estimate of immune function, was performed by either a standard fluorescent activated flow cytometric method or by immunofluorescent technique. RESULTS: Thirty-eight cases of varicella (9.7%) and seven cases of zoster (1.8%) were adequately documented among the 391 records reviewed. The duration of varicella was prolonged; in 57% of the children it was greater than 10 days. Forty percent of children with varicella developed a complication, including superinfection of the skin, pneumonia, or thrombocytopenia. None of the children developed clinical hepatitis or encephalitis. Two children (5%) died during varicella, both of respiratory failure. None of the 7 children with zoster had chronic, recurrent, or disseminated lesions. Lymphocyte subset analysis was available for 22 of 38 children with varicella and 3 of 7 children with zoster. Fifteen of the 22 children had normal, age-adjusted, absolute CD4 counts within 3 months of the diagnosis of varicella. All 3 children with zoster who had lymphocyte subset analysis had low CD4 counts and absolute numbers. None of the 45 children received antiretroviral therapy and only 1 child with varicella and 1 with zoster received acyclovir. CONCLUSIONS: The spectrum of VZV infection in this hospitalized group of HIV-infected children was broad. The majority (57%) experienced a prolonged course of disease and a higher rate of complications than normal children hospitalized with varicella.
The aim of this study was to determine whether the speed of technetium-labelled diethylene-triamine-pentacetate (99mTc-DTPA) clearance from the lung is predictive of disease progression in fibrosing alveolitis, as judged by changes in respiratory function tests. 82 nonsmoking patients with fibrosing alveolitis were studied (progressive systemic sclerosis, n = 53; lone cryptogenic fibrosing alveolitis, n = 29). Normal 99mTc-DTPA clearance at initial measurement predicted stable disease; rapid 99mTc-DTPA clearance identified patients at risk of deterioration. Repeat measurement of clearance, approximately 12 months later, enabled the definition of a subgroup at higher risk, with persistently abnormal 99mTc-DTPA clearance, and a smaller subgroup in whom reversion of clearance to normal was associated with a sustained improvement in respiratory function indices. These findings were not attributable to differences in treatment between subgroups. We conclude that the speed of 99mTc-DTPA clearance discriminates between stable and progressive disease in fibrosing alveolitis.
OBJECTIVES: To determine whether cell-mediated and humoral immune responses to recall antigens develop in children infected with the human immunodeficiency virus (HIV) and, if so, whether these responses are retained. METHODS: Children infected with HIV and uninfected children born to mothers infected with HIV were compared with respect to lymphoproliferative responses to recall antigens and protective levels of antibody to bacterial toxoids during the first 4 years of life. RESULTS: Children infected with HIV who were enrolled in a prospective study of the natural history of the infection were relatively normal (1) in their lymphoproliferative responses to diphtheria toxoid, tetanus toxoid, and Candida, and (2) in their ability to make protective diphtheria and tetanus antitoxins during the first 2 years of life. During the next 2 years, attrition was noted in both lymphoproliferative and humoral responses. Attrition in response was not necessarily correlated with declining numbers of helper T cells. CONCLUSIONS: These results suggest that both cellular and humoral immune responses develop early in life in most children infected with HIV, while they remain relatively well both clinically and immunologically. Previously reported severe immune deficits in these children were probably attributable to advanced clinical disease when they were first studied.
The immunological basis of resistance to Brugia pahangi infection in rats was studied. Infections were investigated in athymic rnu/rnu rats and in rats treated with the immuno-suppressive agents cyclosporin A (CsA) or cyclophosphamide (Cy). The recovery of adult worms in normal rats was 1-2% in comparison to 12.2% recovery in athymic rats. CsA and Cy treated rats did not have increased adult worm burdens. Microfilarial (Mf) levels (expressed as Mf per ml per adult worm) were highly elevated in both athymic and Cy treated rats but not in CsA treated rats. IgG and IgM levels to B. pahangi antigens were severely depressed in both athymic and Cy treated rats. IgG levels but not IgM levels were abrogated in CsA treated rats. These results implied that control of larval establishment or adult killing, and regulation of Mf levels are separate T-cell dependent mechanisms and act independently of IgG antibody. Control of Mf levels is associated with a specific IgM response which is Cy sensitive but CsA resistant.
An 84 years old male patient presented with hypercalcemic encephalopathy and mild azotemia while on anti-tuberculous treatment for glandular tuberculosis. He recovered fully during treatment with hydration, intravenous frusemide and oral prednisolone while continuing on the antituberculous therapy.