Bilateral iris neovascularization as the initial sign of obesity-hypoventilation (Pickwickian) syndrome: hypoxia/hypercapnia as a stimulus for angiogenesis.
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Adult↗
Biomedical subjects
G Kaplan
Publications and source records attributed to G Kaplan.
Systemic inflammatory response with plasma C-reactive protein elevation in disk-related lumbosciatic syndrome.
OBJECTIVE: To look for a systemic inflammatory response in patients with disk-related lumbosciatic syndrome by using an ultrasensitive (US) plasma C-reactive protein (CRP) assay, and to determine whether plasma CRP-US levels correlated with clinical and/or laboratory features. PATIENTS AND METHODS: Plasma CRP was assayed using an enzyme-linked immunosorbent assay (ELISA) (detection limit, 5 microg/L) in patients with sciatica shown by computed tomography to be due to a disk herniation. Levels in 35 patients aged 23 to 64 years were compared to those in age- and sex-matched controls. RESULTS: Mean CRP-US levels measured by ELISA were significantly higher in the patients than in the controls (1.68 vs 0.74 mg/L; P = 0.002). There was a trend toward higher CRP-US levels in the patients with more severe nerve root symptoms. CONCLUSION: The significantly higher plasma CRP-US levels by ELISA in our patients with disk-related lumbosciatic syndrome is consistent with a systemic inflammatory response to the local nerve root impingement.
Acute-Phase Reaction↗
Relation between income inequality and mortality: empirical demonstration.
OBJECTIVE: To assess the extent to which observed associations at population level between income inequality and mortality are statistical artefacts. DESIGN: Indirect "what if" simulation by using observed risks of mortality at individual level as a function of income to construct hypothetical state level mortality specific for age and sex as if the statistical artefact argument were 100% correct. SETTING: Data from the 1990 census for the 50 US states plus Washington, DC, were used for population distributions by age, sex, state, and income range; data disaggregated by age, sex, and state from the Centers for Disease Control and Prevention were used for mortality; and regressions from the national longitudinal mortality study were used for the individual level relation between income and risk of mortality. RESULTS: Hypothetical mortality, while correlated with inequality (as implied by the logic of the statistical artefact argument), showed a weaker association with states' levels of income inequality than the observed mortality. CONCLUSIONS: The observed associations in the United States at the state level between income inequality and mortality cannot be entirely or substantially explained as statistical artefacts of an underlying individual level relation between income and mortality. There remains an important association between income inequality and mortality at state level over and above anything that could be accounted for by any statistical artefact. This result reinforces the need to consider a broad range of factors, including the social milieu, as fundamental determinants of health.
Adult↗
Thalidomide stimulates T cell responses and interleukin 12 production in HIV-infected patients.
We performed a placebo-controlled study to evaluate the effects of immunomodulatory treatment with thalidomide on HIV levels, TNF-alpha levels, and immune status of 31 HIV-infected individuals, after temporary suppression of viral replication with antiretroviral drugs. Treatment with a combination of zidovudine and lamivudine (ZDV/LMV) for 14 days resulted in a median decline in plasma viremia of 1.94 log10 RNA equivalents/ml. After discontinuation of ZDV/LMV, thalidomide therapy (200 mg/day for 4 weeks) did not retard the prompt return of HIV titers to the pretreatment levels, and had no effect on plasma levels of TNF-alpha. In contrast, thalidomide treatment resulted in significant immune stimulation. We observed increased levels of plasma soluble IL-2 receptor, soluble CD8 antigen, and IL-12 (p < 0.01 for all parameters), as well as increased cutaneous delayed-type hypersensitivity reactions to recall antigens (p < 0.01) in thalidomide-treated patients. These changes were associated with a median increase in HIV titer of 0.2 log10 RNA equivalents/ml in the thalidomide-treated group (p < 0.05), which resolved after stopping the drug. Further studies were performed in vitro to elucidate the mechanism of thalidomide-induced immune stimulation. When purified T cells from HIV-infected individuals were stimulated by immobilized anti-CD3 in the presence of thalidomide, a costimulatory effect of the drug was observed, resulting in increased production of IL-2 and IFN-gamma, and increased T cell-proliferative responses. Further experiments showed that thalidomide increased IL-12 production by antigen-presenting cells in a T cell-dependent manner. Our findings suggest a potential application for thalidomide as a novel immune adjuvant in HIV disease.
Adult↗
Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.
TNF-alpha mediates both protective and detrimental manifestations of the host immune response. Our previous work has shown thalidomide to be a relatively selective inhibitor of TNF-alpha production in vivo and in vitro. Additionally, we have recently reported that thalidomide exerts a costimulatory effect on T cell responses. To develop thalidomide analogues with increased anti-TNF-alpha activity and reduced or absent toxicities, novel TNF-alpha inhibitors were designed and synthesized. When a selected group of these compounds was examined for their immunomodulatory activities, different patterns of cytokine modulation were revealed. The tested compounds segregated into two distinct classes: one class of compounds, shown to be potent phosphodiesterase 4 inhibitors, inhibited TNF-alpha production, increased IL-10 production by LPS-induced PBMC, and had little effect on T cell activation; the other class of compounds, similar to thalidomide, were not phosphodiesterase 4 inhibitors and markedly stimulated T cell proliferation and IL-2 and IFN-gamma production. These compounds inhibited TNF-alpha, IL-1beta, and IL-6 and greatly increased IL-10 production by LPS-induced PBMC. Similar to thalidomide, the effect of these agents on IL-12 production was dichotomous; IL-12 was inhibited when PBMC were stimulated with LPS but increased when cells were stimulated by cross-linking the TCR. The latter effect was associated with increased T cell CD40 ligand expression. The distinct immunomodulatory activities of these classes of thalidomide analogues may potentially allow them to be used in the clinic for the treatment of different immunopathological disorders.
3',5'-Cyclic-AMP Phosphodiesterases↗
[Gougerot-Sjögren syndrome. Diagnostic criteria and therapeutic methods].
UNLABELLED: CLASSIFICATION CRITERIA: Several systems of classification criteria have been developed for Sjögren's syndrome. These systems allow patient classification but do not constitute diagnostic criteria. The most widely used is based on the Fox criteria which are totally specific but have low sensitivity. The European criteria have satisfactory sensitivity and specificity. IN CLINICAL PRACTICE: In all cases, the elements comprising the sicca syndrome must be identified. A labial biopsy for histology of the accessory salivary glands may be helpful. A less extensive search is sometimes sufficient if the aim is uniquely diagnostic. TREATMENT OF SJOGREN'S SYNDROME: Symptomatic treatment of the sicca syndrome with local procedures is aimed at reducing the functional disorder. The systemic route is used to treat the dysimmune component. As in most connective tissue diseases, most patients can be stabilized, limiting the functional consequences of the disease, but cure remains illusive.
Biopsy↗
Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production.
Thalidomide, (1), is a known inhibitor of TNF-alpha release in LPS stimulated human PBMC. Herein we describe the TNF-alpha inhibitory activity of amino substituted analogs of thalidomide (1) and its isoindolin-1-one analog, EM-12 (2). The 4-amino substituted analogs were found to be potent inhibitors of TNF-alpha release in LPS stimulated human PBMC.
Blood↗
Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates.
Mycobacterium tuberculosis CDC1551, a clinical isolate reported to be hypervirulent and to grow faster than other isolates, was compared with two other clinical isolates (HN60 and HN878) and two laboratory strains (H37Rv and Erdman). The initial (1-14 days) growth of CDC1551, HN60, HN878, and H37Rv was similar in the lungs of aerosol-infected mice, but growth of Erdman was slower. Thereafter, the growth rate of CDC1551 decreased relative to the other strains which continued to grow at comparable rates up to day 21. In the lungs of CDC1551-infected mice, small well-organized granulomas with high levels of TNF-alpha, IL-6, IL-10, IL-12, and IFN-gamma mRNA were apparent sooner than in lungs of mice infected with the other strains. CDC1551-infected mice survived significantly longer. These findings were confirmed in vitro. The growth rates of H37Rv and CDC1551 in human monocytes were the same, but higher levels of TNF-alpha, IL-10, IL-6, and IL-12 were induced in monocytes after infection with CDC1551 or by exposure of monocytes to lipid fractions from CDC1551. CD14 expression on the surface of the monocytes was up-regulated to a greater extent by exposure to the lipids of CDC1551. Thus, CDC1551 is not more virulent than other M. tuberculosis isolates in terms of growth in vivo and in vitro, but it induces a more rapid and robust host response.
Aerosols↗
Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system.
The pathogenesis of tuberculous meningitis, a devastating complication of tuberculosis in man, is poorly understood. We previously reported that rabbits with experimental tuberculous meningitis were protected from death by a combination of antibiotics and thalidomide therapy. Survival was associated with inhibition of tumor necrosis factor alpha (TNF-alpha) production by thalidomide. To test whether cerebrospinal fluid (CSF) levels of TNF-alpha correlated with pathogenesis, the response of rabbits infected in the central nervous system (CNS) with various mycobacterial strains was studied. CNS infection with Mycobacterium bovis Ravenel, M. bovis bacillus Calmette-Guérin (BCG) Pasteur, and M. bovis BCG Montreal were compared. M. bovis Ravenel induced the highest levels of TNF-alpha in the CSF in association with high leukocytosis, protein accumulation, and severe meningeal inflammation. BCG Pasteur had intermediate effects, and BCG Montreal was the least virulent. In addition, M. bovis Ravenel numbers were highest in the brain and CSF and the bacilli also disseminated more efficiently to distant organs, compared with BCG Pasteur and BCG Montreal. In subsequent experiments, rabbits were infected with either recombinant M. bovis BCG Montreal (vector), or BCG Montreal expressing the murine gene for TNF-alpha (BCG mTNF-alpha). BCG Montreal was rendered virulent by the expression of murine TNF-alpha, as demonstrated by high CSF leukocytosis, high protein accumulation, severe meningeal inflammation, persistent bacillary load, and progressive clinical deterioration. Taken together, these results demonstrate that the level of TNF-alpha produced during mycobacterial CNS infection determines, at least in part, the extent of pathogenesis.
Animals↗
Thalidomide in toxic epidermal necrolysis.
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Dermatologic Agents↗
Molecular mechanism of nerve infection in leprosy.
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Humans↗
Thalidomide and a thalidomide analogue inhibit endothelial cell proliferation in vitro.
Angiogenesis is a crucial process in inflammatory reactions as well as in tumor implantation and growth. Tumors with high rates of invasion and recurrence such as gliomas, are specially dependent on neovascularization. This suggests that inhibition of angiogenesis might reduce the growth of these tumors. Thalidomide has been previously shown to inhibit angiogenesis induced by basic fibroblast growth factor in vivo, using the rabbit corneal micropocket assay. Therefore, the effect of thalidomide and a thalidomide analogue (cc-1069) on the proliferation in vitro of endothelial and glioma cells was tested. We observed a decrease in endothelial cell proliferation in cultures treated with thalidomide or the thalidomide analogue cc-1069. The analogue inhibited endothelial cell proliferation more efficiently than thalidomide. The inhibition occurred in association with a marked decrease in the activity of the nuclear factor SP1 and a moderate inhibition of NF-kappaB activation in nuclear extracts of endothelial cells. The drugs did not impair cell viability. There was no effect of thalidomide or the thalidomide analogue on the proliferation of the glioma cell line (U251) in vitro.
Animals↗
Thalidomide analogue CC1069 inhibits development of rat adjuvant arthritis.
The cytokine tumour necrosis factor-alpha (TNF-alpha) has been implicated in the aetiology of rheumatoid arthritis in humans as well as of experimental arthritis in rodents. Thalidomide, and to a greater extent the new thalidomide analogue CC1069, inhibit monocyte TNF-alpha production both in vitro and in vivo. The aim of the present study is to establish whether these drugs block production of TNF-alpha as well as IL-2 by rat leucocytes and whether this inhibition affects the development of rat adjuvant arthritis (AA). Cultured splenocytes were stimulated with either lipopolysaccharide (LPS) or concanavalin A (Con A) in the presence of thalidomide, CC1069, or solvent, and the production of TNF-alpha and IL-2 were compared. Next, adjuvant was injected into the base of the tail of rats without or with daily intraperitoneal injections with 100-200 mg/kg per day thalidomide or 50-200 mg/kg per day CC1069. Disease activity, including ankle swelling, hind limb radiographic and histological changes, weight gain, and ankle joint cytokine mRNA levels, were monitored. CC1069, but not the parent drug thalidomide, inhibited in vitro production of TNF-alpha and IL-2 by stimulated splenocytes in a dose-dependent manner. In vivo, a dose-dependent suppression of AA disease activity occurred in the CC1069-treated animals. In contrast, thalidomide-treated rats experienced comparable arthritis severity to placebo-treated animals. There was also a reduction in TNF-alpha and IL-2 mRNA levels in the ankle joints of CC1069-treated rats compared with thalidomide- and placebo-treated arthritic rats. Early initiation of CC1069 treatment suppressed AA inflammation more efficiently than delayed treatment. We conclude that thalidomide, which did not suppress TNF-alpha or IL-2 production in vitro by Lewis rat cells, did not suppress development of rat AA. However, the development of rat AA can be blocked by the thalidomide analogue CC1069, which is an efficient inhibitor of TNF-alpha production and IL-2 in vitro.
Animals↗
Fetal yawning activity in normal and high-risk fetuses: a preliminary observation.
OBJECTIVE: To study yawning activity in healthy fetuses and in fetuses at high risk. METHODS: Yawning activity was studied in 16 healthy and 22 high-risk fetuses. Studies were performed in the postprandial state at 09.00 and 12.00 in a quiet room with the woman in the lateral recumbent position. All ultrasound examinations were performed using a 3.5-MHz Acuson 128 PX curvilinear probe. Fetal lips, mouth, tongue, pharynx, larynx, trachea and esophagus were surveyed in serial coronal and sagittal planes. All fetal mouthing movements were analyzed by a review of the videotape in slow motion. RESULTS: In both normal and high-risk fetuses, yawning was represented by isolated mouthing movements and consisted of slow opening of the mouth with simultaneous downward movements of the tongue. This phase occupied 50-75% of the yawning cycle. After reaching its maximum opening, the mouth remained wide open for 2-8 s and returned to its resting position within seconds. Growth-restricted fetuses demonstrated yawning patterns consisting of isolated yawns similar to those seen in healthy fetuses. Unusual bursts of fetal yawning activity were recorded in anemic fetuses. CONCLUSION: Yawning activity in anemic fetuses may represent a compensatory process to increase venous return to the heart.
Female↗
Group B streptococcal vertebral osteomyelitis with bacteraemia in an adult with no debilitating condition.
A previously healthy 62-year-old immunocompetent woman presented with group B streptococcal vertebral osteomyelitis. Group B Streptococcus was recovered in 3 consecutive blood cultures. The patient recovered fully after treatment including antibiotic therapy, bed rest and physical rehabilitation. Group B streptococcal vertebral osteomyelitis is uncommon and has not previously been reported in patients with no immunosuppressive condition.
Bacteremia↗
Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro.
Mycobacterium tuberculosis has a relatively high resistance to killing by hydrogen peroxide and organic peroxides. Resistance may be mediated by mycobacterial catalase-peroxidase (KatG) and possibly by alkyl hydroperoxide reductase (AhpC). To determine the interrelationship between sensitivity to H2O2, catalase and peroxidase activities, and bacillary growth rates measured both intracellularly in human monocytes and in culture medium, we examined one laboratory strain, two clinical isolates, and three recombinant strains of M. tuberculosis with differing levels of KatG and AhpC. Five of the mycobacterial strains had intracellular doubling times of 27 to 32 h, while one KatG-deficient clinical isolate (ATCC 35825) doubled in approximately 76 h. Killing of mycobacteria by exogenously added H2O2 was more pronounced for intracellular bacilli than for those bacilli derived from disrupted monocytes. Strains with no detectable KatG expression or catalase activity were relatively sensitive to killing (43 to 67% killing) by exogenous H2O2. However, once even minimal catalase activity was present, mycobacterial catalase activity over a 10-fold range (0.56 to 6.2 U/mg) was associated with survival of 85% of the bacilli. Peroxidase activity levels correlated significantly with resistance of the mycobacterial strains to H2O2-mediated killing. An endogenous oxidative burst induction by 4beta-phorbol 12beta-myristate 13alpha-acetate treatment of infected monocytes reduced the viability of the KatG null strain (H37Rv Inhr) but not the KatG-overexpressing strain [H37Rv(pMH59)]. These results suggest that mycobacterial resistance to oxidative metabolites (including H2O2 and other peroxides) may be an important mechanism of bacillary survival within the host phagocyte.
Bacterial Proteins↗
Survival of Mycobacterium avium and Mycobacterium tuberculosis in acidified vacuoles of murine macrophages.
Despite the antimicrobial mechanisms of vertebrate phagocytes, mycobacteria can survive within the phagosomes of these cells. These organisms use various strategies to evade destruction, including inhibition of acidification of the phagosome and inhibition of phagosome-lysosome fusion. In contrast to mycobacteria, Coxiella burnetii, the etiologic agent of Q fever, inhabits a spacious acidified intracellular vacuole which is prone to fusion with other vacuoles of the host cell, including phagosomes containing mycobacteria. The Coxiella-infected cell thus provides a unique model for investigating the survival of mycobacteria in an acidified phagosome-like compartment. In the present study, murine bone marrow-derived macrophages were infected with either Mycobacterium avium or Mycobacterium tuberculosis and then coinfected with C. burnetii. We observed that the majority of phagocytosed mycobacteria colocalized to the C. burnetii-containing vacuole, which maintained its acidic properties. In coinfected macrophages, the growth of M. avium was not impaired following fusion with the acidified vacuole. In contrast, the growth rate of M. tuberculosis was reduced in acidified vacuoles. These results suggest that although both species of mycobacteria inhibit phagosome-lysosome fusion, they may be differentially susceptible to the toxic effects of the acidic environment in the mature phagolysosome.
Animals↗
Immunomodulation by thalidomide and thalidomide analogues.
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Humans↗