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Biomedical subjects

D Adam

Publications and source records attributed to D Adam.

At least 91 records · Page 5Linked to original sources
PubMed2000

Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death.

Tumor necrosis factor (TNF) signals cell death and simultaneously induces generation of ceramide. To evaluate the contribution of ceramide to TNF-dependent cell death, we generated clones of the TNF-sensitive cell line L929 that constitutively overexpress human acid ceramidase (AC). Ceramidase, in concert with sphingosine kinase, metabolizes ceramide to sphingosine-1-phosphate (SPP), an inducer of proliferation. In response to TNF, parental L929 cells display a significant increase in intracellular ceramide correlated with an "atypical apoptosis" characterized by membrane blebbing, DNA fragmentation and degradation of poly(ADP-ribose) polymerase despite a lack of caspase activity. These features are strongly reduced or absent in AC-overexpressing cells. Pharmacological suppression of AC with N-oleoylethanolamine restored the accumulation of intracellular ceramide as well as the sensitivity of the transfectants to TNF, implying that an enhanced metabolization of intracellular ceramide by AC shifts the balance between intracellular ceramide and SPP levels towards cell survival. Correspondingly, inhibition of ceramide production by acid sphingomyelinase also increased survival of TNF-treated L929 cells.

Acid Ceramidase↗
PubMed2000

Activation of ERK1/2 and cPLA(2) by the p55 TNF receptor occurs independently of FAN.

The generation of proinflammatory eicosanoids in response to tumor necrosis factor (TNF) involves the activation of cytosolic phospholipase A(2) (cPLA(2)), presumably by phosphorylation through extracellular signal-regulated kinases (ERK). Earlier results had suggested that a pathway involving the p55 TNF receptor (TNF-R55), neutral sphingomyelinase (N-SMase), and c-Raf-1 activates ERK and cPLA(2). We have previously shown that a cytoplasmic region of TNF-R55 distinct from the death domain regulates the activation of N-SMase through binding of the adapter protein FAN. Analysis of embryonal fibroblasts from FAN knockout mice revealed that TNF-induced activation of both ERK and cPLA(2) occurs without involvement of FAN. Furthermore, we provide evidence that the TNF-dependent activation of ERK and cPLA(2) requires the intact death domain of TNF-R55. Finally, we demonstrate that in murine fibroblasts cPLA(2) is phosphorylated in response to TNF solely by ERK, but not by p38 mitogen-activated protein kinase, suggesting a signaling pathway from TNF-R55 via the death domain to ERK and cPLA(2).

Animals↗
PubMed2000

Short-course antibiotic treatment of 4782 culture-proven cases of group A streptococcal tonsillopharyngitis and incidence of poststreptococcal sequelae.

A large-scale study with a 1-year follow-up was performed to compare 10 days of penicillin V with a short-course treatment (5 days) of other oral antibiotics in the treatment of group A beta-hemolytic streptococcus (GABHS) tonsillopharyngitis, to evaluate the efficacy and the incidence of poststreptococcal sequelae. The clinical response rates after completion of therapy were 94.5% in the 5-day group and 93.4% in the penicillin group (P<.001, equivalence test). The GABHS eradication rates were 83.3% in the 5-day group and 84.4% in the penicillin group (P=.022, equivalence test). Poststreptococcal sequelae were rare (5 patients) and did not occur in the context of this study. The efficacy of 5-day antibiotic regimens was equivalent to 10 days of penicillin V, but resolution of clinical symptoms was faster in the 5-day group (P<.001, Fisher's exact test). Recurrent tonsillopharyngitis occurs more frequently after treatment with penicillin (P=.03, Fisher's exact test).

Adolescent↗
PubMed2000

Simultaneous cytofluorometric measurement of phagocytosis, burst production and killing of human phagocytes using Candida albicans and Staphylococcus aureus as target organisms.

OBJECTIVE: Polymorphonuclear leukocytes (PMN) play a central role in the elimination of most extracellular pathogens, and an impairment of their functions predisposes an individual towards local and systemic bacterial and fungal infections. Here we describe a rapid and easy-to-perform cytofluorometric assay for investigation of PMN activity using Candida albicans and Staphylococcus aureus as target organisms. METHODS: Phagocytes were stained with anti-CD13-RPE antibody, and microorganisms were stained with calcein-AM. Oxidative burst production was measured by oxidation of dihydroethidium. The percentage of killed target organisms after ingestion was determined by staining with ethidium-homodimer-1 after lysis of human cells. The dyes and procedures used in this method were chosen after comparison of different stains and cell preparation techniques described in previous assays. RESULTS: Concerning phagocytosis, the percentages of active phagocytes and of ingested microorganisms were determined. Furthermore, the method allowed measurement of the resulting percentage of PMNs producing respiratory burst, and of the percentage of killed microorganisms. We minimized artifactual changes, which might have been the reason for the difficulties and conflicting results of other cytofluorometric methods. CONCLUSIONS: The described method provides a new whole blood cytofluorometric assay, which combines rapid and simple handling with high reproducibility of results obtained by investigation of PMN activity using Candida albicans and Staphylococcus aureus as target organisms.

Adult↗
PubMed2000

Comparison of short-course (5 day) cefuroxime axetil with a standard 10 day oral penicillin V regimen in the treatment of tonsillopharyngitis.

Oral penicillin V given three times daily in doses of 50,000-100,000 IU daily has been the standard treatment for tonsillopharyngitis for the last few decades. These regimens, initially recommended by the American Heart Association, were extrapolated from i.v. dosing with long-acting forms of penicillin which had been shown to prevent post-streptococcal sequelae. More recently, several antibiotics, including cefuroxime axetil, have been shown to be at least as effective as penicillin G in eradicating group A beta-haemolytic streptococci (GABHS) but their influence on post-streptococcal sequelae has never been assessed in a large-scale trial. The German Society for Pediatric Infectious Diseases (DGPI) undertook a large study of culture-proven tonsillopharyngitis involving several agents and included a 1 year follow-up to establish the effect on sequelae. In one arm of this study, cefuroxime 250 mg bid was compared with 50,000 IU penicillin V given in three divided doses. Cefuroxime axetil was more effective than oral penicillin V in eradicating GABHS at the assessment 2-4 days post-treatment (441/490 (90%) patients versus 1196/1422 (84%) patients; P = 0.001). Clinically, the two agents were equivalent in efficacy, and carriage rates were similar (11.1% and 13.8%, respectively) in patients receiving cefuroxime axetil and penicillin V, 7-8 weeks post-treatment. One case of glomerular nephritis occurred in a patient given penicillin V. There were no post-streptococcal sequelae confirmed for patients treated with cefuroxime axetil. The findings confirm the previously reported efficacy of short-course (4-5 day) treatments with cefuroxime axetil and indicate that short-course treatment is comparable to the standard oral penicillin V regimen in preventing post-streptococcal sequelae.

Adenoids↗
PubMed2000

An analysis of an inflammatory bowel disease practice in an urban community hospital.

OBJECTIVES: To review an individual community gastroenterologist's experience with inflammatory bowel disease (IBD). The aspects studied were distribution of disease, need for hospital admission, immunosuppressants, systemic steroids, and surgery and its indications. The incidence of cancer was also reviewed. PATIENTS AND METHODS: The charts of all IBD patients (n=373) seen between 1993 and 1996 by an individual gastroenterologist in an urban community hospital were reviewed for the aforementioned information. Patients seen during this period may have been diagnosed with IBD before or during the period of 1993 to 1996. RESULTS: Of the 373 patients, 219 had Crohn's disease (CD) and 154 had ulcerative colitis (UC). The most common age of onset for both groups was 20 to 29 years. Distal UC and distal Crohn's colitis patients rarely required surgery, hospitalization, systemic steroids or immunosuppressants. Eighty per cent of patients with small bowel CD and 51% of those with ileocolonic CD required at least one operation. Of the UC patients, 10.4% required surgery. Of the UC patients undergoing surveillance for cancer, none developed cancer but one developed significant dysplasia. CONCLUSIONS: In both CD and UC the site of the inflammation plays a major role in determining the need for hospitalization, surgery, systemic steroids and immunosuppressants. Distal UC, the most common form of UC in this group of patients, is a very benign disease. Of all forms of IBD, small bowel CD had the greatest need for hospitalization, surgery and systemic steroids.

Adult↗
PubMed2000

The management of bacterial infections of the upper respiratory tract in children: pharyngitis and otitis media.

Despite changes in the activities of infectious microorganisms, particularly variations in their prevalences in different parts of the body, in clinically defined diseases, and in their susceptibilities to antibiotics, the established first-line agents for the empiric treatment of otitis media and pharyngitis are still valid. Nevertheless, a number of the newer antimicrobials have become valuable as second- and third-line medications when the first-choice drugs fail or are contraindicated. In terms of fundamental principles, the question of whether pharyngitis in children warrants routine antibiotic therapy remains unresolved; in practical terms, antibiotic treatment should be considered routinely.

Anti-Bacterial Agents↗
PubMed2000

Short-course antibiotic therapy for infections with a single causative pathogen.

Studies evaluating short-course therapy have focused on prevalent infections with demonstrable aetiology. Metaanalyses of clinical trials demonstrate that uncomplicated acute otitis media in children can be successfully treated with a 5-day course of cefuroxime axetil. In the treatment of tonsillopharyngitis, 4 - 5-day courses of oral cephalosporins compared favourably with the standard 10-day penicillin V regimen. The clinical cure rate and the bacteriological eradication rate were both significantly higher for cephalosporins than for penicillin V. Bacteriological failure rates for cephalosporins were about half those for penicillin. In studies on acute bacterial exacerbations of chronic bronchitis, no difference in the clinical cure rates or relapse rates was found between short-course therapy using cephalosporins and standard courses. The short courses had the advantage of improved gastrointestinal tolerance compared with longer durations of treatment. The results suggest that new short-course dosing regimens are viable and may be favourable in terms of increased tolerability, reduction in healthcare costs, enhanced patient compliance and the control of the development of antibiotic resistance.

Anti-Bacterial Agents↗
PubMed1999

Inhibition of receptor internalization by monodansylcadaverine selectively blocks p55 tumor necrosis factor receptor death domain signaling.

The 55-kDa receptor for tumor necrosis factor (TR55) triggers multiple signaling cascades initiated by adapter proteins like TRADD and FAN. By use of the primary amine monodansylcadaverine (MDC), we addressed the functional role of tumor necrosis factor (TNF) receptor internalization for intracellular signal distribution. We show that MDC does not prevent the interaction of the p55 TNF receptor (TR55) with FAN and TRADD. Furthermore, the activation of plasmamembrane-associated neutral sphingomyelinase activation as well as the stimulation of proline-directed protein kinases were not affected in MDC-treated cells. In contrast, activation of signaling enzymes that are linked to the "death domain" of TR55, like acid sphingomyelinase and c-Jun-N-terminal protein kinase as well as TNF signaling of apoptosis in U937 and L929 cells, are blocked in the presence of MDC. The results of our study suggest a role of TR55 internalization for the activation of select TR55 death domain signaling pathways including those leading to apoptosis.

Antigens, CD↗
PubMed1998

Pharyngo-laryngeal histoplasmosis: one case in an immunocompetent child.

We report a very rare case of disseminated pharyngo-laryngeal histoplasmosis with systemic spread in a 10-year-old, immunocompetent child from Guyana. The main signs were a marked deterioration in his general condition, hepato-splenomegaly, multiple lymphadenopathy and ulcerated pharyngo-laryngeal lesions. The diagnosis was made from brushings of the ulcerative lesions, a lymph node biopsy and serological tests performed in the national reference center for histoplasmosis. The initial treatment was with amphotericin B, which was then replaced by oral itraconazole. We report here the main epidemiological, clinical and therapeutic characteristics.

Amphotericin B↗
PubMed1998

Induction of stress-activated protein kinases/c-Jun N-terminal kinases by the p55 tumour necrosis factor receptor does not require sphingomyelinases.

Ceramide has been implicated in the activation of stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK). Binding of tumour necrosis factor (TNF) to its 55 kDa receptor (TR55) leads to the generation of ceramide through activation of either acid or neutral sphingomyelinase (A/N-SMase) as well as to potent activation of SAPK/JNK. We have examined a putative role of both N- and A-SMase in the TR55-dependent activation of SAPK/JNK. The analysis of TR55 deletion mutants expressed in 70Z/3 pre-B cells revealed that activation of SAPK/JNK occurs independently of N-SMase. Although both SAPK/JNK and A-SMase are activated by the death domain of TR55, pharmacological prevention of the TR55-dependent activation of A-SMase, or proteolytic degradation of A-SMase in 70Z/3 cells, did not impair SAPK/JNK activation, indicating that SAPK/JNK are not secondary to A-SMase. In addition, proteolytic degradation of A-SMase also did not affect SAPK/JNK activation by ultraviolet (UV-C) irradiation, arguing against a general role of A-SMase in stress-mediated responses. Furthermore, fibroblasts from Niemann-Pick A patients deficient in A-SMase did not show altered activation of SAPK/JNK in response to either TNF or UV-C. These results suggest that TR55 can activate SAPK/JNK without direct participation of sphingomyelinases or ceramide.

Animals↗
PubMed1998

Distinct adapter proteins mediate acid versus neutral sphingomyelinase activation through the p55 receptor for tumor necrosis factor.

Ceramide, generated by the enzymatic function of sphingomyelinases (SMases) has emerged as an important signaling pathway transducing diverse biological effects of various cytokine receptors. The 55-kDa receptor for tumor necrosis factor (TNF-R55) activates two types of SMases through distinct cytoplasmic domains. The death domain that is responsible for the initiation of the apoptotic pathway also signals for the activation of an acid SMase (A-SMase). The adapter protein TRADD binds to TNF-R55 in a ligand-dependent manner and serves as anchor for the subsequent recruitment of other proteins into the signaling complex that directly lead to cell death or nuclear factor-kappaB (NF-kappaB) induction. Notably, the two pro-apoptotic adapter proteins TRADD and FADD are also involved in the activation of A-SMase. In contrast, the NF-kappaB-inducing adapters TRAF2 and RIP do not signal for A-SMase. Thus, activation of A-SMase appears to belong to signals leading to TNF-induced cell death. A second signaling domain (NSD) is located upstream of the death domain and directly links the TNF-R55 to the activation of a neutral SMase (N-SMase). A novel adapter protein, FAN, has been identified that specifically binds to the NSD. FAN contains five WD repeats at its carboxy terminus, while it shows significant sequence homology with the mouse beige protein and its human homolog, the CHS protein, in the center portion of the protein. Overexpression of full-length FAN enhanced N-SMase activity in TNF-treated cells, whereas truncated mutants of FAN produced dominant negative effects. FAN, however, did not interfere with any of the TNF responses signaled for by the death domain. Taken together, our data suggest that distinct cytoplasmic domains of TNF-R55 initiate independent signaling pathways by binding different adapter proteins.

Adaptor Proteins, Signal Transducing↗