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Biomedical subjects

M U Rahman

Publications and source records attributed to M U Rahman.

At least 19 recordsLinked to original sources
PubMed2001

Autoimmune vestibulo-cochlear disorders.

Autoimmune vestibulo-cochlear disorders (AVCD) represent a group of syndromes with overlapping clinical features, manifesting as sensorineural hearing loss, often associated with vertigo, tinnitus, and aural fullness, and believed to be caused by an autoimmune mechanism. Although definitive evidence of a classic "autoimmune process" is still lacking, substantial indirect evidence has accumulated to strongly indicate such a pathogenesis. Rapidly progressing AVCD is analogous to rapidly progressive glomerulonephritis in that inner ear inflammation progresses to severe, irreversible damage within 3 months of onset (and often much more quickly). Thus patients with rapidly progressive AVCD are treated with a sense of urgency. Prompt treatment with corticosteroids and other antirheumatic/immunosuppressive agents can preserve hearing and vestibular functions. We are not aware of any randomized controlled clinical trials evaluating the efficacy of antirheumatic/immunosuppressive agents in AVCD. In this article we review reports of various therapies that have been tried in this condition and our experience of etanercept therapy in AVCD.

Antirheumatic Agents↗
PubMed2001

Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study.

OBJECTIVE: Immune-mediated cochleovestibular disorders (IMCVDs) continue to present a management challenge to the otolaryngologist. Antirheumatic agents, commonly used for IMCVDs, are associated with variable efficacy and sometimes with serious side effects. The authors describe the preliminary result of their experience in patients with IMCVDs who have been treated with etanercept, a tumor necrosis factor alpha receptor blocker, recently approved by the United States Food and Drug Administration for the treatment of rheumatoid arthritis. STUDY DESIGN: Retrospective case series. SETTING: Tertiary care hospital. PATIENTS: Twelve patients suspected of having IMCVD who did not respond to conventional therapies or experienced side effects of the conventional therapies. INTERVENTION: Etanercept 25 mg by subcutaneous injection twice per week. MAIN OUTCOME MEASURES: The main outcome measurement was assessment of hearing change by air conduction pure tone audiograms and/or word discrimination. When present, vertigo, tinnitus, and aural fullness were assessed as well. RESULTS: Follow-up of more than 5 months was available for all patients (range, 5-12 months). Eleven (92%) of 12 patients had improvement or stabilization of hearing and tinnitus, seven (88%) of eight patients who had vertigo and eight (89%) of nine patients who had aural fullness had resolution or significant improvement of their symptoms. The benefit persisted until the last visit (5-12 months after etanercept was begun). The condition of one patient improved dramatically at first but deteriorated after 5 months. The patient's hearing was rescued and stabilized with the addition of leflunomide to etanercept. Similarly, three other patients required a second antirheumatic agent to stabilize their hearing. There were no significant side effects from the etanercept therapy. CONCLUSIONS: Our limited data suggest that etanercept therapy is safe and may be efficacious in carefully selected patients with IMCVDs, at least on a short-term basis. These preliminary efficacy and safety results appear encouraging enough to warrant further follow-up and studies for better determination of the potential clinical utility of etanercept for IMCVDs.

Adult↗
PubMed2001

The immunomodulatory effects of gentamicin, imipenem, piperacillin and amphotericin B on LAK effector function in vitro.

An understanding of the immunomodulating effects of anti-microbial regimens on recombinant interleukin-2 (rIL-2) induced peripheral leukocyte function, i.e. lymphokine-activated killer (LAK)-cell efficacy, would be clinically useful in the selection of commonly employed bone marrow transplantation (BMT) antibiotics to avoid post-transplant complications and optimize anti-microbial, anti-viral, anti-tumor therapies. In this report we evaluated the modulatory effects of a number of antibiotics used in BMT on LAK-cell cytotoxicities, in vitro. Our data showed that, even at serum trough titer, amphotericin B was significantly (P < or =0.05) immunostimulatory, whereas gentamicin, imipenem, and piperacillin, individually, were significantly (P < or =0.05) immunosuppressive. Statistical analysis detected no modulation due to aztreonam, amikacin, cotrimoxazole, or ceftazidime, or any of the six cephalosporins tested at molar equivalent concentration. We conclude that certain antibiotics may be more suitable for infection prone BMT hosts.

Adjuvants, Immunologic↗
PubMed2000

Rapid communication: Cervical Chlamydia trachomatis in women at low risk for infection.

BACKGROUND: Evidence suggests that the bacterium Chlamydia trachomatis can cause asymptomatic genital infection in persons at risk for acquisition of the organism. We employed 2 independent molecular screening systems to assess such inapparent cervical chlamydial infections in low-risk female patients attending general (non-STD) clinics in 2 locations. METHODS: Three hundred seventy-five cervical swab samples were obtained in duplicate from patients attending a general women's clinic (278 samples) and a colposcopy clinic (97 samples). One set of samples from the general clinic was screened by a highly-specific molecular hybridization system, using a probe targeting the chlamydial 16S ribosomal RNA; the other set was screened with the use of the Chlamydiazyme test. Samples from the colposcopy clinic were screened using a sensitive and specific polymerase chain reaction (PCR) assay system targeting chlamydia; the duplicates were assayed by direct fluorescent antibody assay (DFA). RESULTS: Of the 278 patients screened by RNA-directed hybridization, 6.5% were positive for C. trachomatis, in contrast to screening of duplicate samples via Chlamydiazyme, which indicated that 3.6% were infected. PCR-based screening of the additional 97 patients gave a positivity rate of 17.5% for the organism, whereas DFA on duplicate samples from this group showed only 7.5% positive. CONCLUSIONS: These observations suggest that the level of asymptomatic cervical C. trachomatis infection is significant even in women who are at low risk for such infections; the data also indicate that results from standard laboratory screening for chlamydia should be viewed with caution.

Adolescent↗
PubMed1996

A probable cis-regulatory element on yeast mitochondrial DNA responsible for cAMP-mediated transcription.

Studies from this laboratory have suggested that mitochondrial (mt) transcription in yeast (Saccharomyces cerevisiae) is governed by changing cellular cAMP levels, and that the mechanism of such transcriptional regulation requires cAMP-dependent protein kinase (PKA) activity; these observations, in turn, suggest a trans-activation process for nucleotide-dependent mt transcriptional control. Here we demonstrate a sequence-specific mtDNA-phosphorylated protein interaction, a requisite part of such a control mechanism, using filter-binding and gel mobility shift assays with mt protein extracts and mtDNA from rho- strains whose retained mt genes show cAMP-sensitive expression. We demonstrate that the protein-mt DNA interaction depends on PKA activity, that it specifically involves a tripartite GC-rich sequence element on yeast mtDNA, and that it does not involve mt coding or promoter sequences. Sequence analysis indicates that the GC-rich element undergoing protein interaction is present in ten copies on the yeast mt genome, and that each copy is located 5' to a strong mt promoter; the elements appear in both orientations relative to, and at varying distances upstream from, the putatively associated mt promoter elements. The mt element shows no sequence homology to relevant nuclear cis-elements examined and is unrelated to published vertebrate mt cis-elements. Several lines of evidence and argument strongly suggest that this GC-rich element functions as the cis-regulatory sequence involved in cAMP-mediated transcriptional control in yeast mitochondria.

Cyclic AMP↗
PubMed1996

Identification of a cAMP-dependent protein-DNA interaction at a sequence near the yeast mitochondrial rRNA genes.

We have shown that expression of yeast mitochondrial (mt) rRNA genes (S. cerevisiae) is controlled in a cAMP-dependent manner via PKA, suggesting a trans-activation process involving phosphorylation-dependent protein-mt DNA interaction. We used filter-binding assays, mt protein extracts, and mt DNA from a rho-mutant strain retaining the 21S rRNA gene to demonstrate such an interaction. Competition assays with the cloned 21S-related mt DNA fragment undergoing interaction showed that a sequence in that fragment is present in mt DNA from a rho-strain retaining the 16S mt rRNA gene, but not in a VAR1-retaining rho-strain that lacks cAMP-mediated mt transcription. The sequence of the 21S-related mt DNA fragment undergoing protein interaction includes a GC cluster; that GC cluster sequence is also present near the 16S gene but not near VAR1. These and other data are consistent with a role for the GC cluster in cAMP-mediated expression of mt rRNA genes.

Cyclic AMP↗
PubMed1995

Substrates for yeast mitochondrial cAMP-dependent protein kinase activity.

We showed that transcription of mitochondrial (mt) genes in Saccharomyces cerevisiae is governed in part by cellular cAMP levels, and that such transcriptional control is mediated via cAMP-dependent protein kinase (cAPK) activity. Here we use in vitro protein kinase assays with intact mitochondria from respiring cells to define protein substrates for mt cAPK. Our data show that there are at least eight mt proteins phosphorylated in a cAMP-dependent manner, ranging in M(r) from 96000 to 9500. Similar assays with organelles from an mtf1 mutant and its wild-type parent strain show no loss of any mt cAPK target proteins, suggesting that Mtflp (M(r) = 40000), the mt RNA polymerase specificity factor, does not require phosphorylation for activity. We further show, using double mutants for TPK1, TPK2, and TPK3, which encode catalytic subunits of the mt cAPK, that each of the eight mt substrate proteins is not phosphorylated equivalently by the individual catalytic subunits.

Cyclic AMP-Dependent Protein Kinases↗
PubMed1995

Nature and transcriptional role of catalytic subunits of yeast mitochondrial cAMP-dependent protein kinase.

We have shown that mitochondrial (mt) transcription in yeast (S. cerevisiae) is governed in part by cAMP via a mt cAMP-dependent protein kinase (cAPK), and that the BCY1 gene product acts as regulatory subunit for that organellar enzyme, as it does for cytoplasmic cAPK. Here we assess mt cAPK activity and mt transcription in mutants for the TPK1, TPK2, and TPK3 genes, which encode catalytic subunits of cytoplasmic cAPK. Protein extracts from purified mitochondria from each of the three possible double TPK mutants show mt cAMP-dependent protein phosphorylation. Relative mt transcript levels in these mutants, however, suggest that TPK2 functions less well than does TPK1 or TPK3 in organellar transcriptional control. Thus, both mt and cytoplasmic cAPKs employ the same species of regulatory and catalytic proteins, and versions of the enzyme having various combinations of catalytic species function differentially in cAMP-dependent mt transcriptional control.

Cyclic AMP-Dependent Protein Kinases↗
PubMed1994

Regulation of mitochondrial cAMP-dependent protein kinase activity in yeast.

We have shown that transcription of the yeast (S. cerevisiae) mitochondrial (mt) genome is cAMP-sensitive, via a mt cAMP-dependent protein kinase (cAPK). In relation to that work, we examined whether the BCY 1 gene product functions as regulatory subunit for mt cAPK, as it does for the cytoplasmic enzyme. We demonstrate that mt protein extracts from a bcy 1 strain show no cAPK activity, whereas similar extracts from an otherwise isochromosomal BCY 1 strain show high levels of such activity. Partial purification of mt cAPK from each strain confirms this difference. Photoaffinity labeling with 8-N3[32P]cAMP and highly-purified mt protein extracts from the BCY 1 strain identifies one cAMP-binding protein (M(r) approximately 47000), while similar mt extracts from the bcy 1 strain lack all cAMP-binding proteins. These data suggest that BCY 1 regulates yeast mt cAPK, and that inactivation of BCY 1 removes that mt activity from cAMP control.

Affinity Labels↗
PubMed1993

Transcription of the yeast mitochondrial genome requires cyclic AMP.

Using various mutant strains and nutritional manipulations, we investigated a potential role for cyclic AMP (cAMP) in the regulation of mitochondrial (mt) gene expression in the yeast Saccharomyces cerevisiae. In RAS mutants known to have either abnormally low or high cellular levels of this nucleotide, we show that both mt transcription rate and overall mt transcript levels vary directly with cellular cAMP levels. We further show that nutritional downshift of actively growing cells causes a severe, rapid fall in cAMP levels, and that this fall is concomitant with the stringent mt transcriptional curtailment that we and others have previously shown to follow this nutritional manipulation. In in vitro mt transcription assays using intact organelles from downshifted and actively growing cells, stringently curtailed mt gene expression can be restored to 75% of control levels by addition of cAMP to the assay mix. Consistent with these observations a RAS2vall9 mutant strain, which cannot adjust cAMP levels in response to external stimuli, shows no mt stringent response following nutritional downshift. We also demonstrate a significant but transient increase in both mt transcript levels and mt transcription rate following shift of actively respiring wild-type cells to glucose-based medium, a manipulation known to cause a short-lived pulse of cAMP in yeast; similar manipulation of the RAS2vall9 mutant strain generates no such response. Taken together all these observations indicate that cellular cAMP levels are involved in the regulation of mt transcription in yeast. Moreover, the lack of a mt stringent transcriptional response following downshift in a strain in which the BCY1 gene had been insertionally inactivated suggests that cAMP may influence mt transcription via a mt cAMP-dependent protein kinase. These results link mt gene expression with mechanisms governing growth control and nutrient adaptation in yeast, and they provide a means by which mt gene expression might be coordinated with that of related nuclear genes.

Cyclic AMP↗
PubMed1992

Molecular evidence for the presence of chlamydia in the synovium of patients with Reiter's syndrome.

OBJECTIVE: There is much evidence indicating that chlamydial antigens in the synovium may be critical in the pathogenesis of Reiter's syndrome (RS), but it is not known whether intact organisms are present in that tissue in any stage of the disease. The present study was undertaken to begin to address this question. METHODS: We used a highly specific and sensitive molecular hybridization screening system which detects chlamydial RNA, to examine synovial biopsy samples from 22 patients with various arthropathies, including 9 with RS. RESULTS: Seven of the 9 RS patients were positive for chlamydial RNA, while 3 of the 13 non-RS patients were also positive; positive results in the non-RS patients probably indicate the actual presence of the organism, since these patients had arthritis that was otherwise incompletely explained. CONCLUSION: The detection of chlamydial RNA, in combination with previous findings of chlamydia-like particles and/or chlamydial antigens in the synovium of RS patients, suggests that whole bacterial cells are present in that tissue.

Adolescent↗
PubMed1992

Recognition of heterogeneous lymphokine-activated killer (LAK) receptors on Kaposi's sarcoma cells, endothelial cells, and monocytes/macrophages: evidence of distinct LAK-cell antigen on Kaposi's sarcoma cells--potential for use of LAK cells for immunotherapy.

The purpose of this study was to determine the potential use of lymphokine-activated killer (LAK) cells against Kaposi's sarcoma (KS) cells. We used chromium release cold-target inhibition assay for understanding the expression of heterogeneous LAK-cell antigens (Ags) on KS cells, endothelial cells (ECs), and monocytes/macrophages (M phi) which could allow for the utilization of LAK-cell immunotherapy in KS without side effects. Our data show that (i) all three cell types express the CD18 Ag of LFA-1 or Leu-CAM, (ii) rare KS cells from eyes cannot cold target-inhibit ECs, (iii) KS cells express a distinct LAK-cell Ag, which we have called LAK-KS Ag, and (iv) LAK-KS Ag allows for cold-target inhibition between different KS cells. The identification of LAK-KS Ag and a monoclonal antibody capable of inhibiting lysis of ECs and M phi without obstructing LAK-KS Ag would be important.

Antigens, CD↗
PubMed1992

Recurrent arthritis in Reiter's syndrome: a function of inapparent chlamydial infection of the synovium?

Present or prior infection with any of several common bacterial pathogens has been strongly implicated in the development of Reiter's syndrome (RS). However, because Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in the western hemisphere, this organism has emerged as a major causative agent of the disease. An important but as yet poorly understood aspect of chlamydia-related RS is the recurrence of active arthritis in the absence of any overt infection or reinfection with the organism. In this article, a large body of published clinical and experimental observations strongly suggesting that some chlamydial infections in humans can be inapparent--not detectable by standard culture or antibody-based laboratory screening methods--is reviewed. The authors' own initial molecular genetic studies, which support that contention, are summarized. Based on these data, the argument is developed that not only does inapparent chlamydial infection occur in humans, but such infections may have significant consequences in terms of the pathogenesis of RS, including the possible causation of recurrent episodes of disease in the absence of active infection. The therapeutic implications of potential inapparent chlamydial infections as they relate to RS are discussed.

Arthritis, Infectious↗
PubMed1992

Inapparent genital infection with Chlamydia trachomatis and its potential role in the genesis of Reiters syndrome.

An infectious etiology has been suggested for Reiter's syndrome (RS) because the disease has often been observed to follow episodes of urethritis or dysentery. Despite demonstrations of bacterial antigens in the synovial tissues of RS patients, it is not clear whether viable organisms are present in the synovium in any particular stage of this disease. Furthermore, it is not clear how either viable organisms or their product(s) might reach the joints. Infection with the bacterium Chlamydia trachomatis is the most common sexually transmitted disease in the United States, and as such this organism has emerged as a primary pathogen associated with RS. Previous work from our group has shown that synovial biopsy tissues from a majority of RS patients studied show significant levels of apparently intact chlamydial RNA, even when synovial or urethral cultures from the same patients are unequivocally negative for the organism. We show here that inapparent urethral infection with chlamydia occurs with high prevalence in men, and that inapparent cervical infection with the organism occurs at high prevalence in women. These data provide an important link in the relationship between initial chlamydial infection and possible subsequent genesis of RS, and they may give useful insight into mechanisms by which chlamydial infection can lead to development of this disease. Our data argue further that inapparent infection may be a significant factor in pathogenesis for all chlamydia-related diseases, and they suggest that, contrary to current ideas, C. trachomatis can generate disseminated infection.

Arthritis, Reactive↗
PubMed1992

Chlamydia and Reiter's syndrome (reactive arthritis).

The etiology of RS is not clear, but there is a strong correlation with infectious episodes and some genetic factor(s). Chlamydia have emerged as the most common pathogen associated with RS. We have presented evidence that chlamydia or its antigens may be present in the synovium and may be important in the pathogenesis of RS. The possibility of latent chlamydial infection has also been discussed. Although previous attempts to treat RS with antibiotics were not encouraging, recent reports suggest some favorable effects from antibiotic therapy. There is still a need to further assess the state of the infectious agent and to consider new, more effective regimens.

Anti-Bacterial Agents↗