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Biomedical subjects

W Khan

Publications and source records attributed to W Khan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Expression of heat shock protein 27 in adult human third molar dental pulp.

This study is the first to define the expression of hsp 27 in the pulp of the adult human third molar. Using a monoclonal antibody against human hsp 27, immunoreactivity was demonstrated in the odontoblasts, odontoblast processes, pulp fibroblasts, and smooth muscle and endothelial cells of vessel walls. Nerves were negative. Pulp fibroblasts were characterized by cytoplasmic staining and variable nuclear staining. Odontoblasts also displayed consistent cytoplasmic staining and variable nuclear staining. Western, Northern, and RT-PCR analysis confirmed the expression of hsp 27 mRNA and protein. Hsp 27 was also shown to be present in both the unphosphorylated and phosphorylated isoforms. In general, nuclear localization and phosphorylation of hsp 27 has been correlated with cells responding to stress or other stimuli. This study demonstrates that pulp from a single human third molar provides sufficient material to support a detailed molecular analysis of gene expression.

Adult↗
PubMed1995

Stem cell factor enhances the survival of murine intestinal stem cells after photon irradiation.

Recombinant rat stem cell factor (SCF) has been shown to decrease lethality in mice exposed to total-body irradiation (TBI) in the lower range of lethality through radioprotection of hematopoietic stem cells and acceleration of bone marrow repopulation. This study evaluates the effect of SCF on the survival of the intestinal mucosal stem cell after TBI. This non-hematopoietic stem cell is clinically relevant. Gastrointestinal toxicity is common during and after abdominal and pelvic radiation therapy and limits the radiation dose in these regions. As observed with bone marrow, the administration of SCF to mice prior to TBI enhanced the survival of mouse duodenal crypt stem cells. The maximum enhancement of survival was seen when 100 micrograms/kg of SCF was given intraperitoneally 8 h before irradiation. This regimen increased the survival of duodenal crypt stem cells after 12.0 Gy TBI from 22.5 +/- 0.7 per duodenal cross section for controls to 30.0 +/- 1.7 after treatment with SCF (P = 0.03). The TBI dose producing 50% mortality at 6 days (LD50/6) was increased from 14.9 Gy for control mice to 19.0 Gy for mice treated with SCF (dose modification factor = 1.28). These findings demonstrate that SCF has radioprotective effects on a non-hematopoietic stem cell population and suggest that SCF may be of clinical value in preventing radiation injury to the intestine.

Animals↗
PubMed1994

Membrane filtration method for bacteriological testing of water: enhanced colony visualization and stability on purification of phenol red indicator.

Commercially-available phenol red indicator, purified by adsorption chromatography was incorporated into lauryl sulphate broth (LSB) used in the membrane filtration method for the detection of Escherichia coli and other coliform bacteria. Relative to LSB containing the impure dye or its major contaminant, the purified phenol red provided clear visualization of discrete yellow colonies observed against a white background. The colonies remained stable for at least 24 h at 25 degrees C under standard laboratory lighting conditions. This simple procedure will enhance the detection of coliforms in samples.

Color↗
PubMed1993

Cefixime vs. cefaclor in the treatment of acute otitis media in children: a randomized, comparative study.

The efficacy of cefixime was compared with that of cefaclor in the treatment of 63 patients with acute otitis media. Patients received either a single dose of cefixime (8 mg/kg/day) or 3 divided doses of cefaclor (40 mg/kg/day). On the basis of otoscopic and tympanometric results at 10 to 14 days after the start of treatment, 28 (97%) of 29 cefixime-treated patients and 25 (78%) of 32 cefaclor-treated patients had resolution of acute otitis media. The clinical cure rate associated with all organisms was 94% for cefixime (16 of 17 isolates) and 68% (13 of 19 isolates) for cefaclor. The cure rate for Streptococcus pneumoniae was 12 of 12 (100%) for cefixime and 7 of 7 (100%) for cefaclor; the cure rate for Haemophilus influenzae (which includes 2 patients with mixed infections) was 3 of 4 (75%) for cefixime and 2 of 7 (29%) for cefaclor. One clinical relapse occurred among 29 cefixime-treated patients; however, at 28 days 9 recurrences were observed. Three of 25 (9%) cefaclor-treated patients failed and 4 (13%) relapsed at 10 to 14 days, an additional 2 (10%) experienced recurrence by Day 28. Eight (28%) cefixime-treated patients experienced adverse events (7 gastrointestinal and 1 diarrhea and rash); 8 (25%) cefaclor-treated patients experienced adverse events (all gastrointestinal). Our data suggest that both at end of therapy and for 14 days thereafter, cefixime given once a day for acute otitis media is clinically equivalent to cefaclor given 3 times a day.

Acute Disease↗
PubMed1993

Electrical and freeze-fracture analysis of the effects of ionic cadmium on cell membranes of human proximal tubule cells.

We previously reported that cell cultures of human proximal tubule (HPT) cells respond to ionic cadmium in a manner consistent with well-defined Cd(2+)-elicited responses reported for in vivo systems. However, one unique finding was that the transepithelial electrical resistance and tight junction sealing strands were altered as a result of Cd2+ exposure at micromolar concentrations. These alterations are reexamined in detail in the present report to determine whether the Cd(2+)-induced alterations are specific alterations in the tight junction structure or reflect a general alteration in the cell membrane. Exhaustive analysis of tight junction sealing strands demonstrated no significant alterations due to Cd2+ exposure, even at the concentration that elicited a significant reduction in transepithelial resistance. Further analysis of intramembrane particle distribution demonstrated a significant increase in apical intramembrane particles, indicating that Cd2+ exposure altered the characteristics of the apical cell membrane. Overall, the results were consistent with evidence of Cd(2+)-induced alteration in the apical cell membrane of the HPT cell.

Cadmium↗
PubMed1993

High-dose chemotherapy-induced platelet defect: inhibition of platelet signal transduction pathways.

Patients receiving high-dose chemotherapy and autologous bone marrow transplantation acquire a platelet secretion defect. The role of chemotherapeutic agents and their metabolites in mediating this platelet defect was investigated. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), but not cyclophosphamide or cis-platinum, was found to inhibit platelet aggregation in vitro in response to activation by either ADP, thrombin, or collagen. Inhibition by BCNU was dose dependent and required preincubation of platelets with BCNU. After a 60-min preincubation, 30 microM BCNU produced 50% inhibition of platelets in platelet-rich plasma. The cyclophosphamide metabolites acrolein and 4-hydroperoxycyclophosphamide also inhibited platelet aggregation in a dose-dependent manner, with a requirement for preincubation. Platelet inhibition occurred at clinically relevant concentrations of BCNU and metabolites of cyclophosphamide. The effects of acrolein were totally prevented by coincubation with the sulfhydryl-protecting agents N-acetylcysteine and 2-mercaptoethanesulfonic acid, whereas the effects of BCNU were incompletely prevented. The mechanism of platelet inhibition was investigated next by examining protein phosphorylation in response to platelet agonists. Acrolein inhibited thrombin- and phorbol ester-induced phosphorylation of a 40-kDa polypeptide and other substrates, indicating a cellular defect in protein kinase C signaling. BCNU did not interfere with protein phosphorylation, indicating preservation of initial signaling pathways. Thus, chemotherapeutic agents and their metabolites inhibit platelet function by inhibiting distinct components of the intracellular activation pathways.

Acrolein↗
PubMed1992

Retinoblastoma protein dephosphorylation induced by D-erythro-sphingosine.

The retinoblastoma gene product (Rb), a nuclear phosphoprotein, functions as a tumor suppressor that is inactivated in retinoblastoma and other malignancies. The hypophosphorylated forms of Rb are observed in the G0/G1 phase of the cell cycle, whereas the hyperphosphorylated forms predominate in S and G2/M phases, suggesting that phosphorylation/dephosphorylation of Rb may regulate progression through the growth cycle. However, little is known about the intracellular signals that regulate phosphorylation/dephosphorylation of Rb. We show that D-erythro-sphingosine potently induces early dephosphorylation of Rb. Initial dephosphorylation was observed as early as 1 h after treatment of hematopoietic cells with sphingosine, whereas complete shift to the dephosphorylated form was seen 4 h after treatment. These effects occurred at concentrations of sphingosine as low as 100-500 nM, with maximal effects observed at 1-2.5 microM. These effects were specific to sphingosine, inasmuch as other lipids, amphiphiles, and long chain amino bases, as well as structural analogs of sphingosine, failed to induce dephosphorylation of Rb. Also, activation of second messenger systems including protein kinase C, cAMP-dependent kinases, and calcium ionophores, as well as inhibition of serine/threonine protein phosphatases, failed to induce dephosphorylation of Rb. Induction of Rb dephosphorylation by sphingosine preceded inhibition of growth and a specific arrest in the G0/G1 phase of the cell cycle. These studies, for the first time, identify an intracellular activator of Rb.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Arachidonic and cis-unsaturated fatty acids induce selective platelet substrate phosphorylation through activation of cytosolic protein kinase C.

The ability of arachidonic acid and other fatty acids to induce phosphorylation of endogenous substrates and the role of protein kinase C in mediating these effects were examined. In a cell-free cytosolic system derived from human platelets, arachidonic, oleic, and other cis-unsaturated fatty acids induced a dose-dependent phosphorylation of several endogenous substrates. These substrates form a subset of phorbol ester-induced phosphorylations. Multiple lines of evidence suggested the direct involvement of protein kinase C in mediating fatty acid-induced phosphorylations. These observations suggest that arachidonic acid and other unsaturated fatty acids are capable of activating protein kinase C in a physiologic environment resulting in the phosphorylation of multiple endogenous substrates.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Bacterial isolates in neutropenic febrile patients.

One hundred consecutive patients with documented bacteremia and neutrophil count of 0.5 x 10(9)/L or below were retrospectively studied to determine the pattern of infection at the Aga Khan University Hospital in Karachi. These included patients with primary haematologic malignancies presenting with low counts, and those patients with cancer who developed neutropenia as a result of chemotherapy. The gram negative organism pseudomonas aeruginosa was the most common bacterial organism isolated constituting 31% of all positive blood cultures. Gram positive organisms were frequently isolated comprising 24% of all isolates of which 15% were Staph.aureus. Staph. epidermidis was not isolated in this series. Salmonella species were isolated in 9 patients. The other gram negative rods included non-lactose fermenting organisms frequently isolated in a nosocomial setting including Serratia and Acinetobacter. Four patients had positive fungal blood cultures. A single positive anaerobic culture was obtained. Sensitivities of the Pseudomonas aeruginosa reflected the high frequency of resistance seen in nosocomial isolates and those from the community. More than half (54.8%) of the isolates were resistant to carbenicillin and 9.6% resistant to gentamicin. Although 3.2% were resistant to cefotaxime, none were resistant to ofloxacin or ceftazidime reflecting the relatively recent arrival of the latter. In contrast, 23% of Staph. aureus were still sensitive to penicillin. Methicillin (cloxacillin) resistant Staph. aureus did not occur. However 26.6% of the Staph. aureus were resistant to erythromycin. Knowledge of the prevailing pattern of infection permits the development of investigative and therapeutic approaches of optimal efficacy.

Developing Countries↗
PubMed1991

Diacylglycerol overcomes aspirin inhibition of platelets: evidence for a necessary role for diacylglycerol accumulation in platelet activation.

Aspirin, an inhibitor of cyclooxygenase, inhibits platelet aggregation in response to many stimuli. Previous studies suggested an important and necessary role for protein kinase C (PKC) in platelet aggregation and secretion. Therefore, the effects of aspirin on sn-1,2-diacylglycerol (DAG), the endogenous activator of PKC, were investigated. Specifically, we sought to determine whether inhibition of DAG production is critical for aspirin action on platelets. Total DAG mass was measured using the DAG kinase assay. At low doses of gamma-thrombin (4 nM), aspirin (5 mM) completely inhibited secondary aggregation; this inhibition was associated with near-complete inhibition of DAG production. Inhibition of collagen-induced aggregation by aspirin (50 microM) was also associated with complete inhibition of collagen-stimulated DAG production and secondary aggregation. Concomitantly, aspirin reduced phosphorylation of the 40-kDa protein, a specific PKC substrate strongly suggesting inhibition of PKC in response to aspirin. To determine the physiologic significance of the inhibition of DAG production by aspirin, reconstitution studies were conducted with dioctanoylglycerol (diC8), a cell-permeable DAG. Under conditions in which aspirin completely inhibited secondary aggregation induced by gamma-thrombin, collagen, or arachidonic acid, diC8 overcame aspirin inhibition of agonist action and reconstituted secondary aggregation. DiC8 exerted these effects at low concentrations (2-3 microM), which caused minimal aggregation of control platelets. Phorbol 12,13-dibutyrate, a phorbol ester that directly activates PKC, mimicked the effects of diC8 in overcoming aspirin inhibition of collagen-induced platelet activation. However, subthreshold concentrations of the calcium ionophore ionomycin, arachidonic acid, or gamma-thrombin were unable to overcome aspirin inhibition of collagen-induced platelet aggregation, suggesting that the ability to overcome aspirin inhibition is not shared by other second messengers and is not due to nonspecific synergy. These studies constitute evidence that inhibition of DAG production and subsequent PKC activation are crucial to the antiaggregatory effects of aspirin. They also support the hypothesis that DAG production and PKC activation may be the final common pathway for induction of secondary aggregation.

Aspirin↗
PubMed1990

Regulation of platelet protein kinase C by oleic acid. Kinetic analysis of allosteric regulation and effects on autophosphorylation, phorbol ester binding, and susceptibility to inhibition.

The regulation of protein kinase C by oleic acid was studied, and parameters that characterize the activation of protein kinase C by oleic acid and distinguish its effects from those of diacylglycerol (DAG) and phosphatidylserine (PS) were delineated. Activation of protein kinase C by sodium oleate required the presence of calcium and showed mild cooperative behavior (Hill number of 1.25) suggesting that Ca(oleate)2 is the active species. Kinetic analysis of the interaction of sodium oleate with substrates indicated that sodium oleate acted to increase the activity of the enzyme without modulating the KM for either MgATP or histone substrates. In this respect, sodium oleate action resembled that of DAG but not PS. However, multiple parameters distinguished the effects of sodium oleate from those of DAG. Unlike DAG, sodium oleate was unable to inhibit phorbol dibutyrate binding to protein kinase C. Sodium oleate also failed to interact with micelle-bound protein kinase C and preferentially activated "soluble" protein kinase C. The addition of histone caused protein/lipid aggregation in the presence of DAG but not in the presence of oleate. Activation of protein kinase C by sodium oleate or by PS/DAG demonstrated differential susceptibility to the action of inhibitors. Sphingosine and NaCl were more potent in inhibiting activation of protein kinase C by PS/DAG than by sodium oleate. Sodium oleate also expressed PS-like activity in that calcium and oleate acted as cofactors in activation of protein kinase C by DAG. Similar to PS, the ability of oleate to act in synergy with DAG resulted from "competitive" activation with a decrease in KM(app) of protein kinase C for DAG. Finally, sodium oleate was unable to induce autophosphorylation of protein kinase C. These studies demonstrate that oleate activates protein kinase C by a mechanism that is distinct from PS/DAG but partially overlaps the kinetic effects of both PS and DAG. The significance of these studies is discussed in relation to mechanisms of protein kinase C activation and to the possible physiological relevance of activation of protein kinase C by fatty acids.

Adenosine Triphosphate↗
PubMed1985

Diagnostic ultrastructural markers in alveolar cell carcinoma.

Two, difficult-to-diagnose cases of metastatic alveolar cell carcinoma were examined with the electron microscope. In the first case, the prominent feature was the occurrence of intranuclear tubular inclusions and the rare occurrence of surfactant-like material between tumour cells. Only after a prolonged search in sections from several blocks were typical neoplastic type II alveolar cells with secretory granules containing myelin figures (myelinosomes) found and the diagnosis of alveolar cell carcinoma established. In the second case, the tumour cells contained single-membrane-bound bodies enclosing material resembling pulmonary surfactant. Here also, after much searching, rare cells containing myelinosomes resembling those found in type II alveolar cells were found and the diagnosis of alveolar cell carcinoma established. The value of these various markers (myelinosomes, intranuclear tubular inclusions and surfactant-like material) in establishing the diagnosis of alveolar cell carcinoma with the electron microscope are reviewed and discussed.

Aged↗
PubMed1979

The nasopharyngeal culture in acute otitis media. A reappraisal of its usefulness.

Simultaneous cultures of the nasopharynx and middle ear exudate (obtained by tympanocentesis) were obtained from 225 children (mean age, 34 months; median age, 41 months) with suppurative otitis media. A 72% prediction rate for middle ear pathogens was obtained by examining the nasopharyngeal cultures after the strict observance of two essential prerequisites: (1) the nasopharyngeal culture was immediately plated on appropriate solid agar and (2) a semiquantitative method for bacterial enumeration was employed in the reading of the nasopharyngeal culture plates. The technique was most valuable where 2+ (greater than 25% up to 50% of total number of colonies was a single pathogen) or greater of a single pathogen was recovered from the nasopharynx. In only one instance, the semiquantitative nasopharyngeal culture incorrectly predicted the middle ear pathogen if one was recovered. Quantitative nasopharyngeal cultures were particularly useful in predicting the presence of ampicillin-resistant Haemophilus influenzae and group A streptococci as causative agents in otitis media.

Acute Disease↗
PubMed1979

Cefaclor in the treatment of susceptible infections in infants and children.

Cefaclor is a new oral cephalosporin with in vitro activity against a wide variety of organisms including S. aureus, S. pneumoniae, S. pyogenes and H. influenzae (including ampicillin-resistant strains). Seventy-nine patients ranging in age from 2 months to 14 years with soft tissue infections (17 cases), otitis media (17), and streptococcal pharyngitis (45) were studied. They received cefaclor orally at a dose of 40 mg/kg per day in three or four divided doses for a minimum of five days. Results were generally good with favourable clinical and bacteriological responses obtained in 90% of cases. Most patients became afebrile within 48 hours after starting cefaclor. Two patients with H. influenzae cellulitis and bacteraemia defervesced within 24 hours and their blood cultures became negative promptly. Hepatic, renal and haematopoietic studies showed no adverse reactions except for an occasional increase in the eosinophil count with no clinical counterpart of hypersensitivity. Pharmacokinetic studies revealed that following a 10 mg/kg oral dose, peak serum levels of 8 micrograms/ml were observed at one hour, followed by a rather rapid tapering off so that at the end of four hours, virtually no cefaclor was detectable in serum.

Adolescent↗
PubMed1978

The increasing incidence of Ampicillin-resistant Haemophilus influenzae. A cause of otitis media.

Middle ear exudate was obtained by myringotomy or aspiration from 625 suburban children, aged 1 month to 12 years, who had acute otitis media; bacterial pathogens were isolated from 71%. Haemophilus species were isolated from 212 (29%), and Streptococcus pneumoniae from 205 (28%). From 1975 to August 1977, the number of Haemophilus isolates found to be resistant to ampicillin has appreciably increased. Currently, 8% of all cases of acute otitis media in the Washington, DC, area are due to H influenzae resistant to ampicillin. Thirty-one of 35 patients with resistant H influenzae otitis were treated with an erythromycin/sulfisoxazole combination with an impressive clinical response. Twenty-six of these 31 cases had failed to have H influenzae eradicated by an average of ten days of oral ampicillin in recommended doses.

Acute Disease↗
PubMed1978

Gingivitis and cellulitis in diffuse pneumococcal infection.

Gingivitis occurring with a cystic lesions in young patients with facial cellulitis is highly suggestive of a pneumococcal etiology. Two cases of pneumococcal cellulitis and gingivitis with bacteremia are reported, and the pertinent literature is reviewed.

Cellulitis↗
PubMed1977

Clindamycin in the treatment of osteomyelitis in children: a report of 29 cases.

Clindamycin phosphate was used in the treatment of 29 children with osteomyelitis of whom 25 had an acute and four a chronic type of infection. The usual dose was 50 mg/kg/day intravenously for approximately three weeks followed by oral clindamycin palmitate at home in a dose of 30 mg/kg/day for an additional six weeks. Staphylococcus aureus was isolated in 22 of 29 cases: 96% of strains were penicillin resistant. The clinical and bacteriologic results in the present series were good to excellent. There was prompt clinical and bacteriologic response shortly after initiation of clindamycin therapy. Good bone penetration of the drug was observed. Long-term evaluation revealed satisfactory clinical and roentgenographic progress in all patients. No diarrhea or manifestations of enterocolitis appeared in any patient in spite of high doses of the drug for intervals up to nine weeks.

Acute Disease↗