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Biomedical subjects

A U Khan

Publications and source records attributed to A U Khan.

At least 19 recordsLinked to original sources
PubMed2001

A new injectable bulking agent for treatment of stress urinary incontinence: results of a multicenter, randomized, controlled, double-blind study of Durasphere.

OBJECTIVES: To assess the safety and effectiveness of Durasphere compared with bovine collagen in the treatment of stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD). METHODS: This multicenter, randomized, controlled, double-blind trial was composed of 355 women diagnosed with SUI due to ISD and used a standardized pad test and the Stamey continence grade as the primary endpoints. The participants' ages ranged from 26 to 84 years. All patients had an abdominal leak point pressure of less than 90 cm H(2)O (average 51). RESULTS: At 12 months after the first injection, the two materials were equivalent with respect to the improvement in continence grade and pad weight testing. Less Durasphere was injected to obtain comparable clinical results (Durasphere 4.83 mL versus bovine collagen 6.23 mL, P <0.001). When examined 1 year after the date of the last treatment, 49 (80.3%) of the 61 women treated with Durasphere showed improvement of 1 continence grade or more compared with 47 (69.1%) of 68 women treated with bovine collagen (P value for difference = 0.162). Although the adverse events reported for both groups were similar, the Durasphere group had an increased short-term risk of urgency and urinary retention. CONCLUSIONS: The use of Durasphere for the treatment of SUI due to ISD was equally effective as bovine collagen and used less material. The U.S. Food and Drug Administration granted market approval for Durasphere on September 13, 1999. The product design and initial clinical data suggest the potential for greater durability of the clinical benefit, with the possibility of a permanent solution for SUI due to ISD in some patients.

Adult↗
PubMed2001

A unique group of self-splicing introns in bacteriophage T4.

We describe in this review, the salient splicing features of group I introns of bacteriophage T4 and propose, a hypothetical model to fit in the self-splicing of nrdB intron of T4 phage. Occurrence of non-coding sequences in prokaryotic cells is a rare event while it is common in eukaryotic cells, especially the higher eukaryotes. Therefore, T4 bacteriophage can serve as a good model system to study the evolutionary aspects of splicing of introns. Three genes of T4 phage were found to have stretches of non-coding sequences which belonged to the group IA type introns of self-splicing nature.

Bacteriophage T4↗
PubMed2000

Chlorination of pyridinium compounds. Possible role of hypochlorite, N-chloramines, and chlorine in the oxidation of pyridinoline cross-links of articular cartilage collagen type II during acute inflammation.

Reactive oxygen species produced by activated neutrophils and monocytes are thought to be involved in mediating the loss of collagen and other matrix proteins at sites of inflammation. To evaluate their potential to oxidize the pyridinoline (Pyd) cross-links found in collagen types I and II, we reacted hydrogen peroxide (H(2)O(2)), hypochlorous acid/hypochlorite (HOCl/OCl(-)), and singlet oxygen (O(2)((1)delta g)) with the Pyd substitutes, pyridoxamine dihydrochloride and vitamin B(6), which share the same chemical structure and spectral properties of Pyd cross-links. Neither H(2)O(2) (125-500 microm) nor O(2)((1)delta g) (10-25 microm) significantly changed the spectral properties of pyridoxamine or vitamin B(6). Reaction of HOCl/OCl(-) (12.5-50 microm) with pyridoxamine at pH 7.2 resulted in a concentration-dependent appearance of two new absorbance peaks and a decrease in fluorescence at 400 nm (excitation 325 nm). The new absorbance peaks correlated with the formation of an N-chloramine and the product of its subsequent reaction with pyridoxamine. In contrast, the extent to which HOCl reacted with vitamin B(6), which lacks a primary amine group, was variable at this pH. At lysosomal pH 5.5, Cl(2)/HOCl/OCl(-) reacted with both pyridoxamine and vitamin B(6). Four of the chlorinated products of this reaction were identified by gas chromatography-mass spectrometry and included 3-chloropyridinium, an aldehyde, and several chlorinated products with disrupted rings. To evaluate the effects of Cl(2)/HOCl/OCl(-) on Pyd cross-links in collagen, we exposed bone collagen type I and articular cartilage type II to HOCl. Treatment of either collagen type with HOCl at pH 5. 0 or 7.2 resulted in the oxidation of amine groups and, for collagen type II, the specific decrease in Pyd cross-link fluorescence, suggesting that during inflammation both oxidations may be used by neutrophils and monocytes to promote the loss of matrix integrity.

Cartilage, Articular↗
PubMed2000

The decomposition of peroxynitrite to nitroxyl anion (NO-) and singlet oxygen in aqueous solution.

The mechanism of decomposition of peroxynitrite (OONO(-)) in aqueous sodium phosphate buffer solution at neutral pH was investigated. The OONO(-) was synthesized by directly reacting nitric oxide with superoxide anion at pH 13. The hypothesis was explored that OONO(-), after protonation at pH 7.0 to HOONO, decomposes into (1)O(2) and HNO according to a spin-conserved unimolecular mechanism. Small aliquots of the concentrated alkaline OONO(-) solution were added to a buffer solution (final pH 7.0-7.2), and the formation of (1)O(2) and NO(-) in high yields was observed. The (1)O(2) generated was trapped as the transannular peroxide (DPAO(2)) of 9, 10-diphenylanthracene (DPA) dissolved in carbon tetrachloride. The nitroxyl anion (NO-) formed from HNO (pKa 4.5) was trapped as nitrosylhemoglobin (HbNO) in an aqueous methemoglobin (MetHb) solution. In the presence of 25 mM sodium bicarbonate, which is known to accelerate the rate of decomposition of OONO(-), the amount of singlet oxygen trapped was reduced by a factor of approximately 2 whereas the yield of trapping of NO(-) by methemoglobin remained unaffected. Because NO(3)(-) is known to be the ultimate decomposition product of OONO(-), these results suggest that the nitrate anion is not formed by a direct isomerization of OONO(-), but by an indirect route originating from NO(-).

Animals↗
PubMed2000

Restoration of mRNA splicing by a second-site intragenic suppressor in the T4 ribonucleotide reductase (small subunit) self-splicing intron.

The nrdB gene of bacteriophage T4 codes for the small subunit of ribonucleotide reductase and contains a 598-base self-splicing intron which is closely related to other group I introns of T4 and eukaryotes. Thirty-one mutants causing splicing defects in the nrdB intron were isolated. Twenty-three EMS-induced revertants for these 31 primary mutants were isolated by the strategic usage of the white halo plaque phenotype. We mapped these revertants by marker rescue using subclones of the nrdB gene. Some of these second-site mutations mapped to regions currently predicted by the secondary structure model of the nrdB intron. One of these suppressor mutants (nrdB753R) was found to be intragenic by marker rescue with the whole nrdB gene. However, this mutation failed to map within the nrdB intron. Splicing assays showed that this pseudorevertant restored splicing proficiency of the nrdB primary mutation to almost wild-type conditions. This is the first example of a mutation within the exons of a gene containing a self-splicing intron that is capable of restoring a self-splicing defect caused by a primary mutation within the intron. In addition, two other suppressor mutations are of interest (nrdB429R and nrdB399R). These suppressors were able to restore their primary 5' defect but in turn create a 3' splicing defect. Both of these revertants mapped in different regions of the intron with respect to their primary mutations.

Bacteriophage T4↗
PubMed1998

Cladribine in the treatment of advanced relapsed or refractory low and intermediate grade non-Hodgkin's lymphoma.

BACKGROUND: Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with cytotoxic activity against both resting and proliferating cells. Clinical studies with cladribine have reported antitumor activity against various hematologic malignancies. METHODS: The authors studied responses to cladribine among patients with low and intermediate grade non-Hodgkin's lymphoma that had been refractory to or relapsed after prior chemotherapy. Cladribine was given intravenously over 2 hours at a dose of 0.14 mg/kg daily for 5 consecutive days, repeated every 4 weeks. RESULTS: Twenty-eight patients (16 males, 12 females) with a median age of 58 years (range, 41-75 years) were accrued. Twenty-three patients had low grade and 5 had intermediate grade lymphoma. Stage IV disease was present in 22 (79%), and 17 (61%) had systemic B-symptoms. The majority (57%) had received 2 or more prior chemotherapy regimens (median, 2; range, 1-5); 6 had had prior fludarabine therapy. Major responses were documented in 32% (9 of 28 patients), with 4 complete remissions (CR) and 5 partial remissions (PR) after a median of 4 cycles (range, 1-9). One CR occurred in one patient with intermediate grade diffuse large cell lymphoma, and three of six patients who had had prior fludarabine therapy experienced CR or PR with cladribine. Severe hematologic toxicities included reversible neutropenia, protracted thrombocytopenia, and lymphopenia. Other reported adverse effects included mild-to-moderate fatigue, nausea, and diarrhea. CONCLUSIONS: Cladribine is an active single agent in the treatment of patients with refractory or relapsed advanced stage indolent lymphoma, with major responses in one third of patients.

Adult↗
PubMed1998

Isolation and characterization of EMS induced splicing defective point mutations within the intron of the nrdB gene of bacteriophage T4.

The nrdB gene of bacteriophage T4 codes for the small subunit of ribonucleotide reductase and contains a 598-base-pair self-splicing intron which is closely related to other group I introns of T4 and eukaryotes. The screening, isolation, and mapping of 31 nrdB intron mutations were conducted by the strategic usage of the white halo phenotype exhibited by T4 mutants defective in dyhydrofolate reductase or thymidylate synthase. These intron mutations cluster towards the ends, mainly the 3' end, and show a defect in self-splicing. These mutations map in regions of conserved structural elements, thus supporting secondary structure predictions. A distinct pattern of clustering is observed with the highest number of mutations mapping within three of the smaller regions (A, C, and D) of the nrdB intron and no mutations mapping in the largest (B) region. The highest density of mutations mapped in the smallest region (C) of the intron, containing only 96 bases, thus showing a distinct pattern of clustering within the catalytic core.

Bacteriophage T4↗
PubMed1998

Evaluation of prostate specific antigen as a tumor marker in cancer prostate.

The present study was undertaken to evaluate the prostate specific antigen (PSA) alongwith other diagnostic methods as an application for a screening test, tumor marker and its relation to post surgical situation. The PSA has shown a sensitivity of 73.3% and specificity of 77.2%. The predictive value for positive PSA was 57% and for negative test was 66.6%. Local standards for PSA values in Pakistani community need to be established. The PSA test, inspite of its low specificity holds good promise for its contributory role as a tumor marker in prostate cancer.

Adult↗
PubMed1995

Reactive oxygen species as cellular messengers.

Reactive oxygen species (ROSs) have recently been found to be important signaling molecules in several cellular responses. Individual species have characteristic reactive properties, yet are easily interconverted, making it difficult to identify the ROSs involved in each response.

Animals↗
PubMed1995

Near fatal gas embolism during laparoscopic cholecystectomy.

Laparoscopic cholecystectomy has been greeted with enthusiasm by surgeons and patients alike. However, with the passage of time reports of complications related to this new approach are being published. We report an unusual complication of gas embolism in laparoscopic cholecystectomy. A high index of suspicion along with vigilant intraoperative monitoring will help in the early diagnosis and reduction of morbidity associated with gas embolism.

Cholecystectomy, Laparoscopic↗
PubMed1994

Singlet molecular oxygen evolution upon simple acidification of aqueous hypochlorite: application to studies on the deleterious health effects of chlorinated drinking water.

A study of the pH profile of the decomposition of aqueous hypochlorite has revealed the evolution (onset at pH 8) of single (1 delta g) molecular oxygen (singlet spin state dioxygen) detected spectroscopically (1268 nm), prior to the appearance of chlorine (onset at pH 5.5). The possible mechanism of the singlet state dioxygen evolution is presented, and the origin of its chloride ion dependence is discussed, especially in reference to chloride ion dependence of singlet molecular oxygen evolution in biological systems. Recent epidemiological analyses of the correlation of human cancer with chlorinated water supplies focus attention on the singlet oxygen mechanisms of DNA lesion formation.

Chlorine↗
PubMed1994

Singlet molecular oxygen in the Haber-Weiss reaction.

Characteristic chemiluminescence emission of singlet (1 delta g) molecular oxygen at 1268 nm is reported from a Haber-Weiss reaction. The reaction consists of mixing aqueous hydrogen peroxide with a solution of potassium superoxide, solubilized by 18-crown-6 ether in carbon tetrachloride or in dry acetonitrile at room temperature. Since the discovery of the enzyme superoxide dismutase by J.M. McCord and I. Fridovich [(1968) J. Biol. Chem. 243, 5733-5760], the identity of the reactive oxidant in superoxide-generating systems in biology has remained a chemical mystery. The results presented here suggest strongly that the reactive species is singlet oxygen generated via the Haber-Weiss reaction and not, as usually assumed, the hydroxyl radical, .OH, generated by the same reaction.

Acetonitriles↗
PubMed1993

Extracellular production of singlet oxygen by stimulated macrophages quantified using 9,10-diphenylanthracene and perylene in a polystyrene film.

The extracellular production of singlet oxygen (O2(1 delta g)) by stimulated macrophages was measured using a modification of our quantitative method initially developed to measure the intracellular production of O2(1 delta g) by neutrophils (Steinbeck, M. J., Khan, A. U., and Karnovsky, M. J. (1992) J. Biol. Chem. 267, 13425-13433). Glass coverslips were coated with the specific chemical trap for O2(1 delta g), 9,10-diphenylanthracene (DPA) and perylene, which is an internal standard, in a methylene chloride solution containing 0.3 mg/ml polystyrene. On evaporation, the polystyrene formed an even coating of DPA and perylene over the surface of a glass coverslip (PDP film). Unstimulated macrophages or macrophages stimulated with 4 beta-phorbol 12-myristate 13-acetate (PMA) or formyl-methionyl-leucyl-phenylalanine (fMLP) were then added to the PDP film in a darkened room and incubated at 37 degrees C for 30 min in a humidified 5% CO2 atmosphere. Both unstimulated and stimulated cells adhered to the PDP film in approximately equivalent numbers. Only stimulated cells produced measurable amounts of O2(1 delta g) in a dose-dependent response to either PMA or fMLP. The production of O2(1 delta g) by macrophages stimulated with PMA was maximal in response to 25 ng, 17.8 +/- 1.3 nmol of O2(1 delta g)/approximately 1.00 x 10(6) cells. The maximal response for fMLP was at a concentration of 1 microM, 18.4 +/- 1.0 nmol of O2(1 delta g)/approximately 1.00 x 10(6) cells. The specific detection of O2(1 delta g) by this method was confirmed by thermally releasing O2(1 delta g) from the DPA-O2(1 delta g) reaction product, DPA-endoperoxide, regenerating the original DPA compound. Production of O2(1 delta g) by the stimulated cells was inhibited 80-89% by the addition of 60-120 micrograms of superoxide dismutase, an enzyme that converts superoxide to hydrogen peroxide and ground state molecular oxygen or 79-84% with the addition of 2 mM histidine, an avid quencher of O2(1 delta g). Neither of these additions interfered with adhesion of the cells to the PDP film. The ability of superoxide dismutase to inhibit the production of O2(1 delta g) suggested that O2(1 delta g) was produced via a superoxide-dependent route. The ability of an oxidase to produce O2(1 delta g) secondary to superoxide production was substantiated further using a xanthine oxidase-acetaldehyde system. Purified xanthine oxidase produced both superoxide and O2(1 delta g), and their production was inhibited by the addition of superoxide dismutase.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The DAB-Mn++ cytochemical method revisited: validation of specificity for superoxide.

We wished to assess whether the previously developed 3,3'-diaminobenzidine (DAB)-Mn++ cytochemical method, purportedly specific for superoxide localization, is detecting superoxide O2.- and/or the superoxide product, O2(1 delta g). We show here that polymorphonuclear leukocytes (PMNs) produce O2(1 delta g) extracellularly in response to non-phagocytic stimuli and that this production is inhibited by addition of superoxide dismutase, an enzyme typically used to demonstrate that a reaction is mediated by O2.-. Because O2(1 delta g) is highly reactive and can be generated from O2.-, the reactivity of a pure chemical source of O2(1 delta g) with the cytochemical probe DAB was examined in the presence and absence of Mn++. Reactions between DAB and O2(1 delta g), thermally released from 1,4-dimethyl-napthalene-1,4-endoperoxide (DNE), indicated that O2(1 delta g) directly reacted with DAB, forming an insoluble DAB polymer, and that this reaction was increased by the presence of Mn++. The direct reaction of O2(1 delta g) with DAB was confirmed using near-IR emission spectroscopy. The near-IR emission spectrum of DNE as it was warmed showed the characteristic energy emission peak of O2(1 delta g) and the intensity of this peak was reduced by the addition of DAB; kq = 1.7 x 10(8) M-1 sec-1. The requirement of Mn++ for oxidation of DAB by O2.- was reconfirmed using potassium superoxide as a pure chemical source of O2.-. In cell studies, however, DAB deposits were not observed in PMNs stimulated under conditions that lead to O2(1 delta g) production [e.g., 0.040 or 0.162 microM 4B-phorbol-12-myristate-13-acetate (PMA)], regardless of whether Mn++ was present in the cytochemical medium. Nor were DAB deposits found in cells stimulated with PMA in the absence of Mn++ or in unstimulated PMNs. Only cells incubated in cytochemical medium containing Mn++ and stimulated to produce large amounts of O2.- (e.g., 3.24 microM PMA) contained DAB deposits. In summary, the DAB-Mn++ cytochemical method remains an excellent method for localizing the production sites of O2.-, since the concentration of O2(1 delta g) within vesicles of stimulated cells is too low to directly oxidize DAB to an electron-dense deposit.

3,3'-Diaminobenzidine↗
PubMed1992

A proposed function for spermine and spermidine: protection of replicating DNA against damage by singlet oxygen.

Like all aliphatic amines, the polyamines spermine and spermidine are physical quenchers of singlet molecular oxygen (1O2*). The rate constants of these processes were determined in vitro with photochemically generated 1O2* and the hydrocarbon rubrene as substrate, in pyridine. At millimolar concentration, spermine and spermidine should quench 1O2* in vivo and prevent it from damaging DNA. It is proposed that a biological function of polyamines is the protection of replicating DNA against oxidative damage.

DNA↗
PubMed1992

Spermine and spermidine protection of plasmid DNA against single-strand breaks induced by singlet oxygen.

Oxidative damage to DNA induced by singlet molecular oxygen (1O2*) includes single-strand breaks, which the biologically occurring 1O2* quenchers spermine and spermidine are shown to prevent. These polyamines at a physiological concentration (10 mM) reduce the percentage of the open circular form of pBR322 plasmid DNA, which is generated at the expense of the native supercoiled form when the plasmids are incubated with a chemical source of 1O2*, the water-soluble endoperoxide of 3,3'-(1,4-naphthylidene)dipropionate. Spermine and spermidine can be expected to protect DNA against other damaging effects of 1O2*.

DNA↗