Biomedical subjects
A Keyhani
Publications and source records attributed to A Keyhani.
Carbohydrate and amino acid degradation pathways in L-methionine/D-[13C] glucose model systems.
Maillard model systems consisting of labeled D-[(13)C]glucoses, L-[(15)N]methionine, and L-[methyl-(13)C]methionine, have been utilized to identify the amino acid and carbohydrate fragmentation pathways occurring in the model system through Py-GC/MS analysis. The label incorporation analyses have indicated that the carbohydrate moiety produces 1-deoxy- and 3-deoxyglucosones and undergoes C(2)/C(4) and C(3)/C(3) cleavages to produce glycolaldehyde, tetrose, and C(3)-reactive sugar derivatives such as acetol, glyceraldehyde, and pyruvaldehyde. Glycolaldehyde was found to incorporate C-1, C-2 (70%) and C-5, C-6 (30%) glucose carbon fragments, whereas the tetrose moiety incorporates only C-3, C-4, C-5, C-6 glucose carbon atoms. In addition, the major source of reactive C(3) fragments was found to contain C-4, C-5, C-6 sugar moiety. On the other hand, methionine alone also generated Strecker aldehyde as detected by its condensation product with 3-(methylthio)propylamine. Plausible mechanisms were proposed for the formation of the interaction products between sugar and amino acid degradation products on the basis of the label incorporation patterns.
Increased CD38 expression is associated with favorable prognosis in adult acute leukemia.
CD38 is expressed in acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) blasts and its prognostic significance is unknown. We investigated CD38 expression in 304 AML and 138 ALL patients. CD38 was lower in AML-M3 compared to other FAB subtypes (5% vs. 41%; P < 0.001), but was similar among ALL subtypes (56.6%; P = 0.69). Ph + ALL and AML with t(15; 17) patients showed lower CD38 expression than the other cytogenetic groups. Overall survival favored AML and ALL patients with higher CD38 levels. Multivariate analysis revealed CD38 expression to be an independent outcome predictor in AML, but not in ALL.
Origin of carbohydrate degradation products in L-Alanine/D-[(13)C]glucose model systems.
Maillard model systems consisting of labeled D-[(13)C]glucoses and L-[(13)C]alanines have been utilized to identify the origin of carbon atoms in glycolaldehyde, pyruvaldehyde, 1-hydroxy-2-propanone (acetol), 2,3-butanedione, 3-hydroxy-2-butanone, 2,3-pentanedione, and compounds containing C(5) and C(6) intact glucose carbon chains. The origin of carbon atoms in glycolaldehyde and pyruvaldehyde was inferred from the analysis of label incorporation pattern of methyl and dimethylpyrazines. The origin of carbon atoms in the remaining compounds was determined by direct analysis. The data indicated that glycolaldehyde incorporated intact C5-C6 and C1-C2 carbon chains of glucose. Acetol and pyruvaldehyde incorporated intact C1-C2-C3 and C4-C5-C6 carbon chains of glucose. On the other hand, 2, 3-butanedione and 3-hydroxy-2-butanone incorporated intact C3-C4-C5-C6 carbon chain of glucose. In addition, analysis of compounds containing intact glucose C(5) carbon chains have indicated that glucose in the presence of L-alanine can lose either C-1 atom to produce a pentitol moiety responsible for the formation of furanmethanol or it can lose the C-6 atom to produce a pentose moiety responsible for the formation of furfural. Plausible mechanisms, consistent with the observed label incorporation, were proposed for the formation of sugar degradation products.
Formation of sugar-specific reactive intermediates from (13)C-labeled L-serines.
Analysis of the pyrolysis products of [1-(13)C], [2-(13)C], and [3-(13)C]-labeled L-serines has indicated the presence of three initial degradation pathways. Decarboxylation followed by deamination produces aminoethanol and acetaldehyde, respectively; a retro-aldol pathway generates formaldehyde and glycine. Dehydration of L-serine can lead to the formation of pyruvic acid, which eventually can be converted into the amino acid alanine. Formation of alanine and glycine was confirmed due to the detection of 2, 5-diketo-3,6-dimethylpiperazine and cycloglycylalanine. Most of the advanced decomposition products of L-serine can be rationalized on the basis of these initial degradation products. Label incorporation studies have elucidated the origin of carbonyl precursors of methyl- and 2,3-dimethylpyrazines formed in the thermal decomposition mixture of L-serine. Three mechanistic pathways were identified for the formation of carbonyl precursors of methyl- and 2, 3-dimethylpyrazines. The major pathway (70%) for the formation of the precursor of methylpyrazine involved aldol addition of formaldehyde to glycolaldehyde to form glyceraldehyde. On the other hand, the major pathway (60%) for the formation of the precursor of 2,3-dimethylpyrazine involved an aldol condensation of acetaldehyde with glycolaldehyde to form 2,3-butanedione.
Origin of 2,3-pentanedione and 2,3-butanedione in D-glucose/L-alanine Maillard model systems.
Model studies using independently labeled D-[(13)C]glucoses and L-[(13)C]alanines have indicated that 2,3-butanedione is formed by a single pathway involving only glucose carbon atoms, whereas 2, 3-pentanedione is formed by two pathways, one involving glucose carbon atoms (10%) and the other (90%) through the participation of C2'-C3' atoms of L-alanine and a C(3) carbon unit from D-glucose. Analysis of label incorporation into selected mass spectral fragments of 2,3-pentanedione have indicated that the C(3) carbon unit originates either from C1-C2-C3 or from C4-C5-C6 fragments of D-glucose. In addition, model studies with pyruvaldehyde and glyceraldehyde have implicated these intermediates as plausible C(3) glucose carbon units capable of producing 2,3-pentanedione upon reaction with L-alanine. The labeling studies have also confirmed a previously identified chemical transformation of alpha-keto aldehydes affected by the amino acid that leads to the addition of the C-2 atom of the amino acid to the aldehydic carbon atom of alpha-keto aldehydes.
Quantitation of minimal residual disease in acute myelogenous leukemia and myelodysplastic syndromes in complete remission by molecular cytogenetics of progenitor cells.
Detection of karyotypic clonal abnormalities are prognostically useful in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS), but cytogenetic methods are not sensitive enough to detect low numbers of residual leukemic cells in patients who have achieved complete remission (CR). Fluorescence in situ hybridization (FISH) and fluorescence activated cell sorting (FACS) were used to investigate the frequency and presence of minimal residual disease (MRD) in AML and MDS patients (n = 28) with monosomy of chromosomes 7, 17 and 18 and trisomy of chromosomes 6, 8, 9 and 10 in CR. MRD was detected in all patients with monosomy 7 (n = 10) and followed by relapse in eight patients after 4.8 +/- 3.1 months. In contrast, persistent leukemic cells occurred in 11/12 patients with trisomy 8, but only three of them relapsed after 7.7 +/- 4.0 months. Cox regression analysis showed that cytogenetic class and levels of clonal cells at CR were related to time to relapse (P = 0.001). The level of MRD identified patients at high and low risk of relapse. High absolute levels of proliferating residual leukemic cells correlated with monosomy 7 and high risk of relapse.
Generation and the fate of C2, C3, and C4 reactive fragments formed in Maillard model systems of [13C]glucose and [13C]glycine or proline.
Model studies with pyrolysis/GC/MS using labeled [13C] glucoses with labeled [15N/13C]glycines and proline have indicated that the Maillard model systems consisting of glucose and glycine or proline generate similar C2, C3, C4 fragments such as acetic acid, and pyruvaldehyde. Furthermore, the labeling studies have enabled the identification of the origin of these reactive intermediates and their stable end-products such as N-acetylpyrrolidine, 1-(1'-pyrrolidinyl)-2-propanone amd 1-(1'-pyrrolidinyl)-2-butanone in proline model system and pyrazines and pyrazinones in glycine. In glycine model system, pyruvaldehyde and 2,3-butandione were found to be formed either from the degradation of the carbohydrate moiety (90 and 35%, respectively) or by an aldol-type interaction of glycine with alpha-ketoaldehydes. The same intermediates in proline system are formed exclusively from the carbohydrate degradation pathway.
Multilineage involvement of Philadelphia chromosome positive acute lymphoblastic leukemia.
Acute lymphocytic leukemia (ALL) is considered a clonal disease restricted to the lymphoid compartment. The Philadelphia chromosome (Ph) is found in a subset of ALL with poor prognosis. Here we present the largest series of Ph+ ALL analyzed for involvement of the myeloid compartment. For the first time at a single cell level the presence of Ph in lineages other than lymphoid is demonstrated. Granulocytes from nine patients diagnosed with BCR-ABL + ALL (eight Ph+, one Ph-) were purified using two layer density gradient separation. They were further identified by the morphology of DAPI-stained nuclei and studied for the presence of the Ph by fluorescence in situ hybridization (FISH) using a BCR-ABL dual-color probe. Ph was demonstrated in 30 to 93% of granulocytes in all patients. FISH identified major and minor BCR gene breakpoints (M-bcr and m-bcr). In one patient, with CD19+/34+/33-/2-/3-/7-/10- lymphoblasts, involvement of B cells (CD19+), T cells (CD3+), myeloid (CD13+), erythroid (glycophorin A+) cells was found by FISH following fluorescence-activated cell sorting (FACS). The diagnosis of ALL as opposed to lymphoblastic transformation of CML was established based on clinical and laboratory data including Western blot results demonstrating the presence of p190/m-bcr in five of the nine cases studied. Results suggest that Ph+ ALL originates from a pluripotent stem cell.
Minimal residual disease in acute myelogenous leukaemia and myelodysplastic syndromes: a follow-up of patients in clinical remission.
The majority of patients with acute myelogenous leukaemia (AML) and myelodysplastic syndromes (MDS) relapse, especially those with unfavourable cytogenetics. This study was designed to investigate the presence and frequency of minimal residual disease (MRD) in patients with AML or MDS (n=35) and numerical abnormalities of chromosomes 6, 7, 8, 9, 10, 17 and 18 in clinical remission by using a combination of fluorescence activated cell sorting (FACS), fluorescence in-situ hybridization (FISH) and labelling with bromodeoxyuridine (BUdR). The technique enables the detection of as few as three leukaemic cells in 10(5) normal cells. MRD was detected in 33/35 patients in complete remission (CR). 16 patients relapsed (8/11 with monosomy 7, 4/17 with trisomy 8, and 4/7 with other cytogenetic abnormalities) after a median of 4.8 months (range 3-13). Levels of MRD (P=0.007) and proliferation index (P=0.011) were significantly higher in patients with monosomy 7 than in patients with trisomy 8 or other cytogenetic abnormalities. The percentage of cells in S-phase, the number of abnormal cells and cytogenetic class were related to time to relapse (P=0.001) with S-phase being the single most important prognostic factor (P=0.0001). We conclude that the combination of FACS/FISH/BUdR, which determines the number, phenotype and proliferation rate of very rare leukaemic cells in patients with AML or MDS in clinical remission, provides information that is useful in the identification of patients with high and low likelihood of relapse.
In vitro activities of free and liposomal drugs against Mycobacterium avium-M. intracellulare complex and M. tuberculosis.
We compared MICs and MBCs of various free- and liposome-incorporated antimicrobial agents against several patient isolates of Mycobacterium avium-M. intracellulare complex and certain American Type Culture Collection strains of M. avium, M. intracellulare, and Mycobacterium tuberculosis. Seven of 19 agents were selected for incorporation into liposomes. The MICs of these agents for 50 and 90% of isolates tested (MIC50s and MIC90s, respectively) ranged from 0.5 to 62 micrograms/ml. Members of the M. avium-M. intracellulare complex were resistant to killing by most of the other agents tested in the free form. However, clofazimine, resorcinomycin A, and PD 117558 showed complete killing of bacteria at concentrations ranging from 8 to 31 micrograms/ml, represented as MBC90s. Among the liposome-incorporated agents, clofazimine and resorcinomycin A had the highest killing effects (MBC90s, 8 and 16 micrograms/ml, respectively). Furthermore, both free and liposome-incorporated clofazimine had equivalent growth-inhibitory and killing effects on all American Type Culture Collection strains of M. avium, M. intracellulare, and M. tuberculosis tested. These results show that the antibacterial activities of certain drugs, particularly those of clofazimine and resorcinomycin, were maintained after the drugs were incorporated into liposomes.
Roles of liposome composition and temperature in distribution of amphotericin B in serum lipoproteins.
The role of liposome composition and temperature in the distribution of amphotericin B (AmB) with serum lipoproteins and the role of particle charge in AmB transfer to serum lipoproteins were determined. Serum obtained from healthy volunteers was incubated with known concentrations of AmB or different liposomal formulations of AmB (1 to 100 micrograms/ml) at 37 degrees C for various time intervals (5, 10, 20, 30, 45, and 60 min). After each interval, serum was removed and separated into high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions by an LDL-direct assay. The distribution of AmB (Fungizone) at 5 min through 1 h of incubation at 25 degrees C remained constant and was similar in the HDL and LDL fractions. At 37 degrees C, at 5 through 45 min of incubation, 54 to 61% of AmB was recovered in the HDL fraction; however, at 1 h more than 75% of the AmB concentration was recovered in the HDL fraction. In contrast, 87.5 to 92% AmB was recovered in the HDL fraction throughout the incubation when negatively charged liposomal AmB (dimyristoylphosphatidylcholine [DMPC]:dimyristoylphosphatidylglycerol [DMPG], 7:3 [wt/wt]) was used. With positively charged liposomes, 75 to 87.7% of AmB was recovered in the HDL fraction through the different time points studied. AmB incorporated into DMPC (neutral) and DMPG (negative) liposomes, and AmB was distributed in an HDL:LDL ratio of 6:4 following 1 h of incubation. Ninety percent of AmB and 80% of the lipid were found in the HDL fraction in a 3:1 molar DMPG:AmB ratio and in the LDL fraction in a 6:1 molar ratio. Lipid charge and temperature play a role in AmB distribution into serum lipoproteins. AmB and DMPG may contransfer as an intact drug-lipid complex to serum lipoproteins.
Liposomal hamycin: reduced toxicity and improved antifungal efficacy in vitro and in vivo.
Hamycin has been used to treat a variety of yeast and other fungal infections by oral, topical, and intraperitoneal routes. However, its parenteral use has been reported to be associated with high toxicity. Multilamellar liposomes composed of dimyristoyl phosphatidyl choline, dimyristoyl phosphatidyl glycerol, and various amounts of cholesterol were used as drug carriers for hamycin. The antifungal activity of hamycin was maintained after liposome encapsulation (MIC range, 0.6-1.2 micrograms/ml), and toxicity was reduced in vitro and in vivo as the concentration of cholesterol was increased to an appropriate ratio. Mice were treated with various doses of free or liposomal hamycin 2 days after infection. Although free drug did not significantly improve survival, liposomal hamycin at an equivalent dose (0.6 mg/kg) increased the survival from 18 to 38 days. Higher doses (1.2 and 1.8 mg/kg) showed further improvement in survival and reduction in numbers of colony-forming units in the kidneys. Liposome encapsulation resulted in improved therapeutic index of hamycin.
Antifungal activity of HWA-138 and amphotericin B in experimental systemic candidiasis.
HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice.
Proteolytic enzymes released by liver macrophages may promote hepatic injury in a rat model of hepatic damage.
Using macrophages isolated from the livers of normal rats and from rats injected intravenously with Corynebacterium parvum 6 days previously, N-acetyl-glucosaminidase (NAG) and plasminogen activator (PA) production have been measured during in vitro culture. There was a significant increase (p less than 0.02) in the supernatant activity of NAG by the C. parvum recruited macrophages 8.05 +/- 1.17 nmol product/mg protein/h as compared with normal, 3.86 +/- 0.77 nmol product/mg protein/h. There was a similar increase in cellular NAG content by recruited macrophages 412 +/- 66 nmol product/mg protein compared with 153 +/- 35 nmol product/mg protein (p less than 0.01) in normals. When macrophages of either group were exposed in vitro to endotoxin alone or a combination of endotoxin followed by latex particles, NAG values were similar to those obtained from nonexposed cells. In contrast, PA supernatant production increased significantly (p less than 0.02) on exposure to endotoxin with a corresponding reduction in cellular PA content, but the cellular PA content and supernatant release were similar for each group of cells. There was a fourfold increase in the number of macrophages isolated from the C. parvum-treated livers/g liver weight. Thus, the hepatocytes in this model of liver injury are potentially exposed to a 10-fold increase in the concentration of the acid hydrolase NAG; potentiation of cell damage by the administration of endotoxin may be mediated through the observed increase in production of secretory enzymes such as plasminogen activator. In conclusion, this study supports the hypothesis that proteolytic products released by recruited and activated macrophages may result in hepatocyte damage.
Comparison of clinical behavior of melanoma of the hands and feet: a study of 283 patients.
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Carcinoma of the thyroid gland in Iran.
Of the 1698 cases of thyroid disease seen during the 17 years 1956-72 in the Taj Cancer Institute, Tehran, 398 were cases of carcinoma, an incidence of 23.4 per cent. The factors involved in this high incidence of malignancy are discussed and the treatment of these patients is described.
Pleomorphic rhabdomyosarcoma.
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