Biomedical subjects
Publications and source records attributed to O Rasool.
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Previous studies have indicated that a candidate tumor suppressor gene resides telomeric of the RB1 gene at 13q14, a region that is commonly deleted in B-cell chronic lymphocytic leukemia (B-CLL). In this study, we have evaluated the frequency and minimal region of overlap for 13q deletions in malignant cells from various lymphoid neoplasms. We observed losses at 13q14 in 33/75 (44%) B-CLL cases, four of 16 (25%) non-Hodgkin's lymphoma (NHL) cases, eight of 29 (28%) patients with acute lymphocytic leukemia (ALL), and one of 15 T-cell lines. In some ALL cases, inactivation of the RB1 gene is suggested as the important event in the 13q deletions. The most commonly deleted marker in CLL and NHL was D13S319, between RBkpt and the D13S25 loci. Homozygous deletions of this marker were observed in 10 of 75 B-CLL cases, in six of which the homozygous deletions included only the D13S319 locus. Our data suggest that 13q deletions are common in lymphoid neoplasms, and that deletion of a candidate tumor suppressor gene(s) in the vicinity of the D13S319 marker is a tumorigenic event in these diseases.
Malignant cells from 52 children with acute lymphocytic leukemia (ALL) were investigated for inactivation of the p15ink4B and p16ink4 genes and other genetic alterations on chromosome 9p21. Homozygous deletions of the p15ink4B and/or the p16ink4 genes were detected in 16 cases and a further 9 cases showed evidence of allelic loss either by hemizygous deletion or loss of heterozygosity (LOH) for 9p21 markers. Most cases had loss of both genes, but 5 patients had lost only p16ink4 and 2 cases had homozygous loss of p15ink4B only. Sequence analysis of all exons of p15ink4B and p16ink4 was performed in patients with hemizygous deletions or LOH for 9p21 markers. A frame shift mutation of p16ink4 exon 1 was shown in 1 case, whereas all other clones carried the wild-type sequence of p15ink4B and p16ink4 in the remaining allele. The data suggest that both the p15ink4B and p16ink4 genes can be inactivated in ALL. The existence of a hitherto undefined tumor-suppressor gene on chromosome 9p cannot be ruled out.
A tetranucleotide repeat located in intron 20 of the RB gene consists of 16-26 CTTT(+/- T) repeats in 99% of the alleles. In the remaining 1% of alleles the segment is extended to a length of > 60 repeats. Sequence analysis revealed that the prolonged alleles either consisted of perfect CTTT(+/- T) repeats or irregular repeat sequences with variable combinations of C and T. The data provide clues to the mechanisms causing unstable expansions of repeats.
Activation of polymorphonuclear leucocytes (PMN) was investigated after incubation of adult human PMN and group B streptococci (GBS) type Ia with a type-specific polyclonal antiserum and a modified porcine surfactant (Curosurf). The level of oxidative metabolism of PMN was studied using a micromethod modification of the nitroblue tetrazolium (NBT) reduction test. GBS alone did not stimulate significant oxygen metabolite release from PMN, and incubation of PMN with surfactant alone resulted in decreased NBT reduction. After opsonization of GBS with a specific antibody, PMN were activated and the increased oxygen metabolite release was not suppressed when surfactant was added to the system. We conclude that the encapsulated GBS strain investigated needs opsonization with specific antibody to increase oxidative metabolism of PMN, and that incubation of PMN and opsonized GBS with surfactant does not interfere with NBT reduction.
We studied bacterial proliferation in relation to surfactant treatment in a model of neonatal group B streptococcal (GBS) pneumonia. Surfactant (Curosurf) was isolated from pig lungs with a method preserving only polar lipids and hydrophobic proteins. Near-term rabbit fetuses were ventilated in a body plethysmograph system. At 15 min, a suspension of GBS strain 090 Ia LD (5 mL/kg, concentration approximately 10(9)/mL) was instilled intratracheally. At 30 min, surfactant (n = 12) or sterile saline (n = 13) was administered via the airways (2.5 mL/kg). A control group (n = 12) received the same volumes of saline. After 5 h the animals were killed, and samples for blood cultures and blood gases were taken from the heart. The left lung was aseptically removed, weighed, homogenized, serially diluted, and cultured on blood agar plates. The results were expressed as mean log10 colony forming units/g lung +/- SD. Compared with animals (n = 12) killed immediately after GBS instillation (8.13 +/- 0.54), there was a significant increase in bacterial numbers in both groups ventilated for 5 h, but values for surfactant-treated animals (8.96 +/- 0.38) were lower than those for animals receiving saline (9.46 +/- 0.50; p < 0.05). After 5 h, 96% of GBS-infected animals had positive blood cultures. Light microscopic examination of the right lung of GBS-infected animals revealed inflammatory changes that tended to be less prominent in surfactant-treated rabbits. We conclude that intratracheal inoculation of near-term rabbits with GBS resulted in a significant bacterial proliferation during 5 h of ventilation and that bacterial growth was mitigated by treatment with surfactant.
Groups of eight rabbits were inhalation-exposed to iron, 1.4 +/- 0.7 mg/m3 (low Fe), or 3.1 +/- 1.8 mg/m3 (high Fe) as FeCl3 or to filtered air (controls) for 2 months, 5 days/week and 6 hours/day. The alveolar macrophages were increased in number in both exposed groups. Noduli of granular macrophages were found in lungs of all the rabbits in the high-Fe group, in one from the low-Fe group, and in one control rabbit. Especially in the high-Fe group there were prominent changes in the macrophages such as enlarged lysosomes containing fibrous-looking structures, iron-rich inclusions, and densely packed, 5-nm electron-dense granules. The number of cells filled with surfactant-like inclusions as well as a smooth surface was increased in the high-Fe group and the macrophages had enhanced phagocytic capacity. There was an increase in the phospholipid concentration and in the volume density of type II cells in the high-Fe group but the level of phosphatidylcholines was not significantly changed. The fact that Fe3+ affected mainly the alveolar macrophages might be due to the relatively high concentration of iron in these cells caused by the precipitation of iron in their lysosomes.
Eight rabbits were exposed to 0.7 +/- 0.4 mg/m3 Co2+ as CoCl2 and 1.2 +/- 0.7 mg/m3 Cr3+ as Cr(NO3)3 (group Co + Cr), eight to 0.6 +/- 0.5 mg/m3 Co2+ (group Co), and eight to filtered air (control group), for 4 months, 5 days/week, and 6 hr/day. All rabbits in group Co + Cr and group Co showed nodular aggregation of alveolar epithelial type II cells. Volume density of the type II cells was significantly higher in group Co + Cr than in group Co and the control group. There was intraalveolar macrophage accumulation in seven rabbits in group Co + Cr, one in group Co, and one in the control group. In lavage fluid the numbers of macrophages and the percentage of these cells with smooth surface and intracellular surfactant-like inclusions were more increased in group Co + Cr than in group Co as were oxidative metabolic and phagocytic activities of the macrophages. Total phospholipids, phosphatidylcholines, and especially 1,2-dipalmitoylphosphatidylcholine was markedly increased in group Co + Cr whereas only 1,2-dipalmitoylphosphatidylcholine was slightly increased in group Co. One mechanism behind the high amount of surfactant phospholipids in group Co + Cr seems to be an enhanced production of surfactant by the type II cells. Another mechanism is probably that Cr3+ reduces the capacity of alveolar macrophages to catabolize surfactant. The results imply that it is important to investigate effects of combinations of cobalt and chromium in the occupational environment.
Activation of neutrophils by lipid A, O-antigen polysaccharides (PS) and smooth lipopolysaccharides (LPS) isolated from Salmonella choleraesuis (O-6,7) and Salmonella typhimurium (O-4,5,12) was investigated. The methods used were assays for lysozyme release and for nitroblue tetrazolium (NBT) reduction which measures the level of oxidative metabolism of neutrophils. LPS from both species stimulated neutrophils to the same extent in the presence of autologous plasma. In the absence of plasma only the O-6,7 LPS activated neutrophils. Lipid A or PS isolated from both LPS either did not activate neutrophils or did so only at very high concentrations when tested in the presence of plasma; in the absence of plasma no activation occurred. The data indicate that both PS and lipid A segments of LPS are required for activation of neutrophils by LPS. We also deduce that plasma, probably complement, is required for the interaction of some LPS, e.g. O-4,5,12 with neutrophils whereas other LPS, e.g. O-6,7 can interact directly and activate neutrophils.
Both Brucella abortus lipopolysaccharide (LPS) and lipid A were low activators of nitroblue tetrazolium reduction and lysozyme release in human neutrophils. The stimulation was dose dependent and was higher in the presence of autologous plasma than in its absence. The comparison between Brucella LPS and lipid A versus Salmonella LPS revealed that at least 100 times more LPS and 1,000 times more lipid A of the former genus were required to induce significant nitroblue tetrazolium reduction and a corresponding lysozyme release in neutrophils. Low Brucella LPS-mediated superoxide and lysozyme production might contribute to the survival of these facultative intracellular bacteria in phagocytic cells.
Human neutrophils were incubated either with purified cell envelope lipopolysaccharides (LPS) of salmonella or with different concentrations of LPS combined with Intralipid. Incubation of neutrophils with LPS alone increased their oxidative metabolism with increased release of oxygen radicals as measured by the nitroblue tetrazolium (NBT) test and chemiluminescence response. The amount of lysozyme released by the cells also increased during incubation with LPS. However, when the neutrophils were incubated with LPS together with Intralipid, the LPS induced stimulation of the neutrophil NBT reduction, chemiluminescence and lysozyme release was significantly decreased. Intralipid might substitute for plasma high density lipoproteins (HDL), which are known to inhibit the LPS effects on the neutrophils in the acute stage of an infection with Gram-negative bacteria.