Biomedical subjects
Publications and source records attributed to R Bashir.
Myocardial stunning is defined as a prolonged myocardial dysfunction with gradual return of contractile activity after a brief episode of severe ischemia. Usually it is seen in patients with myocardial infarction following treatment with thrombolytic agents, in patients with angina, and in patients recovering from cardiopulmonary bypass surgery. We report an interesting case of myocardial stunning following respiratory arrest.
The effects of lead on haematological parameters were studied in 51 occupationally exposed individuals comprising of 27 lead furnace workers, 24 lead pellet handlers and 20 healthy age and service matched controls. Blood lead levels were estimated by atomic absorption spectrometer AAS-180-80 and haematological parameters by Technicon H.1 system. The lead furnace workers had highest blood lead levels (median 71.20 ug/dl, range 21.2-171.10 ug/dl) and low Hb (median 106 g/l, range 73-144 g/l) as compared to healthy subjects (median lead levels 29.80 ug/dl, range 10.20-54.10 ug/dl and Hb median 135 g/l, range 101-153 g/l). The workers handling pellets had moderately increased blood lead levels (median 45.50 ug/dl, range 8.50-130.6 ug/l) and low Hb (median 114 g/l, range 74-158 g/l). The furnace exposed workers had higher blood lead levels and low Hb compared to the lead pellet handlers. TRBC, Hct, MCV, MCH and MCHC did not reveal any significant difference in all groups. It is concluded that chronic lead exposure causes normocytic normochromic anaemia and shows a dose response relationship between lead levels and severity of anemia.
Darier disease is a dominantly inherited skin disorder in which there appears to be abnormal adhesion between keratinocytes. We and others have shown that the disease in some British pedigrees is closely linked to markers mapping to 12q23-q24.1. In the present study we have defined crossovers that enable us to narrow the location of the disease gene to the interval between the D12S105 and the D12S129 markers. This interval may be expected to be on the order of about 4 cM on the basis of linkage data obtained using the primary CEPH reference families. Our data provide further evidence for locus homogeneity: each of four large British pedigrees, two of which have previously been subjected to preliminary characterization, shows statistically significant evidence for linkage to markers mapping to 12q23-q24.1.
Tissue from primary central nervous system lymphoma (PCNSL) which developed in five patients with acquired immuno deficiency syndrome (AIDS), nine patients without immunodeficiency, and two Epstein-Barr virus (EBV)-positive control cell lines (B95-8 and Raji) were examined for the presence of EBER-1 RNA. The tissues were hybridized with digoxigenin-labeled sense or anti-sense EBER-1 riboprobes. In all five AIDS-related PCNSLs, strong hybridization signals were found with the EBER-1 anti-sense probe. Signals could be eliminated by preincubation of the tissues with RNase-A. Hybridization with the EBER-1 sense probe showed no signal. All PCNSLs from immunocompetent patients (five paraffin-embedded, four frozen) showed no hybridization signals with EBER-1 sense or antisense probe but good hybridization signals with probes to immunoglobulin kappa or lambda light chain indicating RNA preservation. The paraffin-embedded B95-8-positive control cell-line showed positive hybridization in most cells with the anti-sense EBER-1 probe, and up to one percent of the cells had a weak signal with the sense probe. Most Raji cells showed a uniform signal with the anti-sense EBER-1 probe only. We conclude that, PCNSLs that arise in AIDS patients are associated with latent EBV infections, whereas PCNSLs from immunocompetent patients are not indicating a probable role for EBV in pathogenesis of these tumors.
The limb-girdle muscular dystrophies are a clinically and genetically heterogeneous group of disorders. We have studied two large inbred families of different ethnic origin and excluded linkage to LGMD2 on chromosome 15q and SCARMD on chromosome 13. Proceeding to a genomic linkage search, we have now identified linkage to markers D2S134 and D2S136 on chromosome 2p (maximum lod score 3.57 at zero recombination). The phenotype in the two families was similar, with onset in the pelvic girdle musculature in the late teens and usually relatively slow progression. This work identifies a second locus for autosomal recessive limb-girdle muscular dystrophy.
The clinical presentation, risk factors, laboratory data, and neuroimaging and neuropathological findings in 26 patients with autopsy proved central nervous system (CNS) aspergillosis are reviewed. Eleven patients had hematological malignancies (8 underwent bone marrow transplantation), 8 patients underwent liver transplantation, and 3 patients had acquired immunodeficiency syndrome. Four had illnesses resulting in immunosuppression (systemic lupus erythematosus, infected aortic graft, neuroblastoma, and fulminant hepatic failure). The most common presenting clinical symptoms of CNS aspergillosis were fever and a strokelike syndrome. Risk factors for developing CNS aspergillosis included neutropenia, immunosuppressive therapy, low CD4 counts, and retransplantation. Spinal fluid findings were nondiagnostic. Computed tomograms and magnetic resonance scans of the head showed low-density lesions or hemorrhagic infarctions. Most aspergillosis cases occurred in the setting of widely disseminated disease commonly arising from the lung. Pathologically, multiple areas of necrosis throughout the brain were seen. Aspergillus invasion of blood vessel walls was seen microscopically. Amphotericin B with or without flucytosine was not effective treatment.
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We analyzed 168 consecutive patients with Hodgkin's disease who were treated at the University of Nebraska Medical Center between 1985 and 1990 with high-dose chemotherapy followed by autologous bone marrow transplantation (BMT) or peripheral stem-cell transplantation (PSCT), and describe their neurologic complications. All these patients had relapsed or had failed to achieve a remission with initial chemotherapy. Early complications, defined as those occurring during the first 6 weeks following the transplantation, occurred in 65 patients (39%) and included encephalopathy, seizures, psychiatric symptoms, and cerebral hemorrhage; these were mild and reversible in 47 and fatal in 18 patients. The major cause of these early neurologic complications was pulmonary failure. Late neurologic complications, defined as those occurring 6 weeks after the BMT or PSCT was performed, occurred in 21% of patients and included encephalopathy, peripheral neuropathy, cerebral hemorrhage, and spinal cord compression. Serious nervous system complications following autologous BMT or PSCT for Hodgkin's disease are less frequent than those following allogeneic BMT and are usually a result of injury to other organ systems.
One hundred and forty-nine lead factory workers comprising of 46 fume exposed, 78 handling lead materials and 25 controls were screened for chronic lead poisoning. Blood lead level was determined by atomic absorption spectrometery and urinary ALA by ion-exchange chromatography. Fume exposed workers had significantly higher (P < 0.01) blood lead (median 61.20 micrograms/dl, range 21.20-171.10 micrograms/dl) and urinary ALA levels (median 4.10 mg/l, range 01.0-22.9 mg/l) than workers handling lead materials and controls. Urinary ALA was found to be a more sensitive and specific test for lead poisoning than estimation of blood lead levels.
Autosomal dominant retinitis pigmentosa (adRP) is known to result from mutations in two different retinal genes--rhodopsin and peripherin--while a third locus has been implicated by linkage data. However, families have been reported in which all three known loci have been excluded. We report linkage of adRP in one such family to two microsatellite markers on chromosome 7p. D7S435 has previously been localized to 7p13-15.1; D7S460, previously only localized to chromosome 7, maps to within 2 cM of D7S435 with a lod score of 12.15. Two point linkage analysis between these markers and adRP gave lod scores of 5.65 (theta = 0) and 4.19 (theta = 0.046) for D7S460 and D7S435, respectively. Multipoint analysis gave a maximum lod score of 8.22. These data strongly suggest a new adRP locus on chromosome 7p.
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We examined the expression of the Epstein-Barr virus (EBV)-induced proteins (LMP [latent membrane protein], EBNA-2, and CD23) and a lytic protein, viral capsid antigen (VCA), in five acquired immune deficiency syndrome (AIDS)-related primary CNS lymphomas (PCNSLs). We compared that expression with the expression of the same proteins in PCNSL from six immunocompetent patients and severe combined immune deficiency (SCID) mouse brains injected with EBV-infected lymphoblastoid cell lines (LCLs). Brain biopsy tissue from an AIDS patient with progressive multifocal leukoencephalopathy (PML) and a normal brain was also studied. Three of the AIDS PCNSLs expressed both human immunoglobulin kappa and lambda light chains and two expressed lambda light chain only. All non-AIDS-related PCNSLs expressed a single light-chain isotype. All five AIDS-related PCNSLs expressed LMP-1 (> 40%), EBNA-2 (> 60%), and VCA (1 to 5%) of tumor cells. These proteins were similarly expressed in the SCID/human chimeras. None of the PCNSLs from immunocompetent subjects, the normal brain, or the brain of the patient with PML expressed these proteins. PCNSL in AIDS patients bears greater similarity to EBV-infected LCLs than to PCNSL from immunocompetent patients.
We examined a possible role for the adhesion molecules LFA-1 and ICAM-1 in localizing central nervous system non-Hodgkin's lymphomas (CNS-NHLs) to the brain. Fresh frozen sections from 12 monoclonal CNS NHLs (11 primary, one secondary) were stained with monoclonal antibodies to LFA-1 alpha chain (CD11a), beta chain (CD18) and, ICAM-1 (CD54). Additional staining made use of rat monoclonal antibodies to the human and mouse high endothelial venule antigens HECA 452 and MECA 79 and mouse ICAM-1. The expression of these same molecules was also studied in mice with severe combined immunodeficiency (SCID) mice, bearing intracranial human lymphoblastoid cells. Eleven of the CNS-NHL tumors expressed LFA-1 alpha (one strongly, one intermediate, nine weakly). Nine of the tumors weakly expressed LFA-1 beta.. Nine of twelve tumors weakly expressed ICAM-1. In six of seven tumors definite blood vessels stained for ICAM-1. Non-tumor brain from two patients and non-tumor cerebral blood vessels showed no staining with CD11a, CD18 or CD54 antibodies. Strong expression of LFA-alpha and LFA-beta as well as ICAM-1 was noted in human lymphoblastoid cells (LCLs)/SCID mouse CNS lymphomas. Tumor blood vessels in these mice stained for mouse ICAM-1. Normal SCID mouse brains showed no staining with CD11a, CD18, CD54 or mouse ICAM-1 antibodies. Human, human/mouse CNS lymphomas, normal human, and mouse brains showed no staining with either HECA 452 or MECA 79.(ABSTRACT TRUNCATED AT 250 WORDS)
Type 1 collagen is the predominant collagen in cirrhotic livers. Each type 1 collagen molecule contains three subunits, two are identical (the alpha 1 chains) and the sequence of the third (alpha 2) is very similar. They are encoded at the non-synthenic loci, COL1A1 and COL1A2 and restriction site dimorphisms have been described at each locus. Genetic factors have been invoked as a basis for increased susceptibility to alcoholic cirrhosis. One hypothesis is that genetically determined differences in type 1 collagen may be involved in this predisposition. We have examined this by analysing restriction fragment length polymorphisms at each type 1 collagen locus in leucocyte DNA from 56 unrelated patients with alcoholic cirrhosis and 74 local unrelated healthy controls. Based on the presence or absence of these restriction site dimorphisms four possible haplotypes were generated at COL1A1 and COL1A2. We found no significant difference in allele frequencies between alcoholic cirrhotics and controls and, unlike a previous small study, we found no particular haplotype of either gene was associated with alcoholic cirrhosis. Our study provides no evidence for involvement of type 1 collagen structural genes in a genetic predisposition to cirrhosis in alcoholics.
Genetic studies have revealed that 25 to 30% of autosomal dominant retinitis pigmentosa (adRP) families have mutations in the rhodopsin gene, while the remainder do not. More recently linkage data and mutation detection have demonstrated two further loci implicated in adRP, at an as yet unidentified gene on chromosome 8p and at the human gene homologue of the mouse Rds (Retinal Degeneration Slow) gene on chromosome 6p. We have previously reported exclusion of adRP from the rhodopsin locus on 3q in two large adRP families. We now report exclusion data for both families, on chromosomes 6 and 8, demonstrating that the adRP phenotype results from mutations in at least four locations.
Recently it has been demonstrated that some families with autosomal dominant retinitis pigmentosa (adRP) have mutations in the rhodopsin gene while others do not. Previously we have identified six such mutations in seven adRP families in this laboratory, one of which was previously described in US patients. We now present a completed screen of the rhodopsin gene in a panel of 39 adRP families, by a rapid screening technique which will be of use for routine diagnosis. Nine different mutations were ultimately found, in a total of twelve of the 39 families. These include the six previously identified mutations, in codons 68-71, 190, 211, 255, 296 and 347, two new ones in codons 53 and 106, and another mutation first identified in a single US patient, in codon 58. Thus approximately 30% of adRP families have 'Rhodopsin RP' while the remainder probably have a defect elsewhere in the genome. Of those families in which rhodopsin mutations have been found, four have been classified D type, three as sectorial RP and the remainder are of uncertain classification. All families excluded from chromosome 3q by linkage have been classified R type. These data suggest a correlation between clinical sub-classification and the underlying rhodopsin/non-rhodopsin heterogeneity.
BACKGROUND: Recently established Epstein-Barr virus immortalized lymphoblastoid cell lines express polyclonal immunoglobulins, are diploid, and grow into invasive tumors when injected intracerebrally into mice with severe combined immunodeficiency (SCID). It is unclear whether clonal selection of neurotropic cell lines occurs during long-term growth in the brain and the effect of this selection on brain invasiveness. EXPERIMENTAL DESIGN: Epstein-Barr immortalized lymphoblastoid cell lines from a normal Epstein-Barr negative donor were serially passaged seven times intracerebrally within groups of SCID/SCID CB 17 mice. Each cell line was injected into five or more animals during each passage. Clonality of the rescued cell lines, genotype, and brain invasiveness were examined. RESULTS: All mice developed extensive intracerebral lymphoproliferative disease within 10-18 days after injection. Intracerebral, subarachnoid, intraventricular, and perivascular lymphoid lesions were noted. Infiltrates were similar in all animals studied regardless of the passage number. Clonal B cell populations were detectable in lesions after the first passage by Southern blot hybridization using JH probe. Immunohistochemically, polyclonal tumors were seen initially, but after the fourth passage, monoclonal cytoplasmic immunoglobulin was predominantly expressed by all tumors. Minor bands seen in the early passages disappeared subsequently. Random chromosomal abnormalities appeared in the rescued cell lines after the third passage; however, after the sixth passage, the abnormalities became more consistent. Clonability in agarose was very low initially in both cell lines and increased significantly after the sixth passage. CONCLUSIONS: These experiments demonstrate that within the immunoprivileged conditions of the SCID mouse brain, the evolution of Epstein-Barr immortalized lymphocytes from polyclonal to oligo- and monoclonal cell lines with chromosomal abnormalities occurs very early. This evolution is not paralleled by increased invasiveness in vivo.
Autosomal dominant retinitis pigmentosa (adRP) has shown linkage to the chromosome 3q marker C17 (D3S47) in two large adRP pedigrees known as TCDM1 and adRP3. On the basis of this evidence the rhodopsin gene, which also maps to 3q, was screened for mutations which segregated with the disease in adRP patients, and several have now been identified. However, we report that, as yet, no rhodopsin mutation has been found in the families first linked to C17. Since no highly informative marker system is available in the rhodopsin gene, it has not been possible to measure the genetic distance between rhodopsin and D3S47 accurately. We now present a linkage analysis between D3S47 and the rhodopsin locus (RHO) in five proven rhodopsin-retinitis pigmentosa (rhodopsin-RP) families, using the causative mutations as highly informative polymorphic markers. The distance, between RHO and D3S47, obtained by this analysis is theta = .12, with a lod score of 4.5. This contrast with peak lod scores between D3S47 and adRP of 6.1 at theta = .05 and 16.5 at theta = 0 in families adRP3 and TCDM1, respectively. These data would be consistent with the hypothesis that TCDM1 and ADRP3 represent a second adRP locus on chromosome 3q, closer to D3S47 than is the rhodopsin locus. This result shows that care must be taken when interpreting adRP exclusion data generated with probe C17 and that it is probably not a suitable marker for predictive genetic testing in all chromosome 3q-linked adRP families.