Biomedical subjects
Publications and source records attributed to F Aziz.
A case of meningioma that developed at a site of a previously performed burr hole is reported. To the best of our knowledge, this is the first reported case of a meningioma arising at a previous burr hole site. The possible reasons for its causation are discussed.
We report the case of a 65-year-old patient who had complete excision of an atrial myxoma and subsequently presented to our unit with recurrent cerebral metastasis. The case demonstrates that cardiac myxoma despite benign histological appearance is capable of metastatic spread.
The fossil calvaria known as the Mojokerto child's skull was discovered in 1936, but uncertainties have persisted about its paleoenvironmental context and geological age because of difficulties in relocating the discovery site. Past relocation efforts were hindered by inaccuracies in old base maps, intensive post-1930s agricultural terracing, and new tree and brush growth. Fortunately geologic cross sections and site photographs from 1936-1938-not fully utilized in past relocation fieldwork-closely circumscribe site geography and geology. These documents match the conditions at just one sandstone outcrop. It is situated on the southern margin of a topographic nose at the upper end of a approximately 18 m-wide gully ( approximately 0663760 m E, 9183430 m N, UTM Zone 49 M), approximately 15 m southeast of the Kumai et al. (1985) relocation. The relocated discovery bed is approximately 3.3 m of fossiliferous pebbly sandstone, a river-channel deposit cut into tuffaceous mudstone. The sandstone and mudstone beds correspond to original site descriptions. Pebbly sandstone is also found within the skull. The calvaria is well-preserved and taphonomically similar to large and fragile specimens found among several hundred vertebrate fossils excavated from the sandstone in 2001-2002. Since no well-preserved fossils were found intact at the surface of the sandstone, the good condition of the Mojokerto skull suggests that it was buried fully when discovered. The relocated hominin bed is the uppermost fluvial sandstone of a marine-deltaic sequence in the upper Pucangan Formation. The Mojokerto child probably died along the ancient seacoast, judging from the large extent of the deltaic facies and evidence that the calvaria experienced minimal transport. The relocated discovery bed is approximately 20 m stratigraphically above the horizon from which the widely cited 1.81+/-0.04 Ma (40)Ar/(39)Ar date for the skull was obtained. Additional field and laboratory results will be required to determine the skull's age.
OBJECTIVE: To assess the diagnostic efficacy of Fine Needle Aspiration Cytology in differentiating neoplastic and non-neoplastic dysfunctional ovarian cysts--cytological findings to be verified with histology of excised cyst. METHODS: In this prospective study fifty-three cases with unilocular nonseptate ovarian cystic masses,detected on ultrasound examination were subjected to ultrasound guided fine needle aspiration of the cyst contents at Department of Pathology, Allama Iqbal Medical College Lahore, from January 1999 - January 2000. Aspirated fluid was examined cytologicaly using Giemsa stain on the smears prepared from centrifuged deposit. The same cyst removed surgically was examined histologicaly and cytohistological correlation was carried out. RESULTS: In this series of 53 cases, histologically confirmed break up of various types of cysts was follicular cysts (n=25), leuteal cysts (n=6), serous cysts (n=15), mucous cysts (N=4) and Endometriotic cysts (n=3). Non-diagnostic fine needle aspirate was obtained in 19/53 cases, majority being the follicular cysts. The cytohistological correlation revealed no false positive but 40% false negative results for follicular cysts on cytological examination of the aspirate. Hence the specificity and sensitivity for cytological diagnosis of follicular cyst was 100% and 60% respectively. For leuteal cysts, false positive and false negative results on cytological examination were 0% and 16.6% respectively with a specificity and sensitivity value of 100% and 83% respectively. For neoplastic serous cysts cytologically false positive and false negative diagnosis was 0% and 46.6% respectively with specificity and sensitivity of 100% and 53%. For mucinous cystadenomas sensitivity and specificity of cytological diagnosis was 100%. For endometriotic cysts a sensitivity of 67% and specificity of 100% was procured with cytological evaluation. CONCLUSION: Guided fine needle aspiration cytology may prove to be one of the most valuable and acceptable tools in the differential diagnosis of ovarian cystic lesions.
Rinderpest is an acute and highly contagious viral disease of ruminants, often resulting in greater than 90% mortality. We previously reported the development of first- and second-generation recombinant vaccinia virus vaccines which provide complete protection against rinderpest virus (RPV) and peste-des-petits ruminants virus (PPRV). These vaccines are safe even for immunodeficient mice and macaques with acquired immunodeficiency syndrome. We developed a third-generation recombinant vaccinia virus vaccine (v2RVFH) that expresses the fusion and haemagglutinin genes of RPV under strong synthetic vaccinia virus promoters. Cattle vaccinated intramuscularly with as little as 10(3) plaque-forming units (PFU) of v2RVFH were completely protected from rinderpest. Vaccinated animals did not develop pock lesions or transmit v2RVFH to contact animals. Cattle vaccinated with a standard dose of 10(8) PFU of v2RVFH developed long-term, sterilizing immunity against rinderpest. Thus, v2RVFH is safe, efficacious, heat stable, inexpensive, easily administered, and allows serological differentiation between vaccinated and infected animals. To aid in diagnosis and differentiation of vaccinated from infected animals, we developed indirect ELISAs (iELISAs) that use baculovirus-expressed RPV or PPRV nucleoprotein as coating antigens. A single larva contains enough viral antigen to test more than 10,000 serum samples, in duplicate. African scientists trained at the ILMB successfully transferred the iELISA kit technology to more than 30 countries in Africa, providing a model for technology transfer among developing countries. Vaccination with v2RVFH, in conjunction with the iELISA kits, greatly enhances the prospects for global eradication of rinderpest, as developing nations achieve independence in control efforts.
SETTING: Sputum samples were collected from suspected tuberculosis patients attending out-patient clinics at the Ojha Institute of Chest Diseases, Karachi, Pakistan. OBJECTIVE: To evaluate the performance of the FASTPlaqueTB assay for rapid diagnosis of pulmonary tuberculosis. DESIGN: A comparative study of 584 sputum samples using acid-fast smear microscopy, Lowenstein-Jensen culture and FASTPlaqueTB. RESULTS: A total of 514 samples yielded complete results. Seventy specimens were lost to analysis due to the overgrowth of contaminants. The addition of antimicrobials inhibited growth of gram-positive contaminants, and reduced the overall contamination rate from 18.2% to 7.2%. Mycobacterium tuberculosis was isolated from 175 smear-positive and 70 smear-negative specimens. FASTPlaqueTB detected M. tuberculosis in 81.6% of specimens, with a specificity of 97.7%. The sensitivity and specificity of the assay for smear-positive specimens were respectively 87.4% and 88.2%. For smear-negative specimens, the sensitivity of the assay was 67.1% and the specificity was 98.4%. The combined sensitivity of smear and FASTPlaqueTB for M. tuberculosis was 90%. Test results were available in 48 hours. CONCLUSION: FASTPlaqueTB is a sensitive and specific test for rapid diagnosis of pulmonary tuberculosis in high prevalence areas. The test is sensitive enough to confirm a large number of clinically suspected smear-negative cases and improve case finding.
The Sangiran dome is the primary stratigraphic window for the Plio-Pleistocene deposits of the Solo basin of Central Jawa. The dome has yielded nearly 80 Homo erectus fossils, around 50 of which have known findspots. With a hornblende (40)Ar/(39)Ar plateau age of 1.66 +/- 0.04 mega-annum (Ma) reportedly associated with two fossils [Swisher, C.C., III, Curtis, G. H., Jacob, T., Getty, A. G., Suprijo, A. & Widiasmoro (1994) Science 263, 1118-1121), the dome offers evidence that early Homo dispersed to East Asia during the earliest Pleistocene. Unfortunately, the hornblende pumice was sampled at Jokotingkir Hill, a central locality with complex lithostratigraphic deformation and dubious specimen provenance. To address the antiquity of Sangiran H. erectus more systematically, we investigate the sedimentary framework and hornblende (40)Ar/(39)Ar age for volcanic deposits in the southeast quadrant of the dome. In this sector, Bapang (Kabuh) sediments have their largest exposure, least deformation, and most complete tephrostratigraphy. At five locations, we identify a sequence of sedimentary cycles in which H. erectus fossils are associated with epiclastic pumice. From sampled pumice, eight hornblende separates produced (40)Ar/(39)Ar plateau ages ranging from 1.51 +/- 0.08 Ma at the Bapang/Sangiran Formation contact, to 1.02 +/- 0.06 Ma, at a point above the hominin-bearing sequence. The chronological sequence of (40)Ar/(39)Ar ages follows stratigraphic order across the southeast quadrant. An intermediate level yielding four nearly complete crania has an age of about 1.25 Ma.
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Histone genes display a peak in transcription in early S phase and are ideal models for cell cycle-regulated gene expression. We have previously shown that the transcription factor interferon regulatory factor 2 (IRF-2) can activate histone H4 gene expression. In this report we establish that a mouse histone H4 gene and its human homolog lose stringent cell cycle control in synchronized embryonic fibroblasts in which IRF-2 has been ablated. We also show that there are reduced mRNA levels of this endogenous mouse histone H4 gene in the IRF-2(-/-) cells. Strikingly, the overall mRNA level and cell cycle regulation of histone H4 transcription are restored when IRF-2 is reintroduced to these cells. IRF-2 is a negative regulator of the interferon response and has oncogenic potential, but little is known of the mechanism of these activities. Our results suggest that IRF-2 is an active player in E2F-independent cell cycle-regulated gene expression at the G1/S phase transition. IRF-2 was previously considered a passive antagonist to the tumor suppressor IRF-1 but can now join other oncogenic factors such as c-Myb and E2F1 that are predicted to mediate their transforming capabilities by actively regulating genes necessary for cell cycle progression.
Cell cycle control of histone H4 gene transcription is mediated by the multipartite promoter domain H4-Site II, which supports transcriptional activation at the G1/S phase transition and modulates basal H4 gene transcription. Proliferation-specific transcription is determined by the integrated activities of three distinct promoter factors interacting with H4-Site II: the interferon regulatory factor IRF-2 (synonymous with HiNF-M), HiNF-D (a complex between the homeodomain protein CDP-cut and the cell cycle mediators CDC2, cyclin A and pRB), as well as HiNF-P/H4TF-2. However, the contribution of HiNF-D to the enhancement and/or suppression of H4 gene transcription at specific cell cycle stages remains to be established. We used a panel of synchronized HeLa S3 cell lines containing stably integrated H4 promoter/CAT reporter gene constructs with mutations in H4-Site II. The temporal regulation of CAT mRNA accumulation under the control of the H4 promoter was analyzed by RNase protection analysis. Our main finding is that mutation of the HiNF-D/CDP-cut binding site alters the timing of histone gene activation during the cell cycle. Furthermore, our data indicate that HiNF-P/H4TF-2 may functionally compensate for HiNF-M/IRF-2 at Site II to regulate histone H4 gene transcription in HeLa S3 cervical carcinoma cells during early S phase. We postulate that HiNF-D (CDP-cut/cyclin A/CDC2/pRB containing complex) promotes HiNF-M/IRF-2 (and/or HiNF-P/H4TF-2) dependent histone H4 gene activation at the G1/S phase transition and attenuates H4 gene transcription at later cell cycle stages. The mechanistic division in the gene regulatory functions of the three H4-Site II binding proteins may ensure that histone H4 gene expression is stringently coupled with the onset of S phase in response to growth factor/cytokine-induced cell cycle progression.
Maximal transcription of a prototypical cell cycle controlled histone H4 gene requires a proliferation-specific in vivo genomic protein/DNA interaction element, Site II. Three sequence-specific transcription factors interact with overlapping recognition motifs within Site II: interferon regulatory factor IRF-2 (HiNF-M), the putative H4 subtype-specific protein H4TF-2 (HiNF-P), and HiNF-D which represents a complex of the homeodomain protein CDP/cut, CDC2, cyclin A and pRB. However, natural sequence variation in the Site II sequences of different human H4 genes abolishes binding of specific trans-acting factors; the functional consequences of these variations have not been investigated. To address the precise contribution of H4 promoter factors to the level of H4 gene transcription, we performed a systematic mutational analysis of Site II transcriptional motifs. These mutants were tested for ability to bind each of the Site II cognate proteins, and subsequently evaluated for ability to confer H4 transcriptional activity using chimeric H4 promoter/CAT fusion constructs in different cell types. We also analyzed the effect of over-expressing IRF-2 on CAT reporter gene expression driven by mutant H4 promoters and assessed H4 transcriptional control in cells nullizygous for IRF-1 and IRF-2. Our results show that the recognition sequence for IRF-2 (HiNF-M) is the dominant component of Site II and modulates H4 gene transcription levels by 3 fold. However, the overlapping recognition sequences for IRF-2 (HiNF-M), H4TF-2 (HiNF-P) and CDP/cut (HiNF-D) together modulate H4 gene transcription levels by at least an order of magnitude. Thus, maximal activation of H4 gene transcription during the cell cycle in vivo requires the integrated activities of multiple transcription factors at Site II. We postulate that the composite organization of Site II supports responsiveness to multiple signalling pathways modulating the activities of H4 gene transcription factors during the cell cycle. Variations in Site II sequences among different H4 genes may accommodate differential regulation of H4 gene expression in cells and tissues with unique phenotypic properties.
The histone H4 gene promoter provides a paradigm for defining transcriptional control operative at the G1/S phase transition point in the cell cycle. Transcription of the cell cycle-dependent histone H4 gene is upregulated at the onset of S phase, and the cell cycle control element that mediates this activation has been functionally mapped to a proximal promoter domain designated Site II. Activity of Site II is regulated by an E2F-independent mechanism involving binding of the oncoprotein IRF2 and the multisubunit protein HiNF-D, which contains the homeodomain CDP/cut, CDC2, cyclin A, and the tumor suppressor pRb. To address mechanisms that define interactions of Site II regulatory factors with this cell cycle control element, we have investigated these determinants of transcriptional regulation at the G1/S phase transition in FDC-P1 hematopoietic progenitor cells. The representation and activities of histone gene regulatory factors were examined as a function of FDC-P1 growth stimulation. We find striking differences in expression of the pRb-related growth regulatory proteins (pRb/p105, pRb2/p130, and p107) following the onset of proliferation. pRb2/p130 is present at elevated levels in quiescent cells and declines following growth stimulation. By contrast, pRb and p107 are minimally represented in quiescent FDC-P1 cells but are upregulated at the G1/S phase transition point. We also observe a dramatic upregulation of the cellular levels of pRb2/p130-associated protein kinase activity when S phase is initiated. Selective interactions of pRb and p107 with CDP/cut are observed during the FDC-P1 cell cycle and suggest functional linkage to competency for DNA binding and/or transcriptional activity. These results are particularly significant in the context of hematopoietic differentiation where stringent control of the cell cycle program is requisite for expanding the stem cell population during development and tissue renewal.
Recent evidence indicates that chronic autoimmune disease can result from breakdown of regulation and subsequent activation of self-reactive T cells. In many murine autoimmune disease systems and in the Lewis rat, antigen-specific T cells utilizing the T cell receptor (TCR) Vbeta8.2 gene segment play a major role. In the myelin basic protein-induced experimental autoimmune encephalomyelitis (EAE) model in H-2(u) mice, we had shown that T cells recognizing a peptide determinant within the framework 3 region of the Vbeta8.2 chain have a critical role in influencing the course of the disease. Here, we report experiments in another disease system, collagen II (CII)-induced arthritis (CIA) in DBA/1LacJ (H-2(q)) mice, indicating a remarkably parallel control circuit to that found for EAE. A critical role is played by CII-specific Vbeta8.2-bearing T cells in the CIA system, which we have confirmed. Animals treated with the superantigen SEB before CII administration are significantly protected from CIA. Next, we tested the ability of peptides encompassing the entire Vbeta8.2 chain to induce proliferative responses. Only TCR peptide B5 (amino acids 76-101), a regulatory peptide in EAE, induced proliferation. B5 was then used to vaccinate DBA/1LacJ mice and was shown to reduce greatly the severity and incidence of CIA as measured by joint inflammation or histology. Furthermore, similar protection was found when B5 was administered after CII immunization. It was shown that there is physiological induction of a proliferative response to B5 during CIA and that the determinant within B5 is produced from a single chain TCR construct containing the entire Vbeta8.2 chain. Finally, the regulation of CIA is discussed in the context of other experimental autoimmune diseases, especially EAE, with emphasis on what appear to be strikingly common mechanisms.
The human histone H4 gene FO108 is regulated during the cell cycle with a peak in transcription during early S phase. The cell-cycle element (CCE) required for H4 histone activation is a sequence of 11 base pairs that binds a protein factor in electrophoretic mobility shift assays that has been designated histone nuclear factor M (HiNF-M). Here we report the purification of HiNF-M, and show it to be a protein of relative molecular mass (M(r)) 48K that is identical to interferon (IFN) regulatory factor 2 (IRF-2), a negative transcriptional regulator of the IFN response. Recombinant IRF-2 (as well as the related protein IRF-1 (ref. 5)) binds the CCE specifically and activates transcription of this H4 histone gene. IRF-2 has been shown to have oncogenic potential, and our results demonstrate a link between IRF-2 and a gene that is functionally coupled to DNA replication and cell-cycle progression at the G1/S phase transition.
The promoter of the cell cycle regulated histone FO108 H4 gene is mediated by two in vivo protein/DNA interaction domains, sites I and II. We have shown previously that site II mediates the cell cycle controlled enhancement of H4 gene transcription at the G1/S phase boundary. Here we show that site I, an element containing both G-rich and ATF-like consensus sequences, confers maximal levels of transcription in proliferating cells. By the combined application of gel shift assays with site-directed mutagenesis, DNase I footprinting, oligonucleotide competition, in vitro expression of recombinant proteins, and specific antibody supershift studies, we demonstrate that the proximal G-rich sequence within site I interacts with the transcription factor Sp1, while the distal portion of site I interacts with members of the ATF family of proteins, including ATF-1. In vitro transcription studies as well as expression assays of transiently and stably transfected genes in HeLa cells reveal that the deletion of site I causes a dramatic decrease in expression. Mutation of the Sp1 element, which abolishes Sp1 binding, results in a 6-10-fold reduction in reporter activity. In addition, overexpression of Sp1 in Sp1-deficient cells results in the dramatic activation of the histone promoter. In contrast, mutation of the asymmetric ATF binding site, located distally within site I, has a more limited effect upon expression. Interestingly, the contribution of the Sp1 site to maximal transcription was cell type dependent. Thus, we demonstrate that the Sp1 binding site of the site I histone H4 promoter in particular is critical for maximal expression in living cells and postulate that this site may act to amplify the cell cycle response.
To evaluate transcriptional mechanisms during cytokine induction of myeloid progenitor cell proliferation, we examined the expression and activity of transcription factors that control cell cycle-dependent histone genes in interleukin-3 (IL-3)-dependent FDC-P1 cells. Histone genes are transcriptionally upregulated in response to a series of cellular regulatory signals that mediate competency for cell cycle progression of the G1/S-phase transition. We therefore focused on factors that are functionally related to activity of the principal cell cycle regulatory element of the histone H4 promoter: CDC2, cyclin A, as well as RB- and IRF-related proteins. Comparisons were made with activities of ubiquitous transcription factors that influence a broad spectrum of promoters independent of proliferation or expression of tissue-specific phenotypic properties. Northern blot analysis indicates that cellular levels of cyclin A and CDC2 mRNAs increase when DNA synthesis and H4 gene expression are initiated, supporting involvement in cell cycle progression. Using gel-shift assays, incorporating factor-specific antibody and oligonucleotide competition controls, we define three sequential period following cytokine stimulation of FDC-P1 cells when selective upregulation of a subset of transcription factors is observed. In the initial period, the levels of SP1 and HiNF-P are moderately elevated; ATF, AP-1, and HiNF-M/IRF-2 are maximal during the second period; while E2F and HiNF-D, which contain cyclin A as a component, predominate during the third period, coinciding with maximal H4 gene expression and DNA synthesis. Differential regulation of H4 gene transcription factors following growth stimulation is consistent with a principal role of histone gene promoter elements in integrating cues from multiple signaling pathways that control cell cycle induction and progression. Regulation of transcription factors controlling histone gene promoter activity within the context of a staged cascade of responsiveness to cyclins and other physiological mediators of proliferation in FDC-P1 cells provides a paradigm for experimentally addressing interdependent cell cycle and cell growth parameters that are operative in hematopoietic stem cells.
Cell cycle-controlled human histone genes are coordinately expressed during S phase, and transcriptional regulation involves a series of trans-acting factors (HiNFs). The proliferation-specific factor HiNF-D interacts with multiple recognition motifs in histone H4, H3, and H1 promoters. Using gel shift immunoassays, we show that CDC2, cyclin A, and an RB-related protein are ubiquitous subunits of HiNF-D binding activity isolated from several cell types. HiNF-D levels in vivo are sensitive to okadaic acid and staurosporine, indicating that HiNF-D activity and/or assembly is influenced by phosphorylation status. Thus, HiNF-D appears to be a multicomponent phosphoprotein that participates in coordinate control of multiple histone H4, H3, and H1 genes during the cell cycle. The presence of cell cycle mediators in the HiNF-D complex suggests linkage between transcriptional control of histones, enzymes involved in DNA synthesis, and the onset of DNA replication during the G1/S phase transition.