Biomedical subjects
M Gibson
Publications and source records attributed to M Gibson.
The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway.
The molecular pathway of p53-dependent apoptosis (programmed cell death) is poorly understood. Because p53 binds to the basal transcription-repair complex TFIIH and modulates its DNA helicase activities, we hypothesized that TFIIH DNA helicases XPB and XPD are members of the p53-mediated apoptotic pathway. Whereas transfer of a wild-type p53 expression vector by microinjection or retroviral infection into primary normal human fibroblasts resulted in apoptosis, primary fibroblasts from individuals with xeroderma pigmentosum (XP), who are deficient in DNA repair and have germ-line mutations in the XPB or XPD gene, but not in the XPA or XPC gene, have a deficiency in the apoptotic response. This deficiency can be rescued by transferring the wild-type XPB or XPD gene into the corresponding mutant cells. XP-D lymphocytes also have a decreased apoptotic response to DNA damage by adriamycin, indicating a physiologically relevant deficiency. The XP-B or XP-D mutant cells undergo a normal apoptotic response when microinjected with the Ich-L, and ICE genes. Analyses of p53 mutants and the effects of microinjected anti-p53 antibody, Pab421, indicate that the carboxyl terminus of p53 may be required for apoptosis. Direct microinjection of the p53 carboxy-terminal-derived peptide (amino acid residues 319-393) resulted in apoptosis of primary normal human fibroblasts. These results disclose a novel pathway of p53-induced apoptosis.
Meeting the skills crisis in nursing homes.
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Neuropsychological performance, disease severity, and depression in progressive supranuclear palsy.
To investigate the relationship between disease severity, cognitive impairment and depression in progressive supranuclear palsy (PSP) we studied a group of 25 patients who fulfilled strict research criteria and 25 matched controls. Disease severity was judged from the duration of symptoms, level of physical disability using the Columbia Rating Scale (CRS), and the degree of eye movement abnormality. The neuropsychological battery was designed to assess attention and executive function, visual and auditory perception, semantic memory and language production. Although the PSP group were significantly impaired on almost all of these measures, the most profound deficits were on tests of sustained and divided attention. There was no correlation between cognitive impairment and either disease duration or scores on the CRS, but performance on tests of attention correlated significantly with the degree of ocular motor impairment. Depression was found to be common in PSP but did not correlate with any other parameters. It is concluded that the cognitive deficit in PSP is widespread and independent of depression. The association between the severity of eye movement disorder and deficits in sustained and divided attention leads us to postulate that pathology involving the midbrain periaqueductal region may be critical for breakdown in these fundamental processes.
Analysis of the human gene encoding latent transforming growth factor-beta-binding protein-2.
Transforming growth factor (TGF)-beta is secreted as an inactive complex, which frequently contains a large molecular weight binding protein designated latent TGF-beta-binding protein (LTBP). Recently, the LTBPs have been shown to be a gene family that contains three known members and exhibits a multidomain structure containing cysteine-rich motifs that are also found in the fibrillin gene family. The present work seeks to characterize the gene encoding LTBP-2 and to compare its features to that of the other LTBPs and to the fibrillins. Human fibroblast libraries were used to isolate cDNA encoding LTBP-2 which was then used to identify LTBP-2 transcripts and to isolate the corresponding LTBP-2 gene. The cloned cDNA encodes a 195 kDa protein containing 20 epidermal growth factor (EGF)-like repeats, three repeats containing eight cysteines, and one segment that appears to be a hybrid of the two. Single exons encode EGF repeats while the eight-cysteine repeats are encoded in two exons. Northern analysis identified two transcripts of 7.5 and 9.0 kb, with the presently analyzed cDNA probably corresponding to the 7.5 transcript. Phylogenetic sequence comparisons demonstrated that LTBP-3 is more similar to LTBP-1 than LTBP-2, while LTBP-2 shows the most similarity to the fibrillins. These analyses suggest that LTBP-1 diverged from LTBP-3, and that LTBP-2 diverged from LTBP-1. Within the fibrillin family, fibrillin-1 is nearest to the LTBPs. While the domain structure of LTBP-2 is similar to that of the other LTBPs, LTBP-2 possesses unique regions that make it the largest member of the LTBP family. LTBP-2 may have dual functions as a member of the TGF-beta latent complex and as a structural component of microfibrils.
Technical report: fluoroscopically controlled retrieval of intra-uterine contraceptive devices.
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Radial artery approach for outpatient peripheral arteriography.
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The association of intrauterine filling defects on hysterosalpingogram with endometriosis.
OBJECTIVE: To determine whether there is a significant association between the presence of polyps or polypoid endometrium on hysterosalpingogram (HSG) with the presence of pelvic or peritoneal endometriosis. DESIGN: Retrospective chart review. SETTING: Department of Reproductive Endocrinology and Infertility at the University of Vermont, College of Medicine. PATIENTS: One hundred twenty patients, all of whom had a HSG, hysteroscopy, and laparoscopy by a member of our department between 1989 and 1993. MAIN OUTCOME MEASURE: Hysterosalpingograms were assessed for the presence of hypertrophic or polypoid endometrium. The presence of endometriosis was documented laparoscopically and scored according to The American Fertility Society classification and HSG findings were documented by hysteroscopy. RESULTS: Endometriosis was found in 27 of 32 women with polyps or polypoid endometrium but in only 19 of 88 women without. chi 2 analysis revealed a significant association between the demonstration of polyps or polypoid endometrium on HSG and the presence of endometriosis, chi 2(1) = 33.97. The predictive value of a positive test was 84% and the negative predictive value was 75%. CONCLUSION: The presence of polyps or polypoid endometrium on HSG is significantly associated with the presence of pelvic or peritoneal endometriosis.
A putative Mg chelatase subunit from Arabidopsis thaliana cv C24. Sequence and transcript analysis of the gene, import of the protein into chloroplasts, and in situ localization of the transcript and protein.
We have isolated and sequenced a cDNA from Arabidopsis thaliana cv C24 that encodes a putative Mg chelatase subunit. The deduced amino acid sequence shows a very high level of identity to a gene previously characterized from Antirrhinum majus (olive and also high similarity to bchH, a bacterial gene involved in the Mg chelatase reaction of bacteriochlorophyll biosynthesis. We suggest that this gene be called CHL H. Northern blot analyses were used to investigate the expression of CHL H, another putative Mg chelatase gene, ch-42, and ferrochelatase. The CHL H transcript was observed to undergo a dramatic diurnal variation, rising almost to its maximum level by the end of the dark period, then increasing slightly at the onset of the light and declining steadily to a minimum by the end of the light period; in contrast, transcripts for ch-42 and ferrochelatase remained constant. A model is proposed in which the CHL H protein plays a role in regulating the levels of chlorophyll during this cycle. In situ hybridization revealed that the transcripts are located over the surface of the chloroplasts, a feature in common with transcripts for the ch-42 gene. The CHL H protein was imported into the stromal compartment of the chloroplast and processed in an in vitro assay. Immunoblotting showed that the distribution of CHL H protein between the stroma and chloroplast membranes varies depending on the concentration of Mg+. In situ immunofluorescence was used to establish that the CHL H and CH-42 proteins are localized within the chloroplast in vivo.
Intracranial imaging.
This article concentrates on the imaging of intracranial structures and outlines some basic imaging strategies for common clinical presentations.
Imaging the spine.
This article on neuroradiology concerns the imaging of the spine. The imaging modalities are discussed, and some basic imaging strategies are outlined.
Homogentisic acid interference in the measurement of urinary protein using benzethonium chloride.
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Health promotion for a group of elderly clients.
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Reproductive health and polycystic ovary syndrome.
Women with hyperandrogenic disorders represent a unique group among those with infertility due to anovulation. Although antiestrogens are effective in restoring ovulation in most women, it remains unclear whether these treatments restore fecundability per ovulatory cycle and the ability to maintain pregnancy in these individuals. Moreover, antiestrogens are ineffective in restoring ovulation in some hyperandrogenic anovulatory women, whose condition poses unique and vexing challenges for the infertility therapist. Gonadotropin treatment in antiestrogen-resistant women often leads to ovarian hyperstimulation syndrome, which has been addressed by modification of dosing schedules (e.g., low-dose administration), pretreatment with gonadotropin-releasing hormone (GnRH) analogs, and elimination of luteinizing hormone from the administered gonadotropins. Surgical reduction in ovarian volume has met with some success, although there may be a risk of inducing surgical adhesions of the adnexa. The second major reproductive adversity facing these patients is their elevated risk of endometrial cancer. Unopposed estrogen exposure probably contributes to this risk, but hyperandrogenicity and hyperinsulinism may act independently or in concert with estrogen to amplify the risk in these women. While the risks and strategies for preventive care in these women need to be better defined, reproductive health specialists are urged to continue using presently accepted measures, including education, to maintain these women's reproductive health.
Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning?
BACKGROUND: Ischemic preconditioning has been shown to reduce myocardial infarct size in experimental models, but its role in patients remains unclear. Angina before myocardial infarction reflects brief episodes of ischemia and may be a marker of preconditioning. As part of the Thrombolysis in Myocardial Infarction (TIMI) 4 study, we performed an analysis on the effect of a history of previous angina on in-hospital outcomes for patients with acute myocardial infarction. METHODS AND RESULTS: Patients eligible for thrombolytic therapy were enrolled into the study. Data were collected from case report forms regarding previous history of angina, in-hospital outcome and 6-week follow-up. Two hundred eighteen patients had a history of previous angina at any time before acute myocardial infarction, and 198 patients did not have previous angina. Patients with any previous history of angina were less likely than with those without angina to experience in-hospital death (3% versus 8%) (P = .03), severe congestive heart failure (CHF) or shock (1% versus 7%, P = .006), or the combined end point of in-hospital death, severe CHF, or shock (4% versus 12%, P = .004). Moreover, patients with any history of angina were more likely to have a smaller creatine kinase (CK)-determined infarct size (119 versus 154 CK integrated units; P = .01) and were less likely to have Q waves on their ECG (57% versus 69%; P = .01). In the subset of patients who experienced angina within the 48 hours before infarction (compared with those who did not), there was a trend toward less likely in-hospital death (3% versus 6%; P = .09), a lower incidence of severe CHF or shock (1% versus 6% P = .008), a lower combined end point of death, CHF, or shock (3% versus 10%; P = .006), smaller infarct size assessed by CK (115 versus 151 CK units; P = .03), and a trend toward fewer Q-wave infarcts. However, patients with a history of previous angina did have a trend toward more recurrent ischemic pain. Of importance is that the beneficial in-hospital effects of previous angina were not dependent on angiographically visible coronary collaterals. CONCLUSIONS: Previous angina confers a beneficial effect on in-hospital outcome after acute myocardial infarction. The reasons for this benefit are uncertain, but one potential mechanism for this observation may be ischemic preconditioning.
Elevated conversion of alpha-2-macroglobulin to the complexed form in gingival crevicular fluid from adult periodontitis patients.
The broad spectrum protease inhibitor, alpha 2-macgrolobulin (alpha 2M), is one of the host's principal regulators of both endogenous and exogenous proteases and is likely to have an important role in the regulation of proteolytic activity at inflammatory sites. We have determined the amount of complexed (com alpha 2M) and total alpha 2M (tot alpha 2M) in gingival crevicular fluid (GCF) harvested from shallow and deep sites in adult periodontitis (AP) patients (n = 21). An ELISA technique was developed to measure both forms of alpha 2M in the same sample utilizing a monoclonal antibody (MAb) specific for the complexed form. In addition, protease activity towards human serum albumin (Prot1), transferrin (Prot2) and N alpha-benzoyl-L-arginine 7-amido-4-methylcoumarin-hydrochloride (BAAMc; Prot3) were determined in a second GCF sample from the same site. Plasma alpha 2M concentrations were only positively correlated (p = 0.0163) with GCF tot alpha 2M from highly inflamed sites. We observed a significant positive correlation between tot alpha 2M and proteolytic activity in GCF from deep sites but not from shallow sites (Prot1: p = 0.002; Prot2: p = 0.005). A similar correlation between tot alpha 2M and proteolytic activity was found at highly inflamed sites (Prot1: p = 0.014; Prot2: p = 0.002). A very high proportion of the tot alpha 2M in GCF was in the complexed form at both shallow (71.14% +/- 29.13) and deep sites (68.17% +/- 28.5) Com alpha 2M was positively correlated with proteolytic activity only in deep sites (Prot1: p = 0.015; Prot2: p = 0.031). Our results suggest that the concentration of tot alpha 2M in the gingival crevice is positively associated with the amount of proteolytic activity at the site and that protease activities in GCF may only partly explain the high percentage conversion alpha 2M to the complexed form. The high level of alpha 2M inactivation in GCF from AP patients reported here may have significance not only in view of its role as a broad spectrum protease inhibitor but also through the differential effects of native vs complexed alpha 2M on the regulation of immune responses.
Properties of a progesterone-induced relaxation in human placental arteries and veins.
To study the effects of progesterone on placental vascular tone, we used isolated (1-2 mm in diameter) placental arteries and veins from term uncomplicated pregnancies. These vessels, incubated in Krebs buffer (pH 7.4) under 5% O2-5% CO2 (balance N2, PO2 approximately 35 torr) and precontracted with serotonin were exposed to incremental doses of progesterone (0.01-30 mumol/L) in the presence or absence of endothelium, 10 mumol/L indomethacin (inhibits prostaglandin synthesis), 10 mumol/L methylene blue (a soluble guanylate cyclase inhibitor), 100 mumol/L nitro-L-arginine (inhibits L-arginine metabolism), 1 mmol/L isobutylmethylxanthine (a cAMP phosphodiesterase inhibitor), or 30 mumol/L mifepristone (RU 38486, an antiprogestin). Progesterone elicited an acute dose-dependent relaxation in both arteries and veins that was not altered by removal of the endothelium or pretreatment with indomethacin, nitro-L-arginine, or methylene blue, excluding a role for prostaglandins, L-arginine products, or cGMP in mediating this relaxation. However, isobutylmethylxanthine significantly enhanced the relaxation in response to progesterone, suggesting a role for cAMP. RU 38486 inhibited the relaxation by 50-100%, depending on the progesterone dose, consistent with a role for progesterone receptors. These results suggest that progesterone causes a dose-dependent endothelium-independent relaxation of human placental arteries and veins. This relaxation seems to be mediated by a receptor-activated cAMP mechanism and could be physiologically important in maintaining low resistance and adequate blood flow in the placental circulation.
Case report: renal transplant artery stenosis--three cases where magnetic resonance angiography was superior to conventional arteriography.
Stenosis of renal transplant arteries is a common cause of graft dysfunction and hypertension. Conventionally it is investigated by intraarterial digital subtraction angiography (IA DSA). Recently three-dimensional phase contrast magnetic resonance angiography (MRA) has been used successfully as a non-invasive method of assessing renal transplant arteries. We report three cases where MRA was superior to IA DSA in the detection of renal transplant artery stenosis.