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Biomedical subjects

M Lindsay

Publications and source records attributed to M Lindsay.

At least 19 recordsLinked to original sources
PubMed2002

Hysterectomy and ovarian function: levels of follicle stimulating hormone and incidence of menopausal symptoms are not affected by hysterectomy in women under age 45 years.

OBJECTIVE: To investigate levels of follicle stimulating hormone (FSH), as a measure of ovarian function and menopausal symptoms prior to and following hysterectomy in women under the age of 45 years. DESIGN: This was a prospective controlled study. SAMPLE: A total of 56 hysterectomy patients and 34 controls, up to the age of 42 years, were recruited. METHODS: Women undergoing hysterectomy were recruited prior to their operation and were matched, where possible, with controls for age, parity and smoking. Five blood samples were taken over 2 years, two before the operation (or at a 1-month interval in the control group) and then at 6 months, 1 year and 2 years. Questionnaires were completed at each sampling to assess symptoms associated with reduced estrogen secretion. RESULTS: No significant differences in FSH levels between patients and controls were found. Modest differences in FSH levels between different time-points were identified (p = 0.03), but this disappeared if age and smoking were included as covariates. For the questionnaire data, there were no significant differences between the two groups on the somatic and vasomotor scales, but for psychological symptoms the patients scored significantly higher than the controls (p = 0.007), particularly at the pre-operation time-point. CONCLUSION: The study found no evidence of compromise of ovarian function, as reflected in FSH levels, within 2 years of hysterectomy. Psychological symptoms were higher in women undergoing hysterectomy both before and after the operation.

Adult↗
PubMed2001

Myosin VI isoform localized to clathrin-coated vesicles with a role in clathrin-mediated endocytosis.

Myosin VI is involved in membrane traffic and dynamics and is the only myosin known to move towards the minus end of actin filaments. Splice variants of myosin VI with a large insert in the tail domain were specifically expressed in polarized cells containing microvilli. In these polarized cells, endogenous myosin VI containing the large insert was concentrated at the apical domain co-localizing with clathrin- coated pits/vesicles. Using full-length myosin VI and deletion mutants tagged with green fluorescent protein (GFP) we have shown that myosin VI associates and co-localizes with clathrin-coated pits/vesicles by its C-terminal tail. Myosin VI, precipitated from whole cytosol, was present in a protein complex containing adaptor protein (AP)-2 and clathrin, and enriched in purified clathrin-coated vesicles. Over-expression of the tail domain of myosin VI containing the large insert in fibroblasts reduced transferrin uptake in transiently and stably transfected cells by >50%. Myosin VI is the first motor protein to be identified associated with clathrin-coated pits/vesicles and shown to modulate clathrin-mediated endocytosis.

Amino Acid Sequence↗
PubMed2001

Mobilization of MHC class I molecules from late endosomes to the cell surface following activation of CD34-derived human Langerhans cells.

Langerhans cells are a subset of dendritic cells (DCs) found in the human epidermis with unique morphological and molecular properties that enable their function as "sentinels" of the immune system. DCs are pivotal in the initiation and regulation of primary MHC class I restricted T lymphocyte immune responses and are able to present both endogenous and exogenous antigen onto class I molecules. Here, we study the MHC class I presentation pathway following activation of immature, CD34-derived human Langerhans cells by lipopolysaccharide (LPS). LPS induces an increase in all components of the MHC class I pathway including the transporter for antigen presentation (TAP), tapasin and ERp57, and the immunoproteasome subunits LMP2 and LMP7. Moreover, in CD34-derived Langerhans cells, the rapid increase in expression of MHC class I molecules seen at the cell surface following LPS activation is because of mobilization of MHC class I molecules from HLA-DM positive endosomal compartments, a pathway not seen in monocyte-derived DCs. Mobilization of class I from this compartment is primaquine sensitive and brefeldin A insensitive. These data demonstrate the regulation of the class I pathway in concert with the maturation of the CD34-derived Langerhans cells and suggest potential sites for antigen loading of class I proteins.

Antigens, CD34↗
PubMed2001

A caveolin dominant negative mutant associates with lipid bodies and induces intracellular cholesterol imbalance.

Recent studies have indicated a role for caveolin in regulating cholesterol-dependent signaling events. In the present study we have analyzed the role of caveolins in intracellular cholesterol cycling using a dominant negative caveolin mutant. The mutant caveolin protein, cav-3(DGV), specifically associates with the membrane surrounding large lipid droplets. These structures contain neutral lipids, and are accessed by caveolin 1-3 upon overexpression. Fluorescence, electron, and video microscopy observations are consistent with formation of the membrane-enclosed lipid rich structures by maturation of subdomains of the ER. The caveolin mutant causes the intracellular accumulation of free cholesterol (FC) in late endosomes, a decrease in surface cholesterol and a decrease in cholesterol efflux and synthesis. The amphiphile U18666A acts synergistically with cav(DGV) to increase intracellular accumulation of FC. Incubation of cells with oleic acid induces a significant accumulation of full-length caveolins in the enlarged lipid droplets. We conclude that caveolin can associate with the membrane surrounding lipid droplets and is a key component involved in intracellular cholesterol balance and lipid transport in fibroblasts.

Amino Acid Sequence↗
PubMed2001

Vaginal birth after cesarean among women with gestational diabetes.

OBJECTIVE: We sought to determine the pregnancy and infant outcomes of women with gestational diabetes who attempted vaginal birth after previous cesarean delivery. STUDY DESIGN: We conducted a retrospective cohort study to compare women with gestational diabetes with matched control subjects without diabetes who attempted vaginal birth after cesarean at Grady Memorial Hospital, Atlanta, from January 1, 1989, through December 31, 1999. One hundred fifty-six women with gestational diabetes were matched with 272 control subjects. Data were analyzed with the Student t test, chi2 analysis, and the Fisher exact test. RESULTS: The parities of the women with gestational diabetes and the control subjects were similar, with most having had only one previous pregnancy. Women with gestational diabetes were significantly older than control subjects and more likely to be white or Hispanic. Women with gestational diabetes who attempted a trial of labor were significantly more likely than control subjects to be delivered abdominally. Women with gestational diabetes who had a successful vaginal birth after cesarean were significantly more likely than control subjects to have an operative delivery with forceps or vacuum. CONCLUSION: Women with gestational diabetes are less likely than those without diabetes to have a successful trial of labor. Women with gestational diabetes considering vaginal birth after cesarean should be appropriately counseled about the risk of attempting a trial of labor after previous cesarean delivery.

Adult↗
PubMed2001

Trends in operative vaginal delivery rates and associated maternal complication rates in an inner-city hospital.

OBJECTIVE: The aims of this study were to determine trends in operative vaginal delivery rates in a large inner-city hospital and to assess associated risks. STUDY DESIGN: We performed a retrospective cohort study (1980-1996) of women with singleton term pregnancies who underwent operative vaginal delivery at Grady Memorial Hospital, Atlanta. Maternal complication rates were compared between forceps-assisted and vacuum-assisted methods. RESULTS: There was a decline in forceps-assisted deliveries during the 1980s and an increase during the 1990s. The vacuum-assisted delivery rate was exceedingly low during the 1980s and increased during the 1990s. Women who underwent forceps-assisted delivery were more likely to be <24 years old, to be nulliparous, and to have had regional anesthesia, midline episiotomies, and infant presentations other than occipitoanterior (P <.001). Women who underwent forceps-assisted deliveries had increased risks of postpartum infection, cervical laceration, prolonged hospital stay, perineal laceration, and postpartum complications. CONCLUSION: There were upward trends in the rates of operative vaginal delivery at this inner-city hospital. Women who underwent forceps-assisted delivery had greater rates of maternal complications than did those who underwent vacuum-assisted delivery.

Adult↗
PubMed2001

Postoperative morbidity associated with cesarean delivery among human immunodeficiency virus-seropositive women.

OBJECTIVE: The aim of this study was to compare the complication rates associated with cesarean delivery between human immunodeficiency virus-seropositive women with those among a matched group of human immunodeficiency virus-seronegative subjects. STUDY DESIGN: We conducted a case-control study of 86 human immunodeficiency virus-seropositive women undergoing cesarean delivery between the years 1992 and 2000 at a large, urban teaching institution and a control group of 86 human immunodeficiency virus-seronegative women matched for age, race, year of delivery, and delivery indications. Data were analyzed with the chi2 test and odds ratios. Among human immunodeficiency virus-seropositive women, complications were further stratified according to maternal disease status and use of antiretroviral therapy. RESULTS: Human immunodeficiency virus-seropositive women were significantly more likely than control women to have minor postoperative complications (66.3% vs 41.8%; odds ratio, 2.73; 95% confidence interval, 1.40-6.10), of which febrile morbidity was the most common (62.8% vs 42.7%; P =.003). There was no difference between the groups in the rate of major complications (9.3% vs 3.4%; odds ratio, 2.84; 95% confidence interval, 0.65-14.06). Zidovudine use was associated with a decrease in the maternal morbidity rate (odds ratio, 0.31; 95% confidence interval, 0.07-1.03). CONCLUSION: Postoperative morbidity among human immunodeficiency virus-seropositive women undergoing cesarean delivery was not different from that in a matched control population.

Anti-HIV Agents↗
PubMed2000

Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells.

Phosphatidylinositol 3-kinase (PI3K) regulates several vital cellular processes, including signal transduction and membrane trafficking. In order to study the intracellular localization of the PI3K product, phosphatidylinositol 3-phosphate [PI(3)P], we constructed a probe consisting of two PI(3)P-binding FYVE domains. The probe was found to bind specifically, and with high affinity, to PI(3)P both in vitro and in vivo. When expressed in fibroblasts, a tagged probe localized to endosomes, as detected by fluorescence microscopy. Electron microscopy of untransfected fibroblasts showed that PI(3)P is highly enriched on early endosomes and in the internal vesicles of multivesicular endosomes. While yeast cells deficient in PI3K activity (vps15 and vps34 mutants) were not labelled, PI(3)P was found on intralumenal vesicles of endosomes and vacuoles of wild-type yeast. vps27Delta yeast cells, which have impaired endosome to vacuole trafficking, showed a decreased vacuolar labelling and increased endosome labelling. Thus PI(3)P follows a conserved intralumenal degradation pathway, and its generation, accessibility and turnover are likely to play a crucial role in defining the early endosome and the subsequent steps leading to multivesicular endosome formation.

Animals↗
PubMed2000

The tetraspanin CD63/lamp3 cycles between endocytic and secretory compartments in human endothelial cells.

In the present study, we show that in human endothelial cells the tetraspanin CD63/lamp3 distributes predominantly to the internal membranes of multivesicular-multilamellar late endosomes, which contain the unique lipid lysobisphosphatidic acid. Some CD63/lamp3 is also present in Weibel-Palade bodies, the characteristic secretory organelle of these cells. We find that CD63/lamp3 molecules can be transported from late endosomes to Weibel-Palade bodies and thus that CD63/lamp3 cycles between endocytic and biosynthetic compartments; however, movement of CD63/lamp3 is much slower than that of P-selectin, which is known to cycle between plasma membrane and Weibel-Palade bodies. When cells are treated with U18666A, a drug that mimics the Niemann-Pick type C syndrome, both proteins accumulate in late endosomes and fail to reach Weibel-Palade bodies efficiently, suggesting that P-selectin, like CD63/lamp3, cycles via late endosomes. Our data suggest that CD63/lamp3 partitions preferentially within late endosome internal membranes, thus causing its accumulation, and that this mechanism contributes to CD63/lamp3 retention in late endosomes; however, our data also indicate that the protein can eventually escape from these internal membranes and recycle toward Weibel-Palade bodies to be reused. Our observations thus uncover the existence of a selective trafficking route from late endosomes to Weibel-Palade bodies.

Androstenes↗
PubMed2000

Syntaxin 7 is localized to late endosome compartments, associates with Vamp 8, and Is required for late endosome-lysosome fusion.

Protein traffic from the cell surface or the trans-Golgi network reaches the lysosome via a series of endosomal compartments. One of the last steps in the endocytic pathway is the fusion of late endosomes with lysosomes. This process has been reconstituted in vitro and has been shown to require NSF, alpha and gamma SNAP, and a Rab GTPase based on inhibition by Rab GDI. In Saccharomyces cerevisiae, fusion events to the lysosome-like vacuole are mediated by the syntaxin protein Vam3p, which is localized to the vacuolar membrane. In an effort to identify the molecular machinery that controls fusion events to the lysosome, we searched for mammalian homologues of Vam3p. One such candidate is syntaxin 7. Here we show that syntaxin 7 is concentrated in late endosomes and lysosomes. Coimmunoprecipitation experiments show that syntaxin 7 is associated with the endosomal v-SNARE Vamp 8, which partially colocalizes with syntaxin 7. Importantly, we show that syntaxin 7 is specifically required for the fusion of late endosomes with lysosomes in vitro, resulting in a hybrid organelle. Together, these data identify a SNARE complex that functions in the late endocytic system of animal cells.

Animals↗
PubMed2000

H-ras but not K-ras traffics to the plasma membrane through the exocytic pathway.

Ras proteins must be localized to the inner surface of the plasma membrane to be biologically active. The motifs that effect Ras plasma membrane targeting consist of a C-terminal CAAX motif plus a second signal comprising palmitoylation of adjacent cysteine residues or the presence of a polybasic domain. In this study, we examined how Ras proteins access the cell surface after processing of the CAAX motif is completed in the endoplasmic reticulum (ER). We show that palmitoylated CAAX proteins, in addition to being localized at the plasma membrane, are found throughout the exocytic pathway and accumulate in the Golgi region when cells are incubated at 15 degrees C. In contrast, polybasic CAAX proteins are found only at the cell surface and not in the exocytic pathway. CAAX proteins which lack a second signal for plasma membrane targeting accumulate in the ER and Golgi. Brefeldin A (BFA) significantly inhibits the plasma membrane accumulation of newly synthesized, palmitoylated CAAX proteins without inhibiting their palmitoylation. BFA has no effect on the trafficking of polybasic CAAX proteins. We conclude that H-ras and K-ras traffic to the cell surface through different routes and that the polybasic domain is a sorting signal diverting K-Ras out of the classical exocytic pathway proximal to the Golgi. Farnesylated Ras proteins that lack a polybasic domain reach the Golgi but require palmitoylation in order to traffic further to the cell surface. These data also indicate that a Ras palmitoyltransferase is present in an early compartment of the exocytic pathway.

Animals↗
PubMed2000

Interaction of anti-phospholipid antibodies with late endosomes of human endothelial cells.

Anti-phospholipid antibodies (APLAs) are associated with thrombosis and/or recurrent pregnancy loss. APLAs bind to anionic phospholipids directly or indirectly via a cofactor such as beta(2)-glycoprotein 1 (beta(2)GPI). The lipid target of APLA is not yet established. Recently, we observed that APLAs in vitro can bind lysobisphosphatidic acid (LBPA). The internal membranes of late endosomes are enriched in this phospholipid. The current study was undertaken to determine to what extent binding of APLA to LBPA is correlated with binding to cardiolipin and to beta(2)GPI and to determine whether patient antibodies interact with late endosomes of human umbilical vein endothelial cells (HUVECs) and thus modify the intracellular trafficking of proteins. Binding of patient immunoglobulin G (n=37) to LBPA was correlated significantly with binding to cardiolipin. Although LBPA binding was correlated to a lesser extent with beta(2)GPI binding, we observed that beta(2)GPI binds with high affinity to LBPA. Immunofluorescence studies showed that late endosomes of HUVECs contain LBPA. Patient but not control antibodies recognized late endosomes, but not cardiolipin-rich mitochondria, even when we used antibodies that were immunopurified on cardiolipin. Incubation of HUVECs with patient plasma samples immunoreactive toward LBPA resulted in an accumulation of the antibodies in late endosomes and led to a redistribution of the insulinlike growth factor 2/mannose-6-phosphate receptor from the Golgi apparatus to late endosomes. Our results suggest that LBPA is an important lipid target of APLA in HUVECs. These antibodies are internalized by the cells and accumulate in late endosomes. By modifying the intracellular trafficking of proteins, APLA could contribute to several of the proposed pathogenic mechanisms leading to the antiphospholipid syndrome.

Antibodies, Antiphospholipid↗
PubMed1999

The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies.

BACKGROUND: To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. METHODS: North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic-regression analysis was used to adjust for other factors known to be associated with vertical transmission. RESULTS: The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. CONCLUSIONS: The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine.

Anti-HIV Agents↗
PubMed1999

Is the postanesthesia care unit becoming an intensive care unit?

The increasing number of critically ill patients requiring prolonged lengths of stay in the surgical intensive care unit has led hospitals to examine ways of using the PACU as a short-term area for critically ill patients. This article identifies common problems associated with this situation, and offers suggestions/guidelines to facilitate a smooth transition and ensure competent care of these patients. This article will not focus on financial issues related to patient charges. The criteria established in this article are based on personal experience.

Clinical Competence↗
PubMed1999

Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport.

The fate of free cholesterol released after endocytosis of low-density lipoproteins remains obscure. Here we report that late endosomes have a pivotal role in intracellular cholesterol transport. We find that in the genetic disease Niemann-Pick type C (NPC), and in drug-treated cells that mimic NPC, cholesterol accumulates in late endosomes and sorting of the lysosomal enzyme receptor is impaired. Our results show that the characteristic network of lysobisphosphatidic acid-rich membranes contained within multivesicular late endosomes regulates cholesterol transport, presumably by acting as a collection and distribution device. The results also suggest that similar endosomal defects accompany the anti-phospholipid syndrome and NPC.

Animals↗
PubMed1999

Exploitation of major histocompatibility complex class I molecules and caveolae by simian virus 40.

Simian virus 40 (SV40), a non-enveloped DNA virus, is transported from the cell surface to the nucleus where virus replication occurs. This pathway of virus uptake involves binding to surface MHC class I molecules, entry via non-coated pits, and subsequent transport to the endoplasmic reticulum (ER). At some stage in this pathway the virus must cross a membrane to reach the cytosol. In the present review, the cellular machinery which the virus has utilized to enter the cell will be examined. In particular, we will consider recent evidence for the involvement of caveolae in the infectious entry step and propose a model involving recruitment of caveolar proteins around the membrane-bound virus. We also speculate that a similar mechanism may have been exploited by bacterial pathogens. The subsequent steps by which SV40 reaches the ER remain unclear but recent evidence suggests that this pathway may be shared with several other proteins that are transported from surface caveolae to the ER.

Animals↗
PubMed1999

Cerebral vascular accident after cardiac surgery: its impact on nursing care.

The number of patients undergoing coronary artery bypass grafting (CABG) per year is increasing. Despite advances in surgical techniques, cerebral vascular accident (CVA) post cardiac surgery is increasing. CVA is a severe neurological complication of cardiac surgery which increased length of stay, morbidity and mortality, and rehabilitation. It is important to identify patients at increased risk and utilize appropriate screening techniques to decrease the incidence of CVA. Nursing assessment, interventions, and postoperative neurological assessment is crucial in identifying patients at increased risk for CVA.

Cerebrovascular Disorders↗