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Biomedical subjects

C M Lynch

Publications and source records attributed to C M Lynch.

At least 19 recordsLinked to original sources
PubMed2006

Selective cerebral vascular dysfunction in Mn-SOD-deficient mice.

We tested the hypothesis that the mitochondrial form of superoxide dismutase [manganese superoxide dismutase (Mn-SOD)] protects the cerebral vasculature. Basilar arteries (baseline diameter approximately 140 microm) from mice were isolated, cannulated, and pressurized to measure vessel diameter. In arteries from C57BL/6 mice preconstricted with U-46619, acetylcholine (ACh; an endothelium-dependent vasodilator) produced dilation that was similar in male and female mice and abolished by an inhibitor of nitric oxide synthase. Vasodilation to ACh was not altered in heterozygous male or female Mn-SOD-deficient (Mn-SOD+/-) mice compared with wild-type littermate controls (Mn-SOD+/+). Constriction of the basilar artery to arginine vasopressin, but not KCl or U-46619, was increased in Mn-SOD+/- mice (P<0.05), and this effect was prevented by tempol, a scavenger of superoxide. We also examined responses of cerebral (pial) arterioles (branches of the middle cerebral artery, control diameter approximately 30 microm) to ACh in anesthetized mice using a cranial window. Responses to ACh, but not nitroprusside (an endothelium-independent agonist), were reduced (P<0.05) in cerebral arterioles in Mn-SOD+/- mice, and this effect was prevented by tempol. Thus these are the first data on the role of Mn-SOD in cerebral circulation. In the basilar artery, ACh produced nitric oxide-mediated dilation that was similar in male and female mice. Under normal conditions in cerebral arteries, responses to ACh were not altered but constrictor responses were selectively enhanced in Mn-SOD+/- mice. In the cerebral microcirculation, there was superoxide-mediated impairment of responses to ACh.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2003

Effect of mechanical ventilation on carotid artery thrombosis induced by photochemical injury in mice.

BACKGROUND: Increasing use of transgenic and gene targeting techniques for the investigation of hemostasis and vascular biology has generated interest in experimental models of carotid artery thrombosis in mice. OBJECTIVES: We tested the hypothesis that hypoventilation in anesthetized mice may cause hypercapnia, increased carotid artery blood flow, and altered thrombotic responses to photochemical injury of the carotid artery. METHODS: Arterial blood gases and carotid artery blood flow were measured in pentobarbital-anesthetized BALB/c or C57BL/6 J mice with and without mechanical ventilation. Photochemical injury of the carotid artery was induced using the rose bengal method. RESULTS: Compared with ventilated mice, unventilated mice had a 45% increase in carotid artery blood flow (0.74 +/- 0.04 vs. 0.41 +/- 0.03 mL min-1; P < 0.001) that was associated with an elevation of arterial PCO2 (58 +/- 4 vs. 33 +/- 4 mmHg; P < 0.05) and a decrease in arterial pH (7.18 +/- 0.05 vs. 7.32 +/- 0.03; P < 0.05). Time to first occlusion of the carotid artery after photochemical injury was shorter in ventilated than in unventilated mice (29 +/- 6 vs. 73 +/- 9 min; P < 0.001). Time to stable occlusion was also shorter in ventilated mice (49 +/- 8 vs. 81 +/- 6 min; P < 0.05). Elevated carotid artery blood flow, hypercarbic acidosis, and prolonged occlusion times also were observed in mice ventilated with supplemental carbon dioxide. CONCLUSIONS: General anesthesia without mechanical ventilation has the potential to confound studies of experimental thrombosis in vivo by producing hypoventilation, hypercapnia, acidosis, and altered carotid artery blood flow. Mechanical ventilation with maintenance of normal blood gases may enhance the physiological insight gained from experimental models of carotid artery thrombosis in mice.

Anesthesia↗
PubMed2001

Pregnancy complicated by a suburethral sling: a case report.

Incontinence surgery is rarely performed prior to the completion of a woman's childbearing. The literature is sparse in regard to women with prior incontinence surgery. There are no reports of pregnancy complicated by a sling procedure. A 26-year-old gravida 3, para 2-0-0-2 with prior surgical history of a Pereyra urethropexy followed by a Vesica suburethral sling, was referred at 18 weeks' gestation for assessment of the sling. Her antenatal course was complicated by pyelonephritis and intermittent urethral obstruction requiring Foley catheter placement. She delivered by scheduled cesarean section at 37 weeks' gestation. Three months following delivery she presented with pyelonephritis and recurrence of her incontinence. Pregnancy complicated by prior suburethral sling procedure may result in urinary outlet obstruction, pyelonephritis and disruption of the surgical repair.

Adult↗
PubMed2000

Use of methergine for the prevention of postoperative endometritis in non-elective cesarean section patients.

OBJECTIVE: Methergine increases constriction of uterine musculature which may facilitate sloughing of endometrial debris, close uterine vessels, and prevent post-cesarean endometritis. The objective of this study was to evaluate the efficacy of methergine in preventing endometritis in patients undergoing non-elective cesarean section delivery. METHODS: Eighty patients undergoing non-elective cesarean section were enrolled in a prospective randomized clinical trial of methergine (41) versus no methergine (39) administration during the postpartum period. The hospital records were abstracted after discharge to compare the postpartum course. RESULTS: There were no significant demographic differences between the two groups. The women receiving methergine had a significant reduction in the rate of postoperative endometritis (10% vs. 36%, P < 0.005). In addition, the mean postoperative hemoglobin was significantly higher in the methergine treated group (P < 0.001). CONCLUSIONS: The use of methergine postpartum in women undergoing non-elective cesarean sections significantly reduces the incidence of postoperative endometritis and blood loss.

Adult↗
PubMed1999

Lymphogranuloma venereum presenting as a rectovaginal fistula.

Lymphogranuloma venereum (LGV) is a rare form of the sexually transmitted disease caused by Chlamydia trachomatis. In the United States, there are fewer than 350 cases per year. In a review of the world's literature, there has not been a case reported in the last thirty years of a case of LGV presenting as a rectovaginal fistula. We present a case of an otherwise healthy American woman who presented with a rectovaginal fistula. Although uncommon, LGV does occur in developed countries and may have devastating tissue destruction if not recognized and treated before the tertiary stage.

Adult↗
PubMed1999

Gene therapy for hemophilia.

Hemophilia is a genetically inherited bleeding disorder caused by a deficiency of the blood clotting factors VIII (hemophilia A) or IX (hemophilia B). Hemophiliacs suffer prolonged bleeding which can be life threatening and often leads to chronic disabilities. Current hemophilia treatment involves infusions of plasma-derived or recombinant clotting factor in response to bleeding crises. Prophylactic treatment is not available and current treatments remain problematic. The development of a gene therapy for hemophilia has been under investigation for the past decade. An overview is presented of the initial efforts using retroviral and adenoviral vectors for ex vivo and in vivo gene delivery strategies, respectively. Recent progress in developing FIX and FVIII adeno-associated virus vectors is reviewed. Sustained expression of therapeutic levels of FIX and FVIII have been demonstrated in mice. Phenotypic correction of hemophilia B has been shown in the murine and dog models of disease. A phase I human clinical trial has been initiated involving intramuscular injection of FIX. Prospectsfor hemophilia gene therapy look bright and the hopefor a cure has now moved from the realm of the possible to the probable.

Animals↗
PubMed1998

Minilaparotomy hysterectomy.

OBJECTIVE: This article reports our experience with minilaparotomy hysterectomy. STUDY DESIGN: Minilaparotomy was defined as a skin incision < or = 6 cm in length. From January 1, 1996, to June 30, 1997, data were collected on all patients who underwent hysterectomy by means of a minilaparotomy. RESULTS: During the study a total of 250 hysterectomies were performed. Twenty-six of those were performed by means of a minilaparotomy. The mean age of the patients was 54 years. Seven had endometrial cancer and 8 had an adnexal mass. In 1 patient the incision was extended for staging of an ovarian cancer. The only intraoperative complication was rupture of a 6-cm ovarian tumor. After operation, 2 patients had febrile morbidity, 1 had a prolonged ileus, and in 1 atrial fibrillation developed. The mean uterine weight was 123 g. Median day of Foley catheter removal and mean day of ambulation, regular diet, and discharge were 1 day, 1.2 days, 2.4 days, and 3.4 days, respectively. CONCLUSION: Minilaparotomy is a safe and feasible route of hysterectomy for a selected group of patients.

Adult↗
PubMed1997

GaLV pseudotyped vectors and cationic lipids transduce human CD34+ cells.

High transduction frequency of hematopoietic stem/progenitor cells is essential to derive clinical benefits for treating certain inherited and acquired diseases. We demonstrate here stable gene transfer into human bone marrow-derived CD34+ progenitors using cationic lipids to facilitate GaLV and amphotroic pseudotyped retroviral-mediated transductions. Furthermore, the transgene was detected only in the progeny of flow cytometer sorted CD34+ population transduced by the LAPSN (PG13) viral vector in the presence of cationic lipids but not when transduction was facilitated with conventional polycations Polybrene or protamine sulfate. Thus, a combination of GaLV pseudotyped vectors and cationic lipids results in increased transduction frequencies of the CD34+ cells without a requirement of extended in vitro culture, or co-cultivation with producer cell lines. These improvements may result in the production of therapeutically significant quantities of genetically modified hematopoietic cells.

Alkaline Phosphatase↗
PubMed1997

New prospects for cardiovascular gene therapy.

Cardiovascular gene therapy has been hampered by the lack of suitable gene delivery vectors for in vivo applications. Low transduction efficiencies, lack of persistent transgene expression and undesirable inflammatory and immune responses have limited the prospects for human gene therapy in the cardiovascular system. New prospects for cardiovascular gene therapy are a result of recent vector developments, in particular with the use of adeno-associated virus (AAV) based vectors in the heart and peripheral vasculature.

Journal Article↗
PubMed1997

Adeno-associated virus vectors for vascular gene delivery.

A variety of delivery systems have been used to genetically modify vascular endothelial cells and smooth muscle cells (SMCs), but currently available systems suffer from either inefficient in vivo gene transfer, transient episomal vector expression, or significant immune responses and inflammation. In the present study, we evaluated an alternate vector system, recombinant adeno-associated virus (rAAV) for transduction of vascular cells in culture and in vivo. Primary cultures of rabbit, monkey, and human SMCs; macaque and human microvascular endothelial cells; and human umbilical vein endothelial cells were efficiently transduced at a dose of 100 to 1000 DNase-resistant particles per cell. rAAV-mediated transduction of the vasculature in vivo was observed after intraluminal gene delivery or after intra-adventitial injection in carotid arteries of atherosclerotic cynomolgus monkeys. Whether vector delivery was intraluminal or adventitial, transduction was observed in the adventitia, particularly within microvessels (vasa vasorum) but not in cells of the intima or media. Transduction of adventitial microvessels was enhanced by balloon injury 4 days before gene transfer. This was particularly true for adventitial delivery. We have previously shown that adventitial cell proliferation increases significantly 4 days after balloon injury (45%) in this animal model. Together, these data suggest that cell proliferation may enhance AAV transduction in vivo in the vasculature. AAV vectors exhibited a tropism in vivo for the microvascular endothelium at the doses used in the present study, which may provide the opportunity for targeting gene delivery. In summary, we have demonstrated the utility of rAAV vectors for ex vivo vascular cell gene delivery and present an initial experience with rAAV for in vivo vascular gene delivery. This alternate vector system may overcome some of the limitations hampering the development of gene therapy for vascular disorders.

Animals↗
PubMed1996

Acceleration of cheese ripening.

The characteristic aroma, flavour and texture of cheese develop during ripening of the cheese curd through the action of numerous enzymes derived from the cheese milk, the coagulant, starter and non-starter bacteria. Ripening is a slow and consequently an expensive process that is not fully predictable or controllable. Consequently, there are economic and possibly technological incentives to accelerate ripening. The principal methods by which this may be achieved are: an elevated ripening temperature, modified starters, exogenous enzymes and cheese slurries. The advantages, limitations, technical feasibility and commercial potential of these methods are discussed and compared.

Cheese↗
PubMed1995

Chemical structures of the core region of Campylobacter jejuni O:3 lipopolysaccharide and an associated polysaccharide.

The complete structure for the core oligosaccharide region of the water-insoluble low-M(r) lipopolysaccharide of Campylobacter jejuni serotype O:3 from phenol/water extraction of bacterial cells was assigned through studies on derivatives of the liberated oligosaccharide. Structure determinations were performed using 1H-NMR and 31P-NMR spectroscopies, methylation analysis supported by fast-atom-bombardment mass spectrometry, and Smith degradation experiments. It was concluded that the complete chains in the core oligosaccharide had the following structure in which a proportion of the terminal residues were phosphorylated: [formula: see text] From a similar series of experiments, it was concluded that an associated polysaccharide, which was isolated from the water phase of the phenol/water extracts, had the following repeating unit in which a proportion of the previously unknown L-glycero-D-ido-heptose (L-alpha-D-ido-Hep) residues were present as 3-hydroxypropanoyl esters, and were not covalently linked to the lipopolysaccharide: [formula see: text]

Campylobacter jejuni↗
PubMed1994

Colorectal anastomosis on a gynecologic oncology service.

This is an evaluation of our experience with colorectal reanastomosis on a gynecologic oncology service. A retrospective review was carried out on all patients who underwent colorectal resection and reanastomosis on the gynecologic oncology service from October 1, 1987 to September 30, 1992. Thirty-nine procedures were performed: Nine patients underwent sigmoidectomy alone, 20 also underwent cytoreduction, and 10 also underwent exenteration. Thirty-eight percent of the patients had undergone prior radiotherapy. The level of anastomosis above the anal verge was 3-5 cm in 9 patients, 6-9 cm in 20 patients, and 10-14 cm in 10 patients. Sixteen had a protective colostomy which included 13 of the 15 patients with prior radiotherapy. Thirteen of the protective colostomies were taken down, although three of these required a second permanent colostomy. Three other patients required colostomy at a later date, one of whom developed a rectovaginal fistula 10 days following exenteration for postradiation recurrent carcinoma of the cervix. A total of 30 of the 37 evaluable patients (81%) had an ultimately functional colorectal reanastomosis. Problems related to colorectal function included stricture (4), fistula (4), chronic diarrhea (3), tenesmus (1), and fecal incontinence (1). Colorectal anastomosis is a worthwhile endeavor in selected patients with gynecologic cancer.

Adult↗
PubMed1994

Long-term biological response of injured rat carotid artery seeded with smooth muscle cells expressing retrovirally introduced human genes.

Cultured vascular smooth muscle cells (SMCs) containing retrovirally introduced genes are a potential vehicle for gene replacement therapy. Because the cultured SMCs are selected for their ability to proliferate in vitro, it is possible that the SMCs might be permanently altered and lose their capacity to respond to growth-suppressing conditions after being seeded back into blood vessels. To investigate this possibility we measured SMC proliferation and intimal thickening in balloon-injured Fischer 344 rat carotid arteries seeded with SMCs stained with the fluorescent marker 1,1'-dioctadecyl-3,3,3',3'-tetramethylindo-carbocyanine perchlorate (DiI) and infected with replication-defective retrovirus expressing human adenosine deaminase or human placental alkaline phosphatase. The majority of the seeded SMCs remained in the intima while a few of the cells appeared to migrate into the first layer of the media. Intimal SMC proliferation returned to background levels (< 0.1% thymidine labeling index) by 28 d. At late times (1 and 12 mo) the morphological appearance of the intima was the same for balloon-injured arteries with or without seeded SMC, except that the seeded arteries continued to express human adenosine deaminase or alkaline phosphatase. These results support the conclusion that cultured SMC infected with a replication-defective virus containing human adenosine deaminase or alkaline phosphatase are not phenotypically altered and do not become transformed. After seeding onto the surface of an injured artery, they stop replicating but continue to express the introduced human genes even over the long term.

Adenosine Deaminase↗
PubMed1993

Sequences in the coding region of clotting factor VIII act as dominant inhibitors of RNA accumulation and protein production.

A variety of retroviral vectors for transduction and expression of clotting factor VIII (FVIII) were constructed by using truncated forms of a FVIII cDNA lacking part or all of the nonessential B-domain sequences. Both the titer of virus and FVIII protein production from the vectors was about 2 orders of magnitude lower than the virus titer and protein production from identical retroviral vectors containing other cDNAs, including clotting factor IX. These decreases could be entirely explained by an observed 100-fold lower accumulation of vector RNAs containing the FVIII sequences in comparison to vectors containing other cDNA sequences. Deletion analysis of one of the FVIII vectors demonstrated that diffuse sequences within the FVIII coding region had a deleterious effect upon vector titer and RNA accumulation. One inhibitory signal could be localized to a 1.2-kb stretch of DNA, but further localization was not possible as additional size reduction abolished the activity. These results indicate that expression of FVIII is regulated by signals within FVIII coding sequence that result in decreased RNA accumulation and FVIII protein production. Alteration of these inhibitory signals to permit high-level FVIII production may be difficult due to the wide distribution of these signals within the coding region of the protein.

3T3 Cells↗
PubMed1992

Long-term expression of human adenosine deaminase in vascular smooth muscle cells of rats: a model for gene therapy.

Gene transfer into vascular smooth muscle cells in animals was examined by using recombinant retroviral vectors containing an Escherichia coli beta-galactosidase gene or a human adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) gene. Direct gene transfer by infusion of virus into rat carotid arteries was not observed. However, gene transfer by infection of smooth muscle cells in culture and seeding of the transduced cells onto arteries that had been denuded of endothelial cells was successful. Potentially therapeutic levels of human adenosine deaminase activity were detected over 6 months of observation, indicating the utility of vascular smooth muscle cells for gene therapy in humans.

Adenosine Deaminase↗
PubMed1991

Construction and properties of retrovirus packaging cells based on gibbon ape leukemia virus.

We have constructed hybrid retrovirus packaging cell lines that express the gibbon ape leukemia virus env and the Moloney murine leukemia virus gag-pol proteins. These cells were used to produce a retrovirus vector at over 10(6) CFU/ml, with a host range that included rat, hamster, bovine, cat, dog, monkey, and human cells. The gag-pol and env expression plasmids were separately transfected to reduce the potential for helper virus production, which was not observed. The NIH 3T3 mouse cells from which the packaging lines were made are not infectable by gibbon ape leukemia virus; thus, the generation and spread of possible recombinant viruses in the packaging cells is greatly reduced. These simian virus-based packaging cells extend the host range of currently available murine and avian packaging cells and should be useful for efficient gene transfer into higher mammals.

Animals↗