Search PubMed⌕ Search

Biomedical subjects

C Spencer

Publications and source records attributed to C Spencer.

At least 19 recordsLinked to original sources
PubMed2006

Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.

Dose-Response Relationship, Drug↗
PubMed2006

Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women.

OBJECTIVE: To analyse the fertility rates, complications and recurrences in a group of women who have undergone radical vaginal trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. DESIGN: An observational series. SETTING: A Gynaecological Oncology Centre. POPULATION: One hundred and twenty-three consecutive women who underwent radical vaginal trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. METHODS: Data were collected prospectively. MAIN OUTCOME MEASURES Complications, recurrences, pregnancies and live births are presented as percentages of the total population. Fertility is presented as a 5-year cumulative rate, with women attempting to conceive as the denominator. RESULTS: A total of 123 women were followed up for an average of 45 months. Eleven (8.9%) had completion treatment (two radical hysterectomies and nine chemoradiotherapy) at the time of initial treatment. There were three recurrences (2.7%) among the women who did not have completion treatment and two (18.2%) in those who did. There were 6 perioperative and 26 postoperative complications. Sixty-three women attempted pregnancy. There were 55 pregnancies in 26 women and 28 live births in 19. Three women had continuing pregnancies. The 5-year cumulative pregnancy rate among women trying to conceive was 52.8%. All but two women were delivered by classical caesarean section and seven (25.0%) babies were born at 31+6 weeks or less. CONCLUSIONS: For selected women with early-stage cervical cancer, radical vaginal trachelectomy and pelvic lymphadenectomy are fertility-sparing options, with a low incidence of recurrence and acceptable cumulative conception rates. Complications are few, although there is a high premature labour and miscarriage rate among pregnant women.

Abortion, Spontaneous↗
PubMed2005

Surgical morbidity associated with radical trachelectomy and radical hysterectomy.

OBJECTIVES: To examine intra-operative, short and longer term morbidity associated with Radical Trachelectomy (RT) within our cohort of patients, compared with conventional Radical Hysterectomy (RH). METHODS: A retrospective case note review comprising 29 RT and 50 RH patients. Patients who required adjuvant treatment were excluded. Operative data, short-term and long-term complications were recorded. Long-term problems were included only if they had been of persistent nature. RESULTS: The median age and follow up period for the RH group were 40 years and 60 months and for RT group 30.5 years and 25 months. There were significant differences between RH and RT groups in median operative time (260 versus 187 min), blood loss (1000 versus 400 ml), transfusion requirement (75% versus 12%), analgesic requirement (8 versus 3.5 days) and hospital stay (11 versus 6 days). Bladder hypotonia requiring prolonged catheterisation was more frequent in RH group (P = 0.004). There was no apparent difference in psychosexual problems between the two groups (17 versus 16%). Complications of deep dyspareunia (P = 0.009), excessive vaginal discharge (P = 0.01), and upper thigh parasthesia (P = 0.05) were noted to be significantly higher in the RT group. Specific problems encountered in the RT group included; dysmenorrhea (24%), irregular menstruation (17%), recurrent candidiasis (14%), cervical suture problems (14%), isthmic stenosis (10%) and prolonged amenorrhea (7%). CONCLUSION: RT is associated with less operative and short-term morbidity compared with conventional RH. In addition to specific complications associated with RT, in our experience, there are long-term morbidities that are not as commonly observed in RH.

Adult↗
PubMed2005

Comparison of haloacetic acids in the environment of the Northern and Southern Hemispheres.

Haloacetic acids (HAAs) are a family of compounds whose environmental concentrations have been extensively studied, primarily in Europe. Depending on the compound, their sources are believed to be both natural and anthropogenic. To better understand possible sources and contribute to the knowledge of the global distribution of these compounds, especially between the Northern and Southern Hemispheres, samples of precipitation, soils, and conifer needles were collected from Canada, Malawi, Chile, and the U.K. Precipitation samples exhibited highest HAA concentrations in collections from Canada, and lowest in those from Malawi. Malawi samples contained measurable levels of monobromoacetic acid (MBA) (56 ng/ L) unlike those from most other locations (< 9 ng/L). Soil HAA concentration levels were highest in the U.K. (e.g., 7.3 ng/g average TCA) and lowest in Malawi (0.8 ng/g average TCA), with Chile having higher levels (4.8 ng/g average TCA) than Canada (3 ng/g average TCA). Malawi soils contained small amounts of MBA (2 ng/g), in common with the two most southern of the 11 Chilean sites. Analysis of soil cores (10-cm depth sliced at 1 cm) from sites in Malawi and Chile showed that trichloroacetic acid (TCA) generally declined with depth while mono- and dichloroacetic acid (MCA and DCA) showed no trend. MCA, DCA, and TCA concentrations in archived U.K. soil samples increased by factors of 2, 4, and 5-fold over 75 years while TFA showed no consistent trend. Monochloroacetic acid (MCA) was detected in pine needles collected from Malawi. U.K. needle samples had the highest concentrations of all chloroacetic acids (CAAs): MCA, 2-18 ng/g; dichloroacetic acid (DCA), 2-38 ng/g; and trichloroacetic acid (TCA), 28-190 ng/g. Conifer needles from Canada and Chile contained CAAs at levels ranging from < 2 to 16 ng/g wet wt. Trifluoroacetic acid concentrations generally declined with increasing elevation in the samples from the Rocky Mountains in western Canada. The results indicate that concentrations of HAAs are greatest in the industrialized Northern Hemisphere but there are significant amounts of these compounds in the less industrialized Southern Hemisphere.

Acetates↗
PubMed2005

Trifluoroacetate profiles in the Arctic, Atlantic, and Pacific Oceans.

A series of depth profiles was collected at 22 sites in the Arctic, North and South Atlantic, and Pacific Oceans to determine spatial patterns for trifluoroacetate (TFA) concentrations in the marine environment and to investigate possible natural sources of TFA. Profiles were also taken over underwater vents in the North and South Pacific and the Mediterranean Sea. At the profile sites, TFA values ranged from <10 ng/L in the Pacific Ocean to greater than 150 ng/L in the Atlantic Ocean. Samples from the Canada Basin of the Arctic Ocean exhibited variable TFA concentrations (60-160 ng/L) down to 700 m. Below this depth, in water having 14C ages exceeding 1000 years, the TFA concentrations were constant (150 ng/L). Water returning to the Atlantic through the Canadian Arctic Archipelago had constant high TFA values. Profiles from the Northern Atlantic exhibited high values at all depths but were more consistent in the Western Atlantic. The northwestern Pacific Ocean surface profile sites exhibited low TFA concentrations in the top 100 m increasing to a maximum of 60 ng/L with depth. Samples from the South Pacific Ocean site had generally low values with a few depths (>800 m) having concentrations of 50 ng/L or more. To determine if underwater vents could contribute to the TFA concentrations in the oceans, profiles were taken over three vents in the Pacific and Mediterranean Oceans. The results suggest that some deep-sea vents may be natural sources of TFA.

Arctic Regions↗
PubMed2005

Development of anti-human leukocyte antigen class 1 antibodies following allogeneic islet cell transplantation.

Currently there is minimal concern that islet allograft failure could result from the development of anti-human leukocyte antigen (HLA) antibodies reactive to the allograft. We report here a case of islet allograft failure where the recipient developed immunoglobulin G anti-HLA class I antibodies reactive to HLA antigens present in two of the three islet cell donors. The patient had no detectable anti-HLA antibodies prior to the transplant but these antibodies were detected approximately 4 months posttransplant. Of concern, these antibodies developed despite induction with anti-IL2R antibodies (Zenapex) prior to intraportal islet cell infusion, low-dose tacrolimus (12-hour troughs 3 to 5 ng/mL) and rapammune (target troughs 12 to 15 ng/mL). The patient was not presensitized with blood products or a previous allograft. Her husband, however, shared antigens present in one of the islet donors and the recipient could have been presensitized to her husband during her two pregnancies. This case clearly demonstrates that islet allografts can lead to development of anti-HLA antibodies, which can cause islet allograft failure, as is the case with solid organ transplants, and hence emphasizes the need to monitor for such antibodies pre- and posttransplant. Additionally it appears that currently recommended immunosuppression may not be sufficient to inhibit a humoral response to both alloantigens and autoantigens.

Adult↗
PubMed2004

A group intervention which assists patients with dual diagnosis reduce their drug use: a randomized controlled trial.

BACKGROUND: There is a well-recognized association between substance use and psychotic disorders, sometimes described as 'dual diagnosis'. The use of substances by people with psychosis has a negative impact in terms of symptoms, longitudinal course of illness and psychosocial adjustment. There are few validated treatments for such individuals, and those that do exist are usually impracticable in routine clinical settings. The present study employs a randomized controlled experimental design to examine the effectiveness of a manualized group-based intervention in helping patients with dual diagnosis reduce their substance use. METHOD: The active intervention consisted of weekly 90-min sessions over 6 weeks. The manualized intervention was tailored to participants' stage of change and motivations for drug use. The control condition was a single educational session. RESULTS: Sixty-three subjects participated, of whom 58 (92%) completed a 3-month follow-up assessment of psychopathology, medication and substance use. Significant reductions in favour of the treatment condition were observed for psychopathology, chlorpromazine equivalent dose of antipsychotics, alcohol and illicit substance use, severity of dependence and hospitalization. CONCLUSIONS: It is possible to reduce substance use in individuals with psychotic disorders, using a targeted group-based approach. This has important implications for clinicians who wish to improve the long-term outcome of their patients.

Adult↗
PubMed2002

HLA matching for simultaneous pancreas-kidney transplantation in the United States: a multivariable analysis of the UNOS data.

BACKGROUND: As the incidence of diabetic nephropathy increases, especially in minority populations, more simultaneous pancreas-kidney (SPK) transplants are being performed both in the United States and worldwide. The role of matching on SPK outcomes and organ allocation remains controversial. The purpose of this analysis was to determine the influence of HLA matching using currently employed criteria on 5-year SPK graft survival. METHODS: We performed an analysis of all 3,316 SPK transplants performed in the United States reported to the United Network for Organ Sharing (UNOS) between December 31, 1988 and December 31, 1994. Kaplan-Meier unadjusted 1- and 5-year graft survival with log rank comparisons and Cox multivariable regression models that adjusted for 12 confounding variables were used to analyze the influence of HLA matching on outcomes. RESULTS: Despite low-grade HLA or DR matching or high levels of common reactive groups (CREG) mismatching, 1- and 5-year allograft survival rates were 90% and 78% for kidney, and 85% and 75% for pancreas transplantation. CONCLUSIONS: SPK transplantation is associated with excellent outcomes independent of the level of HLA matching. These data support the hypothesis that SPK transplants need not be allocated based on matching criteria, thus minimizing organ ischemia time and promoting a more racially equitable allocation for SPKs in the US today.

Adult↗
PubMed2001

Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling.

In an effort to identify novel therapeutic targets for autoimmunity and transplant rejection, we developed and performed a large-scale retroviral-based functional screen to select for proteins that inhibit antigen receptor-mediated activation of lymphocytes. In addition to known regulators of antigen receptor signaling, we identified a novel adaptor protein, SLAP-2 which shares 36% sequence similarity with the known Src-like adaptor protein, SLAP. Similar to SLAP, SLAP-2 is predominantly expressed in hematopoietic cells. Overexpression of SLAP-2 in B and T cell lines specifically impaired antigen receptor-mediated signaling events, including CD69 surface marker upregulation, nuclear factor of activated T cells (NFAT) promoter activation and calcium influx. Signaling induced by phorbol myristate acetate (PMA) and ionomycin was not significantly reduced, suggesting SLAP-2 functions proximally in the antigen receptor signaling cascade. The SLAP-2 protein contains an NH2-terminal myristoylation consensus sequence and SH3 and SH2 Src homology domains, but lacks a tyrosine kinase domain. In antigen receptor-stimulated cells, SLAP-2 associated with several tyrosine phosphorylated proteins, including the ubiquitin ligase Cbl. Deletion of the COOH terminus of SLAP-2 blocked function and abrogated its association with Cbl. Mutation of the putative myristoylation site of SLAP-2 compromised its inhibitory activity and impaired its localization to the membrane compartment. Our identification of the negative regulator SLAP-2 demonstrates that a retroviral-based screening strategy may be an efficient way to identify and characterize the function of key components of many signal transduction systems.

Adaptor Proteins, Signal Transducing↗
PubMed2001

TNFalpha inhibits insulin's antiapoptotic signaling in vascular smooth muscle cells.

Tumor necrosis factor alpha (TNFalpha) interferes with insulin signaling in adipose tissue and may promote insulin resistance. Insulin resistance is associated with vascular injury, but little is known about the interaction of TNFalpha and insulin in the vasculature. By activating the Insulin receptor (IR) --> IRS-1 --> phosphatidylinositol-3-kinase (PI3K) --> Akt-pathway, insulin protects vascular smooth muscle cells (VSMC) from undergoing apoptosis. We therefore investigated the effect of TNFalpha on insulin's antiapoptotic signaling in rat aortic VSMC. Insulin induced rapid tyrosine-phosphorylation of the IR and IRS-1 and caused a 2.8-fold increase of IRS-1-bound PI3K. TNFalpha had no effect on insulin-induced tyrosine-phosphorylation of IR or IRS-1, but inhibited insulin-stimulated IRS-1/PI3K-association by 84%. Insulin-induced phosphorylation of Akt downstream of PI3K was inhibited by TNFalpha in a similar pattern. We next examined the effect of TNFalpha on insulin's protective actions on H(2)O(2)-induced apoptosis. Insulin alone prevented 72.8% of H(2)O(2)-induced apoptosis, which was significantly inhibited by TNFalpha. TNFalpha alone did not induce apoptosis. In contrast, TNFalpha had no effect on PDGF-induced antiapoptotic signal transduction via Akt. Thus, TNFalpha selectively interferes with insulin's antiapoptotic signaling in VSMC by inhibiting the association of IRS-1/PI3K and the downstream activation of Akt.

Animals↗
PubMed2001

Segregation analysis of cancer in families of glioma patients.

A small proportion of brain tumors are attributed to a genetic predisposition; however, the hereditary proportion is undetermined. This study evaluates the degree of familial aggregation of cancer in a large series of brain tumor patients. Our study included 5,088 relatives of 639 probands (3,810 first- and 1,278 second-degree), diagnosed with a glioma between June 1992 and June 1995 at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, with diagnosis under age 65 years, and residents of the United States or Canada. We conducted an in-person or telephone interview with patients and/or their next-of-kin, and obtained family histories for the probands' first-degree (parents, siblings, offspring) and selected second-degree relatives (aunts, uncles, grandparents) using a sequential sampling strategy. Reported cancers were documented by medical records and/or death certificates (if the relative was deceased and medical records were unavailable). We conducted segregation analysis using the Pedigree Analysis Program (PAP). The analyses were divided into two categories: (1) all 639 families, and (2) a subset of families whose gliomas stained positive on p53 immunohistochemistry analysis. We demonstrated that a multifactorial Mendelian model was favored, while a model postulating a purely environmental cause of brain cancer was rejected. This study indicates that familial cancer in relatives of glioma patients are probably a result of multigenic action, and familial clustering of cancer among relatives of glioma patients may involve unknown environmental exposures.

Adolescent↗
PubMed2001

Initial results of ultrasound screening for aneurysm of the abdominal aorta in Western Australia: relevance for endoluminal treatment of aneurysm disease.

BACKGROUND: Increased life expectancy in men during the last thirty years is largely due to the decrease in mortality from cardiovascular disease in the age group 29--69 yr. This change has resulted in a change in the disease profile of the population with conditions such as aneurysm of the abdominal aorta (AAA) becoming more prevalent. The advent of endoluminal treatment for AAA has encouraged prophylactic intervention and fueled the argument to screen for the disease. The feasibility of inserting an endoluminal graft is dependent on the morphology and growth characteristics of the aneurysm. This study used data from a randomized controlled trial of ultrasound screening for AAA in men aged 65--83 yr in Western Australia for the purpose of determining the norms of the living anatomy in the pressurized infrarenal aorta. AIMS: To examine (1) the diameters of the infra-renal aorta in aneurysmal and non-aneurysmal cases, (2) the implications for treatment modalities, with particular reference to endoluminal grafting, which is most dependent on normal and aneurysmal morphology, and (3) any evidence to support the notion that northern Europeans are predisposed to aneurysmal disease. METHODS: Using ultrasound, a randomized control trial was established in Western Australia to assess the value of a screening program in males aged 65--83 yr. The infra-renal aorta was defined as aneurysmal if the maximum diameter was 30 mm or more. Aortic diameter was modelled both as a continuous (in mm) and as a binary outcome variable, for those men who had an infra-renal diameter of 30 mm or more. ANOVA and linear regression were used for modelling aortic diameter as a continuum, while chi-square analysis and logistic regression were used in comparing men with and without the diagnosis of AAA. FINDINGS: By December 1998, of 19,583 men had been invited to undergo ultrasound screening for AAA, 12,203 accepted the invitation (corrected response fraction 70.8%). The prevalence of AAA increased with age from 4.8% at 65 yr to 10.8% at 80 yr (chi(2)=77.9, df=3, P<0.001). The median (IQR) diameter for the non-aneurysmal group was 21.4 mm (3.3 mm) and there was an increase (chi(2)=76.0, df=1, P<0.001) in the diameter of the infra-renal aorta with age. Since 27 mm is the 95th centile for the non-aneurysmal infra-renal aorta, a diameter of 30 mm or more is justified as defining an aneurysm. The risk of AAA was higher in men of Australian (OR=1.0) and northern European origin (OR=1.0, 95%CL: 0.9, 1.2) compared with those of Mediterranean origin (OR=0.5, 95%CL: 0.4, 0.7). CONCLUSION: Although screening has not yet been shown to reduce mortality from AAA, these population-based data assist the understanding of aneurysmal disease and the further development and use of endoluminal grafts for this condition.

Age Distribution↗
PubMed2001

Differential expression of vasopressin, oxytocin and corticotrophin-releasing hormone messenger RNA in the paraventricular nucleus of the prairie vole brain following stress.

Forced swimming, as an effective stressor, has been found to facilitate the development of pair bonds in male but to interfere with this behaviour in female prairie voles (Microtus ochrogaster). In the present study, we found that forced swimming differentially influenced the expression of messenger RNA for vasopressin, oxytocin and corticotrophin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN) in the prairie vole brain. Forced swimming did not alter vasopressin mRNA labelling, but did induce a sustained decrease in oxytocin mRNA labelling and a progressive increase in CRH mRNA labelling in the PVN. The elevated CRH mRNA labelling appeared to be due to an increased number of cells synthesizing CRH mRNA and an enhanced ability of individual cells to produce CRH mRNA. Male and female prairie voles did not differ in the vasopressin, oxytocin or CRH mRNA expression either at the basal levels or in response to swimming stress. Together, these data indicate that the hypothalamic response of vasopressin, oxytocin and CRH messenger RNAs to swimming stress is regulated by distinct transcriptional factors. In addition, it seems unlikely that these changes are involved directly in the sex differences in pair bond formation.

Animals↗
PubMed2000

CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology.

The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.

Animals↗