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Biomedical subjects

M Wood

Publications and source records attributed to M Wood.

At least 55 records · Page 3Linked to original sources
PubMed2001

Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health.

The longitudinal changes in isokinetic strength of knee and elbow extensors and flexors, muscle mass, physical activity, and health were examined in 120 subjects initially 46 to 78 years old. Sixty-eight women and 52 men were reexamined after 9.7 +/- 1.1 years. The rates of decline in isokinetic strength averaged 14% per decade for knee extensors and 16% per decade for knee flexors in men and women. Women demonstrated slower rates of decline in elbow extensors and flexors (2% per decade) than men (12% per decade). Older subjects demonstrated a greater rate of decline in strength. In men, longitudinal rates of decline of leg muscle strength were approximately 60% greater than estimates from a cross-sectional analysis in the same population. The change in leg strength was directly related to the change in muscle mass in both men and women, and it was inversely related to the change in medication use in men. Physical activity declined yet was not directly associated with strength changes. Although muscle mass changes influenced the magnitude of the strength changes over time, strength declines in spite of muscle mass maintenance or even gain emphasize the need to explore the contribution of other cellular, neural, or metabolic mediators of strength changes.

Aged↗
PubMed2001

A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI.

BACKGROUND: A prospective randomized study was carried out in two centres to compare the number of oocytes retrieved after two different starting doses of recombinant human FSH (rhFSH) (Gonal-F) in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) cycles using the multiple dose regimen of the gonadotrophin-releasing hormone (GnRH) antagonist cetrorelix (Cetrotide) to prevent induction of the premature LH surge. METHODS: Sixty women were randomized to receive rhFSH 150 IU ('low'), and 60 women to receive rhFSH 225 IU ('high') as the starting dose for the first 5 days of stimulation. From stimulation day 6 and onwards, including the day of human chorionic gonadotrophin (HCG) administration, the women received 0.25 mg of cetrorelix as a daily dose. The primary endpoint was the number of oocytes retrieved. RESULTS: The mean number (+/- SD) of oocytes was 9.1 +/- 4.4 and 11.0 +/- 4.6 in the 'low' and 'high' groups respectively (P = 0.024). The mean number of 75 IU ampoules of rhFSH was significantly lower in the 'low' group (23.0 +/- 6.3 versus 30.5 +/- 5.6, P < 0.0001). The ongoing pregnancy rate per started cycle and per embryo transfer were 25.9 and 28.8% versus 25.4 and 26.8% respectively in the 'low' and 'high' rhFSH groups (P = NS). CONCLUSIONS: When using a starting dose of 225 IU rhFSH combined with the multiple dose of 0.25 mg cetrorelix from stimulation day 6, significantly more oocytes were obtained than with a starting dose of 150 IU rhFSH.

Cell Count↗
PubMed2001

Investigation of myo-inositol catabolism in Rhizobium leguminosarum bv. viciae and its effect on nodulation competitiveness.

Three discrete loci required for growth on myo-inositol in Rhizobium leguminosarum bv. viciae have been characterized. Two of these are catabolic loci that code for malonate semialdehyde dehydrogenase (iolA) and malonate semialdehyde dehydrogenase (iolD). IolD is part of a possible operon, iolDEB, although the functions of IolE and IolB are unknown. The third locus, int, codes for an ABC transport system that is highly specific for myo-inositol. LacZ analysis showed that mutation of iolD, which codes for one of the last steps in the catabolic pathway, prevents increased transcription of the entire pathway. It is likely that the pathway is induced by an end product of catabolism rather than myo-inositol itself. Mutants in any of the loci nodulated peas (Pisum sativum) and vetch (Vicia sativa) at the same rate as the wild type. Acetylene reduction rates and plant dry weights also were the same in the mutants and wild type, indicating no defects in nitrogen fixation. When wild-type 3841 was coinoculated onto vetch plants with either catabolic mutant iolD (RU360) or iolA (RU361), however, >95% of the nodules were solely infected with the wild type. The competitive advantage of the wild type was unaffected, even when the mutants were at 100-fold excess. The myo-inositol transport mutant (RU1487), which grows slowly on myo-inositol, was only slightly less competitive than the wild type. The nodulation advantage of the wild type was not the result of superior growth in the rhizosphere. Instead, it appears that the wild type may displace the mutants early on in the infection and nodulation process, suggesting an important role for myo-inositol catabolism.

ATP-Binding Cassette Transporters↗
PubMed2001

Results of cataract surgery in young children in east Africa.

BACKGROUND: Cataract is the leading cause of blindness in children in east Africa. The results of surgery are poor, partly because of inadequate correction of aphakia. METHODS: A retrospective survey of 118 eyes in 71 children with bilateral cataract. All eyes had implantation of an IOL at the time of cataract surgery. The average age at surgery was 3.5 years. 28 patients(39%) were less than 2 years old at the time of surgery on their first eye. RESULTS: Preoperatively, 75.4% of eyes and 76.1% of patients were blind. A follow up of at least 3 months was available in 91 (77.1%) eyes. In these eyes, 44% had a latest corrected vision of 6/18 or better and 91.2% had a latest corrected vision of 6/60 or better. Eyes with zonular cataract, and eyes operated after the age of 2 years were more likely to obtain a vision of 6/18 or better. 3.3% of eyes and 1.8% of patients had an acuity of less than 3/60. Nystagmus was present in 42.3% of patients before surgery. In those patients followed up for a minimum of 6 months, 10.2% still had nystagmus. The most frequent complication was severe fibrinous uveitis, which occurred in 36 (30.5%) eyes. 62 (52.5%) eyes had a posterior capsulotomy at the time of cataract extraction. Of the remaining 56 eyes, 20 (35.7%) had so far required a posterior capsulotomy. The leading cause of poor visual outcome was amblyopia. Two patients developed severe complications related to the intraocular lens. CONCLUSIONS: Insertion of a lens implant at the time of cataract extraction appears to be well tolerated in the short term, and may offer significant advantages in an African setting.

Amblyopia↗
PubMed2001

PRL, placental lactogen, and GH induce NA(+)/taurocholate-cotransporting polypeptide gene expression by activating signal transducer and activator of transcription-5 in liver cells.

We investigated the transcriptional regulation of the Na(+)/taurocholate cotransporting polypeptide gene by PRL, placental lactogen, and GH. In primary hepatocytes, ovine PRL induced a dose-dependent phosphorylation and nuclear translocation of signal transducers and activators of transcription-5a and -5b, but not -1 or -3, whereas mouse placental lactogen I and rat GH activated -5a, -5b, and -1. In EMSAs, ovine PRL, mouse placental lactogen I, and rat GH increased the specific DNA binding of nuclear signal transducer and activator of transcription-5 to its consensus element in both transfected HepG2 cells and primary hepatocytes. PRL, placental lactogen I, and GH also increased Na(+)/taurocholate cotransporting polypeptide mRNA expression in hepatocytes from control and pregnant (mouse placental lactogen I) rats. Genistein, a phosphotyrosine kinase inhibitor, inhibited PRL-induced signal transducer and activator of transcription-5 activation and Na(+)/taurocholate-cotransporting polypeptide mRNA. In HepG2 cells transiently cotransfected with either the long form of the rat PRL receptor or rat GH receptor, signal transducer and activator of transcription-5a and a -5-responsive luciferase expression vector containing the Na(+)/taurocholate-cotransporting polypeptide promoter, mouse placental lactogen I, like ovine PRL, activated -5a via the long form of the rat PRL receptor; whereas rat GH activated -5a via rat GH receptor, leading to transactivation of the Na(+)/taurocholate-cotransporting polypeptide promoter. These data establish that PRL and placental lactogen I induce Na(+)/taurocholate-cotransporting polypeptide gene expression via signal transducer and activator of transcription-5 proteins in liver, and indicate that these hormones play an important role in regulating liver metabolic function.

Animals↗
PubMed2000

Simultaneous measurement of 8-oxo-2'-deoxyguanosine and 8-oxo-2'-deoxyadenosine by HPLC-MS/MS.

An assay with high selectivity and sensitivity has been developed which, for the first time, allows quantitative, simultaneous measurement in DNA of both 8-oxo-2'-deoxyguanosine (8-oxodG) and 8-oxo-2'-deoxyadenosine (8-oxodA)-important biomarkers of oxidative DNA damage in vivo. Using reversed-phase HPLC coupled to electrospray tandem mass spectrometry (HPLC-MS/MS) in multiple reaction monitoring (MRM) mode it was possible to detect background levels of these lesions in commercially available calf thymus DNA (85 +/- 3 and 7.1 +/- 0.2 per 10(6) DNA bases for 8-oxodG and 8-oxodA respectively; n = 3). Levels of 8-oxodG determined by HPLC coupled to an electrochemical detection system (HPLC-EC) were found to be similar (75 +/- 6 per 10(6) DNA bases; n = 3) to those obtained using tandem mass spectrometry.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study.

O6-Methylguanine-DNA methyltransferase (MGMT) is a major determinant of resistance to temozolomide. Its levels are depleted in lymphocytes after drug administration, but there is partial recovery by 24 hr, the usual time of subsequent dosing. Administering subsequent doses of temozolomide at the MGMT nadir could enhance its effectiveness, by increasing the amount of O6-methylguanine (O6-meG) in DNA. We evaluated the efficacy of such a schedule of temozolomide and determined the kinetics of MGMT depletion and O6-meG formation in DNA following treatment. Thirty patients with advanced malignant melanoma were treated with temozolomide 1,000 mg/m2 equally split into 5 doses over a 16 hr period every 28 days. O6-meG formation was determined in peripheral blood mononuclear cell (PBMC) DNA and, in a subset of patients, in tumor tissue during the first treatment cycle. MGMT levels fell rapidly with dosing, reaching a nadir in PBMCs of 18.0 +/- 2.26% of initial levels. O6-meG levels increased during the treatment period, peaking at 11.1 +/- 1.25 micromol/mol dG in PBMCs and at 4.25 +/- 0.79 micromol/mol dG in tumor biopsies. The main toxicities were grade IV thrombocytopenia in 12 patients (42.8%) and grade IV neutropenia in 11 patients (39.2%), associated with fever in 8 cases. There were 7 responses (1 complete), for an overall response rate of 23.3%; median overall survival was 6.1 months. The compressed schedule has activity against melanoma, with greater MGMT depletion and O6-meG formation than previously reported for O6-alkylating agent regimens. Myelosuppression precludes its wider application, but MGMT in PBMCs predicted the dose intensity of temozolomide that patients could sustain, suggesting a means by which individuals suitable for this approach might be identified.

Adult↗
PubMed2000

Defining promiscuous MHC class II helper T-cell epitopes for the HER2/neu tumor antigen.

It is accepted that both helper and CTLs play a critical role in immune antitumor responses. Thus, the design of effective immune-based therapies for cancer relies in the identification of relevant tumor-associated antigens (TAAs) capable of eliciting strong helper and cytotoxic T-cell responses against tumor cells. The product of the HER2/neu oncogene is considered as a prototype TAA, because it is found overexpressed in a large variety of malignancies, whereas normal cells only produce low levels of this product. Several cytotoxic T-cell epitopes for HER2/neu have been identified that enable the design of peptide-based therapeutic vaccines for tumors expressing this TAA. Nevertheless, it is expected that inclusion of peptide epitopes capable of eliciting HER2/neu-specific T helper responses into these vaccines may enhance their effectiveness in the clinic. We describe here a strategy to identify helper T-cell epitopes for HER2/neu that focuses on peptides predicted to bind to numerous histocompatibility alleles (promiscuous epitopes), which would encourage their use in therapeutic vaccines for the general cancer patient population. Following this approach, we successfully identified several peptides that elicited T helper (CD4+) proliferative responses to peptides derived from HER2/neu. Most of the T-cell responses appeared to reflect a low affinity for antigen, which could be the result of immune tolerance because HER2/neu is expressed in low levels in normal cells and possibly including lymphocytes and monocytes. Interestingly, one of these peptides, HER2(883), was recognized by T cells in the context of either HLA-DR1, HLA-DR4, HLA-DR52, and HLA-DR53, indicating a high degree of histocompatibility promiscuity. Furthermore, T cells that reacted with peptide HER2(883) could also recognize antigen-presenting cells that process HER2/neu recombinant protein. These results may be relevant for the design of more effective therapeutic vaccines for tumors expressing the HER2/neu oncogene product.

Amino Acid Sequence↗
PubMed2000

Formation and persistence of O(6)-methylguanine in the mouse colon following treatment with 1,2-dimethylhydrazine as measured by an O(6)-alkylguanine-DNA alkyltransferase inactivation assay.

Female SWR mice were treated with 1,2-dimethylhydrazine (DMH: 6.8 mg/kg i.p. injection) once weekly for up to 10 weeks, a dosing regime that produced tumours principally within the distal colon (Jackson et al., 1999. Carcinogenesis 20, 509-513). O(6)-Methylguanine (O(6)-MeG) levels, measured using a simple [3H]-based O(6)-alkylguanine-DNA alkyltransferase (ATase) inactivation assay, ranged from 0.6 to 16.7 fmol/microg DNA with: (i) highest levels in the distal colon; and (ii) higher levels after 68 mg/kg total DMH than 6.8 mg/kg DMH. Basal ATase activity varied between 0.97 and 1.22 fmol/microg DNA within the colon but was not associated with adduct levels or tumour induction. After 6.8 mg/kg DMH, the half life of O(6)-MeG in colonic tissue was 36-42 h whereas after 68 mg/kg DMH, t1/2 was approximately 25, 57 and 96 h in the proximal, mid and distal colon, respectively. Tumour induction was thus associated with the levels and persistence of O(6)-MeG in the distal colon.

1,2-Dimethylhydrazine↗
PubMed2000

Antagonist activity of meta-chlorophenylpiperazine and partial agonist activity of 8-OH-DPAT at the 5-HT(7) receptor.

This study compared the use of adapter G-proteins to link G(s) coupled G-protein receptors to a Ca(2+) signal, enabling high throughput functional studies using a fluorescent imaging plate reader (FLIPR, Molecular Devices). The pharmacological profile of the human 5-hydroxytryptamine (5-HT(7)) receptor was studied using the adapter G-proteins G(alpha16) and G(qs5) and compared to previously published adenylyl cyclase and receptor binding data. Human embryonic kidney (HEK) 293 cells stably expressing the human 5-HT(7(a)) receptor were transiently transfected with the adapter G-proteins. Changes in intracellular Ca(2+) were monitored using the fluorescent Ca(2+)-indicator Fluo-4.5-Carboxamidotryptamine (5-CT) induced an increase in fluorescence in transfected cells only, which was attenuated by N-ethylmalaeimide and abolished by thapsigargin, consistent with a G-protein mediated mobilisation of intracellular Ca(2+). The pharmacological profile of agonists at the 5-HT(7) receptor was similar using either adapter G-protein. Agonist potency estimates were similar to that reported in binding studies but were greater than that seen in adenylyl cyclase studies. 8-Hydroxy-N, N-dipropylaminotetralin (8-OH-DPAT) and tryptamine acted as partial agonists using the adapter G-proteins, but were full agonists in recombinant systems using adenylyl cyclase. meta-Chlorophenylpiperazine (mCPP) and trifluoro-methylphenyl piperazine (TFMPP) were antagonists on intracellular Ca(2+). Antagonist pharmacological profiles were similar between adapter G-proteins, receptor binding, and adenylyl cyclase studies. These results show that adapter G-proteins can be used to study G(s)-linked receptors using the high throughput FLIPR system measuring changes in intracellular Ca(2+) and provide novel information on mCPP and 8-OH-DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and CNS penetration in the rat.

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.

Animals↗
PubMed2000

Colonic adenocarcinoma occurring in an Indiana pouch: report of a case and review of the literature.

Colonic adenocarcinoma has been frequently reported after ureterosigmoidostomy based on carcinogenic substances created when feces and urine are mixed. However, colonic adenocarcinoma has never been reported arising in an Indiana pouch after cystectomy. We report a case of adenocarcinoma arising in a urinary pouch after cystectomy for transitional cell cancer. We believe this to be caused by hereditary nonpolyposis colon cancer (an autosomal dominant syndrome that puts individuals at risk for genitourinary, colonic, and several other cancers) rather than carcinogenic effects of urine on colonic mucosa. When planning urinary reconstruction after cystectomy for malignancy, it is important to consider the possibility that an individual may suffer from hereditary nonpolyposis colon cancer before selecting the colon as a urinary reservoir.

Adenocarcinoma↗
PubMed2000

Biosafety of in vivo adenovirus-p53 intravesical administration in mice.

OBJECTIVES: To evaluate the biosafety and in vivo biodistribution of intravesical instillation of an adenovirus that contains human p53 gene. Mutations of p53, which are found in as many as 40% of transitional cell carcinomas, are associated with a poor prognosis and resistance to chemotherapy and radiation therapy. Restoration of wild-type p53 status by means of adenoviral-mediated therapy may enhance apoptosis and improve the response to therapy, but the issues of biosafety and toxicity have not yet been addressed. METHODS: Adenovirus-p53 (1 x 10(8), 1 x 10(9), and 5 x 10(9) pfu/mL) and luciferase reporter gene (5 x 10(9)) were instilled into the bladders of anesthetized female BALB/c mice. The mice were killed on days 1, 3, 6, and 13, and representative samples of the bladder, ureter, kidney, adrenal gland, ovary, liver, heart, and lung were removed for histologic evaluation. RESULTS: No histologic signs of toxicity were found. The hematologic and biochemical profiles of the mice were normal, with the exception of a transient elevation in liver function tests on day 1 in the three treatment groups. CONCLUSIONS: Intravesical instillation of adenovirus-p53 was well tolerated; the bladder urothelium appeared to prevent systemic dissemination. The results of these experiments support the safety of intravesical gene transfer by intravesical instillation.

Adenoviridae↗
PubMed2000

Identification of alanine dehydrogenase and its role in mixed secretion of ammonium and alanine by pea bacteroids.

N2-fixation by Rhizobium-legume symbionts is of major ecological and agricultural importance, responsible for producing a substantial fraction of the biosphere's nitrogen. On the basis of 15N-labelling studies, it had been generally accepted that ammonium is the sole secretion product of N2-fixation by the bacteroid and that the plant is responsible for assimilating it into amino acids. However, this paradigm has been challenged in a recent 15N-labelling study showing that soybean bacteroids only secrete alanine. Hitherto, nitrogen secretion has only been assessed from in vitro 15N-labelling studies of isolated bacteroids. We show that both ammonium and alanine are secreted by pea bacteroids. The in vitro partitioning between them will depend on whether the system is open or closed, as well as the ammonium concentration and bacteroid density. To overcome these limitations we identified and mutated the gene for alanine dehydrogenase (aldA) and demonstrate that AldA is the primary route for alanine synthesis in isolated bacteroids. Bacteroids of the aldA mutant fix nitrogen but only secrete ammonium at a significant rate, resulting in lower total nitrogen secretion. Peas inoculated with the aldA mutant are green and healthy, demonstrating that ammonium secretion by bacteroids can provide sufficient nitrogen for plant growth. However, plants inoculated with the mutant are reduced in biomass compared with those inoculated with the wild type. The labelling and plant growth studies suggest that alanine synthesis and secretion contributes to the efficiency of N2-fixation and therefore biomass accumulation.

Alanine↗
PubMed2000

In vivo administration of O(6)-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine.

Clinically relevant cancer chemotherapeutic alkylating agents such as temozolomide and dacarbazine induce apoptosis and are mutagenic via the formation of O(6)-alkylguanine adducts in DNA. The DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) functions by dealkylating such adducts and can thus prevent apoptosis and mutagenesis. In attempts to maximize the clinical effectiveness of these alkylating agents, inhibitors of AGT such as O(6)-benzylguanine (BeG) have been developed. We show here that within murine small intestinal crypt cells, BeG administration does not alter the apoptotic response to the direct-acting methylating agents N-methyl-N-nitrosurea (MNU), temozolomide and N-methyl-N'-nitro-N-nitrosoguanidine. Furthermore, we show that BeG pretreatment fails to elevate the mutation frequency at the murine Dlb-1 locus following exposure to MNU. Consistent with these results, we show that intestinal AGT activity is effectively abolished by administration of 100 mg/kg temozolomide, even in the absence of BeG. In contrast, pretreatment with BeG transiently abolished the apoptotic response to the methylating prodrug dacarbazine. Activation of dacarbazine to its reactive intermediate has previously been shown to be cytochrome P450 dependent and we show here that pretreatment of mice with the cytochrome P450 inhibitor metyrapone also inhibits dacarbazine-induced apoptosis. Thus BeG increases neither the prevalence of apoptosis nor mutation frequency in the murine small intestine, but is capable of inhibiting P450-dependent prodrug activation. The positive implication from this study is that BeG treatment may not exacerbate the toxic and mutagenic effects of methylating agents within normal cells, although it may engender other adverse reactions through the suppression of cytochrome P450-dependent processes.

Animals↗
PubMed2000

Obstetric outcome of pregnancies following ICSI, classified according to sperm origin and quality.

The aim of this study was to report the outcome of all clinical pregnancies obtained after intracytoplasmic sperm injection (ICSI) performed during a 5 year period at two fertility clinics, with special reference to delivery outcome associated with different sperm origin and quality and the transfer of fresh or frozen-thawed pre-embryos. A total of 1293 clinical pregnancies was analysed. Deliveries occurred in 75.9% (n = 982) and early spontaneous abortion, late spontaneous abortion and ectopic pregnancy in 21.4, 1.0 and 1.2% respectively. Multiple birth occurred in 21.3% (208 sets of twins and one set of triplets) of the deliveries, with the highest incidence in the epididymal sperm group (30.2%) and lowest in the cryopreserved group (13.7%). A total of 1192 infants was born. Preterm birth occurred in 15.7% of all deliveries. Preterm birth was not related to sperm origin or quality but was related to multiple birth. The prematurity rate was 8.4%, 42.3% and 100% for singletons, twins and triplets respectively. Singleton infants born after cryopreservation as embryos had a significantly higher birthweight than the ejaculated sperm group with fresh embryo transfer. The perinatal mortality rate was 11.7 per 1000 born infants. Eighty-seven of the 1192 infants (7.3%) had a malformation, 40 of which were minor. The perinatal mortality rate and the malformation rate were similar in the different subgroups. Prenatal karyotyping was performed on 149 fetuses (12.5%) and abnormal results were found in four cases (2.7%). In conclusion, obstetric outcome of ICSI pregnancies was similar to that of conventional IVF and was not influenced by sperm origin or quality. The high incidence of multiple births is still the major concern.

Abnormalities, Multiple↗