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Biomedical subjects

C Martin

Publications and source records attributed to C Martin.

At least 145 records · Page 8Linked to original sources
PubMed2001

Neurosteroid hydroxylase CYP7B: vivid reporter activity in dentate gyrus of gene-targeted mice and abolition of a widespread pathway of steroid and oxysterol hydroxylation.

The major adrenal steroid dehydroepiandrosterone (DHEA) enhances memory and immune function but has no known dedicated receptor; local metabolism may govern its activity. We described a cytochrome P450 expressed in brain and other tissues, CYP7B, that catalyzes the 7alpha-hydroxylation of oxysterols and 3beta-hydroxysteroids including DHEA. We report here that CYP7B mRNA and 7alpha-hydroxylation activity are widespread in rat tissues. However, steroids related to DHEA are reported to be modified at positions other than 7alpha, exemplified by prominent 6alpha-hydroxylation of 5alpha-androstane-3beta,17beta-diol (A/anediol) in some rodent tissues including brain. To determine whether CYP7B is responsible for these and other activities we disrupted the mouse Cyp7b gene by targeted insertion of an IRES-lacZ reporter cassette, placing reporter enzyme activity (beta-galactosidase) under Cyp7b promoter control. In heterozygous mouse brain, chromogenic detection of reporter activity was strikingly restricted to the dentate gyrus. Staining did not exactly reproduce the in situ hybridization expression pattern; post-transcriptional control is inferred. Lower level staining was detected in cerebellum, liver, and kidney, and which largely paralleled mRNA distribution. Liver and kidney expression was sexually dimorphic. Mice homozygous for the insertion are viable and superficially normal, but ex vivo metabolism of DHEA to 7alpha-hydroxy-DHEA was abolished in brain, spleen, thymus, heart, lung, prostate, uterus, and mammary gland; lower abundance metabolites were also eliminated. 7alpha-Hydroxylation of 25-hydroxycholesterol and related substrates was also abolished, as was presumed 6alpha-hydroxylation of A/anediol. These different enzyme activities therefore derive from the Cyp7b gene. CYP7B is thus a major extrahepatic steroid and oxysterol hydroxylase and provides the predominant route for local metabolism of DHEA and related molecules in brain and other tissues.

Animals↗
PubMed2001

Ontogeny of the neurosteroid enzyme Cyp7b in the mouse.

The function of the major adrenal steroid dehydroepiandrosterone (DHEA) is not known. It has been reported to improve learning and memory in mice and can exert neuroprotective and trophic effects, particularly in the hippocampus. We recently described a cytochrome P450 (Cyp7b), that catalyses the 7alpha-hydroxylation of DHEA and related steroids and sterols. In this paper, we have used mRNA in situ hybridisation to map the ontogeny of cyp7b in the foetal and adult mouse. Cyp7b mRNA is highly expressed throughout from embryonal (E) day 12.5 (the earliest day studied). There is also expression throughout the body, including the spine, thymus, developing kidneys, lungs and urogenital region. Widespread expression becomes more restricted towards birth: in newborn mice expression is largely limited to the hippocampus, with some expression being detected in kidney. The overall decline in mRNA, and increasing restriction to the hippocampus, is reflected in the DHEA hydroxylation activity of brain homogenates. This pattern of cyp7b mRNA expression in specific organs could be consistent with a protective role in foetal development, with highest expression seen when the foetus is most vulnerable to steroid excess (i.e.) early gestation.

Animals↗
PubMed2001

Variations in chemical mimicry by the ectoparasitic mite Varroa jacobsoni according to the developmental stage of the host honey-bee Apis mellifera.

The ectoparasitic mite Varroa jacobsoni poses a major threat to the survival of European honey-bee populations. Development of effective control methods is therefore much needed. Study of interspecific chemical communication between the parasite and host is a particularly promising avenue of research. Previous study has shown that the cuticular hydrocarbons of the parasite mite Varroa jacobsoni are qualitatively identical to those of its honey-bee host Apis mellifera (Nation J.L., Sanford M.T., Milne K., 1992. Cuticular hydrocarbons from Varroa jacobsoni. Experimental and Applied Acarology 16, 331-344). The purpose of the present study was to compare the cuticular hydrocarbon patterns of the two species at different stages of bee development. Cuticular components were identified by gas chromatography/mass spectrometry. The proportion of each component was calculated at three stages of bee development (larvae, pupa, emerging bee). The degree of chemical mimicry between the parasite and host was evaluated by multivariate analyses using the resulting proportions for each category of individuals. There were four main findings. The first was that the proportions of some components are different at the larval, pupal and imago stage of bee development. Second, Varroa profiles vary depending on the developmental stage of the host. Third, the cuticular profile of adult mites is more similar to that of the stage of the host than that of later and/or earlier stages except for parasites collected from emerging adult bees. Fourth, the degree of mimicry by Varroa is greater during larval and pupal stages than during the emerging adult bee stages. The role of chemical mimicry - although it is not perfect - in enabling parasites to infest bee colonies by the parasite is discussed.

Animals↗
PubMed2001

Phase II trial of paclitaxel plus gemcitabine in patients with locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: Given the cisplatin-related myelotoxicity and nonhematologic toxicities, we were prompted to undertake a study of the noncisplatin combination of paclitaxel plus gemcitabine to evaluate the efficacy, tolerance, and survival of this combination in patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received gemcitabine 2,000 mg/m(2) and paclitaxel 150 mg/m(2) on days 1 and 15 of a 28-day cycle, for a maximum of eight cycles. RESULTS: Between December 1997 and June 1998, 89 untreated NSCLC patients were enrolled; 30 (34%) had stage IIIB disease (23 with malignant pleural effusion and seven without), and 59 (66%) had stage IV disease. Eighty-six percent of patients had a performance status of 0 or 1. The median number of cycles administered was four (range, one to eight cycles). The mean dose-intensity for both paclitaxel and gemcitabine was nearly 100%. Hematologic and nonhematologic toxicities were mild. Thirty-eight patients received second-line chemotherapy after completion of the study. The overall intent-to-treat response rate was 32.2%, with a higher response rate for stage IIIB patients (43.3%) than for stage IV patients (26.3%). Overall median survival was 9.9 months, and 1-year survival was 38.8% (14.2 months for stage IIIB and 7.7 months for stage IV; P =.007). Median survival was 10.2 months for patients with a performance status of 0 or 1 and 4.8 months for patients with a performance status of 2 (P =.007). CONCLUSION: A biweekly paclitaxel/gemcitabine regimen was well tolerated, with an acceptable response rate and a reasonable median survival time, especially in patients with good performance status. It merits further exploration in future studies.

Adult↗
PubMed2001

Carbon isotopic ratios of atmospheric CO(2) affect the delta(13)C values of heterotrophic growth in Nicotiana tabacum.

Heterotrophic Nicotiana tabacum (L. CV. Wisconsin 38) plants are enriched in 13C relative to the carbon sources in their growth medium. We examined whether carboxylation via phosphoenolpyruvate carboxylase contributes to the enrichment. Achlorophyllous plants were produced using an inhibitor of carotenoid synthesis and were grown on sucrose with known delta(13)C values. Groups of plants were exposed to air with different delta(13)C values as well as to CO(2)-free air. The delta(13)C values of heterotrophic plants were greater than the sucrose source in all treatments and this enrichment increased as 13CO(2)/12CO(2) ratios increased in the source air. Rubisco activity was ruled out as a cause for the enrichment observed as 13CO(2)/12CO(2) ratios increased because the delta(13)C values of heterotrophic plants were similar when exposed to high 13CO(2) while grown in the light or dark. Neither was enrichment due to the adsorption of 13CO(2) in the high 13CO(2) treatment because dead plants did not exhibit this effect when subjected to the same atmospheric treatments. Carboxylation by PEP carboxylase is a likely mechanism causing the 13C-enriched values of living white tissues relative to their organic carbon sources. These results experimentally support suggestions that the anaplerotic activity of PEP is responsible for the 13C-enrichment commonly observed where heterotrophic inputs to growth are large such as in very young leaves.

Journal Article↗
PubMed2001

Ultrafast formation of nonemissive species via intermolecular interaction in single crystals of conjugated molecules.

We investigate the influence of interchain interactions on the photoluminescence processes in a sexithiophene single crystal by applying hydrostatic pressure. We perform transient photoluminescence spectroscopy in the time domain of 100 fs for pressures up to 60 kbar. The combined use of steady-state and time-resolved optical spectroscopies allows us to show that the pressure-induced quenching of the photoluminescence is caused by an ultrafast (approximately 100 fs) formation of intermolecular species.

Journal Article↗
PubMed2001

Intra-operative MR guidance during trans-sphenoidal pituitary resection: preliminary results.

The use of intra-operative MR image guidance has the potential to improve the precision, extent, and safety of trans-sphenoidal pituitary resections. The trans-sphenoidal approach to pituitary surgery has been performed for some time (1--3). Until now these surgeries have relied on direct visualization without the aid of image guidance. An open-bore configuration 0.5T SIGNA SP MR system (GE Medical Systems, Milwaukee, Wisconsin) has been used to provide image guidance for seventeen trans-sphenoidal pituitary adenoma resections (4). The intra-operative MRI system allowed the radiologist to successfully direct the surgeon toward the sella turcica while avoiding the cavernous sinus, optic chiasm and other critical structures. Imaging performed during the surgery monitored the extent of resection and allowed for removal of tumor beyond the surgeon's view in seven cases. Dynamic MR imaging was used to distinguish residual tumor from normal gland and postoperative changes, permitting more precise tumor localization. A heme-sensitive long TE gradient echo sequence was used to find the presence of hemorrhagic debris. All patients tolerated the procedure well without significant complications. J. Magn. Reson. Imaging 2001;13:136-141.

Adenoma↗
PubMed2001

Chondroitin sulphate proteoglycan is involved in lens vesicle morphogenesis in chick embryos.

Proteoglycans have been implicated in the invagination and formation of various embryonal cavitied primordia. In this paper the expression of chondroitin sulphate proteoglycan (CSPG) is analysed in the lens primordium during lens vesicle formation, and demonstrate that this proteoglycan has a specific distribution pattern with regard to invagination and fusion processes in the transformation of placode into lens vesicle. More specifically, CSPG was detected in: (1) the apical surface of lens epithelial cells, where early CSPG expression was observed in the whole of the lens placode whilst in the vesicle phase it was restricted to the posterior epithelium; (2) intense CSPG expression in the basal lamina, which remained constant for the entire period under study; (3) CSPG expression in the intercellular spaces of the lens primordium epithelium, which increased during the invagination of the primordium and which at the vesicle stage was more evident in the posterior epithelium; and (4) CSPG expression on the edges of the lens placode both prior to and during fusion. Treatment with beta- D -xyloside causes significant CSPG depletion in the lens primordium together with severe alterations in the invagination and fusion of the lens vesicle; this leads to the formation of lens primordia which in some cases remain practically flat or show partial invagination defects or fusion disruption. Similar results were obtained by enzyme digestion with chondroitinase AC but not with type II heparinase, which indicates that alterations induced by beta- D -xyloside were due to interference in CSPG synthesis. The findings demonstrate that CSPG is a common component of the lens primordium at the earliest developmental stages during which it undergoes specific modifications. It also includes experimental evidence to show that 'in vivo' CSPG plays an important role in the invagination and fusion processes of the lens primordium.

Animals↗
PubMed2001

The importance of cholesterol in maintenance of P-glycoprotein activity and its membrane perturbing influence.

In tumour cell lines that display multidrug resistance, expression of P-glycoprotein (P-gp) alters many aspects of biomembrane organization in addition to its well-characterized drug transport activity. We have developed a reconstitution system to directly investigate the effect of purified P-gp on the biophysical properties of lipid bilayers. Using a mixed detergent system it was possible to efficiently reconstitute P-gp at lipid:protein ratios as low as 2.5 (w/w) by removal of detergent using adsorption to SM-2 BioBeads. P-gp was able to alter many biophysical parameters associated with lipid organization within bilayers. For example, the changes in overall fluidity and excimer formation by lipid analogues indicate modified packing organization of bilayer constituents. Surprisingly, given its role in conferring drug resistance, P-gp insertion into bilayers also caused significantly increased permeability to aqueous compounds, also reflecting a modified phospholipid environment. Translocation of various phospholipid species between leaflets of the bilayer was increased in the presence of P-gp; however, the effect was not dependent on ATP hydrolysis by the protein. Physiological concentrations of cholesterol modified P-gp function and the degree to which it perturbed bilayer organization. The basal ATPase activity of P-gp was increased in a dose-dependent fashion by the incorporation of cholesterol in PC:PE liposomes. In addition, the degree to which the modulator verapamil was able to stimulate this basal ATPase activity was reduced by the presence of cholesterol in proteoliposomes. However, the potency of verapamil was unaltered, suggesting a specific effect, not simply caused by lower drug penetration into the cholesterol containing bilayers. In summary, P-gp is able to cause perturbation in the organization of bilayer constituents. Cholesterol imparted "stability" to this perturbation of bilayer organization by P-gp and moreover this led to altered protein function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Relationships between muscle mitochondrial metabolism and stress-induced corticosterone variations in rats.

In order to determine the effect of chronic and acute stress on muscle mitochondrial metabolism, two strains of rats were selected on the basis of their different hypothalamo-pituitary-adrenal (HPA) axis responses to different stressors [Spontaneous Hypertensive Rats (SHR) and Lewis rats]. For 8 weeks animals were stressed by daily exposure to either a novel environment (SHR: n=16, Lewis: n=16) or forced exercise (SHR: n=16, Lewis: n=16). An unstressed group was left undisturbed (SHR: n=5, Lewis: n=5). Half of the stressed animals (n=32) were submitted to an acute stress (1-h immobilization). The mitochondrial responses of plantaris muscle [cytochrome-c-oxidase (COX), citrate synthase and succinate dehydrogenase activities, the latter two being measured as indices of functional mitochondrial amount] in the presence of different physiological plasma corticosterone (CORT) concentrations were analyzed. The novel environment and forced exercise stress induced different levels of plasma CORT which were negatively correlated with the amount of functional mitochondria in the plantaris muscle. Therefore, a chronic intermittent stress is able to induce an increase in plasma CORT which may be related to deleterious changes in muscle mitochondrial metabolism. Lastly, the acute stress was not associated with a decrease in functional mitochondria but with an increase in COX activity. This suggests that the relationship between CORT and muscle mitochondrial metabolism depends both on the level and duration of endogenous glucocorticoids exposure.

Acute Disease↗
PubMed2001

A control theoretic model of the forearm.

In this paper, a control theoretic model of the forearm is developed and analyzed, and a computational method for predicting muscle activations necessary to generate specified motions is described. A detailed geometric model of the forearm kinematics, including the carrying angle and models of how the biceps and the supinator tendons wrap around the bones, is used. Also, including a dynamics model, the final model is a system of differential equations where the muscle activations play the role of control signals. Due to the large number of muscles, the problem of finding muscle activations is redundant, and this problem is solved by an optimization procedure. The computed muscle activations for ballistic movements clearly recaptures the triphasic ABC (Activation-Braking-Clamping) pattern. It is also transparent, from the muscle activation patterns, how the muscles cooperate and counteract in order to accomplish desired motions. A comparison with previously reported experimental data is included and the model predictions can be seen to be partially in agreement with the experimental data.

Biomechanical Phenomena↗
PubMed2001

Does treatment delay affect survival in non-small cell lung cancer? A retrospective analysis from a single UK centre.

We analysed survival in relation both to time to treatment and other clinical parameters in the care pathway of non-small cell lung cancer (NSCLC) patients. Medical notes of 189 patients diagnosed with NSCLC presenting in 1998 were reviewed. Median time to treatment in all patients was 48 days. In multivariate analysis, time to treatment did not affect survival in patients with any stage of disease. Referral from general practitioner to chest department (P=0.032, HR=0.08), and absence of use of surgery (P=0.006, HR=30.30) were independently significant predictors of survival in stages 1 and 2 subgroup. In stage 3 patients, absence of laboratory abnormality (P=0.002, HR=0.39), and use of combined treatment (P=0.015, HR=0.17) were independent prognosticators. Lastly, in patients with stage 4 disease, presence of bone and/or liver metastasis (P=0.005, HR=2.65), and absence of use of chemotherapy (P<0.001, HR=6.25) were significantly associated with shorter survival. As survival is dependent on classical prognosticators, but not on time from referral to treatment (hospital delay), expanding resources in oncology (equipment, drugs and personnel), and, perhaps, reducing patient delay, rather than reducing hospital delay alone, could be better strategies to improve NSCLC survival.

Adult↗
PubMed2001

Attention influences sensory integration for postural control in older adults.

This study investigated the influence of attention on the sensory integration component of postural control in young and older adults. Eighteen young and 18 older healthy subjects performed information-processing tasks during different postural challenge conditions. Postural conditions included seated, standing on a firm surface, standing on a sway-referenced floor, and standing on a sway-referenced floor while viewing a sway-referenced scene. During each condition, reaction time (RT) was measured during two simple and one inhibitory RT tasks. For the inhibitory task, the time required to inhibit an action was derived, termed the inhibitory time (IT). Performing a RT task was associated with increased postural sway in older subjects, but not in young subjects. The greatest influence of RT task on sway of older subjects was found during the sway-referenced floor/sway-referenced scene condition. Conversely, postural condition had an influence on RT task performance in both young and older subjects. The IT was increased in both young and older subjects only during the sway-referenced floor/scene condition. These results suggest that the sensory integration component of postural control in particular seems to require attention. Further, our data suggest that attentional processes related to inhibitory control are engaged when sensory integration requirements are high.

Age Factors↗
PubMed2001

Shaping in plant cells.

Plant cells adopt a diversity of different shapes that are adapted to their specific functions. Central to the development of specialised form is the modification of cell-wall composition and organisation. A number of recent papers emphasise the importance of the cell wall to cell shaping, in the definition of both localised regions that are expandable and regions that are more resistant to mechanical forces. The organisation and activity of the cytoskeleton, and the activity of signalling pathways, are also essential in defining regions of the cell wall that will grow and those that will not. Although turgor has long been assumed to be a rather passive contributor to cell shaping, recent reports show that, in some cells, differential changes in turgor may have a role in establishing specialised cell form.

Cell Size↗
PubMed2001

Modifications of the cuticular hydrocarbon profile of Apis mellifera worker bees in the presence of the ectoparasitic mite Varroa jacobsoni in brood cells.

Varroa jacobsoni is an ectoparasite of Apis mellifera which invades brood cells, on 8-day-old larvae several hours before cell capping. Reproduction of the parasite takes place in the capped brood cells during the nymphose of the bee. Cuticular hydrocarbons of unparasitized bees and of bees parasitized by Varroa jacobsoni were extracted and analysed by gas chromatography (GC) coupled with mass spectrometry (GC-MS). Three developmental stages of worker honey bees were studied: larvae, pupae and emergent adults. The comparison between unparasitized and parasitized hosts was performed with Principal Components Analysis coupled with a multivariate variance analysis. The cuticular hydrocarbon profiles of honey bees were qualitatively similar, for the 3 developmental stages and regardless of the presence of Varroa in the cells. Nevertheless, comparison of the relative proportions of hydrocarbons showed that the cuticular profiles of pupae and emergent adults parasitized by 1 mite and of larvae parasitized by 2 mites were significantly different from the corresponding unparasitized individuals. Such modifications could be regarded (i) as a cause of the multi-infestation in larvae during invasion of brood and (ii) as a consequence of stress and/or removal of proteins contained in the haemolymph of the host during its development.

Animals↗