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T Savage

Publications and source records attributed to T Savage.

At least 19 recordsLinked to original sources
PubMed1998

Multiple elements regulate Mash1 expression in the developing CNS.

Mash1, a transcription factor of the basic helix-loop-helix class, is expressed during embryogenesis in restricted regions of the nervous system. An essential role for Mash1 in neural development was demonstrated previously in mice carrying a targeted disruption of the Mash1 gene. Regulation of the precise temporal and spatial expression of Mash1 is thus likely to be important for proper neural development. In this study, sequences that regulate Mash1 expression in the central nervous system were characterized by assaying the expression of lacZ reporter genes in transgenic embryos. A 1158-bp enhancer localized approximately 7 kb upstream of the Mash1 coding region was identified. Deletions within this enhancer region reveal the presence of both positive and negative cis-acting elements. Analysis of multiple sequences within the enhancer demonstrate that different elements preferentially function in different regions within the Mash1-specific CNS expression domain. In addition, a role for sequences 3' of the Mash1 coding region is revealed, providing evidence for posttranscriptional control of Mash1 expression in multiple CNS domains.

Animals↗
PubMed1998

Estrogenic and progestational activity of 7alpha-methyl-19-nortestosterone, a synthetic androgen.

Synthetic androgens exhibit estrogenic/antiestrogenic and progestational activities in addition to their androgenic effects. To investigate the pharmacological action of the synthetic androgen, 7alpha-methyl-19-nortestosterone (MENT), we examined its action in female rodents. The criteria employed for estrogenic/antiestrogenic effects were, uterine weight increase, vaginal cornification, induction of progesterone receptors (PR) synthesis and stimulation of peroxidase activity in the uteri of ovariectomized rats and mice. MENT increased uterine weight in a dose dependent manner, but did not cause vaginal cornification or stimulate PR synthesis in the uterus. The uterotropic activity of MENT was 200-fold lower than that of estradiol. Estrogen receptor (ER) bound [3H]-E2 was displaced by E2 and MENT with ED50 values of 70 pg and 250 ng, respectively, a 3,500 fold difference in their binding affinity. The low binding of MENT to ER, in contrast to its relatively high uterotropic action, suggested that receptors other than ER may be involved in its action on the uterus. The progestational activity of MENT in immature rabbits using the McPhail index assay was comparable to that of progesterone. Binding affinities of MENT and progesterone to PR were also comparable. However, the action of MENT on the uterus does not seem to be a progestational effect since mifepristone, an antiprogestin, had no effect on MENT-induced uterine growth. Specific androgen receptors (AR) in uterine cytosol were demonstrated. The involvement of AR in MENT action was confirmed by using an antiandrogen (flutamide) and an antiestrogen (ICI-182) in ovariectomized mice. Although MENT did not block the uterotropic effect of E2, it inhibited the E2-induced cornification of vaginal epithelium, induction of uterine PR synthesis and increase in uterine peroxidase activity in ovariectomized rats. The antiestrogenic effect of MENT was also blocked by flutamide. These results suggest that the uterotropic and antiestrogenic effects of androgens are mediated via AR. It is concluded that the increase in uterine weight caused by MENT is attributable to its anabolic effects.

Animals↗
PubMed1998

Increased myogenic tone precedes structural changes in mild experimental uraemia in the absence of hypertension in rats.

1. Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodelling and the localization of atherosclerotic plaque. Uraemia is a proatherogenic process and is expected to be associated with impaired vascular reactivity.2. To study this, 12 male Wistar rats were rendered uraemic by five-sixths nephrectomy and 12 control rats were sham operated simultaneously. After 8 weeks a tail-cuff systolic blood pressure was recorded, blood samples were taken and the animals killed. Isolated femoral arteries were dissected and mounted on a pressure myograph and myogenic tone was assessed over a range of intravascular pressures from 40 to 160 mmHg. Histologically the arteries were comparatively examined for gross morphology, calcification and deposition of collagen.3.Biochemically the serum urea and creatinine were greater in the uraemic compared with the control rats (urea: 23.5+/-6 mmol/l and 6.8+/-01 mmol/l respectively, P not significant; creatinine: 130.7+/-13 mmol/l and 70.3+/-5 mmol/l respectively, P<0.01) but systolic blood pressure was the same in both groups (control, 97+/-1 mmHg; uraemic, 98+/-2 mmHg), compatible with mild uraemia.4. Myogenic tone was significantly greater in uraemic vessels (7.3+/-1.8% versus 2.3+/-0. 4% in control, P=0.01). The actual vessel lumen diameter was also smaller in pressurized uraemic vessels compared with control vessels (471+/-30 microm versus 604+/-33 microm, P<0.01) after equilibration in physiological salt solution. However, when incubated in calcium-free physiological salt solution, the passive internal diameter was similar in uraemic vessels (538+/-25 microm compared with 595+/-31 microm in control). Histologically, there were no differences between the two groups.5. We conclude that some aspects of vascular reactivity are altered in mild experimental uraemia as shown by a reduced internal lumen diameter and increased myogenic tone. Furthermore, these changes are apparent in the absence of hypertension and precede structural changes.

Animals↗
PubMed1998

Calcified plaque is common in the carotid and femoral arteries of dialysis patients without clinical vascular disease.

BACKGROUND: Cardiac and vascular mortality are common in end-stage renal disease (ERSD) and are often attributed to accelerated atherosclerosis. SUBJECTS AND METHODS: We studied 24 non-diabetic ESRD patients without cardiac or vascular disease (M = 12, F = 12) and 24 age-, sex- and race-matched healthy controls. All underwent B-mode ultrasound for carotid and femoral intima media thickness (IMT) and plaque (% stenosis) together with blood pressure (BP), and echocardiograms to determine left ventricular mass. RESULTS: Both BP and mean IMT were similar in patients and controls. However, discrete plaque was present in 71% (17/24) of patients compared with 21% (5/24) of controls (P = 0.001), and % stenosis was greater in patients (carotid 12.2 +/- 11% vs 2.3 +/- 5.9%, P < 0.0004; femoral 16.4 +/- 19.1% vs 3.1 +/- 6.4%, P < 0.003). Plaque was soft/atheromatous in 3 of the 5 controls, but not in any of the 17 patients (P = 0.007), all of whom had calcified lesions. BP and cholesterol were not correlated with IMT or plaque in patients, but in control subjects carotid IMT was correlated with systolic BP (r = 0.66, P < 0.0005) and diastolic BP (r = 0.45, P < 0.03). In patients, the only independent variables related to vascular morphology were serum albumin which was inversely related to IMT (P < 0.03) and to plaque (carotid P < 0.05, femoral P < 0.02) and age, which was related to femoral plaque only (P < 0.04). Left ventricular end-diastolic internal dimension, not LVMI, correlated positively with carotid IMT (P < 0.04). CONCLUSION: Our results show that calcified plaque is common in ESRD patients and hypoalbuminaemia may be an associated factor.

Adult↗
PubMed1998

Gender differences in mediators of left ventricular hypertrophy in dialysis patients.

Left ventricular hypertrophy (LVH) is known to be a strong predictor of cardiovascular death in dialysis patients, but the mediators for its development remain to be clarified. In the non-renal population risk factors for LVH differ between the genders. We therefore studied 46 non-diabetic patients (26 male, 19 female) on maintenance hemodialysis (n = 25) or continuous ambulatory peritoneal dialysis (CAPD) (n = 20) all free from clinically evident cardiac disease, who underwent 48-hour ambulatory blood pressure (BP) monitoring, 2-D and M-mode echocardiography for left ventricular mass index (LVMI) and bloods for hemoglobin, parathyroid hormone (PTH), urea and electrolytes and liver function tests. Thirty-two out of 45 patients were taking antihypertensive drugs at the time of the study. The mean 48-hour BP was 135 +/- 19/83 +/- 13 mmHg and the mean LVMI was 144 +/- 50 g/m2. LVH (LVMI > 131 g/m2 men, > 100 g/m2 women) was present with equal frequency in both sexes: men 72% (18/25) and women 68% (13/19). Simple regression analysis showed that LVMI was correlated with 48-hour pulse pressure (r = 0.52, p < 0.00033), 48-hour systolic BP (r = 0.37, p < 0.05), PTH (r = 0.31, p < 0.04) and inversely with serum calcium (r = -0.29, p < 0.05) and hemoglobin (r = -0.33, p < 0.03). However, on multiple regression analysis pulse pressure (R2 = 28.7%), day systolic BP (R2 = 15.4%) and 48-hour systolic BP (R2 = 14.1%) were the only variables linked to LVMI. When the patients were split by gender, stepwise linear regression in the men showed a highly significant relationship between LVMI and pulse pressure (R2 = 37.1%) which was stronger at nighttime (R2 = 42.6%), but in females this was not apparent (R2 = 4.39%) and indeed no variable was linked to LVMI. Our study confirms that LVH is not only prevalent in dialysis patients but is present with equal frequency in both sexes. However the determinants of its development are different for each gender. In males pulse pressure, and therefore by implication vascular compliance, is important but in females, other unidentified factors predominate.

Adult↗
PubMed1997

Power pair.

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Chicago↗
PubMed1997

Interdialytic weight gain and 48-h blood pressure in haemodialysis patients.

BACKGROUND: Hypertension, which is often associated with hypervolaemia, is common in haemodialysis patients and is a known determinant of target organ damage. Interdialytic weight gain due to volume overload has also been associated with mortality in haemodialysis patients. METHODS: We therefore studied 27 chronic haemodialysis patients who underwent 48-h ambulatory blood pressure monitoring between two midweek dialysis sessions, and 2D and M-mode echocardiography for determination of left ventricular mass index. RESULTS: Left ventricular hypertrophy (left ventricular mass index in men > 131 g/m2, women > 100 g/m2) was present in 70% (19/27) patients despite a mean 48-h blood pressure of 132 +/- 19/81 +/- 15 mmHg. Mean interdialytic weight gain was 1.6 +/- 0.8 kg and was not related to left ventricular mass index. Two patterns of interdialytic blood pressure change were apparent: in group 1 (16 patients) 48-h blood pressure increased (+19 +/- 12/13 +/- 9 mmHg), whereas in group 2 (11 patients) blood pressure fell (-10 +/- 13/-8 +/- 10 mmHg P < 0.0001). In both groups the number of hypertensive patients (group 1, 10/16; group 2, 6/11), the 48-h blood pressure (132 +/- 20/80 +/- 15 vs 132 +/- 18/82 +/- 15 mmHg) and interdialytic weight gain (+1.9 +/- 0.7 vs +1.3 +/- 0.7 kg) were similar. There was also no correlation between interdialytic blood pressure change and weight gain in either group. CONCLUSIONS: We conclude that interdialytic blood pressure changes cannot be directly related to interdialytic fluid gain, even in apparent volume-dependent hypertension, emphasizing the importance of additional factors in the control of blood pressure in end-stage renal disease.

Adult↗
PubMed1996

Lineage-specific regulation of the neural differentiation gene MASH1.

Mash1 is a transcription factor required during embryogenesis for the development of multiple neural lineages. It is expressed in restricted domains at specific stages in the developing central and peripheral nervous systems and in the developing olfactory epithelium. We have investigated the regulation of Mash1 expression during embryogenesis using transgenic mice containing Mash1/lacZ reporter constructs. Cis-acting regulatory elements controlling Mash1 expression in the central nervous system are located within an 8-kb sequence upstream of the Mash1 coding region. This 8-kb sequence does not contain elements directing expression to the peripheral nervous system, olfactory epithelium, or retina. Sequences outside this 8 kb but within 36 kb of the Mash1 locus contain elements responsible for expression in the autonomic division of the peripheral nervous system. However, transgene expression in embryos containing the 36-kb sequence was never detected in the olfactory epithelium and retina. Thus, regulatory elements driving expression in these lineages may be at even greater distances from the Mash1 coding region. These data provide evidence for complex regulation of Mash1 expression in which multiple lineage-specific cis-acting regulatory regions span greater than 36 kb of the Mash1 locus. Further characterization of these regions will facilitate the study of factors that regulate the temporal and spatial expression of Mash1 during development. In addition, the regulatory sequences identified here can direct expression of heterologous genes to developing neural lineages that normally express Mash1, thus providing an important tool for examining the function of candidate regulatory genes in mammalian nervous system development.

Animals↗
PubMed1996

Inside outsourcing.

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Contract Services↗
PubMed1993

Methods for measuring dermal penetration of pesticides.

The quantitation of percutaneous absorption of pesticides is required as part of the registration, re-registration or hazard assessment process. There is a paucity of regulatory guidelines in this area. This paper presents three protocols that can be used to quantitate percutaneous absorption, primarily as a result of continuous skin exposure over a period equivalent to a working day (8 hr). A rat in vivo protocol, an in vitro protocol and a human in vivo protocol are described. None of these protocols is considered to be ideal and/or to represent a preferred method. The final choice of protocol must take into account the toxicity and physicochemical properties of the test molecule as well as cost and resource/technical ability. Nevertheless, the protocols described allow percutaneous absorption to be quantitated, and it is believed that, if adopted, they will prove useful in the regulatory and research areas for the acquisition of data under standard defined conditions.

Animals↗
PubMed1988

Haemodynamic and metabolic effects of prophylactic nitroglycerin infusion in the immediate period following coronary artery bypass grafting.

This is a preliminary report of work in progress to assess the effects of prophylactic nitroglycerin infusion in patients undergoing coronary artery vein grafting. So far 14 patients have been studied. They were divided into two groups to receive either nitroglycerin (1 microgram kg-1 min-1) or placebo (5% dextrose). The infusion was commenced on removal of the aortic cross-clamp after completion of the distal anastomoses of the grafts. During cardiopulmonary bypass myocardial protection was provided by cold potassium cardioplegia and systemic hyopthermia. For 2 hours after cessation of cardiopulmonary bypass simultaneous samples of coronary sinus and femoral arterial blood were taken to estimate lactate concentrations and oxygen saturation. No differences were found between the groups. At the same times haemodynamic measurements were made. There was a statistically significant increase in cardiac index in the nitroglycerin group up to 30 minutes post cardiopulmonary bypass. There was also a statistically significant fall in systemic and pulmonary vascular resistances with no differences in systemic or pulmonary arterial pressures. There was no difference in central venous or pulmonary capillary wedge pressures. Patients receiving nitroglycerin seemed more stable cardiovascularly than those receiving placebo. In conclusion nitroglycerin improves cardiac output in the immediate post bypass period following cold potassium cardioplegia.

Bicarbonates↗
PubMed1982

Effects of divalent cations on the glycolipids from cultured mouse neuroblastoma cells.

The influence of divalent cations on glycosphingolipid metabolism was examined in the NB41A mouse neuroblastoma clonal cell line. HPLC methods were utilized to quantitate the effects on neutral glycolipids and monosialogangliosides. NB41A cells were shown to contain GM3, GM2, GM1, GD3, and GD1a by HPLC and TLC. The neutral glycosphingolipids consisted of glucosylceramide (GlcCer), lactosylceramide (LacCer), GalNAc (beta 1 leads to 4) Gal(beta 1 leads to 4)Glc(beta 1 leads to 1)Cer (GgOse3Cer), and GalNAc(beta 1 leads to 3)Gal(alpha 1 leads to 4) Gal(beta 1 leads to 4)Glc(beta 1 leads to 1)Cer (GbOse4Cer) according to their HPLC behavior. Cells grown in the presence of 1.85 mM-EGTA showed a two-to threefold increase in GM3 whereas other glycosphingolipids were only slightly affected. When cells were grown in the presence of 1.45 mM-EGTA plus 0.4 mM-EDTA a similar increase in GM3 was observed but this change was now accompanied by decreases in GM2, GM1, GgOse3Cer. The EGTA-EDTA effects were reversed when growth was in the presence of Ca2+ sufficient to bind all chelator. Mn2+ replacement reversed the chelator effects differentially; GM2 and GM1 levels were the most sensitive to increases in Mn2+ concentration; GgOse3Cer and GbOse4Cer were also sensitive, whereas GM3 was the least affected. These results suggest calcium serves an important regulatory role on GM3 levels and that manganese concentration may regulate the levels of galactosamine-containing glycolipids in mouse NB41A neuroblastoma cells.

Animals↗