Biomedical subjects

N Caswell

Publications and source records attributed to N Caswell.

6 recordsLinked to original sources

PubMed2004

"Constitutive" skin pigmentation: a marker of breast cancer risk?

There is much evidence to support a link between oestrogen and breast cancer. Both adult and foetal oestrogen may have this predisposing effect, and between-individual and between-population differences in oestrogen may account for much of the variation in risk for breast cancer. Here we suggest that "constitutive" skin colour in women is a marker for prenatal and adult oestrogen levels such that within ethnic groups light-skinned women have experienced higher in utero and adult oestrogen than dark-skinned women. Scores for 'constitutive' skin pigment may therefore be predictive of risk for breast cancer and low scores could be used to identify individuals at high risk.

Biomarkers, Tumor↗

PubMed1998

Reducing a peritoneal dialysis program's cost by changing from a vendor-provided to a program-provided system for general medical supplies: significant savings in CCPD.

An examination of the costs associated with outpatient chronic peritoneal dialysis prompted us to investigate the charges for general medical supplies used by patients on continuous ambulatory peritoneal dialysis (CAPD) and continuous cycling peritoneal dialysis (CCPD) in our hospital-owned, not-for-profit peritoneal dialysis program. The items used by patients to perform their dialysis exchanges and daily exit site care included 4 x 3 and 2 x 2 sterile gauze pads, antibacterial soap, masks, tape, and betadine swabsticks. The charges for these supplies when purchased from the dialysis vendor were compared with charges for the same items if purchased directly from hospital stores by the peritoneal dialysis program and then distributed to the patients. This initial analysis suggested a considerable savings if the peritoneal dialysis program provided the supplies. Based on this estimated savings, in July 1995, the peritoneal dialysis program changed from a vendor-provided to a program-provided system for general supplies used by CAPD and CCPD patients. This study examined the differences in charges expressed as $/patient-month for two periods: July 1994 to June 1995 (when all general medical supplies were provided by dialysis vendors directly to the CAPD and CCPD patients) and July 1995 to May 1996 (when the peritoneal dialysis program purchased general medical supplies from hospital stores and distributed these supplies directly to the patients). The median vendor charges for CAPD patients (n = 21 during 1994 to 1995 and n = 18 during 1995 to 1996) were not significantly different between the two periods. In fact, the charges were slightly higher during the 1995 to 1996 period ($1,264/patient-month v $1,193/patient-month during the vendor-provided period of July 1994 to June 1995, P = 0.67). The median vendor charges for patients on CCPD were significantly lower during the 1995 to 1996 period when the peritoneal dialysis program provided the general medical supplies used for CCPD ($1,110/patient-month v $1,389/patient-month during 1994 to 1995, P = 0.003). There were 30 CCPD patients during the 1994 to 1995 period and 27 patients on CCPD during 1995 to 1996. The total charges for CAPD and CCPD patients combined included dialysis vendor charges (dialysis solution, tubing, cycler rental) and charges from hospital stores. These total charges were lower in the July 1995 to May 1996 period when general medical supplies were purchased directly from hospital stores rather than from the dialysis vendors: $1,201/patient-month versus $1,360/patient-month (P = 0.03). The median hospital store charges rose slightly during the July 1995 to May 1996 period when supplies were purchased by the peritoneal dialysis program from hospital stores ($31/patient-month v $21/patient-month, P = 0.37, during the July 1994 to June 1995 period when general medical supplies were purchased directly from dialysis vendors). However, despite the rise in charges from hospital stores, an overall savings of $149/patient-month was achieved when the peritoneal dialysis program purchased and provided general medical supplies used by the peritoneal dialysis patients. This $149/patient-month equals $1,788 savings per dialysis year for each patient on peritoneal dialysis for that year. Significant savings in the cost of a chronic peritoneal dialysis program may therefore occur if less expensive sources for the general medical supplies used by CAPD and, especially, CCPD patients are found.

Contract Services↗

PubMed1985

Differential susceptibility of rat and guinea pig colon mucosa DNA to methylation by methylazoxymethyl acetate in vivo.

Methylazoxymethanol (MAM) and methylazoxymethyl acetate (MAMOAc) are powerful colon carcinogens in rats, mice and hamsters. In contrast, these agents are not carcinogenic to the colon of the guinea pig. To probe the mechanism responsible for this species difference, we determined the levels of DNA methylation in the livers and colon mucosae of F344 rats and strain-2 guinea pigs after the s.c. administration of 25 mg/kg MAMOAc. While no significant difference was observed between the two species with respect to the degree of liver DNA methylation, the level of O6-methylguanine in guinea pig colon mucosa DNA was 19 times lower than in rat colon mucosa DNA, and the level of 7-methylguanine was below detection limits. However, significant colon mucosa DNA methylation was observed in the guinea pig after the intrarectal administration of 1.25 mg methylnitrosourea. The methylation of colon mucosa DNA in response to MAMOAc in the two species correlated with the activity of alcohol dehydrogenase, an enzyme believed to be involved in the activation of MAM. Thus the resistance of the guinea pig colon to the carcinogenicity of MAM/MAMOAc may be ascribed to the lack of metabolic activation of MAM in this organ.

Alcohol Dehydrogenase↗

PubMed1984

Pyruvate carboxylase activity in subacute necrotizing encephalopathy (Leigh's disease).

Leigh's disease is a heterogeneous group of disorders, in which clinical and biochemical features suggest abnormal pyruvate metabolism. In two patients with Leigh's disease, diagnosed according to rigorous clinical, radiographic, and histologic criteria, we tested the hypothesis that pyruvate carboxylase deficiency might be the primary etiology. Pyruvate carboxylase specific activities in extracts of cultured skin fibroblasts from both patients were in the normal range. These results, together with other evidence, suggest that isolated pyruvate carboxylase deficiency does not cause the Leigh's disease phenotype.

Brain Diseases↗

PubMed1984

Acetyl CoA carboxylase in cultured fibroblasts: differential biotin dependence in the two types of biotin-responsive multiple carboxylase deficiency.

In biotin-responsive multiple carboxylase deficiency, a characteristic organic aciduria reflects in vivo deficiency of mitochondrial propionyl CoA carboxylase, 3-methylcrotonyl CoA carboxylase, and pyruvate carboxylase. A possible primary or secondary defect in biotin absorption leads to an infantile-onset syndrome, while abnormal holocarboxylase synthetase activity has been identified in the neonatal-onset form. While distinct mitochondrial and cytosolic holocarboxylase synthetase biotinylation systems may exist in avian tissues, the system has not been characterized in humans. Toward this objective, we studied the biotin dependence of a cytosolic carboxylase, acetyl CoA carboxylase (ACC), in cultured skin fibroblasts of both types of multiple carboxylase deficiency. ACC specific activities in control and infantile-onset cells were not distinguishable at all biotin concentrations: with decreasing biotin availability (+ avidin), there were only modest decrements in ACC activity in both these cell types. In contrast, there were pronounced declines of ACC activity in neonatal-onset (holocarboxylase synthetase-deficient) cells after growth in low biotin concentrations, and activity was undetectable in + avidin. ACC activity was rapidly restored with biotin repletion to biotin-starved holocarboxylase synthetase-deficient cells, and this restoration was largely independent of protein synthesis. The behavior of the cytosolic carboxylase, ACC, is in all these respects identical to that of the mitochondrial carboxylases, an observation consistent with the existence of similar biotinylation mechanisms in the two cell compartments. Further, the data support the notion that at least some components of the holocarboxylase synthetase system are shared by mitochondria and cytosol in humans, and are consistent with the suggestion that restoration of activity in biotin-depleted cells represents biotinylation of preexisting enzyme protein. The modest decrements in ACC activity in normal and infantile-onset cells may be related to the compromised epidermal integrity observed in that form of multiple carboxylase deficiency. Finally, ACC and mitochondrial carboxylase activities were compared in cells from mutants representing a spectrum of clinical severity. Cells from later-onset patients of intermediate clinical severity were ultimately classifiable as putative holocarboxylase synthetase-deficient cells on chemical criteria. Accurate etiologic classification cannot be based on clinical presentation alone, and biochemical studies should be performed on all patients. Accordingly, we propose a classification of multiple carboxylase deficiency based on biochemical criteria.

Acetyl-CoA Carboxylase↗

PubMed1984

Non-alcohol dehydrogenase-mediated metabolism of methylazoxymethanol in the deer mouse, Peromyscus maniculatus.

The concept that alcohol dehydrogenase (ADH) is involved in the metabolism of methylazoxymethanol (MAM) was examined in a model consisting of two strains of the deer mouse, Peromyscus maniculatus, one of which has a normal complement of the enzyme [ADH(+)], and the other, which completely lacks it [ADH(-)]. Both the ADH(+) and the ADH(-) strains rapidly metabolized [14C]MAM, administered in the form of the acetic acid ester, [14C] MAMOAc , to 14CO2, and the rates and extents of metabolism were virtually identical. Determination of O6-methylguanine and 7-methylguanine in liver DNA 6 and 24 hr after MAMOAc (25 mg/kg) administration showed that the levels of DNA methylation induced by the carcinogen were not significantly different in the two strains, indicating that both are capable of the metabolic activation of MAM to methylating species. Pyrazole, a potent inhibitor of ADH, inhibited MAM metabolism as well as liver DNA methylation in the ADH(+) strain; however similar inhibition of these processes also occurred in the ADH(-) strain. 3-Methylpyrazole, a weak or noninhibitor of ADH, also decreased the levels of MAM metabolism in both the ADH(+) and the ADH(-) strains. From these results, we conclude that ADH is not obligatory either in the metabolism or in the metabolic activation of MAM. As a possible alternative to ADH, liver microsomes were examined for their ability to metabolize MAM. In the presence of a NADPH-generating system, liver microsomes from both strains converted [14C]MAM to 14CH3OH and 14CH2O , although liver microsomes from the ADH(-) strain were more active in this respect. The microsomal metabolism was sensitive to inhibition by CO as well as to inhibition by pyrazole and 3-methylpyrazole.

Alcohol Dehydrogenase↗