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Biomedical subjects

A M Wallace

Publications and source records attributed to A M Wallace.

At least 55 records · Page 3Linked to original sources
PubMed2000

Differences in circulating concentrations of total, free and bound leptin relate to gender and body composition in adult humans.

We describe a radioimmunoassay (RIA) for total leptin and a gel filtration procedure for the separation of free and bound leptin in human serum. The RIA, based on a locally prepared antibody, has a minimum detection limit of 0.9 ng/mL, a working range (CV < 10%) of 2.5-50 ng/mL, inter-assay precision of 10.2, 7.2 and 8.9%CV at 7.9, 15.4 and 30.0 ng/mL, respectively, 94% recovery of exogenous leptin (range 81.1-120.6%), exhibited parallelism and demonstrated no significant cross-reactivity or interferences. A difference plot of results from this method and those from a commercially available kit (Linco Research) demonstrated satisfactory agreement up to concentrations of 50 ng/mL total leptin, with no significant bias. A gender-dependent correlation was obtained between body mass index (BMI) and total leptin (r = 0.91, P<0.001, n = 75 for men; r = 0.79, P<0.001, n = 72 for women), with women having higher leptin concentrations than men for any given BMI. Gel filtration studies (inter-assay precision: 4.7%CV, n = 18) demonstrated that a variable fraction (between 10% and 40%) of total leptin in serum was bound with high affinity (Keq = 1.0-1.45 x 10(9) L/mol) to a non-albumin, non-lipid macromolecule. Binding affinities were found to be similar irrespective of gender or fat mass. A significant positive correlation between free or bound leptin concentrations and BMI was obtained for both men and women (r = 0.87-0.94); free and bound leptin concentrations were also significantly higher in women (P<0.01) than in men for any given BMI, and higher in obese (P<0.01) than in lean individuals. We conclude that leptin 'resistance' associated with obesity cannot be accounted for by reduced free leptin concentrations in serum and that the methods described are suitable for the investigation of total, free and bound leptin for both clinical and research purposes.

Body Mass Index↗
PubMed2000

Phenotypic variability and origins of mutations in the gene encoding 3beta-hydroxysteroid dehydrogenase type II.

Mutations in HSD3B2, the gene for 3beta-hydroxysteroid dehydrogenase type II (3beta-HSD II) have been detected and activities analysed through the in vitro expression of mutant cDNAs. Two full sibs with male pseudohermaphroditism were found to be double heterozygotes: N100S/266DeltaA. This genotype leads to the most profound loss of 3beta-HSD II enzyme activity (1.3% of normal) described to date in cases without severe salt-loss. One sib (N100S/266DeltaA) is the first reported male case of type II deficiency affected with premature adrenarche. Three apparently independent kindreds had propositi affected with the HSD3B2 mutation A82T/A82T, which is associated with a non salt-losing phenotype with variable expressivity in females. These three families had the same extended HSD3B haplotype and are likely to have inherited the same ancestral mutation. The significance of this finding is discussed in the light of the presence of A82T mutation at a homologous position in pseudogene varphi5 that is present in the HSD3B cluster.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Cloning, expression, and physical mapping of the 3beta-hydroxysteroid dehydrogenase gene cluster (HSD3BP1-HSD3BP5) in human.

Seven members of the human 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene family (HGMW-approved symbols HSD3BP1-HSD3BP5) have been cloned and physically mapped. HSD3B1 and 2 express 3beta-HSD enzymes; HSD3Bpsi1-5 are unprocessed pseudogenes that are closely related to HSD3B1 and 2 but contain no corresponding open reading frames. mRNA is expressed from psi4 and psi5 in several tissues, but with altered splice sites that disrupt reading frames. A 0.5-Mb contig of 3 yeast artificial chromosome and 32 bacterial artificial chromosome genomic clones contained no additional members of the gene family. The seven genes and pseudogenes mapped within 230 kb in the order HSD3Bpsi5-psi4-psi3-HSD3B1-psi1-psi2 -HSD3B2. HSD3B1 and 2 are in direct repeat, 100 kb apart. Six HSD3B2 mutations involve substitutions that are present in several of the pseudogenes. In four cases, mutations arose in CpG sites that are conserved within the gene cluster. The tendency for CpG sites to mutate by transition provides an adequate explanation for these HSD3B2 mutations, which are unlikely to be due to recombination or conversion within the gene family.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Two distinct forms of the 64,000 Mr protein of the cleavage stimulation factor are expressed in mouse male germ cells.

Polyadenylation in male germ cells differs from that in somatic cells. Many germ cell mRNAs do not contain the canonical AAUAAA in their 3' ends but are efficiently polyadenylated. To determine whether the 64,000 Mr protein of the cleavage stimulation factor (CstF-64) is altered in male germ cells, we examined its expression in mouse testis. In addition to the 64,000 Mr form, we found a related approximately 70,000 Mr protein that is abundant in testis, at low levels in brain, and undetectable in all other tissues examined. Expression of the approximately 70,000 Mr CstF-64 was limited to meiotic spermatocytes and postmeiotic spermatids in testis. In contrast, the 64,000 Mr form was absent from spermatocytes, suggesting that the testis-specific CstF-64 might control expression of meiosis-specific genes. To determine why the 64,000 Mr CstF-64 is not expressed in spermatocytes, we mapped its chromosomal location to the X chromosome in both mouse and human. CstF-64 may, therefore, be absent in spermatocytes because the X chromosome is inactivated during male meiosis. By extension, the testis-specific CstF-64 may be expressed from an autosomal homolog of the X chromosomal gene.

Animals↗
PubMed1999

Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1.

A 36-yr-old woman was referred to the endocrine clinic for investigation of oligomenorrhea, hirsutism, and acne. She was plethoric and overweight with central fat distribution. Plasma cortisol was normal, but her adrenal glands were enlarged (CT scan). Urinary tetrahydrocortisone excretion rate was consistently high, raising the possibility of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) deficiency. In addition, 5beta- reduction of cortisol and cortisone was markedly enhanced. The levels of all cortisol metabolites were suppressed normally with dexamethasone, but conversion of oral cortisone acetate to plasma cortisol was delayed and subnormal compared with that of healthy volunteers. This was accompanied by a larger than normal increase in plasma cortisone concentration. Thus, the defect appears to be in 11beta-HSD1 activity and not in 5beta-reductase activity. Three close relatives of the subject showed no comparable abnormalities, and analysis of the coding region and exon/intron boundaries of the 11beta-HSD1 gene of the case revealed no differences from the consensus sequence. The defect may lie outside the coding region. Alternatively, some other inherited or acquired defect may lead to inhibition of this enzyme system.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Neutralase reverses the anti-coagulant but not the anti-thrombotic activity of heparin in a rabbit model of venous thrombosis.

Neutralase (heparinase I; E.C. 4.2.2.7) is a heparin-degrading enzyme undergoing clinical evaluation as an alternative to protamine for reversing the anticoagulant effects of heparin in coronary bypass surgery. The objective of this study was to assess the relative effects of Neutralase and protamine on reversal of heparin-dependent elevations in coagulation parameters and inhibition of clot formation in a rabbit vena caval stasis model. Rabbits were treated with saline or heparin (300 U/kg) for 10 minutes, followed by saline, protamine (2.6 mg/kg), or Neutralase (10 or 30 microg/kg, representing 1.23 IU/kg and 3.69 IU/kg, respectively). Twenty minutes later, venous stasis was induced, and vena caval clots were excised, weighed, and characterized. Coagulation parameters [activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT)] and antiFactor IIa and Xa levels were measured throughout the protocol. Both protamine and Neutralase reversed heparin-mediated increases in aPTT (>300 seconds to 26-35 seconds) and TCT (>300 seconds to 29-56 seconds) to values that were not different from saline-treated, nonheparinized animals. Thrombus weight in the nonheparinized saline group was 62+/-7 mg; heparin-treated animals had no detectable clots. Protamine reversal of heparin was associated with clot formation (89+/-20 mg) while Neutralase reversal was not (no clots). Heparin-induced increases in antiFactor IIa activity were reversed similarly by protamine and Neutralase (from 4.3-8.8 U/ml to 0.2-0.3 U/ml) while antiFactor Xa activity was differentially reversed (from 3.9-5.9 U/ml to 0.7-1.3 U/ml Neutralase; 5.5 U/ml to 0.02 U/ml protamine). These results are consistent with a hypothesis that Neutralase cleaves heparin into fragments, which are devoid of antiFactor IIa activity that retain modest antiFactor Xa activity, resulting in reversal of anticoagulant, but not antithrombotic, heparin activity. This property of Neutralase may be beneficial in reducing post-surgical thrombotic events after reversal of heparin.

Animals↗
PubMed1998

A practical guide to preemption for self-insured plans.

This article discusses the circumstances under which federal law preempts state law regulating self-insured plans. In particular, the author describes four recent cases in which ERISA preemption was challenged, including relevant issues of debate and conclusions. The article points out that the decisions that result from such cases are contributing to the guidelines that states are developing to regulate ERISA plans.

Employee Retirement Income Security Act↗
PubMed1998

Type I collagen as a marker of bone metabolism in sickle cell hemoglobinopathies.

Avascular necrosis of the skeletal system is a complication of sickle cell hemoglobinopathies. Type I collagen, which is synthesized by osteoblasts, comprises about 90% of the total organic matrix of bone. This preliminary study of skeletal changes in sickle cell hemoglobinopathies measured type I collagen formation and degradation using specific radioimmunoassays to determine the plasma concentrations of carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal pyridinoline cross-linked telopeptide of type I collagen (ICTP), respectively. Plasma ICTP concentrations were increased significantly in sickle cell patients with no clinical or radiologic symptoms of bone complications than in controls. Mean plasma ICTP concentration was moderately high in all patients. Plasma PICP levels did not differ significantly between patients and controls. This preliminary results indicate that measurements of plasma ICTP might be helpful in predicting bone changes in sickle cell hemoglobinopathies and also useful in the early detection of skeletal complications of the disease.

Adolescent↗
PubMed1998

Leptin levels in pregnancy: marker for fat accumulation and mobilization?

BACKGROUND: Leptin, an adipose tissue-derived signalling factor encoded by the obese gene has been shown to be present as a 16-kDa protein in the blood of mice and humans. Resistance to leptin occurs in human obesity. Leptin has also been shown to associate with plasma insulin concentrations and there is currently considerable debate about the potential link between insulin resistance and resistance to leptin. In non-pregnant individuals, circulating leptin concentrations associate strongly with both total body fat mass and body mass index (BMI). In normal human pregnancy, the maternal fat stores increase to a peak in the late second trimester, before declining towards term as fat stores are mobilized to support the rapidly growing fetus. Insulin resistance increases during late pregnancy and is believed to be further enhanced in pregnancies complicated by pre-eclampsia. The aim of this study was to examine if leptin levels were altered in pregnancy and, if so, whether the pattern of change in circulating leptin related to previously established changes in fasting insulin concentrations or fat mass. METHODS: We measured third trimester plasma leptin concentrations in 12 uncomplicated pregnant women, nine women with pre-eclampsia matched for age and booking BMI, and 18 non-pregnant women similarly matched. We also examined the longitudinal course of leptin concentrations occurring throughout gestation (from 10 weeks gestation and at five week intervals thereafter), in five normal pregnancies and two women with gestational-onset diabetes. RESULTS: Leptin concentrations were significantly higher in the normal pregnant women (37.1 microg/L, [15.4-117.0], geometric mean, [range]; p=0.049), and women with pre-eclampsia (45.3 microg/L, [21.3-98.4]; p=0.001), than in non-pregnant controls (17.85 microg/L, [1.3-36.5]), however, there was no significant difference between uncomplicated and pre-eclamptic pregnancies (p=0.22). On examination of the longitudinal course of leptin concentrations occurring throughout gestation, in all seven women plasma leptin concentrations initially increased relative to booking (10 weeks) concentrations, but did so by varying amounts (ranging between 30-233%). Significantly, however, in all seven women plasma leptin concentrations peaked at around 20-30 weeks of gestation before declining towards term. CONCLUSION: On the basis of these observations, we postulate that plasma leptin levels increase significantly in human pregnancies and that the pattern of change in circulating leptin parallels the process of fat accumulation and mobilization.

Adult↗
PubMed1998

Serum concentrations of laminin P1 and aminoterminal propeptide of type III procollagen in sickle cell disease.

We determined serum levels of laminin and aminoterminal propeptide of type III procollagen (PIIINP) in 20 patients with sickle cell hemoglobinopathies. Elevated levels of soluble laminin and PIIINP were observed in the patients--1.5 +/- 0.3 U/ml (mean +/- SD) (range 1.1-1.9 U/ml) and 0.90 +/- 0.2 U/ml (range 0.6-1.4 U/ml), respectively, compared to normal controls, 1.3 +/- 0.1 U/ml (range 1.2-1.4 U/ml) for laminin and 0.7 +/- 0.1 U/ml (range 0.6-0.9 U/ml) for PIIINP. The serum laminin and PIIINP were significantly elevated (p < 0.02 and p < 0.001, respectively, in patients with sickle cell hemoglobinopathies). There was no correlation between serum laminin and PIIINP levels in the patient group. The study indicates that aminoterminal propeptide of type III procollagen and laminin can be utilized as valuable non-invasive markers of possible alterations in extracellular matrix in bone marrow, spleen, kidney or other tissues in sickle cell hemoglobinopathies.

Adolescent↗
PubMed1998

Effect of weight loss and the inflammatory response on leptin concentrations in gastrointestinal cancer patients.

Animal research suggests that leptin may have an important role in the regulation of energy balance. The role of leptin in the progressive involuntary weight loss associated with cancer in humans is of considerable interest. However, such studies are limited. In this study, we compared circulating leptin concentrations in gastrointestinal cancer patients and weight loss (n = 27) with those of healthy subjects (n = 27). The effect of the presence of an inflammatory response on leptin concentrations was also examined. There were significantly lower leptin concentrations in male (median, 2.4 microg/liter; range, <0.5-6.0 microg/liter) and female (median, 3.4 microg/liter; range, <0.5-9.8 microg/liter) cancer patients than there were in male (median, 6.5 microg/liter; range, 3.1-10.9 microg/liter) and female (median, 18.7 microg/liter; range, 8.0-31.5 mcirog/liter) healthy subjects (P < 0.001). However, the leptin concentrations in both patients and normal subjects were related to the predicted percentage of body fat (r = 0.731; P < 0.001). Circulating leptin concentrations in the cancer patients were not altered by the presence of an inflammatory response. These results suggest that cancer anorexia/cachexia is not due to a simple dysregulation of leptin production.

Adult↗
PubMed1997

Plasma lipids, dehydroepiandosterone sulphate and insulin concentrations in elderly overweight angina patients, and effect of weight loss.

OBJECTIVE: To investigate the effect of moderate weight loss in older overweight subjects with angina pectoris on plasma dehydroepiandosterone sulphate (DHEAS), urinary steroid metabolites, insulin and plasma lipid concentrations. DESIGN: Single stranded study of dietitian led dietary intervention for weight loss in a volunteer outpatient group of 41 subjects with angina (22 males, 19 females), BMI 29.1 s.d. 4.2 kg/m2 aged 61.3 s.d. 6.5 y. MEASUREMENTS: Body weight and composition by anthropometry, REE by indirect calorimetry, dietary intake by seven day inventory, plasma DHEAS, insulin and lipids. RESULTS: After 12 weeks dietary supervision there were reductions in body weight (3.3 s.d. 2.3 kg, BMI 1.2 s.d., P = 0.00001) and in reported energy intake (-1179 s.d. 1393 kJ daily, P = 0.0001. No significant change was seen in plasma DHEAS or insulin but there were reductions in plasma cholesterol (-0.5 s.d. 0.6 mmol/l, P = 0.0001) HDL cholesterol (-0.1 s.d. 0.1 mmol/l, P = 0.0048) and triglyceride (-0.1 mmol/l s.d. 0.5, P = 0.055). CONCLUSION: Weight loss of 4% body weight by conventional dietary means over 12 weeks does not alter plasma DHEAS, urinary steroid metabolites or insulin concentrations, but does reduce plasma cholesterol in older moderately overweight subjects with angina.

Age Factors↗
PubMed1997

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens.

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.

Adrenal Cortex Hormones↗
PubMed1996

Pain after breast surgery: a survey of 282 women.

Breast surgery is a common procedure performed in women. Many women who undergo breast surgery suffer from ill-defined pain syndromes. Although there exists a few reports on the incidence of post mastectomy pain, there are no published reports on chronic pain after breast reconstruction. This investigation attempts to characterize the pain after four types of breast surgery: (1) mastectomy, (2) mastectomy with reconstruction, (3) cosmetic augmentation, and (4) breast reduction. A questionnaire was mailed to 479 women who underwent breast surgery at the University of California, San Diego Medical Center between January 1988 and December 1992. A second mailing was sent to women who did not respond to the first mailing. Women were divided into four groups; mastectomy, mastectomy with reconstruction, cosmetic augmentation, and breast reduction. In the mastectomy and mastectomy with reconstruction groups, only women who had a lumpectomy with axillary dissection, a modified radical mastectomy, or a radical mastectomy were used in the study. 59% of the women responded. The incidence of pain occurring at least one year after surgery in the mastectomy + reconstruction group (49%) was significantly higher than the mastectomy (31%) and breast reduction (22%) groups. Thirty-eight percent of the women with breast augmentation complained of pain. Women who had reconstruction using breast implants had a higher incidence of pain (53%) than those without (30%). The pain incidence in women who had reconstruction without implants was identical to women who had a mastectomy without reconstruction. There was no relationship between the use of silicone or saline implants and pain (22% and 33% respectively). However, the submuscular placement of the implants resulted in a significantly higher incidence of pain (50%) than the subglandular placement (21%). Of the women that reported pain, arm pain was significantly higher in the mastectomy and mastectomy + reconstruction group (56% and 42%, respectively) as compared to the breast reduction group (0%). Most patients reported intermittent pain in all groups. Of the women that reported pain, the mastectomy and mastectomy + reconstruction group had higher pain related to movement (41% and 42%, respectively) than the augmentation and breast reduction groups (15% and 9%, respectively). The peak pain intensity was significantly higher in the augmentation group as compared to the mastectomy group. Our incidence of post mastectomy pain is higher than most reports. The incidence of breast pain is highest in the mastectomy + reconstruction and augmentation groups which is assumed to be secondary to breast implants. Every effort should be made to achieve the best cosmetic result in breast reconstruction which in many cases justifies the use of breast implants. However, these women should be counseled on the possibility of developing chronic pain.

Adult↗