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Biomedical subjects

P Smith

Publications and source records attributed to P Smith.

At least 271 records · Page 15Linked to original sources
PubMed1998

Differential regulation of ventricular adrenomedullin and atrial natriuretic peptide gene expression in pressure and volume overload in the rat.

1. Adrenomedullin is a recently discovered vasodilating and natriuretic peptide whose physiological and pathophysiological roles remain to be established. Like atrial natiuretic peptide adrenomedullin is expressed in the left ventricle. Ventricular expression of atrial natriuretic peptide is known to be markedly increased by volume or pressure overload. In this study we investigated whether ventricular expression of adrenomedullin is similarly stimulated under such conditions. 2. Ventricular adrenomedullin and atrial natriuretic peptide mRNA levels as well as those of a loading control mRNA (glyceraldehyde-3-phosphate dehydrogenase) were quantified by Northern blot analysis in (a) rats with severe post-infarction heart failure induced by left coronary ligation at 30 days post-surgery and (b) in rats with pressure-related cardiac hypertrophy induced by aortic banding at several time points (0.5, 1 and 4 h, and 1, 4, 7 and 28 days) after surgery. Levels were compared with those in matched sham-operated controls. 3. The mRNA level of atrial natriuretic peptide was markedly increased (8-10-fold) in the left ventricle of animals with post-infarction heart failure. In contrast, there was only a modest (40%) increase in the level of adrenomedullin mRNA. In rats with pressure-induced cardiac hypertrophy the ventricular level of atrial natriuretic peptide mRNA was again markedly increased (maximum 10-fold). The increase was first noticeable at 24 h post-banding and persisted until 28 days. In contrast, there was no change in adrenomedullin mRNA level compared with sham-operated rats at any time point. 4. Despite having similar systemic effects, the expression of adrenomedullin and atrial natriuretic peptide in the left ventricle is differently regulated. The findings imply distinct roles for the two peptides. The results do not support an important role for ventricular adrenomedullin expression in the remodelling process that occurs during the development of cardiac hypertrophy but suggest that ventricular adrenomedullin participates in the local and/or systemic response to heart failure.

Adrenomedullin↗
PubMed1998

Preservation of pectoralis minor in axillary clearance for breast cancer.

BACKGROUND: There has been a gradual shift away from radical surgery towards conservation treatment for breast cancer. The pectoralis minor muscle is increasingly preserved in women undergoing axillary clearance as part of either breast conservation or mastectomy. METHODS: A retrospective study was conducted to determine the axillary node count in 578 patients who underwent axillary clearance, 276 with removal of pectoralis minor and 302 who had the muscle preserved. RESULTS: The mean number of nodes excised in the group who had pectoralis minor excised was 25.5 (range 8-50) compared with 24.5 (range 9-68) in the preservation group. CONCLUSION: For the majority of patients with operable breast cancer, retention of the pectoralis minor muscle is not associated with understaging or undertreatment of the axilla.

Adult↗
PubMed1998

Time in hospital.

This article is based on research into patients' perceptions of being in hospital. Time, ordinarily taken for granted, becomes a significant problem for people in hospital. Patients seek control over time that they do not seem to have during their stay in hospital. They try to keep track of time and find ways of passing it, while believing that precious personal time is lost to them. The insight gained into differing perceptions of time and how patients coped with these can be used to reduce some of the tensions and negative aspects of the way time is experienced in hospital.

Adaptation, Psychological↗
PubMed1998

Modified cuspal relationships of mandibular molar teeth in children with Down's syndrome.

A total of 50 permanent mandibular 1st molars of 26 children with Down's syndrome (DS) were examined from dental casts and 59 permanent mandibular 1st molars of normal children were examined from 33 individuals. The following measurements were performed on both right and left molars (teeth 46 and 36 respectively): (a) the intercusp distances (mb-db, mb-d, mb-dl, db-ml, db-d, db-dl, db-ml, d-dl, d-ml, dl-ml); (b) the db-mb-ml, mb-db-ml, mb-ml-db, d-mb-dl, mb-d-dl, mb-dl-d angles; (c) the area of the pentagon formed by connecting the cusp tips. All intercusp distances were significantly smaller in the DS group. Stepwise logistic regression, applied to all the intercusp distances, was used to design a multivariate probability model for DS and normals. A model based on 2 distances only, mb-dl and mb-db, proved sufficient to discriminate between the teeth of DS and the normal population. The model for tooth 36 for example was as follows: p(DS) = (e(30.6-5.6(mb-dl)+25(mb-db)))/(1 + e(30.6 5.6(mb-dl)+25(mb db))). A similar model for tooth 46 was also created, as well as a model which incorporated both teeth. With respect to the angles, significant differences between DS and normals were found in 3 out of the 6 angles which were measured: the d-mb-dl angle was smaller than in normals, the mb-d-dl angle was higher, and the mb-dl-d angle was smaller. The dl cusp was located closer to the centre of the tooth. The change in size occurs at an early stage, while the change in shape occurs in a later stage of tooth formation in the DS population.

Adolescent↗
PubMed1998

Nephrectomy decreases amylin and pramlintide clearance in rats.

Amylin is a 37 amino acid hormone, co-secreted with insulin from the pancreatic beta-cell in response to nutrient stimuli. Because the human amylin analog, pramlintide, is being tested in patients with diabetes mellitus, a known risk factor for nephropathy, we examined the role of the kidney on amylin and pramlintide metabolism and action in functionally nephrectomized rats. Nephrectomy markedly altered amylin metabolism: it increased incremental area under the plasma amylin concentration curve 3.6-fold (P<0.001) and increased the elimination half-life from 17+/-1 to 26+/-2 minutes (P < 0.01) after subcutaneous injection of 100 microg amylin. Nephrectomy decreased plasma amylin clearance from 20.3+/-1.1 to 7.9+/-0.4 mL/min (P < 0.0001). Thus, at these doses in the rat, the kidney is important for metabolizing amylin and pramlintide.

Amyloid↗
PubMed1998

Effects of rat amylin on renal function in the rat.

Amylin is a peptide secreted from the pancreatic beta-cell along with insulin in response to nutrient stimuli. Amylin has been reported to delay gastric emptying, inhibit glucagon secretion and gastric acid secretion, increase plasma lactate, plasma glucose and plasma renin activity, and decrease plasma calcium. Receptors for amylin have been found in the rat nucleus accumbens and the kidney. In the present experiments, amylin was administered to anesthetized rats by continuous intravenous infusions at varied rates. Amylin significantly increased urine flow at an infusion rate resulting in a plasma concentration of approximately 52 pM, and at a concentration of approximately 193 pM, it increased sodium excretion, glomerular filtration rate and renal plasma flow. Renal calcium and potassium excretion were significantly elevated at plasma amylin concentrations of approximately 52 pM and 193 pM, respectively. Higher concentrations of plasma amylin decreased plasma calcium and potassium and blunted urinary excretion of these electrolytes. Thus, of the renal responses tested, diuresis and natriuresis appeared to be the most sensitive to infused amylin. These renal effects occurred only at plasma concentrations above the normal range, but within the range of concentrations reported in insulin resistant rats.

Amyloid↗
PubMed1998

The Ranawat Award. Comparison of surgical approaches in total knee arthroplasty.

A series of 123 revision total knee replacements performed at three centers and followed up for 2 to 4 years was evaluated. In cases in which exposure could be obtained with undue tension on the patellar tendon, the surgical approach was modified using either quadriceps turndown (14 cases) or tibial tubercle osteotomy (15 cases). The remaining 94 patients underwent a standard operative approach that consisted of a medial parapatellar capsular incision which in 31 cases was combined with a quadriceps snip. The results were compared using the Knee Society clinical score, a patient satisfaction survey, and a patellofemoral questionnaire. Postoperatively, the group of patients who had a quadriceps snip was equivalent to the group of patients who underwent a standard approach in every parameter measured, and the groups therefore were combined for comparison purposes. The patients who had quadriceps turndown and the tibial tubercle osteotomy had equivalent scores postoperatively both of which were significantly lower than the standard group. The group of patients who had quadriceps turndown had a significantly greater increase in arc of motion than the tibial tubercle osteotomy group. The tibial tubercle osteotomy group had a lower degree of extension lag but a higher percentage of patients who had difficulty with kneeling and stooping and a higher percentage of patients who had difficulty with kneeling and stooping and a higher percentage of patients who thought the surgery was unsuccessful in relieving pain and unsuccessful in returning them to normal daily activities.

Activities of Daily Living↗
PubMed1998

Pneumococcal diversity: considerations for new vaccine strategies with emphasis on pneumococcal surface protein A (PspA).

Streptococcus pneumoniae is a problematic infectious agent, whose seriousness to human health has been underscored by the recent rise in the frequency of isolation of multidrug-resistant strains. Pneumococcal pneumonia in the elderly is common and often fatal. Young children in the developing world are at significant risk for fatal pneumococcal respiratory disease, while in the developed world otitis media in children results in substantial economic costs. Immunocompromised patients are extremely susceptible to pneumococcal infection. With 90 different capsular types thus far described, the diversity of pneumococci contributes to the challenges of preventing and treating S. pneumoniae infections. The current capsular polysaccharide vaccine is not recommended for use in children younger than 2 years and is not fully effective in the elderly. Therefore, innovative vaccine strategies to protect against this agent are needed. Given the immunogenic nature of S. pneumoniae proteins, these molecules are being investigated as potential vaccine candidates. Pneumococcal surface protein A (PspA) has been evaluated for its ability to elicit protection against S. pneumoniae infection in mouse models of systemic and local disease. This review focuses on immune system responsiveness to PspA and the ability of PspA to elicit cross-protection against heterologous strains. These parameters will be critical to the design of broadly protective pneumococcal vaccines.

Animals↗
PubMed1998

Leptin attenuates respiratory complications associated with the obese phenotype.

A profile of respiratory complications has been associated with the onset and development of obesity in humans. Similar phenotypes have been routinely demonstrated in genetic animal models of obesity such as the ob mouse (C57BL/6J-Lepob). The objective of the present study was to test the hypothesis that a constellation of respiratory complications are attenuated with leptin (i.e., protein product of the ob gene) replacement. Daily leptin administration during a 6-wk period was conducted to control body weight of mutant ob mice similar to genotypic control groups. During the treatment period, repeated baseline ventilatory measurements were assessed by using whole body plethysmography while quasistatic pressure-volume curves were performed to further explore the role of leptin in improving lung mechanics. Diaphragmatic myosin heavy chain (MHC) isoform phenotype was examined to determine proportional changes in MHC composition. In room air, breathing frequency and minute ventilation were significantly (P < 0.01) different among ob treatment groups, suggesting that leptin opposed the development of a rapid breathing pattern observed in vehicle-treated ob mice. Quasistatic deflation curves indicated that the lung volume of leptin-treated ob mice was significantly (P < 0.05) greater relative to vehicle-treated ob mice at airway pressures between 0 and 30 cmH2O. Diaphragm MHC composition of leptin-treated ob mice was restored significantly (P < 0.05) to resemble the control phenotype. In this genetic mouse model of obesity, the results suggested that respiratory complications associated with the obese phenotype, including rapid breathing pattern at baseline, diminished lung compliance, and abnormal respiratory muscle adaptations, are attenuated with prolonged leptin treatment.

Animals↗
PubMed1998

Beneficial effect of diazoxide in obese hyperinsulinemic adults.

UNLABELLED: Hyperinsulinemia, insulin resistance, and increased adipose tissue are hallmarks of the obesity state in both humans and experimental animals. The role of hyperinsulinemia as a possible preceding event in the development of obesity has been proposed. We previously demonstrated that administration of diazoxide (DZ), an inhibitor of insulin secretion, to obese hyperinsulinemic Zucker rats resulted in less weight gain, enhanced insulin sensitivity, and improved glucose tolerance. Assuming that hyperinsulinemia plays a major role in the development of human obesity, then its reversal should have therapeutic potential. To test this hypothesis, we conducted a randomized placebo-controlled trial in 24 hyperinsulinemic adults [body mass index (BMI) > 30 kg/m2]. All subjects were placed on a low-calorie (1260 for females and 1570 for males) Optifast (Sandoz, Minneapolis, MN) diet. After an initial 1-week lead-in period, 12 subjects (mean +/- SE for age and BMI, 31 +/- 1 and 40 +/- 2, respectively) received DZ (2 mg/kg BW.day; maximum, 200 mg/day, divided into 3 doses) for 8 weeks; and 12 subjects (mean +/- SE for age an BMI, 28 +/- 1 and 43 +/- 1, respectively) received placebo. Compared with the placebo group, DZ subjects had greater weight loss (9.5 +/- 0.69% vs. 4.6 +/- 0.61%, P < 0.001), greater decrease in body fat (P < 0.01), greater increase in fat-free mass to body fat ratio (P < 0.01), and greater attenuation of acute insulin response to glucose (P < 0.01). However, there was no significant difference in insulin sensitivity and glucose effectiveness, as determined by the insulin-modified i.v. glucose tolerance test (Bergman's minimal model) and no significant difference in glycohemoglobin values. CONCLUSION: 8 weeks treatment with DZ had a significant antiobesity effect in hyperinsulinemic obese adults without inducing hyperglycemia.

Adult↗
PubMed1998

The role of oxygen free radicals in isoniazid-induced hepatotoxicity.

Isoniazid and its metabolites acetylisoniazid, hydrazine and monoacetylhydrazine were investigated for generation of oxygen free radicals during incubation with rat liver slices. Lipid peroxidation was assessed by the thiobarbituric acid reactive substances test using malonaldehyde as the external standard, while hepatotoxicity was assessed by histopathology studies. Malonaldehyde formed in liver slices after 10 hours of incubation with the drugs was 1.28 +/- 0.24 nmol/mg for isoniazid (control 1.12 +/- 0.17 nmol/mg); 0.88 +/- 0.45 nmol/mg for acetylisoniazid (control 0.84 +/- 0.42 nmol/mg); 1.43 +/- 0.14 nmol/mg for monoacetylhydrazine (control 1.10 +/- 0.12 nmol/mg) and 1.36 +/- 0.02 nmol/mg for hydrazine (control 1.13 +/- 0.04 nmol/mg). Histologically, all slices exhibited hepatic necrosis by 4 hours. However, hydrazine-induced hepatotoxicity was characterized by nuclear hyperchromatsia, karyolysis and karyohexis while monoacetylhydrazine exhibited hydropic karyomegaly only. Isoniazid and acetylisoniazid cytotoxicity exhibited a mixture of the above features such that it could be attributed to the two metabolites, hydrazine and monoacetylhydrazine. In conclusion, there was no evidence implicating oxygen free radicals in isoniazid-induced hepatotoxicity; however, the histopathology findings indicate a need for a review of our knowledge on pathognomonic features of isoniazid hepatotoxicity.

Animals↗
PubMed1998

Steroid contents of and steroidogenesis in vitro by the developing gonad and mesonephros around sexual differentiation in fetal sheep.

The aim of the present study was to establish whether the steroids, progesterone, androstenedione, testosterone and oestradiol, were present in the mesonephric-gonadal complex of female and male sheep fetuses around sexual differentiation (that is, from day 28 to day 45 of gestation, with sexual differentiation occurring at approximately day 32). A second aim was to test whether the mesonephric-gonadal complex, mesonephros (days 35-45 only) and gonad (days 35-45 only) were capable of steroid synthesis in vitro. The steroid contents in the mesonephric-gonadal complex were not detectable before sexual differentiation. However, from day 35 of gestation onwards, the mesonephric-ovarian complex contained mainly oestradiol and the mesonephric-testicular complex contained mainly testosterone: from day 35 until day 45 the increase in content of these two steroids exceeded the increase in the mass of tissue by more than fivefold. From day 40 to day 45 of gestation, the contents of the other steroids in the pathways to oestradiol increased progressively in both sexes but more in parallel with the increase in tissue mass. In contrast to the steroid contents in the tissue at recovery, the mesonephric-gonadal tissue from both sexes in tissue culture was able to synthesize most steroids before and after sexual differentiation and also to metabolise supplementary androstenedione to oestradiol. These findings suggest that many, if not all, of the steroidogenic enzymes in the pathway from cholesterol to oestradiol are present before sexual differentiation. Most of the aforementioned steroids were present in detectable amounts in isolated mesonephros and gonad of both sexes after sexual differentiation. Moreover, for both the isolated mesonephros and gonad, there were increases in the mean contents of most steroids after culture relative to the contents in the tissues at recovery. These data suggest that the mesonephros, as well as the gonad, in both sexes is capable of synthesizing steroid. It is concluded that, in the sheep fetus, the female and male gonads are steroidogenically active after sexual differentiation, that the steroidogenic enzymes develop before sexual differentiation, and that the mesonephros is a site of steroid synthesis.

Androstenedione↗
PubMed1998

Serological diagnosis of nasopharyngeal carcinoma by enzyme linked immunosorbent assay: optimization, standardization and diagnostic criteria.

OBJECTIVES: To produce an enzyme linked immunosorbent assay (ELISA) to detect antibodies against Epstein Barr virus (EBV) specified nuclear antigen 1 (EBNA 1) and the 18 kD EBV matrix protein, and to determine and optimize its sensitivity and specificity for the diagnosis of nasopharyngeal carcinoma (NPC). METHODS: We used a combination of highly purified glutathione transferase fusion proteins of the 40 kD carboxy domain of EBNA1 and the 18 kD EBV matrix protein for coating ELISA plates. In three separate studies, we tested for IgA antibodies in serum specimens from 28 EBV seronegative donors, 284 EBV seropositive donors and 160 newly diagnosed NPC patients. By comparing the sensitivity and specificity of diagnosis obtained for different cutoff values, we derived several quantitative parameters to evaluate assay performance, establish objective diagnostic criteria which optimize the intrinsic diagnostic capability of the assay and assess the significance of individual test results, respectively. Optimum cutoff optical density (OD) is defined as the cutoff OD where sensitivity of the assay equals its specificity, and resolution of the assay is indicated by the value of sensitivity (or specificity) determined at the optimum cutoff OD. Diagnosis of NPC was achieved by setting a cutoff zone at +/- 20% of this value. RESULTS: All the EBV seronegative donors tested were not reactive, and most of the EBV seropositive donors were weakly reactive, while the majority of NPC patients were moderately or strongly reactive. While the assay was thus shown to be specific for EBV, there was an overlap in the level of these serum antibodies between few individuals of the two latter groups. It was shown that the assay performed equally well in two separate studies conducted under different testing conditions and using different collections of sera in that assay resolution determined on these occasions were 86% and 87% respectively. Diagnosis of NPC can be achieved at the same expected sensitivity of 89% and 83% determined at the lower and upper limits of the cutoff zones, with the corresponding values of specificity being 78% and 91%. It was further shown in the third study that resolution of the assay can be increased to 90% using an assay produced with a higher concentration of the same antigens, and that diagnosis of NPC can be achieved at a higher sensitivity ranging between 86% and 95% at a corresponding specificity of 93% and 86%. CONCLUSIONS: After optimization and standardization, the ELISA can achieve a sensitivity ranging from 86% to 95%, with corresponding specificities of 93% and 86% respectively for the diagnosis of NPC.

Antibodies, Viral↗
PubMed1998

Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression.

Stromelysin 3 (ST3) is a matrix metalloproteinase implicated in mammary carcinoma progression. To date, localization of ST3 expression in breast cancer by in situ hybridization and immunocytochemistry has shown that the expression of the enzyme is limited to only the stromal fibroblasts surrounding the cancer cells. We have immunostained a large group of ductal carcinoma in situ and invasive breast carcinomas using a monoclonal antibody (5ST-4A9) raised against the hemopexin-like domain of human ST3. We show that invasive lobular carcinomas express significantly less ST3 than invasive ductal carcinomas (IDCs) (P = 0.002). We also show, for the first time, that certain breast carcinoma cells that have undergone a degree of epithelial-to-mesenchymal transition, the so-called metaplastic carcinomas, can express ST3 mRNA and protein, which may in part explain the increased metastatic propensity seen in a number of these tumors. In addition, patients with IDC who had moderate to strong ST3 levels had significantly shorter disease-free survival than those with negative or weak ST3 levels (P = 0.02). Furthermore, in node-positive IDC patients, multivariate analysis revealed that ST3 level was a strong, independent prognostic parameter for disease-free survival (P = 0.005).

Adult↗
PubMed1998

Distribution of tissue plasminogen activator insertion/deletion polymorphism in myocardial infarction and control subjects.

An insertion (I)/deletion (D) polymorphism in the tissue plasminogen activator (TPA) gene locus has recently been reported to be associated with the risk of myocardial infarction (MI) with increased risk in II/ID subjects compared with DD subjects. To investigate this further, we analysed 529 acute MI cases and 525 population-based control subjects recruited in two centers (Leicester and Sheffield, UK). We found no difference between cases and controls in TPA I/D allele frequencies (cases I = 0.574, controls I = 0.582, p = 0.74) or genotype distribution (cases II 33%, ID 48%, DD 19%; controls II 34%, ID 49%, DD 17%, p = 0.88). Compared with the DD genotype, the age, sex and centre adjusted odds ratios for MI for II genotype was 0.95 (95% confidence interval, 0.64-1.40, p = 0.85) and that for ID genotype was 0.89 (0.62-1.27, p = 0.56). There was no significant effect modification by smoking status, body mass index or cholesterol level. There was no difference in the reported frequency of positive family history of coronary heart disease or mean age at MI in the different genotype groups. We conclude that in our populations the TPA I/D polymorphism is not a major independent risk factor for myocardial infarction.

Aged↗