Biomedical subjects
Publications and source records attributed to C Ray.
To determine whether plasma levels of homocyst(e)ine are affected by the acute phase response, we studied 10 subjects serially after acute myocardial infarction. Our data indicate that measurement of homocyst(e)ine in patients with myocardial infarction should ideally be deferred for 7 days if spuriously low levels are to be averted.
The serine protease granzyme B, which is secreted by cytotoxic cells, is one of the major effectors of apoptosis in susceptible targets. To examine the apoptotic mechanism of granzyme B, we have analyzed its effect on purified proteins that are thought to be components of death pathways inherent to cells. We demonstrate that granzyme B processes interleukin 1beta-converting enzyme (ICE) and the ICE-related protease Yama (also known as CPP32 or apopain) by limited proteolysis. Processing of ICE does not lead to activation. However, processing by granzyme B leads directly to the activation of Yama, which is now able to bind inhibitors and cleave the substrate poly(ADP-ribose) polymerase whose proteolysis is a marker of apoptosis initiated by several other stimuli. Thus ICE-related proteases can be activated by serine proteases that possess the correct specificity. Activation of pro-Yama by granzyme B is within the physiologic range. Thus the cytotoxic effect of granzyme B can be explained by its activation of an endogenous protease component of a programmed cell death pathway.
While many studies have demonstrated a nephrogenic diabetes insipidus syndrome (NDI) with prolonged lithium (Li) treatment, experiments in the isolated rat papillary collecting duct have suggested that the defect may be due to a circulating factor that inhibits the action of arginine vasopressin (AVP). Since Li-treatment can produce a form of hyperparathyroidism and parathyroid hormone (PTH) can act as a partial agonist to AVP, in vivo and in vitro studies were performed on rats made polyuric by daily intraperitoneal (i.p.) Li (4 mmol/kg) treatment. Li-treatment for three weeks produced an increase in PTH (194 +/- 20 compared with 118 +/- 18 pg/ml in control rats; P < 0.01) as well as an increase in the plasma calcium concentration (2.38 +/- 0.05 compared with 2.25 +/- 0.04 mmol/liter; P < 0.05). Clearance studies were performed on water loaded Li-treated and control rats, and the defect in urine concentration was only observed with a low physiological concentration of AVP (10 mU/kg body wt over 5 min). Maximal urine osmolality was 328 +/- 31 compared with 613 +/- 81 mOsm/kg (P < 0.05) in controls. There was no detectable difference with a prolonged maximal physiological AVP concentration (10 mU bolus and 50 mU/kg body wt per hr) and papillary solute concentrations were unchanged. When Li-treated rats had been parathyroidectomized (PTX), a significant difference in urine concentration with the low AVP concentration could not be demonstrated when compared to non-PTX control rats. In the isolated papillary collecting duct preparation a medium was used that contained fresh plasma from Li-treated or control rats, both intact and PTX. Experiments using plasma from Li-treated intact rats produced only a 25.4 +/- 5.1% increase in diffusional water permeability with the addition of AVP (200 microU/ml) compared to 52.6 +/- 9.0% in control rats (P < 0.01). However, when plasma from Li-treated PTX rats was used, the AVP induced increase in water permeability (54.7 +/- 11.2%) was not significantly different from that observed in PTX control rats. These studies show that the NDI-like defect in Li-treatment is small and easily overcome by higher concentrations of AVP and suggests that the concentration defect is at least in part due to increased circulating levels of PTH acting as a partial agonist to AVP and thereby inhibiting its hydroosmotic action.
Since iron has been implicated as a potential nephrotoxin, we examined the effect of iron on several aspects of cultured renal tubular epithelial cell biology. We found that exposure to 10(-4) M of either the ferrous or ferric form of iron impaired healing of denuded areas made within confluent monolayers of LLC-PK1 cells. This impairment required 30 to 80 hours of exposure to iron to occur and was also seen in another renal tubular epithelial cell line (MDCK cells). To delineate the potential mechanism(s) of this impairment, we examined the expression of a key integrin subunit involved in cell-matrix adhesion. Exposure of LLC-PK1 cells to 10(-4) M ferric citrate for 72 hours significantly decreased expression of the beta 1 integrin subunit as determined by flow cytometry. To determine if iron impairs another process that occurs at the basolateral surface, the effects of 72 hours of exposure to iron on adenylate cyclase activity were examined. Both ferric and ferrous citrate significantly enhanced vasopressin- and forskolin-stimulated adenylate cyclase activity. To examine if iron can regulate proliferation, the effect of iron on 3H-thymidine uptake was measured. We found that ferric citrate diminished proliferation and this decrease required the presence of either serum or transferrin. To ascertain if iron affected ultrastructure, we used transmission electron microscopy and found that iron accumulation within cells was much more apparent with ferric than ferrous citrate. Ferric iron induced mild-to-moderate cytopathic changes. These results indicate that iron is capable of inducing multiple changes in renal tubular epithelial function. The effect of iron to impair wound healing may be related to diminished expression of the beta 1 integrin subunit and perhaps to impaired proliferation.
The mechanism(s) whereby hepatocytes restore denuded areas remains unknown. We therefore studied the recovery of denuded areas made in monolayers of primary cultures of rat hepatocytes. Minimal recovery occurred in cells plated on plastic. Plating on Matrigel produced modest recovery (25% at 24 h), whereas plating on a type I collagen substrate resulted in > 70% recovery at 24 h. The rate of recovery on collagen could be attenuated by a monoclonal antibody directed against the extracellular domain of the beta 1-integrin subunit. Monoclonal antibodies directed against CD44 (the hyaluron receptor) and E-cadherin did not influence the rate of recovery. Recovery could be stimulated, in a dose-dependent fashion, by epidermal and hepatocyte growth factors. The effects of epidermal and hepatocyte growth factors to promote recovery occurred in the absence of 5-bromo-2'-deoxyuridine uptake, suggesting a proliferation-independent mechanism. Transforming growth factor-beta 1 inhibited recovery. Exposure to selected cytokines (interleukins 1 and 2), an adenine nucleotide [adenosine 5'-O-(3-thiotriphosphate)], adenosine, pertussis toxin, and selected agents that bind to fibronectin and other matrix component adhesive sites (heparin and the RGD peptide) did not influence the rate of recovery of hepatocytes. However, the peptide DGEA, which can bind to collagen adhesive sites, attenuated recovery. These studies demonstrate that primary cultures of rat hepatocytes require a particular type of extracellular matrix to renew denuded areas and that the beta 1-integrin subunit may be involved in this recovery process. Hepatocyte recovery of denuded areas can be modulated by growth factors in both a stimulatory (epidermal and hepatocyte growth factors) and an inhibitory (transforming growth factor-beta 1) fashion.
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The implications of patients' approaches to managing chronic fatigue syndrome were examined in a cross-sectional study. With severity of fatigue controlled, attempting to maintain activity was associated with less functional impairment, while accommodating to the illness was positively related to impairment; behavioural disengagement was related not only to higher levels of impairment but also to greater emotional disturbance. Fatigue itself was positively associated with focusing on symptoms and with behavioural disengagement; it was associated also with illness accommodation, but only for illness of longer duration. The causal direction of relationships between coping and fatigue severity is ambiguous, and a follow-up study will address the effects of coping on changes in the illness over time.
Life-events have been implicated in the onset and course of various illnesses. The present study examined their role in chronic fatigue syndrome, in the context of the ongoing illness. Using the PERI list, events experienced during the past year were elicited in interviews with 130 patients. The analyses were restricted to those events implying moderate or major life change, and separate analyses were carried out for positive and negative events. Positive events were found to be associated with lower scores for fatigue, impairment, anxiety and depression, as assessed at the time of the life-events interview, and these relationships were also significant when prior scores at the beginning of the year were statistically controlled. Negative life-events were associated with higher anxiety, but were unrelated to the other measures. It was concluded that positive life-events and experiences may contribute to the process of recovery in chronic fatigue syndrome, though their occurrence may also be facilitated by a preceding lifting of symptoms.
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A monoclonal antibody, 7A9, specific for antigens in the subventral esophageal glands of adult female Meloidogyne incognita and for antigens in the longitudinal muscles of second-stage juveniles, was used to isolate a clone from a M. incognita cDNA expression library. The corresponding genomic DNA was isolated by hybridization and the gene designated sec-1. DNA sequence analysis of sec-1 revealed the presence of 9 introns having structural similarities to introns from the free-living nematode Caenorhabditis elegans. The sec-1 message was also trans-spliced and the leader sequence differed in one position from the sequence of the C. elegans trans-spliced leader SL1. Sequences analogous to sec-1 were specific to the genus Meloidogyne, and regulation of sec-1 expression did not involve differences in overall rates of transcript accumulation. The deduced amino acid sequence of the protein encoded by sec-1 had some similarities to the rod portions of several myosin heavy chains.
The initial study was designed to determine whether all granulosa cells (GCs) undergo apoptosis in vitro. GCs were isolated from immature rat ovaries and separated on a 15-45% Percoll gradient. Twelve fractions were collected, and GCs were pooled according to size: small GCs (approximately 50 mu 2; fractions 2-5) and large GCs (> or = 75 mu 2; fractions 6-8). GCs were cultured in serum-free medium for 24 h. After 24 h of culture, fragmented DNA, detected by in situ end labeling of the 3'OH ends of DNA fragments, was observed within 70-80% of large GCs. Similarly, in situ DNA staining demonstrated that at least 50% of large GCs possessed apoptotic nuclei. These degenerative changes in DNA were observed within < or = 5% of small GCs. These studies demonstrate that in serum-free medium, most large GCs die via an apoptotic mechanism within 24 h. Subsequent studies focused on the mechanism by which epidermal growth factor (EGF) inhibits large GC apoptosis. EGF reduced the percentage of large GCs with apoptotic nuclei from 47 +/- 1% for controls to 18 +/- 2% (p < 0.05). EGF also increased progesterone (P4) secretion from large GCs (6.3 +/- 0.7 for controls vs. 18.7 +/- 1.0 ng/ml for EGF treatment; p < 0.05). The effect of EGF on apoptosis was mimicked by P4 and attenuated by the P4 antagonist, RU 486, and aminoglutethimide (AG), an inhibitor of P4 synthesis. The effect of AG was overridden by P4. Therefore, EGF reduces large GC apoptosis by stimulating P4 synthesis, with P4 mediating its action through its receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
1. Chronic adrenal insufficiency impairs maximal urine concentration, probably in part due to reduced medullary tonicity but also possibly by inhibition of distal nephron water transport. This latter defect has been demonstrated in rabbit but not in rat. 2. Since the time between adrenalectomy and experiment was different in rabbit and rat studies, diffusional water permeability was evaluated in the papillary collecting duct in the absence and presence of submaximal (20 microU/mL) and supramaximal (200 microU/mL) arginine vasopressin (AVP) in adrenalectomized rats at 7, 14 and 21 days. 3. Experimentation 7 days after adrenalectomy failed to demonstrate significantly altered basal or AVP-induced water permeability which increased by 23 and 78% with submaximal and supramaximal concentrations, respectively. Submaximal AVP concentrations also induced a comparable change in water permeability in adrenalectomized rats at 14 days; however, 21 days after adrenalectomy, diffusional water permeability was not increased by 20 microU/mL AVP (3.31 +/- 0.22 to 3.31 +/- 0.24 microns/s). Nevertheless, the effect of a supramaximal AVP concentration (200 microU/mL) was not altered by adrenalectomy (4.54 +/- 0.39 to 8.08 +/- 0.96; P < 0.01). Incubation of collecting ducts in aldosterone for 2 h did not reverse the inhibitory effect of chronic adrenalectomy on AVP-stimulated water transport. 4. These studies suggest that mineralocorticoid withdrawal does impair the hydro-osmotic action of AVP in the rat papillary collecting duct but that this effect takes between 14 and 21 days to occur.
BACKGROUND: Usual 'Yes/No' definitions of a family history of heart disease do not allow for 'Don't know' responses. In some families, misclassification of family history may result if these are not considered. AIMS: To study the accuracy of family history reporting and the impact of 'Don't know' responses. METHODS: We compared reported family history of coronary heart disease (CHD) and cancer among 360 deceased relatives of 59 probands with 'gold standard' diagnoses recorded on official death certificates. RESULTS: For first degree relatives, sensitivity of reporting was 81% for CHD, 86% for any heart disease and 60% for cancer, while for second degree relatives, sensitivity was 73%, 69% and 90%, respectively. When 'Don't know' responses were classified as 'No', sensitivity in first degree relatives was not affected, but in second degree relatives, it fell to 49%, 41% and 60%, respectively. Specificities were unchanged. These data show that in families where information beyond first degree relatives is considered, failing to account for 'Don't know' responses is likely to lead to misclassification of family history of CHD.
OBJECTIVE: To produce standard curves of birth weight according to gestational age validated by ultrasonography in the British population, with particular reference to the effects of ethnic origin. DESIGN: Retrospective analysis of computerised obstetric database. SETTING: Three large maternity units associated with Nottingham University with over 16,000 deliveries a year. PATIENTS: 41,718 women with ultrasound dated singleton pregnancies and delivery between 168 and 300 days' gestation. MAIN OUTCOME MEASURES: Length of gestation, ethnic origin, parity, maternal height and weight at booking, smoking during pregnancy; the effect of these variables on birth weight. RESULTS: Birth weights from ultrasound dated pregnancies have a higher population mean and show less flattening of the birthweight curve at term than those of pregnancies dated from menstrual history. Significant differences were observed in mean birth weights of babies of mothers of European origin (3357 g), of Afro-Caribbean origin (3173 g), and from the Indian subcontinent (3096 g). There were also significant interethnic differences in length of gestation, parity, maternal height, booking weight, and smoking habit which affected birth weight. The ethnic differences in birth weight were even greater when the effect of smoking was excluded. CONCLUSIONS: Birthweight standards require precise dating of pregnancy and should describe the population from which they were derived. In a heterogeneous maternity population the accurate assessment of an individual baby's weight needs to take the factors which affect birthweight standards into consideration.
OBJECTIVE: To determine the usefulness of three-dimensional imaging in addition to computed tomography in presurgical examination of patients with head and neck tumors. DESIGN: Two-dimensional computed tomographic information from 31 patients with oral facial tumors was converted to three-dimensional images. SETTING: University teaching hospital. PATIENTS OR OTHER PARTICIPANTS: A consecutive sample of 31 patients with oral facial tumors. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Improved treatment planning with the use of three-dimensional images used in conjunction with computed tomographic scans. RESULTS: The three-dimensional images from patients with minimal tumor invasion of bone or with massive soft-tissue tumors allowed easy appreciation of tumor dimensions, an important factor in treatment planning. In patients with small soft-tissue tumors with no evidence of bone involvement on two-dimensional scans, massive tumors with complete bone destruction, and recurrent tumors, the three-dimensional representations added little to the obvious presentation of the two-dimensional scans. CONCLUSIONS: Three-dimensional imaging is a useful adjunct to diagnosis and treatment planning in patients with minimal tumor invasion of bone or with massive soft-tissue tumors.
CMHOs are the heirs to a rich tradition of coordinated and comprehensive services and appropriate clinical outcomes in the least restrictive settings. The early CMHO focus on prevention, coordination of services, continuity of care, and partial and residential services, as well as psychosocial and case management methodologies, underlies contemporary managed behavioral health programs. This provides CMHOs with a great opportunity to be major participants in the new programs.