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Biomedical subjects

R Saunders

Publications and source records attributed to R Saunders.

At least 19 recordsLinked to original sources
PubMed1992

Functionally crossed pipelines. An intermittent condition by a faulty ventilator.

Unexpectedly high blood oxygen tension in intensive care patients occurring over a 5-year period were found to have been caused by an apparently normally functioning ventilator which was intermittently acting as a conduit between the oxygen and air pipelines. Responses to a circular letter sent to Quality Control Pharmacists in England and Wales suggest that similar faults may have occurred at least five times in the past 10 years. Recommendations are given for the prevention of this problem, including monitoring of gas pipeline composition.

Accident Prevention↗
PubMed1991

N2,N4,N6-tri(hydroxymethyl)-N2,N4,N6-trimethylmelamine (trimelamol) is an efficient DNA cross-linking agent in vitro.

An investigation of the mechanism of action of the antitumour agent trimelamol has established that it is an efficient interstrand DNA cross-linker in vitro, comparable to nitrogen mustards such as melphalan. Studies have shown that the cross-linking reaction is acid-catalysed but, unlike the nitrogen mustards, only partially reversible after treatment with piperidine. The bisalkylation (cross-linking) reaction appears to be concerted, and no "second arm" reaction has been detected. The results of thermal denaturation studies are consistent with general DNA binding, and suggest a preference for GC-rich sites. The acid-catalysed reaction of trimelamol with a model nucleophile (thiophenol) has also been investigated and an adduct resulting from displacement of the three carbinolamine functions has been isolated and characterized.

Antineoplastic Agents↗
PubMed1991

Studies on the stability of trimelamol, a carbinolamine-containing antitumor drug.

The stability of trimelamol (N2,N4,N6-trimethylol-N2,N4,N6-trimethylmelamine) a synthetic carbinolamine-containing antitumor drug, has been studied. Two major degradation pathways have been characterized and a unified mechanism proposed to rationalize the chemistry involved. One degradation pathway involves the consecutive loss of hydroxymethylene units by elimination of formaldehyde until the parent trimethylmelamine (4) results. An HPLC method was used to obtain kinetic data for the loss of trimelamol and to monitor the order of appearance of three degradation products. This pathway was shown to follow first-order kinetics at all pH values studied at both 18 and 37 degrees C. The second pathway involves the coupling of two trimelamol molecules via a methylene bridge to form bis(trimelamol) (6) which had been previously referred to in the literature as a "polymer". This reaction is acid catalyzed and temperature dependent. Bis(trimelamol) is virtually water insoluble and adheres strongly to glass surfaces. Finally, t1/2 values have been determined for trimelamol in aqueous solution at different temperatures, and the kinetics of formation of degradation products has been studied over a period of 30 h under a variety of conditions of pH and temperature. The data reported here are relevant to both the formulation and clinical administration of trimelamol, and may contribute to an understanding of mechanism of action and future analogue development studies.

Chromatography, High Pressure Liquid↗
PubMed1990

Hip fractures in young patients: is this early osteoporosis?

Hip fracture in patients under age 50 is rare, and is often not attributable solely to the energy of injury. Our aim was to determine if trabecular bone mineral density (BMD) is abnormal in young patients with hip fractures. We reviewed all hip fractures treated at our institution between 1979 and 1986 and contacted 20 patients under the age of 50 at the time of injury, all of whom wished to be studied. The mean age at the time of injury was 39 (range 24-47). Subjects were questioned for osteoporosis risk factors, classified by level of energy producing their injury, and then underwent quantitative computed tomography (QCT) bone densitometry of trabecular bone in the lumbar spine. Bone mineral density by QCT was below the mean for age in 90% of the patients, and was greater than 1 SD below the mean in 75%. Mean percentage BMD decrease from age-matched controls was 34% (P less than 0.005) in women and 19% (P less than 0.005) in men. There was an inverse correlation in the degree of BMD decrease and the energy level of injury. There was a direct correlation of the severity of BMD decrease and the cumulative number of osteoporosis risk factors. This investigation has found that 1-7 years following hip fracture, otherwise presumedly healthy young patients demonstrate a statistically significant decrease in spinal BMD from age/sex-matched controls. These data do not determine if osteopenia is the cause or the result of injury, nor do we wish to infer that measurement of bone density at one site can predict future fractures at other sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Monocyte-macrophage release of IL-1 is inhibited by type-1 plasminogen activator inhibitors.

Interleukin-1 (IL-1) release from monocyte-macrophages (Mo) appears dependent on pericellular proteolysis mediated by plasmin. Thus plasminogen activator inhibitors (PAI) which bind the serine proteases responsible for the conversion of plasminogen to plasmin, may inhibit IL-1 release from Mo. We have examined the effect of purified PAI from a hepatoma cell line Hep G2, on IL-1 release from Mo with secondary effects on lymphocyte proliferation in vitro. Fast acting inhibitors of both urokinase (u-PA) and tissue plasminogen activator (two chain t-PA) were noted in harvest fluids of Hep G2 cells. These inhibitors were stable at pH 3 but lost activity at 45 degrees C. They were SDS-stable and migrated with Mr53 and 104 kDa. These properties conformed to characteristics of type-1 plasminogen activator inhibitor (PAI-1). Partially purified PAI-1 added to human Mo cultured on 125I fibrin layer both in the presence and absence of plasminogen inhibited secretion of IL-1 by Mo in response to LPS. This effect, however, did not correlate with the inhibition of plasminogen dependent fibrinolysis. This suggested a degree of sequestration and inaccessibility of membrane bound u-PA of LPS activated Mo to PAI-1. PAI-1, in addition, inhibited mitogen stimulated peripheral blood mononuclear cell (PBMC) proliferation at similar concentration ranges. This effect was abrogated by the addition of specific antisera to PAI-1. PAI-1 may be released as part of an acute phase response. In addition to influencing fibrinolysis, PAI-1 may constitute a negative feedback pathway on Mo IL-1 release and subsequent immune activation in vivo.

Acute-Phase Reaction↗
PubMed1989

Correlation of structure and function in developing proximal tubule of guinea pig.

Unlike the case in rat, rabbit, and other species in which nephron formation continues into the newborn period, nephrogenesis in the guinea pig is completed well before the time of birth. Therefore, the marked increase in proximal tubule reabsorption that occurs during the postnatal period in that species can be attributed entirely to an increase in the absorptive capacity of existing nephron units. The purpose of the present morphometric studies was to correlate that change in proximal tubule function with changes in the apical and basolateral cell membrane surface areas. The apical and basolateral membrane surface densities were found to be approximately equal to each other and to remain constant throughout development. Because of increasing tubule volume, however, both membranes doubled in size between 1 and 3 wk of age and eventually increased by a factor of 3.5 in the adult. At the same time, there was little change in the length of tight function complexes measured in the plane of the luminal surface. Using previously published functional data and tubule length data, a good correlation was found between absolute absorption and total basolateral membrane surface area throughout the entire period of development in proximal tubules. Absorption per unit area of basolateral membrane was approximately 0.55, 0.41, 0.56, and 0.42 X 10(-6) nl.min-1.micron-2 in the 1st, 2nd, and 3rd wk, and in adult animals, respectively, and thus was similar to that reported for proximal tubule segments of adult rabbit and juvenile to adult rat.

Absorption↗
PubMed1987

Receptor antagonist of platelet activating factor inhibits inflammatory injury induced by in situ formation of immune complexes in renal glomeruli and in the skin.

Experiments were designed to test the effect of a receptor antagonist of platelet activating factor (PAF), SRI63072, on inflammatory injury induced by in situ formation of immune complexes in two vascular districts of the rat that have different structural and hemodynamic characteristics: unilateral glomerulonephritis induced by perfusion of the left kidney of preimmunized animals with cationic human IgG, and passive reversed Arthus reaction in the skin. Three days after perfusion the left kidneys of rats not treated with SRI63072 (group I) were greatly enlarged, and pale and severe exudative and proliferative lesions were present in glomeruli. Granular deposits of human IgG, rat IgG, and rat C3 were seen by immunofluorescence microscopy, and subepithelial electron-dense deposits were visualized by electron microscopy. The right kidneys were consistently normal. The animals were severely proteinuric and had increased levels of PAF in the circulation. In contrast, rats treated with SRI63072 (group II) and studied at the same interval of time developed only mild, focal glomerulonephritis in the perfused kidneys. By immunofluorescence microscopy the glomerular deposits of human IgG and rat IgG were similar in quantity and distribution to those observed in rats of group I. Despite the fact that SRI63072 did not influence the level or the activity of the rat serum complement system, the deposits of C3 were less abundant and more focal. As in animals of group I, electron-dense deposits were present at the epithelial side of the glomerular basement membrane. Proteinuria was slight, and levels of circulating PAF were not significantly increased. These effects cannot be ascribed to interference of SRI63072 with antigen "implantation," antibody binding, or local hemodynamic conditions, because the amounts of glomerular human and rat IgG were the same in treated and untreated rats; SRI63072 did not decrease the glomerular filtration rate; and SRI63072 prevented the increase in vascular permeability and the exudative lesions in passive Arthus reaction in the skin, a model less affected by hemodynamic changes than glomerulonephritis. The beneficial effect of SRI63072 indicates that PAF is an important mediator of the inflammatory process generated either in glomeruli or in the skin by in situ immune complex formation.

Animals↗
PubMed1987

Disseminated histoplasmosis in the acquired immunodeficiency syndrome. Report of five cases from a nonendemic area.

Disseminated histoplasmosis is predominantly a disease of the immunocompromised. However, it has been reported infrequently in patients with the acquired immunodeficiency syndrome (AIDS), and then almost exclusively from patients residing in endemic areas. We report five cases of disseminated histoplasmosis in patients with AIDS in a nonendemic area. The initial diagnosis was made by fiberoptic bronchoscopy in three patients and by bone marrow and liver biopsy specimens in one patient each. All patients had fungemia, septic shock, and multiple organ involvement. Three patients had a fulminant course and died within four weeks. Two patients had more prolonged courses, with one survival period of ten months. We conclude that patients with AIDS are at high risk to contract disseminated histoplasmosis with an extremely high morbidity and mortality. This risk is not limited to residents of endemic areas.

Acquired Immunodeficiency Syndrome↗
PubMed1986

A cluster of Pallister-Hall syndrome cases, (congenital hypothalamic hamartoblastoma syndrome).

We report on three infants with hand anomalies and congenital hypopituitarism. In two of the cases, a hypothalamic tumor was found; the third infant died without postmortem brain studies. Family history in the first case suggested possible familial recurrence; the mother's sister had died at 17 hr of age with polydactyly, microglossia, and flat nasal bridge (no autopsy done). Our second case was born by cesarean section after a pregnancy complicated by extremely low maternal estriols. At birth, hypopituitarism was diagnosed, a cranial CT scan was read as normal, and hormonal replacement was begun with thyroxine, hydrocortisone, and growth hormone. At 11.5 mo of age she developed seizures; and a repeat CT scan showed a mass extending beneath the hypothalamus. This tumor was removed surgically at 12 mo, the first successful treatment of this disorder. Our third possible case had a bifid epiglottis, hypopituitarism, and hand anomalies. A CT scan at birth failed to reveal a mass in the hypothalamus. This child died from complications of untreated hypopituitarism, and no neuropathology studies were done. These three cases were conceived between March 10th and April 17th in three different years in three geographically contiguous counties of Vermont. Clustering in time and space and possible familial recurrence, in one of these cases, suggest a possible gene/environment interaction.

Abnormalities, Multiple↗
PubMed1986

The effects of thiazide diuretics upon plasma lipoproteins.

In a double-blind, placebo-controlled, crossover study in 16 hypertensives, 4 weeks of 50 mg hydrochlorothiazide twice daily, caused significant elevations in total plasma cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, very low density lipoprotein (VLDL)-cholesterol and triglycerides. Significant elevations in fasting plasma glucose and in plasma insulin were observed, but no correlation between individual lipid elevations and either glucose or insulin elevations was apparent. The metabolic effects developed within 2 weeks, and dissipated within 4 weeks. Changes induced within 4 weeks of treatment with hydrochlorothiazide were unaltered at 6 months. Hydrochlorothiazide induces elevation of all lipoprotein cholesterol fractions and VLDL-triglyceride. However, as the important ratio between LDL- and HDL-cholesterol is unchanged, coronary risk may be unchanged.

Adult↗
PubMed1986

Comparative double-blind trial of the effectiveness and antigenicity of semisynthetic human insulin and purified porcine insulin in newly treated diabetic subjects.

A double-blind comparative trial of the effectiveness and antigenicity of semisynthetic human insulin (Novo) and highly purified (Monocomponent) porcine insulin was performed over a 12 month period in 20 diabetic subjects newly treated with insulin. Human insulin was shown to be indistinguishable from porcine insulin of comparable purity with respect to plasma glucose and glycosylated hemoglobin levels and insulin dose requirements. Human insulin was no less antigenic than porcine insulin; significant IgG-associated insulin binding activity was detected in six of the ten patients in the human insulin treated group and four of the ten patients in the porcine insulin treated group. In all patients, the binding activity was of low capacity. No adverse reactions to human insulin were noted. It is concluded that semisynthetic human insulin, like purified porcine insulin, is safe and effective. Although there may be advantages for human insulin in the setting of insulin allergy, this study does not indicate that human insulin has advantages over purified porcine insulin with respect to elicitation of antibodies of the IgG class.

Adult↗