Biomedical subjects
Publications and source records attributed to B Benson.
For companies seeking investors, money is available, but it is not as easy to obtain as it has been in recent years. Although the medical device industry remains an attractive proposition, several factors have contributed to the downturn in public-offering investment. This article outlines these factors and discusses the types of medical technologies that are likely to attract investment in the immediate future.
Surfactant protein D (SP-D) is a carbohydrate-binding glycoprotein containing a collagen-like domain that is synthesized by alveolar type II epithelial cells. The complete primary structure of rat SP-D has been determined by sequencing of a cloned cDNA. The protein consists of three regions: an NH2-terminal segment of 25 amino acids, a collagen-like domain consisting of 59 Gly-X-Y repeats, and a COOH-terminal carbohydrate recognition domain of 153 amino acids. There are 6 cysteine residues present in rat SP-D: 2 in the NH2-terminal noncollagenous segment and 4 in the COOH-terminal carbohydrate-binding domain. The collagenous domain contains one possible N-glycosylation site. The protein is preceded by a cleaved, NH2-terminal signal peptide. SP-D shares considerable homology with the C-type mammalian lectins. Hybridization analysis demonstrates that rat SP-D is encoded by a 1.3-kilobase mRNA which is abundant in lung and highly enriched in alveolar type II cells. Extensive homology exists between rat SP-D and bovine conglutinin.
Dietary fish oil has been reported to have both beneficial and deleterious effects in animal models of renal disease, which may be related to alterations in renal eicosanoid metabolism. The influence of dietary fish oil on glomerular and renal tubular responses that are linked to arachidonic acid metabolism was examined. Dietary fish oil had antidiuretic and antinatriuretic effects, which correlated with reduced renal cortical endogenous prostaglandin E2 (PGE2). Fish oil altered the renal balance of dienoic prostacyclin (PGI2) to thromboxane (TXA2) in favor of vasodilation, which may explain the observed exaggerated compensatory increases in glomerular function in response to uninephrectomy. Intact rats fed fish oil for 6 months developed proteinuria and impaired glomerular filtration rates (GFR). These deleterious effects were associated with evidence of increased renal lipid peroxidation. These results suggest that dietary fish oil modifies glomerular and renal tubular function in rats, and worsens age-associated proteinuria and declines in GFR. These effects may reflect the impact of dietary fish oil on renal fatty acid composition and arachidonic acid metabolism.
The predictive value of initial clinical evaluation in the management of alkaline corrosive ingestion remains unclear. This multicenter study was designed to determine if specific clinical signs and symptoms following ingestion of alkaline corrosives could predict significant esophageal injury. Alkaline corrosives were defined by a pH greater than or equal to 12. Signs and symptoms previously suggested as predictive of significant esophageal injury were documented on a standardized data form. Esophagoscopy reports were reviewed blinded to initial symptoms. Three hundred thirty-six alkaline-corrosive ingestions were analyzed. The mean number of symptoms reported in patients who did not have esophagoscopy was 1.2, in patients who had esophagoscopy was 3.0, and in patients that had visualized second or third degree esophageal burns was 4.8. Of 88 patients who had esophagoscopy, 63 (72%) had both the esophagoscopy report and initial symptom assessment available. Esophagoscopy was positive, defined as second or third degree esophageal burns, in 18 of 63 cases (29%). All patients with significant burns were symptomatic. No single or group of initially reported signs and symptoms could identify all patients with potentially serious esophageal burns.
Marine oils contain eicosapentaenoic acid, a fatty acid that competes for cyclooxygenase and reduces the synthesis of dienoic prostanoids including prostaglandin E2 (PGE2). Since PGE2 plays an important role in the estrogen-stimulated release of hypothalamic GnRH on proestrus, it was postulated that a diet containing fish oil would delay first ovulation through inhibitory effects on GnRH release. Thirty, 22-day-old female Sprague-Dawley rats were fed a diet containing fish oil ad libitum. Controls were pair-fed an identical diet with the substitution of safflower oil as the dietary fat. All rats were killed on the morning of first metestrus after vaginal opening and the display of an estrous smear(s). Fish oil feeding did not affect growth as indicated by the lack of an observed effect on body weights or femur lengths. On the other hand, pituitary, ovarian, and uterine weights were significantly lower in the rats fed fish oil (p < 0.001). The age at first estrus of the rats fed fish oil was significantly increased compared with the controls (42.9 +/- 1.0 vs. 36.1 +/- 0.3 days; p < 0.001), whereas the number of rats with corpora lutea (CL), as well as the number of CL per ovary (2.3 +/- 0.4 vs 4.8 +/- 0.6 for controls; p < 0.001) was significantly reduced by fish oil feeding. GnRH concentration in the preoptic area/hypothalamus was significantly increased in the fish oil-fed rats (21.4 +/- 4.0 pg/mg vs. 7.6 +/- 2.2 pg/mg for controls; p < 0.01); radioimmunoassable hypothalamic PGE2 was concomitantly reduced (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
The present study was undertaken to critically examine the hypothesis that circulating renotropin is the primary stimulus for compensatory renal growth. Blood was collected before and after either left nephrectomy or sham operation from a total of 34 rabbits and the serum renotropic activity assessed by the uptake of 3H-thymidine in primary cultures of rabbit kidney cells. Sera obtained after uninephrectomy had significantly more renotropic activity than sera collected before surgery. In some cases, sera obtained after sham operation had more renotropic activity than those collected before, but the mean response was not increased after sham operation. The difference between sera collected before and after uninephrectomy was not transferrable to primary cultures of rabbit liver cells. These data confirm a modest but significant influence of uninephrectomy on the renotropic activity of blood in rabbits.
Renal hypertrophy occurs early in the natural history of human and experimental diabetes and may be a manifestation of the same pathophysiological process which ultimately results in diabetic nephropathy. The precise biological events which stimulate and regulate this growth process remain incompletely understood. We postulated that renal eicosanoids contribute to the development of renal hypertrophy in diabetes. We elected to test the effects of suppression of dienoic eicosanoid metabolism (arachidonic acid metabolism) on renal hypertrophy in diabetic rats by feeding fish oil. Diabetic rats fed fish oil had markedly reduced insulin requirements compared to control rats pair-fed a beef tallow-rich diet. The concentrations of prostaglandin E2, 6-keto-prostaglandin F1 alpha, and thromboxane B2 were depressed in the renal cortex of diabetic rats fed fish oil. This alteration in eicosanoid metabolism was associated with a substantial enhancement of diabetic renal hypertrophy. These results indicate that dietary fish oil has profound effects on renal eicosanoid metabolism in experimental diabetes and that these autocoids may participate in the biological events which regulate diabetic renal hypertrophy.
Compensatory growth of the kidney occurs in response to a partial reduction in renal mass. This compensatory renal growth may be regulated by a circulating renotropic factor. Prostaglandin synthesis has been shown to be increased in kidneys undergoing compensatory renal growth in vivo. In the present study we observed that the addition of rabbit sera obtained after uninephrectomy enhanced DNA synthesis in primary cultures of rabbit kidney cells compared to sera obtained prenephrectomy. The stimulated kidney cells produced more prostaglandin E2 than control cells. Furthermore, the addition of prostaglandin E2 to rabbit kidney cells in the presence of control sera also stimulated DNA synthesis. These results provide further evidence that prostaglandins may participate in the biological events which regulate renal growth in response to a circulating renotropic factor.
The basic mechanisms of renal growth remain poorly understood. The work hypertrophy theory holds that after an acute reduction in renal mass, the growth of the kidney occurs as a consequence of increased renal function. Pharmacological inhibition of renal prostaglandin synthesis impairs the acute adaptive increases in both renal function and mass following partial nephrectomy. The present study examines the effects of four weeks of dietary fish oil on renal growth, function and arachidonic acid metabolites in intact and uninephrectomized male Sprague-Dawley rats. Dietary fish oil interferes with dienoic prostaglandin and thromboxane production in favor of synthesis of trienoic analogues. Control animals were pair-fed an identical diet with the exception that the fat was replaced by beef tallow. Renal cortical concentrations of arachidonic acid metabolites were reduced in animals fed fish oil, and urinary excretion of prostaglandin E2 was impaired. Fish oil feeding resulted in increased kidney weight without concomitant increases in renal function in intact animals. Glomerular filtration rate and renal plasma flow were greater in uninephrectomized rats fed fish oil compared to uninephrectomized controls pair-fed beef tallow. Augmentation of the compensatory increases in renal function observed with fish oil feeding was not associated with any additional renal hypertrophy. These data indicate that dietary fish oil has a profound impact on renal growth and function, which may be the consequence of altered renal and/or extrarenal arachidonic acid metabolism. Furthermore, the direction of the alterations in renal mass oppose that of renal function, providing clear and unique evidence against the work hypertrophy theory of renal growth.
A large number of reports have demonstrated the presence of neurohypophysial hormone-like peptides in mammalian pineal glands and an antigonadotropic function has been ascribed to pineal arginine vasotocin (AVT). We have undertaken large scale purification of bovine pineal neurohypophysial hormone-like substances which demonstrate mouse mammary milk-ejection activity (ME-activity) in vitro. Peptides with ME-activity were extracted from more than 5 kg of bovine pineal glands. ME-activity containing peptides were found in both high (Mr approximately 10,000-15,000) and low (Mr approximately 500-1000) Mr species from Sephadex G-25 chromatography of 0.2 N acetic acid extracts. After ultrafiltration in 5% formic acid, the neurohypophysial hormone-like peptides were localized to an ultrafiltration Mr 500-1000 retentate. A homogeneous peptide, which shared an identical retention time (RT) and amino acid sequence with synthetic 8-arginine vasopressin (AVP), was isolated by serial semipreparative high performance liquid chromatography. On the other hand, the non-mammalian nonapeptide AVT was not identified.
We examined the effects of interferon-gamma (IFN-gamma) on development of the surfactant system in alveolar epithelial cells of fetal lung. Explants of second-trimester human fetal lung were cultured for 1 to 6 days in serum-free medium containing recombinant human IFN-gamma (0.03 to 30 ng/ml) and/or dexamethasone (10 or 100 nM). Treatment for 3 days with IFN-gamma alone, dexamethasone alone, and IFN plus dexamethasone increased the content of surfactant protein A (SP-A, 28 to 36 kD) by approximately 3-, 2.5-, and 10-fold, respectively. The biphasic response pattern of SP-A to dexamethasone (stimulation initially and inhibition with continued culture) was not altered by the presence of IFN-gamma. IFN-gamma also stimulated accumulation of SP-A mRNA (2.7-fold at 24 h) but did not affect the levels of mRNAs for surfactant protein B (18 kD) and surfactant protein C (5 kD). To assess the effect of IFN-gamma on synthesis of surfactant lipids, we determined the content of phosphatidylcholine, the rate of labeled choline incorporation into phosphatidylcholine, saturation of newly synthesized phosphatidylcholine, and the activity of fatty acid synthetase, a glucocorticoid-inducible enzyme. Treatment of explants for 5 days with IFN-gamma had no effect on these parameters. Studies by light and electron microscopy revealed little difference between control and IFN-treated explants with regard to cell viability and epithelial cell differentiation. We conclude that IFN-gamma has a selective stimulatory effect on SP-A among surfactant components.(ABSTRACT TRUNCATED AT 250 WORDS)
The two objectives of the study were to determine whether a procedure could be developed for measuring cancer procoagulant (CP) activity in human serum and if this procedure provided a method for distinguishing people with cancer from those without cancer. A procedure was developed for processing human serum such that the activity of other coagulation enzymes would be minimized and the activity of cancer procoagulant could be measured. In a blinded study, we collected serum from 61 individuals in serum separator tubes, removed the clot by centrifugation, extracted the serum with a simple, single step procedure and analyzed the extract for CP activity. The results indicate that this test could correctly identify about 92% of the cancer patient serum samples and about 75% of the non-cancer patients serum samples, for an overall accuracy of about 85%.
Adult, male rats were maintained under 12L:12D with lights on at 06.00h. Their pineal glands were incubated at 37 degrees C in the presence or absence of 10(-4)M norepinephrine (NE). 5-HT and various metabolites were quantitated in post-incubation media and pineal glands by high performance liquid chromatography coupled with electrochemical detection. No differences were observed in the quantities of 5-HT released by pineal glands in four hour incubations starting at either 06.00, 13.00 or 18.00 h; however, a highly significant decrease below these levels was observed at 01.00h. NE significantly stimulated 5-HT release at 13.00 and 18.00 h, but was ineffective at 01.00 and 06.00h. These results confirm recently reported stimulatory effects of NE on the release of 5-HT into pineal gland incubation medium and further suggest a diurnal rhythm of pineal gland sensitivity to NE in vitro with maximum stimulation of 5-HT release at midphotophase.
When injected into rodents, the bovine pineal tripeptide threonylseryllysine (TSL) elicits diverse antireproductive effects in a number of animal models. Extensive studies of its effects on pubertal development have not been carried out, however. In the present study, 1.0 microgram of T-S-L was administered daily to female Charles River CD rats throughout the peripubertal period, and effects on vaginal opening time, ovarian histology, and serum luteinizing hormone (LH) levels were observed. Since TSL is known to alter the action of luteinizing hormone releasing hormone (LHRH), it was postulated that this antireproductive tripeptide would delay the time of vaginal opening associated with first ovulation. Two hundred eighty-seven weanling females were housed at 22 degrees C under a 14L:10D photoperiod. They were divided into three groups for daily intraperitonal injections of either saline (SAL), 1.0 micrograms TSL, or 5.0 micrograms melatonin (aMT) beginning on the 23rd day of life. Subgroups of nine to ten rats from each treatment group were sacrificed on days 28, 30, 32, 33, 34, 35, 36, 37, 38, and 40. Although the body weights of all animals increased significantly during the course of the study, no significant differences were observed in this parameter among rats treated with saline, aMT, or TSL. Vaginal opening time was significantly delayed by TSL between days 32 and 40, and uterine weights were significantly lower in this group. Prepubertal increases in serum levels of LH were also significantly reduced. At the dose utilized, aMT was without significant effects on these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Anestrus brought about after 2-4 weeks of short photoperiod (SP) exposure in LSH/SsLak hamsters is preceded by impaired follicular development. Since the latter is critically dependent on adequate FSH levels, this study tested the hypothesis that SP might alter baseline or compensatory FSH levels prior to the onset of anestrus. Regularly cycling females in 141:10 (LP) were transferred to SP (8L:16D). Between 0800 and 0900 h on days 20 through 24 of SP exposure, half of the animals in diestrus II were unilaterally ovariectomized (UO), and the remaining animals were sham-operated (Sham-UO). Seven hours after surgery, blood samples were taken via cardiac puncture. All animals were killed the following morning at 0900 h. Uterine weights were significantly reduced in SP-exposed hamsters, yet the compensatory increase in FSH following unilateral ovariectomy was not affected; a tendency for higher levels was noted. On proestrus, serum and pituitary FSH levels of SP-exposed Sham-UO animals were significantly elevated over similarly treated LP-exposed hamsters. Interestingly in animals with severe follicular impairment, the highest FSH levels correlated with the lowest uterine weights. The data suggest that SP exposure does not impair compensatory FSH release or the ability of the ovaries to respond to UO. SP-induced elevations in FSH levels may result from reduced follicular secretion and reduced inhibin and/or estrogen levels.
The object of this study was to compare the effects of short photoperiod (SP) and melatonin (MEL) treatment on the reproductive axis in ovariectomized LSH/SsLak hamsters. Animals acclimatized in long photoperiods (LP) (14L:10D) and showing regular estrous cycles were ovariectomized. Half of the operated hamsters received Silastic capsules containing 17-beta estradiol (E2). On the following day the animals were further subdivided into three groups: the animals in one group received daily afternoon injects of melatonin (MEL), those in a second group were given the vehicle, and animals in the third group were transferred from LP to SP (8L:16D). All animals were killed after 30 days. In hamsters without E2 replacement, MEL or SP exposure significantly suppressed serum and pituitary FSH levels, although MEL was more effective in this regard. On the other hand, SP exposure did not change serum FSH levels in animals with E2 implants, whereas MEL effectively suppressed them. SP or MEL reduced serum LH levels to a similar extent in the absence of E2 replacement, yet in animals with E2 implants only MEL significantly lowered LH levels below LP E2-treated controls. This was in contrast to effects on the pituitary where both treatments were equally effective in the depression of LH content. Serum PRL levels were similarly suppressed by MEL or SP exposure in E2-treated hamsters. On the other hand, pituitary PRL levels were not affected by either treatment in animals with E2-containing capsules, whereas SP or MEL treatment both significantly depressed pituitary PRL contents in hamsters without E2 replacement. SP treatment lowered MBH LHRH contents in animals with E2-containing capsules; no other significant changes in hypothalamic LHRH were noted. The data suggest that daily treatment with 25 micrograms of MEL is generally more effective in the suppression of gonadotropin levels than SP exposure. It is suspected that the mode of administration of MEL, and its quantity, may interact with estrogen differently than SP in the induction of physiological changes and regulation of the LHRH system.
Administration of TCDD produced a significant decrease in the serum concentration of prolactin (PRL) detected in rats after 4 hr compared to pair-fed vehicle controls and noninjected controls. This effect of TCDD was reversed by pimozide, a dopamine receptor antagonist. These data suggest that TCDD decreased the release of PRL from the adenohypophysis either by a direct effect on the gland or by altering the dopamine concentration in the median eminence (ME). Concentrations of TCDD from 5 to 500 ng/ml had no direct effect on the ability of the adenohypophysis to secrete PRL in vitro. However, the dopamine concentration increased to 3.24 +/- 0.07 ng per ME in TCDD-treated rats compared to 2.81 +/- 0.08 ng in vehicle controls. This is a dramatic alteration in the dopamine concentration, since the dopamine is being measured in the portal circulation which exhibits a rapid turnover. The rate constant of dopamine depletion after alpha-methyl-p-tyrosine and the turnover rate were also significantly elevated in the ME of TCDD-treated rats. These data provide the first biochemical evidence for a hypothalamic site of action of TCDD. Since dopamine is inhibitory to PRL release from the adenohypophysis, increased ME steady-state concentrations and turnover of this catecholamine may be responsible for the decreased concentration of serum PRL detected within 4 hr of TCDD injection. Thus, one of the early modes and sites of action of TCDD is to elevate the dopaminergic activity of the tuberoinfundibular nucleus. A hypothalamic site of action for TCDD may result in a number of the endocrinological effects known to be produced by exposure to TCDD.
The milk-ejecting response of lactating mouse mammary gland tissue to ovine pineal extracts indicated the presence of a neurohormone-like bioactivity in this tissue. After successive fractionation on gel permeation chromatography and reversed-phase liquid chromatography (HPLC) in conjunction with radioimmunoassays (RIA), it was demonstrated that the milk-ejection response to ovine pineal components with an Mr less than 1,000 corresponded to a biologically active peptide sequence that probably differs from that of arginine vasopressin, arginine vasotocin, and oxytocin and from peptides with a COOH-terminal Pro-Arg-Gly-amide ending. Gel permeation chromatography in formic acid appeared also to indicate the presence of a noncovalent interaction of the neurohormone-like bioactivity with proteins (Mr greater than 25,000) of the pineal.