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Biomedical subjects

R A Roth

Publications and source records attributed to R A Roth.

At least 217 records · Page 12Linked to original sources
PubMed1988

Expression and characterization of a functional human insulin-like growth factor I receptor.

Stable transfectants of Chinese hamster ovary (CHO) cells were developed that expressed the protein encoded by a human insulin-like growth factor I (IGF-I) receptor cDNA. The transfected cells expressed approximately 25,000 high affinity receptors for IGF-I (apparent Kd of 1.5 X 10(-9) M), whereas the parental CHO cells expressed only 5,000 receptors per cell (apparent Kd of 1.3 X 10(-9) M). A monoclonal antibody specific for the human IGF-I receptor inhibited IGF-I binding to the expressed receptor and immunoprecipitated polypeptides of apparent Mr values approximately 135,000 and 95,000 from metabolically labeled lysates of the transfected cells but not control cells. The expressed receptor was also capable of binding IGF-II with high affinity (Kd approximately 3 nM) and weakly recognized insulin (with about 1% the potency of IGF-I). The human IGF-I receptor expressed in these cells was capable of IGF-I-stimulated autophosphorylation and phosphorylation of endogenous substrates in the intact cell. This receptor also mediated IGF-I-stimulated glucose uptake, glycogen synthesis, and DNA synthesis. The extent of these responses was comparable to the stimulation by insulin of the same biological responses in CHO cells expressing the human insulin receptor. These results indicate that the isolated cDNA encodes a functional IGF-I receptor and that there are no inherent differences in the abilities of the insulin and IGF-I receptors to mediate rapid and long term biological responses when expressed in the same cell type. The high affinity of this receptor for IGF-II also suggests that it may be important in mediating biological responses to IGF-II as well as IGF-I.

Animals↗
PubMed1988

Structure of the receptor for insulin-like growth factor II: the puzzle amplified.

The insulin-like growth factor II (IGF-II) is a polypeptide hormone with structural homologies to insulin and insulin-like growth factor I (IGF-I). In contrast to these other hormones, the in vivo function of IGF-II is not known. Although IGF-II can stimulate a broad range of biological responses in isolated cells, these responses have usually been found to be mediated by the insulin and IGF-I receptors. Recently, the receptor for IGF-II was found to also be the receptor for mannose-6-phosphate. Since this latter receptor has been implicated in targeting of lysosomal enzymes, the question is now raised of whether the same protein can also mediate metabolic responses to IGF-II.

Animals↗
PubMed1988

Pulmonary platelet sequestration is increased following monocrotaline pyrrole treatment of rats.

111In-labeled platelets were used to study the localization and survival of circulating platelets at various times after a single, intravenous administration of 3.5 mg/kg monocrotaline pyrrole (MCTP) to rats. Lung injury, assessed from elevated lung weight, lavage fluid total protein and albumin concentrations, and lactate dehydrogenase activity, was evident at Days 8 and 14. In addition, right ventricular hypertrophy was manifested by 14 days after MCTP administration. Pulmonary sequestration of 111In-labeled platelets was also elevated by Days 8 and 14, while circulating blood platelet number remained unchanged. Concomitantly, the hemoglobin concentration and total hemoglobin content of the lung homogenate supernatant in MCTP-treated rats on these days was decreased when compared to those in controls. A decrease in splenic platelet sequestration on Day 14 was accompanied by an increase in the combined radioactivity of the heart and kidneys. Platelet half-life and mean life span were increased only on Day 14. A higher dose of MCTP (35 mg/kg) caused moderate lung injury at 6 hr. However, this treatment did not result in increased platelet sequestration in the lungs, although a trend was observed. Data from this study support the hypothesis that platelets are involved in the development of the pulmonary hypertensive response following MCTP-induced lung injury.

Animals↗
PubMed1988

Platelets and the puzzles of pulmonary pyrrolizidine poisoning.

Pyrrolizidine alkaloids such as monocrotaline (MCT) are toxic plant constituents which poison livestock and humans. Low doses of MCT given to rats result in cardiopulmonary pathophysiologic sequelae similar to forms of chronic pulmonary hypertension in man. This provides a useful model of human disease. The toxicology of MCT is complex, and the mechanisms by which it causes lung injury, pulmonary hypertension, and right heart enlargement have remained elusive despite intensive study by numerous investigators. MCT is bioactivated by the liver to a reactive, electrophilic pyrrole (MCTP) that travels via the circulation to the lung, where injury results. When low, intravenous doses of MCTP are given to rats, a delay of several days occurs before lung injury and pulmonary hypertension become apparent. Moderate depletion of blood platelets around the time of the onset of lung injury lessens the subsequent development of right ventricular enlargement, suggesting a reduction in the pulmonary hypertensive response to MCTP. This observation prompted a study of the role of platelet-derived mediators in the cardiopulmonary response to MCTP. A stable analog of thromboxane A2(TxA2) caused a greater increase in right ventricular pressure in MCTP-treated rats compared to controls, and lungs isolated from MCTP-treated rats produced more TxB2 than those of controls. However, administration of drugs that either inhibited thromboxane synthesis or antagonized the effects of thromboxane did not afford protection from MCTP in vivo. Serotonin (5HT), another vasoactive mediator released by platelets, caused an exaggerated vasoconstrictor response in isolated lungs from rats treated with MCTP. Moreover, removal and inactivation of circulating 5HT by the pulmonary vasculature was impaired by treatment of rats with MCTP. However, administration of 5HT receptor antagonists did not attenuate the cardiopulmonary effects of MCTP in vivo. These results suggest that neither TxA2 nor 5HT is the sole mediator of the pneumotoxicity due to MCTP. Thus, the mechanism by which platelets are involved in the pathogenesis of the pneumotoxic response to MCTP remains an unsolved puzzle.

Animals↗
PubMed1988

Dieldrin activates rat neutrophils in vitro.

Suppression of phagocytic cell function has been proposed as a possible mechanism for the enhanced sensitivity to certain infectious agents exhibited by animals exposed to the organochloride insecticide, dieldrin. In the present study, we examined the effects of dieldrin on superoxide production by glycogen-elicited peritoneal neutrophils (PMNs) from the rat. Dieldrin caused a concentration-dependent increase in superoxide production by PMNs incubated in vitro at 37 degrees C. Superoxide release was increased significantly with 10 microM dieldrin and reached a maximum of 17 nmol/10 min/2.0 X 10(6) PMNs at a dieldrin concentration of 35 microM. Preincubation of PMNs for 5 min at room temperature with a barely suprathreshold concentration of either phorbol 12-myristate 13-acetate (PMA) or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) enhanced dieldrin-stimulated superoxide release by as much as ninefold or threefold, respectively. Maximum enhancement was obtained with 10 microM dieldrin for both PMA and FMLP. Time course studies with PMA-pretreated cells revealed that the rate of superoxide release was dependent on the concentration of dieldrin. Extracellular calcium played an important role in dieldrin-stimulated superoxide release, since PMNs treated with dieldrin in the absence of extracellular calcium did not release superoxide. Also, pretreatment with calcium ionophore A23187 greatly enhanced superoxide release from dieldrin-stimulated PMNs. These results show that dieldrin has a stimulatory effect on superoxide release from rat PMNs in vitro and that this stimulation is dependent on extracellular calcium.

Animals↗
PubMed1988

Bile and bile salts potentiate superoxide anion release from activated, rat peritoneal neutrophils.

Certain bile salts cause hepatotoxicity as well as injury to extrahepatic organs when administered to animals. Activated neutrophils (PMNs) may cause tissue injury by releasing reactive oxygen species and other products. Since PMNs may come in contact with biliary components, such as bile salts, following chemical insult to the liver or during cholestasis, we examined the capacity of bile and bile salts to stimulate superoxide anion (O2-) release from rat peritoneal PMNs in vitro. Neither bile nor bile salts, with the exception of lithocholate, could by themselves stimulate O2- release from PMNs. Lithocholate (32 microM) caused small but statistically significant release of O2- from PMNs. When PMNs were primed with a barely suprathreshold concentration of 12-O-tetradecanoyl-phorbol-13-acetate (PMA), a classic stimulus for PMNs, the addition of bile and certain bile salts markedly enhanced O2- release from PMNs. The monohydroxy bile salt, lithocholate, had the greatest stimulatory activity toward PMA-primed PMNs, causing approximately an eightfold increase in O2- release. The enhancing effect of lithocholate was maximal between 10 and 32 microM, and it also occurred with PMNs isolated from rat blood. Dihydroxy bile salts, deoxycholate and chenodeoxycholate (100 microM), caused more modest enhancement of O2- release (two- to threefold) from primed PMNs. Cholate, a trihydroxy bile salt, was not active at these concentrations. Conjugation of either lithocholate or chenodeoxycholate with either glycine or taurine markedly reduced the ability of the bile salt to enhance O2- release from primed PMNs. Structural alterations on the hydrophilic side chain or within the planar, hydrophobic portion of the bile salt molecule reduced the capacity to enhance O2- release from PMA-primed PMNs. These results indicate that bile salts can potentiate the respiratory burst in PMNs and suggest a role for this interaction in toxicoses or disease states characterized by elevated serum bile salts.

Animals↗
PubMed1988

6-Ketoprostaglandin F1 alpha and thromboxane B2 in isolated, blood-perfused lungs from monocrotaline pyrrole-treated rats.

Monocrotaline pyrrole (MCTP) causes pulmonary vascular injury and pulmonary hypertension in rats. Although the mechanism by which MCTP causes pulmonary hypertension is unknown, vasoconstriction may play a role. Thromboxane (Tx) A2 is a vasoconstrictor released from platelets and other blood cells. Following treatment with MCTP in vivo, the release of stable metabolites of TxA2 and prostacyclin [TxB2 and 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha), respectively] was determined in isolated lungs perfused with blood. Early in the development of pulmonary hypertension, the concentrations of TxB2 and 6-keto-PGF1 alpha in the effluent plasma of lungs from treated rats were not different from control rats. When pulmonary hypertension was well established, the concentration of TxB2 was higher in the effluent plasma of lungs from MCTP-treated rats, although the concentration of 6-keto-PGF1 alpha was not affected by treatment.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Complement is not involved in monocrotaline pyrrole-induced pulmonary injury.

Monocrotaline pyrrole (MCTP) causes pulmonary vascular injury, pulmonary hypertension, and right ventricular hypertrophy in rats. The mechanisms by which MCTP causes lung injury are not known. After treatment with a moderate dose of MCTP, several days pass before major lung injury is detected, thus suggesting that the damage is caused indirectly. Since activation of the complement system can cause lung injury, it was of interest to test whether complement activation may be important in lung injury due to MCTP. Accordingly, rats were given a single dose of MCTP (3.5 mg/kg iv), and serum hemolytic complement activity was measured at several times after rats were treated. Neutrophil aggregometry also was used to determine whether complement activation products could be detected in serum after MCTP was given in vivo. The effect of complement depletion on MCTP-induced pulmonary injury was tested by cotreating rats with purified cobra venom factor and MCTP. MCTP treatment did not cause detectable complement activation in vivo, and complement depletion did not protect rats from lung injury. The direct effect of MCTP on serum complement also was tested by exposing fresh rat serum to MCTP in vitro and measuring serum complement activity. MCTP decreased serum hemolytic complement activity in vitro, but it did not interfere with subsequent zymosan-induced activation of complement. These results suggest that complement does not play a role in the development of major lung injury that occurs several days after treatment of rats with MCTP.

Animals↗
PubMed1988

Pulmonary hypertension due to monocrotaline pyrrole is reduced by moderate thrombocytopenia.

To elucidate further the role of the platelet in the development of monocrotaline pyrrole (MCTP)-induced lung injury and pulmonary hypertension, MCTP-treated rats were made thrombocytopenic by cotreatment with an anti-rat platelet serum (PAS). Lung injury was assessed from increases in lung weight, lavage fluid protein concentration, and lactate dehydrogenase activity and from accumulation in lung tissue of 125I-labeled albumin. These indexes of injury were not different in MCTP-treated rats with normal or reduced platelet numbers at day 4,8, or 14. In MCTP-treated rats not receiving the PAS, pulmonary arterial pressure was elevated by day 8. However, pulmonary arterial pressure was the same as controls at both day 8 and day 14 in MCTP-treated rats made moderately thrombocytopenic by cotreatment with PAS. More marked reduction of platelet number abolished the protective effect of thrombocytopenia against pulmonary hypertension. In a separate series of experiments, treatment with antibodies to platelet-derived growth factor (PDGF), a potential mediator in the response to MCTP-induced injury, did not protect rats from the cardiopulmonary effects of MCTP. These data indicate that moderate reduction of the number of circulating platelets prevents MCTP-induced pulmonary hypertension but not MCTP-induced lung injury, suggesting that the platelet is involved in the pulmonary hypertensive response to MCTP-induced lung injury by unknown mechanisms.

Animals↗
PubMed1988

Complications of extracorporeal shock-wave lithotripsy and percutaneous nephrolithotomy.

The serious complications of ESWL associated with the Dornier HM-3 lithotripter are well known. It is incumbent on operators to recognize these problems and, when possible, to anticipate them and utilize a treatment plan that will minimize their occurrence. Appropriate use of percutaneous techniques, double-J stents, and ureteroscopy and aggressive use of antibiotics can minimize the serious complications associated with ESWL. It will be of interest to see whether newer generation lithotripters will produce an incidence of complications similar to that of the Dornier HM-3 or whether unique problems will call for new strategies. We have described the clinically important complications of ESWL and percutaneous nephrolithotomy. At this time, these modalities should be looked on as complementary procedures. Each has specific indications, and, when used appropriately, often in concert, both will provide safe, effective treatment for patients with renal calculus disease.

Anesthesia↗
PubMed1988

Complications of ureteroscopy.

Ureteroscopy with the rigid instrument is now an integral part of the endourologic armamentarium for the management of patients with ureteral calculi. Our experience demonstrates that ureteroscopy can be a safe, efficacious, and less invasive modality. Morbidity will be lowered with proper patient selection, meticulous attention to technique, and use of the proper equipment. Prevention is the best way to avoid serious complications of ureteroscopy. The following guidelines are recommended: Ureteroscopy should be used primarily for patients with distal ureteral calculi. A guidewire should be in place at all times during ureteroscopy. Fragmentation devices should be available. No forceful manipulations should be undertaken during either introduction of the instrument or manipulation of the calculus. When access or manipulation is difficult, a stent should be placed in the ureter for ureteroscopy at a later date. When perforation occurs, a stent should be placed in the ureter and the injured dry unstented ureter complex avoided. Alternative endourologic modalities should be used when appropriate. When practicing urologists are aware of the indications, potentials, and limitations, ureteroscopy and other endourologic methods will permit safe successful treatment of most patients with ureteral calculi.

Adult↗
PubMed1987

Interactions of the receptor for insulin-like growth factor II with mannose-6-phosphate and antibodies to the mannose-6-phosphate receptor.

Recently, the sequence of the human receptor for insulin-like growth factor II (IGF-II) was found to be 80% identical [Morgan et al., (1987) Nature 329, 301-307] to the sequence of a partial clone of the bovine cation-independent mannose-6-phosphate receptor [Lobel et al., (1987) Proc. Natl. Acad. Sci. USA 84, 2233-2237]. In the present study, the purified receptor for insulin-like growth factor II (IGF-II) was found to react with two different polyclonal antibodies to the purified mannose-6-phosphate receptor. Moreover, mannose-6-phosphate was found to stimulate the binding of labeled IGF-II to the IGF-II receptor by two-fold. This effect had the same specificity and affinity as the reported binding of mannose-6-phosphate to its receptor; mannose-1-phosphate and mannose had no effect on the binding of labeled IGF-II to its receptor, and the half-maximally effective concentration of mannose-6-phosphate was 0.3 mM. Also, mannose-6-phosphate did not affect labeled IGF-II binding to the insulin receptor. These results support the hypothesis that a single protein of Mr-250,000 binds both IGF-II and mannose-6-phosphate. Furthermore, they indicate that mannose-6-phosphate can modulate the interaction of IGF-II to its receptor.

Carrier Proteins↗