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Biomedical subjects

C W Putnam

Publications and source records attributed to C W Putnam.

At least 55 records · Page 3Linked to original sources
PubMed1988

Venous complications of sclerotherapy for esophageal varices.

Although endoscopic sclerotherapy is effective in controlling bleeding from esophageal varices, the effects of sclerosing agents on the extrahepatic portal and splenic veins have not previously been investigated. This study of 21 men with portal hypertension and variceal bleeding compares the morphology of the portal and splenic veins in 11 who had received endoscopic sclerotherapy versus 10 patients who did not. The mean number of injections per patient was 11 +/- 5, the mean volume of 1.5 percent sodium tetradecyl injected was 23 +/- 15 ml, and the interval between the last injection and surgery was 15 +/- 6.5 days. Among the 11 patients who had endoscopic sclerotherapy, portal vein thrombosis occurred in 4 (36 percent). Two of these patients died from acute liver failure; the other two had shunt procedures. Histologic changes included intimal thickening and medial fibrosis in seven patients, thrombus in four patients, and destruction of the venous architecture in two patients. Of the 10 patients with portal hypertension who did not have endoscopic sclerotherapy, all had medial fibrosis of the portal vein, with thrombus and intimal thickening present in only 1. These findings suggest that endoscopic sclerotherapy for esophageal varices should be used cautiously in patients who may later require a shunt. Moreover, further studies are necessary to evaluate the long-term effects of injecting sclerosing agents into the portal circulation before widespread use of prophylactic sclerotherapy can be recommended.

Adult↗
PubMed1987

Hepatic protein kinase C: translocation stimulated by prolactin and partial hepatectomy.

Prolactin stimulates a hepatotrophic response similar to that caused by phorbol esters or partial hepatectomy in rats. Since phorbol esters, which activate protein kinase C, mimic prolactin action in liver, the relationship between prolactin administration and subsequent hepatic protein kinase C translocation was assessed. Prolactin administration rapidly stimulated a 4-fold elevation of membrane protein kinase C activity. The effect of prolactin on hepatic protein kinase C was specific for lactogenic hormones but could be duplicated by phorbol esters. Further, an increase in serum prolactin was demonstrated subsequent to partial hepatectomy and preceding hepatic protein kinase C translocation. Therefore, translocation of hepatic protein kinase C appears important for hepatic proliferation in response to prolactin administration and to partial hepatectomy.

Animals↗
PubMed1987

Prolactin-dependent mitogenesis in Nb 2 node lymphoma cells: effects of immunosuppressive cyclopeptides.

Prolactin (PRL)-stimulated ornithine decarboxylase (ODC) activity and subsequent proliferation are inhibited by the cyclopeptides cyclosporine (CsA) and didemnin B (DB) in Nb 2 node lymphoma cells. Similar concentrations of these agents also inhibit 125I-PRL binding, suggesting that their inhibitory effects on these PRL-dependent physiologic responses are mediated at least in part at the level of PRL receptor interactions. The phorbol ester TPA stimulated ODC activity and [3H]thymidine incorporation to 54% and 31% that of a near-optimal mitogenic concentration of PRL (10 ng/ml), suggesting that mitogenesis in these cells is coupled to some degree to the activation of protein kinase C (PKC). The calcium ionophore A23187 increased ODC activity only slightly and actually decreased [3H]thymidine incorporation to a value below the "cells only" controls. The addition of TPA plus A23187 did not further enhance the effects of TPA to elevate ODC activity and [3H]thymidine incorporation. However, A23187 significantly elevated PRL-stimulated ODC activity with a subsequent inhibition of [3H]thymidine incorporation, suggesting a block of entry into S phase. Both cyclopeptides decreased the elevation of ODC activity in G1 phase of cell cycle in response to PRL, suggestive of a site of action for these agents in early G1, a conclusion compatible with their ability to inhibit PRL binding to these cells. Addition of CsA or DB 2 hr after PRL had no effect on PRL-stimulated ODC activity detectable at 6 hr, but addition of either as late as 6 hr still affected the extent of mitogenesis. This is in line with the requirement for PRL to be present in the culture medium for a minimum of 3 to 6 hr to invoke a maximal effect on mitogenesis. Addition of either cyclopeptide after the cells were in S phase had no effect on the extent of [3H]thymidine incorporation. An inhibitor of the cyclooxygenase pathway (indomethacin) enhanced both PRL-stimulated ODC activity and proliferation, whereas inhibition of the lipoxygenase pathway by NDGA attenuated only proliferation, suggesting that in Nb 2 cells, products of the lipoxygenase pathway may contribute to the mechanism of PRL-stimulated mitogenesis. Because Nb 2 lymphoma cells were derived from estrogenized rats, estrogen was tested as a mitogen. By itself it was not mitogenic, but in conjunction with PRL, estradiol-17 beta elevated the ODC response and inhibited proliferation. Inhibitors of PKC known to have minimal effects on RNA synthesis, quercetin and gossypol, totally inhibited both the elevations of ODC activity and [3H]thymidine incorporation in response to PRL in Nb 2 lymphoma cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Prolactin administration stimulates rat hepatic DNA synthesis.

Prolactin is an important growth modulatory hormone in fetal and adult tissues. Its administration stimulates enzymatic markers of the G1 phase of cell cycle in rat liver and other tissues. To determine the effects of prolactin administration on hepatic DNA synthesis (S phase), rats received prolactin at 12 hour intervals for 48 hours and DNA synthesis was assessed by [3H]-thymidine incorporation. Prolactin administration stimulated DNA synthesis 2-4 fold above controls in the livers of adult and weanling animals. Increased incorporation of radiolabel was associated with the nucleus of hepatoparenchymal cells. These data support the hypothesis that prolactin may be a physiological regulator of hepatic DNA synthesis. Further, since stress stimulates prolactin secretion, we suggest that prolactin may participate in the hepatic compensatory hyperplasia elicited by the stress associated with partial hepatectomy.

Age Factors↗
PubMed1986

Prolactin stimulation of ornithine decarboxylase and mitogenesis in Nb2 node lymphoma cells: the role of protein kinase C and calcium mobilization.

The tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with calcium ionophores has been shown to bypass the requisite antigen- or lectin-induced signal for lymphocyte mitogenesis. This suggests that protein kinase C activation and calcium mobilization may be early events required for lymphocyte proliferation. Therefore, the relationship(s) of protein kinase C activation and calcium mobilization to ornithine decarboxylase induction and cellular proliferation were examined in a rat node lymphoma cell line (Nb2) which is dependent upon prolactin (PRL) for mitogenesis. TPA enhanced PRL-stimulated Nb2 node lymphoma cell ornithine decarboxylase induction and [3H]thymidine incorporation. Addition of a calcium ionophore (A23187) to cultures containing TPA plus PRL increased ornithine decarboxylase above PRL alone or PRL plus TPA but inhibited proliferation compared to the PRL plus TPA regimen. Exposure of cells to TPA or TPA plus A23187 increased [3H]thymidine incorporation in a similar manner to that demonstrated for low-dose PRL. However, optimal concentrations were only 20-25% as effective as mitogens as was optimal PRL. Protein kinase C and calmodulin antagonists inhibited PRL-stimulated ornithine decarboxylase induction and proliferation. Ca2+ chelation or cation channel antagonism inhibited both PRL-stimulated responses. The cyclic AMP analogue, 8Br-cAMP, inhibited PRL-stimulated ornithine decarboxylase activity as well as cellular proliferation processes assessed by [3H]thymidine incorporation. Finally, tumor-promoting phorbol esters inhibited 125I-rPRL binding. These data strongly suggest that protein kinase C activation and calcium mobilization are requisite events for PRL-stimulated ornithine decarboxylase induction and cellular proliferation in Nb2 node lymphoma cells. An additional component that is linked to alterations in K+ channeling is also implicated. These data support a role for protein kinase C in PRL-coupled mitogenesis. However, other critical Ca2+ and/or ion-induced events are also required.

Animals↗
PubMed1985

Prolactin is a tumor promoter in rat liver.

Since prolactin, like the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate, induces ornithine decarboxylase and plasminogen activator activities, biochemical markers of a trophic response, this hormone might likewise promote neoplasia. To test this theory, rats were initiated with a hepatocarcinogen followed by six weeks of ovine prolactin. This regimen caused hepatomegaly and the development of enzyme-altered foci. Promotion with prolactin for 23 weeks further increased the numbers of enzyme-altered foci. We suggest that prolactin is an endogenous tumor promoter for chemically initiated cells.

Animals↗
PubMed1985

In vivo induction of rat hepatic ornithine decarboxylase and plasminogen activator by 12-O-tetradecanoylphorbol 13-acetate.

Rapid and substantial elevations in ornithine decarboxylase and plasminogen activator have been linked to tumor promotion in mouse epidermis and in vitro. Systemic administration of 12-O-tetradecanoylphorbol 13-acetate (TPA) rapidly increased both enzymic activities in rat liver. Pretreatment with either cycloheximide or actinomycin D attenuated both enzyme inductions. It is concluded that: (1) systemic TPA rapidly induces plasminogen activator and ornithine decarboxylase activities in rat liver; and (2) both inductions reflect de novo enzyme synthesis.

Animals↗
PubMed1985

Dynamic organ culture of precision liver slices for in vitro toxicology.

The lack of a reproducible method for the production of thin tissue slices has hindered the use of liver slices as an in vitro tool for hepatotoxicity studies. Fresh human, rat, and rabbit liver was processed using a mechanical slicer. With this instrument, precision (5% of thickness) liver slices in the submillimeter range could be produced at a rapid rate. Slices were prepared from fresh livers in chilled, oxygenated buffer to minimize trauma. Following incubation for up to 20 h in a dynamic organ culture system, histology of incubated slices suggested that 250 m precision-cut slices were optimum in regard to morphology relative to liver slices incubated under conventional organ culture conditions. Addition of bromobenzene to the culture showed time-dependent hepatotoxicity based on two classic parameters of cell degeneration. Histological evidence is presented which suggests the usefulness of this system for hepatotoxicity studies and the production of focal necrosis in vitro.

Animals↗
PubMed1984

The hydroxylation, dechlorination, and glucuronidation of 4,4'-dichlorobiphenyl (4-DCB) by human hepatic microsomes.

Since chlorine placement and the degree of chlorination of the biphenyl nucleus play an important role in the metabolism and ultimate elimination of polychlorinated biphenyls (PCBs), we have studied the metabolism of 4,4'-dichlorobiphenyl (4-DCB) by human hepatic microsomes. This low molecular weight PCB congener is substituted at the preferred site of metabolism (para-position). 4-DCB was metabolized by human microsomes with a Km of 0.43 microM and a Vmax of 1.2 pmoles/mg microsomal protein/min. Six metabolites were identified: 4,4'-dichloro-3,3'-biphenyldiol, 4'-chloro-3-biphenylol, 4'-chloro-4-biphenylol, 4,4'-dichloro-2-biphenylol, 4,4'-dichloro-3-biphenylol (most abundant), and 3,4'-dichloro-4-biphenylol. [14C]-4-DCB equivalents were found to covalently bind to microsomal protein. Addition of a 1 mM concentration of reduced glutathione decreased the degree of covalent binding. These data suggest that human microsomes metabolize this PCB through an arene oxide and that an "NIH shift" occurs. When UDPGA was added to the incubation, human microsomal glucuronosyltransferase catalyzed the formation of the glucuronide of the major metabolite, 4,4'-dichloro-3-biphenylol. These and previous in vitro results show that the biotransformation of PCBs by humans is governed by the same principles established for the in vivo biotransformation of PCBs by the rat, mouse and monkey. That is, PCBs without two adjacent unsubstituted carbon atoms are poorly metabolized and that an unsubstituted para-position facilitates metabolism.

Aged↗
PubMed1984

Rapid elevation of plasminogen activator activity in rat tissues by prolactin.

Administration of ovine prolactin resulted in a rapid and significant induction of plasminogen activator activity within two hours in the rat adrenal gland, heart, aorta and liver. Prolactin exposure reduced baseline proteolytic activity in lung and skeletal muscle at 6-8 hours following hormonal challenge. This was coincident with a return toward baseline levels in enzyme activity demonstrated in other tissues. Pretreatment with actinomycin D or cycloheximide ameliorated the enzymic induction in the liver and adrenal and partially inhibited the aortic response. These data suggest that prolactin exposure leads to increased proteolytic activity through de novo biosynthesis in a variety of solid organs. In addition, pro-enzyme activation may also occur in vascular tissue.

Animals↗
PubMed1984

The mechanism of hepatoprotection by epsilon aminocaproic acid and putrescine.

Hepatic neutral serine proteases (including plasminogen activator) and ornithine decarboxylase (ODC) are induced by the hepatotoxin galactosamine (GALN). We examined the hepatoprotection conferred by epsilon-aminocaproic acid (EACA), a fibrinolytic inhibitor, putrescine (PUTR), the polyamine generated from ornithine by ODC, and alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. GALN, 450 mg/kg, was administered intraperitoneally to Wistar-Lewis rats (group I). Groups II, III, and IV were also given EACA (80 mg/kg), PUTR (0.3 mmol/kg), or DFMO (0.3 mmol/kg), respectively, 1 hour before and 3, 7, and 12 hours after GALN. Rats were killed 2 hours after an intraperitoneal dose of 3H-thymidine was administered, 30 or 45 hours after GALN. EACA and PUTR were effective protectants against necrosis as judged by enzymes and histologic findings. Neither increased thymidine incorporation above the levels seen with GALN only. DFMO offered no protection even though thymidine incorporation at 45 hours was increased. Both EACA and PUTR, which have similar chemical structures, possessed significant antiprotease activity in vitro, suggesting that they act by inhibiting toxin-induced neutral serine protease activity and not by accelerating regeneration.

Aminocaproates↗
PubMed1983

Metabolism of 2,2',3,3',6,6'-hexachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl by human hepatic microsomes.

Since the metabolism of polychlorinated biphenyls (PCBs) is the critical factor that determines whether or not they accumulate in adipose tissue, we have studied the metabolism of two hexachlorobiphenyls (HCBs), 2,2'3,3',6,6'-hexachlorobiphenyl (236-HCB) and 2,2'4,4',5,5'-hexachlorobiphenyl (245-HCB), by human hepatic microsomes. Human microsomes were isolated from patients undergoing liver resection and were found to have cytochrome P-450 levels (0.28 nmoles/mg microsomal protein) and cytochrome P-450-dependent enzymatic activities similar to those reported by other workers. 245-HCB was not metabolized by human microsomes under various conditions, while 236-HCB was metabolized with an apparent Km of 8.8 microM and a Vmax of 5.1 pmoles/mg microsomal protein/min. Two major metabolites were formed and identified by gas chromatography-mass spectrometry as 2,2',3,3',6,6'-hexachloro-4-biphenylol and 2,2',3,3'6,6'-hexachloro-5-biphenylol. [14C]236-HCB equivalents were found to covalently bind to microsomal protein. Addition of 1 or 5 mM reduced glutathione decreased the degree of covalent binding. These data suggest that HCBs are metabolized through an arene oxide. The fact that 245-HCB was not metabolized explains why it is the predominant PCB found in human adipose tissue.

Aged↗
PubMed1983

Techniques of ultrasonic dissection in resection of the liver.

The ultrasonic device allows dissection of hepatic parenchyma without damage to vascular or ductal structures. With it, both standard hepatic resections and more radical ones are made safer. It is an instrument useful for hepatic operations.

Hepatectomy↗