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Highlights • The diagnosis and management of cases with acute biliary pancreatitis. • Minimally invasive techniques gave encouraging results with minimal complications. • Cholecystectomy is recommended to prevent the recurrence of acute gallstone induced pancreatitis., Background Acute pancreatitis (AP) is considered one of the most common gastrointestinal disorders; the annual worldwide incidence for AP is 4.9–73.4 cases / 100,000 people and the total mortality rate is 4–8%, increasing to 33% in patients with infected necrosis. This study aims to assess the outcome of providing standardized evidence-based care to patients with acute biliary pancreatitis. Methods Thirty patients diagnosed with acute biliary pancreatitis, were enrolled in this study and managed according to the Japanese guidelines, 2015 with a complementary scope on other recent guidelines. Results Out of 30 patients in the study, 60% were females. Twenty-five cases were presented in the early phase of the disease while the rest presented in the late phase. Gallstones were the commonest cause (80%). The complications encountered were a systemic complication in one case, organ failure in three cases, and the local complications in the form of fluid collections in (43.3%) of cases.Out of 30 patients, 6 patients had an intervention. The main approach was minimally invasive techniques (4 cases), Open approach was performed in 2 cases. The total mortality rate was 10%. Most mild cases were discharged within one week from admission. Cases readmitted with recurrent attacks of acute pancreatitis were 3 cases, one male and 2 females. Conclusion By applying guidelines in the management of acute biliary pancreatitis, we can reduce disease-related morbidity and mortality. Besides, we can reduce the costs of medical services with the proper investment of healthcare resources.

Donor-derived hepatitis C (dd-HCV) infection may increase the risk of renal impairment (RI) among heart transplantation (HT) recipients. Sofosbuvir, an integral component of HCV direct-acting antivirals (DAAs) has also been linked to RI. To date, no study has examined the trends in renal function for HT recipients of dd-HCV infection and assessed safety and efficacy of Sofosbuvir-based DAAs. Between September 2016 and June 2018, 46 HCV-naive patients and one patient with a history of HCV treated pretransplant, underwent HT from HCV-positive donors (follow-up available through October 10, 2018). Patients were treated with Ledipasvir-Sofosbuvir (genotype 1) or Sofosbuvir-Velpatasvir (genotype 3) for 12 or 24 weeks; no dose adjustments were made for renal function. Data on renal function were available for 23 patients who achieved a sustained virologic response at 12 weeks after the treatment (SVR12; cohort A) and 18 patients who completed 1 year of follow-up (cohort B). Treatment of dd-HCV infection was initiated at a median of 6 weeks post-HT. In both cohorts, a nonsignificant reduction in median estimated glomerular filtration rate (eGFR; ml/min/1.73 m) was noted (cohort A: pretransplant eGFR: 62 [interquartile range {IQR}: 1-84] to SVR12 eGFR: 49 [IQR: 37-82]; p = 0.43; cohort B: pretransplant eGFR: 65 [IQR: 54-84] to 1 year post-HT eGFR: 56 [IQR: 39-75]; p = 0.29). Pretreatment renal function had no significant impact on changes in renal function during treatment. All patients tolerated DAAs well with 100% completion rate to the assigned therapy and duration and 100% success at achieving SVR12. In this first and largest reported case series to date of HT recipients with dd-HCV infection, we observed that neither the dd-HCV infection nor its treatment with Sofosbuvir-based DAAs increased the risk of RI. Sofosbuvir-based DAAs appear safe, tolerable, and effective for HCV treatment even in presence of severe RI.

Importance For patients awaiting heart transplant, hepatitis C–positive donors offer an opportunity to expand the donor pool, shorten wait times, and decrease wait-list mortality. While early reported outcomes among few heart transplant recipients have been promising, knowledge of 1-year outcomes in larger cohorts of patients is critical to shared decision-making with patients about this option. Objective To better define the association of hepatitis C–positive donors with heart transplant volumes, wait-list duration, the transmission and cure of donor-derived hepatitis C, and morbidity and mortality at 1 year. Design, Setting, and Participants This was a prospective, single-center observational study of 80 adult (age 18 years or older) patients who underwent heart transplant using hearts from hepatitis C–positive donors between September 2016 and April 2019 at a large academic medical center. Among donors, who were considered hepatitis C–positive if results from hepatitis C antibody and/or nucleic acid testing were positive, 70 had viremia and 10 were seropositive but did not have viremia. Follow-up was available through May 15, 2019. Comparisons were drawn with patients who underwent transplant with hearts from hepatitis C–negative donors during the same period. Exposures In addition to standard posttransplant management, transplant recipients who developed donor-derived hepatitis C infection were treated with direct-acting antivirals. Main Outcomes and Measures The main outcomes included wait-list duration and 1-year survival in all patients, and for those who developed donor-derived hepatitis C, the response to direct-acting antiviral treatment. Results Of 80 patients, 57 (71.3%) were men, 55 (68.7%) were white, and 17 (26.3%) were black; the median age at transplant was 54.5 years (interquartile range, 46-62 years). Following consent to accept hearts from hepatitis C-exposed donors, the median days to heart transplant was 4 (interquartile range, 1-18). No recipients of donors with negative nucleic acid testing results (10 [12.5%]) developed donor-derived hepatitis C. Of 70 patients who were recipients of donors with positive nucleic acid testing results, 67 (95.7%) developed donor-derived hepatitis C over a median follow-up of 301 days (interquartile range, 142-617). Treatment with direct-acting antivirals was well tolerated and yielded sustained virologic responses in all treated patients. Within the cohort with infection, 1-year patient survival was 90.4%, which was not significantly different compared with the cohort without infection or with patients who received transplants from hepatitis C–negative donors during the same period. Conclusions and Relevance In the era of direct-acting antivirals, hepatitis C–positive donors are a viable option to expand the donor pool, potentially reducing wait-list duration and mortality. In heart transplant recipients with donor-derived hepatitis C, infection is well-tolerated and curable, and 1-year survival is equivalent to that in recipients of hepatitis C–negative donors.

We compared results using Neoral versus Sandimmune, each in combination with steroid and azathioprine immunosuppression, in primary liver transplantation recipients. There were 15 patients in each group with similar demographic distributions. Intravenous cyclosporine was stopped at 4.3 ± 1.9 days in the Neoral group vs 7.8 ± 4.9 days in the Sandimmune group (P < 0.025). Cyclosporine levels in the first 10 days were higher (mean 306 ng/ml vs 231 ng/ml) in the Neoral group than the Sandimmune group (P < 0.05). The Neoral dose was less than the Sandimmune dose (mean 5.5 ng/kg per day vs 7.9 ng/kg per day) to achieve these levels in that time period (P < 0.05). Two patients (13 %) experienced three episodes of biopsy-proven rejection in the Neoral group compared to nine patients (60 %) with 12 episodes of rejection in the Sandimmune group (P < 0.025). Incidences of neurological and renal complications were similar between the groups. Infections requiring treatment were also similar. Liver function, renal function, and marrow function, evaluated at days 7, 14, 21, 28, and 2, 4, 6, and 12 months post-transplant, were not different between the groups. In summary, shorter use of intravenous cyclosporine and quicker stabilization of trough cyclosporine levels was achieved with Neoral than with Sandimmune. In the early posttransplant period, higher levels with lower doses were achieved with Neoral than with Sandimmune. In our experience, the incidence of rejection was lower with Neoral than with Sandimmune. There were similar lengths of hospitalization, mortality, adverse events, retransplantation, and similar liver, renal, and marrow function up to 1 year posttransplantation. Because of this experience, we continued to use Neoral in a total of 59 primary liver transplant recipients. We have not used intravenous cyclosporine in the last 44 patients. Follow-up was a mean of 11.4 months, ranging from 1 to 27 months. The incidence of rejection was 24 % in these 59 patients compared to our historical experience of 70 % using Sandimmune.

The isoprostanes (IsoPs) are novel bioactive prostaglandin-like compounds produced in vivo by free radical-catalyzed peroxidation of arachidonyl-containing lipids. Previously, we have identified IsoPs containing F-type and D- and E-type prostane rings that are formed by reduction and rearrangement of IsoP endoperoxide intermediates, respectively. We now explore whether thromboxane B2 (TxB2)-like compounds, termed B2-isothromboxanes (B2-IsoTxs), are formed by rearrangement of IsoP endoperoxides. Detection of these compounds was carried out using a stable isotope dilution mass spectrometric assay originally developed for quantification of cyclooxygenase-derived TxB2. Incubations of arachidonic acid with Fe/ADP/ascorbate for 30 min in vitro generated a series of peaks representing putative B2-IsoTx at levels of 62.4 +/- 21.0 ng/mg arachidonate. Using various chemical modification and derivatization approaches, it was determined that these compounds contained hemiacetal ring structures and two double bonds, as would be expected for B2-IsoTx. Analysis of the compounds by electron ionization mass spectrometry yielded multiple mass spectra similar to those of TxB2. B2-IsoTxs are also formed esterified to phospholipids; oxidation of arachidonyl-containing phosphatidylcholine in vitro followed by hydrolysis resulted in the release of large amounts of these compounds. To explore whether B2-IsoTxs are also formed in vivo, a well characterized animal model of lipid peroxidation consisting of orogastric administration of CCl4 to rats was used. Levels of B2-IsoTx esterified in lipids in the liver increased 41-fold from 2.5 +/- 0.5 to 102 +/- 30 ng/g of liver. In addition, circulating levels of free compounds increased from undetectable (5 pg/ml) to 185 +/- 30 pg/ml after CCl4, a 37-fold increase. Thus, we have provided evidence that IsoTxs constitute another novel class of eicosanoids produced in vivo nonenzymatically by free radical-catalyzed lipid peroxidation. These studies thus expand our understanding of products of lipid peroxidation formed in vivo from the free radical-catalyzed peroxidation of arachidonic acid.

Background Halothane can be reductively metabolized to free radical intermediates that may initiate lipid peroxidation. Hypoxia and phenobarbital pretreatment in Sprague-Dawley rats increases reductive metabolism of halothane. F(2)-isoprostanes, a novel measure of lipid peroxidation in vivo, were used to quantify halothane-induced lipid peroxidation in rats. Methods Rats were exposed to 1% halothane or 14% O(2) for 2 h. Pretreatments included phenobarbital, isoniazid, or vehicle. Rats also were exposed to halothane, enflurane, and desflurane at 21% O(2). Lipid peroxidation was assessed by mass spectrometric quantification of F(2)-isoprostanes. Results Exposure of phenobarbital-pretreated rats to 1% halothane at 21% O(2) for 2 h caused liver and plasma F(2)-isoprostane concentrations to increase fivefold compared to nonhalothane control rats. This halothane-induced increase was enhanced by 14% O(2), but hypoxia alone had no significant effect. Alanine aminotransferase activity at 24 h was significantly increased only in the 1% halothane/14% O(2) group. The effect of cytochrome P450 enzyme induction on halothane-induced F(2)-isoprostane production and liver injury was determined by comparing the effects of isoniazid and phenobarbital pretreatment with no pretreatment under hypoxic conditions. Halothane caused 4- and 11-fold increases in plasma and liver F(2)-isoprostanes, respectively, in non-pretreated rats, whereas isoniazid pretreatment had no effect. Phenobarbital pretreatment potentiated halothane-induced lipid peroxidation with 9- and 20-fold increases in plasma and liver F(2)-isoprostanes, respectively. Alanine aminotransferase activity was increased only in this group. At ambient oxygen concentrations, halothane but not enflurane or desflurane, caused F(2)-isoprostanes to increase. Conclusions Specific halothane-induced lipid peroxidation was demonstrated in Sprague-Dawley rats using quantification of F(2)-isoprostanes and was increased by hypoxia and phenobarbital pretreatment, but not isoniazid pretreatment.

We previously reported the extraction of a factor from bovine sperm that activated adenylyl cyclases of rat brain and human platelets, and identified it as a trypsin-like protease that was referred to as "ninhibin." This proteolytic activity was purified to near homogeneity from an alkaline extract of washed sperm particles by sequential chromatography on p-aminobenzamidine agarose and CM-Sephadex. Purification was greater than 100-fold with nearly 30% recovery of protease activity exhibiting a major band of approximately 40 kDa. An approximately 45-kDa form of the protease was also evident in crude extracts and was preferentially isolated when the enzyme was prepared in the presence of a mixture of protease inhibitors. The larger form of the protease was substantially less effective in stimulating adenylyl cyclase than was the smaller form; it is likely to be a zymogen form from which the smaller, more active form is derived. Purified forms of acrosin and ninhibin exhibited similar mobilities on PAGE, similar capacities for activating adenylyl cyclase, similar patterns of proteolytic fragmentation, and similar immunoblot patterns obtained with an antibody against purified bovine acrosin. More importantly, the N-terminal amino acid sequence of bovine ninhibin was found to be identical with that of bovine acrosin and caprine acrosin and more than 75% identical with porcine acrosin. The data support the conclusion that the adenylyl cyclase-activating protease previously referred to as ninhibin is, in fact, acrosin.

Growth factors and tumor promoters have been shown to play a role in intestinal epithelial growth regulation and transformation. In this study, transforming growth factor-alpha (TGF alpha) and the tumor promoter, tetradecanoyl phorbol acetate (TPA), are shown to stimulate the production of eicosanoids by rat intestinal epithelial (RIE-1) cells in culture. A 4.5-kb mRNA, which hybridizes to the mouse cyclooxygenase-2 cDNA probe, is elevated 18-fold within 30 min after TGF alpha or TPA treatment. Stimulation of RIE-1 cells with TGF alpha leads to the increase of a protein (M(r) approximately 69,000), which binds a monospecific antibody to the mouse cyclooxygenase-2 protein. Dexamethasone markedly inhibits the increase of the 4.5-kb mRNA. Pretreatment of TGF alpha or TPA-stimulated RIE-1 cells with dexamethasone or cyclooxygenase inhibitors prevents the increase in eicosanoid production by these cells. Treatment of quiescent RIE-1 cells with TGF alpha stimulates mitogenesis. This mitogenic activity is blocked by pretreating the cells with dexamethasone or cyclooxygenase inhibitors. A mitogen-inducible cyclooxygenase gene is thus shown to be regulated by TGF alpha and TPA in rat intestinal epithelial cells. We suggest that products of an intestinal growth factor-inducible cyclooxygenase may play a role in the regulation of mitogenesis.

This study was designed to determine whether transforming growth factor alpha (TGF alpha) protects rat gastric mucosa against ethanol- and aspirin-induced injury. Systemic administration of TGF alpha dose-dependently decreased 100% ethanol-induced gastric mucosal injury; a dose of 50 micrograms/kg delivered intraperitoneally 15 min before ethanol decreased macroscopic mucosal injury by > 90%. At the microscopic level, TGF alpha prevented deep gastric necrotic lesions and reduced disruption of surface epithelium. Pretreatment with orogastric TGF alpha (200 micrograms/kg) only partially (40%) decreased macroscopic ethanol damage. Intraperitoneal administration of TGF alpha at a dose of 10 micrograms/kg, which does not significantly inhibit gastric acid secretion, decreased aspirin-induced macroscopic damage by > 80%. TGF alpha protection does not seem to be mediated by prostaglandin, glutathione, or ornithine decarboxylase-related events, as evidenced by lack of influence of the inhibition of their production. Pretreatment with the sulfhydryl blocking agent N-ethylmaleimide partially abolished (40%) the protective effect of TGF alpha. In addition, systemic administration of TGF alpha resulted in a two-fold increase in tyrosine phosphorylation of phospholipase C-gamma 1 and in a time- and dose-dependent increase in levels of immunoreactive insoluble gastric mucin; these events occurred in a time frame consistent with their participation in the protective effect of TGF alpha.

Objective. Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F 2 -like compounds, termed F 2 -isoprostanes, produced in vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress. Methods. As a measure of oxidative stress, we determined urinary concentrations of a tetranordicarboxylic acid metabolite of F 2 -isoprostanes (F 2 IP-M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects. Results. F 2 IP-M concentrations were significantly higher in patients with scleroderma (mean ± SEM 3.41 ± 0.64 ng/mg of creatinine) than in healthy controls (1.22 ± 0.14 ng/mg of creatinine) (P = 0.002). These elevations occurred in patients with limited disease and in those with diffuse disease. Conclusion. The increased level of urinary F 2 IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.

These studies examine the in vivo formation of a unique series of PGF2-like compounds (F2-isoprostanes) derived from free radical-catalyzed nonenzymatic peroxidation of arachidonic acid. We have previously shown that levels of these compounds increase up to 50-fold in rats administered CCl4. To understand further the formation of these compounds in vivo, we carried out a series of experiments assessing factors influencing their generation. After CCl4 (2 ml/kg) was administered to rats, plasma F2-isoprostanes increased 55-fold by 4 h. Levels declined thereafter, but at 24 h, they were still elevated 21-fold, indicating continued lipid peroxidation. Pretreatment of rats with isonicotinic acid hydrazide and phenobarbital to induce cytochrome P-450 enhanced the production of F2-isoprostanes after CCl4 administration eightfold and fivefold, respectively, whereas inhibition of the cytochrome P-450 system with SKF-525A and 4-methylpyrazole decreased formation of F2-isoprostanes after CCl4 by 55 and 82%, respectively. Further, the glutathione-depleting agents buthionine sulfoximine and phorone augmented the F2-isoprostane response to CCl4 by 22- and 11-fold, respectively. F2-isoprostanes are formed in situ esterified to lipids and, in addition to increases in levels of free F2-isoprostanes in the circulation, levels of F2-isoprostanes esterified to lipids in various organs and plasma also increase sharply during CCl4 poisoning. The measurement of F2-isoprostanes may facilitate investigation of the role of lipid peroxidation in human diseases.

We recently reported the discovery of a series of bioactive prostaglandin F2-like compounds (F2-isoprostanes) that are produced in vivo by free radical-catalyzed peroxidation of arachidonic acid independent of the cyclooxygenase enzyme. Inasmuch as phospholipids readily undergo peroxidation, we examined the possibility that F2-isoprostanes may be formed in situ on phospholipids. Initial support for this hypothesis was obtained by the finding that levels of free F2-isoprostanes measured after hydrolysis of lipids extracted from livers of rats treated with CCl4 to induce lipid peroxidation were more than 100-fold higher than levels in untreated animals. Further, increased levels of lipid-associated F2-isoprostanes in livers of CCl4-treated rats preceded the appearance of free compounds in the circulation, suggesting that the free compounds arose from hydrolysis of peroxidized lipids. This concept was supported by demonstrating that free F2-isoprostanes were released after incubation of lipid extracts with bee venom phospholipase A2 in vitro. When these lipid extracts were analyzed by HPLC, fractions that yielded large quantities of free F2-isoprostanes after hydrolysis eluted at a much more polar retention volume than nonoxidized phosphatidylcholine. Analysis of these polar lipids by fast atom bombardment mass spectrometry established that they were F2-isoprostane-containing species of phosphatidylcholine. Thus, unlike cyclooxygenase-derived prostanoids, F2-isoprostanes are initially formed in situ on phospholipids, from which they are subsequently released preformed, presumably by phospholipases. Molecular modeling of F2-isoprostane-containing phospholipids reveals them to be remarkably distorted molecules. Thus, the formation of these phospholipid species in lipid bilayers may contribute in an important way to alterations in fluidity and integrity of cellular membranes, well-known sequelae of oxidant injury.

The interaction of forskolin with adenylate cyclase was studied by evaluating its effect on metal and metalATP kinetics and by measuring its protective effect when the enzyme was subjected to denaturation conditions. The solubilized calmodulinand forskolin-sensitive adenylate cyclase from brain and the particulate enzyme from platelets were inactivated upon preincubation with N-ethylmaleimide. Forskolin protected against this inactivation in a concentration-dependent manner and demonstrated Kd values of 6.3 and 7.6 PM for the brain and platelet adenylate cyclases, respectively. Protection against N-ethylmaleimide inactivation of the brain enzyme was also afforded by calmodulin, but not to the extent seen with forskolin. Forskolin also protected against thermal inactivation of the adenylate cyclases from brain, platelets, erythrocytes, and 549 lymphoma wild type and cycvariants. The adenylate cyclase of bovine sperm, which is insensitive to activation by forskolin, was not protected by forskolin against inactivation by either N-ethylmaleimide or heat. Half-maximal activation of the platelet adenylate cyclase was seen with 3 to 10 ~ C M forskolin, and the Kd for forskolin, determined from heat inactivation kinetics, was 9 to 11 PM. Activation of the platelet adenylate cyclase by forskolin was negatively cooperative (n = 0.59) with respect to forskolin. This activation occurred without change in Michaelis or dissociation constants for free M&’, but coincided with a &fold increase in the corresponding constants for MgATP and a 2-fold increase in the K , for MnATP. However, forskolin did not affect the K , app for MnATP of the solubilized adenylate cyclase from brain. These results imply binding of forskolin by adenylate cyclase. The data suggest that the same binding site for forskolin is involved in both protection and activation and that this binding site is distinct from those to which the substrates bind.

Mammalian spermatozoa contain a membranebound adenylate cyclase which is not sensitive to fluoride, guanine nucleotides, forskolin, or cholera toxin, and which exhibits a striking dependency on Mn’+ relative to Mg2+ for activity [1,2]. Available data suggest that the sperm enzyme lacks a functional guanine nucleotide regulatory component, but may be reconstituted from human erythrocytes [3]. The lack of responsiveness of the sperm adenylate cyclase and the possibility that regulation could be imparted to it, suggested to us that the sperm enzyme may be a useful test system for identifying other components of the adenylate cyclase and for characterizing the interactions of the enzyme’s various subunits. In studies with brain adenylate cyclase analogous to those reported with erythrocytes [3], we found unexpectedly large increases in cyclase activity when preparations from sperm and brain were combined. As we report here, rather than being due to a contribution of a component from brain to the sperm, the superadditive activity was found to be due to a factor in sperm which activated the brain adenylate cyclase. slaughterhouse. Sperms were removed by rinsing the epididymal ducts. After several washes in isotonic buffer, sperms were frozen in small aliquots in liquid nitrogen. Frozen sperm (-10’ cells/ml) were thawed with the addition of 1 or 2 volumes of 10 mM triethanolamine-HCl (pH 7.4) and were homogenized with a motor-driven glassTeflon homogenizer. The particulate material was then collected by centrifugation at 30000 x g for 10 min. The particles were resuspended in 10 mM triethanolamine-HCI (pH 7.4) and were then used for assay of adenylate cyclase. Detergent-dispersed adenylate cyclase from rat brain was prepared as in [4] with the modification that the initial centrifugation speeds were increased from 3000 to 17000 x g. The Lubrol-PX dispersed enzyme was chromatographed on DEAESephadex (A-25) as in [5], with the following modification. Proteins were first eluted with 600 mM NaCl containing 1 mM ethyleneglycol-bis-@aminoethyl ether)N,N’-tetraacetic acid (EGTA) (instead of only 300 mM NaCl). The column was then washed with 600 mM NaCl to wash out the EGTA. The enzyme was then eluted with a solution of 0.25% Lubrol-PX, containing neither salt nor EGTA.

Oral administration of niacin (nicotinic acid) at pharmacologic doses that reduce serum cholesterol levels induces intense flushing in humans. We have recently shown that the vasodilation following ingestion of niacin is due to the release of prostaglandin (PG) D2. However, the site from which PGD2 is released is not known. It has previously been shown that topical application of methylnicotinate causes local cutaneous erythema. Thus, we investigated whether topical methylnicotinate causes a release of PGD2 locally from skin and the possibility that skin may be a major contributor to the release of PGD2 when niacin is administered by mouth. Topical administration of methylnicotinate (10(-1) M) to the forearms of human volunteers resulted in 58- to 122-times increases in levels of PGD2 and 25- to 33-times increases in levels of the metabolite of PGD2, 9 alpha,11 beta-PGF2, in blood drawn from the antecubital vein draining the treated sites. Increased levels of PGD2 and 9 alpha,11 beta-PGF2 were not found in blood drawn simultaneously from veins in the contralateral arm, indicating that the PGD2 was released from the site of methylnicotinate application. The release of PGD2 in response to topically applied methylnicotinate occurred in a dose-dependent manner over the concentration range of 10(-3) to 10(-1) M. The release of PGD2 was not accompanied by a release of histamine, suggesting that the release of PGD2 was not from the mast cell. Following oral ingestion of niacin, levels of PGD2 in superficial venous blood draining the skin were 14 to 1200 times higher than the level in arterial blood supplying the skin of the same arm. This finding indicates that the skin is a major site from which PGD2 is released following oral ingestion of niacin. These studies thus indicate that the cutaneous vasodilation that occurs following oral administration of niacin is primarily due to a release of PGD2 from a niacin responsive cell that resides in the skin.