On the activities of parathyroid hormone-like factor and transforming growth factors in extract of pancreatic cancer associated with humoral hypercalcemia of malignancy

Extract of exocrine pancreatic cancer associated with humoral hypercalcemia of malignancy was examined for biological activities of PTH-like factor and transforming growth factor (TGFA and TGFB), both of which are possible causes of hypercalcemia. The crude extract had both PTH-like and TGF activities. On Bio Gel P-60 column chromatography, PTH-like and TGFA activities were eluted at around 10 kD, whereas TGFB activity was eluted at around void fractions, 10 kD and 6 kD. Liver extract, used as a control material, exhibited only TGFB activity at around 6 kD. CM-cellulose column chromatography of 10 kD fractions resulted in a subtle distinction between PTH-like activity and TGF activities. Further fractionation of the peak with PTH-like activity on reverse-phase high performance liquid chromatography separated PTH-like activity distinctly from TGFB activity. TGFA activity was lost through the procedure. It was concluded that the exocrine pancreatic cancer associated with hypercalcemia produced not only PTH-like activity but also TGFA and TGFB activities. Several chromatographic analyses suggested that PTH-like activity and at least TGFB activity stem from distinct molecules and that the PTH-like factor has no significant TGFB activity intrinsically.     

KCl inhibits hypothalamic activity to attenuate hypertension in DOCA-salt rats

Potassium supplementation attenuated the development of hypertension in DOCA-salt rats but did not affect blood pressure in control rats. However, it caused a decrease in body weight in both groups of rats. Sympathetic nerve and pressor responses either to electrical stimulation of the hypothalamus or to intracisternal injections of hypertonic NaCl were enhanced in DOCA-salt rats but were normalized by KCl supplementation. Since the pressor responses to injected norepinephrine or tyramine remained unaltered by KCl treatment, a peripheral inhibition of cardiovascular reactivity was considered unlikely. Pretreatment with methyclothiazide also attenuated the elevation in blood pressure but did not affect the responsiveness to hypothalamic stimulation; hence increased natriuresis or diuresis alone could not account for the effects induced by KCl. These findings are consistent with the conclusion that KCl supplementation attenuates the development of DOCA-salt hypertension in rats by acting on the central nervous system to reduce sympathetic output.     

A valid model for the mechanism of oxidation of tryptophan to formylkynurenine-25 years later

The dye-sensitized photooxygenation of DL-tryptophan in aqueous solution leads to the tricyclic compound 2-carboxy-3a-hydroperoxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole which, on reduction with dimethyl sulfide, furnishes two diastereoisomeric alcohols separable by fractional crystallization into a higher melting (mp 254°-256°) and a lower melting (mp 228°) diastereoisomer. Each of these alcohols was correlated with one of the analogous pair of isomeric 1,2-dicarbomethoxy analogs by alkaline hydrolysis and by x-ray analysis. In this way, the 3a-hydroxy-1,2-dimethoxycarbonyl- 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole, mp 163°-164°, was shown to have the trans configuration with regard to the relative positions of the hydroxyl and carbomethoxy groups and that, on alkaline hydrolysis, it produced the isomer with mp 228°, which therefore also has the trans configuration. The mechanism of the smooth thermal rearrangement of the (presumably ring-chain tautomeric) tryptophan hydroperoxy intermediates to formylkynurenine is discussed with its implications for the biological oxidation by tryptophan 2,3-dioxygenase.     

Centrally-induced vasopressor responses to carbachol are augmented in DOCA-salt hypertensive rats

Increased sympathetic nervous system activity and vasopressin release has been demonstrated in established DOCA-salt hypertension in the rat. To determine the importance of these mechanisms in centrally-mediated pressor responses in this model of hypertension, both awake rats and rats anaesthetised with urethane were given intracerebroventricular injections of carbachol. The systolic blood pressure after implanting a silicon rubber mould containing DOCA, and with subsequent substitution of 1% saline in tap water, increased from 112 +/- 3 mmHg to a stable 188 +/- 7 mmHg by the end of 4 weeks, measured using a tail-cuff method. The blood pressure consistently became elevated when carbachol was injected into the cerebral ventricles of awake rats. Of the three groups of normotensive rats (NTR), sham-operated rats (SHAM) and DOCA-salt hypertensive rats (DOCA), the magnitude of the pressor phase was largest in the DOCA rats. The heart rate in all three groups of rats decreased similarly. When the rats were later anaesthetised with urethane to allow recording of abdominal sympathetic nerve activity, the carbachol injections caused biphasic blood pressure responses and sympathetic nerve discharge consisting of initial vasodepression and sympathetic nerve inhibition of short duration. This was followed by a sustained pressor phase accompanied by a corresponding increase in sympathetic nerve activity. The magnitude of the pressor response was again larger in the DOCA than in the SHAM rats. Spinal section abolished the initial depressor phase but did not much affect the sustained pressor phase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rho-Associated Kinase Inhibitor Reduces Tumor Recurrence After Liver Transplantation in a Rat Hepatoma Model

Tumor recurrence after liver transplantation still remains a significant problem in patients with hepatocellular carcinoma. The small GTPase Rho/Rho-associated kinase (ROCK) pathway is involved in the motility and invasiveness of cancer cells. We investigated whether tacrolimus activated the Rho/ROCK signal pathway to promote the invasiveness of rat hepatocellular carcinoma cells. We also investigated whether the ROCK inhibitor Y-27632 suppressed tumor recurrence after experimental liver transplantation in a rat hepatocellular carcinoma model. Orthotopic liver transplantation was performed in hepatocellular carcinoma cell line McA-RH7777-bearing rats. Tacrolimus was administered to liver transplant rats and these rats were divided into two groups: the Y-27632-treated (10 mg/kg, for 28 days) group and the Y-27632-untreated group. Tacrolimus enhanced the cancer cell migration and stimulated phosphorylation of the myosin light chain (MLC), a downstream effector of Rho/ROCK signaling. Y-27632 suppressed the cancer cell migration and tacrolimus-induced MLC phosphorylation. Suppression of tumor recurrence after liver transplantation and significant prolongation of survival were observed in the Y-27632-treated rats in comparison with theY-27632-untreated rats. Tacrolimus stimulates the Rho/ROCK signal pathway to enhance the invasiveness of hepatocellular carcinoma, and the ROCK inhibitor Y-27632 can be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.     

The successful surgical management of perforation after endoscopic sphincterotomy: Report of two cases

Retroperitoneal performation following endoscopic sphincterotomy (EST) is an infrequent but serious complication with a high mortality rate in patients who do not receive prompt treatment. We report herein two cases of perforation, diagnosed 3 and 7 days after EST, one of whom was treated by choledochojejunostomy (Roux-en-Y) and suturing of the perforation site with jejunal patching, and the other by pancreatoduodenectomy. Both operations were successful as emergency treatments and therefore we consider that radical surgery should be attempted for cases of perforation after endoscopic sphincterotomy with a delayed diagnosis.     

Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection: a subgroup analysis of patients without chronic hepatitis viral infection

Background

Statins have been reported to reduce the risk of hepatocellular carcinoma (HCC). The effect of perioperative statin use on the prognosis of HCC patients undergoing liver resection remains unclear.