Assessment of future remnant liver regeneration after portal vein embolization using three‐dimensional CT and MR volumetric analyses

The purpose of this study is to portray right portal vein embolization (PVE) as a valuable technique that helps in expanding the volume of the left liver lobe and discuss the relevant published work. We describe our experience with four patients who underwent PVE and analyse the value of CT and MRI in the preoperative evaluation of these patients. Four patients with hepatic malignancy (hepatocellular carcinoma) (n = 2) and metastatic liver disease (n = 2) underwent portal vein occlusion. PVE was carried out in three patients using polyvinyl alcohol and stainless steel coils. Portal vein ligation was carried out in the fourth patient. In patients who were candidates for right hepatectomy, CT volumetric analysis was carried out before the surgery to assess the total liver volume and the future remnant liver, which is the residual left hepatic volume (in cases of right hepatectomy) or left lateral segment volume (in cases of right tri‐segmentectomy). Because the left lobe volumes were insufficient, patients were selected to undergo right PVE. Computed tomography volumetry was carried out 2–4 weeks after embolization to assess left hepatic lobe regeneration. Magnetic resonance volumetric analysis was carried out in two patients before and after embolization. All four patients had significant regeneration of the left lobe and tolerated the surgery with uneventful postoperative recovery.     

Morphine-induced cardiovascular stimulation: the effects of two doses on healthy subjects

In humans, morphine induces hypotension, probably because of histamine liberation. Earlier animal studies have, however, suggested that morphine can induce immediate cardiovascular stimulation when given as a sole medication. The aim of this study was to evaluate the initial effects of morphine on circulation, oxygen consumption, and plasma histamine and catecholamine concentrations. Oxycodone was used as a reference drug. Eight healthy volunteers received, in a random, cross-over, double-blinded fashion: 0.07 mg/kg morphine (M1); 0.14 mg/kg morphine (M2); 0.14 mg/kg oxycodone (O); and placebo (P) as a 2-min IV injection for pain. Mean arterial blood pressure (MAP), heart rate (HR), and oxygen consumption (VO(2)) were recorded. Plasma histamine and catecholamine concentrations were determined. Both M1 and M2 elicited an initial, but transient, increase in MAP from 84 +/- 5 to 96 +/- 9 mm Hg (P < 0.05) and from 83 +/- 8 to 100 +/- 10 mm Hg (P < 0.05), respectively. A parallel increase in HR was also seen after M1 (from 62 +/- 12 to 70 +/- 10 bpm, P < 0.05) and M2 (from 67 +/- 9 to 78 +/- 8 bpm, P < 0.05). After M2, this was accompanied by a simultaneous increase in VO(2) from 295 +/- 39 mL/min to 322 +/- 61 mL/min (P < 0.05). After O, as well as P, no increase in MAP or HR was detected. Plasma histamine and catecholamine concentrations were not clearly affected by any of the treatments. We conclude that the immediate effect of morphine on the hemodynamics of healthy volunteers was stimulation, not hypotension. This effect was not seen in conjunction with oxycodone, a morphine-like mu-receptor agonist. IMPLICATIONS: In this double-blinded, randomized study, we evaluated whether morphine could induce immediate cardiovascular stimulation, as seen previously in animal studies. In healthy volunteers, during a painful stimulus, morphine caused an initial, transient hemodynamic stimulation, accompanied by increased oxygen consumption, without detectable release of histamine or catecholamines into the plasma. Oxycodone caused only minor hemodynamic alterations.     

Delayed ontogenesis of histamine in the hypothalamus of the homozygous Brattleboro rat

The ontogenetic development of histamine was studied in the diabetes insipidus rat to clarify the possible interference between the lack of vasopressin and the development of histaminergic systems in the hypothalamus. Rat pups were decapitated at different ages between the 2nd and 38th postnatal days. In addition to homozygous Brattleboro (diabetes insipidus) rats, Long Evans controls and heterozygous animals were studied. In all three genotypes hypothalamic histamine was almost equal during the first 6 postnatal days. In homozygous Brattleboro rats the period of most rapid increase occurred between days 14 to 26, which was significantly later than in Long Evans rats. In the remainder of the brain no such difference was seen. On the contrary, histamine values were highest in the youngest animals. It remains to be elucidated whether the delayed ontogenesis is causally related to vasopressin deficiency and what is the underlying mechanism.     

Effect of repeated L-histidine administration on plasma prolactin and growth hormone levels in rats

OBJECTIVE AND DESIGN: To explore the mechanisms by which liver-infiltrating T lymphocytes cause hepatocyte damage in the liver injury induced by delayed-type hypersensitivity to picryl chloride. MATERIALS AND METHODS: Nonparenchymal cells (NPC) were isolated 12 h after liver injury elicitation and fractionated into Kupffer cell-enriched (Fr. A) and lymphocyte-enriched populations (Fr. B). They were used as the effectors for coculture with hepatocytes. RESULTS: The cells in total NPC and Fr. B harvested at 12 h of liver injury were increased two- and six-fold respectively compared with those at 0 h. Fr. B, mainly including CD4+ and CD8+ T cells, exhibited a significantly stronger hepatotoxicity than total NPC did, while Fr.A did not. NPC at 12 h showed remarkably increased matrix metalloproteinase-2 and -9 activities indicative of infiltration potential through extracellular matrix. When NPC and hepatocytes were cultured in separated compartments in Transwell chamber, no hepatotoxicity was observed. However, 30 min-pre-contact with hepatocytes as stimulator significantly triggered NPC hepatotoxicity. The acquisition of such hepatotoxic potential was significantly abolished by anti-LFA-1 pretreatment for NPC or anti-ICAM-1 treatment for hepatocytes before contact. Both aprotonin and superoxide dismutase dose-dependently inhibited the hepatotoxicity. CONCLUSIONS: Liver-infiltrating T lymphocytes may be triggered by hepatocytes via LFA-1/ICAM-1 interaction to release toxic substances, such as proteases and oxygen radicals, which consequently lead to the hepatocyte damage.     

Effects of nimodipine,Bay K 8644 and pinacidil on α1- and α2-adrenoceptor-mediated vasoconstriction in human hand veins

The effects of nimodipine, Bay K 8644 and pinacidil, three drugs interfering with transmembrane Ca²⁺ fluxes in different ways, were investigated in isolated human hand veins. Their ability to influence the concentration-response relationship for noradrenaline (NA) was assessed in the absence and presence of prazosin or rauwolscine. The contractile response to NA was almost abolished in Ca²⁺-free medium. Nimodipine and pinacidil depressed the NA concentration-response curve both in the absence and presence of α-adrenoceptor blockers. The NA response was only partially inhibited by nimodipine, indicating that NA may activate nimodipine-insensitive influx pathways, presumably receptor-operated calcium channels. Pinacidil inhibited the contractile response to 124 mM K⁺ and reduced the NA-induced contraction in the presence of nimodipine, suggesting that pinacidil has actions other than the opening of potassium channels and subsequent membrane hyperpolarization. Bay K 8644 increased the NA potency fourfold in the presence of rauwolscine, whereas it had no effect on the NA response in the presence of prazosin and in the absence of α-adrenoceptor blockade. Such an action of Bay K 8644 can be reconciled with α-adrenoceptor activation causing membrane depolarization and opening of potential-operated calcium channels. It may be concluded that both α₁- and α₂-adrenoceptor-mediated contractions in human hand veins are highly dependent on Ca²⁺ influx, although the mechanisms utilized to bring about this influx partly differ between the two receptor subtypes.     

Increased neuronal histamine in thiamine-deficient rats

Previous studies have indicated that thiamine deficiency is associated with clearly elevated histamine concentrations in the rat hypothalamus, whereas other brain regions contain normal amounts of the amine. The purpose of this study was to find out if the increased hypothalamic histamine concentrations are due to increased numbers of mast cells or changes in neuronal histamine stores.Thiamine-deficiency was induced by daily injections of pyrithiamine until the animals lost the righting reflex. Control animals were pair-fed with either thiamine-deficient or normal thiamine-supplemented food. A significant increase in histamine concentration was observed in the hypothalamus and pons-medulla of the pyrithiamine-treated rats, but not in the cerebellum, thalamus, cerebral cortex or pituitary gland. Immunohistochemically, no histamine-containing mast cells were found in the hypothalami of the pyrithiamine-treated rats or control animals. The histaminergic tuberomammillary neurons were very intensely immunofluorescent, and the density of histamine-immunoreactive nerve fibers in the hypothalamus was also increased in the pyrithiamine-treated animals.     

Vasopressin levels in the cerebrospinal fluid of rats with lesions of the paraventricular and suprachiasmatic nuclei

The circadian rhythm and dehydration-induced response of vasopressin (AVP) levels in rat cerebrospinal fluid (CSF) were studied after lesions had been made in the paraventricular (PVN) and suprachiasmatic (SCN) nuclei. The rhythmic fluctuation of AVP levels in CSF was abolished after SCN lesions, whereas lesions of the PVN had no effect. Dehydration seems to increase AVP levels in CSF of both sham-operated and lesioned animals. These data further suggest that the circadian rhythm of AVP in CSF is preferentially generated by SCN. In contrast, several areas of the brain may contribute to the overall AVP levels in CSF, both under normal physiological conditions and under osmotic stress.     

The endothelium mediates a nitric oxide-independent hyperpolarization and relaxation in the rat hepatic artery

The rat hepatic artery responds to acetylcholine (ACh) with an endothelium-dependent relaxation, which is unaffected by nitric oxide (NO) synthase and cyclooxygenase inhibition. The purpose of this study was to investigate whether the NO-independent relaxation is caused by hyperpolarization of the smooth muscle cells. In vessels with endothelium ACh induced a hyperpolarization in the presence of 0.3 mM Nw-nitro-l -arginine (l -NOARG) and 10μm indomethacin. The hyperpolarization, which slowly decayed after an initial maximum, generally lasted for at least 20 min. ACh in contrast to levcromakalim failed to hyperpolarize the smooth muscle cells in endothelium-denuded vessels. In vessels contracted by phenylephrine (PhE) ACh caused a concentration-dependent hyperpolarization and relaxation, and both events occurred over the same concentration interval. Curve fitting using the Hill equation showed a close correlation between the hyperpolarization and the relaxation. Exposure to a 30 mM K⁺ solution abolished the hyperpolarization and suppressed the relaxation induced by ACh. Nimodipine did not affect the ACh-induced hyperpolarization, whereas the relaxation induced by ACh and levcromakalim, but not that evoked by the NO donor 3-morpholino-sydnonimin, were attenuated. Glibenclamide had no effect on the ACh-induced hyperpolarization and relaxation, but abolished the corresponding responses to levcromakalim. The results demonstrate a NO-independent hyperpolarization and relaxation in the rat hepatic artery. The hyperpolarization and relaxation were endothelium-dependent, and apparently causally related to each other, since interference with the hyperpolarization or the subsequent effector pathway inhibited the relaxation.     

Regional differences in endothelium-dependent relaxation in the rat: contribution of nitric oxide and nitric oxide-independent mechanisms

Relaxant effects of acetylcholine (ACh), histamine, calcitonin gene-related peptide (CGRP) and the calcium ionophore A23187 were examined in rat femoral (Ø ? 0.2 mm), mesenteric (0.2 mm), intrarenal (0.2 mm) and hepatic (0.3 mm) arteries, and aorta (2 mm). Acetylcholine elicited an endothelium-dependent relaxation in all arteries. Histamine induced an endothelium-dependent relaxation in aorta, and mesenteric and intrarenal arteries, whereas a partly endothelium-dependent and mainly endothelium-independent relaxation was observed in hepatic and femoral arteries, respectively. In hepatic, mesenteric and intrarenal arteries, CGRP induced an endothelium-independent relaxation, whereas either small or no relaxation was obtained in aorta and femoral arteries respectively. A23187 induced an endothelium-dependent relaxation in the aorta and hepatic artery, whereas A23187 had no relaxant effect in femoral, mesenteric and intrarenal arteries. Nω-nitro-l -arginine (l -NOARG, 0.3 mM) reduced the maximum ACh-induced relaxation (in the presence of 10 μM indomethacin) by 66% in the aorta, and abolished the relaxation in femoral and intrarenal arteries. A marked l -NOARG/indomethacin-resistant relaxation was obtained in mesenteric and hepatic arteries. Levcromakalim induced a concentration-dependent and almost complete relaxation in all arteries. When contracted by a 60 mM K⁺ solution, all arteries responded to ACh with a relaxation that was abolished by l -NOARG. These results demonstrate marked regional differences with regard to the vascular effects of ACh, histamine, CGRP and A23187. Whereas nitric oxide appears to mediate endothelium- dependent relaxation regardless of the vascular region, an l -NOARG/indomethacin-resistant relaxation, presumably mediated by an endothelium-derived hyperpolarizing factor, was observed only in mesenteric and hepatic arteries, and aorta.     

The survival motor neuron protein in spinal muscular atrophy

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non- SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.