Liver-Regenerative Transplantation: Regrow and Reset.

Liver transplantation, either a partial liver from a living or deceased donor or a whole liver from a deceased donor, is the only curative therapy for severe end-stage liver disease. Only one-third of those on the liver transplant waiting list will be transplanted, and the demand for livers is projected to increase 23% in the next 20 years. Consequently, organ availability is an absolute constraint on the number of liver transplants that can be performed. Regenerative therapies aim to enhance liver tissue repair and regeneration by any means available (cell repopulation, tissue engineering, biomaterials, proteins, small molecules, and genes). Recent experimental work suggests that liver repopulation and engineered liver tissue are best suited to the task if an unlimited availability of functional induced pluripotent stem (iPS)-derived liver cells can be achieved. The derivation of iPS cells by reprogramming cell fate has opened up new lines of investigation, for instance, the generation of iPS-derived xenogeneic organs or the possibility of simply inducing the liver to reprogram its own hepatocyte function after injury. We reviewed current knowledge about liver repopulation, generation of engineered livers and reprogramming of liver function. We also discussed the numerous barriers that have to be overcome for clinical implementation.

Coexistent End-stage Nonalcoholic Steatohepatitis and Colon Cancer: Should We Do Liver Transplantation?

BACKGROUND: Colon cancer accompanying decompensated liver cirrhosis is a rare clinical condition. Usually, treatment of colon cancer is prioritized, with cirrhosis dealt with later. CASE REPORT: We present a case of end-stage liver disease due to nonalcoholic steatohepatitis evaluated for living donor liver transplant. During the pretransplant examination, an ascending colon cancer was detected. Liver function was too poor to perform colon resection first. Simultaneous living donor liver transplant and colonic resection were carried out. The patient developed left lung metastasis at 2 different times during the first postoperative year, and both of them were resected. The patient received the standard chemoradiotherapy. Now, the patient is alive at 42 months postprocedure and recurrence-free at 31 months postoperatively. CONCLUSION: Simultaneous liver transplantation and colon resection are possible with acceptable long-term outcomes. Immunosuppressive therapy after transplantation increases the risk for cancer recurrence. So the patient should undergo close surveillance.

Troglitazone prevents and reverses dyslipidemia, insulin secretory defects, and histologic abnormalities in a rat model of naturally occurring obese diabetes.

Troglitazone has been shown to improve insulin sensitivity and thereby exert hypoglycemic effects in various animal models and humans with insulin resistance and diabetes. The recently established animal model of naturally occurring obese diabetes, the Otsuka Long-Evans Tokushima fatty (OLETF) rat, has many similarities with human type 2 diabetes mellitus and is characterized by a high degree of insulin resistance. In the present study, we examined the effect of pharmacologic intervention with troglitazone on metabolic and histopathologic changes in OLETF rats. Two groups of rats received a troglitazone-rich diet (200 mg/100 g normal chow) from age 12 weeks (ie, before the onset of diabetes) or 28 weeks (ie, after the onset of diabetes) to age 70 weeks, while a third group received standard rat chow. The addition of troglitazone to the diet did not alter food intake or body weight gain. Troglitazone had no influence on visceral adipose depots, but it significantly reduced fasting glucose, insulin, cholesterol, triglyceride (TG), and free fatty acid (FFA) levels. Troglitazone reduced the insulin resistance and maintained the postglycemic insulin response at a normal level, and thus inhibited the development of insulin insensitivity and frank diabetes in OLETF rats up to 70 weeks of age. The pancreatic wet weight and insulin content were significantly higher in the treated rat groups versus the control rats. The morphologic changes observed in the control rats, such as fibrosis and structural disarrangement of islets, were minimal in the troglitazone-treated rats. Our study demonstrates that troglitazone, albeit at a dosage 10 to 15 times higher than that in humans, not only prevents but also reverses the metabolic derangement and histopathologic changes in genetically determined obese diabetes.

Metabolic abnormalities in the genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty rat can be prevented and reversed by alpha-glucosidase inhibitor.

The recently developed Otsuka Long-Evans Tokushima Fatty (OLETF) rat is known to develop insulinopenic diabetes after a prolonged period in a condition resembling non-insulin-dependent diabetes mellitus (NIDDM). We examined the effect of pharmacological intervention with a potent intestinal alpha-glucosidase inhibitor, acarbose, on the metabolic and histopathologic changes in this rat model. The first two groups of rats received an acarbose-rich diet (150 mg/100 g normal chow) from 12 weeks of age (ie, before the onset of diabetes) or from 28 weeks of age (ie, after the onset of diabetes), while a third group received the acarbose-rich diet for the initial 16 weeks only (from 12 to 28 weeks of age). A control group received standard rat chow. Acarbose-fed rats gained less weight or lost weight despite increased food intake when switched to the acarbose-rich diet. Acarbose also reduced visceral adipose depots and fasting triglyceride (TG), glucose, and insulin levels. At the end of the study at 72 weeks, the pancreatic wet weight and insulin content were significantly higher in the treated groups versus control rats. The morphological changes observed in control rats, such as atrophy of the pancreas and reduced number and size of islets, were not present in acarbose-treated rats. Rats fed acarbose from 12 to 28 weeks of age gradually gained weight after switching to standard chow, and hyperinsulinemia, hyperglycemia, and hyperlipidemia appeared (in that order). The pancreatic insulin content in these rats was significantly higher and the visceral adipose depot was significantly smaller than in control rats. Our study demonstrates that acarbose prevented and reversed the metabolic derangement and histopathological changes in genetically diabetic rats. Moreover, treatment with acarbose even for a short period produced a marked delay in the development of insulin insensitivity and frank diabetes.

Chronic oral administration of protease inhibitor decreases CCK-A receptor mRNA expression but increases pancreatic growth in rats.

It is well-known that chronic oral administration of trypsin inhibitors induces pancreatic hypertrophy and hyperplasia via stimulation of endogenous cholecystokinin (CCK) release. Because the growth-promoting effect of CCK on the pancreas is specifically mediated by the CCK-A receptor, we examined the plasma CCK concentrations, the expression of CCK mRNA in the intestine and CCK-A receptor mRNA in the pancreas, and pancreatic growth in rats after chronic oral administration of synthetic protease inhibitor (PI). PI at a dose of 100 mg/kg body weight was administered via an orogastric tube once daily for 20 days. Plasma CCK concentrations at 24 hours after the first PI administration were significantly higher than those in randomly fed rats (6.57 +/- 0.67 pmol/L vs 4.31 +/- 0.51 pmol/L; p < 0.001), and further increased to 14.24 +/- 1.63 pmol/L after PI for 10 days and decreased to 10.05 +/- 0.72 pmol/L after 15 days of PI administration. Treatment with PI for 20 days significantly increased the pancreatic weight, and the total pancreatic protein and DNA content by 190%, 290%, and 170%, respectively, when compared to the control rats. Chronic oral administration of PI, however, reduced CCK-A receptor mRNA expression in the pancreas by 60%. These findings suggest that chronic oral administration of PI induces an elevation of endogenous CCK release and stimulates pancreatic growth, but down-regulates the biosynthesis of CCK-A receptor at the transcriptional level in the pancreas.

Effects of pentazocine and other opioids on the potassium-evoked release of [3H]noradrenaline from guinea pig cortical slices.

Noradrenaline release and its modulation via presynaptic opioid receptors were examined in guinea pig cortical slices. Slices preloaded with [3H]noradrenaline were superfused in the presence of desipramine (1 microM) and were stimulated by 16 mM K+. 1-Pentazocine inhibited the K+-evoked release of [3H]noradrenaline in a dose-dependent manner (3 x 10(-7)-10(-5) M), while d-pentazocine did not inhibit. This inhibitory effect of 1-pentazocine was antagonized by Mr 2266 (10(-6) M) but not by naloxone (10(-6) M). Among other opioids, dynorphin A-(1-13) and ethylketocyclazocine (kappa agonists) decreased the K+-evoked release of [3H]noradrenaline. Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO, mu agonist) also inhibited [3H]noradrenaline release but was less potent than the kappa agonists. [D-Pen2,D-Pen5]enkephalin (DPDPE, delta agonist) and phencyclidine (sigma agonist) had no effects on the stimulated release of [3H]noradrenaline. Thus, it was shown that kappa receptors are the major subtype of opioid receptor involved in modulation of noradrenaline release in guinea pig cortex, and that 1-pentazocine inhibits the K+-evoked release of noradrenaline through activation of these receptors.

Defects of cholecystokinin (CCK)-A receptor gene expression and CCK-A receptor-mediated biological functions in Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

Recent studies in genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats suggest defects of cholecystokinin (CCK)-A receptor gene expression and CCK-A receptor-mediated biological functions such as pancreatic juice, protein, and gastric acid secretion. The present studies were undertaken to further examine CCK-A receptor gene expression and CCK-A receptor-mediated biological functions in the pancreas, stomach, and brain of OLETF rats. Expression of the CCK-A receptor gene could not be detected in the stomach, pancreas and brain by the reverse-transcription polymerase chain reaction (RT-PCR) method and Southern blotting of the PCR products. Southern blot analysis of genomic DNA from OLETF and control Long-Evans Tokushima Otsuka (LETO) rats with CCK-A receptor fragment as a probe revealed different restriction bands. Expression of the CCK-B receptor gene was observed in the stomach, pancreas, and brain in both OLETF and LETO rats by the RT-PCR method, with expression of the CCK-B receptor gene markedly enhanced in OLETF rats compared with that in LETO rats. Consistent with the defect of CCK-A receptor gene expression, CCK-A receptor-mediated biological functions were not observed in these organs. Perfused exocrine and endocrine pancreas of OLETF rats were insensitive to CCK stimulation but not to carbamylcholine stimulation. Basal gastric acid and pepsinogen secretions in OLETF rats were higher than in LETO rats. OLETF rats showed a significantly higher average daily food intake, gained body weight faster, and were heavier than LETO rats. The present study confirmed that OLETF rats have CCK-A receptor gene anomalies and demonstrated deficient CCK-A receptor-mediated biological function in the pancreas, stomach, and brain.

Stereospecific effects of d- and l-pentazocine on contractions of the mouse vas deferens.

The effects of the d- and l-isomers of pentazocine were compared to that of racemic pentazocine on contractions of the mouse isolated vas deferens. L-pentazocine inhibited electrically evoked contractions of the mouse vas deferens (MVD) in a dose-dependent manner (ID50 0.37 +/- 0.04 microM). In contrast, d-pentazocine augmented field stimulated contractions dose-dependently; per cent increases in contractions at 10 and 30 microM were 57.8 +/- 18.0 and 98.0 +/- 15.1%, respectively. Racemic pentazocine produced an intermediate effect between the two isomers. The effect of 1-pentazocine was antagonized by naloxone, whereas that of d-pentazocine was not. L-pentazocine did not effect the response of the MVD to exogenous norepinephrine at any concentration tested, while d-pentazocine depressed the response of the MVD to exogenous norepinephrine at one dose (0.3 microM). These findings demonstrate that d- and l-pentazocine produce opposite effects on the MVD. The effects of l-pentazocine are opioid mediated, while those of d-pentazocine are not. In the racemic mixture the opposing effects of the two isomers modulate each other, resulting in a diminished effect.

Pentazocine-induced catecholamine efflux from the dog perfused adrenals.

This study has been undertaken to determine whether pentazocine induces catecholamine efflux from the adrenal medulla as a mechanism for its sympathomimetic effect. Dog isolated adrenals were perfused retrogradely with modified Locke's solution. The efflux of catecholamines from dog perfused adrenals was increased from the resting output of 0.18 +/- 0.04 micrograms min-1 (mean +/- s.e.), to 0.47 +/- 0.13 micrograms min-1 by the administration of pentazocine (50 microM). The pentazocine-induced catecholamine efflux was dose-dependent in the 50-400 microM dose range. This effect of pentazocine was not inhibited by either a combination of atropine and (+)-tubocurarine, or verapamil, in contrast to acetylcholine-induced catecholamine release. There was no significant difference in potency among stereoisomers, i.e. (+)-, (-)- and (+/-)-pentazocine, in inducing catecholamine efflux. Naloxone did not influence the effects of either (+)- or (-)-pentazocine. The interaction of pentazocine with acetylcholine-induced catecholamine release was also examined. Both (+)- and (-)-pentazocine inhibited acetylcholine-induced catecholamine release dose-dependently, and these inhibitory effects were not reversed by naloxone. Acetylcholine-induced catecholamine release was accompanied by increased dopamine-beta-hydroxylase release, whereas pentazocine-induced catecholamine efflux was not. These results suggest that pentazocine directly acts on the adrenal medulla to induce catecholamine efflux via a non-exocytotic mechanism, and that opioid receptors do not play a role in this action.

Effect of local anaesthetics on the stimulus-secretion coupling in bovine adrenal chromaffin cells.

This study was carried out to determine the relative potencies of local anesthetics to inhibit the cholinergic synaptic transmission using cultured bovine adrenal chromaffin cells, and to clarify if the inhibitory action would correlate with biophysical and pharmacological properties. Local anaesthetics (bupivacaine, etidocaine, tetracaine, lignocaine and procaine; 0.02-2 mM) inhibited carbachol-induced catecholamine release from the cells in a concentration-dependent manner. This inhibition was completely reversible. IC50 (concentration of 50% inhibition) of each anaesthetic showed no correlation with the lipid solubility. The local anaesthetics showed greater inhibitory potency at a higher extracellular pH. The results suggest that clinically relevant concentrations of local anaesthetics inhibit the stimulus-secretion coupling in the chromaffin cells. The un-ionized based form plays a major role, and the inhibitory potency does not depend on the lipid solubility of the anaesthetics.

A case of chromomycosis with tumor-like growth.

A 66-year-old woman who lived on Tokunoshima Island, a small and remote southern island of the Japanese archipelago, had suffered from chromomycosis for more than 30 years and presented with a tumor-like growth on the posterior crural region of his right leg. Fonsecaea pedrosoi was identified as the pathogen from its growth pattern and micromorphological characteristics. The patient was successfully treated with 5-fluorocytosine, itoraconazole, and topical thermotherapy.

[Anesthetic management involving difficult intubation in a child with Gaucher disease].

Gaucher disease is the most common of the glycolipid storage disorders caused by the deficiency of glucocerebrosidase, an enzyme which hydrolyzes glucocerebroside to glucose and ceramide. Accumulation of the substrate leads to multiorgan dysfunction involving the brain, spleen, liver, lymph node and bone marrow. In anesthetic management, gastroesophageal reflux leading to recurrent aspiration, pancytopenia and airway difficulties due to trismus, neck extension and upper airway infiltration with glucocerebroside must be considered. We report a case of a 9-year-old boy presenting developmental delay, mild pancytopenia, splenomegary gastroesophageal reflux. He was scheduled for measurement of intra-esophageal pressure, total splenectomy and Nissen fundoplication. Preoperative examination showed trismus and opisthotonic posturing. We predicted difficult airway maintenance and assessed his airway with airway radiograph. Airway narrowing was not shown. For this difficult airway, we made a special mask that has an introducer port for fiberbronchoscope. For the first time, we tried to insert a laryngeal mask, but the insertion was difficult due to trismus and narrowed oral cavity. Then, we used this special mask for the next time. Tracheal intubation was much safer by using this mask for fiberoptic intubation. In Gaucher disease, preoperative assessment of airway difficulties and preparation for this situation are necessary and anesthesiologist must be concerned about aspiration and airway difficulties.

[Anesthetic management for newborn pharyngeal teratoma].

Epignathus (pharyngeal teratoma) is a rare disease of newborns associated with a high mortality secondary to airway obstruction in the neonatal period. We report anesthetic management of a newborn with epignathus who underwent tumor resection. He was delivered vaginally at 39 weeks of gestation and Apgar scores were 9 at 1 and 5 min. The tumor originated from the palate, almost filled the oral cavity and protruded through the mouth with its external part 6 x 7 cm in size. He could breathe with the head and mass turned to the left. The excision of the tumor was scheduled on the fifth day of life. Mask ventilation and laryngoscopy were considered impossible. Fiberoptic nasal intubation was successfully performed with topical anesthesia without sedation. Tumor was resected with blood loss of 103 gm. The trachea was extubated on the third postoperative day and the postoperative course was uneventful. For safe management of cases of pharyngeal teratoma, careful preoperative assessment of the airway is most important and sufficient preparation and careful intubation are mandatory to keep airway patent. The perioperative bleeding from the tumor and the airway obstruction by the tumor or its remnant after the excision could also be hazardous to the airway.

[A new bite block also serving as an endotracheal tube holder for infants].

We developed a new type of bite block with a combined function as an endotracheal tube (ETT) holder for infants and small children to prevent airway troubles caused by tube kinking, dislodging, extubation and oral membrane trauma. One mm thick plastic plate sized 3.5 x 2 cm was curved to make an open roll. The outer surface of the roll was covered and glued with soft plastic tube (5.0 mm ID endotracheal tube), cut in 3.5 cm length to give an elastic outer surface for the patient's comfort. The rolled ends were diagonally cut to make an oblique slit of 3 mm width. A t-shaped flange made of soft vinyl plate was fixed at a third of the length of the roll to maintain the block's position relative to the lips and to make the fixation of the tube easier. In practical use, after endotracheal intubation is performed as usual, this bite block is put into the mouth and positioned at the oral angle with the flange on the patient's skin. The ETT is fit into the slit of the roll. The skin-facing surface of the flange is pasted to the skin with the double stick material usually used for colostomy stoma. The ETT and the bite block are fixed en bloc with fixing tapes around the mouth. Our bite block has following advantages over other types of bite blocks and tube holders especially for children; 1) the volume of foreign bodies (ETT and bite block) occupying the oral cavity can be reduced and this attenuates the patient's discomfort, 2) good holding of the ETT can prevent its dislodging and decrease the incidence of accidental extubation and 3) suctioning is easier because of wide oral space. The four sizes of the bite block suitable for 4.0, 4.5, 5.0, 5.5 and 6.0 mm ID ETTs are manufactured. We applied this device to several ICU patients and found its use practical and safe.

[Congenital ventricular diverticulum in a neonate: anesthetic considerations].

Congenital diverticulum of the ventricle is a rare cardiac malformation and the reports of its surgical repair are scarce. We experienced anesthesia for a neonate with an isolated congenital left ventricular diverticulum diagnosed in utero. A male infant presented with ventricular arrhythmias and congestive heart failure. At 9 days of life the resection of the diverticulum was performed under moderately hypothermic cardio-pulmonary bypass (CPB) Major anesthetic considerations include the possible life-threatening arrhythmias, cardiac failure due to diverticulum and cardiac dysfunction after resection. Premature ventricular contractions were noted before CPB but greatly decreased under anesthesia. The operation was performed safely and arrhythmias disappeared completely after resection. Intra- and post-operative course was uneventful without any sign of cardiac dysfunction.

[Anesthesia and perioperative management in infants with Chiari type II malformation].

From July 1991 to June 1997. 15 neonates with Chiari type II malformation were treated at our institution. Four of them required posterior fossa decompression and cervical laminectomy for hindbrain decompression. We report anesthesia and postoperative management in these four patients. They had a fetal diagnosis of hydrocephalus and was delivered by caesarean section. They underwent Ommaya reservoir placement for drainage and repair of myelomeningocele in the neonatal period. They developed respiratory depression as apneic spells or retraction with or without swallowing difficulties and underwent posterior fossa decompression and cervical laminectomy at 20-87 days of life. One patient died of asthma at the age of 2 years and 8 days and others are doing well. Patients with this malformation may develop respiratory depression such as apneic spells and vocal cord paralysis even if the intracranial pressure is well controlled and they should be monitored carefully for the signs of apnea and the compromised airway.

[Recovery characteristics of propofol anesthesia in pediatric outpatients; comparison with sevoflurane anesthesia].

We compared recovery characteristics of propofol anesthesia with those of sevoflurane anesthesia in pediatric outpatients. One hundred and four children, 3 months to 6 years of age, ASA physical status 1 or 2, were randomly assigned to following four groups; sevoflurane (group S), propofol (group P), sevoflurane with premedication (group MS), or propofol with premedication (group MP). Midazolam 0.5 mg.kg-1 and famotidine 1 mg.kg-1 were administered orally 30 min before the induction in the MS and MP group. Recovery from anesthesia, agitation, and postoperative pain were evaluated. The time intervals from the end of surgery to extubation and to discharge from the hospital were recorded. The incidence of vomiting and use of analgesic drugs were also checked. The emergence from anesthesia was slower with propofol anesthesia than with sevoflurane anesthesia, but the time to discharge from the hospital was not significantly different among the four groups. Incidence of agitation was higher in S group compared with P group, but there were no differences between MS and MP. Postoperative pain was similar among the four groups. There were no differences in the incidence of vomiting. Propofol anesthesia provided slower emergence and less agitation compared with sevoflurane anesthesia.

[Anesthetic management for the correction of pectus excavatum using pectus bar under video-assistance].

We report anesthetic management for a child undergoing Nuss operation, a minimally invasive operation which requires neither cartilage incision nor its resection for correction of pectus excavatum. The patient was a 7-year-old boy with the funnel index 5 and the mediastinal shift to the left. General anesthesia with endotracheal intubation was induced and maintained with nitrous oxide, sevoflurane and fentanyl. Thoracic epidural anesthesia was used with 0.125% bupivacaine to supplement analgesia. When the curved bar was passed under the sternum with the aid of an endoscope, sinus tachycardia occurred and continued for 5 minutes but subsided without medication. Otherwise operative course was uneventful with negligible blood loss. After surgery, the patient was kept at bed rest for 2 days, receiving epidural patient-controlled analgesia combined with sedation with midazolam with good results. He was allowed to sit 3 days, to walk 5 days and discharged 10 days postoperatively.

[Perioperative management of a child with congenital nephrogenic diabetes insipidus].

The key point in perioperative management of a patient with congenital nephrogenic diabetes insipidus is fluid and electrolytes management. Since the urine of these patients consists mainly of solute free water, replacement fluids should be fluids which provide free water. A 2-year-old girl with congenital nephrogenic diabetes insipidus was scheduled for dental extraction. Her daily fluid intake was 10 liter. She had a history of recurrent fever, polyuria and polydipsia since 2 months of age. Her previous perioperative course for gastric volvulus at another hospital was complicated with postoperative hyponatremia and convulsion. A venous line was secured the day before surgery and 5% dextrose in water was infused at a rate of 12 ml.kg-1.hr-1. Intraoperative infusion was mainly with 5% dextrose in water combined with maintenance fluid. Five hours after surgery oral intake was started. Her intraoperative electrolytes levels were low (Na 133 mEq.l-1, K 2.8 mEq.l-1), but otherwise her perioperative course was uneventful.

[Cesarean section in a pregnant patient with placenta percreta involving the urinary bladder].

Placenta percreta involving adjacent structures is serious complication of pregnancy with a high mortality rate. A 32-year-old woman, gravida 4, para 3, who had previously undergone a cesarean section, was admitted to our hospital at 31 weeks' gestation for placenta previa. At 33 weeks' gestation, the diagnosis of placenta percreta with involvement of the urinary bladder was made by ultrasonography and magnetic resonance imaging. At 34 weeks' gestation, an elective cesarean section was scheduled. Anesthesia was maintained with sevoflurane in oxygen before delivery, and with nitrous oxide in oxygen, fentanyl and midazolam after delivery. During the operation, attempts to remove the placenta resulted in massive hemorrhage. Blood loss for the procedure was 13,800 g. Because of the extreme hemorrhage, we encountered hemorrhagic shock and postoperative complications despite the preoperative preparation. In case of placenta percreta, it is essential to prepare adequate volume of blood for transfusion at the start of surgery and secure large bore intravenous lines. A rapid transfusion device may be recommended. Regarding the anesthetic management, general anesthesia is preferable in consideration of the risk of hemorrhagic shock and the length of operation time. Furthermore, we need team approach and preoperative management to prevent the uncontrolled hemorrhage in such a severe case.