Preoperative airway evaluation using multi-slice three-dimensional computed tomography for a patient with severe tracheal stenosis.

A 71-yr-old female with a malignant thyroid tumour was to undergo thyroidectomy under general anaesthesia. Preoperative chest x-ray and plain computed tomography (CT) showed severe tracheal stenosis. Three-dimensional figures of the trachea and a virtual bronchoscopic movie were obtained from multi-slice CT to evaluate the stenotic region and to simulate fibroscopic tracheal intubation, respectively. After induction of general anaesthesia with propofol, a tracheal tube was successfully passed through the stenotic region under the guide of a fibroscope as simulated in the virtual movie. We conclude that multi-slice CT is useful for preoperative airway evaluation for patients with stenosis and distortion of the trachea.

The effect of pre-operative administration of midazolam on the development of intra-operative hypothermia.

(Midazolam is often used for premedication; it is known to promote vasodilation and may therefore affect redistribution of heat during surgery. We examined the effect of pre-operative administration of midazolam on the development of intra-operative hypothermia. Forty-five patients were randomly allocated to one of three groups to receive no premedication (Group C), IM midazolam 0.04 mg.kg(-1) (Group M1) or 0.08 mg.kg(-1) (Group M2) 30 min prior to anaesthesia. Sedation levels were assessed, and then general anaesthesia was induced and maintained using propofol and fentanyl. During surgery, core temperature, which was similar for the three groups prior to induction of anaesthesia, decreased significantly less in the midazolam groups M1 and M2 compared to the control group C. Patients who were more heavily sedated prior to induction of anaesthesia, had significantly lower core temperatures peri-operatively than those who were less sedated, and core temperatures in unpremedicated patients fell to significantly lower levels during surgery than those who were drowsy. We conclude that pre-operative administration of midazolam produces an effect on the development of peri-operative hypothermia. We found that moderate pre-operative sedation reduces the peri-operative heat loss, possibly by affecting core-to-peripheral heat distribution.

Pharmacological preconditioning with doxorubicin. Implications of heme oxygenase-1 induction in doxorubicin-induced hepatic injury in rats.

Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme into biliverdin, carbon monoxide, and iron. HO-1, an inducible form, is thought to contribute to resistance to various types of oxidative stress. Doxorubicin (DOX) produces clinically useful responses in a variety of human cancers. We reported previously that prior administration of DOX ameliorated subsequent hepatic ischemia and reperfusion injury. The aim of this study was to examine whether this pharmacological preconditioning was useful for another type of hepatic injury induced by a non-surgical method. When a high dose of DOX (10 mg/kg body weight) was administered directly to rat liver via the portal vein, serum aspartate transaminase (AST) and alanine transaminase (ALT) levels increased markedly 24 hr after the injection. Under this condition, zinc-protoporphyrin IX, a specific inhibitor of HO-1, caused both serum AST and ALT levels to be elevated further. When a low dose of DOX (5 mg/kg body weight) was administered to rats via the tail vein as pharmacological preconditioning 3 days before the injection of a high dose of DOX via the portal vein, the levels of serum AST and ALT in rats clearly were improved as compared with rats without the preconditioning. Expression of HO-1 in the liver was confirmed 3 days after the administration of a low dose of DOX. In addition, prior administration of zinc-protoporphyrin IX abolished the effect of DOX preconditioning. Immunohistochemical analysis showed that the positive staining of HO-1 protein induced by a low dose of DOX was localized to histiocytes infiltrating periportal areas. These results strongly suggest that pharmacological preconditioning with DOX may generally help to attenuate subsequent oxidant-induced hepatic injury.

Hemin pretreatment ameliorates aspects of the nephropathy induced by mercuric chloride in the rat.

Mercuric chloride (HgCl(2)) is known to be a nephrotoxicant. When HgCl(2) is administered into rats, acute renal failure (ARF) is induced. Heme oxygenase-1 (HO-1) is antioxidative enzyme and is known to play a protective role against the oxidative injury. To elucidate the cytoprotective role of HO-1 against the nephrotoxicant-induced ARF, we examined the effect of hemin, HO-1 inducer, on HgCl(2)-induced ARF. Subcutaneous administration of hemin (30 mg/kg body weight) into rats once a day for two successive days obviously induced HO-1 protein in the kidneys at 24 h after the last injection. Under this situation, when HgCl(2) (1 mg/kg body weight) was intraperitoneally injected into rats at 24 h after the last injection of hemin improved the serum creatinine (SCr) and blood urea nitrogen (BUN) levels, markers for renal injury, at 24 h after the HgCl(2) injection as compared with the control rats without hemin pretreatment (HgCl(2) treatment alone). This result was further confirmed by histopathological analysis. These findings strongly suggest that the preinduction of HO-1 ameliorates the subsequent HgCl(2)-induced acute renal injury.

Doxorubicin preconditioning: a protection against rat hepatic ischemia-reperfusion injury.

Doxorubicin produces clinically useful responses in a variety of human cancers. However, the toxicity of doxorubicin has limited its usefulness. This side effect is mainly due to the doxorubicin-mediated free radical formation. Administration of doxorubicin (10 mg/kg body weight) to rats intravenously induces heme oxygenase-1 (HO-1) in the liver. The levels of HO-1 protein were first detected at 6 hours and peaked at about 18 to 24 hours after the injection. It is known that HO-1 plays a protective role against the oxidative injury. Therefore, we have examined the protective effect of doxorubicin preconditioning against the hepatic ischemia-reperfusion injury. Partial hepatic ischemia was produced in the left and medium lobes for 45 minutes followed by 120 minutes reperfusion. When low doses of doxorubicin (1 mg/kg body weight) was intravenously administered to rats 2 days before the ischemia, the serum alanine transaminase (ALT) levels in the preconditioning rat were clearly improved compared with those in the rat without preconditioning. Under this situation, zinc-protoporphyrin IX, a specific inhibitor of HO-1, was injected subcutaneously to rats at 3 and 16 hours before the ischemia, the ALT levels were not improved by doxorubicin preconditioning. Histopathologic examination also supported these results. Although the HO-1 protein level was fairly low 2 days after the doxorubicin administration, significant amounts of HO-1 protein were detected. Our results indicated that the induction of HO-1 played a protective role against hepatic ischemia-reperfusion injury and that doxorubicin preconditioning is more clinically useful than other preconditioning methods.

Activation of epidermal growth factor receptor in the early phase after renal ischemia-reperfusion in rat.

In order to estimate a regenerative response in the early phase after renal ischemia-reperfusion in rat, we examined the time course of the activation of epidermal growth factor receptor (EGFR) as a response of signal transduction pathway after 45 min ischemia in kidney. The activation of EGFR was observed 5-30 min after the start of reperfusion. Simultaneously, superoxide anion/hydrogen peroxide generated in the mitochondrial fraction was elevated during the same period. On the other hand, the level of EGF decreased in a time-dependent manner. These results suggested that superoxide anion/hydrogen peroxide generated during the ischemia-reperfusion other than EGF could act as an activator for the EGFR. In summary, the activation of EGFR is important as a regenerative response at an early stage after the start of reperfusion in ischemic kidney.

Extracellular signal-regulated kinase mediates renal regeneration in rats with myoglobinuric acute renal injury.

In vitro data support that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), members of mitogen-activated protein (MAP) kinases, mediate the signal transduction pathways responsible for the cell proliferation. However, in vivo role of these MAP kinases is poorly understood. Intramuscular injection of 50% glycerol solution induces acute renal failure in rats. This injury is known as a model of rhabdomyolysis in human. To investigate the molecular mechanism of the signaling pathway in this injury, we examined the role of ERK and JNK. After the glycerol injection JNK was rapidly and transiently activated at about 4 h, while the activation of ERK was gradually increased and the levels were sustained at least to 24 h. Next, we examined the expression of cell-cycle related proteins after the glycerol injection using Western blot analysis. The levels of proliferating cell nuclear antigen (PCNA) protein as a marker for cell proliferation were induced at 2 h and significantly increased to 24 h after the injection. In addition, cyclins D1, D2, and D3 as markers for G1 phase also increased with similar time courses. To examine whether activation of ERK and/or JNK are involved in the renal regeneration after the glycerol injection, we examined the effect of genistein, which is an inhibitor of tyrosine kinase, on the activation of ERK and JNK. Administration of genistein to rats with this injury decreased the activation of ERK, but not JNK. The induction of PCNA and cyclin D1 was also prevented by this treatment. In this condition, renal function was further worsened as compared to control rats. These results provide the first evidence that ERK may be involved in the repair process of renal tubules damaged by this injury.

Regenerative response in acute renal failure due to vitamin E deficiency and glutathione depletion in rats.

In this study, we investigated some factors contributing to renal regeneration after acute renal failure (ARF) induced by vitamin E (VE) deficiency and glutathione (GSH) depletion. Acute renal failure was induced by feeding rats a vitamin E-deficient diet for 6 weeks and then injecting buthionine sulfoximine (BSO), a glutathione-depleting agent. The level of hepatocyte growth factor (HGF), a renotropic factor for regeneration in the kidney, showed a transient increase at 5 hr after the BSO treatment. Subsequently, renal ornithine decarboxylase (ODC) activity, a marker of G1 phase, and labeling index (LI) of proliferating cell nuclear antigen (PCNA), a marker of DNA synthesis (S phase), reached peaks at 10 and 53 hr after the injection, respectively. Thus, it appears that the increase in ornithine decarboxylase activity and subsequent elevation in proliferating cell nuclear antigen labeling index following the increase in the hepatocyte growth factor level in the kidneys are closely related to the renal regenerative response after acute renal failure.

The repetitive activation of extracellular signal-regulated kinase is required for renal regeneration in rat.

In this study, we investigated the activation of p42 extracellular signal-regulated kinase (ERK2) during renal regeneration after HgCl2-induced acute renal failure (ARF) in rat. ERK2 activation was observed at 5 and 29 hr after HgCl2 injection, respectively. The tyrosine phosphorylation of hepatocyte growth factor receptor (c-MET) occurred between 2.5 and 5 hr after the treatment. On the other hand, the phosphorylation of epidermal growth factor receptor (EGFR) was transiently observed at 29 hr after the injection. The peak of ornithine decarboxylase activity as a marker of G1 phase was at 10 hr, and subsequently the labeling index of proliferating cell nuclear antigen as a marker of S phase increased at 53 hr. These results indicate that the repetitive activation of ERK2 related to the phosphorylation of c-MET and EGFR is required for the renal regeneration in HgCl2-induced ARF of rat.

Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation.

A patient with chronic eosinophilic leukemia and a unique complex chromosomal translocation 46,XY,t(3;9;5)(q25;q34;q33) who had elevated blood interleukin-5 is reported. Complete cytogenetic remission was induced by interferon-alpha after treatment failure with corticosteroids and cytotoxic drugs. Severe cardiopulmonary symptoms due to hypereosinophilia and thromboembolic complication improved dramatically in the first 6 months of interferon therapy. Since it is known that the gene encoding for interleukin-5 resides on the long arm of chromosome 5, it may be possible that the chromosomal translocation in our patient resulted in overproduction of this cytokine, and our findings may be helpful for understanding the pathogenesis of this disorder.

Technetium-99m-HMPAO SPECT in patients with hemiconvulsions followed by Todd's paralysis.

We performed technetium-99m-hexamethylpropylene- amineoxime (Tc-HMPAO) single photon emission computed tomography in two patients with prolonged hemiconvulsions followed by transient hemiparesis (Todd's paralysis). In both cases, a prolonged post-ictal cerebral hyperperfusion state of approximately 24 h was observed, even after the neurological deficits had resolved. The cerebral hyperperfusion in both cases was of much longer duration than that in previously reported cases of single and uncomplicated focal seizures. The prolonged cerebral hyperperfusion might have been due to impairment of the cerebrovascular autoregulation in seizures followed by Todd's paralysis.

Induction of heme oxygenase-1 in toxic renal injury: mercuric chloride-induced acute renal failure in rat.

It is known that mercuric chloride (HgCl2) is a nephrotoxicant. When HgCl2 (1 mg/kg body weight) was intraperitoneally injected into rats, acute renal failure was induced. Histological changes in the kidneys were exclusively observed in the proximal tubules and the severe necrosis was found as early as 24 h after HgCl2 injection. The heme oxygenase-1 (HO-1) mRNA was strongly and promptly induced at about 2.5 h, the earliest time examined and abruptly decreased after the injection. Whereas the time course of HO-1 protein level was delayed as compared with that of HO-1 mRNA level. The levels of HO-1 mRNA and protein similarly increased with dose-dependent manner. The localization of HO-1 protein was restricted to the tubule cells. These findings suggest the potential involvement of HO-1 induction in the response to HgCl2-induced acute renal injury.

Regulation and immunohistochemical analysis of stress protein heme oxygenase-1 in rat kidney with myoglobinuric acute renal failure.

Intramuscular injection of hypertonic glycerol solution to rats results in acute renal injury. In this model, the proximal tubules are characteristically damaged. After glycerol injection renal glutathione (GSH) levels drastically decreased. On the other hand, stress protein heme oxygenase-1 (HO-1) was induced. When N-acetyl cysteine was administered to rats before 1 h glycerol injection, renal function was obviously improved. In this condition, the renal GSH content were sustained in the normal levels and HO-1 protein levels were decreased compared with those of glycerol-treated rats. Induction of HO-1 was accompanied by reduced renal GSH content. In addition, to investigate whether the location of HO-1 protein induced by glycerol injection is restricted to injured region or not in the kidney, we determined the localization of HO-1 protein using immunohistochemical staining. HO-1 protein was identified in the epithelia of the distal tubules, Henle's loop and collecting ducts, but not in the injured proximal tubules.

Molecular cloning of rat p38 mitogen-activated protein kinase and it's osmotic regulation in rat kidney.

Rat p38 mitogen-activated protein (MAP) kinase cDNA was isolated from rat kidney cDNA library using a PCR cloning strategy. The deduced amino acid sequence consists of 360 amino acids and shares 95.3% similarity with human p38 MAP kinase. The message for rat p38 MAP kinase was about 3.4 kilobases and was highly expressed in the kidney. In water-deprived rat kidneys, the steady-state levels of p38 MAP kinase mRNA increased about 2.7-fold as compared with those of control rats. This result suggests that p38 MAP kinase may play an important role in the osmoregulation in the kidney.

Changes in serum levels of creatol and methylguanidine in renal injury induced by lipid peroxide produced by vitamin E deficiency and GSH depletion in rats.

A novel creatinine metabolite, creatol (5-hydroxycreatinine), is a key precursor in the synthesis of the uremic toxin methylguanidine (MG). Creatinine is converted to creatol within the mammalian body and this conversion is mediated specifically by hydroxyl radicals. We investigated the production of creatol and MG from creatinine in rats with renal failure induced by the lipid peroxide produced as a consequence of vitamin E deficiency and depletion of the reduced form of glutathione (GSH). In addition, we examined serum levels of other guanidino compounds, namely guanidinoacetic acid (GAA) and guanidinosuccinic acid (GSA). The injury to kidneys induced by the depletion of GSH in combination with vitamin E deficiency caused markedly elevated serum levels of creatol, MG and GSA and decreased serum GAA. The molar ratio of creatol to creatinine in the serum, which should be an index of the oxygen stress mediated by hydroxyl radicals, increased with time. Therefore, the enhanced production of creatol in vitamin-E-deficient rats that have been depleted of GSH might be due to the enhanced production of oxygen radicals in this system.

Effects of vitamin E deficiency and glutathione depletion on stress protein heme oxygenase 1 mRNA expression in rat liver and kidney.

Heme oxygenase 1 (HO-1) is a stress protein and has been suggested to provide defense mechanisms against agents that may induce oxidative injury. Vitamin E (VE) is considered to function as an important cellular antioxidant. Rats were fed a VE-deficient (0E) or a VE-sufficient (10E) diet for 6 weeks and then were intraperitoneally administered buthionine sulfoximine (BSO), a glutathione (GSH)-depleting reagent. Whereas HO-1 mRNA levels were undetectable in untreated 0E and 10E rat livers, BSO administration induced HO-1 mRNA expression in both 0E and 10E rat livers. High levels of HO-1 mRNA expression were observed in particular in BSO-treated 0E rat livers. The time-course of changes in HO-1 mRNA expression in 0E rat liver after BSO administration showed that HO-1 mRNA expression was transiently induced at 2.5 hr after BSO treatment, the earliest time examined. In addition, to determine whether VE deficiency and GSH depletion affect the expression of HO-1 mRNA in other tissues, we also examined the time-course of HO-1 mRNA expression in BSO-treated 0E rat kidney. The expression pattern of HO-1 mRNA in the kidney was very similar to that in the liver, and the peak was also observed at about 2.5 hr after BSO administration. Interestingly, histologic assessment of liver and kidney showed that VE deficiency and GSH depletion induced injury in the kidney, but not in the liver.

Expression of S-adenosylmethionine synthetase isozyme genes in regenerating rat liver after partial hepatectomy.

Mammalian S-adenosylmethionine (AdoMet) synthetase exists as two isozymes, liver-type and non-hepatic-type enzymes. To investigate the possible role of AdoMet synthetase in proliferating cells, we have examined the expression of these two isozyme genes in regenerating rat liver after partial hepatectomy using Northern blot analysis. In normal adult rat liver the non-hepatic-type isozyme mRNA was not detectable, however, when partial hepatectomy was performed, there was an obvious appearance of the non-hepatic-type enzyme mRNA after operation. The levels of non-hepatic-type isozyme mRNA was peaked at 4h and maintained the level at least till 8 h after operation, then decreased. In addition, the liver-type AdoMet synthetase gene expression was also induced by partial hepatectomy with similar time course. These results indicate that these two AdoMet synthetase isozymes may play an important role during the prereplicative phase which precedes DNA synthesis.

Soluble transferrin receptor-transferrin complex in serum: measurement by latex agglutination nephelometric immunoassay.

The transmembrane protein, transferrin receptor (TfR), exists in serum as a soluble form that lacks cytoplasmic and transmembrane domains (residues 1-100). The level of soluble TfR in serum is a sensitive indicator of total erythropoiesis and iron deficiency. This study revealed that the major part of soluble TfR was saturated by transferrin (Tf) in serum, forming a stable complex which was more immunoreactive than intact TfR. Thus, we proposed that serum soluble TfR should be measured as the TfR-Tf complex (TRC), using prepared TRC for assay standardization. We developed a new assay for TRC, employing antibody-coated latex agglutination nephelometry (LA). Rapid and reproducible measurements were achieved using an automated analyzer. The values obtained by this LA assay were closely correlated with those obtained by conventional enzyme immunoassay (r = 0.967). The mean level of TRC in 179 adult healthy subjects was 1.62 mg/l. Patients with iron-deficient anemia showed significantly higher TRC levels than the healthy subjects.

Successful percutaneous closure of a coronary artery fistula with a detachable balloon.

Percutaneous transcatheter closure technique of a coronary artery fistula with a detachable balloon was performed for a 14 year old male student. Complete closure of the fistula without any complications was confirmed by angiography after the procedure. When the patient underwent a second angiography 6 months after the closure, it was confirmed that the position of the balloon had not changed, that the interruption of the flow of the fistula had been maintained and that the diameter of the left coronary artery and the fistula were reduced. Percutaneous closure technique using a detachable balloon may become the primary treatment for a coronary artery fistula in place of surgical ligation.