Intraoperative factors associated with delayed recovery of liver function after hepatectomy: analysis of 1969 living donors.

BACKGROUND: The safety of healthy living donors who are undergoing hepatic resection is a primary concern. We aimed to identify intraoperative anaesthetic and surgical factors associated with delayed recovery of liver function after hepatectomy in living donors. METHODS: We retrospectively analysed 1969 living donors who underwent hepatectomy for living donor liver transplantation. Delayed recovery of hepatic function was defined by increases in international normalised ratio of prothrombin time and concomitant hyperbilirubinaemia on or after post-operative day 5. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with delayed recovery of hepatic function after living donor hepatectomy. RESULTS: Delayed recovery of liver function after donor hepatectomy was observed in 213 (10.8%) donors. Univariate logistic regression analysis showed that sevoflurane anaesthesia, synthetic colloid, donor age, body mass index, fatty change and remnant liver volume were significant factors for prediction of delayed recovery of hepatic function. Multivariate logistic regression analysis showed that independent factors significantly associated with delayed recovery of liver function after donor hepatectomy were sevoflurane anaesthesia (odds ratio = 3.514, P < 0.001), synthetic colloid (odds ratio = 1.045, P = 0.033), donor age (odds ratio = 0.970, P = 0.003), female gender (odds ratio = 1.512, P = 0.014) and remnant liver volume (odds ratio = 0.963, P < 0.001). CONCLUSIONS: Anaesthesia with sevoflurane was an independent factor in predicting delayed recovery of hepatic function after donor hepatectomy. Although synthetic colloid may be associated with delayed recovery of hepatic function after donor hepatectomy, further study is required. These results can provide useful information on perioperative management of living liver donors.

Effect of stroke volume variation-directed fluid management on blood loss during living-donor right hepatectomy: a randomised controlled study.

Reducing blood loss is beneficial in living liver donor hepatectomy. Although it has been suggested that maintaining a low central venous pressure is important, it is known that low stroke volume variation may be associated with increased blood loss. Therefore, we compared the effect on blood loss of 40 patients randomly assigned to a high stroke volume variation group (maintaining 10-20% of stroke volume variation) vs 38 patients in a control group (maintaining < 10% stroke volume variation) during living-donor right hepatectomy. Mean (SD) blood loss during donor hepatectomy was significantly lower in the high stroke volume variation group than in the control group: 476 (131) ml vs 836 (341) ml, respectively (p < 0.001). Blood pressure and peri-operative laboratory values did not differ between the two groups. However, in the high stroke volume variation group, central venous pressure values were also significantly lower. We were unable to disentangle the effects of stroke volume variation and central venous pressure, but our results confirm that the two together appear beneficial.

Glucose metabolism in sporadic Creutzfeldt-Jakob disease: a statistical parametric mapping analysis of (18) F-FDG PET.

BACKGROUND AND PURPOSE: Reports describing functional neuroimaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), in sporadic Creutzfeldt-Jakob disease (sCJD) have consistently suggested that these tools are sensitive for the identification of areas of hypoperfusion or hypometabolism, even in the early stages of sCJD. However, there are few reports on the use of [18F]fluoro-2-deoxy-D-glucose (FDG) PET in sCJD, and most of them are single case reports. Only two small cohort studies based on visual inspection or a region of interest method have been published to date. Using a statistical parametric mapping (SPM) analysis of (18) F-FDG PET, we investigated whether there are brain regions preferentially affected in sCJD. METHODS: After controlling for age and gender, using SPM 2, we compared the glucose metabolism between (i) 11 patients with sCJD and 35 controls and (ii) the subset of five patients with the Heidenhain variant of sCJD and 35 controls. RESULTS: The patients with sCJD showed decreased glucose metabolism in bilateral parietal, frontal and occipital cortices. The Heidenhain variant of sCJD showed glucose hypometabolism mainly in bilateral occipital areas. CONCLUSIONS: Glucose hypometabolism in sCJD was detected in extensive cortical regions; however, it was not found in the basal ganglia or thalamus, which are frequently reported to be affected on diffusion-weighted images. The medial temporal area, which is possibly resistant to the prion deposits, was also less involved in sCJD.

Transient expression of iron transport proteins in the capillary of the developing rat brain.

Iron is essential for normal brain function and its uptake in the developing rat brain peaks during the first two weeks after birth, prior to the formation of the blood­brain barrier (BBB). The first step of iron transport from the blood to the brain is transferrin receptor (TfR)-mediated endocytosis in the capillary endothelial cells. However, the subsequent step from the endothelium into interstitium has not been fully described. The goal of this study was to examine the expression of iron transport proteins by immunodetection and RT­PCR in the developing rat brain. Tf and TfR are transiently expressed in perivascular NG2+ cells of the capillary wall during the early postnatal weeks in the rat brain. However, MTP-1 and hephaestin were expressed in endothelial cells, but not in the NG2+ perivascular cells. Immunoblot analysis for these iron transfer proteins in the developing brain generally confirmed the immunochemical findings. Furthermore, the expression of Tf and TfR in the blood vessels precedes its expression in oligodendrocytes, the main iron-storing cells in the vertebrate brain. RT­PCR analysis for the primary culture of endothelial cells and pericytes revealed that Tf and TfR were highly expressed in the pericytes while MTP-1 and hephaestin were expressed in the endothelial cells. The specific expression of Tf and TfR in brain perivascular cells and MTP-1 and hephaestin in endothelial cells suggest the possibility that trafficking of elemental iron through perivascular cells may be instrumental in the distribution of iron in the developing central nervous system.

Two different variants of the jugulocephalic vein with supraclavicular course.

The jugulocephalic anastomosis is a rare anatomical variant which normally undergoes atrophy during embryonic development. We found 2 cases of the jugulocephalic vein variant with supraclavicular course in Korean male cadavers. In a 50-year-old cadaver, the right cephalic vein ascended anterior to the clavicle, and terminated into the external jugular vein as well as to the axillary vein through a classic branch. In a 76-year-old cadaver, the left cephalic vein ascended supraclavicular course without any branch to the axillary vein, and terminated to the external jugular vein. We discussed the embryological explanation as well as its frequency since this jugulocephalic vein variant could cause unpredicted danger during clinical procedures.

Cerebral glucose metabolism in oculopalatal tremor.

No study adopted the statistical parametric mapping (SPM) analyses of (18)F-fluorodeoxy glucose (FDG) PET in a large number of patients with oculopalatal tremor (OPT). To determine regional cerebral glucose metabolism in patients with OPT, nine patients with OPT underwent FDG-PET of the brain. Their glucose metabolism was compared with that of 50 normal controls (NC) by using SPM analyses. Three patients had bilateral and six showed unilateral pseudohypertrophic degeneration of the inferior olivary nucleus (ION) on MRI. Compared with NC, OPT patients did not show any metabolic derangement in the anterolateral medulla where the pseudohypertrophic ION locates. Instead, six patients with unilateral ION changes had hypometabolism in ipsilesional pontine tegmentum and hypermetabolism in contralesional thalamus. Their metabolic changes did not depend on the lateralization of ION changes. Our study failed to present any metabolic evidence for the role of ION in the generation of OPT. In part, the failure might originate from the different pathomechanism between OPT and pure palatal tremor or sensitivity/specificity issues of PET and SPM analyses. But, our results suggest that impaired cell groups of the paramedian tract and thalamic tremor cells may contribute to the generation of OPT.

Cholesterol synthesis is required for cutaneous barrier function in mice.

Previous studies have shown that topical acetone treatment results in the removal of stratum corneum lipids and disruption of the permeability barrier. This disruption stimulates epidermal lipid synthesis which is associated with the rapid restoration of stratum corneum lipids and barrier function. The aim of this study was to determine the role of cutaneous cholesterol synthesis in the barrier recovery. Here we show that topical lovastatin, a competitive inhibitor of HMG CoA reductase, inhibits cholesterol synthesis. After acetone disruption of the barrier, the normal rapid return of cholesterol to the stratum corneum and recovery of barrier function is impaired in animals treated topically with lovastatin. When lovastatin animals are simultaneously treated topically with either mevalonate, the immediate product of HMG CoA reductase, or cholesterol, the final end product of the pathway, the recovery of the barrier is normalized. Lovastatin resulted in the delayed secretion and abnormal appearance of lamellar bodies. These results provide the first evidence demonstrating that cholesterol synthesis is required for the maintenance of barrier structure and function and suggests a crucial role for cholesterol synthesis in allowing for terrestrial existence.

Glucose metabolism in early onset versus late onset Alzheimer's disease: an SPM analysis of 120 patients.

The aims of this cross-sectional study were (i) to compare the overall glucose metabolism between early onset and late onset Alzheimer's disease in a large sample of patients; and (ii) to investigate the pattern of glucose metabolism as a function of dementia severity in early onset versus late onset Alzheimer's disease, using a statistical parametric mapping (SPM) analysis. Subjects consisted of four groups: 74 patients with early onset Alzheimer's disease, 46 patients with late onset of the disease, and two control groups age matched to each patient group. All the subjects underwent 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET under the same scanning conditions. Severity of dementia was rated with the Clincial Dementia Rating (CDR). Voxel-based SPM99 was used for statistical analyses. Overall glucose hypometabolism of early onset Alzheimer's disease patients was much greater in magnitude and extent than that of late onset patients, though both groups were similar in dementia severity: the early onset group showed more severe hypometabolism in parietal, frontal and subcortical (basal ganglia and thalamus) areas. When the decline of glucose metabolism was compared as a function of CDR stage, the slope was steeper in early onset than in late onset Alzheimer's disease. The rapid decline occurred at CDR 0.5-1 in the early onset group, whereas similar changes occurred at CDR 2-3 in the late onset group. The greater hypometabolism in early onset than in late onset patients is required to reach the same severity of dementia, probably reflecting greater functional reserve in younger than in older subjects. Alternatively, the metabolic decline curve suggests that the early onset patients may take a more rapid course in the reduction of glucose metabolism than the late onset patients.

Correlation of ventricular asymmetry with metabolic asymmetry in frontotemporal dementia.

BACKGROUND AND PURPOSE: The clinical presentation of frontotemporal dementia (FTD) is often asymmetrical in terms of both its clinical features and atrophy on MRI. Asymmetry in the lateral ventricle size on structural neuroimaging in FTD patients may have clinical significance. However, this has not been systematically investigated yet. This study compares the ventricular asymmetry seen on MRI with that of the asymmetric glucose metabolism using FDG-PET in patients with FTD. METHODS: Nineteen FTD patients who underwent both brain MRI and FDG-PET were retrospectively selected. As control groups, 23 and 11 age and sex-matched healthy normal subjects underwent either brain MRI or FDG-PET, respectively. The ventricular asymmetry index (VAI) was obtained in two ways: by visual rating (VAI-V) and by measuring the lateral ventricular volumes (VAI-ROI). The hemispheric asymmetry of the glucose metabolism on FDG-PET (MAI) was assessed in three ways: 1) by visual rating (MAI-V), 2) by counting the FDG activity of each hemisphere on normalized and smoothed PET images (MAI-ROI) and 3) by counting the number of voxels with significant hypometabolism based on statistical parametric mapping results (MAI-SPM). RESULTS: The VAIs on MRI (VAI-V and VAI-ROI) were highly correlated, as were the MAIs (MAI-V, MAI-ROI, and MAI-SPM) on FDG-PET. More importantly, the VAIs on MRI and the MAIs on FDG-PET showed high correlation. CONCLUSIONS: Ventricular asymmetry in FTD patients was common (78.9%) and there was a high correlation between the ventricular structural asymmetry and the hemispheric metabolic asymmetry. Therefore, it would be reasonable to interpret that the hemisphere with larger ventricle on MRI in FTD patients is undergoing a more active degenerative process.

Intracardiac echocardiographic guidance and monitoring during percutaneous endomyocardial gene injection in porcine heart.

In an effort to develop a guiding and monitoring tool for transmyocardial gene transfer, we have evaluated the feasibility of intracardiac echocardiography (ICE) to guide percutaneous endomyocardial gene transfer (PEGT), and monitor complications, in a pig model. ICE (5.5-10 MHz), complemented by fluoroscopy, was utilized to guide a needle injection into the heart in 19 normal pigs. Using this system, we injected Evans blue dye into eight pigs (group I), a mixture of pCK-CAT plasmid and India ink into seven pigs (group II), and pCK-LacZ plasmid into four pigs (group III). In all pigs, ICE contributed to the injection procedure by guiding the catheter to anatomically distinct sites, and by assisting stabilization of the catheter-endocardial contact. ICE predicted the injection sites correctly in 56 of 64 sites (87.5%) in group I, and in 42 of 42 sites (100%) in group II. Leakage of injectate into the left ventricular cavity could be detected by the microbubbles generated. The sites of injections appeared as foci of bright myocardial echodensity, which persisted until the end of the procedure. The procedures were not associated with significant morbidity or mortality. The expression of the chloramphenicol acetyltransferase (CAT) gene was identified in 40 sites from 42 injections (95.2%) in group II. In group III, histology showed positive beta-galactosidase staining of myocytes limited around the needle track with low transfection efficiency (<1%). These results suggest that real-time ICE monitoring proves safe and useful during PEGT for guiding needle injection, monitoring leakage, ensuring delivery of injectate into the myocardium, and instantly diagnosing cardiac complications, resulting in successful gene transfer.

Distribution of transferrin binding protein immunoreactivity in the chicken central and peripheral nervous systems.

Transferrin binding protein (TfBP) is a glycoprotein originally purified from chicken oviduct that exhibits transferrin binding activity. Recent work has shown that TfBP is a post-translationally modified form of the heat shock protein (HSP108), the avian homologue of a glucose regulated protein, GRP94. The function of this protein, however, has not yet been clearly defined. Antiserum to TfBP was found to selectively stain oligodendrocytes of the avian brain. In this study, we further describe these oligodendrocytes and other cell types positive to anti-TfBP in the chick nervous system. In accordance with previous studies, the most prominent cell type that labels with antiserum to TfBP is the oligodendrocyte. At the electron microscopic level, the immunoreactive product is confined to the perinuclear cytoplasm and fine processes of the oligodendrocytes, whereas myelin and axoplasm are devoid of staining. The immunoreactive product is found both in the cytoplasmic matrix and bound to the endoplasmic reticulum and plasma membrane, suggesting that TfBP may have properties of both a soluble and an integral membrane protein. There is great variability in the number of TfBP-oligodendrocytes in different areas of the central nervous system (CNS); large numbers of cells are associated with the white matter regions and are found in the myelinated tracts, whereas few cells are present in the gray matter regions. In the retina, TfBP is localized specifically in the cells, that are morphologically oligodendrocytic and is present in the optic nerve fiber layer and the ganglion cell layer. Obvious staining is also seen in the Bergmann glial cells of the cerebellum and in the Schwann cells of the sciatic nerve. Furthermore, the choroid plexus cells similarly exhibit a strong reaction. The association of TfBP in these specific cell types responsible for myelination and sequestering iron and transferrin implies that TfBP may be involved in myelination and iron metabolism of the chick nervous system, perhaps through a role in transferrin concentration in these cells. A putative role of TfBP, as HSP108, is considered.

3-Aryl-1,2-diacetamidopropane derivatives as novel and potent NK-1 receptor antagonists.

Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists 5-7 led to the discovery that the potency of the series could be markedly increased by moving the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R stereoisomeric series (IC50's = 100 pM to > 5 microM). Compounds in this series were shown to be competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-driven [Ac-[Arg6,Sar9,Met(O2)11]- substance P 6-11 (Ac-Sar9)] nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral administration in this model, (R)-32 was observed to be very potent (ID50 = 91 ng/kg) and have a long duration of action (> 8 h at 1 micrograms/kg). Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action.

Glial cells in the bird retina: immunochemical detection.

The avian retina is remarkably different from its mammalian counterpart in macroglial cell appearance. First, it is completely devoid of astrocytes. Thus, Müller cells constitute the only astrocytic-like cell population in avian retinae, whereas mammalian retinae also contain astrocytes in close association with blood vessels. Second, axons in the optic nerve layer of the retina of birds are myelinated, unlike those found in most mammalian species, with the exception of the rabbit, in which the medullary rays of the retina are myelinated by oligodendrocytes. Recent studies have revealed evidence that bird retinae contain a large number of oligodendrocytes, but which glial cell type myelinates axons intraretinally is still controversial. Apart from macroglial appearance, microglia in the bird retina show a very similar pattern of distribution to that of mammalian counterparts. This article reviews the existing data, including our new observations, and discusses the issues that remain to be resolved.

In situ localization of p53, bcl-2 and bax mRNAs in rat ocular tissue.

We mapped p53, bcl-2 and bax mRNAs, which are known to have correlation with apoptotic cell death, in the rat ocular tissue. p53 mRNA signals were present in several layers of retina, optic nerve, corneal epithelium, ciliary process and posterior surface of the iris. While almost the same pattern as p53 was recognized in the case of bcl-2 mRNA, bax signals were not found in ocular tissue except for ganglion cell layer (GCL). These results suggest that in the normal ocular tissue, p53 and bcl-2 genes play opposing parts in the physiological control of cell survival and death. A p53 mediated tumor-suppressing action might occur through the induction of transcriptional targets other than bax because only in GCL were p53 and bax mRNA expression co-localized.

The ontogeny of transferrin receptors in the embryonic chick retina: an immunohistochemical study.

Transferrin receptor (TfR) immunoreactivity in the developing chick retina was examined. Immunoreactivity was detectable in the ganglion cells of embryonic day (E) 4 retina. At E9, diffuse TfR immunoreactivity appeared in the outer portion of the inner nuclear layer. Amacrine cells were the most intensely TfR-positive cells in the inner nuclear layer. At E11, the inner segment of photoreceptor cells showed moderate immunoreactivity. With the appearance of the outer segments, positive immunoreactivity was observed in these structures. TfR's developmental distribution in the retina may reflect the developmental and physiological role of transferrin.

Immunocytochemical study with an anti-transferrin binding protein serum: a marker for avian oligodendrocytes.

We have investigated immunocytochemically the localization of a transferrin binding protein (TfBP) in adult CNS of avian and mammalian species using a polyclonal antibody raised against the protein purified from hen oviduct membranes (alpha OV-TfBP). TfBP has recently been shown to be HSP108. An overall strong immunoreactivity was revealed in most parts of the avian brains, especially in the white matter. The main immunoreactivity originated in small, intensely reacting cells interpreted as oligodendrocytes. The density of TfBP-labeled oligodendrocytes of the avian brains was generally proportional to the degree of myelination. There were no marked differences in TfBP-immunostaining pattern between avian species (chick, pigeon and lovebird). On the other hand, in rat, rabbit and cat brains we could not find any TfBP-immunoreactivity. Immunoelectron microscopy has further revealed that TfBP is present in the light and medium types of oligodendrocytes which are known to have high metabolic activities. TfBP reaction product was homogeneously dispersed throughout the perinuclear cytoplasm and fine processes of oligodendrocytes. The intracytoplasmic organelles such as mitochondria and Golgi apparatus were devoid of reaction product. The presence of TfBP in oligodendrocytes implies that this protein may play an important role in transferrin-mediated iron metabolism in the CNS. The complete lack of cross-reactivity between alpha OV-TfBP and mammalian tissues suggests that there is species variability in TfBP structure. We conclude that this chick TfBP antiserum will prove useful in studies of oligodendrocytes and myelination in the avian CNS.

Transferrin binding protein is expressed by oligodendrocytes in the avian retina.

It has been documented that some axons of ganglion cells in the nerve fiber layer of avian retina are wrapped in a myelin sheath. However, the identity of myelin-forming cells has not been established. In this study we demonstrated immunohistochemical evidence for the existence of a large population of oligodendrocytes in avian retina, using an antiserum against transferrin binding protein (TfBP), the avian homologue of the mammalian GRP 94 family of stress-regulated proteins. TfBP+ cells were mostly confined to the ganglion cell and optic nerve fiber layers of the retina, in which they were closely associated with the soma and axons of ganglion cells. The double-labeling experiments clearly show that TfBP is specific to oligodendrocytes. The morphology, distribution, and antigenic properties indicated by our findings suggest that TfBP+ cells are retinal oligodendrocytes that may be responsible for the myelination of ganglion cell axons in avian retina. A putative tropic role of TfBP+ oligodendrocytes to the ganglion cells is also discussed in conjunction with the physical properties of TfBP and avascular retinae of birds.

Localization of transferrin binding protein in relation to iron, ferritin, and transferrin receptors in the chicken cerebellum.

We have demonstrated that transferrin binding protein (TfBP), ferritin, and iron, are specifically localized in Bergmann glia, while the transferrin receptor is confined to Purkinje cells in the chicken cerebellum. The results of this study suggest that Bergmann glia have previously undescribed functions related to iron regulation such as sequestration of iron and the maintenance of iron homeostasis in the cerebellum.

Cerebellar alterations induced by chronic hypoxia: an immunohistochemical study using a chick embryonic model.

A model of fetal aerogenic hypoxia was developed in which fertilized chicken eggs were half-painted with melted wax and incubated under normal conditions. The cerebellum of the hypoxic chick embryos at a later stage of development (E18-20) was analyzed immunochemically. Hypoxic insult resulted in considerable neurocytological deficits of the Purkinje cells and altered glial fibrillary acid protein (GFAP) immunoreactivity in the fetal cerebellum. Purkinje cells in the hypoxic embryos were marked by small cell size, poorly developed dendrites, low cell density, deletion and ectopia. On the other hand, enhanced GFAP immunoreactivity was found in astrocytes and Bergmann glia of the hypoxic embryos. Our results indicate that chronic hypoxia in the chick fetus can cause severe disorders of neuronal development as well as glial activation. We suggest that our hypoxic model of chick embryos could be an accessible animal model for further elucidating fetal hypoxia.

Constitutive expression of c-myb mRNA in the adult rat brain.

In this study, we demonstrated the c-myb mRNA expression in the adult rat brain using an in situ hybridization technique. We found c-myb mRNA signals in the various regions of the forebrain and midbrain including the cerebral cortex, thalamus, hippocampus, hypothalamus, superior and inferior colliculi and central gray. In the cerebellum, a diffuse signal was found in the granular layer while some positive cells were detected in the molecular layer as well. In addition, a number of cells showed intense signals in many nuclei of the medulla oblongata. The constitutive expression of c-myb mRNA in the different kinds of neural cells suggests that this gene might be involved in the normal function of these neurons.