A missense mutation in the proteolipid protein gene responsible for Pelizaeus--Merzbacher disease in a Japanese family

We investigated the proteolipid protein (PLP) gene of two boysin a Japanese family with Pelizaeus—Merzbacher disease(PMD), an X-linked neurologic disorder characterized by dysmyelinationin the central nervous system (CNS). The patients showed similarclinical signs from birth and autopsy on the elder brother confirmeda connatal type of PMD. Direct sequencing of the PLP gene andPLP mRNAs from the brain of the PMD patient revealed a G toT transition in exon V of the PLP gene, which leads to a glycineto cystein substitution at residue 220. Allele-specific oligonucleotidehybridization revealed that this mutation was also present inhis brother, but was absent in 100 X chromosomes of normal Japaneseindividuals. Northern blot analysis showed that the mRNA levelsof PLP and myelin basic protein, two major myelin proteins producedby oligodendrocytes, were much reduced in the PMD brain, hence,there was a specific loss of oligodendrocytes. It seems likelythat the substitution is responsible for PMD (connatal type)in this particular family and causes oligodendrocytes deathin the CNS.     

Tetraethylammonium-insetisitive,Ca2+-activated whole-cell K+ currents in rat submandibular acinar cells

Using whole-cell patch-clamp techniques, we demonstrate, for the first time, that rat submandibular acinar cells contain a tetraethylammonium (TEA)-insensitive, Ca²⁺-activated K⁺ conductance which is not attributable to large conductance, voltage-sensitive, Ca²⁺-dependent K⁺ channels (maxi-K⁺ channels). Taken together with our recent K⁺ efflux and fluid secretion studies in intact rat submandibular gland, we postulate that the K⁺ conductance reported here may be involved in the basolateral K⁺ efflux pathway activated by cytosolic Ca²⁺ concentration during secretion by this gland.     

ASO Author Reflections: Perspectives of Laparoscopic Hepatectomy with Venous Tumor Thrombectomy for Hepatocellular Carcinoma

Annals of Surgical Oncology -     

ASO Author Reflections: Laparoscopic Arantius’ Approach as Shortcut Access for Major Hepatic Veins

Annals of Surgical Oncology -     

Changes in circulating blood volume following isoflurane or sevoflurane anesthesia

Changes of circulating blood volume (CB volume) measured by the dual indicator dilution method were observed in 33 chronically instrumented mongrel dogs following either alpha-chloralose-urethane (C group), additive isoflurane (I group) or sevoflurane anesthesia (S group). These anesthetic groups were each divided into two subgroups with regard to respiratory care, namely Cp, Ip and Sp for those with intermittent positive pressure ventilation (six animals per subgroups), and Cs, Is and Ss for those with spontaneous breathing (five animals per subgroups).The CB volume under positive pressure ventilation remained unchanged in the Ip and Sp groups at both 0.5 and 1.0 MAC, and in the Cp group. The CB volume remained essentially unchanged in the Cs and Is groups at both 0.5 or 1.0 MAC, but the plasma volume tended to increase slightly in the Is group at 1.0 MAC.In the Ss group under spontaneous breathing, however, the CB volume increased from 84.4 ± 7.0 to 91.4 ± 7.7 at 0.5 MAC, and to 91.4 ± 10.2ml·kg^–1 at 1.0 MAC (0.01 P 0.05). These increases were caused by an increase in the plasma volume.The above data suggests that a concomitant increase in the venous pressure associated with an increase in the intrathoracic pressure produced by positive pressure ventilation would attenuate changes in the CB volume during sevoflurane anesthesia.(Hamada H, Takaori M, Kimura K, et al.: Changes in circulating Blood volume following isoflurane or sevoflurane anesthesia. J Anesth 7: 316–324, 1993)     

Interaction of cyclosporin derivatives with the ATPase activity of human P-glycoprotein

1. P-glycoprotein, a 170–180 kDa membrane glycoprotein that mediates multidrug resistance, hydrolyses ATP to efflux a broad spectrum of hydrophobic agents. In this study, we analysed the effects of three MDR reversing agents, verapamil, cyclosporin A and [3′-keto-Bmt]-[Val^*]-cyclosporin (PSC 833), on the adenosine triphosphatase (ATPase) activity of human P-glycoprotein.
2. P-glycoprotein was immunoprecipitated with a monoclonal antibody (MRK-16) and the P-glycoprotein-MRK-16-Protein A-Sepharose complexes obtained were subjected to a coupled enzyme ATPase assay.
3. While verapamil activated the ATPase, the cyclosporin derivatives inhibited both the substrate-stimulated and the basal P-glycoprotein ATPase. No significant difference was observed between PSC 833 and cyclosporin A on the inhibition of basal P-glycoprotein ATPase activity. PSC 833 was more potent than cyclosporin A for the substrate-stimulated activity.
4. Kinetic analysis indicated a competitive inhibition of verapamil-stimulated ATPase by PSC 833.
5. The binding of 8-azido-[α-³²P]-ATP to P-glycoprotein was not altered by the cyclosporin derivatives, verapamil, vinblastine and doxorubicin, suggesting that the modulation by these agents of P-glycoprotein ATPase cannot be attributed to an effect on ATP binding to P-glycoprotein.
6. The interaction of the cyclosporin derivatives with ATPase of P-glycoprotein might present an alternative and/or additional mechanism of action for the modulation of P-glycoprotein function.

     

Unilateral Multicentric Breast Carcinoma Studied by Whole Mammary Gland Serial Sectioning

The incidence and clinicopathologic features of unilateral multicentric breast cancer (UMBC) were studied by mammary gland serial sectioning in 116 cases of clinically defined monocentric breast cancer (MONBC) examined histopathologically at the Nagano Cancer Detection Center. UMBC was defined as: 1) histopathologically discontinuous tumors each with an intraductal spread, 2) at least one tumor-free section separating two tumors, and 3) a large primary tumor and other small secondary tumors. UMBC was detected in 23 of 116 cases (19.8%), all with one secondary tumor. Primary and secondary tumors were located in the same quadrant in 34.8% and in different ones in 65.2%. The secondary tumors were <5 mm in size in 56.5%. Secondary tumors, averaging 8.3 mm in size and 25.5 mm in distance from the primary tumor, were almost exclusively noninvasive carcinomas, including 15 (65.4%) noninvasive ductal carcinomas and several special types. The primary and secondary tumors were of the same histologic type in 3 of 23 cases. UMBC patients averaged 6 years younger than MONBC patients, and the incidence of UMBC tended to be higher in younger patients (p<0.1). UMBC tended to occur more frequently in quadrant with an average histologie tumor size significantly smaller than that in MONBC (p<0.01). The histologie types of the primary tumor in UMBC and MONBC were similar, with common types predominant. Lymph node metastases tended to be slightly more frequent in MONBC. This high incidence of UMBC calls for careful attention when considering breast conserving therapy.     

An event-related potential study in schizophrenia using Japanese sentences

To examine the neurophysiological and cognitive characteristics of language disorder in schizophrenia, the N400 component and late positive component (LPC) of event-related potentials (ERPs) were investigated in medicated schizophrenic patients and health comparison subjects. The subjects were required to indicate whether Japanese sentence completions were semantically congruous or incongruous. The ERPs for the range of 300-500 ms to the incongruous completions contained a more negative component (N400), followed by LPC, which was inversely more positive for the incongruous than congruous condition. The N400 effect and the mean amplitude of the LPC were reduced in the patients. The attenuated N400 effect in schizophrenics mainly originated from an enhanced negativity for the congruous completions, suggesting that the use of context is poor in schizophrenia.     

Delayed image of iodine-123 iomazenil as a relative map of benzodiazepine receptor binding: The optimal scan time

Delayed single-photon emission tomograpic (SPET) images after an intravenous bolus injection of iodine-123 iomazenil have been used as a relative map of benzodiazepine receptor binding. We determined the optimal scan time for obtaining such a map and assessed the errors of the map. SPET and blood data from six healthy volunteers and five patients were used. A three-compartment kinetic model was employed in simulation studies and analyses of actual data. The simulation studies suggested that, in the normal brain, the scan time at which a single SPET image best represented the relative receptor binding was 3.0–3.5 h post-injection. This finding was supported by actual data from the volunteers. The simulation studies also suggested that the optimal scan time was not greatly changed by the variability of the input functions, and that the error in the SPET image contrast in the vicinity of the optimal scan time was not increased by changes in the tracer kinetics in the entire brain. The SPET image contrast in the patients at 3.0 h post-injection agreed well with the reference receptor binding estimated by kinetic analysis, with a mean error of 3.6%. These findings support the use of a single SPET image after bolus injection of [¹²³I]iomazenil as a relative map of benzodiazepine receptor binding. For this purpose, a SPET scan time of 3.0-3.5 h post-injection is recommended.