Hypoxia-ischemic insult in neonatal rats induced slowly progressive brain damage related to memory impairment

The present study was designed to determine potential associations between the brain damage induced by hypoxic-ischemic (HI) insult and spatial learning impairment in an eight-arm radial maze task. We first determined the pathological outcomes after 2, 5, 9, and 17 weeks of recovery following the HI insult. The results show that the brain damage progressed from 2 up to 17 weeks of recovery. To clarify the time course of the brain damage changes, we investigated the histological changes of the same individual with magnetic resonance imaging (MRI) after 5, 9, and 57 weeks of recovery following the HI insult. The MRI changes were similar to the histological changes, and the brain damages were exacerbated in the contralateral hemisphere after 57 weeks of recovery following the HI insult. To investigate whether alteration in brain function was correlated with MRI and histological changes, the rats were made to find their way through an eight-arm radial maze was performed at either 7th or 16th weeks of recovery. According to the results, the spatial learning impairments of rats in the maze starting at 16 weeks of recovery were more severe than those at 7 weeks of recovery, indicating that the impairments were progressive and depended on the degree of brain damage. The results of the present study are the first demonstration that the evolutional and specific brain damage following the HI insult is slowly and progressively exacerbated to the contralateral hemisphere and rats who experience the HI are at risk for showing a late impairment of brain function.     

Determination of diquat in biological materials by electron spin resonance spectroscopy

Summary An electron spin resonance (ESR) method already in use for the quantitative analysis of paraquat was applied to the analysis of diquat in blood, serum, urine, tissue homogenates and several drinks without purification of the samples. The diquat radical produced with ascorbic acid at alkaline pH was much more stable than that produced with the commonly used sodium dithionite. Radical decay in solutions covered with n-hexane was less than 5% after 60 min over a wide range of ascorbic acid concentrations. In 0.2N NaOH solution 85% of the radicals was present even after 24h. The limit of detection was 0.3 g/ml and the required amount of sample was 0.1 ml. When both diquat and paraquat were present in a sample the diquat was first extracted with 1-butanol prior to the ESR measurement, because both species were converted to the radicals.     

Is the site of action of ketamine anesthesia the N-methyl-D-aspartate receptor?

Synaptic mechanisms underlying ketamine anesthesia were studied using in vitro preparations of the lamprey CNS. Although lampreys are one of the most primitive vertebrates, the synaptic physiology and pharmacology are similar to those in the higher vertebrates. Axonal conduction, transmitter release from the presynaptic terminal, postsynaptic response to the putative neurotransmitters, and resting and activated membrane properties were studied in the absence and the presence of various concentrations of ketamine. Ketamine markedly reduced N-methyl-D-aspartate (NMDA)-activated responses, such as depolarizations to bath-applied NMDA and bursting rhythm during "fictive locomotion." The 50% block of the responses took place in the presence of 10-20 microM ketamine, whereas those induced by kainate and quisqualate (the other two subclasses of L-glutamate/L-aspartate agonists) were spared at concentrations higher than 600-800 microM. None of the other neuronal events tested were suppressed in the presence of still higher concentrations of ketamine. The results support the hypothesis that ketamine might exert its anesthetic effect by a pharmacologically specific interaction with the NMDA receptor.     

Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogues of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC).

1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.     

Breast-conserving surgery for primary breast cancer: Immediate volume replacement using lateral tissue flap

We have developed a breast-conserving surgery consisting of quadrantectomy and regional lymph node dissection and immediate volume replacement using lateral tissue flap (LTF). The quadrantectomy was employed on the basis of segmental anatomy of the duct lobular system in which breast carcinoma originates. Lateral skin incision was performed from the apex of mid-axillary line to the inframammary fold, without removing the skin overlying the tumor. In the early period of breast reconstruction embraced latissmus dorsi flap (LDF) for 10 patients (reconstruction was not performed on 35 patients), but in the late period we employed LTF for 56 patients. Four of the 101 patients developed ipsilateral breast cancer during a mean follow-up period of 48 months, but none died of breast cancer. Among the 56 patients with LTF replacement no patient developed ipsilateral breast cancer. Fairly good cosmetic outcome was obtained in the patients who underwent the immediate volume replacement. Breast-conserving surgeries are reviewed, and the surgical procedure using LTF for immediate volume replacement is described.     

Enhancement by hyperthermia of the in vivo antitumour effect of doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO)-hydroxyapatite (HAP) complex

We have developed a new type of drug delivery system (DDS) comprising a complex of porous hydroxyapatite (HAP) with the anticancer drug doxorubicin hydrochloride (DOX) and the glutathione inhibitor buthionine sulfoximine (BSO) (DOX and BSO-HAP complex). We then studied the antitumour effect of DOX and BSO-HAP combined with 44 degrees C hyperthermia for 40 min. It was found that in mice this combined treatment suppressed the growth of sarcoma 180 in terms of tumour volume to 36% in comparison viith mice given plain HAP, and was more effective than HAP + hyperthermia or DOX- and BSO-HAP. These results were also confirmed by histological observation.     

Characterization of [3H]brevetoxin binding to voltage-dependent sodium channels in adrenal medullary cells

We have previously reported that in bovine adrenal chromaffin cells Ptychodiscus brevis toxin-3 (PbTx-3) does not alter the veratridine-induced ²²Na influx when given alone, but increases the influx of ²²Na when co-applied with either - or -scorpion venom (Wada et al. 1992). In the present study, we characterized [³H]PbTx-3 binding in bovine adrenal chromaffin cells. [³H]PbTx-3 binding was saturable, reversible and of high-affinity with an equilibrium dissociation constant (K_d) of 32.0±4.9 nmol/1 and a maximum binding capacity B_max of 6.2 ± 1.2 pmol/4 × 10⁶ cells (4.5 ± 0.9 pmol/mg cell protein). A Hill plot revealed the lack of cooperative interaction among the binding sites. Unlabelled PbTx-3 inhibited [³H]PbTx-3 binding with an IC₅₀ of 31 nmol/l. However, tetrodotoxin, veratridine, - and -scorpion venom, or veratridine in combination with either - or -scorpion venom did not alter [³H]PbTx-3 binding. All these results suggest that PbTx-3 binds to a site (site 5) distinct from the previously known four toxin binding sites, which does not gate voltage-dependent Na channels by itself, but is specifically involved in the allosteric modulation of Na channels in adrenal medullary cells. Correspondence to: A. Wada at the above address     

Antitumor effects of oral administration of an interferon-inducing pyrimidinone,Bropirimine, on murine renal-cell carcinoma

Bropirimine [2-amino-5-bromo-6-phenyl-4-(3H)-pyrimidinone] is a low-molecular-weight compound that acts as an inducer of interferon in several animal species. Experiments were designed to explore the possibility of using this drug for the treatment of renal-cell carcinoma (RCC). Euthymic BALB/c mice were inoculated with murine RCC (Renca) cells and given graded doses of Bropirimine p.o. for 5 consecutive days beginning on day 1 following tumor inoculation. These mice were killed and tumors were excised on day 21. Bropirimine significantly (P<0.01) inhibited the tumor growth at a daily dose of 1,000 or 2,000 mg/kg. No adverse effect or toxicity was noted at 1,000 mg/kg, and at 2,000 mg/kg there was only a marginal body-weight reduction without any other appreciable side effect. In addition to the inhibition of tumor growth, there was a small yet significant (P<0.05) increase in the duration of survival (in days) in the Bropirimine-treated animals. When the treatment was delayed to begin on day 6 following tumor inoculation, Bropirimine did not suppress tumor growth in euthymic mice, pointing to the importance of the timing of the treatment. In athymic nude BALB/c mice lacking T-cells or T-cell function, Bropirimine also inhibited tumor growth (P<0.01). The antitumor effect of this drug was abolished by pretreatment with anti-asialo GM1 serum, which eliminated natural killer (NK) activity in euthymic mice. In vivo treatment with Bropirimine augmented the cytotoxicity of lymphocytes isolated from the spleens or lungs of the tumor-bearing mice, which were active against Renca and YAC-1 cells in vitro. This activity was NK-cell-dependent as judged on the basis of the results of the in vitro complement-dependent cytotoxicity assay. Since Bropirimine induced interferon (IFN)-/ production, significantly (P<0.05) elevating its serum concentration, and since this drug mimics the effects of IFN-/, it seemed likely that the Bropirimine-induced NK cell augmentation we found was mediated by IFN-/. These results suggest that Bropirimine, a booster of NK activity, may have potential as an adjunct to other therapeutic modalities in the treatment of human RCC.     

Loving openness as a meta-world hypothesis: expanding our vision of mind and medicine

In 1942, Stephen C. Pepper published a seminal book, World Hypothesis, that sought to explain how people create hypotheses about the world. Pepper proposed that there were four basic world hypotheses: (1) formistic (the hypothesis that nature exists as categories); (2) mechanistic (the hypothesis that nature obeys cause-effect relationships); (3) contextual (the hypothesis that processes in nature are relative and context dependent); and (4) organismic (the hypothesis that processes in nature reflect interactive relationships in systems). Most classical and modern theories of science and medicine implicitly adopt one or more of these foundational hypotheses. In 1997, Schwartz and Russek proposed that there were four additional world hypotheses: (5) implicit process (the hypothesis that nature consists of invisible forces and information, such as energy and consciousness); (6) circular causality (the hypothesis that nature consists of circulating interactions that inherently change over time); (7) creative unfolding (the hypothesis that processes in nature reflect flexible designs or plans that have adaptive function); and (8) integrative diversity (the hypothesis that phenomena in nature reflect complex integrations of diverse processes). Theories in postmodern and integrative science implicitly adopt hypotheses 5 through 8. However, underlying the creation of the eight world hypotheses is an implicit meta-world hypothesis which we term loving openness (the hypothesis that phenomena in nature reflect levels of openness and caring). This paper briefly explains the origin and implications of the loving openness meta-world hypothesis for understanding mind-body healing in medicine, the reordering of values in integrative medicine (with a primary focus on caring with humility), and the fostering of a new vision for twenty-first century frontier science, spirituality, and medicine.     

Definition and pathology of primary sclerosing cholangitis

Although primary sclerosing cholangitis (PSC) is not a common disease, it is important in the differential diagnosis of hepatobiliary tract diseases in clinical practice. A diagnosis of PSC should be made only after the exclusion of similar diseases with well known etiologies or pathogeneses. In this review, the pathology of classical PSC and its variants or related diseases is highlighted. PSC is histologically characterized by progressive periductal fibrosis with luminal stenosis or obliteration, along with the formation of a fibrous core, as well as dilatation (cholangiectasis). Its etiology is unknown. Bacterial ascending cholangitis is superimposed on its long clinical course. Such a heterogeneous distribution of biliary lesions with biliary obliteration and cholangiectasis is responsible for the radiological demonstration of biliary abnormalities, particularly the beaded appearance. Sampling variability is common in needle or wedge biopsied specimens. As a result of biliary damage, the liver shows progressive cholestatic change followed by biliary fibrosis and cirrhosis, and this hepatic progression is divisible into four stages. There are several variants of PSC or related diseases, such as localized biliary sclerosis and stenosis, sclerosing cholangitis associated with inflammatory pseudotumor, and PSC-autoimmune hepatitis overlapping syndrome. Cholelithiasis, including secondary hepatolithiasis and, to a lesser degree, biliary carcinoma and dysplasia, are also known to develop at the perihilar bile ducts as a late complication of PSC. Received for publication on March 8, 1999; accepted on April 30, 1999