Fundamental study on diffuse reflective optical tomography.

We report a simulation study on diffuse reflective optical computed tomography, in which continuous-wave sources and detectors are placed on the plane surface of a semi-infinite body. We adopted a simple Tikhonov regularization in the inverse problem and demonstrated the feasibility of three-dimensional reconstruction of the absorption coefficient change. The spatial resolution of the reconstructed image was shown to be degrading markedly with the depth. The regularization parameter should be chosen appropriately considering the trade-off between the reconstructed image noise and the spatial resolution. We analysed the dependence of the spatial resolution of the reconstructed image on the regularization parameter and the depth, and also the behaviour of the reconstructed image noise on the regularization parameter and the depth.

Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1.

Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [(14)C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.

Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease.

To investigate the pathomechanism of amyloid beta protein (A beta) deposition in brains with Alzheimer's disease (AD), cerebrospinal fluid (CSF) levels of A beta species (CSF-A beta) with different carboxy termini, i.e. A betaX-40 and A betaX-42(43) as well as A beta1-40 and A beta1-42(43), were measured in patients with AD and age-matched controls without dementia (CTR) using sandwich enzyme-linked immunosorbent assays (ELISAs). The present study revealed that both CSF-A betaX-42(43) and A beta1-42(43) levels were significantly lower in the AD patients (P<0.005) than in the CTR group, whereas neither CSF-A betaX-40 nor CSF-A beta1-40 levels showed any differences between the two groups. In addition, although there was no difference between the ratios of A betaX-40 to A beta1-40 in the AD and CTR groups, the ratios of A betaX-42(43) to A beta1-42(43) were increased in the AD group compared with those in the CTR group (P<0.05). Therefore, it can be assumed that the ratios of amino terminal truncations and/or modifications of CSF-A beta42(43) with carboxy termini ending at residue 42(43) were more increased in the AD group than in the CTR group. Increased adsorption of A beta42(43) to A beta deposition in AD brains, decreased secretion of A beta42(43) to CSF and/or increased clearance of A beta42(43) from CSF might explain the diminished levels of A beta42(43) in the CSF of AD patients. In addition, CSF-A beta42(43) could reflect increased amino terminal truncations and/or modifications of A beta42(43) in AD brains.

Antibodies to amyloid beta protein (A beta) crossreact with glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

In the present study, we characterized the epitope of a monoclonal antibody against purified amyloid plaque cores (Am-3). By immunocytochemical experiments, Am-3 stained cerebrovascular and senile plaque amyloid in brain sections of patients with Alzheimer's disease (AD) in a similar manner to that of antibodies against amyloid beta-protein (A beta). By Western blotting experiments, Am-3 recognized only a 35 kDa protein, which was revealed to be glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and not A beta or beta amyloid precursor protein (beta PP). However, Am-3 recognized both GAPDH and purified native A beta in a dot-binding assay. Therefore, we concluded that Am-3 recognized both GAPDH and native A beta. Other monoclonal antibodies (6C6 and AmT-1) against the synthetic peptide corresponding to residues 1-28 of A beta also recognized these proteins. Because the amino acid sequences of these two proteins are not homologous, we propose that the crossreactivity between A beta and GAPDH is a consequence of their similar conformational epitopes. The possibility of crossreactions would complicate immunochemical and immunocytochemical studies of brain aging, AD and Down's syndrome. The implications of crossreactivity in developing immunological assays and in investigating the amyloid deposits of AD are discussed.

Protein L-isoaspartyl methyltransferase: developmentally regulated gene expression and protein localization in the central nervous system of aged rat.

We have cloned a cDNA encoding protein L-isoaspartyl methyltransferase (PIMT) and characterized gene expression in the development, maturation, and the aging process of the central nervous system by RNA blot analysis, western blot analysis, and immunohistochemistry. PIMT transcript was detected in rat embryonic brain and showed a linear up-regulation during the maturation of the brain and maintained its level in aged rat brain. Immunoblot analysis also supported a linear increase in the amount of PIMT in the maturation process of rat brains. An immunohistochemical study showed that PIMT is strongly expressed in neurons and weakly but definitively in glial cells and oligodendrocytes. These immunoreactivities significantly increased in some neurons of the hippocampus, cerebral cortex, and the brain stem of aged rat brain. The present results suggest that the expression of PIMT is associated with the amount of racemized/isomerized proteins accumulated during the developmental and aging process of the central nervous system.

Tau in cerebrospinal fluids: establishment of the sandwich ELISA with antibody specific to the repeat sequence in tau.

Clinical diagnosis for Alzheimer's disease (AD) is provided by the criteria of DSMIV and clinical progress in addition to imaging analysis with MRI after negative screening. The final exclusive diagnosis is confirmed by the neuropathological findings of neurofibrillary tangles and senile plaques in autopsy brains. We developed a new ELISA system to measure the amount of tau in cerebrospinal fluids (CSF) using phosphorylation-independent and sequence-specific antibodies. The present ELISA was sensitive enough to detect tau in CSF of normal subjects. The amount of tau was significantly elevated in CSF of AD subjects compared with those of normal subjects and subjects with dementia of cerebrovascular disease, suggesting that tau in CSF reflects the massive and continuous neuronal cell death in the AD brain. In conclusion, we established an ELISA system which enabled us to detect tau in CSF and demonstrated that tau was significantly and specifically elevated in CSF of AD subjects. This assay system can provide us with a potent diagnostic tool for clinical AD.

Serum inorganic fluoride levels in mildly obese patients during and after sevoflurane anesthesia.

Serum inorganic fluoride levels in obese versus control patients were compared during and after sevoflurane anesthesia. Mean serum inorganic fluoride levels in the obese group increased more rapidly and were significantly higher than in the control group at each sampling time (P < 0.01). The area under the curve of fluoride concentration, versus time up to 24 h and 48 h in the obese patients, was significantly greater than that in the nonobese patients (P < 0.001). Peak serum fluoride level in the obese patients was 51.7 +/- 2.5 mumol/L and exceeded 50 mumol/L for nearly 2 h. Our study showed that serum fluoride concentrations between mildly obese and nonobese patients differed during and after sevoflurane anesthesia.

Lack of the carboxyl terminal sequence of tau in ghost tangles of Alzheimer's disease.

Using seven independent antibodies against the amino terminal to the carboxyl terminal sequence of tau, we biochemically analyzed and compared the neuropathogenesis of two Alzheimer's disease brains from the viewpoint of abnormal processing on tau, the major constituent of paired helical filaments. One showed typical Alzheimer's disease with senile plaques and intracellular neurofibrillary tangles. The other showed advanced Alzheimer's disease with senile plaques and virtually the sole of ghost tangles without intracellular neurofibrillary tangles. We confirmed the previous observation that the carboxyl thirds of tau are tightly associated with paired helical filaments isolated in the presence of SDS. We found that biochemically, ghost tangles were abnormally phosphorylated and lacked the final carboxyl terminal sequence as well as the amino half of tau, unlike intracellular tangles. From these biochemical results taken together with the current evidence for ubiquitin in ghost tangles, we concluded that ghost tangles were extensively processed and irreversibly transformed into highly insoluble extracellular deposits.

Coronary artery fistula with left or right ventricular communication and sinus-node dysfunction.

Coronary artery fistulae that communicate with the left ventricle are quite rare; those accompanied by sinus-node dysfunction are even more unusual. We report 2 cases of congenital coronary-artery-to-left-ventricle fistula with sinus-node dysfunction. In each of these patients, fistulae arose from both left and right coronary arteries. One patient had, in addition, a right coronary artery fistula that communicated with his right ventricle. Sinusnode dysfunction encountered in these 2 patients was likely caused by chronic general ischemia arising from a steal syndrome associated with the fistulae.

Long-term follow-up of patients with sick sinus syndrome: a comparison of clinical aspects among unpaced, ventricular inhibited paced, and physiologically paced groups.

To analyze the prognosis of the sick sinus syndrome (SSS), we compared the clinical aspects among unpaced, ventricular paced, and physiologically paced patients who were followed over a long period. Unpaced intrinsic SSS was not always progressive and patients did not necessarily require permanent pacing. The incidence of concomitant AV conduction disturbance was 65.6% before pharmacologic autonomic block, (PAB), but this was significantly reduced to 31.7% after PAB. Follow-up study of the physiologically paced groups revealed no development of either new or more than second degree AVB. The VVI group had significantly more complications (68%) than the physiologically paced groups, mainly chronic atrial fibrillation (36%) and thromboembolism (20%). In addition, cardiothoracic ratio (CTR) in the VVI group was significantly greater compared with that in the physiologic groups. Nine deaths occurred during the follow-up period in the pacing groups, including six with VVI and three with physiologic pacing. In the VVI pacing group, heart failure and thromboembolism were most commonly the causes of death, while in the physiologic pacing groups, the causes of death were noncardiac. Although the survival rate in the ventricular paced group was not significantly different from that in the physiologic pacing groups, cardiac deaths were fewer in the latter group. Considering our clinical data, the decision to use ventricular pacing needs to be carefully weighed in patients with sick sinus syndrome, and physiologic pacing is more highly recommended.

A morphometric study of the distribution of early coronary atherosclerosis using arteriography.

In order to document the localized prevalence of early atherosclerosis in the major coronary arteries, a study using 50 coronary arteriographies was made from Feb. 1984 to Sep. 1985 in Shinshu University Hospital. Early atherosclerotic stenosis had a spatial distribution with strong incidence on the LAD bifurcations which contained the first diagonal branch, RCA which contained RV branches and LCX which contained the OM branch. Upstream of the bifurcations, the stenotic changes were observed to be concentric with the vessel axes. Downstream of the flowdivider, the lesions were gathered proximally and quickly disappeared distally. Lesions tended to occur eccentrically at the lateral walls of the entrance of the smaller branch. The proximal portions of both the RCA and LCA were almost free of disease. We also tried to investigate the relationship between the bifurcation angle branching off the parent vessels and early sclerotic lesions. We found that the angle between the branches and the plane in contact with the surface of the heart is especially important.

Left atrial myxoma with an unusual tumor vascularity demonstrated by angiography--report of two cases.

We describe two cases of left atrial myxoma, demonstrating an unusual tumor vascularity as revealed by coronary angiograms. Both cases had suffered typical episodes of transient ischemic attack (TIA). Coronary angiography revealed tumor blood supply from coronary arteries in both cases, and also a leakage of contrast medium from the surface of the tumor blood vessels to the left atrium in one case. In the medical literature available in English reviewed so far, no report of such a leakage has been reported. Selective coronary arteriography can be a useful diagnostic method of delineating left atrial myxoma and its blood supply.