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1.  Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice 
Blood Cancer Journal  2013;3(8):e132-.
In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression.
doi:10.1038/bcj.2013.30
PMCID: PMC3763384  PMID: 23955587
17-DMAG; molecular chaperon; Tax; ATL; apoptosis; transgenic model
2.  Dynamic alteration of regional cerebral blood flow during carotid compression and proof of reversibility 
Acta Radiologica Short Reports  2012;1(2):arsr.2012.110015.
Background
It is difficult to non-invasively visualize changes in regional cerebral blood flow caused by manual compression of the carotid artery.
Purpose
To visualize dynamic changes in regional cerebral blood flow during and after manual compression of the carotid artery.
Material and Methods
Two healthy volunteers were recruited. Anatomic features and flow directions in the circle of Willis were evaluated with time-of-flight magnetic resonance angiography (MRA) and two-dimensional phase-contrast (2DPC) MRA, respectively. Regional cerebral blood flow was visualized with territorial arterial spin-labeling magnetic resonance imaging (TASL-MRI). TASL-MRI and 2DPC-MRA were performed in three states: at rest, during manual compression of the right carotid artery, and after decompression. In one volunteer, time-space labeling inversion pulse (Time-SLIP) MRA was performed to confirm collateral flow.
Results
During manual carotid compression, in one volunteer, the right thalamus changed to be fed only by the vertebrobasilar system, and the right basal ganglia changed to be fed by the left internal carotid artery. In the other volunteer, the right basal ganglia changed to be fed by the vertebrobasilar system. 2DPC-MRA showed that the flow direction changed in the right A1 segment of the anterior cerebral artery and the right posterior communicating artery. Perfusion patterns and flow directions recovered after decompression. Time-SLIP MRA showed pial vessels and dural collateral circulation when the right carotid artery was manually compressed.
Conclusion
Use of TASL-MRI and 2DPC-MRA was successful for non-invasive visualization of the dynamic changes in regional cerebral blood flow during and after manual carotid compression.
doi:10.1258/arsr.2012.110015
PMCID: PMC3738342  PMID: 23986833
Territorial arterial spin-labeling magnetic resonance imaging (TASL-MRI); two-dimensional phase-contrast MRA (2DPC-MRA); regional cerebral blood flow; manual carotid artery compression
3.  First observation of two hyperfine transitions in antiprotonic 3He 
Physics Letters. [Part B]  2011;700(1):1-6.
We report on the first experimental results for microwave spectroscopy of the hyperfine structure of p¯3He+. Due to the helium nuclear spin, p¯3He+ has a more complex hyperfine structure than p¯4He+, which has already been studied before. Thus a comparison between theoretical calculations and the experimental results will provide a more stringent test of the three-body quantum electrodynamics (QED) theory. Two out of four super-super-hyperfine (SSHF) transition lines of the (n,L)=(36,34) state were observed. The measured frequencies of the individual transitions are 11.12559(14) GHz and 11.15839(18) GHz, less than 1 MHz higher than the current theoretical values, but still within their estimated errors. Although the experimental uncertainty for the difference of these frequencies is still very large as compared to that of theory, its measured value agrees with theoretical calculations. This difference is crucial to be determined because it is proportional to the magnetic moment of the antiproton.
doi:10.1016/j.physletb.2011.04.029
PMCID: PMC3149286  PMID: 21822351
Antiprotonic helium; Microwave spectroscopy; Hyperfine structure; Three-body QED
4.  Bug22p, a Conserved Centrosomal/Ciliary Protein Also Present in Higher Plants, Is Required for an Effective Ciliary Stroke in Paramecium ▿ † 
Eukaryotic Cell  2010;9(4):645-655.
Centrioles, cilia, and flagella are ancestral conserved organelles of eukaryotic cells. Among the proteins identified in the proteomics of ciliary proteins in Paramecium, we focus here on a protein, Bug22p, previously detected by cilia and basal-body high-throughput studies but never analyzed per se. Remarkably, this protein is also present in plants, which lack centrioles and cilia. Bug22p sequence alignments revealed consensus positions that distinguish species with centrioles/cilia from plants. In Paramecium, antibody and green fluorescent protein (GFP) fusion labeling localized Bug22p in basal bodies and cilia, and electron microscopy immunolabeling refined the localization to the terminal plate of the basal bodies, the transition zone, and spots along the axoneme, preferentially between the membrane and the microtubules. RNA interference (RNAi) depletion of Bug22p provoked a strong decrease in swimming speed, followed by cell death after a few days. High-speed video microscopy and morphological analysis of Bug22p-depleted cells showed that the protein plays an important role in the efficiency of ciliary movement by participating in the stroke shape and rigidity of cilia. The defects in cell swimming and growth provoked by RNAi can be complemented by expression of human Bug22p. This is the first reported case of complementation by a human gene in a ciliate.
doi:10.1128/EC.00368-09
PMCID: PMC2863418  PMID: 20118210
5.  Serial changes in plasma brain natriuretic peptide concentration at the infarct and non-infarct sites in patients with left ventricular remodelling after myocardial infarction 
Heart  2005;91(12):1573-1577.
Objectives: To clarify the role of infarct and non-infarct sites on left ventricular (LV) remodelling after myocardial infarction by measuring brain natriuretic peptide (BNP) from each site.
Methods and results: BNP from the aorta and the anterior interventricular vein (AIV) was measured in 45 patients with first anterior myocardial infarction at one, six, and 18 months. The LV was significantly dilated (> 10 ml/m2 of end diastolic volume from one to 18 months) in 20 patients (remodelling (R) group) but not in 25 others (non-remodelling (NR) group). Patient characteristics and LV functions did not differ significantly at one month but plasma BNP concentration was higher in group R than in group NR (336 (288) v 116 (106) pg/ml, p < 0.01), predicting the degree of LV dilatation. The difference in BNP concentration between the aortic root and AIV (ΔBNP), reflecting BNP secreted from the infarct site, did not differ at one month. In both groups BNP and ΔBNP significantly decreased from one to six months (p < 0.05) and decreased from six months to 18 months, but the change was not significant. BNP and ΔBNP were significantly higher in group R than in group NR after six months, when LV dilatation was not evident in both groups.
Conclusion: Enhanced BNP secretion at one month in the non-infarct and infarct ventricular sites predicts subsequent LV dilatation (that is, remodelling). The slower process of LV remodelling decreased BNP secretion at both sites. Thus, BNP concentration should be useful for monitoring ventricular remodelling after infarction.
doi:10.1136/hrt.2004.049635
PMCID: PMC1769221  PMID: 15774610
brain natriuretic peptide; anterior myocardial infarction; left ventricular dilatation; remodelling; prediction
6.  Variation during the week in the incidence of acute myocardial infarction: increased risk for Japanese women on Saturdays 
Heart  2003;89(4):398-403.
Background: Variations in the incidence of acute myocardial infarction during the week may differ between and within communities, according to lifestyle.
Objective: To identify potential triggering factors for acute myocardial infarction by examining variations in incidence in the days of the week within the Osaka area of Japan.
Patients: Of 2511 consecutive patients in this region who were admitted to hospital for acute myocardial infarction between April 1998 and March 2001 and consented to take part, 2400 who had a definitely identified time of onset were enrolled.
Results: For this group as a whole, no significant difference in incidence was noted between days of the week. However, in subgroup analyses women were shown to have significant variation through the week, peaking on Saturday with a 39% increase in relative risk (p = 0.037); working subjects showed a peak on Monday, with a 26% increase in relative risk (p = 0.038). Stratified analyses showed that in working men there was a prominent Monday peak in the onset of infarction, with a 30% increase in relative risk (p = 0.022), while in working women, there was no significant variation through the week.
Conclusions: Earlier findings of a Monday peak linked to increased physical and mental occupational stress are confirmed. There is also an increase in uncertain risk factors on Saturdays for Japanese women, possibly involving a stressful weekend burden for women. Confirmation of this finding in other communities may help identify triggers of acute myocardial infarction and be useful in prevention.
PMCID: PMC1769260  PMID: 12639867
acute myocardial infarction; weekly variation; occupational stress; Japanese women
7.  Increased smooth muscle contractility of intestine in the genetic null of the endothelin ETB receptor: a rat model for long segment Hirschsprung's disease 
Gut  2002;50(3):355-360.
Background and aims: The endothelin ETB receptor null rat (ETB(−/−)R) has an intestinal segment without ganglia, and this rat is characterised by intestinal obstruction similar to that observed in human Hirschsprung's disease. In the present study, we have examined the myogenic mechanism responsible for obstruction in the ETB(−/−)R.
Results: The ETB(−/−)R had an enlarged belly and the average lifespan was 18.1 days. The bowel from the rectum to the lower part of the small ileum was constricted whereas the upper region was dilated with faecal stasis and thus presented as megaileum. The constricted muscle segments without ganglia had a greater increase in absolute force when stimulated by carbachol, high K+, and endothelin-1 compared with that of normal siblings. In contrast, in the dilated part with ganglia, the absolute contractile force due to these stimulants in the ETB(−/−)R was not different from that in the ETB(+/+)R. Such a functional hypertrophy of the musculature was observed in parts of the colon, caecum, and distal ileum without ganglia but not in the part of the proximal ileum and jejunum with ganglia. Morphological study demonstrated that the thickness of the circular and longitudinal muscle layers was greater in the constricted part of the intestine in the ETB(−/−)R, and these changes were associated with an increase in the number of smooth muscle cells.
Conclusions: Our findings suggest that both increased contractility of smooth muscle and increased thickness of the intestinal muscular wall may contribute to the intestinal obstruction in the ETB(−/−)R.
PMCID: PMC1773131  PMID: 11839714
endothelin receptor null rat; Hirschsprung's disease; megaileum; smooth muscle
8.  Prognostic significance of cardiac 123I metaiodobenzylguanidine imaging for mortality and morbidity in patients with chronic heart failure: a prospective study 
Heart  2001;86(6):656-660.
OBJECTIVE—To determine whether cardiac iodine-123 metaiodobenzylguanidine (123I MIBG) imaging is useful in predicting the prognosis of patients with chronic heart failure.
DESIGN—Cardiac 123I MIBG imaging was done on entry to the study. The cardiac MIBG washout rate was calculated from anterior chest view images obtained 20 and 200 minutes after injection of the isotope. Study patients were divided into two groups with washout rates above and below 27% (the mean value + 2 SD obtained in 20 normal subjects), and were then followed up.
SETTING—Tertiary referral centre.
PATIENTS—79 patients with chronic heart failure in whom the left ventricular ejection fraction was less than 40%.
RESULTS—There were 37 patients in group 1 (washout rate of ⩾ 27%) and 42 in group 2 (< 27%). During a follow up period of between 1 and 52 months, eight patients died suddenly and five died of worsening heart failure in group 1, while none died in group 2; 13 patients in group 1 and four in group 2 were admitted to hospital for progressive heart failure. Kaplan-Meier analysis showed that group 1 had a significantly higher mortality and morbidity (p = 0.001 and p < 0.001, respectively) than group 2.
CONCLUSIONS—Cardiac 123I MIBG washout rate seems to be a good predictor of prognosis in patients with chronic heart failure.


Keywords: chronic heart failure; sudden death; cardiac adrenergic nerve activity
doi:10.1136/heart.86.6.656
PMCID: PMC1730035  PMID: 11711461
9.  Sustained left ventricular diastolic dysfunction after exercise in patients with dilated cardiomyopathy 
Heart  1998;80(3):263-269.
Objective—To investigate the recovery process of exercise induced diastolic dysfunction in heart failure, using Doppler echocardiographic techniques.
Design and patients—Transmitral flow velocity profiles and standard non-invasive haemodynamic indices were obtained serially over seven days after symptom limited bicycle exercise tests in 18 patients with dilated cardiomyopathy and eight normal subjects. In three patients with cardiomyopathy we also measured the pulmonary capillary wedge pressure for 24 hours after exercise.
Results—The intensity of exercise, as assessed by respiratory gas analysis, was lower in patients with dilated cardiomyopathy than in normal subjects. Despite the higher exercise level, all haemodynamic variables returned to baseline within one hour after exercise in normal subjects. In contrast, patients with dilated cardiomyopathy showed a sustained decrease in the peak early diastolic filling velocity and a sustained increase in the deceleration time of early filling for 24 hours or more after exercise. Because other haemodynamic variables recovered within one hour after exercise even in patients with dilated cardiomyopathy, the postexercise changes in ventricular filling were not explained by changes in loading conditions.
Conclusions—Exercise induced diastolic left ventricular dysfunction of the failing heart persists for 24 hours or more after exercise. The efficacy of exercise training on a daily basis in dilated cardiomyopathy requires further evaluation.

 Keywords: exercise;  chronic heart failure;  mitral flow velocity;  diastolic stunning
PMCID: PMC1761094  PMID: 9875086
10.  Prediction of the effectiveness of long term β blocker treatment for dilated cardiomyopathy by signal averaged electrocardiography 
Heart  1998;79(3):256-261.
Objective—To determine whether the effectiveness of long term β blocker treatment for idiopathic dilated cardiomyopathy can be predicted by signal averaged electrocardiography (ECG).
Patients—31 patients with dilated cardiomyopathy and without bundle branch block were included in a retrospective study and 16 in a prospective study.
Methods—A signal averaged ECG was recorded before β blocker treatment, and three variables were measured from the vector magnitude: QRS duration, root mean square voltage for the last 40 ms (RMS40), and duration of the terminal low amplitude signals (< 40 µV) (LAS40). In the retrospective study, these variables were compared among good responders (showing ⩾ 0.10 increase in ejection fraction 12 months after start of β blocker treatment) and poor responders without such improvement. The validity of the signal averaged ECG criteria for prediction of the response to β blocker treatment was examined in the prospective study.
Results—In the retrospective study, good responders (n = 16) had a shorter QRS duration (mean (SD): 122.9 (11) v 138 (14.4) ms, p < 0.005) and LAS40 (33.1 (8.9) v 42.5 (7.8) ms, p < 0.005), and a higher RMS40 (31.6 (16.3) v 19.0 (10.3) µV, p < 0.02) than poor responders (n = 15). Signal averaged ECG criteria for good response were defined as two or more of the following: QRS duration < 130 ms, RMS40 > 20 µV, LAS40 < 40 ms (sensitivity 81%, specificity 73%). In the prospective study, six of seven patients who met these criteria showed a good response to the β blocker treatment, while eight of nine who did not showed a poor response (χ2 = 6.1, p < 0.02). The signal averaged ECG criteria gave a sensitivity of 86% and a specificity of 89% for predicting the effectiveness of β blocker treatment.
Conclusions—A signal averaged ECG might be useful in predicting the effectiveness of β blocker treatment for dilated cardiomyopathy.

 Keywords: signal averaged ECG;  β blockers;  dilated cardiomyopathy
PMCID: PMC1728625  PMID: 9602659
11.  Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs. 
Journal of Clinical Investigation  1998;101(8):1643-1653.
The activation of platelets and the formation of neutrophil- platelet conjugates may lead to the development of thromboemboli. We studied whether blockade of adenosine receptors during coronary hypoperfusion may cause thromboemboli via P-selectin-dependent mechanisms in 30 open-chest dogs. When coronary blood flow was reduced to 20% of the control, it was stable at low levels with increases in adenosine levels. When 8-p-sulfophenyltheophylline, an adenosine receptor antagonist, was infused during coronary hypoperfusion, coronary blood flow decreased gradually and approached almost zero 20 min after its administration. Histological examination revealed thromboemboli in the small coronary vessels. During hypoperfusion in the presence of 8-p-sulfophenyltheophylline, the mAb against P-selectin attenuated both the reduction in coronary blood flow and the formation of thromboemboli, and improved contractile and metabolic dysfunction of the myocardium. Flow cytometric analysis indicated that the expression of P-selectin on platelet and neutrophil-platelet adhesion were increased during coronary hypoperfusion, and that both were further augmented by 8-p-sulfophenyltheophylline. Immunohistochemical examination showed no staining of P-selectin in the ischemic myocardium. Adenosine inhibited the thrombin-induced expression of P-selectin on platelet and neutrophil- platelet adhesion via adenosine A2 receptors. Adenosine appears to inhibit the formation of thromboemboli during coronary hypoperfusion by suppressing the expression of P-selectin on platelets and neutrophil-platelet adhesion.
PMCID: PMC508745  PMID: 9541494
12.  Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells. 
Journal of Clinical Investigation  1997;99(12):2961-2970.
It has been reported that PTH exerts bone-forming effects in vivo when administered intermittently. In the present study, the anabolic effects of PTH(1-34) on osteoblast differentiation were examined in vitro. Osteoblastic cells isolated from newborn rat calvaria were cyclically treated with PTH(1-34) for the first few hours of each 48-h incubation cycle. When osteoblastic cells were intermittently exposed to PTH only for the first hour of each 48-h incubation cycle and cultured for the remainder of the cycle without the hormone, osteoblast differentiation was inhibited by suppressing alkaline phosphatase activity, bone nodule formation, and mRNA expression of alkaline phosphatase, osteocalcin, and PTH/PTHrP receptor. Experiments using inhibitors and stimulators of cAMP/protein kinase A (PKA) and Ca2+/PKC demonstrated that cAMP/PKA was the major signal transduction system in the inhibitory action of PTH. In contrast, the intermittent exposure to PTH for the first 6 h of each 48-h cycle stimulated osteoblast differentiation. Both cAMP/ PKA and Ca2+/PKC systems appeared to be involved cooperatively in this anabolic effect. Continuous exposure to PTH during the 48-h incubation cycle strongly inhibited osteoblast differentiation. Although both cAMP/PKA and Ca2+/PKC were involved in the effect of continuous exposure to PTH, they appeared to act independently. A neutralizing antibody against IGF-I blocked the stimulatory effect on alkaline phosphatase activity and the expression of osteocalcin mRNA induced by the 6-h intermittent exposure. The inhibitory effect induced by the 1-h intermittent exposure was not affected by anti-IGF-I antibody. These results suggest that PTH has diverse effects on osteoblast differentiation depending on the exposure time in vitro mediated through different signal transduction systems. These in vitro findings explain at least in part the in vivo action of PTH that varies with the mode of administration.
PMCID: PMC508148  PMID: 9185520
13.  Intrauterine transmission of human T-cell leukemia virus type I in rats. 
Journal of Virology  1995;69(2):1302-1305.
To analyze intrauterine transmission, MT-2 cells, a human T-cell line producing human T-cell leukemia virus type I (HTLV-I), were injected into eight pregnant F344 rats, and cesarean section was performed at day 23 of pregnancy. HTLV-I provirus was detected by PCR in the liver and spleen taken from one of the eight fetuses. Moreover, 71 offspring were delivered by cesarean section from the remaining seven dams and fostered by seven normal rats. HTLV-I provirus was detected in peripheral blood mononuclear cells in 2 of the 71 offspring 4 weeks after cesarean section. These results indicate for the first time the intrauterine transmission of HTLV-I. To confirm the postnatal transmission, MT-2 cells were injected into a dam within 24 h after delivery, and six offspring were fostered by this dam. HTLV-I provirus was detected in peripheral blood mononuclear cells of all six offspring. This animal model may be useful for analysis and prevention of mother-to-child transmission of HTLV-I.
PMCID: PMC188709  PMID: 7815510
14.  Evidence for deactivation of both ectosolic and cytosolic 5'-nucleotidase by adenosine A1 receptor activation in the rat cardiomyocytes. 
Journal of Clinical Investigation  1994;94(6):2451-2456.
Adenosine, an important regulator of many cardiac functions, is produced by ectosolic and cytosolic 5'-nucleotidase. The activity of these enzymes is influenced by several ischemia-sensitive metabolic factors, e.g., ATP, ADP, H+, and inorganic phosphate. However, there is no clear evidence that adenosine itself affects 5'-nucleotidase activity. This study tested whether adenosine decreases the activity of ectosolic and cytosolic 5'-nucleotidase. Cardiomyocytes were isolated from adult male Wistar rats and suspended in the modified Hepes-Tyrode buffer solution. After stabilization, isolated cardiomyocytes were incubated with and without adenosine (10(-9) - 10(-4) M). Ectosolic and cytosolic 5'-nucleotidase activity was decreased by exogenous adenosine (ectosolic 5'-nucleotidase activity, 20.6 +/- 2.3 vs. 8.6 +/- 1.6 mumol/min per 10(6) cells [P < 0.05]; cytosolic 5'-nucleotidase activity, 2.47 +/- 0.58 vs. 1.61 +/- 0.54 mumol/min per 10(6) cells [P < 0.05] at 10(-6) M adenosine) after 30 min. The decrease in ectosolic and cytosolic 5'-nucleotidase activity was inhibited by 8-phenyltheophylline and pertussis toxin, and was mimicked by N6-cyclohexyladenosine, an adenosine A1 receptor agonist. Neither CGS21680C, and A2 receptor agonist, nor cycloheximide deactivated ectosolic and cytosolic 5'-nucleotidase. Thus, we conclude that activation of adenosine A1 receptors is coupled to Gi proteins and attenuates ectosolic and cytosolic 5'-nucleotidase activity in rat cardiomyocytes.
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PMCID: PMC330077  PMID: 7989602
15.  Induction of manganese superoxide dismutase in rat cardiac myocytes increases tolerance to hypoxia 24 hours after preconditioning. 
Journal of Clinical Investigation  1994;94(6):2193-2199.
Manganese superoxide dismutase (Mn-SOD) is induced in ischemic hearts 24 h after ischemic preconditioning, when tolerance to ischemia is acquired. We examined the relationship between Mn-SOD induction and the protective effect of preconditioning using cultured rat cardiac myocytes. Exposure of cardiac myocytes to brief hypoxia (1 h) decreased creatine kinase release induced by sustained hypoxia (3 h) that follows when the sustained hypoxia was applied 24 h after hypoxic preconditioning (57% of that in cells without preconditioning). The activity and content of Mn-SOD in cardiac myocytes were increased 24 h after hypoxic preconditioning (activity, 170%; content, 139% compared with cells without preconditioning) coincidentally with the acquisition of tolerance to hypoxia. Mn-SOD mRNA was also increased 20-40 min after preconditioning. Antisense oligodeoxyribonucleotides corresponding to the initiation site of Mn-SOD translation inhibited the increases in the Mn-SOD content and activity and abolished the expected decrease in creatine kinase release induced by sustained hypoxia after 24 h of hypoxic preconditioning. Sense oligodeoxyribonucleotides did not abolish either Mn-SOD induction or tolerance to hypoxia. These results suggest that the induction of Mn-SOD in myocytes by preconditioning plays a pivotal role in the acquisition of tolerance to ischemia at a later phase (24 h) of ischemic preconditioning.
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PMCID: PMC330044  PMID: 7989574
16.  High incidence of HAM/TSP-like symptoms in WKA rats after administration of human T-cell leukemia virus type 1-producing cells. 
Journal of Virology  1994;68(11):7221-7226.
We demonstrate a significantly high incidence of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM)-or tropical spastic paraparesis (TSP)-like symptoms in WKA rats after injection with HTLV-1-producing MT-2 cells, while no symptoms were observed in F344 rats injected with MT-2 cells or in control WKA rats. Five of the eight (63%) WKA rats injected with MT-2 cells showed HAM/TSP-like paraparesis at 105 weeks of age, but none of seven MT-2-injected F344 rats or eight control WKA rats showed symptoms. This high incidence of HAM/TSP-like symptoms in WKA rats was statistically significant (P < 0.05). Six of the eight (75%) WKA rats injected with MT-2 cells showed HAM/TSP-like paraparesis at 108 weeks of age. HAM/TSP-like symptoms were also observed in one of the two WKA rats injected with HTLV-1-producing Ra-1 cells at 128 weeks of age. HTLV-1 provirus was detected in peripheral blood mononuclear cells in both WKA and F344 rats. The provirus was detected in the spinal cords of the HAM/TSP-like WKA rats that had severe neuropathological changes. WKA and F344 rats showed no significant difference in antibody response against HTLV-1 Gag antigen. However, the antibody response against the C-terminal half of gp46 HTLV-1 envelope protein was lower in WKA rats than in F344 rats. Pathological analysis of the HAM/TSP-like rats showed degeneration of the white matter of the spinal cord and peripheral nerves. These findings suggest that both the genetic background of the host and HTLV-1 infection are important in neuropathogenesis of HAM/TSP-like paraparesis in rats.
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PMCID: PMC237161  PMID: 7933104
17.  Alpha 1-adrenoceptor activation mediates the infarct size-limiting effect of ischemic preconditioning through augmentation of 5'-nucleotidase activity. 
Journal of Clinical Investigation  1994;93(5):2197-2205.
We have reported that ischemic preconditioning may limit infarct size by increasing 5'-nucleotidase activity. The present study tested whether alpha 1-adrenoceptor stimulation in ischemic preconditioning mediates the infarct size-limiting effect through augmentation of 5'-nucleotidase activity. The coronary artery was occluded four times for 5 min separated by 5 min of reperfusion (ischemic preconditioning) in 82 dogs. Then the coronary artery was occluded for 90 min followed by 6 h of reperfusion. Infarct size normalized by risk area was smaller after ischemic preconditioning than in the control group (40.6 +/- 2.3 vs 6.7 +/- 2.0%, P < 0.001), even though no difference existed in endomyocardial collateral flow during ischemia (8.7 +/- 1.0 vs 8.9 +/- 1.0 ml/100 g per min). Ectosolic and cytosolic 5'-nucleotidase activity was increased after ischemic preconditioning. However, prazosin blunted the infarct size-limiting effect of ischemic preconditioning (infarct size: 42.8 +/- 3.7%). Intermittent alpha 1-adrenoceptor stimulation by methoxamine mimicked the increase in 5'-nucleotidase activity and the infarct size-limiting effect, which were abolished by alpha, beta,-methyleneadenosine 5'-diphosphate. Identical results were obtained in the conscious model (n = 20). Therefore, we conclude that increases in ectosolic 5'-nucleotidase activity due to alpha 1-adrenoceptor activation may contribute to the infarct size-limiting effect of ischemic preconditioning.
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PMCID: PMC294363  PMID: 8182151
18.  Insulin attenuates agonist-mediated calcium mobilization in cultured rat vascular smooth muscle cells. 
Journal of Clinical Investigation  1993;92(3):1161-1167.
Insulin has been shown to attenuate pressor-induced vascular contraction, but the mechanism for this vasodilatory action is unknown. This study examines the effect of insulin on angiotensin II (ANG II)-induced increments in cytosolic calcium in cultured rat vascular smooth muscle cells (VSMC). 20-min incubations with insulin (10 microU/ml to 100 mU/ml) did not alter basal intracellular calcium concentration ([Ca2+]i), but inhibited the response to 100 nM ANG II in a dose-dependent manner (ANG II alone, 721 +/- 54 vs. ANG II + 100 mU/ml insulin, 315 +/- 35 nM, P < 0.01). A similar effect of insulin on ANG II action was observed in calcium poor buffer. Moreover, insulin did not effect calcium influx. ANG II receptor density and affinity were not affected by 24-h incubation with insulin. To further clarify the mechanisms of these observations, we measured ANG II-induced production of inositol 1,4,5-triphosphate (IP3), and IP3-releasable 45Ca. Insulin treatment did not alter ANG II-stimulated IP3 production. However, IP3-stimulated release of 45Ca in digitonin permeabilized cells was significantly reduced after 5-min incubations with 100 mU/ml insulin. Thapsigargin induced release of calcium stores was also blocked by insulin. Thus, insulin attenuates ANG II-stimulated [Ca2+]i primarily by altering IP3-releasable calcium stores. Insulin effects on ANG II-induced [Ca2+]i were mimicked by preincubation of VSMC with either sodium nitroprusside or 8-bromo-cGMP. As elevations in cGMP in vascular tissue lower [Ca2+]i, it is possible that insulin affects IP3 release of calcium by a cGMP-dependent mechanism that would contribute to its vasodilatory effects.
PMCID: PMC288253  PMID: 8397220
20.  A novel Bacillus subtilis gene involved in negative control of sporulation and degradative-enzyme production. 
Journal of Bacteriology  1990;172(4):1783-1790.
We have cloned a 2.5-kilobase fragment of the Bacillus subtilis genomic DNA which caused the reduction of extracellular and cell-associated protease levels when present in high copy number. This fragment, in multicopy, was also responsible for reduced levels of alpha-amylase, levansucrase, alkaline phosphatase, and sporulation inhibition. The gene relevant to this pleiotropic phenotype is referred to as pai. By DNA sequencing, two open reading frames--ORF1 and ORF2, encoding polypeptides of 172 and 207 amino acid residues, respectively--were found. These open reading frames seemed to form an operon. Deletion analysis revealed that an entire region for ORF1 and ORF2 was necessary for the pai phenotype. In addition, it was observed that the presence of the pai gene, in multicopy, caused overproduction of two proteins (molecular masses, 21 and 24 kilodaltons [kDa]). Analyses of the N-terminal amino acid sequences of these two proteins suggested that they were products of ORF1 and ORF2. Disruption of the pai gene at ORF1 in the genomic DNA resulted in the release of repression on protease synthesis and sporulation in glucose-enriched (2%) medium. The mutant carrying insertional disruption at ORF2 could not be constructed, suggesting that the ORF2 product, the 24-kDa protein, is essential for growth. The 21-kDa protein contains a helix-turn-helix domain observed in other DNA-binding proteins. Chromosomal mapping of pai indicated that this gene is located close to thr-5. These results suggest that the pai gene is a novel transcriptional-regulation gene involved in glucose repression.
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PMCID: PMC208669  PMID: 2108124
21.  Beta-lactam resistance in Aeromonas spp. caused by inducible beta-lactamases active against penicillins, cephalosporins, and carbapenems. 
Use of cefoperazone in a patient with Aeromonas caviae in the respiratory tract selected a mutant that constitutively produced beta-lactamase. This mutant, in contrast to its parental strain with an inducible beta-lactamase, showed enhanced resistance to newer cephalosporins and aztreonam. This observation suggested that species of Aeromonas, like those of other genera with inducible beta-lactamases, may pose therapeutic problems associated with the rapid development of multiple beta-lactam resistance. Thus, a study was designed to identify the beta-lactamases in 12 strains representing four species of Aeromonas and assess their role in drug resistance. Eleven strains possessed inducible beta-lactamases. One strain showed no detectable activity. An analysis of substrate and inhibitor profiles, isoelectric points, and beta-lactam susceptibility patterns revealed the presence of at least four distinguishable inducible beta-lactamases. These enzymes were involved in the resistance of strains within the genus to penicillins, cephalosporins, aztreonam, and imipenem but not cefoxitin. Unlike most other organisms with inducible beta-lactamases, all four strains of A. caviae, one of four strains of A. sobria, and one of three strains of A. hydrophila possessed two distinct inducible beta-lactamases. Furthermore, substrate and inhibitor profiles revealed that many of these Aeromonas beta-lactamases were distinct from inducible enzymes that have been characterized in other genera of gram-negative bacteria.
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PMCID: PMC175858  PMID: 3264129
22.  Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus. 
Molecular and Cellular Biology  1986;6(6):2198-2206.
Three benzenoid ansamycin antibiotics (herbimycin, macbecin, and geldanamycin) were found to reduce the intracellular phosphorylation of p60src at a permissive temperature (33 degrees C) in a rat kidney cell line infected with a temperature-sensitive mutant of Rous sarcoma virus. This effect was accompanied by morphological changes from the transformed to the normal phenotype. The filamentous staining pattern of actin fibers was observed in the cells treated with these antibiotics at 33 degrees C. Removal of the antibiotics allowed the cells to revert to the transformed morphology. Ansamitocin, another benzenoid ansamycin, and naphthalenoid ansamycins such as streptovaricin and rifamycins did not show this effect. Pulse-labeling of the antibiotic-treated cultures with 32Pi showed a marked reduction of 32P radioactivity incorporated into p60src. A parallel experiment with [35S]methionine showed that synthesis of p60src was slightly inhibited. The immune complex prepared by mixing the herbimycin-treated cell extracts with antibody against p60src was inactive in vitro in phosphorylating the complex itself. On the contrary, the immune complex derived from untreated cells was active in vitro even in the presence of the antibiotics. These results suggest that benzoquinonoid ansamycins have no direct effect on src kinase but destroy its intracellular environment, resulting in an irreversible alteration of p60src and loss of catalytic activity.
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PMCID: PMC367760  PMID: 3023921
23.  Site and severity of coronary narrowing and infarct size in man. 
British Heart Journal  1980;44(3):271-279.
The relation between the site and severity of coronary artery lesion and infarct size was investigated in 59 patients with acute myocardial infarction. All patients had no prior myocardial infarction and had at least one significant coronary narrowing (greater than or equal to 75%) in one of the major coronary arteries or in the first diagonal branch. Left ventriculography and selective coronary arteriography were performed on average 2.2 months after the onset of infarction to identify the site and severity of coronary narrowing and to assess the extent of the non-contracting segment (akinetic, dyskinetic, or aneurysmal). Thirty-four of 59 patients were studied enzymatically and total CK released was taken as an indication of infarct size. Non-contracting segment and total CK released in group L-I (narrowing proximal to the first diagonal branch) were significantly larger than those in group L-II (a coronary lesion distal to the branch). The data also indicate that the perfusion area of the first diagonal branch is as large as that of the left anterior descending artery below the first diagonal branch. In contrast to left anterior descending artery disease, the involvement of the right ventricular branch did not significantly influence the infarct size. However, infarct size was significantly larger in eight patients with the left ventricular branch of the right coronary artery supplying the predominantly large area of posterior wall of the left ventricle than in nine patients with small left ventricular branches. It was also shown that the severity of coronary narrowing does not correlate with the infarct size in either left anterior descending or right coronary artery disease.
PMCID: PMC482397  PMID: 7426184
24.  Chemiluminescence-linked immunoassay for detection of mumps virus antibodies. 
Journal of Clinical Microbiology  1980;12(2):140-143.
We have developed a simple and sensitive chemiluminescence-linked immunoassay (CLIA) for determining mumps virus antibodies. Luminol molecules were used as markers, and polystyrene balls were used as antigen carriers. The CLIA was compared with an enzyme-linked fluorescence assay and a hemagglutination inhibition test on a total of 40 serum specimens obtained from 29 donors with natural infection or vaccination. There was good correlation between the three methods, and the sensitivity of the CLIA was about 10 times higher than that of the hemagglutination inhibition test, although it was slightly inferior to that of the enzyme-linked fluorescence assay. Moreover, the time course of light emission from the labeled antibody was rapid, and therefore in the CLIA the quantitation of the marker takes only a short time.
PMCID: PMC273543  PMID: 7014604
25.  Evaluation of praecordial ST segment mapping as an index of infarct size in patients with acute myocardial infarction. 
British Heart Journal  1979;42(6):726-733.
We evaluated the usefulness and limitations of praecordial ST segment mapping as a clinical means of assessing the size of acute myocardial infarction in 14 patients with anterior myocardial infarction and 13 patients with inferior myocardial infarction. sigma ST, the sum of ST segment elevations, and nST, the number of leads showing ST segment elevation, were obtained from serial electrocardiograms recorded through 39 praecordial leads. The infarct size and period of the evolution of myocardial infarction were estimated respectively from the total creatine kinase (CK) released and the serial changes of the CK releasing rate. sigma ST and nST obtained at the time when the CK release had ceased correlated closely with the total CK released. Peak sigma ST and nST, and values 48 hours after the onset of myocardial infarction, also correlated well with the total CK released; but those on admission or 12 hours after the onset correlated poorly. These results suggest that sigma ST and nST at the end of evolution of myocardial infarction or 48 hours after the onset may be two useful indices for the assessment of infarct size in patients with either anterior or inferior myocardial infarction.
PMCID: PMC482228  PMID: 534591

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