Washout Ratio in the Hepatic Vein Measured by Contrast-Enhanced Ultrasonography to Distinguish Between Inflammatory and Noninflammatory Hepatic Disorders in Dogs.

BACKGROUND: Perflubutane microbubbles, a second-generation ultrasound contrast agent, are phagocytized by Kupffer cells. This characteristic may be useful to differentiate diffuse hepatic diseases in dogs. HYPOTHESIS/OBJECTIVES: To determine whether the washout ratio in the hepatic vein (HV) measured by contrast-enhanced ultrasonography (CEUS) can distinguish between inflammatory and noninflammatory hepatic disorders in dogs. ANIMALS: Forty-one client-owned dogs with hepatic disorders including 14 with hepatitis, 7 with primary hypoplasia of the portal vein (PHPV), 9 with congenital portosystemic shunt (cPSS), and 11 with other hepatopathy were enrolled. Six dogs without hepatic disease also were evaluated as healthy controls. METHODS: Dogs with hepatic disorders were prospectively included. Contrast-enhanced ultrasonography of the HV was performed for 2 minutes. Washout ratio was defined as the attenuation rate from peak intensity to the intensity at the end of the CEUS study. RESULTS: Washout ratio in the hepatitis group (median, 18.0%; range, 2.0-37.0%) was significantly lower than that of the PHPV (median, 52.2%; range, 11.5-86.3%), cPSS (median, 60.0%; range, 28.6-77.4%), other hepatopathy (median, 70.5%; range, 26.6-88.4%), and normal (median, 78.0%; range, 60.7-91.7%) groups. The area under the receiver operating characteristic curve for hepatitis was 0.960, with a 95% confidence interval (CI) of 0.853-0.990. Washout ratio ≤37.1% resulted in a sensitivity of 100% (95% CI, 78.5-100%) and specificity of 85.2% (95% CI, 67.5-94.1%) for the prediction of hepatitis. CONCLUSIONS AND CLINICAL IMPORTANCE: Washout ratio can distinguish hepatitis from the other noninflammatory disorders with high accuracy. This result might reflect impaired Kupffer cell phagocytosis in dogs with hepatitis.

[Ruptured proximal aorta after operation for type A dissection presenting as opacified left hemothorax; report of a case].

We report an unusual clinical presentation of ruptured proximal aorta as a left hemothorax after operation for type A dissection. A 74-year-old man who had undergone ascending aortic replacement for acute type A dissection 4 months previously developed a loss of consciousness followed by shock state. Both chest X-ray and computed tomography (CT) scan revealed opacified left hemothorax. The patient died during a diagnostic procedure. Post mortem examination showed rupture of proximal aortic dissection extended to the left pleural cavity path through the right atrial wall and the right ventricular wall.

[Transapical aortic cannulation in the operation of acute type A aortic dissection].

From June 2003 to November 2006, transapical aortic cannulation was performed in 73 patients (41 men and 32 women, mean age 63 years, 64 hemiarch repair and 9 total arch replacement) with acute type A aortic dissection. A 1-cm incision was made in the apex of the left ventricle, and a 7-mm soft and flexible cannula was passed through the apex and across the aortic valve until positioned in the ascending aorta under guidance by transesophageal echocardiography. In all cases, cardiopulmonary bypass flow was sufficient. There were no malperfusion events. Our results showed that transapical aortic cannulation was secure and useful for repair of acute type A aortic dissection.

Vasorelaxant effect of olprinone, an inhibitor of phosphodiesterase 3, on mesenteric small artery and vein of rabbits.

The effects of olprinone, a cardiotonic agent that inhibits cyclic GMP (cGMP)-inhibited phosphodiesterase, was studied on isolated rabbit mesenteric small artery and vein. In the presence of indomethacin and propranolol, olprinone at concentrations of 10 nM to 10 microM and 1 microM to 100 microM relaxed norepinephrine-stimulated mesenteric artery and vein in a concentration-dependent manner, respectively. The relaxation was not endothelium-dependent in the artery. Removal of the endothelium, however, increased marginally the response of the vein to olprinone. Olprinone-induced relaxation was less pronounced in arteries contracted with high KCl solution + norepinephrine than in those contracted with norepinephrine alone. Nicardipine inhibited this attenuating effect of high KCl solution on the olprinone-induced relaxation. Olprinone (1 microM) enhanced the relaxation of artery and vein in response to a cAMP-increasing agent, 6-(3-dimethylaminopropionyl) forskolin (NKH477), but not to a cGMP- increasing agent, glyceryl trinitrate. Norepinephrine (10 microM) and caffeine (5 mM) elicited a transient, phasic contraction of the artery in Ca2+-free solution. Both olprinone and NKH477 attenuated more potently the norepinephrine-induced contraction than the caffeine-induced contraction. When norepinephrine (10 microM) and caffeine (5 mM) were successively applied in Ca2+-free solution, the contractile effect of caffeine was diminished compared to that in artery which had not been pretreated with norepinephrine. When the contraction in response to norepinephrine was partially attenuated by 1 microM olprinone, the following contraction evoked by caffeine was enlarged. It is concluded that olprinone relaxes the small artery more strongly than the vein via its direct action on smooth muscles. It is suggested that olprinone attenuates norepinephrine-induced contraction through inhibition of receptor-operated transmembrane Ca2+ influx and Ca2+ release from intracellular storage sites.

TAN-1511 A, B and C, microbial lipopeptides with G-CSF and GM-CSF inducing activity.

The microbial lipopeptides, TAN-1511 A, B and C, were isolated from the culture broth of Streptosporangium amethystogenes subsp. fukuiense AL-23456. Their structures were elucidated on the basis of their reactions and spectroscopic analyses. These lipopeptides were mixtures of molecules having different lengths of fatty acids. The metabolites stimulated the proliferation of bone marrow cells from BALB/c female mice at very low concentrations (concentration giving 30% increase: A and B, 0.313 ng/ml; C, 1.25 ng/ml). We confirmed that chemically synthesized TAN-1511 A analogue [(2R,6R)-2-tetradecanoylamino-6,7- bis(hexadecanoyloxy)-4-thiaheptanoyl-Gly-Gly-Gly-Glu-Thr-Thr -OH] stimulated the proliferation of bone marrow cells in a manner similar to that of natural TAN-1511 A. This analogue induced the secretion of both granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), and potentiated the generation of Gr-1 positive cells in the bone marrow cell culture. Moreover, it effected the G-CSF mediated restoration of granulocytopoiesis in a murine leukopenia model.

[Pharmacokinetics and clinical studies on flomoxef in neonates and premature infants. A study of flomoxef in the perinatal collaboration research group].

We investigated pharmacokinetics and clinical effects of flomoxef sodium (6315-S, FMOX) in neonates and premature infants. These results are summarized as follows: 1. Pharmacokinetics (1) Plasma concentration (Ct) and half-lives (T1/2) were determined upon after intravenous one-shot injection (i.v.) of FMOX to neonates of different day-age groups (0-3 (n = 25), 4-7 (n = 18), 8-28 (n = 32) days of birth). At a dose of 10 mg/kg. i.v., mean C30 (30 minutes concentration) values were 21.2, 21.8 and 21.3 micrograms/ml, respectively, in the different groups mentioned above, and the mean T1/2 values were 3.37, 1.85 and 1.63 hours. At 20 mg/kg i.v., mean C15 (15 minutes concentration) values were 54.4, 51.4 and 50.7 micrograms/ml, and mean T1/2's were 2.99, 2.32 and 1.79 hours, respectively. At a dose of 40 mg/kg i.v., mean C15 values were 104.0, 95.9 and 99.2 micrograms/ml, and the mean T1/2's were 3.40, 1.20 and 1.80 hours, respectively. (2) Plasma concentrations and T1/2 after intravenous one-shot injection of FMOX in premature infants in group (0-3 (n = 14), 4-7 (n = 10), 8-28 (n = 13) days of birth). Mean C15's at doses of 10, 20 and 40 mg/kg in the different groups of infants were 24.0, 28.6, 21.7 and 54.0, 54.6, 55.5 and 98.2, 93.0, 106.0 micrograms/ml, and T1/2's were 4.10, 2.53, 2.57 and 4.28, 2.27, 3.02 and 4.66, 2.86, 2.09 hours, respectively. Mean Cmax values were clearly dose dependent, and mean T1/2 values tended to be longer in premature infants compared to neonates. (3) Urinary recovery rate of FMOX after intravenous injection in neonates and premature infants. Mean urinary recovery rates of FMOX in the first 6 hours after i.v. (one-shot) at doses of 10, 20 and 40 mg/kg to neonates and premature infants were 38.9-62.8% in the neonates and 30.7-61.5% in the premature infants. (4) Plasma concentrations and urinary recovery rates upon 1 hour drip infusion of 20 mg/kg in the neonate groups (or the premature infant groups) as follows: Mean C50 values were 31.0, 32.7 and 23.4 micrograms/ml, and T1/2 were 2.94, 3.68 and 2.25 hours, respectively. The recovery rates were 35.2-52.9% in the first 6 hours after administration. 2. Clinical studies The number of clinically evaluable cases in the FMOX treatment of premature infants was 199, in which the causative pathogens were identified in 71 cases (A group) and not identified in 128 cases (B group).(ABSTRACT TRUNCATED AT 400 WORDS)

[Flomoxef in neonates and young infants; clinical efficacy, pharmacokinetic evaluation and effect on the intestinal bacterial flora].

Forty-three newborn and young infants including 13 low-birth-weight (LBW) infants were treated with flomoxef (FMOX) and the clinical efficacy and side effect were evaluated. The ages of the patients ranged from 0 to 99 days, and their body weights from 797 to 9,000 g. Dose levels were 10.5 to 48.5 mg/kg every 6 to 8 hours for 3 to 12 days. Those patients who responded to the FMOX treatment included 8 infants with sepsis, 14 with suspected sepsis, 6 with intrauterine infection, 2 with meningitis, 7 with pneumonia, 1 with staphylococcal scalded skin syndrome, 1 with epididymitis and 4 with urinary tract infections. The results were excellent in 17 and good in 22 patients. The drug was well tolerated, although diarrhea occurred in 2, slightly elevated serum concentrations of transaminases in 2, and eosinophilia and thrombocytosis in 1 patient each. Pharmacokinetic studies on FMOX with 20 mg/kg dose were done in 19 patients including 8 LBW infants. Serum concentrations at 15 minutes after intravenous bolus injection in five 1- to 6-day-old LBW, five 1- to 6-day-old and four 8- to 19-day-old mature infants were 52.6, 52.7 and 58.0 micrograms/ml, respectively, and those at 4 hours were 22.1, 13.3 and 5.2 micrograms/ml, respectively. Serum half-lives of the drug were 3.93, 2.29 and 1.62 hours, respectively, and excretion rates of this drug into urine in the first 6 hours after administration were 30.4, 45.1 and 58.7%, respectively. Mean serum concentrations just after intravenous 1-hour drip infusion in three 8- to 54-day-old LBW and two 8- and 10-day-old mature infants, were 31.5 and 18.9 micrograms/ml, respectively, and those at 4 hours were 15.3 and 4.3 micrograms/ml, respectively. Serum half-lives of the drug were 2.88 and 1.75 hours, respectively, and excretion rates of the drug into urine in the first 6 hours were 22.6 and 47.5%, respectively. The cerebrospinal fluid level at 3 hours after a dose was 7.09 micrograms/ml on the second day of treatment in a patient with Staphylococcus aureus meningitis receiving 50 mg/kg of the drug every 6 hours per day. Its level at 1 hour after a dose was 3.52 micrograms/ml on the 8th day of treatment in the same patient. The influence of FMOX on the fecal flora was studied in 7 patients. The characteristic pattern observed during the drug administration was the disappearance of Bifidobacterium, the decrease or disappearance of Enterobacteriaceae and the preservation of Streptococcus.(ABSTRACT TRUNCATED AT 250 WORDS)

The dNTP imbalance death.

The mechanism of intracellular deoxyribonucleoside-triphosphates (dNTP) pool imbalance-induced cell death in mouse FM3A (F28-7) cells was studied. When the cells were treated with 5-fluorodeoxyuridine (FdUrd), deoxyadenosine, 2-chlorodeoxyadenosine, or alpha,alpha-bis(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxytolu ene, an imbalance in the cellular dNTP pool was induced. The imbalance was followed by DNA double-strand breaks and subsequent cell death. Fragmented DNA appeared to be approximately 100-200 kbp in size. The base of 5'-termini in the DNA were adenine and thymine. The endonuclease toward double stranded DNA has been found in a fraction of FdUrd treated cell lysate, and isolated using column chromatography. We propose the new mechanism dNTP pool imbalance induced cell death named; dNTP Imbalance Death.

[Clinical and pharmacokinetic evaluation of aztreonam in neonates].

Nine neonates were treated with aztreonam (AZT) and its clinical efficacy and side effects were evaluated. Six of the patients were treated with a combination of AZT and ampicillin. Ages of the patients ranged from 0 to 24 days, and their body weights ranged from 2,290 to 4,260 g. Doses of AZT ranged 18.8 to 23.7 mg/kg every 8 to 12 hours for 3 to 7 days. Three patients with infections including urinary tract infection, cervical abscess, and suspicion of sepsis, appeared to respond to the treatment of AZT alone. Among them, clinical results were excellent in 1, good in 2 patients. Those patients subjected to the combination therapy showed excellent response in 1 and good in 5. The drug was well tolerated, but 1 had diarrhea. The pharmacokinetics of AZT was studied in 9 patients. Their ages ranged from 0 to 30 days, and body weights ranged from 2,000 to 4,000 g. Serum concentrations of AZT were 27.2 to 48.3 micrograms/ml at 1 hour after single 20 mg/kg intravenous bolus injection, and the levels were 3.4 to 15.5 micrograms/ml at 6 hours in 5 infants heavier than 2,500 g. Elimination half-lives of AZT ranged from 1.57 to 3.72 hours (mean 2.72 hours). Serum concentrations of AZT were 21.6 to 41.8 micrograms/ml at 1 hour after single 20 mg/kg intravenous bolus injection, and the levels were 10.2 to 17.0 micrograms/ml at 6 hours in 3 infants lighter than 2,500 g. The elimination half-lives of AZT were 3.63 to 4.86 hours (mean 4.31 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Invention of anti-Leishmania drugs on the basis of the nucleoside structures.

3'-Deoxy-3'-fluoroinosine is a potent inhibitor for the growth of the promastigote form of Leishmania tropica and Leishmania donovani. In culture, the EC50 values of 3'-deoxy-3'-fluoroinosine are 2.3 x 10(-7) and 1.0 x 10(-6) M for the promastigotes of L. tropica and L. donovani, respectively. It is less toxic towards mouse mammary tumor FM3A cells: the EC50 value is 2.0 x 10(-4) M. 3'-Deoxy-3'-fluoroinosine is metabolized by Leishmania promastigotes to give 3'-deoxy-3'-fluoroadenosine-5'-triphosphate. This metabolic conversion provides a mechanism for the parasite-selective toxicity of 3'-deoxy-3'-fluoroinosine.

Detection of deoxyribonucleoside-triphosphate imbalance death-induced DNA double strand breakage in FM3A cells by orthogonal-field-alternation gel electrophoresis (OFAGE).

The mechanism of intracellular deoxyribonucleoside-triphosphate (dNTP) imbalance death of mouse mammary tumor FM3A cells was studied. When the cells were exposed to 5-fluorodeoxyuridine, deoxyadenosine, or 2-chlorodeoxyadenosine, dNTP pool imbalance resulted. The imbalance was followed by DNA double strand breaks and subsequent cell death. The DNA double strand breaks have been directly examined by means of orthogonal-field-alternation gel electrophoresis (OFAGE). Fragmented DNA band appeared to be approximately 100-200 kb in size.

[A case of simple form of sudanophilic leukodystrophy of a child which showed a marked loss of cerebral white matter and fatty liver].

A sporadic case of sudanophilic leukodystrophy of the simple form (Peiffer) was reported. The patient was three-year-old girl who had suffered from progressive developmental retardation and neurological disorders such as ataxia, cortical blindness and spastic paralysis of the extremities for eighteen months after she had showed normal development till one and a half years old and died from respiratory insufficiency. On admission, computerized tomogram scan demonstrated diffuse low density lesions of the cerebral white matter extending subsequently to the subcortical white matter. Examination of cerebrospinal fluid revealed only slight increase of protein. Lysosomal enzyme activities such as arylsulfatase and beta-galactosidase in the white blood cells were normal except for distinctly low activity of a-mannosidase without any clinical symptoms suggesting a-mannosidase deficiency. Amino acids in blood were normal. The brain weighed 900 gm. On the coronal sections most part of the cerebral white matter was so strongly degenerated and disappeared that the lateral ventricular structure was not discernible. Histologically, a diffuse and symmetrical demylination, loss of axons including U fibers and moderate gliosis were observed in the residual white matter in the cerebrum and pons. There was no inflammatory cells and metachromatic substances. Large amount of sudanophilic droplets showing polarizing cross and needle like crystals were found in the intra- and/or extracytoplasm of macrophages. Demyelinated lesions with little tissue reaction were also found in the cerebellum, medulla oblongata and in pyramidal tracts through midbrain to cervical spinal cord. There were slight loss of neurons and moderate astrocytosis in the cerebral cortex and basal ganglia. There were no Rosenthal fibers and no sparing of islets of myelin.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effectiveness of cefotaxime in pediatric infectious diseases].

Cefotaxime (CTX) was administered to 117 pediatric patients. Although 26 of these patients were excluded from the clinical evaluation of the study because other antimicrobial agents were given concomitantly with CTX or because no infectious diseases were proved, these cases were evaluated for adverse effects of the drug. The remaining 91 cases were evaluated for clinical effect; pneumonia in 56 cases, septicemia in 5, suspected septicemia in 5, meningitis (aseptic cases included) in 3, urinary tract infection in 5 and other diseases in 17. No pathogenic organisms were identified in any of the pneumonia cases, even either by bacterial culture or other laboratory test methods. Pathogens of septicemia were E. coli in 3 cases, K. pneumoniae in 1 and E. agglomerans in 1. Those of urinary tract infections were E. coli in 3 cases, a mixed infection of S. aureus and an unidentified species of Gram-negative rods in 1, and unknown in 1. Clinical effectiveness rates of CTX were 78.6% in pneumonia and 100% in septicemia, suspected septicemia and urinary tract infections. One patient with purulent meningitis caused by H. influenzae was also treated with CTX successfully. Adverse reactions and abnormal laboratory findings were observed in 12 cases (12/117 = 10.3%); rash in 2 cases, vomiting in 1, abdominal pain in 1, diarrhea in 5, granulocytopenia and thrombocytopenia in 1, eosinophilia in 3 and elevation of liver enzymes (GOT and LDH) in 1.