Increased level/dose ratio of amphotericin-B in premature infants with renal failure

We introduced continuous intravenous infusion of amphotericin-B (AMPH-B) to extremely low birth-weight (ELBW) infants (< 1000 g) with or without renal failure as a single agent for treating definite or probable systemic candidiasis. The species of Candida isolated from blood or tracheal aspirate or urine were C. albicans in seven infants, C. glablata in two, C. tropicalis in one and C. parapsilosis in one. The minimal inhibitory concentrations (MIC) of AMPH-B required against these isolates were less than 0.2 μg/mL except for that against one strain of C. albicans (0.78 μg/mL). Serum AMPH-B levels were 0.31-0.78 (0.51 ± 0.14) μg/mL when doses of 0.2-0.55 (0.32 ± 0.11) mg/kg per day were being administered. The serum level was higher than the MIC of each isolate in all but one infant who died of disseminated intravascular coagulation and Candida pneumonia. Another infant died of congenital heart disease. The other nine infants survived. The serum level showed no correlation with the daily dose. The ratio of the serum level to the daily dose (L/D ratio) showed a significant correlation to serum creatinine (r = 0.787) and the linear regression curve followed the equation: L/D ratio = 0.223 x serum creatinine + 1.11 (P < 0.01). Few adverse effects due to AMPH-B were noted. Our data may give a simple reference to serum AMPH-B levels during continuous intravenous infusion from the dose and the serum creatinine level.     

Ablation of Idiopathic Ventricular Tachycardia in Two Separate Regions of the Outflow Tract: Prevalence and Electrocardiographic Characteristics

Few studies have clarified the prevalence and characteristics of idiopathic outflow tachycardia (OT-VT) with an altered QRS morphology after radiofrequency catheter ablation (RFCA), requiring additional RFCA applications at a different portion of the outflow tract (OT) to abolish the OT-VT. Among 344 patients (97 VTs and 247 premature ventricular contractions), 12 (3.5%; VTs-7, PVCs-5; 6 women) had dynamic QRS morphology changes following the RFCA, requiring additional RFCA applications at a different portion to abolish the OT-VT. In 8 of 12 patients (67%), this phenomenon occurred following RFCA at right (RVOT; n = 7) or left ventricular (LVOT; n = 1) endocardial sites of the OT: The second OT-VT was consistently associated with an increase in the R-wave amplitude in the inferior leads, and in five it was finally abolished by RFCA at the left sinus of Valsalva (LSV). Conversely, in four patients (33%), the second OT-VT appeared after RFCA at the LSV: two required additional RFCA applications at the LVOT to abolish the second OT-VT, and one at the RVOT, and all were associated with a decrease in the R-wave amplitude in the inferior leads. This kind of dynamic QRS morphology change was often observed when RFCA was applied to either the first or second OT-VT at a right or left ventricular endocardial site, with the other site being the LSV. A detailed continuous observation of the QRS morphology, especially of the R-wave in the inferior leads, is important for identifying changes in the QRS morphology during RFCA .     

Establishment and characterization of human urothelial cancer xenografts in severe combined immunodeficient mice

AIM: To establish and characterize a murine xenograft model of human urothelial cancer in severe combined immunodeficient (SCID) mice for therapeutic simulation. METHODS: Pieces of 30 freshly resected urothelial tumors (24 obtained from bladder and 6 from ureter or pelvis) were implanted subcutaneously into SCID mice, and xenograft tumors were passed in tumorigenic cases. At each passage, histopathology, TP53 mutational status assessed by yeast p53 functional assay, and the Ki-67 labeling index (LI) were examined to evaluate the preservation of original features. A growth delay assay after single-dose irradiation was performed in four representative xenografts. RESULTS: Tumor growth was observed in 18 mice (60%, 18/30). Histologically, 15 of the 18 were epithelial carcinomas similar to the original tumors, whereas the other 3 were Epstein-Barr virus-associated lymphoproliferative disease, resulting in a 50% (15/30) take rate. No correlation was found between the tumor take rate and the clinicopathologic features, TP53 mutational status, or Ki-67 LI of the patients' tumors. Of these 15 xenografts, 11 xenografts were passed from 3 to 10 generations. TP53 mutational status remained stable during the passages, and the Ki-67 LI of eight xenografts was within a range of 50% of the LI of the original tumors, although the other three xenografts increased by over 50%. Specific growth delay after irradiation, independent of the original tumor growth speed and Ki-67 LI, was observed in four xenografts. CONCLUSIONS: SCID mice are useful recipients for investigations of human urothelial cancer with a wide biological range. This easy-to-handle xenograft system can help to develop a better in vivo preclinical evaluation system for therapeutic agents as well as the investigation of tumor pathophysiology.     

Daunorubicin-induced Smooth Muscle Contraction: Involvement of Ca2+ Entry Mechanism

The mechanisms of the smooth muscle contractile action of daunorubicin were investigated using guinea-pig aortae, and the involvement of the Ca²⁺ entry mechanism was compared among different smooth-muscle preparations. In the aorta, daunorubicin showed a concentration-dependent contractile action at concentrations of 10–200 μm . The contractile response to daunorubicin was completely dependent on extracellular Ca²⁺, but only slightly sensitive to verapamil or nifedipine. Trifluoperazine abolished the contraction by daunorubicin, but no significant effect was noted with amiloride, phentolamine, indomethacin or staurosporine. The order of potency (sensitivity) for daunorubicin-induced smooth muscle contraction was oesophagus = gall bladder = iliac artery > bronchus = aorta, while that of maximum reactivity was iliac artery = aorta > bronchus = oesophagus = gall bladder. In the portal vein, daunorubicin showed no contractile action. Although the smooth muscle contraction induced by daunorubicin was strongly dependent on extracellular Ca²⁺ in the aorta, iliac artery, bronchus, oesophagus and gall bladder, its sensitivity to verapamil varied among the different smooth muscle preparations, with the sensitivity being iliac artery = gall bladder > bronchus = oesophagus > aorta. These results suggest that daunorubicin has contractile action on various kinds of smooth muscle, mainly via the transplasmalemmal Ca²⁺ entry mechanism, but the degree of involvement of the voltage-dependent Ca²⁺ channel differs among the different smooth muscle preparations.     

Simultaneous Mapping in the Left Sinus of Valsalva and Coronary Venous System Predicts Successful Catheter Ablation from the Left Sinus of Valsalva

Idiopathic ventricular tachycardia originating from the left epicardium (Epi-VT) can be ablated from the left sinus of Valsalva (LSV) in selected patients. We hypothesized that the analysis of electrograms at the LSV and transitional zone from the great cardiac vein to the anterior interventricular vein (GCV-AIV) could predict the efficacy of radiofrequency catheter ablation (RFCA) from the LSV. Simultaneous mapping in the LSV and coronary venous system was performed in 25 patients (12 VTs and 13 premature ventricular contractions). The earliest ventricular activation (VA) during the arrhythmias was found at the LSV or GCV-AIV in all patients. RF applications from the LSV were successful in 17 patients success group (S-Gr) and failed in 8 failure group (F-Gr). The earliness of the VA recorded in the LSV (VA[LSV]) and in GCV-AIV (VA[GCV-AIV]) was compared between the two groups. (1) The VA[LSV] preceded the QRS onset by 28 ± 11 ms in S-Gr and 14 ± 10 ms in F-Gr (P < 0.01). (2) In S-Gr, the VA[GCV-AIV] was earlier than the VA[LSV] in 5 five patients (35%). However, in F-Gr, the VA[GCV-AIV] was earlier than the VA[LSV] in all patients. (3) In patients in whom the earliest VA was found at the LSV or GCV-AIV, a VA [GCV-AIV] preceding the VA[LSV] by less than 10 ms identified successful RFCA from the LSV with a sensitivity of 88 %, specificity of 100%, and high predictive value. With a detailed analysis of the electrograms recorded from the GCV-AIV and LSV, it was possible to identify the successful catheter ablation of Epi-VT from the LSV.     

Efficacy of antibiotics against influenza-like illness in an influenza epidemic

AIM: To determine if an antibiotic reduces the incidence of complications associated with influenza-like illness during an influenza epidemic. METHODS: During the outbreak of influenza in Kobe in 1998, 85 patients suffering from an influenza-like illness were randomly assigned to two groups. Patients received placebo or sultamicillin orally for 4 days. The incidence of complications of influenza-like illness were compared and statistically assessed. RESULTS: There was no difference in the duration of fever or the incidence of acute otitis media. However, the incidence of pneumonia was significantly lower in the sultamicillin group than the placebo group (2.4 vs 16.3%, P < 0.05). CONCLUSION: Sultamicillin reduced the incidence of pneumonia associated with influenza-like illness during the influenza epidemic. This result suggests that antibiotics can reduce the rate of pneumonia associated with influenza.     

Bone γ-Carboxyglutamic Acid Containing Protein in the Perinatal Period

ABSTRACT. We measured bone γ-carboxyglutamic acid-containing protein (BGP), calcium (Ca), phosphorus (P), and alkaline phosphatase (Al-P) in paired maternal and cord sera, and urinary γ-carboxyglutamic acid (γ-GIa) in neonates. The circulating BGP was 41.21±2.47 ng/ml and 7.44±0.87 ng/ml in the cord (n=15) and the maternal (n=14) sera, respectively. The urinary γ-GIa in the neonates was 147.68 ± 10.75 μ.mol/g creatinine (n=15). The cord serum BGP was significantly higher than the normal adult level. The maternal serum BGP was at the same level as in other adults. It is conceivable that the fetus may produce BGP during gestation, as the cord serum BGP level was significantly higher than the maternal level and there was no correlation between the cord and maternal serum BGP concentrations. The reason for the elevated circulating BGP level in the cord serum is not known, but increased bone turnover may be a factor. The cord serum BGP may include not only carboxylated but also non-γ-carboxylated BGP because of fetal vitamin K deficiency.     

A Classification System to Evaluate Weight Maintainers, Gainers, and Losers

Objectives To study natural weight changes and to develop a weight classification system that can identify weight maintainers, gainers, and losers.Design/outcome A prospective, observational study in which weight changes over five annual measurements were evaluated. In the weight classification system used, changes greater than 5 lb defined weight maintenance, gain, or loss.Subjects/settings Subjects were healthy, normal-weight and overweight, men and women (mean age=44.1+14.1 years) in the Relationships of Energy, Nutrition, and Obesity to Cardiovascular Disease Risk Study. Prospective data for 385 of the original 508 subjects for whom actual weights were available for each of the 5 years (1985 to 1990) were used to classify and characterize subjects by weight-change categories.Statistical analyses Cross-tabulations (with χ² tests) and hierarchical log-linear analyses (with partial χ² tests) to examine the relationships of categorical variables; analyses of variance (with F tests) for continuous measures.Results Over the 4-year interval, 46% of subjects were classified as maintainers, 34% as gainers, and 20% as losers. Over shorter 1-year epochs, more subjects were maintainers (62%) and fewer subjects were gainers (22%) or losers (16%). Maintainers had fewer and smaller magnitudes of weight fluctuations and showed fewer deleterious changes in health risk factors than gainers.Applications Weight changes of greater than ±5 lb can classify a person as a weight maintainer, gainer, or loser. Although annual weight changes were used in this study, a weight change of more than 5 lb between any two points in time may suggest nonmaintenance of weight or weight instability that needs further evaluation.     

Conformationally stabilized gramicidin S analog containing dehydrophenylalanine in place of d-phenylalanine4,4′

Unsaturated gramicidin S analog, [ΔPhe^4,4′]gramicidin S, was synthesized by conventional solution method in order to evaluate the role of the dehydrophenylalanine residues replacing d -phenylalanine^4,4′ in stabilizing the bioactive β-shect conformation. The dehydrophenylalanine (ΔPhe) moiety was introduced by dehydroazlactonization of the β-phenylserine residue. The [ΔPhe^4,4′]gramicidin S prepared by this method showed very strong antimicrobial activities against Gram-positive bacteria, but not against Gram-negative ones. Several lines of spectroscopic evidence indicated that [ΔPhe^4,4′] gramicidin S has a reinforced β-sheet backbone conformation necessary for a full biological activity of gramicidin S. These results suggested that :α,β-dehydrogenation of the amino acid residue in a cyclic peptide can stabilize the turn structure.