Apparently increased trough levels of tacrolimus caused by acute infantile diarrhea in two infants with biliary atresia after liver transplantation

Two infants with biliary atresia who exhibited three-fold increased trough levels of tacrolimus and required reduced doses during episodes of acute infantile diarrhea within 5 months of liver transplantation are described. The cause of the increase was not explained simply by hemoconcentration as a result of significant loss of extracellular fluid during these episodes. It does highlight an important issue: that of the continuing need to carefully monitor the trough levels of tacrolimus in such infants.     

Phase II Study of Mitoxantrone in Patients With Non-Small Cell Lung Cancer

A phase II study of mitoxantrone was performed in 24 patientswith non-small cell lung cancer (NSCLC). Mitoxantrone was administeredby intravenous drip infusion of 12 mg/m² every three weeks.There were no responders among the 21 evaluable patients includingfive patients without prior therapy. The major hematologicaltoxic effect was leukocytopenia. Thrombocytopenia and decreasein hemoglobin were slight. A change in the electrocardiogramwas observed in one patient and one patient experienced cardiogenicshock. Mitoxantrone is not acceptable for the treatment of NSCLC becauseof its low antitumor activity, and careful observation is neededfor administration of this agent to patients with pre-existingrisk factors, such as prior anthracycline exposure, mediastinalradiation or underlying cardiovascular disease.     

Slow-wave photic stimulation relieves patient discomfort during esophagogastroduodenoscopy

Background and Aim: Although pretreatment with a sedative drug is effective in relieving pain during esophagogastroduodenoscopy (EGD), such drugs can cause significant side‐effects. The aim of this study was to examine the effect of slow‐wave photic stimulation on discomfort and/or pain felt during EGD. Methods: Forty consecutive patients (25 men and 15 women) who underwent diagnostic EGD in our hospital were included in the study. Twenty patients received photic stimulation for 25 min, and underwent electroencephalographic recording, in addition to the usual premedications. Twenty control patients received the same treatment but without photic stimulation. All patients evaluated the discomfort/pain felt during endoscopy against a five‐grade scale in comparison with what they had experienced in their previous examination. Results: Patients with an improved discomfort/pain score were 18/20 and 3/20 in the treated and control groups, respectively. Overall comparison of pain scores between both groups was significant (P < 0.0001). The proportion of slow‐wave activity recorded in patients’ electroencephalograms significantly increased in the treated group compared to control values (36.6 ± 6.8% vs 29.1 ± 3.4%, P < 0.001). There was a close correlation between the degree of discomfort/pain felt during endoscopy and the proportion of slow‐wave activity (P < 0.001). Conclusion: Slow‐wave photic stimulation shows promise as a treatment for relieving the discomfort and/or pain felt by patients undergoing EGD.     

Chemokine receptor CCR6 as a prognostic factor after hepatic resection for hepatocellular carcinoma

Background and Aims: Chemokines and their receptors have recently been shown to have major roles in cancer metastasis. The aim of this study was to determine whether the interaction between chemokine receptor 6 (CCR6) and its ligand, macrophage inflammatory protein‐3 alpha (MIP‐3α), correlates with metastasis of hepatocellular carcinoma (HCC). Methods: To observe the reaction of CCR6 expressed cancer cells to MIP‐3α stimulation, chemotactic and actin polymerization assays for both CCR6 high cells (HepG2) and CCR6 low cells (MCF‐7) were performed. CCR6 mRNA levels in tumor specimens from 30 HCC patients were quantified by real‐time polymerase chain reaction. Patients were classified into two groups, high (≥ 20 copies; n = 10) CCR6 and low (<20 copies; n = 20) CCR6 on the basis of CCR6 expression, and the groups were compared with respect to clinicopathological features. Results: When HepG2 cells (CCR6 high) were stimulated with MIP‐3α, they migrated in a dose‐dependent manner, and formation of pseudopodia was observed. These phenomena were not observed in the CCR6 low cells. The incidence of intrahepatic metastasis was higher in the high CCR6 expression group than in the low CCR6 expression group (P < 0.05). Disease‐free survival was significantly poorer in the high CCR6 expression group than in the low CCR6 expression group (P < 0.05). Conclusions: It was indicated that CCR6 might be associated with intrahepatic metastasis of HCC and might be able to become one of the prognostic factor after hepatic resection for HCC.     

Transesophageal Echocardiographic Analysis of the Systolic Pattern of the Anterior Mitral Leaflet in Patients with Flat Chest

Transesophageal echocardiography was conducted to determine the systolic pattern of the anterior mitral leaflet in patients with flat chest, and to differentiate it from that associated with mitral valve prolapse. The fronto-sagittal index (an index of chest flattening) was determined in 50 subjects using chest radiographs, and was used to classify them into a flat chest group (index < 0.38, n = 28) and a normal chest group (index ≥ 0.38, n = 22). We then used transesophageal echocardiography to examine the anterior leaflet in these subjects. A significant positive correlation was observed between the fronto-sagittal index and the short-to long-axis diameter ratio of the left ventricle in all patients. These parameters, and the left atrial dimension were lower in the flat than the normal chest group. The clear zone area of the anterior leaflet during mid-to late-systole was significantly larger in the flat chest group. However, no intergroup differences existed in the rough zone area of the anterior leaflet or in the middle scallop area of the posterior leaflet. Mitral regurgitation was observed in 20 and 12 subjects in the flat and normal chest groups, respectively. The maximum mitral regurgitant area did not differ between the two groups. The clear zone area of the anterior leaflet increased significantly following inhalation of amyl nitrite in 22 subjects of both groups, but the other areas did not increase. The mitral regurgitant area decreased or disappeared after amyl nitrite at a similar rate in each group. Thus, the decrease in the antero-posterior dimension of the thorax in subjects with flat chest affects the systolic pattern of the clear zone of the anterior leaflet more than that of the rough zone of the anterior leaflet or the posterior leaflet. This systolic pattern in such patients differs from that associated with mitral valve prolapse.     

Role of p27Kip1 and Cyclin-Dependent Kinase 2 in the Proliferation of Non-Small Cell Lung Cancer

The cell cycle is governed by a family of cyclin-dependent kinases (Cdks). Cdk2 forms a functional complex with cyclin E and plays a pivotal role in the regulation of G1/S transition. Cdk2 activity is negatively regulated by interactions with inhibitors. p27^Kip1, one of the most potent inhibitors of Cdk2, was recently identified as a powerful negative prognostic marker in non-small cell lung cancer as well as in colorectal and breast cancer. In the present study, the expression of p27 and Ki-67 antigen in nonneoplastic and cancerous lung tissues was determined by immunohistochemistry. After establishing that the antibody-measured p27 labeling index was a good reflection of the level of p27 expression measured by Western blotting, we show that p27 labeling index is decreased in cancerous lung tissues, compared with nonneoplastic lung tissues, and exhibits a significant inverse relation to the proliferation marker Ki-67 antigen, detected with monoclonal antibody MIB-1. Consistent with these data, all cancerous lung tissues showed enhanced degradation activity of p27 compared with nonneoplastic lung tissues and, in addition, increased levels of the phosphorylated form of Cdk2, as determined with Western blot analysis. The H1 histone kinase activity associated with Cdk2 was also increased in non-small cell lung cancers. Statistical analysis showed that proliferative activity as measured by MIB-1 labeling index was highly correlated with Cdk2 activity (r = 0.767, P < 0.0015). These results suggest that p27 and Cdk2 may play an important role in the proliferation of non-small cell cancer.     

Histamine N-methyltransferase inhibitor potentiates histamine- and antigen-induced airway microvascular leakage in guinea pigs

Background: Histamine N-methyltransferase (HMT) modulates histamine- and antigen-induced bronchoconstriction. However, it is unclear whether vascular permeability evoked by an allergic reaction can be exaggerated by inhibition of HMT activity. Methods: We studied the effects of intravenously injected SKF 91488, a specific HMT inhibitor, on increases in plasma extravasation induced by intravenously injected histamine in unsensitized guinea pigs and by intravenously injected ovalbumin antigen in guinea pigs sensitized to ovalbumin in vivo with Evans blue dye as a marker. Results: Pretreatment with SKF 91488 shifted, in a dose-dependent fashion, the dose-response curves of the leakage of dye to histamine to lower concentrations in the trachea, main bronchi, and nasal mucosa. Likewise, pretreatment with SKF 91488 (20 mg/kg intravenously) significantly increased the leakage of dye induced by ovalbumin antigen (200 μg/kg intravenously) in three parts of the airway (p < 0.05). In contrast to SKF 91488, intravenously injected aminoguanidine, a specific inhibitor of diamine oxidase (16 mg/kg intravenously), did not alter the leakage of dye induced by histamine (from 0.001 μg/kg to 10 μg/kg intravenously) (p > 0.20). HMT activities were observed in the nasal mucosa, as well as in the trachea and main bronchi, as shown in a previous study. Conclusion: These findings suggest that HMT modulates the effects of exogenous histamine and endogenously released histamine induced by antigen challenge on plasma extravasation in the airway in guinea pigs in vivo. (J ALLERGY CLIN IMMUNOL 1995;96:910-6.)     

Role of KCNQ1 in the cell swelling-induced enhancement of the slowly activating delayed rectifier K(+) current

Cell swelling enhances a slowly activating delayed rectifier K(+) current (I(Ks)) in cardiac cells. This investigation was undertaken to determine which of the two structural units reconstituting the I(Ks) channel, KCNQ1 (KvLQT1) and KCNE1 (minK/IsK), plays a key role in the cell swelling-induced I(Ks) enhancement and to dissect a possible involvement of tyrosine phosphorylation therein. KCNQ1 was transiently expressed alone or together with KCNE1 in a heterologous mammalian cell line. Two distinct whole-cell membrane currents were separately observed during the exposure of transfected cells to various degrees of hyposmotic solutions. A hyposmotic challenge (0.7 times control osmolarity) resulted in about a twofold increase not only in the heteromeric KCNQ1/KCNE1, but also in the homomeric KCNQ1 channel currents. There was no significant difference in the incremental ratio of current amplitude in response to hyposmotic stress between the two KCNQ1-related currents, and the cells expressing the heteromeric channels swelled less than those with the homomeric channels or without the exogenous ones. The cell swelling-induced I(Ks) enhancement was not affected by a protein tyrosine kinase (PTK) inhibitor, by genistein (50 microM), or by an inhibitor of phosphotyrosine phosphatase (PTP), orthovanadate (500 microM), or a nonhydrolyzable ATP analogue, AMP-PNP (5 mM). Taken together, it is very likely that KCNQ1 might primarily participate in the I(Ks) enhancement by osmotic cell swelling. The obligatory dependence of the I(Ks) augmentation on PTK activity remained to be demonstrated, at least, in this expression system.     

The Preclinical Safety Evaluation of Human Monoclonal Antibody against Cytomegalovirus

The human monoclonal antibody against cytomegalovinis (Mab C23)was examined pharmacokinetically and toxicologically as partof the preclinical studies prior to approval for human use.Rats given repeated intravenous administrations of Mab C23 producedno antibodies against Mab C23 and maintained a blood Mab C23level in a dose-dependent manner. However, pregnant rabbitsproduced antibodies against Mab C23. The half-life of Mab C23in plasma was 15.9 days in rats, which was similar to that ofnormal human serum -globulin (NHSG). Neither behavioral effectsnor circulatory disturbance was found in mice, rats, and dogseven after a single intravenous injection of 100 or 200 mg/kg,which corresponds to 50 or 100 times the intended clinical dosage.The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasionswith 1- or 2-week intervals elicited a transient decrease inleukocyte counts in rats given 10 or 20 mg/kg, but no adverseeffects in cynomolgus monkeys. Mab C23 did not cause any reproductiveor developmental toxicity when administered to rats and rabbitsat dose levels of 20 mg/kg or less. However, pregnant animalsshowed lower plasma levels of Mab C23 than non-pregnant animals.The chromosomal aberration test disclosed no clastogenicityin human lymphocytes. An immunostaining for Mab C23 revealedno localizations in several tissues of cynomolgus monkeys givenintravenous doses of Mab C23. The preclinical safety evaluationin animals other than rabbits, which produced no antibodiesagainst Mab C23, showed that the behavior of Mab C23 is pharmacokineticallysimilar to that of NHSG and is as safe as NHSG, which has longbeen used as a biological agent. However, because there wasa difference in blood levels of Mab C23 between pregnant andnonpregnant animals, its clinical administration to pregnantpatients should differ from that to non-pregnant patients.