A comparative analysis of micafungin and caspofungin for empirical antifungal therapy in antibiotic-unresponsive febrile patients with hematologic malignancies.

This study was retrospectively carried out to compare the efficacy of echinocandins such as micafungin (MCFG) and caspofungin (CPFG) in the treatment of antibiotic-unresponsive febrile patients with hematologic malignancies. A total of 163 patients received either MCFG or CPFG. We evaluated the efficacy of echinocandin against fever decline in all patients. Fever decline, defined as a body temperature of less than 37.5 °C sustained for more than 48 h without scheduled antipyretic medication. Efficacy assessments showed that the incidence of fever decline was not significantly different between the MCFG and CPFG groups (P=0.599). The median number of days from the start of echinocandin administration to fever decline was 5 in both the MCFG and CPFG groups. Multivariate analysis showed that the use of anti-MRSA drugs (HR, 0.64; 95%CI, 0.45-0.90; P=0.011) and a change from echinocandins to voriconazole or liposomal-amphotericin B (HR, 0.50; 95%CI, 0.30-0.74; P<0.001) are significant risk factors for sustained fever. A significant difference (P=0.002) in incidence of fever decline was however associated with differences in the timing of anti-MRSA drug administration. The median number of days from the start of echinocandin administration to fever decline was 5 when administration of the anti-MRSA drug occurred "simultaneously or prior to echinocandin start" and 11 in the "next day or later of echinocandin start" group. In other words, starting anti-MRSA drug treatment after echinocandin treatment is a risk factor. In conclusion, MCFG and CPFG have similar efficacy as empirical antifungal agents in the treatment of antibioticunresponsive febrile patients with hematopoietic malignancies.

Overexpression of the activated form of the AtAREB1 gene (AtAREB1ΔQT) improves soybean responses to water deficit.

Abscisic acid-responsive element binding protein (AREB1) is a basic domain/leucine zipper transcription factor that binds to the abscisic acid (ABA)-responsive element motif in the promoter region of ABA-inducible genes. Because AREB1 is not sufficient to direct the expression of downstream genes under non-stress conditions, an activated form of AREB1 (AREB1ΔQT) was created. Several reports claim that plants overexpressing AREB1 or AREB1ΔQT show improved drought tolerance. In our studies, soybean plants overexpressing AREB1ΔQT were characterized molecularly, and the phenotype and drought response of three lines were accessed under greenhouse conditions. Under conditions of water deficit, the transformed plants presented a higher survival rate (100%) than those of their isoline, cultivar BR 16 (40%). Moreover, the transformed plants displayed better water use efficiency and had a higher number of leaves than their isoline. Because the transgenic plants had higher stomatal conductance than its isoline under well-watered conditions, it was suggested that the enhanced drought response of AREB1ΔQT soybean plants might not be associated with altered transpiration rates mediated by ABA-dependent stomatal closure. However, it is possible that the smaller leaf area of the transgenic plants reduced their transpiration and water use, causing delayed stress onset. The difference in the degree of wilting and percentage of survival between the 35S-AREB1ΔQT and wildtype plants may also be related to the regulation of genes that protect against dehydration because metabolic impairment of photosynthesis, deduced by an increasing internal CO2 concentration, was not observed in the transgenic plants.

Pattern of lymph node metastases of esophageal squamous cell carcinoma based on the anatomical lymphatic drainage system.

The recent anatomical studies of the esophagus showed that submucosal longitudinal lymphatic vessels connect to the superior mediastinal and the paracardial lymphatics and lymphatic routes to periesophageal nodes originate from the muscle layer. Using clinical data for lymph node metastasis, we verify these anatomical bases to clarify the rational areas of lymph node dissection in esophageal cancer surgery. Analysis was performed on 356 consecutive patients who underwent esophagectomy with three-field dissection. Patients were divided into those with tumor limited within the submucosal layer and those with tumor invading or penetrating the muscle layer. Frequency of node metastasis was compared according to supraclavicular, upper mediastinum, mid-mediastinum, lower mediastinum, perigastric and celiac areas. In patients with tumor limited to the submucosal layer, node metastasis was more frequent in the upper mediastinum and perigastric area than the mid- or lower mediastinum. Even in patients with tumor located in the lower esophagus, node metastasis was more frequent in the upper mediastinum than the mid-mediastinum or lower mediastinum. In patients with tumor located in the mid-esophagus, node metastasis was more frequent in the supraclavicular area than the mid-mediastinum or lower mediastinum. In patients with tumor invading or penetrating the muscle layer, node metastasis in the mid- and lower mediastinum increased dramatically, but was still less frequent than those in the upper mediastinum or the perigastric area. Postoperative survival curves did not differ among the involved areas. The most predictive factor associated with lymph node metastasis for postoperative survival was not the area of involved nodes, but the number of involved nodes by multivariate analyses. These clinical results verify recent anatomical observations. The lack of difference in survival rates among the involved areas suggests that these areas should be staged equivalently. For adequate nodal staging, the upper mediastinum should be dissected for the lower esophageal tumor and supraclavicular areas should be dissected for the mid-esophageal tumor even in patients with tumor limited to within the submucosal layer.

Prorenin processing and restricted endoproteolysis by mouse tissue kallikrein family enzymes (mK1, mK9, mK13, and mK22).

Four members of the tissue kallikrein family, mK1, mK9, mK13, and mK22, all of which exhibit extensive homology in amino acid sequence among themselves, were obtained from the submandibular gland of ICR mice and examined for their ability to cleave prorenin. Tissue kallikrein mK13 was confirmed to be a prorenin-converting enzyme; and mK9, which was earlier shown to be an EGF-binding protein, was found to cleave mouse Ren 2 prorenin specifically and convert it to mature renin with an activity of approximately 1/10 of that of mK13. With the same substrate, mK22 (beta-NGF endopeptidase) gave two products, renin and arginyl-renin; whereas mK1 (true tissue kallikrein) did not process it at all. The endoproteolytic activity of tissue kallikreins was examined with various peptide-MCA substrates. The substrates contained three key structures; X(Y)-Arg-Arg, X(Y)-Lys-Arg and X-Lys-Lys motifs (where X and Y are hydrophilic and hydrophobic amino acids, respectively). We found that mK1, mK9 and mK13 preferentially cleaved the former two types of substrate, except Y-Arg-Arg-MCA. The substrate X-Lys-Lys-MCA was hardly cleaved by these three tissue kallikreins but was preferentially cleaved by mK22. The four tissue kallikreins seem to have the ability to process precursor proteins containing a pair of basic amino acid residues; the specificities of three of the enzymes (mK1, mK9 and mK13) were similar to each other but were different from that of mK22.

Expression of an allozyme of prorenin-converting enzyme in the submandibular gland of DBA/2N mice.

A protein product of the tissue kallikrein gene family was isolated from the submandibular gland of DBA/2N mice. Amino acid sequencing showed this protein to be highly homologous to two tissue kallikreins, mK13 and mK26, also known as prorenin-converting enzymes PRECE and PRECE-2, respectively. The cDNA corresponding to the present enzyme was cloned, and its complete nucleotide sequence was determined. The cloned cDNA was different in 6 and 12 bases out of 783 nucleotides from those of mK1k-13 and mK1k-26 cDNAs, respectively, the homologies being 99.2 and 98.5% (nucleotide), or 98.3 and 96.2% (amino acid). Upon incubation with either bovine kininogens or mouse Ren 2 prorenin, this tissue kallikrein generated bradykinin and renin, respectively, as judged by Western blotting and protein sequence analysis. Isoelectric focusing analysis of the submandibular gland tissue kallikreins suggested that the present enzyme was not expressed in CD-1 or ICR mice and that no mK13 protein was present in DBA/2N mice. These data suggest that the enzyme is an allozyme of mK13, a prorenin-converting enzyme highly expressed in the submandibular gland of DBA/2N mice. The mK1k-13 gene in mice is therefore suggested to be polymorphic, having at least two allelic forms with a high sequence homology. The designation mK13(b) and mK1k-13(b) for the protein and gene of this tissue kallikrein is proposed.

Hippocampal minispindle wave in the cat: the different distribution of two types of waves.

Spindle-like waves of 40-85 Hz (minispindle-II) and 85-155 Hz (minispindle-I) were recorded from the cat hippocampus. Minispindle-II, as well as minispindle-I, occurred during drowsy and slow-wave sleep episodes. The minispindle-I type was dominant in the CA1 sector; and, conversely, the minispindle-II type was predominant in the hilus of the dentate gyrus. In addition to the different distribution of minispindle-I and -II, disparity was observed in the concurrency of the minispindles.

A spindle-like wave in the cat hippocampus: a novel vigilance level-dependent electrical activity.

Bursts of spindle-like waves of about 110 Hz (minispindle) were recorded from the cat hippocampus. The minispindle began to appear in parallel with the slowing of neocortical EEG and occurred most frequently during the deep slow-wave sleep episode. The minispindles could be recorded simultaneously at different points not only in the ipsilateral but also in the contralateral hippocampus with a time lag less than 30 ms.

Effect of decerebration on blood pressure during paradoxical sleep in cats.

We investigated the effects of decerebration on long-term variations in arterial blood pressure during paradoxical sleep (PS) in cats. In normal cats, the blood pressure decreased during the transition from slow wave sleep to PS and maintained its lower level throughout PS for several days after surgery. After this early postoperative stage, however, the arterial hypotension was replaced by tonic and phasic rises in blood pressure during PS. Such long-term changes in blood pressure were completely abolished when the brain stem was transected at the ponto-mesencephalic junction, and the cats consistently exhibited a sustained fall in blood pressure throughout the survival periods of 1 month or more.

Induction of C-reactive protein, serum amyloid P component, and kininogens in the submandibular and lacrimal glands of rats with experimentally induced inflammation.

The mRNAs for acute-phase proteins and kininogens were found to be increased in the submandibular gland (SMG) and extraorbital and intraorbital lacrimal gland (ELG and ILG) in response to experimentally induced inflammation in rats; i.e., 24 hours after subcutaneous injection of turpentine oil, mRNAs for C-reactive protein (CRP), serum amyloid P component (SAP), and H- and T-kininogens were induced in the SMG, ELG, and ILG of rats, whereas these mRNAs were not detected in the same tissues of normal control rats. The induction of mRNAs for these inflammatory proteins by turpentine oil was preceded by a transient increase in the level of mRNA for tumor necrosis factor-alpha (TNF-alpha) at 6 hours after subcutaneous injection of the oil. This was confirmed by injection of another inflammation inducer, lipopolysaccharide (LPS), which induced the TNF-alpha mRNA in the same way at 6 hours as turpentine oil did. The up-regulation of acute-phase proteins including kininogens in the SMG, ELG, and ILG suggest the existence of a strict defense system in the exocrine glands.

Reticulo-reticular relationship during sleep and waking.

The mode of interaction between so-called sleep-waking centers during different phases of consciousness was investigated in the cat. Averaged evoked responses were recorded from different centers to electrical stimulation of a center. The results showed that most sleep-waking centers are not simply engaged in the realization of a single phase, but operate during different phases in dynamic relationship with other centers. It was suggested that the mechanism of SS would be more diffusely distributed in the brain stem that presently conceived and that in contrast to the mechanism of PS, that of SS would have more extensive interaction with the mechanisms responsible to other phases.

Long-term variations of arterial blood pressure during sleep in freely moving cats.

Using a new telemetric system for arterial blood pressure recordings, we have investigated long-term postoperative changes in blood pressure during sleep in freely moving cats. Particular attention was paid to the transitional periods at the beginning and end of paradoxical sleep (PS), as well as to the relationship between the blood pressure and ponto-geniculo-occipital (PGO) waves. In the initial postoperative stage lasting 2 to 5 days, the blood pressure decreased during the transition from slow wave sleep (SWS) to PS and maintained its lower level until the end of PS. In contrast, in the later chronic stage, the blood pressure increased tonically during the transition from SWS to PS and maintained its higher level throughout PS on which several phasic rises in blood pressure were superimposed. A significant increase in arterial pressure during the transitional period began shortly after the first appearance of PGO waves. On the other hand, significant phasic rises in arterial pressure during PS shortly preceded the onset of PGO wave bursts.

Serum levels of coenzyme Q10 and lipids in patients during total parenteral nutrition.

Serum levels of coenzyme Q10 (CoQ10) as well as lipids were determined in patients during total parenteral nutrition (TPN). The mean CoQ10 levels (M +/- SD) were 0.77 +/- 0.30 microgram/ml for 108 normal subjects and 0.59 +/- 0.35 microgram/ml for 95 patients before TPN. The mean CoQ10 level of the patients decreased significantly to 0.35 +/- 0.23 microgram/ml one week after the start of TPN, and then remained almost unchanged during TPN for up to 6 weeks. When the patients receiving TPN (TPN patients) were grouped according to their clinical diagnoses, the mean CoQ10 level of patients with cancer was significantly lower than that of the other patients without cancer in 4 week therapy, but there was no difference in the levels between the patients with and without diseases of the gastrointestinal tract. Serum levels of total cholesterol (T-Chol) and esterified cholesterol in TPN patients also declined below their respective normal ranges, but not to the same extent in comparison to CoQ10. The levels of triglycerides (TG), phospholipids (PL), non-esterified fatty acids, low density lipoproteins, very low density lipoproteins, chylomicrons, and cholesterol in the high density lipoprotein fraction in serum of TPN patients were within their normal ranges. The levels of CoQ10 in TPN patients were correlative to those of T-Chol, TG, and PL, and decreased rapidly prior to the latter levels.

Salivary gland tissue kallikrein family and processing of growth factor precursors and proenzymes.

Four major enzymes of the tissue kallikrein family were purified from the mouse submandibular gland and characterized. The sequences indicated that they were mK1, mK9, mK13, and mK22. All four enzymes showed kinin-releasing activity, with mK1 exhibiting the highest activity. Like mK13, mK9 and mK22 also processed prorenin to give renin and/or arginyl renin, although their activities were less than that of mK13. The results suggest that tissue kallikrein family enzymes bearing higher kinin-releasing activity have lower prorenin-converting activity and vice versa. These enzymes may possibly have a physiological role in the tissue renin-angiotensin system.

Power spectral analysis of blood pressure fluctuations during sleep in normal and decerebrate cats.

Arterial blood pressure fluctuations during sleep were investigated with power analysis technique in both normal and decerebrate cats. In the initial postoperative stage lasting about 3 to 4 days, intact cats displayed, during paradoxical sleep, phasic increases in arterial blood pressure which were superimposed on a tonic hypotension. In the later chronic stage, however, the animals showed the phasic hypertension being superimposed on the background of a tonic hypertension. Regardless of these stages, the blood pressure during paradoxical sleep exhibited a 1/f-like spectrum, expressed by the power spectral density which is inversely proportional to the Fourier frequency f. On the other hand, a power spectral profile of the blood pressure during slow wave sleep presented a white noise-like pattern within the same frequency range of 0.1-0.01 Hz. After brainstem transections at the pontomesencephalic border, the cats exhibited consistently a sustained fall in blood pressure during paradoxical sleep and the power spectral density of the blood pressure displayed a white noise-like pattern throughout the survival periods of one month or more. These observations indicate that the blood pressure fluctuations in the 1/f spectrum during paradoxical sleep originate in rostral brain structures.

[Two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of gastric cancer responding to combination chemotherapy with 5-FU and CDDP].

Combination chemotherapy with 5-FU and CDDP was given to two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer. One patient was a primary case associated with lymph-node metastases of portal fissure and periaorta, and the other was a recurrent case associated with lymph-node metastases of hepatoduodenal ligament and periaorta. The regimen consisted of 5-FU 1,000 mg/ m2 (day 1-5, continuous infusion) and CDDP 100 mg/m2 (day 3, 1 hr drip infusion). The interval was from the 6th to 21st day. The response to chemotherapy showed shrinking of intra-abdominal lymph-nodes and reopening of the biliary tract. The patients could be discharged from the hospital without PTBD tube and enjoyed a better quality of life (QOL). This therapy is thought to be effective against obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer.

[Pharmacokinetic study of intraperitoneal cisplatin chemotherapy for gastric cancer as an adjuvant setting].

The pharmacokinetic studies of intraperitoneal cisplatin (CDDP) for gastric cancer were discussed elsewhere, but those studies were investigated in patients with ascites. The purpose of this study is to compare the difference in pharmacokinetics between patients with malignant ascites and those curatively resected without ascites. One hundred mg of CDDP and 300 ml of saline were administered intraperitoneally for 9 curatively resected patients by catheter just after operation, and the same doses of CDDP were administered for 3 advanced or recurrent patients with ascites just after removal of whole fluid. Blood samples were corrected at 6 points after administration. Results were as follows: The 0-t area under the curve (AUC) and the Cmax of both total and free CDDP in the patients without ascites was higher than in the patients with ascites. The 0-infinity AUC and MRT of the ascites patients were higher than in the patients without ascites. These data suggest that intraperitoneal CDDP chemotherapy for gastric cancer as an adjuvant setting is more effective than chemotherapy for advanced malignant ascites patients.

[FLEP therapy for advanced and recurrent gastric cancer].

The FLEP regimen (5-FU, LV, ETP and CDDP) is a combination chemotherapy administered regionally and systemically for the control of both local and disseminated disease in intra- and extra-abdominal regions in patients with advanced and recurrent gastric cancer. Sixty-one patients with advanced and recurrent gastric cancer were entered into this study. The treatment regimen consisted of 5-FU at 370 mg/m2 (days 1 to 5, i.v. 24 h); LV at a dose of 30 mg (days 1 to 5, i.v. bolus); and ETP and CDDP each at 70 mg/m2 (days 7 and 21, ia 2 h). This regimen was repeated every four weeks. The overall response rate was 36.1% (22/61) and the 50% and median survival times were 10.23 and 11.80 months, respectively. The adverse events were Grade 3/4 leukocytopenia (18.0%), Grade 3/4 thrombocytopenia (4.9%), Grade 3 nausea and/or vomiting (3.3%) and Grade 3 stomatitis (1.6%). Of the 17 NAC patients, the six curability B patients showed a statistically higher survival rate than the curability C and unresected patients. Based on the encouraging response rate and the improvement in prognosis, we recommend the FLEP regimen for patients with primary gastric cancer. Neoadjuvant chemotherapy using the FLEP regimen should be performed with curative resection as an objective.

[Neoadjuvant chemotherapy for advanced gastric cancer using FLEP therapy].

Combination chemotherapy with 5-FU, LV, ETP and CDDP (FLEP) for advanced gastric cancer uses a combination of regional and systemic delivery for the control of both local and disseminated disease in the intra- and extra-abdominal regions. We performed this regimen as neoadjuvant chemotherapy (NAC). Fifteen patients with unresectable primary advanced gastric cancer underwent FLEP. The treatment regimen was 5-FU at 370 mg/m2, LV at 30 mg/body (days 1 to 5, i.v. 24 h) and ETP and CDDP each at 70 mg/m2 (days 7 and 21, ia 2 h). This regimen was repeated every four weeks. The overall response rate was 46.7% (7/15), and the 50% and median survival times were 11.43 and 12.35 months, respectively. The adverse events were Grade 3 leukocytopenia, Grade 3 thrombocytopenia, and Grade 3 stomatitis in 20.0%, 13.3%, and 6.7% of the patients, respectively. The 50% and median survival time overall were 11.43 and 12.35 months, respectively. Of the 15 NAC patients, curability B patients showed a statistically higher survival rate than curability C and unresected patients. In conclusion, FLEP was effective for unresectable advanced gastric cancer.

[Neuronal activities of the visual field of the cerebral cortex modulated by reserpine-induced PGO waves].

The modulatory influence of reserpine-induced PGO wave upon the spontaneous activity of visual cortical neurons was examined in acutely prepared cats. Unitary discharge of cortical neurons was recorded extracellularly with glass micropipettes. Of twenty three neurons three showed a vigorous discharge synchronously with a certain phase of PGO wave. One neuron was strongly suppressed by the occurrence of PGO wave. Three neurons showed an increase and one neuron showed a decrease, respectively, in discharge in a loose correlation with PGO wave. This study has demonstrated the presence of a unique group of neurons which show a burst discharge or a complete silence in a precisely phase-lock manner when reserpine-induced PGO wave occurred.