Non-genomic inhibitory effect of glucocorticoids on activated peripheral blood basophils through suppression of lipid raft formation.

We investigated the non-genomic effects of glucocorticoids (GCs) on inhibition of plasma membrane lipid raft formation in activated human basophils. Human basophils obtained from house dust mite (HDM)-sensitive volunteers were pretreated with hydrocortisone (CORT) or dexamethasone (Dex) for 30 min and then primed with phorbol 12-myristate 13-acetate (PMA, 10 ng/ml) or HDM (10 µg/ml). The expression of CD63, a basophil activation marker, was assessed by flow cytometry. Membrane-bound GC receptors (mGCRs) were analysed by flow cytometry and confocal laser microscopy. Lipid rafts were assessed using a GM1 ganglioside probe and visualization by confocal laser microscopy. Pretreatment of basophils with CORT (10(-4) M and 10(-5) M) and Dex (10(-7) M) significantly inhibited CD63 expression 20 min after addition of PMA or HDM. The inhibitory effects of GCs were not altered by the nuclear GC receptor (GCR) antagonist RU486 (10(-5) M) or the protein synthesis inhibitor cycloheximide (10(-4) M) (P < 0·05). CORT coupled to bovine serum albumin (BSA-CORT) mimicked the rapid inhibitory effects of CORT, suggesting the involvement of mGCRs. mGCRs were detectable on the plasma membrane of resting basophils and formed nanoclusters following treatment with PMA or HDM. Pretreatment of cells with BSA-CORT inhibited the expression of mGCRs and nanoclustering of ganglioside GM1 in lipid rafts. The study provides evidence that non-genomic mechanisms are involved in the rapid inhibitory effect of GCs on the formation of lipid raft nanoclusters, through binding to mGCRs on the plasma membrane of activated basophils.

Apnoea-hypopnoea index during rapid eye movement and non-rapid eye movement sleep in obstructive sleep apnoea.

This study investigated the differences in apnoea-hypopnoea index (AHI) during rapid eye movement (REM) sleep (AHI-REM) and AHI during non-REM (NREM) sleep (AHI-NREM) in patients with obstructive sleep apnoea (OSA). Nocturnal polysomnography was performed in 102 Japanese OSA patients and their AHI along with a variety of other factors were retrospectively evaluated. Regardless of the severity of AHI, mean apnoea duration was longer and patients' lowest recorded oxygen saturation measured by pulse oximetry was lower during REM sleep than during NREM sleep. Approximately half of the patients (n = 50) had a higher AHI-NREM than AHI-REM. In subjects with AHI >or= 60 events/h, AHI-NREM was significantly higher than AHI-REM. On multivariate logistic regression, severe AHI >or= 30 events/h was the only predictor of a higher AHI-NREM than AHI-REM. This may indicate that important, but unknown, factors related to the mechanism responsible for the severity of OSA are operative during NREM sleep.

Phase I study of recombinant human tumor necrosis factor.

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.

Fully-automated roller bottle handling system for large scale culture of mammalian cells.

A fully automatic and continuous cell culture system based on roller bottles is described in this paper. The system includes a culture rack storage station for storing a large number of roller bottles filled with culture medium and inoculated with mammalian cells, mass-handling facility for extracting completed cultures from the roller bottles, and replacing the culture medium. The various component units of the system were controlled either by a general-purpose programmable logic controller or a dedicated controller. The system provided four subsequent operation modes: cell inoculation, medium change, harvesting, and medium change. The operator could easily select and change the appropriate mode from outside of the aseptic area. The development of the system made large-scale production of mammalian cells, and manufacturing and stabilization of high quality products such as erythropoietin possible under total aseptic control, and opened up the door for industrial production of physiologically active substances as pharmaceutical drugs by mammalian cell culture.

A case of the Rett syndrome with acute encephalopathy induced during calcium hopantenate treatment.

We report a girl with the Rett syndrome who had acute encephalopathy probably induced by calcium hopantenate (HOPA). This 4-year-6-month-old girl had a history of moderate developmental delay and had received HOPA administration when first admitted at 2 years 6 months of age with hypoglycemia, hyperammonemia, lactic and pyruvic acidemia, and non-ketotic dicarboxylic aciduria. After this episode, she showed the rapid destructive stage of the Rett syndrome, i.e., severe psychomotor retardation with loss of speech, peculiar stereotypic hand movements, autistic behavior and seizures. Despite subsequent investigations, including analysis of urinary metabolites of organic and amino acids, measurement of serum carnitine and a muscle biopsy, we could not clarify the primary metabolic abnormalities in this girl.

Rare earth elements (REEs) in naturally grown plants in relation to their variation in soils.

The concentrations of rare earth elements (REEs) in plant leaves, soils in which they grow, and mother rocks were determined using Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES). Concentration levels of REEs in most plants were low. However, one of the herb species, pokeweed (Phytolacca americana) and two species of ferns (Dicranopteris dichotoma and Athyrium yokoscence) revealed relatively high concentrations of REEs. In the case of pokeweed, the REE distribution pattern reflected well that of its soils. On the whole, high concentrations of REEs in plants were related to REE concentrations in the soils in which they grow. These observations are promising to evaluate the possible contamination of environment by REEs resulting from their increased usage in modern industry.

Heavy metal concentrations in sediments from Manila Bay, Philippines and inflowing rivers.

Concentrations of Fe, Mn, Zn, Cu, Pb, Ni, Cd and Co were determined in surface and core sediments collected from Manila Bay and in surface sediments from inflowing rivers. Core profiles revealed highly fluctuating and enriched Pb, Cd, Zn and Cu concentrations on the surface, suggestive of recent inputs coming from anthropogenic sources. Concentrations of Pb, Zn, and to a lesser extent Cu and Cd were higher in riverine sediments as compared with marine sediments, which may be attributed to the proximity of these riverine sites to pollutant sources. Comparison of metal concentration levels obtained with other areas in the world revealed elevated values for Pb and Cd, indicating a considerable amount of pollution in the area. Continuous monitoring and further studies of the area are recommended to ascertain long-term effects that may have not yet been reached.

Metal accumulation in tissues of seabirds from Chaun, northeast Siberia, Russia.

Concentrations of four essential elements (Fe, Mn, Zn, and Cu) and two toxic metals (Cd and Hg) were determined in selected tissues of 11 seabird species collected in Chaun, northeast Siberia. In oldsquaw, arctic tern and herring gull, zinc concentrations were correlated with Cd concentrations. Cadmium concentrations in all the species were highest in kidney and Hg in liver. Cd levels in the liver and kidney of herring gulls were higher than those observed from other breeding areas. Similarly, Hg concentrations were also high in the liver of herring gull. High concentrations of Cd and Hg found in some birds from Chaun might have arisen from exposure on migration.

Trace element accumulation in Baikal seal (Phoca sibirica) from the Lake Baikal.

Trace element concentrations (Fe, Mn, Zn, Cu, Pb, Ni, Cd, Co and Hg) were determined in 60 Baikal seals and in fishes collected from Lake Baikal in 1992. Low levels of Hg and Cd were found in Baikal seals in comparison with those of marine mammals and it was due to their low concentrations in dietary fish. These results suggest that pollution by Hg and Cd was low in Lake Baikal and these toxic elements were unlikely to be the causative factors for mass mortality of Baikal seal in 1987-1988. Significant correlation of Hg concentration between hair and internal tissues suggested the use of hair for Hg monitoring in pinnipeds. Among essential elements, higher Fe and lower Cu levels were specifically found in the liver of Baikal seal. The noticeable accumulation of essential elements might be related to the unique and specific environment of Lake Baikal.

Distribution of heavy metals in muscle, liver and kidney of northern fur seal (Callorhinus ursinus) caught off Sanriku, Japan and from the Pribilof Islands, Alaska.

The concentrations of iron, manganese, zinc, copper, cadmium, and mercury were determined in muscle, liver and kidney of 67 northern fur seals (Callorhinus ursinus) collected off Sanriku, Japan, and from the Pribilof Islands, Alaska. Almost all the elements except cadmium were highest in liver. Cadmium levels in kidney were higher than those in liver and muscle for all animals analyzed. Concentrations of mercury increased significantly with age in muscle, liver and kidney, as did iron levels in muscle and liver and cadmium levels in muscle, while manganese concentrations decreased with age in muscle and kidney. The kidney also showed decreased copper concentration with age. Cadmium concentrations of the northern fur seals in this study were higher than the other otariids, reflecting a predominantly squid diet. Concentrations of manganese and mercury were found to be higher in the fur seals caught off Sanriku than in animals from the Pribilof Islands, while those of zinc and cadmium were found to be lower. Variable concentrations of cadmium might have been attributed to those in seawaters. Discriminant analysis of heavy metal concentrations was used to identify habitat. Sixty-three of 67 animals (94%) were correctly classified using this technique. Heavy-metal concentrations in tissues may provide a useful method to elucidate the primary feeding grounds of fur seals.

[Clinical results of acute closing aortic dissection].

The therapeutic outcomes of 43 patients with acute closing aortic dissection treated during the past 10 years were evaluated. The patients consisted of 30 men and 13 women with a mean age of 65 +/- 9 years. Ten were classified as Stanford type A, and the remaining 33 as type B. During follow-up (6 to 120 months; average 55 months), recanalization and an enlarged ulcer-like projection (ULP) were observed in 5 and 2 type a patients. Although recanalization was not observed in type B patients, enlarged ULP was observed in 10 of them, in 6 of whom developed aneurysm. During the follow-up period, ULP was observed at 30 sites in 26 patients. Monitoring the change in ULP over time showed that the ascending and the proximal descending aorta frequently tended to be enlarged and progressed to aorta frequently tended to be enlarged and progressed to aneurysm. Surgery was performed in 3 patients with recanalization, 5 with enlarged ULP, and 3 with atheroscloerotic aortic aneurysm. Although one patient died of cerebral complications, the other 10 patients showed favorable postsurgical courses. Among 8 patients who died, the actuarial survival rate was favorable, being 96, 91 and 83% at 1, 3 and 5 years. However, the survival rate free from complications related to aortic dissection, defined as rupture, ercanalization, enlarged ULP and aneurysmal change, was 78, 58 and 54% at 1, 3 and 5 years, indicating that aortic dissection-related complications are likely to develop within 3 years. This being the case, conservative therapy may be selected for closing aortic dissection when there are no serious complications in the acute phase. However, closely following patients with diagnostic imaging techniques is essential as there may be complications such as recanalization or enlarged ULP. Such complications should be surgically treated because they may affect long-term prognosis.

[Clinical experience with cefotiam in pediatric infections (author's transl)].

Cefotiam, one of the new cephem antibiotics, was used in 14 cases with pediatric infections: (10 cases with respiratory tract infections, 2 with urinary tract infections, each 1 with purulent meningitis + sepsis and acute appendicitis). The patients were aged between 15 days and 9 years old. The drug was, a rule, given at a daily dose of 50 mg/kg to 100 mg/kg q.i.d. by bolus intravenous injection. The duration of treatment was between 3 and 38 days. The treatment produced the following clinical responses: Out of the 10 cases, good response in 7 with respiratory tract infections, fair in 1 and poor in the remaining 2. The responses in urinary tract infections were excellent in 1 and good in the other case. An apparently clear response was obtained in 1 case with purulent meningitis + sepsis due to K. pneumoniae. Also, an excellent response was seen in 1 case with acute appendicitis. The response rate including fair response was 85.7%. The suspected pathogens isolated from 5 cases (S. aureus: 1. strain, H. influenzae: 1, K. pneumoniae 2, E. coli: 1) were eliminated after CTM administration. Good clinical responses were also obtained in these cases. No side effect was observed. Mild elevation of GOT and GPT was noted during the treatment in 1 case. It is unclear, however, if CTM was associated with this side effect or not. P. aeruginosa, Serratia appeared after superinfection in 1 case.

[Clinical investigations of cefadroxil in the infections of children (author's transl)].

Clinical investigations were performed on clinical effects of cefadroxil, and the following results were obtained. 1. Cefadroxil was administered at a daily dose of 30 mg/kg divided into 3 times in 24 cases of acute tonsillitis and pharyngitis, and clinical results were obtained; remarkably excellent in 8 cases, good in 13 cases, and poor in 3 cases. 2. It was suggested, though the case numbers were limited, that higher efficacy may be obtained in urinary tract infection. 3. No noteworthy side effect was observed throughout all 29 cases, and cefadroxil will be expected to be administered safely in pediatric field.

[Clinical studies of 9,3"-diacetylmidecamycin in pediatric field (author's transl)].

Clinical trials of 9,3"-diacetylmidecamycin (MOM), a new macrolide antibiotic were carried out on 46 pediatric patients of 1 month to 11 years old with infections (acute pharyngitis 12, acute tonsillitis 1, acute bronchitis 14, asthmatic bronchitis 10, acute pneumonia 1, primary atypical pneumonia 2, Mycoplasma pneumonia 4 and pertussis 2). As a rule, MOM was given orally at a daily dose of 20 approximately 40 mg/kg divided into 3 times. The clinical results were excellent in 5 patients, good in 21, fair in 7 and poor in 13 and the efficacy rate was 56.5%. Side effects were observed in 4 patients (diarrhea, exanthema, urticaria and eosinophilia, 1 patient respectively). MOM is easy to take and a useful antibiotic for treating patients with bacterial infections, in particular, respiratory tract infection caused by Mycoplasma pneumoniae.

[A clinical study of cefoxitin in children (author's transl)].

Clinical trials of cefoxitin, a new cephamycin antibiotic were carried out on 17 infantile patients with infections (respiratory tract infection 15, meningitis 1 and sepsis 1). Two patients of the above patients were excluded from the clinical evaluation except side effects because diseases were out of the object of this study. Cefoxitin was given at a dose of 50-104 mg/kg/day q.i.d. except 1 patient (b.i.d.) by a single intravenous injection for 2-27 days. The clinical efficacy obtained was good in 11 patients, fair in 2 patients and poor in 2 patients. The efficacy rate was 73.3%. Side effects were observed in 4 patients (eosinophilia 1, skin rash 2 and transient elevation of GOT, GPT and LDH 1).

[Clinical studies of ceftazidime in the pediatric field].

Twenty-four pediatric patients with infections were treated with ceftazidime (CAZ) by one-shot intravenous injection in the doses of 39 approximately 149 mg/kg/day in 4 divided doses as a rule. These patients' ages ranged from 2 months to 13 years 4 months. The duration of the administration ranged from 4 to 19 days, and total doses ranged from 1.38 to 57 g. Infections consisted of respiratory tract infections in 19 cases (acute tonsillitis in 3, acute bronchitis in 7, and pneumonia in 9), urinary tract infection in 1 case, acute peritonitis in 1 case, and suspected sepsis in 3 cases. Clinical efficacy was excellent in 18, good in 1, fair in 1, and poor in 4 cases, and the efficacy rate (excellent + good) was 79.2%. Bacteriological response was evaluated on 14 strains of bacteria isolated from lesions, assumed as the causative organisms (7 strains of S. aureus, 3 of P. aeruginosa, 1 of H. influenzae, 1 of K. pneumoniae, 1 of E. coli, and 1 of S. marcescens). Out of these strains, 10 were eradicated, and 1 (P. aeruginosa) decreased, but 2 strains (both S. aureus) persisted. (One strain of S. aureus was not examined.) No adverse effect suspected to be related to the drug was observed either in subjective symptom or in objective findings.

[Clinical study of SM-4300 in infectious diseases of pediatrics].

SM-4300, a new developed immunoglobulin preparation with ion-exchange treatment, was used intravenously for 12 infectious diseases. These 12 cases (under 10 years old) were including 4 sepsises, 3 pneumonias, 1 pyothorax, 1 ventriculitis, 1 purulent meningitis, 1 aseptic meningitis and 1 cellulitis. To evaluate the effect of SM-4300, 2 cases were excluded from evaluation because of blood transfusion or immediately death. Since antibiotics were used at the same time, it was surely difficult to evaluate the effect of SM-4300. In 10 cases, 2 cases were excellent effective, 4 cases were fairly effective and others were not effective. Including fairly effective cases, the rate of efficacy was 60%. In all cases, there were no significant side effects regarding clinical findings and laboratory examinations. SM-4300 may be available for severe infectious diseases with antibiotics therapy.

[Clinical evaluation of cefotetan in pediatrics].

Cefotetan (CTT), a new cephamycin antibiotic, was administered to 21 pediatric patients, 1 year and 1 month to 9 years of age, with moderate or severe infections. CTT was intravenously administered 3 times a day at daily doses of 26.5 to 120 mg/kg for 2 to 14 days, and 0.75 to 31.0 g of the drug were totally given. Total of 21 cases, 12 cases of respiratory tract infections (each 1 case of acute pharyngitis, acute tonsillitis and asthmatic bronchitis, 6 cases of acute pneumonia, 1 case of lung fibrosis and 2 cases of primary atypical pneumonia), 2 cases of urinary tract infections, 1 case of acute appendicitis, 1 case of perianal abscess, 2 cases of sepsis, 1 case of MCLS, 1 case of ReYE's syndrome and 1 case of meningoencephalitis, were received CTT. Five cases were excluded for the evaluation of clinical efficacy, and good response were obtained in 11 cases (effective rate of 68.8%), fair in 1 and poor in 4. Out of 3 strains of causative organisms isolated before the treatment, H. influenzae and K. pneumoniae were disappeared after the CTT treatment, S. faecalis which was resistant against CTT persisted. Neither adverse effects nor abnormal laboratory findings were observed except 1 case of eosinophilia.

[Clinical results of cefuroxime (CXM) therapy in pediatric infections (author's transl)].

Cefuroxime, a new cephalosporin C antibiotic, was administered to 15 children with respiratory tract infection, urinary tract infection, or subcutaneous tumour. The following results were obtained. 1) CXM 30 approximately 100 mg/kg/day were used in treatment of respiratory tract infection. Eight of the eleven patients treated responded to the therapy. 2) CXM 45 approximately 75 mg/kg/day were given to 3 patients with urinary tract infection. Excellent results were obtained in all these cases. 3) One patient with subcutaneous tumour responded to CXM therapy. 4) Clinical isolates from the foci involved, i.e., Staphylococcus aureus (4 strains), Group A Streptococcus hemolyticus (1 strain), Streptococcus pneumoniae (1 strain), Haemophilus influenzae (1 strain), and Escherichia coli (3 strains) were all eliminated by CXM therapy except 2 unassessable strains. 5) No noteworthy side effect was noted.

[Results of application of CS-1170 to pediatric infections (author's transl)].

CS-1170 was administered in a total of 11 cases including respiratory infections, urinary-tract infections, and subacute bacterial endocarditis. It was effective in all of the cases; markedly effective in a case of bronchopneumonia with underlying Down's syndrome and infantile spasm and in 2 cases of urinary-tract infections with E. coli. The fact that it was effective for urinary-tract infection with E. coli which showed no sensitivity to ampicillin or cefazolin demonstrates the clinical significance and usefulness of CS-1170 which is said to have a strong antibacterial activity for bacterial producing beta-lactamase. No side effect was observed.