Ivermectin: a multifaceted drug of Nobel prize-honoured distinction with indicated efficacy against a new global scourge, COVID-19.

In 2015, the Nobel Committee for Physiology or Medicine, in its only award for treatments of infectious diseases since six decades prior, honoured the discovery of ivermectin (IVM), a multifaceted drug deployed against some of the world's most devastating tropical diseases. Since March 2020, when IVM was first used against a new global scourge, COVID-19, more than 20 randomized clinical trials (RCTs) have tracked such inpatient and outpatient treatments. Six of seven meta-analyses of IVM treatment RCTs reporting in 2021 found notable reductions in COVID-19 fatalities, with a mean 31% relative risk of mortality vs. controls. During mass IVM treatments in Peru, excess deaths fell by a mean of 74% over 30 days in its ten states with the most extensive treatments. Reductions in deaths correlated with the extent of IVM distributions in all 25 states with p < 0.002. Sharp reductions in morbidity using IVM were also observed in two animal models, of SARS-CoV-2 and a related betacoronavirus. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein, is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.

Nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy in 2007: general view of the pathogens' antibacterial susceptibility.

For the purpose of a nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens in patients in Japan, the Japanese Society of Chemotherapy conducted their second year survey, during the period from January to August, 2007. A total of 1178 strains were collected from clinical specimens obtained from adult patients with well-diagnosed respiratory tract infections. Susceptibility testing was evaluable for 1108 strains (226 Staphylococcus aureus, 257 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 206 Haemophilus influenzae, 120 Moraxella catarrhalis, 122 Klebsiella pneumoniae, and 171 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 beta-lactams (four penicillins, three penicillins in combination with beta-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standards Institute (CLSI). The incidence of methicillinresistant Staphylococcus aureus (MRSA) was high, at 59.7%, and the incidences of penicillin-intermediateresistant and -resistant Streptococcus pneumoniae (PISP and PRSP) were 30.4% and 5.1%, respectively. Among Haemophilus influenzae strains, 19.9% of them were found to be beta-lactamase-non-producing ampicillin (ABPC)-intermediately-resistant (BLNAI), 29.1% to be beta-lactamasenon-producing ABPC-resistant (BLNAR), and 6.7% to be beta-lactamase-producing ABPC-resistant (BLPAR) strains. Extended-spectrum beta-lactamase-producing Klebsiella pneumoniae was not isolated. Two isolates (1.2%) of Pseudomonas aeruginosa were found to be metallo-beta-lactamase-producing strains, including one (0.6%) suspected multidrug-resistant strain showing resistance to imipenem, amikacin, and ciprofloxacin. These data will be a useful reference for future periodic surveillance studies and for investigations to control resistant infections as well. Continued surveillance is required to prevent the further spread of these antimicrobial resistances.

The first nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy. Part 1: a general view of antibacterial susceptibility.

The Japanese Society of Chemotherapy (JSC) conducted the first nationwide surveillance of bacterial respiratory pathogens during the period from January to August 2006. With the cooperation of 32 medical institutions throughout Japan, a total of 924 strains belonging to seven clinically relevant bacterial species were collected from adult patients with well-diagnosed respiratory tract infections (RTIs). Antimicrobial susceptibility testing of the 887 evaluable strains (205 Staphylococcus aureus, 200 Streptococcus pneumoniae, 9 Streptococcus pyogenes, 165 Haemophilus influenzae, 91 Moraxella catarrhalis, 74 Klebsiella pneumoniae, and 143 Pseudomonas aeruginosa) to 42 antibacterial agents was conducted at the Central Laboratory of the Research Center for Anti-infective Drugs of the Kitasato Institute, according to recommendations issued by the Clinical and Laboratory Standards Institute (CLSI). The antibacterial agents employed were 25 beta-lactams, three aminoglycosides, four macrolides (including one azalide and one ketolide), one lincosamide, one tetracycline, two glycopeptides, five fluoroquinolones, and one oxazolidinone. The incidence of methicillin-resistant S. aureus (MRSA) was 63.4%, and the incidences of penicillin-intermediately resistant S. pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP) were 35.0% and 4.0%, respectively. Among H. influenzae, 21.2% of the strains were found to be beta-lactamase-nonproducing ampicillin (ABPC)-intermediately resistant (BLNAI), 29.1% to be beta-lactamase-nonproducing ABPC-resistant (BLNAR), and 4.8% to be beta-lactamaseproducing ABPC-resistant (BLPAR) strains. The incidence of extended-spectrum beta-lactamase-producing K. pneumoniae was 2.7% (2 of 74 strains). Three (2.1%) of the 143 P. aeruginosa strains were found to be metallo-beta-lactamaseproducing, including 1 (0.7%) multidrug-resistant strain. Through the nationwide surveillance, we obtained fundamental antimicrobial susceptibility data of clinically relevant bacterial pathogens in adult RTI to various antibacterial agents. These data will be a useful reference for future periodic surveillance studies, as well as for investigations to control antimicrobial-resistant pathogens.

T cell-dependent elimination of dividing Trypanosoma grosi from the bloodstream of Mongolian jirds.

Mongolian jirds, Meriones unguiculatus, are susceptible to infection with Trypanosoma grosi, which naturally parasitizes Apodemus spp. The present study investigated T cell dependence of elimination of T. grosi from the bloodstream of jirds by in vivo T cell depletion using a monoclonal antibody (HUSM-M.g.15). In T cell-depleted jirds, elimination of T. grosi, particularly the dividing forms, from the bloodstream was significantly delayed, occurring at around week 3 p.i. The kinetics of serum levels of IgM and IgG specific to trypanosomes in T cell-depleted and control immunocompetent jirds were different; peak levels of IgM were noted on days 6-8 p.i. around the time of peak parasitaemia (day 6 p.i.) in immunocompetent jirds, whereas the serum levels began to increase abruptly after day 10 p.i., peaking at around day 18 p.i. in T cell-depleted jirds. Similarly, serum IgG increased after day 6 p.i. in immunocompetent jirds, in contrast to after day 12 p.i. in T cell-depleted jirds, and the level increased steadily even after disappearance of parasitaemia. Our findings indicate that T cells play a major role at least in the 'first crisis' during elimination of dividing T. grosi from the bloodstream.

Tyrosine phosphorylation of proteins in primary human myeloid leukemic cells stimulated by macrophage colony-stimulating factor: analysis by disease type and comparison with normal human hematopoietic cells.

We investigated tyrosine phosphorylation of proteins in primary human leukemic cells stimulated by macrophage colony-stimulating factor (M-CSF) in 60 patients with acute myeloid leukemia (AML) and 5 patients with chronic myelomonocytic leukemia and compared the findings for leukemic cells with those of normal human monocytes and bone marrow immature hematopoietic cells. M-CSF induced tyrosine phosphorylation of p140-200, p110, p60, p44, and p42 frequently, and that of p95 and p55 less frequently, in primary myeloid leukemic cells, whereas M-CSF-induced phosphorylation of proteins was not detected in the normal human hematopoietic cells tested. Of these phosphoproteins, p140-200 was phosphorylated in all patients who responded to M-CSF and was considered to be almost identical to Fms, a product of the c-fms proto-oncogene. M-CSF-induced tyrosine phosphorylation was observed frequently (89%) in AML of French-American-British class M4 and infrequently in all other subtypes of AML, including M5. In chronic myelomonocytic leukemia, M-CSF-induced protein phosphorylation was prominent in blast crisis but was not detected in the chronic phase. Both bone marrow immature cells and mature monocytes showed low responsiveness to M-CSF. These findings for responsiveness to M-CSF were correlated with the amount of Fms in each type of cell. We also identified tyrosine phosphorylation of Vav, Shc, and extracellular signal-regulated kinase by M-CSF in some cases. These findings clarified an M-CSF-specific pattern of protein tyrosine phosphorylation and the responsiveness to M-CSF of primary human myeloid cells. Particularly, enhanced phosphorylation responses to M-CSF and increased amounts of Fms protein were observed in restricted human hematopoietic cells with a premature myelomonocytic character.

Monoclonal antibodies reactive with dendritic cells of Mongolian gerbils.

Mongolian gerbils (Meriones unguiculatus) serve as an valuable model animal for several infectious diseases of medical and veterinary importance. Reagents available for characterization of the immune response of Mongolian gerbils are strictly limited. We describe three novel murine monoclonal antibodies (mAbs) to dendritic cells of Mongolian gerbils. These include HUSM-M.g.11 of IgG2b isotype, HUSM-M.g. 20 of IgG2a isotype, and HUSM-M.g.30 of IgG1 isotype. All of these mAbs had an identical profile of immunohistochemical reactions with various tissues taken from immune-naive Mongolian gerbils, and were intensively expressed on dendritic cells, including epidermal Langerhans cells, B-cell follicles, and the thymic reticulum. Positive reactions of the epidermis and intestinal mucosa with these mAbs were induced by cutaneous or intestinal infections with parasites. Competitive enzyme-linked immunosorbent assay and immunoblot analysis (western blotting) indicated that all of these mAbs recognize an identical peptide epitope on a molecule with approximate molecular mass of 29 kDa. These data suggest that the mAbs recognize major histocompatibility complex class-II molecules of gerbils. Use of described mAbs would facilitate characterization of immune responses as well as investigations on host responses to infections of medical and veterinary importance, using the gerbil model.

Induction of phagocyte oxidase components during human myeloid differentiation: independent protein expression and discrepancy with the function.

We investigated the content of four components of the O2(-)-producing enzyme (p47, p67, p22, and gp91) and the O2(-)-producing capacity in human myeloid cell lines. The content of the four components of the phagocyte oxidase was minimal before differentiation induction. During differentiation, expression of p22 and gp91 was at consistently low levels, even when the O2(-)-producing capacity was equivalent to that of normal neutrophils. On the other hand, p47 was consistently and rapidly induced to the level comparable to normal neutrophils. The results indicate that low expression of p22 and gp91 is sufficient to obtain normal O2- production, and that p47 might play an important regulatory role in the functional differentiation.

Diverse effects of cytochalasin B on priming and triggering the respiratory burst activity in human neutrophils and monocytes.

Cytochalasin B, despite its potent enhancing effect on superoxide (O2-) release triggered by N-formyl-methionyl-leucyl-phenylalanine (FMLP) and many other agonists, significantly inhibited O2- release triggered by interleukin 8 (IL-8) and platelet-activating factor in human neutrophils. Cytochalasin B also enhanced changes in membrane potential stimulated by FMLP but inhibited those stimulated by IL-8. Using IL-8 as a triggering agonist, we found that the priming effect of tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on O2- release was slightly but significantly potentiated by cytochalasin B. O2- release triggered by TNF and GM-CSF was completely abolished by cytochalasin B. In contrast to these diverse effects of cytochalasin B on O2- release, changes in cytoplasmic pH stimulated by FMLP, IL-8, TNF, and GM-CSF were not or were only minimally affected by cytochalasin B. Unlike human neutrophils, human monocytes stimulated by FMLP showed inhibition of O2- release and changes in membrane potential in response to cytochalasin B, and the priming effect of TNF and GM-CSF on O2- release in human monocytes was completely abolished by cytochalasin B. These findings indicate the diverse effects of cytochalasin B on phagocytes and suggest distinct regulatory mechanisms according to the functions, agonists, and cell types.

[Comparison of combined operation and nasal CPAP treatments for sleep disorders].

UNLABELLED: Uvulopalatopharyngoplasty (UPPP) and nasal CPAP are used for the treatment of obstructive sleep apnea syndrome (OSAS) in different institutions. Although OSAS results from an abnormality in the soft-palate, almost no reports have been made on the selection of UPPP or nasal CPAP procedures according to the type of abnormality. The most probable reason for this is that a comparison of treatment methods in individuals cases is difficult. We performed CPAP titration before and after operations, and compared the treatment methods, and evaluated the medical therapy. METHOD: A sleep polygraph was performed on the first night, and cases diagnosed as OSAS received CPAP titration on the second night. The blocked region was identified by endoscopic examination. The results of the operation were evaluated after 1-2 months, and apnea hypopnea index (AHI) improvements of less than 50% received a second CPAP titration. RESULTS: The operation results were poor for cases where endoscopic examination showed full-circumference palatal type, and good for soft palate and tonsillar type abnormalities. When endoscopic examinations were performed in conjunction with nasal CPAP, the treatment was observed to act on the soft palate and expand the air way in all cases. Nasal CPAP was effective in cases with full-circumference palatal abnormalities because in these cases, the pressure was caused by inflamma. Combined medical treatments were effective in cases where CPAP alone was ineffective because the pressure was too high.

What's new in the antibiotic pipeline.

Many advances have recently been made in the development of chemotherapeutic agents for bacterial infections. As a consequence of problematic antimicrobial-resistant bacteria, research is now directed towards narrow-spectrum agents rather than broad-spectrum agents. Further, orally active agents have always been desirable, but today's cost-saving environment, in line with a desire to minimize treatment costs, values reduced administration costs and keeping patients out of the hospital. There has been a recent increase in research into orally active antibacterial agents, such as carbapenems and cephalosporins, and non-glycopeptide natural products.

Signal transduction pathways in normal human monocytes stimulated by cytokines and mediators: comparative study with normal human neutrophils or transformed cells and the putative roles in functionality and cell biology.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL) -3 induced tyrosine phosphorylation of 92-kDa protein in normal human monocytes. We identified this 92-kDa protein as STAT5, but not as STATs1, 3, and 6 nor c-fes and vav protooncogene products, and demonstrated its translocation to the nucleus, enhancement of specific DNA binding capacity, and potentiation of trancriptional activity by GM-CSF. N-formyl-methionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA) induced tyrosine phosphorylation of 42- and 44-kDa proteins, which were identified as extracellular signal-regulated kinase (ERK), in human monocytes. In marked contrast to neutrophils and MO7e cells, GM-CSF did not induce tyrosine phosphorylation and activation of ERK in monocytes. Among upstream signaling molecules of ERK, Shc was constitutively associated with Grb2 and was not tyrosine-phosphorylated by GM-CSF and FMLP, and Sos1 and c-Raf-1 were not phosphorylated by GM-CSF, IL-3, TNF, and FMLP in monocytes, whereas all these signaling molecules were affected and/or utilized by GM-CSF in MO7e cells. In contrast to neutrophils, p38 was constitutively phosphorylated and agonist-dependent phosphorylation and activation was not detected in human monocytes. Superoxide release stimulated by FMLP was inhibited partially by PD98059 or SB203580, a specific inhibitor of ERK or p38 pathway, and was almost completely inhibited by the combination of both inhibitors, whereas PMA-induced superoxide release was resistant to these two inhibitors in monocytes. PD98059 inhibited GM-CSF-dependent proliferation of MO7e cells. Present results indicate trancriptional roles of STAT5 and functional roles of ERK and/or p38 in normal human monocytes stimulated by physiological receptor-mediated agonists GM-CSF and FMLP. Possible roles of ERK in proliferation of transformed cells were also suggested.

Helminth fauna of carnivores distributed in north-western Tohoku, Japan, with special reference to Mesocestoides paucitesticulus and Brachylaima tokudai.

In the winter of 1998-1999, we collected parasitological data from 54 wild carnivores in the north-western part of Tohoku region, Japan. These consisted of 38 martens (Martes melampus melampus), 14 raccoon dogs (Nyctereutes procyonoides viverrinus) and 2 foxes (Vulpes vulpes japonica). Collected helminth parasites were 11 nematode, 10 trematode, 3 cestode, and a single acanthocephalan species, including 5 hitherto unknown species for this research area or the mainland of Japan (Honshu). Mesocestoides paucitesticulus was for the first time recorded from martens as well as from carnivores distributed in Honshu. Brachylaima tokudai originally recorded from Urotrichus talpoides in the central part of Honshu was for the first time found from a raccoon dog.

Cooperative stimulatory effects of tumor necrosis factor and granulocyte-macrophage colony-stimulating factor on the particular respiratory burst activity in human neutrophils: synergistic priming effect on concanavalin A-induced response, no interactive priming effect on the chemotactic peptide-induced response and additive triggering effect.

Tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) rapidly primed human neutrophils for enhanced superoxide (O2-) release, and membrane depolarization stimulated by chemotactic peptide (N-formyl-methionyl-leucyl-phenylalanine), interleukin 8, concanavalin A (Con A) and ionomycin. Combined stimulation of human neutrophils with the optimal concentrations of TNF plus GM-CSF showed no additive or synergistic effects according to the subsequent stimuli and within the parameters tested. Particularly, a high synergistic priming effect of these two cytokines was observed when Con A was used as a triggering agonist of O2- release. The priming of human neutrophils with the optimal concentrations of TNF plus G-CSF, however, always resulted in the same effect as TNF alone. TNF and GM-CSF triggered O2- release directly in human neutrophils for prolonged time periods, and combined stimulation of human neutrophils with the optimal concentrations of TNF plus GM-CSF triggered an added amount of O2- release. TNF and GM-CSF by themselves induced an increase in cytoplasmic pH (intracellular alkalinization), an important signaling event for functional activation of neutrophils, though combined stimulation of human neutrophils with the optimal concentrations of the two cytokines had no additive effects on cytoplasmic pH. The present results show cooperative interaction between TNF and GM-CSF in their stimulatory effects on particular functions in human neutrophils, and these synergistic effects are probably mediated via a mechanism distal to or independent of intracellular alkalinization.

Successful treatment with polymyxin B immobilized fiber of septic shock complicated by renal stone.

We describe a patient with septic shock that was spontaneously complicated by calyceal diverticular calculus. The patient recovered from shock within a few days with treatment by extracorporeal elimination of endotoxin using a blood purification cartridge consisting of polymyxin B immobilized fiber. Standard open nephrolithotomy was performed, and the patient was discharged from the hospital 2 months after admission.

Trends in development of anti-infective agents in Japan.

Newly developed anti-infective agents have been continuously supplied in the clinics of Japan over the past 50 years, and were beneficial in saving patients from life-threatening infections. However, the emergence of resistant bacteria and uncommon pathogens has caused complications in chemotherapy. Further efforts have been made to develop newer and more effective agents to minimize such complications. The newest and the most effective agents are available even at primary-care clinics, as the health insurance system allows the use of any agents approved by the government. Despite potential risks of the emergence and spread of resistant bacteria and the occurrence of adverse drug reactions, current usage of such effective agents shows more successful results, particularly in prognosis, than that of less effective ones. Because of the extreme changes in infectious diseases over the last 10-15 years, guidelines for the evaluation of anti-infective agents have been proposed. It is essential to harmonize with the USA and the European guidelines for mutual acceptance of clinical data. However, it is true that practices of anti-infective therapy in Japan, in the USA and in Europe are different both in dose regimen and assessments of efficacy and safety. As the leading country in the development of newer anti-infective agents, Japan proposes the most sophisticated way to evaluate those agents to update knowledge in medical science.

Increased neutrophil respiratory burst in myeloproliferative disorders: selective enhancement of superoxide release triggered by receptor-mediated agonists and low responsiveness to in vitro cytokine stimulation.

The neutrophil superoxide (O2-)-producing capacity in 57 patients with chronic myeloproliferative disorders (MPDs) and eight patients with chronic myelomonocytic leukemia (CMML) was investigated. O2- release in neutrophils stimulated by chemotactic peptide was markedly increased in all types of chronic MPD, including chronic myelogenous leukemia in both chronic phase and blastic crisis, polycythemia vera, and essential thrombocythemia, but was normal in CMML, which is thought to be a myelodysplastic disorder rather than MPD. Increase in O2(-)-producing capacity in MPD was also observed when other receptor-mediated agonists such as interleukin-8 and concanavalin A were used, but not when phorbol ester, a direct activator of protein kinase C, was used as the triggering agonist of O2- release. Priming effects of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), and tumor necrosis factor (TNF) on chemotactic peptide-induced O2- release was observed in all patients with MPD and CMML, though fold enhancement of priming effects was much less in MPD compared with normal subjects. In addition, the priming effects of TNF were less than those of GM-CSF in 10 cases, whereas the priming effects of TNF were consistently and markedly greater than those of GM-CSF in normal subjects. Tyrosine phosphorylation of 42-kDa protein stimulated by G-CSF, GM-CSF, and TNF was observed in CML neutrophils to be identical to that in normal neutrophils. Present results indicate specific potentiation of the receptor-mediated route of signaling that is linked to the respiratory burst and downregulated responsiveness to cytokines in neutrophils in patients with all types of chronic MPD, suggesting in vivo priming of patient neutrophils via certain mechanism by cytokines or related stimuli in these hematological disorders.

Superoxide release and NADPH oxidase components in mature human phagocytes: correlation between functional capacity and amount of functional proteins.

We evaluated the interrelationship between the respiratory activity and amount of proteins responsible for this function in normal and subnormal human phagocytes, neutrophils, eosinophils, monocytes, and macrophages. The superoxide-producing capacity was eosinophils > neutrophils > monocytes = macrophages when the cells were stimulated with chemotactic peptide or phorbol ester. Consonant with this finding, the protein content of three essential components of phagocyte oxidase (p22-phox, p67-phox, and p47-phox) was also eosinophils > neutrophils > monocytes = macrophages. On the other hand, the amount of another essential component, gp91-phox, was macrophage > neutrophils > eosinophils > monocytes. These findings together indicate an overall positive interrelationship between protein content and its responsible function, though only gp91-phox was not associated with the functional capacity and low amounts of this component supported the increased respiratory burst activity of eosinophils.

[Pharmacokinetic, bacteriological and clinical studies on cefozopran in neonates and premature infants. A study of cefozopran in the perinatal co-research group].

The following results were obtained in pharmacokinetic, bacteriological and clinical investigations of a cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), administered to neonates and premature infants. 1. Pharmacokinetics (1) Half-lives (T 1/2's) of CZOP in 0-day-old (less than 24 hours after birth) neonates and premature infants were longer than those in 1-day-old or older infants. When half-lives were compared between 0-day-old neonates and 0-day-old premature infants, longer half-lives were observed in premature infants. (2) When CZOP was intravenously administered to 1-day-old or older neonates and premature infants at a dose of 20 mg/kg, no differences were noted in blood concentrations between neonates and premature infants from 30 minutes to 6 hours after administration as well as T 1/2's. (3) Blood concentration of CZOP administered at doses of 10, 20 and 40 mg/kg were dose-dependent. (4) Urine excretion rates of CZOP administered to 1-day-old or older neonates and premature infants were approximately 30 to 60% in the first 6 hours after administration. Urine excretion rates in 0-day-old neonates and premature infants were low. 2. Clinical results (1) Of a total of 136 cases to which CZOP was administered, clinical efficacy evaluation was possible in 96 cases, and safety evaluation in 132 cases. (2) The clinical efficacy rates were 78.6% (22/28) in 28 cases in which causative organisms were detected (Group A), and 97.1% (66/68) in 68 cases in which no such organisms were detected (Group B), with the total efficacy rate (Groups A and B) of as high as 91.7% (88/96). (3) Bacteriological evaluations were made with 33 strains isolated from the 28 cases of Group A. Elimination rates for Gram-positive and Gram-negative bacteria were 88.2% (15/17) and 92.3% (12/13), respectively, with the total elimination rate of 90.0% (27/30). No microbial substitution was noted. (4) As an adverse reaction, diarrhea was noted in one case (0.8%). Abnormal laboratory test values were noted in 15 cases (12.3%) including eosinophilia, elevated GPT, and elevated gamma-GTP. All of these abnormalities were transitory, and none of them critical. As a result of above pharmacokinetic and clinical investigations, CZOP is considered to be highly useful in the treatment of indicated infections in neonates and premature infants. It appears that 20 mg/kg of CZOP can be administered by intravenous injection or intravenous drip infusion to neonates and premature infants aged 0-day (less than 24 hours after birth) once or twice daily, to those aged 1 (24 or more hours after birth) to 7 days twice or three times daily, and to those aged 8 or more days three to four times daily, and that the dose can be increased up to 40 mg/kg in cases of critical or intractable infections.

Activation of human monocyte functions by tumor necrosis factor: rapid priming for enhanced release of superoxide and erythrophagocytosis, but no direct triggering of superoxide release.

Tumor necrosis factor (TNF), like granulocyte-macrophage colony-stimul ating factor (GM-CSF), rapidly primed human monocytes for enhanced release of superoxide (O-2) stimulated by receptor-mediated agonists, N-formyl-methionyl-leucyl-phenylalanine (FMLP) and concanavalin A (Con A), but not by phorbol myristate acetate (PMA), which bypasses the receptors to stimulate the cells. The optimal priming was obtained by pretreatment of suspended monocytes with 10 U/mL TNF for 10 minutes at 37 degrees C. The potency of the maximal priming effect was TNF> GM-CSF, and the combined effect of TNF and GM-CSF was greater than that of each cytokine alone. GM-CSF induced an increase in cytoplasmic pH but TNF did not. These findings suggest that TNF and GM-CSF activate monocytes through different mechanisms. TNF and GM-CSF by themselves never triggered O-2 release in suspended monocytes or monocytes adherent to endothelial cells, although both cytokines triggered massive release of O-2 in human neutrophils. In additions, TNF and GM-CSF induced tyrosine phosphorylation of a 42-kD protein in neutrophils but not in monocytes. These findings suggest that the TNF-receptor- or GM-CSF-receptor-mediated signaling pathways for triggering O-(2) release is active in neutrophils but inactive or defective in monocytes. TNF also enhanced phagocytosis of sialidase-treated autologous erythrocytes by monocytes, and this effect was further potentiated in the presence of autologous fresh serum. The significant enhancement of erythrophagocytosis was obtained at 1 U/mL TNF. At this concentration of TNF, the expression of C3bi-receptor (CD11b/CD18) was upregulated. These findings show that TNF rapidly primes human monocytes for enhanced release of O-(2) and erythrophagocytosis and suggest that TNF activates monocytes through autocrine or paracrine mechanisms at the inflammatory sites inasmuch as TNF is primarily produced by activated monocytes/macrophages.

[A case of sleep apnea syndrome due to a nasopharyngeal tumor].

Obstructive Sleep Apnea Syndrome (OSAS) is children is commonly caused by upper airway obstruction, such as that caused by adeno-tonsillar hypertrophy. We report a rare case of SAS due to a nasopharyngeal tumor. The patient was a 10-year-old boy who complained of snoring and sleep apnea. The tumor was found in the nasopharynx and mesopharyngeal space. We diagnosed this case as OSAS by overnight sleep study (Apnea Hypopnea Index: AHI = 19.67). The tumor was removed under general anesthesia. Histopathology revealed features of nasopharyngeal angiofibroma. After removal of the tumor, his symptoms resolved completely. A follow-up overnight sleep study confirmed resolution of OSAS. At the last follow up, conducted 17 months after the operation there were no signs of tumor recurrence.