CD30+ large cell transformation of mycosis fungoides after psoralen plus ultraviolet A photochemotherapy.

Psoralen plus ultraviolet A (PUVA) photochemotherapy is widely used for the therapy of mycosis fungoides (MF). Clinical progression of MF is often associated with an increase in the size of tumour cells known as transformation. We report two patients with CD30+ large cell transformation that appeared after low-dose PUVA therapy for MF. Clinical data, histopathology, immunohistopathology and T-cell receptor gene rearrangement were studied. Nodules consisted of atypical large cells that expressed CD30. Monoclonal rearrangement of T-cell receptors was observed in one case. Low-dose PUVA therapy may be associated with CD30+ large cell transformation in patients with MF.

Insulin resistance and increased pancreatic beta-cell proliferation in mice expressing a mutant insulin receptor (P1195L).

Several mutations of the tyrosine kinase domain of insulin receptor (IR) have been clinically reported to lead insulin resistance and insulin hypersecretion in humans. However, it has not been completely clarified how insulin resistance and pancreatic beta-cell function affect each other under the expression of mutant IR. We investigated the response of pancreatic beta-cells in mice carrying a mutation (P1195L) in the tyrosine kinase domain of IR beta-subunit. Homozygous (Ir(P1195L/P1195L)) mice showed severe ketoacidosis and died within 2 days after birth, and heterozygous (Ir(P1195L/wt)) mice showed normal levels of plasma glucose, but high levels of plasma insulin in the fasted state and after glucose loading, and a reduced response of plasma glucose lowering effect to exogenously administered insulin compared with wild type (Ir(wt/wt)) mice. There were no differences in the insulin receptor substrate (IRS)-2 expression and its phosphorylation levels in the liver between Ir(P1195L/wt) and Ir(wt/wt) mice, both before and after insulin injection. This result may indicate that IRS-2 signaling is not changed in Ir(P1195L/wt) mice. The beta-cell mass increased due to the increased numbers of beta-cells in Ir(P1195L/wt) mice. More proliferative beta-cells were observed in Ir(P1195L/wt) mice, but the number of apoptotic beta-cells was almost the same as that in Ir(wt/wt) mice, even after streptozotocin treatment. These data suggest that, in Ir(P1195L/wt) mice, normal levels of plasma glucose were maintained due to high levels of plasma insulin resulting from increased numbers of beta-cells, which in turn was due to increased beta-cell proliferation rather than decreased beta-cell apoptosis.

Idiopathic acquired generalized anhidrosis due to occlusion of proximal coiled ducts.

Idiopathic acquired generalized anhidrosis is a very rare disease of unknown pathogenesis. We report a 25-year-old man with acquired generalized anhidrosis due to occlusion of the coiled ducts. He did not have sweat secretion over the entire surface of the body, including the palms and soles. Sweat-inducing stimuli provoked tingling pain on the skin. Pilocarpine iontophoresis on the forearm did not induce sweat secretion. Neurological examination did not reveal any abnormality in the central or peripheral nervous system. Skin biopsy showed that the coiled ducts were occluded by an amorphous eosinophilic substance. This amorphous eosinophilic substance was positive with periodic acid-Schiff (PAS) staining and was resistant to digestion by diastase. Electron microscopy demonstrated that the coiled ducts were completely occluded by an amorphous substance. The substance occluding the coiled ducts contained fibrous structures. These findings suggested that the acquired generalized anhidrosis in this patient was caused by occlusion of the coiled ducts by a PAS-positive substance probably derived from dark cell granules.

Fosfomycin nebulizer therapy to chronic sinusitis.

OBJECTIVE: effects of Fosfomycin (FOM) nebulizer therapy were studied in patients with chronic sinusitis. METHODS: about 28 patients with chronic sinusitis were administered 2 ml of FOM sodium (3% w/v) by nebulizer three times per week for 4 weeks. Levels of IL-1 beta, IL-6, IL-8, and TNF-alpha in nasal lavage were also measured before and at the end of treatment. RESULTS: the overall efficacy of this treatment on the basis of both subjective and objective symptoms, was 'excellent' for 28.6%, 'good' for 10.7%, 'fair' for 39.4%, and yield 'no change' for 21.4% of the patients. Both IL-1 beta and IL-6 concentrations were significantly decreased after treatment. Although the IL-8 level did not significantly decrease, it seems to be related to the overall efficacy. TNF-alpha was not detected in all of the samples. CONCLUSION: FOM nebulization therapy is highly effective in treatment for chronic sinusitis, and efficacy may be due to an immunomodulatory mechanism, as well as its bactericidal effect.

[Primary renal non-Hodgkin's lymphoma presenting as massive macrohematuria and bladder tamponade].

A 43-year-old man with macrohematuria and anuresis was admitted, and diagnosed as having bladder tamponade due to coagulates. Abdominal ultrasonography and computed tomography revealed bilateral renal tumors. Bilateral renal arteriography showed hypovascular lesions. Percutaneous needle biopsy of the left renal tumor was performed, and the final diagnosis was non-Hodgkin's lymphoma (diffuse mixed, B cell type, CSIIA). After six courses of chemotherapy, the tumor lesions were markedly reduced, and at present there is no evidence of recurrence.

Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice.

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

Dendroamides, new cyclic hexapeptides from a blue-green alga. Multidrug-resistance reversing activity of dendroamide A.

Dendroamide A (1), one of three new bistratamide-type cyclic hexapeptides from the terrestrial blue-green alga (cyanobacterium) Stigonema dendroideum Fremy, exhibits multidrug-resistance reversing activity. The gross structures of the three compounds, dendroamides A-C, were determined by NMR and mass spectral analyses. Their absolute stereochemistries were determined by Marfey and chiral GC/MS analyses of derivatives formed from acid hydrolysis of the intact and ozonized peptides.

Preclinical anticancer activity of cryptophycin-8.

Cryptophycin-8 was prepared by the conversion of the epoxide group on cryptophycin-1 to a chlorohydrin. In the studies reported here, cryptophycin-8 was evaluated for preclinical activity against subcutaneous tumors of both mouse and human origin. At the highest non-toxic single course treatment, the following results were obtained (Table A). Cryptophycin-8 was less potent than cryptophycin-1 by approximately 4-fold; however, it was both more water soluble and had greater therapeutic efficacy, as demonstrated by % T/C, tumor cell log kill values, range of dose effectiveness and host cures.

A study on prevention of hospital infection control caused by tooth preparation dust in the dental clinic. Part 1. Preventive measures against environmental pollution in the dental clinic caused by microbial particles.

Tooth preparation dust, an indispensable part of dental treatment, contains bacteria and viruses. In order to examine environmental pollution in the dental clinic during tooth preparation, we monitored microorganism spread by counting colony forming units (CFU) with the "Andersen Microbe Sampler." This test was conducted in a "Clean Booth." Mitis-salivarius medium was used to count the oral-streptococcus species. The ability of the "Extra-Oral Vacuum Aspirator (EOVA)" to effectively eliminate contamination was also tested, and the EOVA was found to reduce the spread of oral-streptococci, significantly. The EOVA was therefore viewed as an effective method for reducing air pollution in the dental clinic, and should be used when treating patients with certain infectious diseases.

[Participation in causing O.M.E. with nasopharyngeal alpha-Streptococcus].

The role of normal pharyngeal flora in the defense mechanism against infections in the upper respiratory tract was studied in 50 children with otitis media with effusion (O.M.E.). In the bacteriological study of the nasopharynx, the incidence of H. influenzae, S. pneumoniae, S. aureus, M. catarrhalis and group A Streptococcus was about 46%, 24%, 20%, 12% and 8%, respectively. The incidence of these species in the cases with O.M.E. was higher than that in the cases with chronic tonsilitis or control cases. In 41 O.M.E. cases with alpha-streptococci (82%), the incidence of alpha-streptococci with inhibitory activity against 5 pathogens (H. influenzae, S. pneumoniae, S. aureus, M. catarrhalis, group A Streptococcus) was examined. The detection rate of alpha-streptococcal strains with inhibitory activity against 5 pathogens derived from the nasopharynx in the cases with O.M.E. was significantly lower than that of the strain in the chronic tonsilitis cases and the control cases. Moreover, the detection rate of inhibitory alpha-streptococci from the nasopharynx was lower than that of from the tonsil. These findings suggest that the decline of inhibitory activity against pathogens by normal flora in nasopharynx is one of the factors causing O.M.E.

[Isolation of alpha-streptococci with inhibitory activity against pathogens, in the oral cavity and the effect of tobacco and gargling on oral flora].

We investigated the distribution of oral alpha-streptococci with inhibitory activity against pathogens, which compose an oral defense mechanism. Detection rate of alpha-streptococci with inhibitory activity against S. pyogenes and S. aureus derived from the tonsil was higher than in other portions, the tongue, cheek, gingiva, or saliva. It has suggested that tonsillar bacterial flora are mainly a defense mechanism. The oral flora in healthy smokers was compared with healthy non-smokers to investigate the influence of tobacco on oral bacterial flora. The results showed that the detection rate of S. aureus in smokers was higher while that of alpha-streptococci with inhibitory activity against S. aureus was lower. However, the detection rate of alpha-streptococci with inhibitory activity against S. pyogenes in smokers was as high as in non-smokers. It is suggested that it was easy for S. aureus to adhere to the oral mucosa in smokers, and was considered to influence the strain which produces beta-lactamase for medical treatment. We investigated the influence of gargling on oral bacterial flora by comparing the amount of bacteria before and after gargling with popidine-iodine gargle and saline solution. It was shown that alpha-streptococci, a main component of normal oral flora were decreased after gargling in both smokers and non-smokers. Furthermore, it was shown that group A Streptococcus was not decreased after gargling, and it was concluded that use of gargle medicinal mouth wash in bacillus carriers should be studied further.

[Effect of 14-member lactone ring macrolides on anti staphylococcal activity and swarming ability of Pseudomonas aeruginosa].

The purpose of this report is to examine the effect of Macrolides (Erythromycin and Roxythromycin) on swarming ability and antistaphylococcal activity of Pseudomonas aeruginosa. The standard strain (ATCC27854) and clinically isolated P. aeruginosa were used as test strains. The influence of Macrolides on antistaphylococcal activity and swarming ability were determined by the agar plate dilution method. The antistaphylococcal activity of P. aeruginosa was not affected at the concentration of 1.56 micrograms/ml of both Erythromycin and Roxythromycin. But the antistaphylococcal activity was not observed at the concentration over 100 micrograms/ml. The swarming ability was not affected at the concentration up to 12.5 micrograms/ml. It has been proved that Macrolides reveal inhibition of virulent factors of P. aeruginosa such as protease, elastase, piocianin and so on. Furthermore our data revealed that Macrolides inhibited swarming ability of P. aeruginosa, and did not affect the antistaphylococcal activity of P. aeruginosa under 1.56 micrograms/ml concentration. Consequently, these results suggest that Macrolides have exhibited a previously unknown pharmacological effect, and may be of interest in that there may be bacterial interaction between MRSA and P. aeruginosa.

Clinical efficacy of Tranilast on otitis media with effusion in children.

In this open randomized study, we evaluated the efficacy of Tranilast, one of the anti-inflammatory drugs, on otitis media with effusion in children. Sixty-two patients (103 ears) were divided into two groups: Group A was given Tranilast and local treatment (nasal and tubal); Group B only received local treatment (control for Group A). The overall improvement rating assessed as "moderately improved or above" for Group A was 63.6%, Group B 47.9%. There was a significant improvement in Group A as compared to Group B (p < 0.05). In subjects who suffered from otitis media with effusion for over 2 months. Group A exhibited 50.0% of efficacy while Group B only 15.4% (p < 0.05).

[Effect of erythromycin on anti staphylococcal activity and dye production of Pseudomonas aeruginosa isolated from clinical materials].

Anti staphylococcal activity by Pseudomonas aeruginosa was investigated through the use of the reversed agar plate and the filter paper stamp methods. Investigation was also conducted on the dye production of different clinical isolates of Pseudomonas aeruginosa, the relationship between drug susceptibility and anti staphylococcal activity, and the influence of erythromycin on anti staphylococcal activity. Seventy four strains of Pseudomonas aeruginosa were prepared which included 20 strains from pus, 34 strains from sputum and 20 strains from urine. These were then inoculated with methicillin resistant Staphylococcus aureus (MRSA). They were then cultured for 48 hours by using the reversed agar plate and the filter paper stamp methods. Anti staphylococcal activity was observed in 16 strains from pus (80%), 19 strains from sputum (55.9%) and 8 strains from urine (40%). The Pseudomonas aeruginosa strains which have no pigment tended to show poor anti staphylococcal activity. Drug susceptibility was tested using PIPC, AMK, IPM, CFS and OFLX. The strains which showed resistance to OFLX tended to show poor anti staphylococcal activity. Erythromycin inhibited the dye production of Pseudomonas aeruginosa but exhibited no effect on anti staphylococcal activity. Consequently, these results suggest erythromycin has exhibited a previously unknown pharmacological effect, furthermore, anti staphylococcal activity was not caused by pigmentation only.

[Significance of normal oral flora, particularly group oral streptococci as defense mechanism against infection in healthy individuals (normal defense mechanism by oral Streptococcus group)].

The alpha-streptococci, consisted of normal oral flora mainly, with inhibitory activity against pathogenic microbes in healthy individuals was investigated by group A Streptococcus (indicator strain 6-22 nonmucoid T-12). Rate of alpha-streptococci with inhibitory activity against group A Streptococcus was increased as aging, and the rate in pre-school children was higher than that in school children. These results suggested that more than 90% of the tested alpha-streptococci with strong inhibitory activities (S. salivarius) against indicator strain had inhibitory activities against group A Streptococcus (mucoid T-6), H. influenzae, S. pneumoniae, group C Streptococcus, and from 40% to 70% of the tested strains had also inhibitory activities against other pathogens. As there were many strains of alpha-streptococci with inhibitory activities against pathogens, that usually detected in the upper respiratory infection, the problem on the strains in the future will explain significance of the defense mechanism against upper respiratory infection and this can be applied clinically.

[Growth inhibitory activity of clinical isolates of Pseudomonas aeruginosa against Staphylococcus aureus (MRSA and MSSA)].

Anti staphylococcal activity by clinical isolates of Pseudomonas aeruginosa was tested by the reversed agar plate and the filter paper stamp methods. Almost 40% of Pseudomonas aeruginosa inhibited the growth of both Methicillin resistant Staphylococcus aureus (MRSA) and Methicillin sensitive Staphylococcus aureus (MSSA). Green pigment (Pyocyanin) produced strains showed a strong inhibitory effect against MRSA and MSSA respectively. But some other pigment (Yellow, Red) strains also showed anti staphylococcal activity. These data suggest the colonization of Pseudomonas aeruginosa with anti staphylococcal activity may not be eradicated by the anti pseudomonic antibiotics.

[Effect of methylrosanilinium chloride to MRSA nasal carriers].

Since the end of 1987, we have noticed an increasing incidence of Methicillin resistant Staphylococcus aureus (MRSA) among the inpatients of Yamanashi Medical College Hospital. MRSA strains were identified in 70-80 percent of the specimens obtained from patients with Staphylococcus aureus. From 1988 we performed yearly bacteriological examinations of the nares of medical personnel at Yamanashi Medical College Hospital. We treated nasal carriers with OFLX drop lotion or Povidone-iodine applied to the nares. In 1991 we treated eight nasal carriers, who had been unsuccessfully treated with Povidone-iodine, with 0.01% Methylrosanilinium Chloride ointment which was applied to the nares once a day for two weeks. A post-bacteriological examination again revealed that MRSA vanished from the nares of six nasal carriers. The minimum inhibitory concentration (MIC) of Methylrosanilinium Chloride was determined by the agar plate dilution method. The 100% MICs of MSSA were 1.0 microgram/ml and of MRSA were 1.0 microgram/ml by Methylrosanilinium Chloride. Moreover we examined the MICs of Methylrosanilinium Chloride against MRSA under the existing 5% Albumin, and consequently the 100% MICs were 4.0 micrograms/ml. Therefore a 0.01% Methylrosanilinium Chloride has sufficient efficacy against MRSA. The reaction of the skin and nasal mucosa to Methylrosanilinium Chloride was examined by using three groups of guinea pigs. 0.1% and 0.01% Methylrosanilinium Chloride ointment and hydrophylic poloid were applied to the nares and skin once a day for two weeks. Post-observation with an opticmicroscope revealed no significant findings. Methylrosanilinium Chloride shows good anti-Staphylococcus aureus ability. Further investigation is needed to determine if Methylrosanilinium Chloride has additional clinical application.