Leukocyte Apheresis Using a Centrifugal Cell Separator in Refractory Ulcerative Colitis: A Multicenter Open Label Trial

Abstract: Recently, successful results of ulcerative colitis (UC) treatments with leukocyte apheresis have been reported by several institutes. To certify the efficacy of leukocyte apheresis in refractory UC patients, a multicenter open label trial was conducted, and results were analyzed. Fifty patients diagnosed with active steroid‐resistant UC were enrolled in this study from 14 medical centers. Using a centrifugal cell separator (Component Collection System, Haemonetics), leukocyte apheresis was performed once a week for 5 weeks. General conditions and abdominal symptoms were recorded daily, and laboratory tests were followed weekly. Changes of colonoscopic and histological manifestations of luminal activity through the study period were evaluated. At the end of the study period, stool frequency was decreased to less than 4 times a day in 68.4% (26 of 38) and serum C‐reactive protein (CRP) concentration was normalized in 56.7% (17 of 30) of the patients. Colonoscopic remission was achieved in 57.7% (26 of 45), and histological improvement was noted in 54.1% (20 of 37) of the patients tested. Improved disease activity was demonstrated in 74% (37 of 50) of the patients by general assessment criteria. Analysis of the trial data confirmed the valid clinical efficacy of leukocyte apheresis by centrifugal cell separator in refractory UC patients.     

TNF-alpha augments the expression of RhoA in the rat bronchus.

While nonspecific airway hyperresponsiveness (AHR) is a central feature of allergic bronchial asthma, the mechanism underlying the development of AHR is not clearly understood. We have previously demonstrated in vitro hyperresponsiveness of bronchial smooth muscle to acetylcholine (ACh) in rats that were actively sensitized and repeatedly challenged with aerosolized antigen. It has also been demonstrated that the ACh-induced, RhoA-mediated Ca(2+) sensitization is markedly augmented concomitantly with an increased expression and activation of RhoA protein in the bronchial smooth muscle of the antigen-treated rats. In the present study, we have investigated whether TNF-alpha, a proinflammatory cytokine which is involved in bronchial asthma, causes upregulation of RhoA mRNA and protein in the rat bronchus. Treatment of rat bronchial smooth muscle preparations with TNF-alpha (300 ng/ml for 24 hr) significantly shifted the concentration-response curve to ACh upwards, but did not alter the response to high K(+), when compared to that of control tissues. Levels of RhoA mRNA and protein in the TNF-alpha-treated bronchus were significantly greater than those in the control group. In conclusion, it is suggested that the augmentation of the ACh-induced contractile response evoked by TNF-alpha might be mediated by an upregulation of RhoA in rat bronchial smooth muscle.     

Rheumatoid arthritis in patients aged above 75 years old at onset]

Elderly onset rheumatoid arthritis (RA) is difficult to diagnose definitively when the patients note their first symptoms of arthritis above the age of 75 years old. In this report, we reviewed the clinical features of elderly onset RA and its diagnosis. The subjects included 4 females, aged 78, 83, 84 and 93 years, respectively. The onsets were abrupt in 2 cases and more slowly arriving in the other 2. Shoulder joints and wrist joints were involved in all cases. Knee joints, finger joints and foot joints were involved in 3 cases and the elbow was involved in one case. Anti-RA treatment quickly attenuated the acute and severe arthritis and brought down the high CRP level associated with vivid inflammatory activity of RA. The RAPA value was very high in all but one of the cases. Severe destructive findings in radiography was undetectable in the major joints (e.g. shoulder, hip and knee joints). Radiographic findings in wrist and finger joints were also very difficult to differentiate from arthrosis and osteoporosis. On the other hand, RA involvement in the cervical spine was certain in the radiographs; 1 case had anterior atlantoaxial subluxation and 2 cases had subaxial intervertebral erosion. Pathological radiographic findings in the cervical spine are useful for the diagnosis of elderly onset RA.     

Potentiating effects of extraluminal oxyhemoglobin to intraluminal 5-hydroxytryptamine in isolated canine internal carotid arteries

The interaction between oxyhemoglobin (oxyHb) and 5-hydroxytryptamine (5-HT) was investigated in an experimental model of isolated canine internal and common carotid arteries with insertion of stainless steel cannulae. Extraluminal application of 10(-5) M oxyHb induced marked and long-lasting vasoconstriction in the internal carotid but not in the common carotid arteries. The 5-HT-induced vasoconstriction was potentiated significantly in both the internal and common carotid arteries. These potentiations were not influenced by the presence or absence of endothelium, a finding which was confirmed by vascular responses to intraluminal acetylcholine. It is concluded that the interaction between extraluminal oxyHb and intraluminal 5-HT may be one of the possible etiological factors behind the chronic phase of vascular spasm following subarachnoid hemorrhage.     

Studies on FK482. II. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives

Various 7 beta-[2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives (Ia--e, IIa--g) were synthesized in order to find a new orally active cephalosporin improving the antibacterial activity of cefixime (CFIX) against Staphylococcus aureus. These derivatives include three types of alpha-substituted 2-(2-aminothiazol-4-yl)acetyl side chain; i) mono or non substituted acetyl moiety, ii) carboxyalkoxyimino acetyl moiety, iii) phosphonomethoxyimino and hydroxyimino acetyl moiety. Their structure-activity relationships and urinary recoveries in rats were studied. As a result, the compound with a hydroxyimino acetyl side chain (IIg, FK482) showed good oral absorption and excellent antibacterial activity against both gram-positive and gram-negative bacteria and was selected as a candidate for clinical trial.     

Analysis of the non-sense mutants of varicella-zoster virus thymidine kinase

Summary.  Three non-sense mutants of varicella-zoster virus (VZV) thymidine kinase (TK) gene, VZTK₃₂₅, VZTK₂₇₈ and VZTK₂₂₄, were isolated. The mutants had a single nucleotide substitution at codons 326, 279 and 225, which changed the codon of TGG (tryptophan) to the stop codon TGA. The wild type (WT) and mutant TKs were expressed in E. coli cells and their characteristics were evaluated. VZTK₂₂₄ lost TK activity, but VZTK₃₂₅ and VZTK₂₇₈ maintained 74.8% and 21.2% of the WT TK activity. On the other hand, all mutants lost the thymidylate kinase activity. Moreover, VZTK₃₂₅ and VZTK₂₇₈ polypeptides were heat-labile. These data suggest that the carboxy-terminal portion of herpesvirus TK plays an important role in the stable folding of TK and thymidylate kinase activity. Received April 21, 1997 Accepted June 16, 1997     

Responses of isolated canine ophthalmic and ciliary arteries to vasoactive substances

The effects of 11 vasoactive substances were compared on the isolated and perfused canine internal and external ophthalmic and ciliary arteries. The vessels were isolated with the optic nerve, and perfused independently with Tyrode solution under a constant flow rate at 37 degrees C and a perfusion pressure of 40-80 mmHg. Drugs used were 5-hydroxytryptamine (5-HT), epinephrine (EPI), norepinephrine (NE), phenylephrine (PHE), prostaglandin F2 alpha (PGF2 alpha), ATP, dopamine (DA), tyramine (TYR), KCl, xylazine (XYL) and clonidine (CLO). Each drug solution was administered by a microinjector into the endothelial side of an artery through a cannula. Responses were obtained as changes in perfusion pressure. Results were as follows: 1) The rank order of potency for inducing a vasoconstriction in external ophthalmic arteries (EOA) was 5-HT greater than or equal to EPI greater than NE greater than PHE much greater than ATP greater than or equal to DA greater than KCl much much greater than TYR, XYL, CLO. Since PGF2 alpha induced only a slight vasoconstriction, it was omitted from the order. 2) In internal ophthalmic arteries (IOA), the responses were similar to those in EOA, although EPI, NE and PHE induced a relatively smaller response. The order was 5-HT greater than EPI = NE greater than PHE much greater than DA = ATP greater than KCl much much greater than TYR, XYL, CLO. 3) In ciliary arteries, the order was EPI greater than NE greater than PHE greater than PGF2 alpha greater than DA greater than ATP greater than KCl much much greater than TYR, XYL, CLO. It was found that 5-HT induced a slight vasoconstriction and the efficacy was low. PGF2 alpha induced a greater response in ciliary arteries than in EOA or IOA. 4) In all three arteries, alpha-2 adrenoceptor agonists, XYL and CLO did not produce significant changes in perfusion pressure. These three arteries might be rich in alpha-1 adrenoceptors but poor in alpha-2 adrenoceptors.