A new clustering system for protein sequences and its application to constraints discovery in protein evolution

A conceptual clustering system, CLUSMOL/S, has been developed to classify protein sequences from a user-defined point of view. Given a grouping of amino acids as a viewpoint, the system constructs taxonomic trees of sequences based on minimum information criterion. Every tree node expresses itself as a generic consensus sequence that consists of specific consensus amino acids, insertionideletion points, and generic amino acids with a specified character. The resulting tree and generic sequences show the similarity-based relationships among sequences and their characteristics. Application to vertebrate cytochromes c yields an acceptable cladrogram only when amino acids are grouped by volume and length of sidechains. The result indicates that the steric factor is the most important constraint in the process of protein evolution. © Munksgaard 1995.     

Structural studies on endothelin receptor subtype B specific agonist IRL 1620 (suc-[Glu9,Ala11,15]ET-1(8-21)) and its analogs with dipalmitoyl phosphatidylcholine vesicles by NMR spectroscopy

IRL 1620 {suc-[Glu⁹,Ala^11,15]ET-1(8-21)} is a potent and specific agonist for the ET_B receptor. Five analogs of IRL 1620 were synthesized in this study. These were all C-terminal linear peptides of endothelin 1 (ET-1) comprising 14 amino acid residues and exhibiting highly potent ET_B receptor binding affinities. The peptides consisted of three pairs and each component of the pairs differed from its partner in only the 18th residue, i.e. Asp was replaced by Gly. The replacements resulted in more than a 10-fold increase in affinity to the ET_A receptor. The structures of these peptides were investigated in the presence of phospholipid vesicles (dipalmitoyl phosphatidylcholine) by NMR spectroscopy. By the replacement of Asp by a less bulky Gly, the C-terminal tripeptide region folded back toward the helical region, making it shorter than the Asp-substituted peptide helical region. Such a folded conformational feature may explain the increased binding affinity to ET_A receptor.     

Treatment of Acute Nonlymphocytic Leukemia by Concurrent Administration of N4-Behenoyl-1-{beta}-D-Arabinofuranosylcytosine, Aclacinomycin A, 6-Mercaptopurine and Prednisolone: A Pilot Study

N⁴-behenoyl-1-ß-d-arabinofuranosylcytosine (BH-AC),a newly synthesized derivative of cytosine arabinoside witha longer plasma half life and marked dose independency in itsanti-L1210 leukemia effect, and aclacinomycin A, a new anthracyclineantibiotic which is as effective as daunorubicin against L1210leukemia and reportedly induces no alopecia and is much lesscardiotoxic, were combined with 6-mercaptopurine and prednisolonein a pilot study of the effect on acute nonlymphocytic leukemiaof adults. The treatment schedule consisted of daily administrationof BH-AC, 116 to 234 mg/m² as a 2-hr intravenous infusion; aclacinomycinA, 12 to 16 mg/m² as a 30-min intravenous infusion; 6-mercaptopurine,100 mg/m² orally; and prednisolone, 40 mg/m² orally. A course of treatment was continued until the bone marrow becameseverely hypoplastic, not extending over 14 days. Eight patientswere entered in the study, one of whom was nonevaluable becauseof early death from renal failure. Six out of the seven evaluablepatients attained complete remission and the other good partialremission. Only one course of treatment was administered tofive of the patients who attained complete remission. It shouldbe noted that complete remission was obtained in two of threepatients not responding to treatment with daunorubicin, cytosinearabinoside, 6-mercaptopurine riboside and prednisolone in combination.The median duration of complete remission and survival were5 + (range: 4 + to 6 +) mo and 9 + (range: 6 + to 27+) mo, respectively. The most frequent side effects were malaise and gastrointestinalsymptoms, which were well tolerated. Flat T waves were notedin the electrocardiogram of one elderly patient; the changewas not clearly attributable to the drugs employed. Mild alopeciawas seen in two patients. This regimen was quite effective asa remission inducer in acute nonlymphocytic leukemia of adults,and deserves further study.     

Interferon therapy for patients more than 60 years of age with chronic hepatitis C

Abstract Nineteen patients aged > 60 years with chronic hepatitis C (CHC) received interferon (IFN) therapy and a complete response (CR) was achieved by five of them (26%). The incidence of CH with severe fibrosis in this elderly group was significantly higher than in another 52 patients with CHC who were < 60 years of age (the younger group; P < 0.05). There was no significant difference in the hepatitis C virus (HCV) genotype distribution between the elderly group and the younger group. However, the HCV-RNA titre was significantly higher in the elderly group than in the younger group ( P < 0.05). There was no significant difference in the efficacy rate of IFN in the elderly and younger groups after standardization of the background factors. In the elderly group, the HCV-RNA titre was significantly lower in the patients achieving CR than in those with no response ( P < 0.05). These data suggest that elderly patients with a low HCV-RNA titre can still respond well to IFN therapy.     

A New Mechanism of Cerebrospinal Fluid Leakage after Lumboperitoneal Shunt: A Theory of Shunt Side Hole—Case Report

Cerebrospinal fluid (CSF) overdrainage after lumboperitoneal (LP) shunt placement for the patients with idiopathic normal pressure hydrocephalus (iNPH) is mainly caused by insufficient management of pressure settings of the shunt valve and/or siphon effect of shunt systems induced by the patient''s postural changes. We here report a unique case of intracranial hypotension (IH) due to CSF leakage after LP shunt placement in which another mechanism leads to the CSF leakage. A 67-year-old man suffered from persistent headache worsening with postural change 2 months after LP shunt reconstruction for iNPH. Brain computed tomography scan showed bilateral chronic subdural hematomas (CSDH). Lumbar images including shuntography and magnetic resonance imaging showed the tip of the lumbar catheter was spontaneously pulled out close to the dura mater with expansion of the epidural space due to CSF leakage from a shunt side hole of the lumbar catheter to the epidural space. Shunt removal and subsequent irrigation of CSDH improved his headache. CSF leakage in our case differs from those in previous reports, because early and enormous CSF leakage into the epidural space can be explained only by a different mechanism through a side hole just located in the epidural space in our case. We must pay attention to the possibility of this rare cause of IH due to CSF leakage in patients suffering from postural headache after LP shunt placement.     

Prediction of interferon-alpha-induced thyroid dysfunction in patients with chronic hepatitis C

To predict interferon-alpha (IFN-α)-induced thyroid dysfunction, anti-thyroglobulin (anti-TgAb) and anti-thyroid peroxidase antibodies (anti-TPOAb) were determined by radio-immunoassay (RIA) before IFN-α treatment in 30 patients with chronic hepatitis C in whom the conventional haemagglutination test had failed to detect anti-thyroid auto-antibodies. Seven patients developed thyroid dysfunction during IFN-α treatment (transient thyrotoxicosis in four patients, transient hypothyroidism in two, and Graves’ disease in one). Anti-TgAb and/or anti-TPOAb were detectable before IFN-α treatment in six of these seven patients, while these antibodies were detected before treatment in only four of 23 patients who did not develop any thyroid dysfunction. The prevalence of these antibodies was significantly higher (P= 0.002) in the former group of patients than in the latter. In four patients with detectable anti-TgAb before treatment but no subsequent thyroid dysfunction, the antibody disappeared during IFN-α treatment. Haemagglutination tests for anti-thyroid microsomal antibodies have previously been reported to be a useful predictive marker of IFN-α-induced thyroid dysfunction. In conclusion, sensitive detection of anti-thyroid auto-antibodies using RIA may also be useful for the prediction of IFN-α-induced thyroid dysfunction in patients with a negative haemagglutination test.     

Entrainment of Ventricular Tachycardia in Arrhythmogenic Right Ventricular Tachycardia

In two patients with arrhythrnogenic right ventricular dysplasia (ARVDJ, sustained ventricular tachycardia (VT) was induced by programmed stimulations during serial drug testings. One patient had five and the other had two VT morphologies, and the sites of origin were determined by endocardial catheter mappings. When overdrive pacing was performed, constant fusion in the QflS complex was observed in the two patients. Constant fusion of a different degree was also observed at different paced cycle lengths. Both patients had dilated right ventricles and wall-motion abnormality, and the diagnosis of ARVD was further confirmed by the specimen resected at the site of origin of VT. Therefore, VT in ARVD can be entrained and reentry is the most likely mechanism of such VT.     

A stone developed within the dilated intravesical ureter following ureteroscopy

A 58-year-old man presented with a stone within the dilated intravesical ureter, which was probably attributable to a previous ureteroscopy. Transurethral incision of the right intravesical ureter and lithotripsy were carried out without subsequent urinary tract impairment. Although some complications resulting from ureteroscopy, such as ureteral stricture, ureteral perforation and vesicoureteral reflux, have been reported, this complication is considered to be very rare.     

Activation of Cellular Immunity and Complement System in Immune-Deficient Aged Subjects by Streptococcal Preparation OK-432 (Picibanil)

In a study of 290 patients without malignancy, 10 aged subjectswere found to have impaired cellular immunity. They were givenlong-term therapy with a streptococcal preparation OK-432, andit was found that OK-432 potentiated cellular immunity in agedindividuals if 1KE of the preparation is given daily. The decreasein the third component of complement C3 in these patients duringtherapy indicates that the complement system was activated viathe alternate pathway.     

Effect of Long-Term Administration of OK-432 (Picibanil), PS-K (Krestin) and Levamisole on Immune Responses in Aged Subjects Without Malignancy

So-called immunomodulators, streptococcal preparation OK-432(Pici-banil), protein polysaccharide PS-K (Krestin) and anthelminthiccompound Levamisole, were investigated for their ability torestore the decreased immune responses in aged patients withoutmalignancy. These immunomodulators exerted their effect on host-immuneresponses during six months of therapy, as determined by theMantoux skin test, the phytohemagglutinin skin test, the endotoxinskin test and in vitro blastoid transformation of lymphocytes.