Risk factors for thromboembolism in patients with paroxysmal atrial fibrillation

There is some controversy concerning which clinical characteristics predict thromboembolism and whether treatment with class I antiarrhythmic drugs reduces thromboembolim in patients with paroxysmal atrial fibrillation (AF). This retrospective, multicenter study was undertaken to determine risk factor or factors for thromboembolism in patients with paroxysmal AF. Seven hundred forty patients with paroxysmal AF (mean age 56 years) without prior thromboembolic events were followed retrospectively. Cerebral thromboembolism, including transient ischemic attack and embolism of peripheral arteries, were selected as primary end points. Independent risk factors were determined with multivariate analysis, and event-free survival curves were estimated. During 3.4-year follow-up period, primary end points occurred in 55 patients (2.2% per year). Patients with thromboembolism had a higher prevalence of underlying heart disease (p <0.01), less frequent treatment with antiarrhythmic drugs (p <0.01), and received diuretics more often (p <0.01) compared with patients without thromboembolism. Age (>/=65 years, RR 3.33, p = 0.0001) and gender (male, RR = 2, p = 0.0291) emerged as predictors of thromboembolism by multivariate analysis with Cox's proportional hazard model. Treatment with antiarrhythmic drugs (RR = 0.57, p = 0.0578) and aspirin (RR = 0.52, p = 0.1094) showed trends toward reducing thromboembolic risks. It is suggested that elderly men (>/=65 years) with paroxysmal AF are at risk for thromboembolism, but the risk tended to be reduced by treatment with antiarrhythmic drugs and aspirin.     

Shosaikoto (a Kampo medicine) modulates changes in cytochrome P450 caused by <Emphasis Type="Italic">Mycobacterium</Emphasis><Emphasis Type="Italic">butyricum</Emphasis> injection

A large number of infectious or inflammatory agents are well known to reduce cytochrome P450-catalyzed drug metabolism in the liver. Changes in the levels of hepatic P450s in infectious or inflammatory diseases can lead to alteration in physiology, therapeutic failure, and disease development. This study was therefore designed to examine the effect of shosaikoto, a Kampo medicine used for treatment of chronic hepatitis and acute flu, on the changes in P450 activity and protein levels following intravenous injection of Mycobacterium butyricum. Intravenous injection of M. butyricum into rats reduced hepatic P450: CYP1A1, 1A2, 2B, and 3A activities and CYP2E1 and 3A2 protein levels. When administered orally to rats for 2 weeks since 1 week before M. butyricum injection, shosaikoto prevented the reduction in CYP1A1, 1A2, 2B, and 3A activities dose dependently and further abrogated the repression of CYP3A2 protein but not CYP2E1 protein. Serum C-reactive protein levels in this rat model were not highly elevated, and neither were significantly influenced by shosaikoto treatment. Taken together, these results suggest that shosaikoto would be capable of modulating the change in hepatic P450 caused by M. butyricum injection and the effect, which might not be brought about by its anti-inflammatory activity but by translational or posttranslational regulation, appears to differ in each P450 isoform.     

Survey of <Emphasis Type="Italic">Ephedra </Emphasis>resources in the Northern Areas of Pakistan and their genetic diversity

More than 400 species of medicinal plants grow in the Northern Areas of Pakistan, including Ephedra plants. To investigate the wild Ephedra plant resources in the area, we surveyed the medicinal plants and collected 71 specimens from 18 collecting sites to analyze their genetic variation. The DNA sequences of the internal transcribed spacers 1 and 2 (ITS 1 and 2) of nuclear ribosomal DNA and a noncoding sequence of chloroplast DNA (trn L/F) were analyzed. This DNA data analysis and external morphological features were used to confirm the species of the specimens, and it was found that E. intermedia was the major species in the area and that E. gerardiana and E. przewalskii were present sporadically. Although it inhabits a relatively small area in comparison with the northwestern Chinese provinces, the DNA sequence of E. intermedia in the Northern Areas of Pakistan was significantly more heterogeneous than the same species grown in those neighboring regions. Most of the E. intermedia specimens contained more than 0.7% ephedrine alkaloids, fulfilling the requirement of the Japanese Pharmacopoeia; thus, the Ephedra plants in the area are a genetic and medicinal resource of great importance.     

Chronic α1 blockade in a patient with Eisenmenger syndromeblockade in a patient with Eisenmenger syndrome

Summary In an 18-year-old male with Eisenmenger syndrome cyanosis and erythrocytosis were increasing. The erythrocytosis diminished following oral bunazosin and phlebotomy was not needed during the treatment. When bunazosin was stopped, the erythrocytosis increased, but when it was resumed, the erythrocytosis and general fatigue diminished.     

Terminal sedation for existential distress

Although sedation for existential distress has been actively discussed in the palliative care literature, empirical reports are limited. A retrospective cohort study was performed to clarify the physical conditions of terminally ill cancer patients who expressed existential distress and received sedation. Of 248 consecutive hospice inpatients, 20 patients expressed a belief that their lives were meaningless and received sedation. The target symptoms for sedation were dyspnea (n = 10), agitated delirium (n = 8), and pain (n = 1). Only one patient received sedation for psychological distress alone, although physical symptoms were acceptably relieved. The Palliative Performance Scale just before sedation was 10 (n = 7), 20 (n = 11), 30(n = 1), and 40(n = 1). All but one patient could take nourishment orally of only mouthfuls or less. Edema, dyspnea at rest, and delirium were observed in 10, 13, and 14 cases, respectively. The Palliative Prognostic Index was greater than 6.0 in all but one case with a mean of 12 +/- 3.3. In conclusion, in our practice, sedation was principally performed for physical symptoms of cancer patients in very late stages. Further research is encouraged to establish standard therapy for existential distress of the terminally ill.     

Immunotherapy using the streptococcal preparation OK-432 for the treatment of uterine cervical cancer. Cervical Cancer Immunotherapy Study Group

The efficacy of immunotherapy using a streptococcal preparation, OK-432, was evaluated in each clinical stage of uterine cervical cancer. The 382 eligible patients were stratified by clinical stage and presence/absence of surgery. Within each stratum, patient's were randomly allocated to OK-432 treatment or to control treatment. OK-432 significantly inhibited recurrence in patients with stage II cervical cancer; the recurrence-free interval and survival time were remarkably prolonged in patients with stage II disease who underwent surgery. However, OK-432 did not significantly prolong these parameters in patients with stage III disease. Retrospective analyses revealed that in patients with or without lymph node metastases who underwent surgery, the recurrence-free interval and survival time were significantly prolonged by OK-432 treatment. These results indicate that OK-432 is an effective and useful postoperative immunotherapeutic agent for uterine cervical cancer.     

Sialyl Lewis-Xi antigen in patients with gynecologic tumors

Sialyl Lewis-Xi antigen was measured by sandwich radioimmunoassay in sera from patients with various gynecologic tumors: 27 uterine myomas, 117 cervical cancers, 46 endometrial cancers, 54 benign ovarian cysts, and 47 ovarian cancers. Among the patients with uterine malignancies, only a few cases showed serum sialyl Lewis-Xi antigen values in excess of the cutoff limit. On the other hand, among the patients with ovarian cancers, serum sialyl Lewis-Xi antigen was elevated significantly in the following order: clinical stage I (44%), stage II (50%), and stage III (62%). The antigen level also correlated with the effect of treatment. However, serum sialyl Lewis-Xi antigen was elevated in 9% of patients with benign ovarian cysts and in 1.4% of normal volunteers. The lack of tumor specificity of sialyl Lewis-Xi antigen limits its diagnostic value for gynecologic malignancies, but serial measurement of this antigen may be useful in evaluating therapy and monitoring patients.     

Characteristics of Papaver somniferum L. cv. ikkanshu cultivated in Izu

The seeds of Papaver somniferum L. cv. Ikkanshu were sown in November (Autumn sowing: AS) and March (Spring sowing: SS) in a field at Izu Experimental Station for Medicinal Plants of National Institute of Health Sciencs, and both AS and SS plants were cultivated to investigate their growth, opium yield and alkaloid content in the opium. Growing periods from the sowing to the opium harvest were approximately six months for AS plants and three months for SS plants. Sizes of plants and capsules in AS were bigger than those in SS, reflecting their growth period. Opium yields per an are in AS and SS were 212.09 g and 142.03 g, respectively. The opium was able to be collected four times in the AS plants though the SS plants ceased to exude opium after the second incision. Therefore higher yield of opium in AS plants seems to be attributed to an amount of opium in the third and fourth incision. Average morphine content in the total opium was 15.61% in AS plants and 15.04% in SS plants, and the estimated amounts of morphine per an are in AS and SS plants were 33.16 g and 21.38 g, respectively.     

Alteration of the p53 Tumor Suppressor Gene Occurs Independently of K-ras Activation and More Frequently in Serous Adenocarcinomas than in Other Common Epithelial Tumors of the Human Ovary

To clarify the role of the p53 tumor suppressor gene in the development of human ovarian epithelial tumors and to study the association of p53 alterations with K-ras activation, a series of 70 common epithelial ovarian tumors from Japanese patients was studied. These included 31 serous adenocarcinomas, 12 mucinous adenocarcinomas, 5 mutinous tumors of borderline malignancy, 13 endometrioid adenocarcinomas, and 9 clear cell carcinomas. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 14 of 36 (39%) informative cases by restriction fragment length polymorphism analysis and by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction(PCR)-amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by SSCP analysis of PCR-amplifled fragments. Mutations were found in 22 of 70 (31%) ovarian tumors, including 1 of 5 mucinous tumors of borderline malignancy. Mutations were subsequently characterized by direct sequencing. Single missense base substitutions were detected in 13 ovarian carcinomas and in one case of mucinous tumor of borderline malignancy. Short (1-8 bp) deletions and insertions were found in 8 cases. Mutations in the p53 gene occurred more frequently in serous adenocarcinomas (14/31, 45%) than in all nonserous types of malignant epithelial tumors combined (7/34, 21%;P=0.032). Point mutations in K-ras were identified by dot blot hybridization analysis of PCR-amplified fragments with mutation-specific oligonucleotides and by direct sequencing. The overall frequency of K-ras mutations was 19/70 (27%).K-ras mutations were found in 12 of 17 (71%) mucinous tumors (8/12 mucinous carcinomas [67%] and 4/5 mucinous tumors of borderline malignancy [80%]), and occurred more frequently than in serous carcinomas (4/31, 13%;P=0.00009) or in all nonmucinous types of ovarian epithelial tumors combined (7/53, 13%; p=0.00002). These data suggest that different combinations of oncogenes and/or tumor suppressor genes may be involved in the genesis and development of histologically distinct categories of common epithelial tumors of the human ovary.     

The anti-tumor arotinoid RO 40-8757 protects bone marrow from the toxic effects of 5-fluorouracil

Combination therapy with 5-Fluorouracil (5-FU) and the arotinoid Ro 40-8757 (mofarotene) of established chemically induced mammary tumors in rats was examined. The cytotoxic drug was administered weekly and Ro 40-8757 was given daily. The dose of Ro 40-8757 used in this study did not have an effect on tumor burden but, in combination with 5-FU, significantly enhanced the reduction in tumor burden and tumor number. In order to determine if Ro 40-8757 had a protective effect on 5-FU-treated animals, several studies were performed with non-tumor-bearing mice. The 5-FU was given once a week for 3 weeks at a dose that was lethal only after the third administration. When this treatment was combined with Ro 40-8757 given 5 times/week, approximately 50% of the mice survived. Examination of the progenitor cell contents of femura and spleens of treated mice indicated that the protective effect of Ro 40-8757 was manifested at the primitive hemopoietic progenitor cell level. Studies with murine bone marrow cells and human breast-cancer cell lines in vitro demonstrated that there was no interaction between the 2 drugs at the cellular level, indicating that the arotinoid does not enhance the ability of cells to metabolize 5-FU. This protective effect of the arotinoid makes it a useful potential partner for combination therapy with 5-FU. © 1994 Wiley-Liss, Inc.