Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk

Although oral contraceptives are protective for ovarian cancer, it is unclear how long this protection persists. The authors prospectively assessed this question as well as associations of other, less studied contraceptive methods (tubal ligation, rhythm method, diaphragm, condoms, intrauterine device, foam, spousal vasectomy) and infertility with ovarian cancer risk among 107,900 participants in the US Nurses' Health Study. During 28 years of follow-up (1976-2004), 612 cases of invasive epithelial ovarian cancer were confirmed. Duration of oral contraceptive use was inversely associated with risk (p-trend = 0.02), but no clear trend was observed for years since last use. However, for women using oral contraceptives for >5 years, the rate ratio for ovarian cancer for 20 years since last use (rate ratio (RR) = 0.92, 95% CI: 0.61, 1.39). Tubal ligation (RR = 0.66, 95% CI: 0.50, 0.87) was associated with decreased ovarian cancer risk, whereas intrauterine device use (RR = 1.76, 95% CI: 1.08, 2.85) and infertility (RR = 1.36, 95% CI: 1.07, 1.75) were associated with an increased risk. Results suggest that the beneficial effect of oral contraceptives on ovarian cancer risk attenuates after 20 years since last use. Furthermore, tubal ligation, intrauterine device use, and infertility were associated with ovarian cancer risk.     

Pain in far-advanced cancer

Hundred patients with far-advanced cancer and pain were interviewed within a few days of admission to a special care unit. Eighty had more than one pain; 34 had four or more. A total of 303 anatomically distinct pains were recorded. Ninety-one patients had pain caused by the cancer itself. Twelve had treatment-related pain; and 19 had pain related to chronic disease or debility ('associated pain'). Thirty-nine patients had one or more pains unrelated to cancer or treatment; the most common of these was myofascial pain. In 41 patients only was all the pain caused directly by the cancer. Bone involvement and nerve compression were the most common forms of cancer-related pain; soft tissue and visceral pains also occurred frequently. Fifty-seven patients had pain for more than 4 months.     

Efficacy of Nitazoxanide against Cryptosporidium parvum in Cell Culture and in Animal Models

Nitazoxanide (NTZ), a drug currently being tested in human clinical trials for efficacy against chronic cryptosporidiosis, was assessed in cell culture and in two animal models. The inhibitory activity of NTZ was compared with that of paromomycin (PRM), a drug that is partially effective against Cryptosporidium parvum. A concentration of 10 μg of NTZ/ml (32 μM) consistently reduced parasite growth in cell culture by more than 90% with little evidence of drug-associated cytotoxicity, in contrast to an 80% reduction produced by PRM at 2,000 μg/ml (3.2 mM). In contrast to its efficacy in vitro, NTZ at either 100 or 200 mg/kg of body weight/day for 10 days was ineffective at reducing the parasite burden in C. parvum-infected, anti-gamma-interferon-conditioned SCID mice. Combined treatment with NTZ and PRM was no more effective than treatment with PRM alone. Finally, NTZ was partially effective at reducing the parasite burden in a gnotobiotic piglet diarrhea model when given orally for 11 days at 250 mg/kg/day but not at 125 mg/kg/day. However, the higher dose of NTZ induced a drug-related diarrhea in piglets that might have influenced its therapeutic efficacy. As we have previously reported, PRM was effective at markedly reducing the parasite burden in piglets at a dosage of 500 mg/kg/day. Our results indicate that of all of the models tested, the piglet diarrhea model most closely mimics the partial response to NTZ treatment reported to occur in patients with chronic cryptosporidiosis.     

Identification and Origin of Some Chloroplast Aminoacyl-tRNA Synthetases and tRNAs

Light-grown, wild type Euglena gracilis contains two aminoacyl-tRNA synthetases for both phenylalanine and isoleucine. Only one of the two synthetases for each amino acid is found in isolated chloroplasts, as are the light-induced phenylalanine and isoleucine tRNAs. In each case the light-induced chloroplast tRNAs can only be acylated by the chloroplast synthetases. The chloroplast isoleucyl-tRNA synthetase is light-inducible and cannot be detected in dark-grown cells or in cells of the bleached mutant W(3)BUL. The presence of the chloroplast phenylalanyl-tRNA synthetase in W(3)BUL, which contains no chloroplast DNA or structure, indicates that this chloroplast enzyme is synthesized in the cytoplasm and is coded by nuclear genes.     

亚太地区炎症性肠病处理共识意见(一)

虽然目前亚太地区尚无炎症性肠病（IBD）的大规模流行病学资料，但一系列研究显示其发病率和患病率呈上升趋势。与西方国家相比仍呈滞后现象。溃疡性结肠炎（UC）的发病率仍较克罗恩病（CD）高。除地域差异外。在一些多民族国家中，IBD尚可见种族差异。亚太地区IBD的遗传背景有异于西方国家。如据报道该地区CD患者未检出NOD2／CARDI5变异。一般而言，该地区IBD患者的临床过程似不如西方国家严重。 亚太地区IBD的诊断存在一些特殊问题。如缺乏IBD诊断金标准。存在多种小肠结肠炎，与IBD临床表现相似，使鉴别诊断特别困难。迄今为止，亚太地区IBD的诊断标准多采用西方国家的诊断标准。诊断必须逐步排除非IBD的小肠结肠炎。确诊应有典型的组织学表现。某些患者需借助随访和诊断性治疗才能确诊。进一步研究IBD发病机制将有助于开发更好的诊断标记物。 亚太地区IBD的治疗亦存在特殊问题。由于诊断困难。IBD患者常未能及时接受适当的药物治疗，但该地区仍广泛采用药物治疗方案。结合西方指南和本地经验可制定类似的处理原则。以利诱导缓解和维持缓解。提倡逐级使用基于病变范围、活动性和严重度的阶梯式治疗方案。对不同病例采用综合性、个体化的方法。随着对IBD发病机制和亚太地区IBD独特性的深入理解。合理、实用的药物治疗指南和应用生物制剂治疗将改善该地区IBD的治疗前景。     

Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation

Culture-based preemptive therapy with ganciclovir was shown to reduce the incidence of cytomegalovirus (CMV) disease after bone marrow transplantation (BMT). Culture techniques did not detect CMV in 12% to 13% of patients before the onset of CMV disease. In a prospective study, 71 patients either received preemptive therapy based on polymerase chain reaction (PCR) technique (37 patients) or on culture assays (34 patients). In both groups, therapy was continued until clinical signs disappeared and PCR negativity was documented. Twenty- two patients in the PCR group and 15 patients in the culture group received antiviral therapy. PCR allowed detection of the virus (median day, +32 v day +49; P = .006) and introduction of antiviral therapy (median day, +44 v day +54; P = .02) earlier than did culture assays. The incidences of CMV disease (2 of 37 v 8 of 34 in PCR group v culture group, respectively; P = .02) and CMV-associated mortality (0 of 37 v 5 of 34 in PCR group v culture group, respectively; P = .02) were decreased, and the duration of ganciclovir therapy (P < .001) was shorter in the PCR-monitored group. Incidence and median duration of severe neutropenia (less than 500/microL) were lower in the PCR group (two v eight episodes, P = .02; median duration, 1.5 v 5 days, P = .04), as was the incidence of nonviral infections during/after antiviral therapy (2 of 37 v 9 of 34; P = .012). Thus, preemptive therapy based on more sensitive detection methods such as the PCR assay reduces the incidence of CMV disease and CMV-related mortality. Additionally, stopping and withholding antiviral therapy in a PCR- negative patient is safe and allows reduction of the duration and side effects of antiviral therapy.     

Correlation of P-glycoprotein expression and function in childhood acute leukemia: a children's cancer group study

Clinical drug resistance may be attributed to the simultaneous selection and expression of genes modulating the uptake and metabolism of chemotherapeutic agents. P-glycoprotein (P-gp) functions as a membrane-associated drug efflux pump whose increased expression results in resistance to anthracyclines, epipodophyllotoxins, vinca alkaloids, and some alkylating agents. This type of resistance occurs as both de novo and acquired resistance to therapy for leukemia. We have studied P- gp expression and function in childhood acute leukemias by developing a series of doxorubicin- and vincristine-selected CEM, T-cell lymphoblastoid cell lines that recapitulate the low levels of expression and resistance seen clinically. These cell lines have been used to develop flow cytometric assays for the semiquantitative measurements of P-gp expression with the MRK16 monoclonal antibody and P-gp function using the enhanced retention of rhodamine 123 in the presence of verapamil, a resistance modulator. Kolmogorov-Smirnov statistics, represented by the D measurement, are used to determine the difference in level of P-gp expression by comparing MRK16 staining to an IgG2a isotype control. When D is > 0.09, there is an excellent correlation (R = 0.82) between P-gp expression and function. The evaluation of 107 bone marrow specimens from 84 children with lymphoblastic or myelogenous leukemia showed a statistically significant (P = .004) increase in P-gp function at relapse. P-gp expression at relapse, however, approached but did not reach a significant level (P = .097). Using this methodology, we can identify patients with levels of P-gp expression and function that we can define clinically, as well as children with discordant multidrug resistance phenotypes. This study supports the role of P-gp-mediated drug resistance in childhood leukemia and confirms that P-gp expression and function are measurable in their leukemic blasts. These assays provide the means for the in vitro testing of resistance modulators and the monitoring of in vivo response to treatment with these agents.     

Fanconi's anemia treated by allogeneic marrow transplantation

Eight patients with Fanconi's anemia were given cyclophosphamide alone (seven patients) or combined with procarbazine and antithymocyte globulin (one patient) followed by marrow grafts from HLA-identical siblings. All patients had engraftment. Seven developed acute and three chronic graft-versus-host disease (GVHD). Three patients died with GVHD and infectious complications (days 19, 56, and 82) and one with an intracerebral hemorrhage (day 540). Four patients are surviving 647- 3435 days after grafting, two are well, and two have chronic GVHD that is improving. These results show that Fanconi's anemia can be treated successfully by allogeneic marrow transplantation.     

Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression

Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6-30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2-4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD.     

Second marrow transplants in patients with aplastic anemia rejecting the first graft: use of a conditioning regimen including cyclophosphamide and antithymocyte globulin

Sixteen (11%) of 146 consecutive patients with severe aplastic anemia prepared for engraftment with cyclophosphamide (200 mg/kg) rejected marrow grafts from their HLA-identical siblings. They were given a second marrow transplant from either the same (n = 13) or a second (n = 3) HLA-identical sibling between 23 and 743 (median 86) days after the first transplant. The preparation for the second transplant included cyclophosphamide, 50 mg/kg, on each of four successive days. Twelve hours after each of the first three doses of cyclophosphamide, antithymocyte globulin, 30 mg/kg/dose, was infused. One of the 16 patients died from infection too early after the second transplant to be evaluated, two had failure of engraftment and died with infection, one rejected the second graft and is surviving almost 5 years later with full autologous marrow recovery, and 12 had successful and sustained second grafts. Of these 12, six are surviving between 11 months and 7 3/4 years. Four of the six have no graft-v-host disease (GVHD), while two have chronic GVHD requiring treatment. Five have Karnofsky scores of 100% and one of 90%. Six of the 12 patients with sustained grafts died between 63 days and 38 months after transplantation, four with infections (related in two patients to chronic GVHD), one with acute GVHD, and one with hemorrhage. The average interval from first to second transplant was 308 days during the past five years, compared to 61 days in earlier patients. Five of seven recent patients are surviving, compared to two of nine earlier patients. In conclusion, successful second transplants after cyclophosphamide and antithymocyte globulin are possible in most patients with aplastic anemia who have rejected their first marrow grafts; however, mortality remains high, with only 40% of the patients becoming long-term survivors.