Costimulation and Autoimmune Diabetes in BB Rats

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55–120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.     

CONGENITAL DISLOCATION OF THE KNEE AS A CONSEQUENCE OF PERSISTENT AMNIOTIC FLUID LEAKAGE

SUMMARY A case congenital dislocation of both knees and dislocation of the left hip in an infant whose mother had a chronic amniotic fluid leakage after mid-trimester amniocentesis.     

Bioethics for clinicians: 5. Substitute decision-making.

Substitute decision-making is a means of making health care decisions on behalf of people who are incapable of making these decisions for themselves. It is based on the ethical principle of respect for autonomy. Substitute decision-making poses two main questions: Who-should make the decision for the incapable person, and, How should the decision be made? Because the applicable statutory and common law varies across Canada, clinicians should become familiar with the legal requirements of their own province or territory.     

Immunogenicity and safety of a recombinant vaccinia virus vaccine expressing the carcinoembryonic antigen gene in a nonhuman primate.

We have previously reported the development of a recombinant vaccinia virus vaccine expressing the human carcinoembryonic antigen (CEA) gene, designated rV(NYC)-CEA. This construct has been shown to elicit specific anti-CEA immune responses and an antitumor effect in a murine tumor model. In the studies reported here, the safety and immunogenicity of this recombinant vaccinia virus were evaluated in a rhesus monkey model. Human CEA is a M(r) 180,000 glycoprotein expressed in approximately 90% of gastrointestinal carcinomas and in some breast and non-small cell lung carcinomas. This family also includes normal cross-reacting antigen (NCA). Rhesus monkeys, like humans, have some NCA on the surface of their granulocytes. Eight monkeys were immunized 3 or 4 times by skin scarification with the recombinant CEA vaccine and four monkeys received wild-type vaccinia virus as control. After three vaccinations, all rV(NYC)-CEA-vaccinated animals exhibited a strong anti-CEA antibody response as measured by enzyme-linked immunosorbent assay. The functional ability of these antibodies to mediate lysis of a CEA-bearing tumor cell was demonstrated using human effector cells. This response could be enhanced by interleukin 2. Cellular immunity to CEA was measured by delayed-type hypersensitivity upon intradermal challenge with purified CEA. Only those animals receiving the recombinant vaccine displayed significant anti-CEA responses. Furthermore, peripheral blood mononuclear cells from immunized monkeys were found to proliferate in response to CEA stimulation. All vaccinated monkeys developed local skin irritation at the site of the vaccination, regional lymphadenopathy, and low-grade fevers after immunization. Following immunization with rV(NYC)-CEA, the response was consistent with the usual constitutional symptoms seen with human smallpox virus immunization. Blood counts, differentials, and hepatic and renal chemistries remained normal in all animals throughout the study and for up to 1 year following the primary vaccination. No evidence of immunological cross-reactivity to NCA was found by either a fall in the granulocyte count or analyses for anti-NCA antibodies. Thus, the rV(NYC)-CEA vaccine appears to be safe in rhesus monkeys. The administration of a CEA recombinant vaccine to rhesus monkeys induces both a humoral and a cell-mediated immune response directed against human CEA.     

高效液相色谱法测定右旋儿茶素血浆浓度及药代动力学参数

本文建立了体液中右旋儿茶素的RP-HPLC测定方法。采用C_(18)键合相硅胶为填料的固相提取柱进行样品预处理,右旋儿茶素的提取回收率为79.8%.应用二极管阵列检测器对色谱峰纯度进行鉴定。该法精密度好,方法回收率近100%,日内、日间的变异系数为2.4～5.6%,血浓69.6～1160 ng/ml范围内呈线性关系,r=0.9993。家兔静注右旋儿茶素18mg/kg,其药代动力学过程符合二室模型,分布相半衰期为0.129 h,消除相半衰期为1.19h。     

Congenital dyserythropoietic anemia type II diagnosed in a 69-year-old patient with iron overload.

Congenital dyserythropoietic anemia type II is a rare disorder that is often diagnosed in patients before age 20 years. Patients with this disorder, which is also called hereditary erythroblastic multinuclearity associated with a positive acidified serum lysis test, may have symptoms of iron overload. The purpose of this case report is to alert physicians to consider the diagnosis of congenital dyserythropoietic anemia type II in elderly patients who have anemia and iron overload.     

Laparoscopic enucleation of a renal cell carcinoma

The purpose of this study was to report on the feasibility of laparoscopic excision of renal cell carcinoma. An 81-year-old female with renovascular disease underwent a laparoscopic excisional operation for a 2-cm tumor localized in the left kidney.Pathological evaluation showed a low-grade tumor without any extension through the renal capsule (grade I Hand Broder, stage I Robson). The postoperative course was uneventful; there was minimal postoperative pain. The patient was discharged home on the sixth day. Laparoscopic excision would appear to be a safe and effective technique in selected cases.     

Pion radiotherapy of unresectable soft tissue sarcomas at the Swiss Institute for Nuclear Research

The Swiss Institute for Nuclear Research SIN at Villigen is one of the three centres in the world (LAMPF, Los Alamos; TRIUMF, Vancouver) where pion therapy is possible. A dynamic, tumour conforming spot scan technique for the treatment of deep-seated tumours has been in use since November 1981. With this technique with a favorable integral dose distribution, curative irradiation also of advanced tumours in the retroperitoneum and pelvis is possible. Only at SIN, the treatment of non-resectable soft tissue sarcomas with pions is part of the clinical program. Between 1983 and 1985 totally nine patients were treated, 1/9 with three manifestations, 1/9 with palliative intent. In 20 fractions over five weeks (four fractions a week) total doses of 30 to 36 Gy (90% isodose) were applied. In a follow-up period of eleven to 43 months (median 18 months) only 1/10 tumour manifestations treated with greater than or equal to 30 Gy failed locally. The two-year survival rate (Kaplan-Meier) is 56%. Metastases were the cause of death in 3/5 patients, 1/5 heart disease, 1/5 local tumour progression. Even though 9/11 tumours were located in the retroperitoneum or pelvis, no radiogenic morbidity of the bowel was found. These preliminary results stimulate the intensification of this clinical program. 1986 the same number of patients with non-resectable soft tissue sarcomas was treated as in the whole period 1982 to 1985 before.