Surface receptors on neutrophils and monocytes from immunodeficient and normal horses.

Surface receptors on peripheral blood neutrophils and monocytes from normal and immunodeficient horses have been studied. Sheep erythrocytes (SRBC) coated with IgG, IgM, and complement but not IgG(T), readily bound to normal equine monocytes and neutrophils. More than 4000 molecules of IgG were required to sensitize each SRBC for adherence to monocytes, and more than 12,000 molecules were required for adherence to neutrophils. Young horses with a severe combined immunodeficiency had an almost total absence of lymphocytes, but normal numbers of monocytes and neutrophils. The number of receptors for immunoglobulin, complement, and phytolectin on monocytes and neutrophils from immunodeficient animals were similar to those on the cells of normal horses. Although the precursor cells of lymphocytes of horses with combined immunodeficiency appear to be defective, no defect in the other cellular products of the bone marrow were apparent.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

The role of CT in the diagnosis of primary lymphedema of the lower limb

Twelve patients with primary lymphedema of the lower limb were examined with computed tomography (CT). A characteristic "honeycomb" pattern of the subcutaneous compartment was seen in 10 of these patients. CT scans in nine other patients with swollen leg secondary to chronic venous disease or lipedema did not show this characteristic pattern. CT may be helpful in the differential diagnosis of a swollen leg, thus obviating venography or lymphangiography.     

Establishing a national HTA program for medical devices in Italy: Overhauling a fragmented system to ensure value and equal access to new medical technologies

Differing contexts have greatly influenced HTA development in various countries, with considerable effort recently made by international HTA networks (e.g., EUnetHTA) and the European Union (EU) to make HTA a more coherent, equal, and efficient process. Medical devices (MDs) present particular challenges for HTA because of frequent, rapid innovation, outcomes influenced by end-user competence, dynamic pricing and often low-quality scientific evidence. Our objective is to describe the development, structure and governance of a National HTA Program for MDs (PNHTADM) in Italy, a highly participatory, stakeholder-engaged, evidence-based process to reform a fragmented system of appraisal and approval. Based largely on EUnetHTA methods, the resulting process delineates a standardized system for proposing MDs by any stakeholders, accrediting HTA producers, setting criteria for prioritization and appraisals, and innovatively linking recommendations with coverage, reimbursement and procurement of MDs. Expected benefits include reduced disparities in pricing and reimbursement policies and improved access to new technologies across 21 regional healthcare systems in Italy's decentralized, universal system, complete with provisions to require additional evidence collection and centrally monitor diffusion. Though devised for Italy, the design, resources and underlying analysis provide a framework for other nations seeking to consolidate HTA initiatives, particularly in light of new EU regulation.     

Phase I-II study of gamma interferon and 5-fluorouracil for patients with metastatic renal cell carcinoma

We have completed a phase I/II trial to evaluate the toxicity and efficacy of the combination of gamma interferon and 5-fluorouracil in metastatic renal cell carcinoma. Gamma interferon was administered at a weekly dose of 100 micrograms. 5-fluorouracil was given as a 5 day continuous infusion days 1-5 of each 21 day cycle. In the phase I portion of the trial, the gamma interferon dose was held constant, while the 5-fluorouracil was escalated from 500 to 800 mg/m2/day. Serum neopterin and beta 2 microglobulin were measured prior to and 48 hours after each dose of gamma interferon for the first six weeks of treatment. Dose limiting toxicity was not encountered in the phase I part of the trial; therefore the phase II study was initiated at the 800 mg/m2/day dose of 5-fluorouracil. No responses were seen among 34 patients treated on the phase II trial. Forty-six percent of patients experienced disease stabilization and the remainder progressed through treatment. In the phase I trial, increments in neopterin and beta 2 microglobulin levels differed significantly between patients treated with lower and higher doses of 5-fluorouracil. We conclude that the addition of 5-fluorouracil to gamma interferon does not appear to enhance the cytokines clinical activity. Incremental increases in macrophage activation markers with escalating 5-fluorouracil doses suggests a role for 5-fluorouracil beyond its usual proposed cytotoxic activity and warrants further investigation into potential immunologic effects of this drug.     

Destruction of WiDr multicellular tumor spheroids with the novel thymidylate synthase inhibitor 1843U89 at physiological thymidine concentrations

The activity of a novel thymidylate synthase inhibitor, 1843U89, against WiDr human colon carcinoma multicellular tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disruption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 caused spheroid disruption 8 days after drug removal. In contrast, treatment with 10 or 100 nM 1843U89 for 6–48 h or treatment with 1 nM 1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM 1843U89 in the presence of 0.05–0.3 M thymidine was as effective in causing spheroid disruption as treatment in the absence of thymidine, but treatment in the presence of 0.7–3.0 M thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that 1843U89 should have potent solid tumor activity in humans but should be less effective in mice due to differences in circulating thymidine levels (0.1 vs 1 M, respectively).     

Clinical audit of the process of referral to genitourinary medicine of patients found to be chlamydia positive in a family planning service

This paper describes a collaborative audit between a large family planning and genitourinary medicine (GUM) service undertaken to ensure that all women presenting for termination of pregnancy (TOP) or IUD fitting were offered screening for chlamydia, were informed of a positive result, and were subsequently referred to GUM for full sexual health screening and contact tracing. Over a six month period in 1996 1072 patients were seen for either TOP (763) or W1) fitting (309) and of these 999 were offered a test which was performed in 988. Overall 38 positive tests were reported (3.8 per cent) but only two of 259 patients tested prior to lUD fitting were found to have chlamydia (<0.8 per cent). Only 27 of these 38 women (74 per cent) had information recorded in their notes that they had been given their result and 24 patients (63 per cent) were seen in GUM. The audit uncovered problems with documentation and cross-referencing of information which largely accounted for the failure to reach some of the standards set. An action plan has been formulated in an attempt to improve this aspect of the screening service. If more widespread screening for chlamydia is to be effectively implemented as recommended by the 31st RCOG Study Group on the Prevention of Pelvic Infection, then it is of importance that workable local protocols are in place including arrangements for partner notification and treatment. This will involve close collaboration between a range of specialities working in the sexual health field.     

Use of HRT and the subsequent risk of cancer

At least 20 million women in developed countries are estimated to be currently using hormone replacement therapy (HRT). Almost 100 epidemiological studies have reported on the relationship between the use of HRT and the risk of cancer of female reproductive organs, namely the breast, uterus or ovary. Cancer at these sites is common and there are a priori reasons why the use of hormonal therapy to 'replace' the endogenous production of ovarian hormones after the menopause might increase the risk of these cancers. The available evidence indicates that the risk of breast cancer or endometrial cancer is increased while women are using HRT, the risk increasing with increasing duration of use. Most of the evidence about these cancers relates to use of HRT preparations containing oestrogens alone. The limited evidence about combination therapy, with oestrogens and progestogens, suggests that, compared to oestrogens alone, the effect on the breast is similar, but the effect on the endometrium is diminished, the diminution in risk being greater the more days each month that progestogens are used. The effect of HRT on breast cancer wears off after use ceases and has disappeared largely, if not wholly, within 5 years, whereas the effects on endometrial cancer take longer to wear off, if at all. The breast and endometrial cancers that are diagnosed in HRT users are less aggressive clinically than cancers in never-users but, as yet, there is little reliable information about the relationship between use of HRT and mortality from these cancers. For other cancer sites, the existing data about the effects of HRT are inconclusive. The longer the period of use of HRT, the greater the excess incidence of cancer of the breast and endometrium is likely to be. Use of HRT for short periods of time should have little effect on the incidence of these cancers. The cumulative excess incidence in 1000 women who used HRT for 10 years, beginning at age 50, is estimated to be six for breast cancer, 42 for endometrial cancer in women with an intact uterus using oestrogen therapy alone and about 20 for endometrial cancer in women with an intact uterus using oestrogen-progestogen combinations. The estimate for combined therapy is based on small numbers and may well vary with the type of preparation used. The overall balance between the excess incidence of these cancers and other effects of HRT needs to be evaluated carefully and will require more reliable data than exist at present.     

Differences in cadmium transport to the testis, epididymis, and brain in cadmium-sensitive and -resistant murine strains 129/J and A/J

Although most animals with scrotal testes are susceptible to cadmium-induced testicular toxicity, strain-related differences are seen in mice. Resistant murine strains demonstrate a decreased cadmium concentration in the testis and also in the epididymis and seminal vesicle. In this study we analyzed cadmium transport into tissues with a vascular barrier, the testis, epididymis, and brain, in an attempt to characterize the mechanisms of strain resistance to cadmium-induced testicular toxicity. In the resistant murine strain A/J, 109Cd transport (administered as 109CdCl2) was significantly attenuated in the testis, epididymis, and brain, when compared to the sensitive murine strain 129/J. The unidirectional influx constant (Ki, in microliter g-1 min-1) for 109Cd was 0.01929 in the A/J testis as compared with 1.174 in the 129/J testis (P <.0001). The percentage of a 109Cd dose that reached the A/J testis by 60 min was over 10 times less than that which reached the 129/J testis. The transport system used by cadmium in the 129/J testis was saturable, with 20 microM unlabeled cadmium chloride inhibiting transport by over 60%. The transporter was competitively inhibited by zinc (P =. 00017), but not by calcium, indicating a specificity in ion transport. Studies with isolated tubules and analysis of testicular fluid compartments demonstrated no significant difference in cadmium uptake or efflux between the strains when corrected for the amount of 109Cd entering the testis. Therefore, murine strain differences in testicular sensitivity to cadmium appear to be related to the variable presence of a transport system for cadmium in the testicular vasculature.