Risk stratification in breast cancer screening: Cost-effectiveness and harm-benefit ratios for low-risk and high-risk women

In mammography screening programmes, women are screened according to a one-size-fits-all principle. Tailored screening, based on risk levels, may lead to a better balance of benefits and harms. With microsimulation modelling, we determined optimal mammography screening strategies for women at lower (relative risk [RR] 0.75) and higher (RR 1.8) than average risk of breast cancer, eligible for screening, using the incremental cost-effectiveness ratio (ICER) of current uniform screening in the Netherlands (biennial [B] 50-74) as a threshold ICER. Strategies varied by interval (annual [A], biennial, triennial [T]) and age range. The number of life-years gained (LYG), breast cancer deaths averted, overdiagnosed cases, false-positive mammograms, ICERs and harm-benefit ratios were calculated. Optimal risk-based screening scenarios, below the threshold ICER of €8883/LYG, were T50-71 (€7840/LYG) for low-risk and B40-74 (€6062/LYG) for high-risk women. T50-71 screening in low-risk women resulted in a 33% reduction in false-positive findings, a similar reduction in costs and improved harm-benefit ratios compared to the current screening schedule. B40-74 in high-risk women led to an increase in screening benefit, compared to current B50-74 screening, but a relatively higher increase in false-positive findings. In conclusion, optimal screening consisted of a longer interval and lower stopping age than current uniform screening for low-risk women, and a lower starting age for high-risk women. Extending the interval for women at lower risk from biennial to triennial screening reduced harms and costs while maintaining most of the screening benefit.     

The nature of care in light of Emmanuel Levinas

Abstract  The discipline of nursing is still struggling with the differences that need to be clearly defined between the notions of care and nursing care. To be able to clarify this distinction, agreement must first be reached on the meaning of care itself. The present article proposes a conception of care in light of the philosophy of Emmanuel Levinas (1906–1995). This philosopher's thought throws considerable light on the ontology of care, thanks especially to his focus on the deeper implications of human encounter. A profound sense of responsibility towards the other enables Levinas to bring out such dimensions of the concept of care as the relation involved, the feeling of affection, and the interventions. We examine here what these entail regarding nursing care.     

Effects of Intermittent Femoral Nerve Injections of Bupivacaine, Levobupivacaine, and Ropivacaine on Mitochondrial Energy Metabolism and Intracellular Calcium Homeostasis in Rat Psoas Muscle

Background: Long-acting local anesthetics cause muscle damage. Moreover, long-acting local anesthetics act as uncoupler of oxidative phosphorylation in isolated mitochondria and enhance sarcoplasmic reticulum Ca2+ release. The aim of the study was to evaluate effects of perineural injections of local anesthetics on mitochondrial energetic metabolism and intracellular calcium homeostasis in vivo.

Methods: Femoral nerve block catheters were inserted in adult male Wistar rats. Rats were randomized and received seven injections (1 ml/kg) of bupivacaine, levobupivacaine, ropivacaine, or isotonic saline at 8-h intervals. Rats were killed 8 h after the last injection. Psoas muscle was quickly dissected from next to the femoral nerve. Local anesthetic concentrations in muscle were determined. Oxidative capacity was measured in saponin-skinned fibers. Oxygen consumption rates were measured, and mitochondrial adenosine triphosphate synthesis rate was determined. Enzymatic activities of mitochondrial respiratory chain complexes were evaluated. Local calcium release events (calcium sparks) were analyzed as well as sarcoplasmic reticulum calcium content in saponin-skinned fibers.

Results: Eight hours after the last injection, psoas muscle concentration of local anesthetics was less than 0.3 [mu]g/g tissue. Adenosine triphosphate synthesis and adenosine triphosphate-to-oxygen ratio were significantly decreased in the muscle of rats treated with local anesthetics. A global decrease (around 50%) in all of the enzyme activities of the respiratory chain was observed. Levobupivacaine increased the amplitude and frequency of the calcium sparks, whereas lower sarcoplasmic reticulum calcium content was shown.     

Radiation therapy in proliferative vitreoretinopathy

In a prospective study of the effect of postoperative radiation therapy for the prevention of reproliferation of membranes and recurrent proliferative vitreoretinopathy (PVR) two similar groups of patients with retinal detachment and PVR grade D1 to D3 in one eye were compared. Half the eyes (30) received a total dose of 3000 cGy after surgery; the other half remained untreated. After a followup of 6 months and 14 months or more (maximum 36 months) the anatomical and functional results of each group were compared. After 6 months in the unirradiated group 57% (17/30) remained attached and 43% (13/30) had detached again. In the irradiated group 63% (19/30) were attached and 37% (11/30) had detached. However, there was no statistically significant difference between the two groups (P=0.479, Fisher's Exact Test). After 14 months the number of cured and uncured eyes remained the same in the unirradiated group, while in four of the eyes in the irradiated group a later onset of reproliferation and detachment occurred (after 7, 8, 12 and 14 months, respectively). A final cure rate of 57% (17/30) was achieved in the unirradiated group and a 50% (15/30) cure rate in the irradiated group. Thus the failure rate was 43% (13/30) in the unirradiated group and 50% (15/30) in the irradiated group (P=0.473, Fisher's Exact Test). No side effects from the radiation were observed in any case and no radiation retinopathy occurred during an observation period of up to 3 years. The visual acuity of the cured treated and cured untreated eyes was similar in the two groups. From these results we conclude that immediate radiation treatment does not improve the long-term results and does not reduce the number of reoperations. In a considerable number of treated eyes the onset of reproliferation was delayed from 7 to 14 months, whereas in the untreated group reproliferation was always observed during the first 6 months. A combination of various antiproliferative and antiinflammatory therapies are needed to suppress recurrent PVR after succesful vitreoretinal surgery and to minimize the side effects of these treatments.Presented in part at the XVIIth Meeting of the Club Jules Gonin, 1–6 September 1990, Lausanne     

ADAMTS-4 activity on a proteoglycan vs. a polypeptide is controlled by the ancillary domains

Introduction In combination with the catalytic domain, the ancillary domains of the ADAMTS' are proposed to regulate activity via interactions with sulfated GAGs, the extracellular matrix (ECM) and cell surface. Interactions with both GAGs and the ECM have been attributed to the thrombospondin (TSP) type 1 motifs and spacer region ( Kuno and Matsushima 1998 ; Flannery et al. 2002 ). ADAMTS‐1, ‐4 and ‐5, all undergo cleavage within their respective spacer regions ( Flannery et al. 2002 ; Rodriguez‐Manzaneque et al. 2000 ; Georgiadis et al. 2002 ), an event which has been reported to increase activity towards the interglobular domain of aggrecan and decrease the heparin affinity of ADAMTS‐4 ( Flannery et al. 2002 ; Gao et al. 2002 ). Materials and methods V5‐ and His‐tagged recombinant human ADAMTS‐4 constructs terminating after the catalytic (?DTS), disintegrin‐like (?TS), TSP (?S) or spacer region (Full) were expressed in High‐Five cells. Proteoglycanase activities of the resultant proteins were assayed with solution digests of aggrecan and a polyacrylamide‐entrapped aggrecan particle assay. Proteolytic activity was measured using a novel, nonglycosylated, reporter substrate assay. Results All forms of ADAMTS‐4 were active to varying degrees in the reporter substrate assay. Digestion of aggrecan in solution digests was apparent in all proteins with the exception of the catalytic domain in isolation (?DTS). Activity towards aggrecan decreased with increasing truncation of the protein. Discussion Removal of the cysteine‐rich‐spacer domain and further C‐terminal truncations decrease the activity of ADAMTS‐4 towards aggrecan, whilst the proteolytic activity remains intact. Cleavages releasing the ancillary domains of ADAMTS' may therefore alter the catalytic activity of these enzymes against proteoglycans and also nonglycosylated polypeptides. More information is required about potential substrates for the processed forms of ADAMTS‐4.     

Distribution of α-integrin subunits in fetal polycystic kidney diseases

An alteration in cell/matrix interactions is one of the suggested mechanisms leading to cyst formation in polycystic kidney diseases. Most of these interactions are mediated by β1-integrins, a subfamily of integrin receptors, formed by the association of the β1-chain with different α-subunits. To date, no study on α-integrin subunit distribution during the early stages of cyst development has been reported. Using immunofluorescence, we analyzed the distribution of α-integrin subunits (α1, α2, α3, α5, and α6) and basement membrane proteins in kidneys of fetuses with autosomal dominant (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The distribution was compared with that observed in normal fetal and post-natal kidneys, and in fetal cystic dysplasia and Meckel syndrome. Marked increase in α1-integrin staining was observed in normal and cystic collecting duct cells of both polycystic diseases (PKD), compared with normal and cystic controls. The distribution of integrin subunits α2, α3, and α6 was irregular in cyst epithelial cells of PKD and cystic controls. The increased expression of the α1-subunit specifically observed in PKD collecting duct cells may be an early consequence of the genetic defect in ARPKD. In ADPKD it parallels the reported expression of polycystin, the protein product of PKD1. The irregular expression of α2, α3, and α6 integrin subunits observed in all types of cysts suggests that cell/matrix interactions are altered early and may participate in the development of cysts, perhaps by contributing to the deregulation of cell survival in cystic diseases. Received May 28, 1996; received in revised form October 2, 1996; accepted October 25, 1996     

Pathogenic role of P-selectin in experimental cerebral malaria: importance of the endothelial compartment

P-selectin is a leukocyte adhesion receptor expressed on the surface of activated platelets and endothelial cells. Its role in the pathogenesis of cerebral malaria was explored in a murine model of cerebral malaria. Infection of mice with Plasmodium berghei ANKA led to P-selectin up-regulation in brain vessels of cerebral malaria-susceptible mice but not of cerebral malaria-resistant mice. Treatment of susceptible mice with anti-mouse P-selectin mAb failed to prevent the development of the neurological syndrome. However, P-selectin-deficient mice infected with Plasmodium berghei ANKA had a cumulative incidence of cerebral malaria which was significantly reduced compared to wild-type animals (4.5% versus 80%, respectively), despite identical levels of parasitemia, platelet and leukocyte accumulation. To determine whether P-selectin on platelets and/or endothelium was responsible for the microvascular pathology, cerebral malaria was assessed in chimeric mice deficient in platelet or endothelial P-selectin, which were generated by bone marrow transplantation. Mice deficient only in endothelial P-selectin did not show any sign of cerebral malaria (vascular plugging, hemorrhages, or edema), while mice lacking only platelet P-selectin showed signs of cerebral malaria similar to that seen in wild-type mice. These results indicate that endothelial P-selectin plays an important role in the pathogenesis of cerebral malaria.     

Characterization of Thymic Nurse-Cell Lymphocytes,Using an Improved Procedure for Nurse-Cell Isolation

Thymic nurse cells (TNC), multicellular complexes consisting of lymphoid cells enclosed within cortical epithelial cells, were isolated from mouse thymus by a modified procedure allowing immunofluorescent labeling and flow cytometric analysis of their lymphoid contents (TNC-L). Collagenase was the only protease used for tissue digestion, to ensure that surface antigen markers remained intact. Zonal unit-gravity elutriation was used to enrich the TNC on the basis of their high sedimentation rate, followed by immunomagnetic bead depletion to remove residual mononuclear cell contaminants and a density separation to remove debris. The TNC-L were then released from inside TNC by a short period of culture. The measured contamination of TNC-L with exogenous thymocytes was around 0.5%. Three-color immunofluorescent labeling revealed that TNC-L included, as well as a maiority of immature CD4⁺8⁺3^low thymocytes, about 12% of apparently mature CD4⁺8^-3^high and CD4^-8⁺3^high thymocytes. TNC are located in the cortex, where mature cells are rare; the occurrence of mature phenotype cells within these structures suggests that they represent a microenvironment for the selection and generation of mature T cells.     

Studies on thymus products: I. Modification of rosette-forming cells by thymic extracts. Determination of the target RFC sub-population

Thymic extracts confer on normal bone marrow rosette-forming cells (RFC) in vitro a high sensitivity to anti-theta serum (AθS) and azathioprine (AZ) which they usually lack. Thymic extracts can also confer high sensitivity to AθS and AZ to spleen RFC from adult thymectomized, neonatally thymectomized `thymus-deprived' and nude mice. However, the amount of thymic extracts necessary to get the effect is significantly higher on thymus-deprived and nude mouse spleen RFC than on RFC from spleens of adult thymectomized mice or normal mouse bone marrow. Thymic extracts are also active in vivo and there is a good correlation between the in vitro minimum concentration giving AθS and AZ sensitivity to spleen RFC from adult thymectomized mice and the in vivo minimum dose giving such an effect after intravenous injection. The effect of extract in vivo does not appear before the fourth hour after the injection and is transient, disappearing after 48 hours. Injection of thymic extracts induces the appearance of a `thymic activity' (TA) in the serum with a short half-life (2 hours). Injection of thymic extracts into normal mice does not modify sRFC characteristics in spleen, lymph nodes and bone marrow. It is suggested that thymic extracts act reversibly on a population of T-RFC precursors.     

Studies on thymus products: II. Demonstration and characterization of a circulating thymic hormone

Normal mouse serum confers on bone marrow rosette-forming cells (RFC) from normal mice a high sensitivity to anti-theta serum (AθS) and azathioprine (AZ) which they otherwise lack. Such an effect can also be demonstrated on spleen cells from adult thymectomized mice, `thymus-deprived' and nude mice, but the amount of serum required is higher in the latter mice. This activity of serum on RFC disappears after thymectomy of the serum donor with a half-life of 2.5 hours and reappears in thymectomized mice within 4 days after grafting of a thymus. Serum thymic activity (TA) is present in different amounts in different mouse strains and in ageing mice it progressively disappears. No TA is found in the serum of 4-week-old nude mice. TA is stable after lyophilization but is thermolabile in solution. It passes through UM 10 Amicon membranes, which suggests that its molecular weight (mol. wt) is probably < 10,000. TA is reversibly suppressed in the presence of a serum inhibitor with a mol. wt between 100,000 and 300,000. This inhibitor is not detectable in the serum of thymectomized mice unless the serum is incubated with TA containing serum for 60 minutes at 37°. The biological significance of TA is still a matter of speculation but its role in maturation or expansion of T-cells is suspected.