Surgery is more cost-effective than splinting for carpal tunnel syndrome in the Netherlands: results of an economic evaluation alongside a randomized controlled trial

Background  

Carpal tunnel syndrome (CTS) is a common disorder, often treated with surgery or wrist splinting. The objective of this economic evaluation alongside a randomized trial was to evaluate the cost-effectiveness of splinting and surgery for patients with CTS.     

Bioethics for clinicians: 14. Ethics and genetics in medicine

Information about a patient's inherited risk of disease has important ethical and legal implications in clinical practice. Because genetic information is by nature highly personal yet familial, issues of confidentiality arise. Counselling and informed consent before testing are important in view of the social and psychological risks that accompany testing, the complexity of information surrounding testing, and the fact that effective interventions are often not available. Follow-up counselling is also important to help patients integrate test results into their lives and the lives of their relatives. Genetic counselling should be provided by practitioners who have up-to-date knowledge of the genetics of and the tests available for specific diseases, are aware of the social and psychological risks associated with testing, and are able to provide appropriate clinical follow-up. Some physicians may elect to refer patients for genetic counselling and testing. However, it is inevitable that all physicians will be involved in long-term follow-up both by monitoring for disease and by supporting the integration of genetic information into patients' lives.     

Adjuvant chemotherapy in resected lung cancer: Two-year experience in a university hospital

BACKGROUND:

Randomized trials have confirmed the benefits of adjuvant chemotherapy in improving survival in resected early-stage non-small-cell lung cancer (NSCLC). The extent to which these results have translated into clinical practice is unknown.

OBJECTIVE:

To examine the referral pattern of patients with resected lung cancer to adjuvant chemotherapy, and to compare compliance and toxicities with current literature.

METHODS:

A retrospective analysis of all patients who underwent a surgical resection for lung cancer at Laval Hospital (Quebec City, Quebec) from March 2004 to January 2006 was conducted.

RESULTS:

A total of 258 patients underwent surgery. Seven patients were excluded because of early postoperative death, and two patients were excluded because of incomplete data. Data from 249 patients were analyzed (94% NSCLC). Fifty per cent were referred to medical oncology for consideration of adjuvant chemotherapy, including 37 of 61 patients with stage II NSCLC. One hundred patients received chemotherapy. No significant difference in age, sex, comorbidities and surgical procedures was observed between those who received chemotherapy and those who did not. Chemotherapy was initiated 47 days (median) after the surgery and consisted mainly of cisplatin-vinorelbine (38%), cisplatin-etoposide (22%) and carboplatin-paclitaxel (20%). Sixty-six per cent of the patients completed all four cycles. Grade 3 or 4 toxicities consisted mainly of fatigue (23%) and cytopenia (40%). No death was registered; 15% had to be hospitalized because of adverse effects.

CONCLUSION:

Although adjuvant chemotherapy is gaining acceptance in clinical practice, more patients should be referred to medical oncology following surgical resection. Compliance and toxicity are similar to or better than those described in published randomized trials.     

Fibrin(ogen) is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway

Fibrin(ogen) (FGN) is important for hemostasis and wound healing and is cleared from sites of injury primarily by the plasminogen activator system. However, there is emerging evidence in plasminogen activator- deficient transgenic mice that nonplasmin pathways may be important in fibrin(ogen)olysis, as well. Given the proximity of FGN and monocytes within the occlusive thrombus at sites of vascular injury, we considered the possibility that monocytes may play an ancillary role in the degradation and clearance of fibrin. We found that monocytes possess an alternative fibrinolytic pathway that uses the integrin Mac- 1, which directly binds and internalizes FGN, resulting in its lysosomal degradation. At 4 degrees C, FGN binds to U937 monocytoid cells in a specific and saturable manner with a kd of 1.8 mumol/L. Binding requires adenosine diphosphate stimulation and is calcium- dependent. At 37 degrees C, FGN and fibrin monomer (FM) are internalized and degraded at rates of 0.37 +/- 0.13 and 0.55 +/- 0.03 microgram/10(6) cells/h by U937 cells, 1.38 +/- 0.02 and 1.20 +/- 0.30 microgram/10(6) cells/h by THP-1 cells, and 2.10 +/- 0.20 and 2.52 +/- 0.18 micrograms/10(6) cells/h by human peripheral blood mononuclear cells, respectively. The serine protease inhibitors, PPACK and aprotinin, and the specific elastase inhibitor, AAPVCK, do not significantly inhibit degradation. However, degradation is inhibited by chloroquine, suggesting that a lysosomal pathway is involved. Factor X, a competitive ligand with FGN for the Mac-1 receptor, also blocks degradation, as does a monoclonal antibody to the alpha-subunit of Mac- 1. Autoradiography of radioiodinated, internalized FGN shows that FGN proteolysis by the pathway produces a unique degradation pattern distinct from that observed with plasmin. In a fibrin clot lysis assay, Mac-1-mediated fibrinolysis contributed significantly to total fibrinolysis. In summary, FGN is internalized and degraded by activated human monocytoid cells via Mac-1 in the absence of plasmin, thereby providing an alternative fibrinolytic pathway. Thus, in addition to the function of cell adhesion, integrins may also act as receptors that mediate the internalization and degradation of bound ligands.     

Vesicular transport of histamine in stimulated human basophils

Human basophils participating in experimentally produced contact allergy display progressive secretion of electron-dense secretory granule contents and retention of cytoplasmic granule containers in the absence of entire granule extrusion, a process termed piecemeal degranulation (PMD) and postulated to be effected by vesicular transport (Dvorak HF, Dvorak AM: Clin Hematol 4:651, 1975). Proof of this hypothesis was sought using models of human basophil-stimulated secretion, partially purified human peripheral blood basophils, and a morphometric analysis of the fraction of total cellular cytoplasmic vesicles loaded with histamine, a major proinflammatory mediator present in basophil secretory granules. The subcellular localization of histamine was accomplished using a new ultrastructural enzyme-affinity- gold method based on the affinity of diamine oxidase for its substrate, histamine (Dvorak et al: J Histochem Cytochem 41:787, 1993). Two models were selected for a kinetic analysis of stimulated vesicle transport of histamine based on known biochemical and ultrastructural characteristics (MacGlashan et al: J Immunol 136:2231, 1986; Warner et al: J Leukoc Biol 45:558, 1989; Dvorak et al: Am J Pathol 141:1309, 1992; Dvorak et al: Lab Invest 64:234, 1991). These models were selected to include the rapid release reaction stimulated by the bacterial peptide, FMLP, and the slow release reaction stimulated by the phorbol diester tumor promoter, TPA. The results of this study showed that the fraction of histamine-loaded cytoplasmic vesicles (%VG/TV/micron2) in TPA-stimulated basophils significantly exceeded the fraction in unstimulated cells, a process that persisted for 45 minutes after TPA stimulation and was associated with extensive PMD and no morphologic evidence of recovery. Similarly, the fraction of histamine- loaded cytoplasmic vesicles after FMLP stimulation significantly exceeded the fraction in unstimulated cells, a process that persisted for 10 minutes after FMLP stimulation and was associated with the morphologic continuum of PMD-->anaphylactic degranulation (characterized by extrusion of granules)-->recovery, a process largely complete in the 10-minute samples. These studies establish for the first time that an important proinflammatory mediator, histamine, traffic from secretory granules to the extracellular milieu in small cytoplasmic vesicles in stimulated human basophils. The association of this process with the ultrastructural release reaction defined as PMD produced primarily by TPA and in part by FMLP establishes vesicular transport as the mechanism for effecting this type of regulated secretion. Vesicular transport of histamine was also significant in the more complex stimulated secretory and recovery model produced by exposure of human basophils to the bacterial peptide FMLP.     

Hemoglobin synthesis in individual bursts from normal adult blood: all bursts and subcolonies synthesize G gamma-and A gamma-globin chains

Gamma-globin chain synthesis has been evaluated in individual bursts and subcolonies that were generated by normal adult blood BFU-Es in methylcellulose cultures containing semipurified erythropoietin (Ep) and then analyzed via either isoelectric focusing (IEF) of globin chains or immunofluorescence techniques. At variance with previously reported results, based on plasma clot culture and immunofluorescence, all bursts and subcolonies analyzed synthesize gamma-globin chains. Identification of gamma-chains has been confirmed by preparative IEF of HbF, followed by either carboxymethylcellulose chromatography or IEF analysis of the resulting globin chains. In all bursts analyzed, the relative synthesis of the two types of gamma-globin chains (G gamma and A gamma) shows an adult ratio (i.e., approximately 1:1). The results obtained via IEF have been confirmed by immunofluorescence studies, which apparently showed presence of at least some HbF-positive cells within all scrutinized bursts or subcolonies. The significance of these studies is discussed in the light of current hypotheses on mechanism(s) underlying HbF synthesis in normal adults.     

Antibody-induced modulation and intracellular transport of CD10 and CD19 antigens in human B-cell lines: an immunofluorescence and immunoelectron microscopy study

Antibody-induced antigenic modulation (AIAM) of CD10 and CD19 was studied on NALM-6, RAJI, and JOK-1 cell lines using fluorescence microscopy (FM), flow cytometry (FCM), and immunoelectron microscopy (IEM). Cross-linking with monoclonal antibodies (MoAbs) induced rapid redistribution of CD10 and CD19 on the cell surface (FM) followed by internalization involving uptake through plasmalemmal pits, transfer through endosomal compartment (receptor-mediated endocytosis), and, finally, delivery to lysosomes for degradation or exocytosis and recycling (IEM). Significant quantitative differences regarding modulation and intracellular processing were shown by FCM and IEM. Thus, 35%, 30%, and 25% of CD10 compared with 80%, 60%, and 40% of CD19 were internalized in NALM-6, RAJI, and JOK-1 cells, respectively. Also, the rate of intracellular transfer as well as externalization and recycling was more pronounced in the case of CD19 than of CD10 and in the NALM-6 and RAJI cells compared with the JOK-1 cells. These differences may possibly reflect the functional significance of CD10 and CD19 as well as the stage of differentiation of the malignant B cells. Although both antigens can be useful in MoAb-targeted immunotherapy, our findings suggest that anti-CD19 MoAbs would be preferable for delivery of cytotoxic agents to malignant B cells.     

Association state of human red blood cell band 3 and its interaction with ankyrin

We have studied the association state of band 3, the anion channel and predominant transmembrane protein of the human red blood cell, and the anomalous stoichiometry and dynamics of its interaction with ankyrin, which acts as a link to the spectrin of the membrane skeletal network. Band 3 exists in benign nonionic detergent solutions as a dimer. Tetramer is formed irreversibly in the course of manipulations, particularly in ion-exchange chromatography. The dimer in solution binds ankyrin without self-associating. In ankyrin-free inside-out membrane vesicles and when incorporated into phosphatidylcholine liposomes, only some 10% to 15% of band 3 chains bind ankyrin at saturation. Moreover, in liposomes this was independent of protein:lipid ratio between 1:2 and 1:40. The bound fraction of band 3 remains with the detergent-extracted membrane cytoskeleton, but is released if the ankyrin has been cleaved with chymotrypsin before detergent treatment; thus, the attachment to the membrane cytoskeleton is entirely through ankyrin and not through other constituents such as protein 4.1. The ratio of band 3 to ankyrin in this complex implies that it consists of two chains of band 3 and one chain of ankyrin, at least after detergent extraction. The bound and free populations of band 3 exchange freely in the membrane. In the artificial liposome membrane binding of ankyrin to band 3 dimers cause association of the band 3 into higher aggregates, as seen in freeze-fracture electron microscopy. Successive manipulations of the red blood cell membrane, which are involved in the preparation of ghosts, of inside-out vesicles, and of inside-out vesicles stripped of peripheral proteins are accompanied by progressive aggregation of intramembrane particles, as judged by freeze-fracture electron microscopy. Thus the intramembrane particles are evidently stabilized in the intact cell by the peripheral protein network and the cytosolic milieu. Aggregation may be expected to limit the number of functional ankyrin binding sites. However, although extraneous ankyrin binds to the unoccupied binding site on the spectrin tetramers in intact ghost membranes, little or no ankyrin can bind to the unoccupied band 3 dimers in situ, perhaps by reason of occlusion of binding sites by the membrane skeletal network.