Endothelin receptors and calcium translocation pathways in human airways

Tension and phosphatidyl inositol (PI) turnover experiments were conducted to investigate the receptors and signal transduction pathways responsible for contractions elicited by endothelin (ET) ligands in human bronchus. Nicardipine (1 μM), the L-type calcium channel inhibitor, or incubation in Ca²⁺-free medium, produced marked inhibition of contractions to the ET_B receptor-selective agonist, sarafotoxin S6c, and especially those induced by KCl. In contrast, Ca²⁺-free medium was without appreciable effect against contraction produced by endothelin-1 (ET-1), the non-selective ET_A and ET_B receptor agonist. In Ca²⁺-free medium, ryanodine (10 μM), which inhibits intracellular calcium mobilization, reduced sarafotoxin S6c- and ET-1-induced responses, but was without effect on responses to KCl. Similarly, nickel chloride (Ni²⁺; 1 mM) caused marked inhibition of contractions induced by sarafotoxin S6c or ET-1, but had no significant effect on KCl concentration-response curves. The mixed ET_A/ET_B receptor antagonist SB 209670 (3 μM) inhibited responses to sarafotoxin S6c and ET-1 such that concentration-response curves were shifted rightward, at the 30% maximum response level, by 10.0- and 3.8-fold, respectively, whereas BQ-123 (3 μM), the ET_A receptor antagonist, was without effect on responses induced by either agonist. ET-1 (1 nM–0.3 μM) caused a concentration-dependent stimulation of PI turnover, whereas sarafotoxin S6c (0.3 nM–0.1 μM) induced only small and variable increases, except at the highest concentration. The increase in PI turnover evoked by ET-1 was inhibited by SB 209670 (3 μM), and also by BQ-123 (3 μM). This is consistent with linkage of ET_A receptors to activation of inositol phosphate generation in human bronchial smooth muscle cells. Collectively, the data suggest that differences exist in the relative contributions of intracellular and extracellular Ca²⁺ mobilization mechanisms elicited by ET_A and ET_B receptor activation. Thus, sarafotoxin S6c-induced, ET_B receptor-mediated contraction in human bronchial smooth muscle appears to be dependent, in part, upon extracellular Ca²⁺, although a significant component of the response was also mediated by intracellular Ca²⁺ release, including from ryanodine-sensitive stores. ET_A receptor-mediated contraction of human airway smooth muscle was activated largely via the release of intracellular Ca²⁺. Received: 21 July 1998 / Accepted: 26 January 1999     

Hürthle cell (oxyphilic) papillary thyroid carcinoma: a variant with more aggressive biologic behavior.

The latest World Health Organization International Classification defines papillary thyroid carcinoma by its "follicular cell differentiation...as well as characteristic nuclear changes". However the oxyphilic (Hürthle cell) papillary carcinoma have nuclei which generally resemble the nuclei seen in oxyphilic follicular carcinomas, and such oxyphilic papillary tumors may behave more aggressively than typical papillary cancers. To further characterize these rare tumors, we identified during a 32-year period 22 patients with oxyphilic papillary cancer and compared them with 1,084 patients with typical papillary cancers and 57 patients with oxyphilic follicular cancers treated by the Mayo surgical group during the same time period. Although typical papillary and oxyphilic papillary cancers were comparable with regards to patient age, tumor size and extent, TNM stage, and prognostic score (AGES), there were significant differences. Compared to typical papillary tumors, oxyphilic papillary cancers had fewer neck nodal metastases at primary diagnosis (5% vs 40%, p less than 0.0001), were more often DNA non-diploid (71% vs 21%, p less than 0.001), and after 10 postoperative years had higher rates of both tumor recurrence (28% vs 11%, p less than 0.0001) and cause-specific mortality (1.7% vs 4%, p less than 0.0005). In these four important respects the oxyphilic papillary cancers more resembled the oxyphilic follicular cancers. For oxyphilic follicular cancers, the frequency of initial neck nodal metastases was 7% (cf 5%); 83% of the oxyphilic follicular tumors were non-diploid (cf 71%), and at 10 years postoperatively the tumor recurrence and cause-specific mortality rates were 28% and 18%, insignificantly different from 28% and 17% seen with the oxyphilic papillary cancers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rheumatoid factors and complex formation. The role of light-chain framework sequences and glycosylation

New information regarding rheumatoid factors (RFs) indicates that the RFs synthesized in synovium and lymphoid tissues of patients with rheumatoid arthritis (RA) are different from monoclonal and nonspecific RFs associated with other inflammatory states. The characteristics of RF associated with RA are as follows. They are of all Ig isotypes (not just IgM), indicating T-cell participation in antibody maturation. They have higher avidity for human IgG than for rabbit IgG. They use the human germline heavy-chain variable region (VH) gene VHIII more frequently than other VH genes, and light chains from multiple families. (In contrast, monoclonal RFs use predominantly VH1 and very commonly the V kappa IIIb germline gene HUMkv325). RA IgG is somatically mutated. (In contrast, monoclonal RFs use unmutated germline Ig genes). This suggests they are matured by stimulation either with specific antigens or other activation signals such as cytokines. They are abnormally glycosylated. In general, during periods of disease activity in adult and juvenile RA, a galactose is missing from the Fc of the IgG molecule, leaving an empty "pocket" between the C gamma 2 domains of heavy chains. The IgG RFs self-associate. This may result at least in part when galactose on the F(ab')2 portion of one IgG molecule fills the empty pocket in the Fc of another Ig molecule. Self-association forms immune complexes capable of fixing complement and probably of causing joint damage and vasculitis.     

Physician-induced demand: an empirical analysis of the consumer information gap

The hypothesis of physician-induced demand is examined empirically in a model where variation in consumer information affects health-care utilization. A theoretical framework is posited under which demand-inducing physicians will provide more services, ceteris paribus, to their medically uninformed patients. Using data from the CHAS-NORC National Survey of Access to Medical uninformed patients. Using data from the CHAS-NORC National Survey of Access to Medical Care 1975-1976, physician office visit demand equations are estimated. The key finding is that medical professionals and their families are as likely, if not more likely, to visit physicians as other people, controlling for sociodemographic factors, price factors, access to care factors and perceived health status.     

Marrow regeneration after mechanical depletion

The origin of marrow regeneration after mechanical depletion was reinvestigated in mouse chimeras. The results were compatible with the local origin of stem cells from remnants of incompletely removed marrow, but not with their origin from a common precursor of both bone and hemopoietic cell lines. In transplanted femurs depleted by a modified technique of in vivo evacuation of marrow, hemopoietic regeneration failed to occur. The presence of hemopoietic stem cells in the Haversian canals was thus excluded. The demonstration of ample hemopoiesis with minimal bone formation in nondepleted controls in which bone marrow initially became necrotic provided new evidence that osteogenesis was not a prerequisite of hemopoietic regeneration.     

Leukotropic herpesviruses in multiple sclerosis

Detection frequency of human herpesvirus 6 (HHV-6) and Epstein Barr virus (EBV) DNA in multiple sclerosis (MS) patients and controls was investigated. DNA of peripheral blood mononuclear leukocytes (PBL) was isolated and amplified by polymerase chain reaction techniques. EBV DNA was detected in all patients and controls. HHV-6 DNA was detected in 7% of MS patients and in 14% of controls. Results are compared with other investigations of HHV-6 DNA in PBL, serum, CSF and brain of patients with MS. Results of the present study and other investigations do not show an association between HHV-6 in PBL and MS. Multiple Sclerosis (2000) 6, 66 - 68     

Electrogustometry: strengths,weaknesses, and clinical evidence of stimulus boundaries

Electrogustometry is well established as a clinical tool for the estimation of taste detection thresholds. Nevertheless, the user is sometimes unaware of the impact of superficially minor procedural and psychophysical factors upon the reliability and comparability of threshold estimates. The inherent strengths and limitations of the procedure are outlined, and aspects of the control and specification of the stimulus that moderate threshold measures are discussed. In addition, threshold estimates from two individuals with severe unilateral taste loss are used to illustrate the level at which anodal dc current may elicit common, rather than taste, sensation. Where chorda tympani section is complete and historical (older than 7–14 days), very high stimulus levels, conservatively over 5 µA/mm² (100 µA linear current with a 5‐mm diameter electrode), are required to activate trigeminal responses.