Morphomechanics of the humero-ulnar joint: II. Concave incongruity determines the distribution of load and subchondral mineralization

Background: A deeper joint socket (concave incongruity) is found at most angles of flexion of the humero-ulnar joint and maintained over a wide range of physiological loading. It is, however, unclear how far this incongruity affects the distribution of load and subchondral mineralization of this joint as compared with a congruous configuration. Methods: Two nonlinear, axisymmetrical finite element models with two cartilage layers were constructed, one congruous and one incongruous, with a joint space of realistic magnitude. The distribution of subchondral mineralization was determined by computed tomography osteoabsorptiometry in the same six specimens that were investigated in the first part of the study, and compared with the biomechanical data obtained there and the predictions of the models. Results: In the congruous case, the center of the socket is highly loaded, whereas the periphery does not experience mechanical stimulation. A central bone density maximum is predicted. With concave incongruity the position of the contact areas shifts from the joint margin towards the center as the load increases, and the peak stresses are considerably lower. A bicentric ventro-dorsal distribution pattern of subchondral mineralization is predicted, and this is actually found in the six specimens. Conclusions: Concave incongruity is shown to determine load transmission and subchondral mineralization of the humero-ulnar joint. It is suggested that this shape leads to a more even distribution of stress, provides intermittent stimulation of the cartilaginous tissue, and has beneficial effects on the metabolism, nutrition, and lubrication of the articular cartilage during cyclic loading. © 1995 Wiley-Liss, Inc.     

KCNE1 reverses the response of the human K+ channel KCNQ1 to cytosolic pH changes and alters its pharmacology and sensitivity to temperature

Previous studies have shown that heteromultimeric KCNQ1/KCNE1 (KvLQT1/minK) channels and homomultimeric KCNQ1 (KvLQT1) channels exhibit different current properties, e.g. distinct kinetics and different sensitivities to drugs. In this study we report on the divergent responses to internal pH changes and further characterize some of the current properties of the human isoforms of KCNQ1 and KCNE1 expressed in Chinese hamster ovary (CHO) cells or Xenopus laevis oocytes. Decreasing the bath temperature from 37 degrees C to 20 degrees C increased the half-activation time by a factor of 5 for KCNQ1/KCNE1 currents (IKs) but by only twofold (not significant) for KCNQ1 currents (IK) in CHO cells. Acidification of cytosolic pH (pHi) increased IKs but decreased 1K whereas intracellular alkalinization decreased I(Ks) but increased IK. pHi-induced changes in intracellular Ca2+ activity ([Ca2+]i) did not correlate with the current responses. At 20 degrees C mefenamic acid (0.1 mM) significantly augmented IKs but slightly decreased IK. It changed the slow activation kinetics of I(Ks) to an instantaneous onset. The form of the current/voltage (I/V) curve changed from sigmoidal to almost linear. In contrast, at 37 degrees C, mefenamic acid also increased I(Ks) but slowed the activation kinetics and shifted the voltage activation to more hyperpolarized values without markedly affecting the sigmoidal shape of the I/V curve. The potassium channel blockers clotrimazole and tetrapentylammonium (TPeA) inhibited I(Ks) with a lower potency than I(K). These results show that coexpression of KCNE1 reversed pH regulation of KCNQ1 from inhibition to activation by acidic pHi. In addition, KCNE1 altered the pharmacological properties and sensitivity to temperature of KCNQ1. The pH-dependence of I(Ks) might be of clinical and pathophysiological relevance in the pathogenesis of ischaemic cardiac arrhythmias.     

Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice

Antibodies to tumor necrosis factor (TNF)-α have been recently proposed as effective treatment for patients with Crohn's disease. Here, we analyze the functional role of TNF-α in a mouse model of chronic intestinal inflammation induced by the hapten reagent 2,4,6,-trinitrobenzene sulfonic acid (TNBS) that mimics some characteristics of Crohn's disease in humans. Macrophage-enriched lamina propria (LP) mononuclear cells from mice with TNBS-induced colitis produced 10–30-fold higher levels of TNF-α mRNA and protein than cells from control mice. When mice with chronic colitis were treated by intraperitoneal injection of antibodies to TNF-α, an improvement of both the clinical and histopathologic signs of disease was found. Isolated macrophage-enriched LP cells from anti-TNF-α-treated mice produced strikingly less pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 in cell culture. The predominant role of TNF-α in the mouse TNBS-induced colitis model was further underlined by the finding that striking colonic inflammation and lethal pancolitis was induced in TNF-α-transgenic mice upon TNBS treatment. Conversely, no significant TNBS-induced colitis could be induced in mice in which the TNF-α gene had been inactivated by homologous recombination. Complementation of TNF-α function in TNF^?/? mice by the expression of a mouse TNF-α transgene was sufficient to reverse this effect. Taken together, the data provide direct evidence for a predominant role of TNF-α in a mouse model of chronic intestinal inflammation and encourage further clinical trials with antibodies to TNF-α for the treatment of patients with Crohn's disease.     

Steinfeld syndrome: Report of a second family and further delineation of a rare autosomal dominant disorder

We report on a fetus with alobar holoprosencephaly, microphthalmia, midline cleft lip and palate, absent nose, dysplastic ears, radial defects, pentalogy of Fallot, unilateral renal aplasia, absent gallbladder, vertebral anomalies, and absence of ribs. The father had a cleft palate, bilateral colobomas of the iris and retina, a bifid uvula, vertebral anomalies, and unilateral congential hearing loss. His sister had a cleft lip. On the basis of this family and the family reported by Steinfeld [1982], this malformation syndrome can be defined as a rare autosomal dominant syndrome whose main component manifestations are holoprosencephaly, predominantly radial limb deficiency, heart defects, kidney malformations, absence of gallbladder, and vertebral anomalies. © 1993 Wiley-Liss, Inc.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

Analysis of foot motion during running using a joint co-ordinate system

The amount and rate of pronation and supination have been the subject of interest to runners for some time. Exact determination of the motions has been hampered by their complexities and use of a two-dimensional data collection protocol. "Rearfoot motion," measured by determining the projection of the angle between a line on the posterior of the shank and a line on the heel, has been a common approach. This projection measures a rotation about a laboratory axis and not a body segment axis and has a potential of error due to projection onto a plane. The angle measured in rearfoot motion is not the true angle between these lines in space and has projection distortion errors which are compounded during plantar and dorsiflexion and medial and lateral foot rotations. The rearfoot motion angle, however, does approximate foot inversion-eversion during much of stance phase. The proposed change in research protocol allows analysis of the three-dimensional position data of targets to construct a "joint coordinate system" which gives more accurate data on inversion-eversion and data on plantar-dorsiflexion and medial-lateral rotation of the foot. This analysis may allow the examination of measurable differences between individuals and running shoes of various design.     

Aktion ?Gesunde Ern?hrung? im Kanton St.Gallen

Zusammenfassung Die Aktion «Gesunde Ernährung» in der Gemeinde-wurde vom Gesundheitsdepartement des Kanton St. Gallen unter der Leitung des kantonalen Präventivmediziners gemeinsam mit den interessierten Gemeinden geplant, koordiniert und durchgeführt.Im Zentrum der Aktion standen gemeindeeigene, individuell gestaltete Aktivitäten von Vereinen, Schulen und des lokalen Gewerbes. Das Gesundheitsdepartement ergänzte die Aktion mit einer Wanderausstellung über Ernährungsfragen, begleitet von einer Ernährungsberaterin. Der Aufbau der Ausstellung erfolgte nach den 10 goldenen Regeln der gesunden Ernährung.Diese Aktion stellt ein konkretes Beispiel der Arbeitsteilung zwischen Kanton und Gemeinde in der Gesundheitsvorsorge dar. Das Beispiel dieser einmaligen Aktion soll Behörden, Vereinen und Einzelpersonen Wege und Methoden aufzeigen, Anliegen der Gesundheitsvorsorge auf längerfristiger Basis in der Gemeinde zu planen.

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Healthy Nutrition an experience of health promotion in the county of St. Gall

Summary The drive Healthy Nutrition in communities was planned, co-ordinated und carried out as a joint action by the Health Department of the County of St. Gall, and 37 communities interested in the idea. The drive centred around the activities of the community itself, individuals, clubs, schools and local industry.The County Health Department supplemented the activity with a travelling exhibition about nutrition problems, attended by an advisor to answer questions. The build-up of the exhibition followed the 10 Golden Rules of sound nutrition.This drive was an excellent example of how health-promotion programms can be shared by county und community.This unique action should set an example to other authorities, clubs, and individuals, and show the ways and means needed to provide long-term planning for health promotion in the community.

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«Alimentation saine»: le programme du canton de St-Gall

Résumé Un programme «Alimentation saine» a été planifié, coordonné et réalisé en étroite collaboration entre le Service cantonal de médecine préventive et les communes intéressées.Les activités développées par les sociétés locales, les écoles et les commerÇants ont été les éléments essentiels du programme. Le canton a, quant à lui, engagé une diététicienne et mis un bus à disposition ce qui a permis d'organiser une exposition itinérante conÇue selon les 10 règles d'or de l'alimentation saine.Ce programme est une expérience de collaboration entre le canton et les communes pour la promotion de la santé. Il devrait servir d'exemple aux autorités, sociétés locales et individus qui désirent répondre au défi de la promotion de la santé.

     

Maintain levels of nicotine but reduce other smoke constituents: A formula for “less-hazardous” cigarettes?

Twenty-two volunteers who smoked more than 20 cigarettes with "high" nicotine yields (0.8 to 1.2 mg) per day participated in an 8-week study designed to test the hypothesis that smoking cigarettes with a constant level of nicotine but reduced deliveries of tar, carbon monoxide, and hydrogen cyanide leads to a decrease in smoke absorption. All subjects smoked their usual high-nicotine brand for the first 3 weeks (P1), and the absorption of smoke constituents was determined from levels of thiocyanate and cotinine in saliva and serum, levels of carbon monoxide in expired air, and levels of carboxyhemoglobin in the blood. During the final 5 weeks (P2), the treatment group (16 subjects) switched to the "light" version of their usual brands (similar yields of nicotine but with reduced yields of tar, carbon monoxide, and hydrogen cyanide); the control group (6 subjects) smoked their usual brands for the duration of the study. Average levels of cotinine for the subjects who switched during P2 were not significantly different from those of the control group as was expected. Slight reductions were noted in average expired-air carbon monoxide levels, blood carboxyhemoglobin, and saliva thiocyanate, but these reductions were smaller than anticipated based on brand characteristics. The results suggest that the ratio of smoke constituents is different when individuals, rather than machines, smoke cigarettes. Yields determined under subject-defined conditions are necessary in order to properly evaluate the role of nicotine in the design of "less-hazardous" cigarettes.     

Plasminogen activators in human malignant melanoma

Metastatic malignant melanomas from 16 patients, extracted with Triton X-100, were analyzed for plasminogen activator activity by azocaseinolysis . In 6 cases tumor explants were set up also in short-term organ culture, and the rate of plasminogen activator secretion into the culture medium was determined. Both the extractable activator content [8.66 +/- 7.8 "Committee on Thrombolytic Agents" (CTA) U/g tissue] and the activator secretion rates (0.90 +/- 1.6 CTA U/g/hr) were low in comparison with values for other human tumors. In addition to the activity, the type of plasminogen activator also was determined by immunoinhibition with goat antihuman urokinase antibody in the azocaseinolytic assay, as well as by sodium dodecyl sulfate (SDS) gel electrophoresis followed by zymography on fibrin-agar, in the presence and absence of antibody. On the average, 77% of the activator activity was of the urokinase type in the extracts, and 90% in the culture fluids. Immunoperoxidase reaction for the detection of urokinase showed this enzyme to be localized mainly in the cell membrane of the melanoma cells; stromal elements showed no specific staining. These results are of interest in view of the findings made recently by investigators in several laboratories that in all but one of the melanoma cell cultures derived from metastatic human tumors, only the vascular type ("tissue activator") was cell associated or was secreted into the culture medium. The possible reasons for this discrepancy are discussed.