Comparative statistical analysis of osteoporosis treatment based on Hungarian claims data and interpretation of the results in respect to cost-effectiveness.

UNLABELLED: The efficacy of interventions used in real life for the treatment of osteoporosis has not been evaluated on a national basis. We analysed the database of the single Hungarian health care provider between 2004 and 2010. A marked reduction in fracture incidence and hospitalization was seen, which also proved to be cost-effective. INTRODUCTION: Osteoporosis and its consequences place a significant burden on the health care systems of developed countries. Present therapeutic modalities are effective in reducing the risk of fractures caused by osteoporosis. However, we do not know whether the interventions introduced in the past 15 years have significantly reduced the number of osteoporotic fractures in real life, and if yes, how cost-effectively. METHODS: The database of the National Health Insurance Fund Administration in Hungary was analysed for the period between 2004 and 2010. Two specific patient groups were identified within the population. Patients, who were under osteoporosis treatment in more than 80% of the potential treatment days in three consecutive years (patients with high compliance), were compared with patients where this ratio was under 20% (patients with low compliance). Several statistical comparative models were implemented in order to capture a complete picture on the differences. Because of natural data heterogeneity of administration databases, propensity matching was applied as well. RESULTS: Comparing treated vs. control subjects, patients with high compliance showed a significant decrease in fracture risk and hospitalization, which was more robust after propensity adjustment. On the basis of the observed statistically significant differences, cost-effectiveness analysis was implemented. Utility loss due the observed fractures was compared with the total cost differences of the two arms based on modelling. Our calculations proved the cost-effectiveness of the long-term high compliance in real world settings. CONCLUSION: Our findings infer that the standardized and uniform health care of osteoporotic patients in a country may reduce general fracture incidence and hospitalization in a cost-effective way.

Evaluation of the effect of Lake Hévíz thermal mineral water in patients with osteoarthritis of the knee: a randomized, controlled, single-blind, follow-up study.

BACKGROUND: Osteoarthritis is the most frequent joint disease and is a leading cause of pain and locomotor disability in elderly people. The treatment of osteoarthritis includes non-pharmacological, pharmacological, and surgical therapies. Silver level evidence has been found concerning balneotherapy in osteoarthritis. AIM OF THE STUDY: The aim of this study was to evaluate how Lake Hévíz thermal mineral water therapy influences pain, knee function, and quality of life in patients with knee osteoarthritis, compared to the control group. STUDY DESIGN: randomized, controlled, single-blind, follow-up study. SETTING: Spa Hévíz and St. Andrew Hospital for Rheumatic Diseases POPULATION: This study included 77 outpatients between 45 and 75 years of age with mild to moderate osteoarthritis of the knee meeting the American College of Rheumatology classification criteria. METHODS: Patients were randomized into two groups. In group I (n = 38), subjects bathed in Lake Hévíz and in group II (N.=39), patients were treated in a pool full of tap water. Water temperature was 34 °C for both groups. Participants underwent 30-minute therapy sessions, five times a week for three weeks. Outcome measures were pain visual analogue scale scores, active flexion degree, knee circumference, stair-climb time, Western Ontario and McMaster Universities osteoarthritis index (WOMAC), and EuroQoL Group 5-Dimension Self-Report Questionnaire score (EQ-5D). Study parameters were recorded at baseline, immediately after treatment, and after 15 weeks. RESULTS: Comparison of the two groups revealed a statistically significant difference in pain visual analogue scale scores (P<0.01), active flexion degree (P<0.01), physical function components of WOMAC (P<0.05), and EQ-5D scores (P<0.05) even after 15 weeks. CONCLUSIONS: Balneotherapy improved pain, function as well as the quality of life in patients with knee osteoarthritis. CLINICAL REHABILITATION IMPACT: Balneotherapy is a potentially useful treatment modality for patients with knee osteoarthritis.

The direct effect of specific training and walking on bone metabolic markers in young adults with peak bone mass.

As a prevention, a physically active lifestyle including the performance of weight-bearing exercises is important to enhance and maintain bone mineral content. Fifty young women were selected for the study. Twenty-five women carried out a specific training directed by a physiotherapist in the training group (TG), while 25 women were walking for 60 minutes in the control group (CG). Total and bone-specific alkaline phosphatase (ALP and BALP) and C-terminal cross-linked telopeptide (CTX) levels were measured at the beginning and at the end of exercise. The most remarkable change was seen in CTX levels (TG -28.89%, p < 0.001; CG -52.54%, p < 0.001), and there was also a significant difference in the values of CTX between TG and CG (p = 0.012). Therefore, walking more significantly reduced the level of CTX than special exercise. The decrease of BALP in TG was considerable but not significant (TG -4.63%, p = 0.091), while BALP levels dropped significantly in CG (-7.65%, p = 0.011), and there was a non-significant difference between the two groups (p = 0.22). Regarding the ALP level, a significant reduction was detected in TG and CG (-6.84%, p < 0.001 vs. -4.57%, p < 0.001). This study reveals that the 60-minute, middle-intensity training and the brisk walking have an immediate effect on bone metabolic markers.

Interactions of stress and reproduction - a personal view.

In the first part of this article, the authors discuss the effect of stress upon reproduction. The paper begins with a discussion of the various stressful factors that influence the functions of reproductive organs under various circumstances, including menarche, gestation and lactation. In general, physical and emotional stress has a negative impact upon reproductive function. Chronic stress may delay pubescence and, during the reproductive years, may impair oogenesis and spermatogenesis. This process may result in transitory infertility in women and permanent sterility in men. If associated with pregnancy, stress may be conducive to spontaneous abortion or premature birth. The second part of the article deals with stressful stimuli attributable to the reproductive process, the problem of infertility, techniques of assisted reproduction, and the management of unwanted gestations including induced abortion, fetal reduction, spontaneous miscarriage as well as in utero fetal death. The stress generating effects of singleton and multiple pregnancies and births are also outlined in some detail. In the third part of this article discuss effect of stress upon the fetus directly or through the maternal organism.

[Term pregnancy with fetus papyraceus]. / Kihordott terhesség iker foetus papyraceus mellett.

The authors describe a case of dichorionic-diamniotic twin gestation diagnosed in the first trimester. One of the twins perished during the 2nd trimester and became compressed against the uterine wall (stuck twin phenomenon). The surviving sibling weighing 3400 g was delivered by cesarean section at term in good condition along with the placenta. A much smaller, pale second placenta was extracted thereafter together with a hardly recognizable fetus papyraceus.

[Recent recurrence of a Biblical case of complicated twin birth]. / Bibliai szövódményes ikerszülés ismétlódése napjainkban.

The authors present a case which appears to resemble the child-birth of Thamar described in the Bible. The arm of one of the sons of Thamar prolapsed during the process of delivery. The same complication occurred in a patient of the authors, involving laid a head the arm of a male fetus. In both instances, the other twin child was born first, in the case of Thamar by the vaginal route, in that of the authors, by cesarean section. The description of this birthing event in the Bible permits the conclusion that complication observed in contemporary obstetric practice already occurred 7000 years ago.

[Single live-birth after twin conception]. / Ikerfogamzások után egy élö magzat születése.

The authors discuss the pregnancy outcome following the demise of one or more embryos or fetuses of the set of a multiple pregnancy. The consequences depend, to great extent, upon the time of the intrauterine demise. Sonographic examination identifies the empty chorionic sacs when death of embryos occurred during the first trimester. Circulatory disturbance at the time of early embryogenesis led to the formation of a fetus acardius amorphus. One fetus died during the second trimester and careful sonographic search revealed laterally displaced fetus papyraceous. An other growth retarded, dead, small fetus was found closely attachd to the uterine wall (stuck twin). All these complications caused spontaneous fetal reduction in multiple gestations.

Delayed cardiac protection against harmful consequences of stress can be induced in experimental atherosclerosis in rabbits.

Multiple brief periods of rapid ventricular pacing confer both short- and long-term protection on the ischaemic heart. The duration of the short-term protection does not exceed 2 h, whereas the long-term protective effect appears several hours after the inducing insults, with maximal protection 24-48 h later. Up to now, delayed cardiac protection by preceding ischaemic insults against harmful consequences of stress has been produced in the normal, healthy animal only. The purpose of this study was, therefore, to test whether delayed cardiac protection can be induced in experimental atherosclerosis in rabbits produced by feeding cholesterol-rich diet over 2 months. Repeated brief periods of rapid ventricular pacing were used to induce delayed protection of the heart. Moderation of post-pacing right intracavitary ST segment elevation and that of the left ventricular end-diastolic pressure (both produced by ventricular overpacing: 500 beats/min for 15 min) were found in normal animals as well as in those fed cholesterol-enriched diet. The short-lived protection induced by a single 'preconditioning' pacing was reproducible only in normal animals. As measured by means of radioimmunoassay, the protective effect of either short- or long-term protection appeared in parallel with an attenuation of ischaemia-induced increase in cardiac cyclic AMP content, in both normal and atherosclerotic rabbits. An increase in cardiac cyclic GMP content was characteristic of the short- but not long-term protection. These results suggest that the delayed cardiac protection by preceding multiple brief rapid pacings operates even in experimental atherosclerosis, but the short-term protection induced by a single preconditioning stimulus is lost.

Increased cardiac workload by adrenoceptor agonists for the estimation of potential antiischemic activity in a conscious rabbit model.

The antiischemic effect of drugs can be detected at a lower dose range if the cardiac workload is increased. A brief period of frequency-loading (ventricular overpacing = VOP) results in well-defined, reproducible changes in cardiac parameters in the conscious, chronically instrumented rabbit; however, rapid pacing frequently evoked ventricular tachycardia or even fatal ventricular fibrillation. Therefore, cardiac workload has been increased by i.v. administration of adrenoceptor agonists, such as isoproterenol (ISO), phenylephrine (PHE), and their combination, respectively. The doses applied (especially the combination of 2 micrograms/kg ISO and 16 micrograms/kg PHE, giving optimal changes) were sufficient to produce a marked elevation of both the ST segment in the intracavital electrogram and the left ventricular end-diastolic pressure, without evoking cardiac arrhythmias. We compared the effect of this adrenergic "test" stimulus with that of VOP on hemodynamic and electrophysiological parameters of the heart, and furthermore, on the modification of responses to both "test" stimuli by oral administration of the coronary vasodilator: Isosorbide-5-mononitrate (IS-5-N), given in a dose of 40 mg/kg. Both VOP- and ISO+PHE-induced changes were significantly attenuated by IS-5-N, and a temporal coincidence of the maximal effects was found as well. We reached the following conclusion: The combined administration of ISO and PHE not evoking fatal arrhythmias in the dose range applied can replace the more risky VOP as a "test" workload in the estimation of antiischemic action.

Prevention by 7-oxo-prostacyclin of the calcium paradox in rat heart: role of the sarcolemmal (Na,K)-ATPase.

It is demonstrated a fast and significant depression in the sarcolemmal (Na,K)-ATPase activity that occurs as early as 25 sec after the onset of Ca2+ depletion, and participates in the development of Ca(2+)-paradox in the rat heart. Pretreatment of the animals with 7-oxo-prostacyclin (PGI2) 24-48 h prior to the experiment prevented fairly the Ca(2+)-depletion-induced depression in (Na,K)ATPase activity and the accompanying structural and functional damage to the heart and sarcolemma during Ca(2+)-depletion as well as the development of Ca(2+)-paradox during the subsequent Ca(2+)-repletion. Pretreatment with PGI2 was chosen intentionally because previous experiments revealed, that in its late effect the drug is acting via stabilizing the membranes due induction of high activity of (Na,K)-ATPase that has increased affinity to ATP. From results obtained the following may be concluded: If during the phase of Ca(2+)-deprivation, the capability of heart sarcolemma to maintain sodium extrusion remains preserved, the expected aggravation of Ca(2+)-overload injury to Ca(2+)-paradox that would develop during Ca(2+)-repletion, may be definitely prevented. Sufficiently preserved (Na,K)-ATPase activity, hand in hand with stabilized sarcolemmal structure, may prevent an accumulation of sodium beneath the sarcolemma and consequently also an overexcessive entry of Ca2+ into the myocytes.

On the mechanism and possible therapeutic application of delayed cardiac adaptation to stress.

Several forms of cardiac adaptation to stress are known, differing in the evoking stress, in the time needed for adaptation and in the duration of the protective effect. A delayed adaptation produced a late appearing, prolonged protection against consequences of ischemia, such as early morphological changes, early and late postocclusion and reperfusion arrhythmias due to coronary artery occlusion or ouabain intoxication. Delayed adaptation was evoked by ischemic stress (repeated brief periods of rapid cardiac pacing or brief coronary occlusions) or by drugs (prostaglandin I2 and its stable derivatives). The protection produced by delayed adaptation proved to be time- and dose-dependent. Optimal effects appeared 24 to 48 h after treatment with an optimal dose of 50 microg/kg 7-oxo-prostacyclin or 10 microg/kg Iloprost. It is suggested that the mechanism of delayed cardioprotection is based on the fact that the stress-evoking adaptation stimulates the adenylate-cyclase/cyclic adenosine monophosphate (cAMP) system; the resulting elevation of cardiac cAMP level triggers the induction of some key enzymes such as Na/K-ATPase and phosphodiesterase (PDE) isoforms I and IV. Increased amount and activity of Na/K-ATPase accounts for preservation of normal membrane function and moderation of ischemic loss of potassium, and accumulation of sodium and calcium in the myocardium, as well as for reduced ouabain toxicity. The detrimental consequences of heavy stress-induced accumulation of cAMP in the heart are mitigated by hydrolysis of the latter, carried out by an enhanced amount and activity of PDE isoforms. Response to beta-adrenergic stimuli is also attenuated. In addition, electrophysiological changes such as prolongation of the effective refractory period and of the action potential duration may attenuate arrhythmias due to ischemia and reperfusion.

Long-term ischaemic preconditioning of the heart induced by repeated beta-adrenergic stress.

In the present study we tested the preconditioning effect of repeated beta adrenergic stress induced by Isoproterenol in chronically instrumented, conscious rabbits. We have found that at least 5 intravenous administrations of Isoproterenol, repeated at 10 min intervals, were necessary to induce a long-term cardiac adaptation manifested by a significant reduction of the harmful ischaemic changes due to cardiac stress 24 and 48 hours after preconditioning. These results suggest that a well-defined threshold level of the preconditioning stress is needed to trigger induction of metabolic changes leading to development of delayed and long-term cardiac adaptation.

Delayed protection of the heart against ischaemia.

Ischaemic preconditioning is the protective adaptive mechanism produced by short periods of ischaemic stress that results in a marked resistance of the myocardium to prolonged periods of the same stress; however, this protection is transient. There is now evidence that protection resulting from preconditioning returns several hours later, and here James Parratt and Laszlo Szekeres highlight the possible importance of this concept, which may lead to novel approaches to the long-term protection of the heart against ischaemic injury.

Left ventricular dysfunction induced by occlusion of coronary arteries in conscious dogs.

The aim of the present study was to investigate stable left ventricular dysfunction resulting from severe myocardial ischemia in conscious dogs, in order to evaluate the action of cardiotonic agents under pathological conditions mimicking moderate cardiac failure. Mongrel dogs with a catheter implanted in the left ventricle were trained on a treadmill and subjected to a standardized exercise before and after a Harris-type ligation of the anterior descending branch of the left coronary artery in two stages. Two weeks later the lower third of the left circumflex coronary branch was also occluded, and the exercise test repeated for at least two additional weeks to evaluate the changes in the left ventricular function indicated by left ventricular systolic pressure, end-diastolic pressure, heart rate, positive and negative dP/dtmax and dP/dt/P. Noninvasive radionuclide investigations of the left ventricular function and myocardial perfusion were done before and after the development of cardiac failure. Following occlusion of the anterior descending and circumflex coronary arteries, the baseline end-diastolic pressure increased from 7.6 +/- 2.3 mmHg to 23.3 +/- 3.0 mmHg (p < 0.05) and increased even further during exercise (to 49.2 +/- 3.5 mmHg, p < 0.05). After the development of cardiac failure, no substantial change occurred in the end-diastolic pressure, either during rest or repeated exercise tests.(ABSTRACT TRUNCATED AT 250 WORDS)

On the mechanism and possible therapeutic application of delayed adaptation of the heart to stress situations.

Mild (not harmful) stress may initiate an adaptive mechanism, protecting the heart from harmful consequences of a more severe stress. There are at least three known types of cardiac adaptation to stress, such as: a) the gradually developing, long lasting adaptation to chronic mechanical overload, leading to cardiac hypertrophy, later to cardiomyopathy and heart failure, b) the rapidly developing adaptation to moderate stress initiated by 'preconditioning' brief coronary occlusion(s) or brief periods of rapid cardiac pacing, protecting for less than 1 h against consequences of a subsequent, severe stress, c) the later appearing, more prolonged cardio-protective adaptation, described by us in 1983, induced by various forms of more severe but not injurious stimuli, such as an optimal dose of prostacyclin or its stable analogues; or a series of brief periods of rapid pacings. This form of cardiac adaptation to stress protects for 24-48 h against consequences of a more severe stress such as: 1. myocardial ischaemia; 2. early and late postocclusion and reperfusion arrhythmias; 3. early morphologic changes secondary to ischaemia and reperfusion; 4. ischaemia induced myocardial loss of K+ and accumulation of Na+ and Ca++; 5. it may increase the tolerance to the toxic effects of cardiac glycosides. A reduced response to beta-adrenergic stimuli and a concomitant increase in activity and amount of PDE I and IV was shown by us earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Long lasting anti-adrenergic effect of 7-oxo-prostacyclin in the heart: a cycloheximide sensitive increase of phosphodiesterase isoform I and IV activities.

Evidence is accumulating that 7-oxo-prostacyclin (7-oxo-PGI2) induces a delayed indirect anti-adrenergic and cytoprotective effect on the myocardium, the mechanism of which is still unclear. To demonstrate that a single application of 7-oxo-PGI2 (50 micrograms/kg i.m.) 48 h prior to starting experiments attenuates the isoprenaline inducible inotropic response and accumulation of cAMP, isolated hearts of pretreated animals were perfused in the Langendorff mode with and without isoprenaline (1 to 100 nM). The late anti-adrenergic effect of the drug was manifested by a significant attenuation in the elevation of cAMP levels as well as in contractile force development. This effect was not due to changes in cAMP generation as there were identical beta 1-adrenoceptor densities and affinities (as calculated from [3H]-CGP binding studies), Gi and G alpha s protein patterns (as taken from Western blots) as well as adenylyl cyclase activity measurements in the hearts studied. The anti-adrenergic potency of 7-oxo-PGI2, however, was found to be related to a significant rise in cyclic nucleotide hydrolysis by phosphodiesterase (PDE). Using the fast-performance liquid chromatographic separation for PDE isoforms, a significant increase in the activity of PDE isoforms I and IV (260 +/- 28 vs 110 +/- 12 pmol cGMP/min x enzyme fraction and 77 +/- 11 vs 34 +/- 3 pmol cAMP/min x enzyme fraction, respectively) was found in the solubilized fraction of cardiac membranes in comparison to untreated controls; PDE IV activity was also increased in the cytosolic fraction (106 +/- 14 vs 65 +/- 6 pmol cAMP/min x enzyme fraction). The hypothesis that the delayed anti-adrenergic effect of 7-oxo-PGI2 is initiated by an induction and accelerated synthesis of PDE I and IV in the heart is underlined by the fact that cycloheximide suppresses completely both the rise in PDE activities and the anti-adrenergic effects studied. It is suggested that an inducible predominance of cAMP degradation over its generation may be of relevance in processes related to heart protection.

Prevention by an inhibitor of the L-arginine-nitric oxide pathway of the antiarrhythmic effects of bradykinin in anaesthetized dogs.

The intracoronary administration of bradykinin (25 ng kg-1 min-1) markedly reduces the severity of arrhythmias that occur during a 25 min occlusion of the left anterior descending coronary artery in chloralose, urethane anaesthetized dogs. This protection was abolished by the prior administration, by the same route, of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the L-arginine-nitric oxide pathway. The protective effect of bradykinin on reperfusion-induced VF was not affected by L-NAME. These results strongly suggest that the antiarrhythmic effect of bradykinin in this model is mediated by nitric oxide release. It also supports the concept that bradykinin might be a 'primary mediator' of the protective, antiarrhythmic effects of ischemic preconditioning.

Suppression of reperfusion induced arrhythmias in the isolated rat heart: pretreatment with 7-oxo prostacyclin in vivo.

OBJECTIVE: The aim was to investigate the late effect of pretreatment with 7-oxo prostacyclin on reperfusion induced arrhythmias in the isolated rat heart. METHODS: Forty eight hours after intramuscular administration of drug in vivo (50 micrograms.kg-1 body weight), isolated Langendorff perfused rat hearts were subjected to 30 minutes of regional ischaemia and 5 minutes of reperfusion. Incidence and duration of ventricular arrhythmias in both pretreated and control groups were evaluated on reperfusion. Morphological examination was also performed. RESULTS: In the untreated group reperfusion induced 75% of sustained ventricular fibrillation. Incidence of ventricular fibrillation, its duration, and arrhythmia score were significantly lower in the pretreated group. Pretreatment with 7-oxo prostacyclin had no effect on heart rate and coronary flow throughout the whole course of perfusion. Neither was the occluded zone size affected. Ultrastructure of ischaemic and reperfused myocardium was better preserved in the pretreated group. CONCLUSIONS: Antiarrhythmic action of 7-oxo prostacyclin was unrelated to changes in haemodynamics, thus suggesting the direct influence of the myocardium. The possible mechanism of action may involve maintenance of intracellular cation homeostasis (particularly of Na+ and Ca2+) due to a stimulation of sarcolemmal Na+ pump activity.