Fracture risk is increased in patients with GH deficiency or untreated prolactinomas--a case-control study

OBJECTIVE: The pituitary secretes many hormones of significance to bone turnover and thus skeletal integrity. The aim of this study was to examine fracture risk in patients with pituitary disorders with special reference to GH deficiency and hyperprolactinaemia. DESIGN: Case-control study. MEASUREMENTS: Fracture occurrence. PATIENTS: A self-administered questionnaire was issued to 537 consecutive patients with pituitary disorders excluding Cushing's disease. A total of 426 (79%) returned the questionnaire and 422 of these could be analysed. Each respondent was compared to three age- and gender-matched control respondents to the same questionnaire drawn randomly from the background population. RESULTS: The patients had a mean age of 51.4 +/- 14.8 years. One hundred and eight patients had acromegaly, 86 had prolactinomas, 136 had non-functioning pituitary adenomas (NFPA), 23 had craniopharyngiomas, and 73 had other types of pituitary disorders. For the total group the fracture risk was not elevated either before or after confirmed diagnosis compared to controls. However, among the patients with prolactinomas, the fracture risk was significantly increased before (relative risk, RR = 1.6, 95% CI: 1.1--2.3) but not after diagnosis. In patients with NFPA, fracture risk was borderline significantly elevated following diagnosis (RR = 1.6, 95% CI: 1.0--2.6). Patients with subnormal stimulated peak GH values suggestive of GH deficiency had a significantly higher risk of fractures after diagnosis than patients who had normal stimulated peak GH values (odds ratio, OR = 4.90, 95% CI: 1.10--21.88). CONCLUSIONS: Untreated prolactinomas were associated with a significant increase in fracture risk. Growth hormone deficiency was also associated with a higher fracture risk.     

Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: population-based study over five years

OBJECTIVE: Postmenopausal women are at increased risk of primary hyperparathyroidism (pHPT). Secondary dyslipidaemia in pHPT has attracted little attention, although morbidity and mortality associated with cardiovascular diseases have been reported to be increased in these patients. DESIGN: A population-based screening programme was used to recruit postmenopausal women with mild, asymptomatic pHPT (mean serum calcium 2.57 +/- 0.12 mmol/l) and matched controls. MEASUREMENTS AND PATIENTS: Serum lipids, lipoprotein fractions and influences of treatment for the parathyroid disease were studied in 87 case-control pairs (mean age 67 years), 69 of whom completed a 5-year follow-up period. RESULTS: pHPT was characterized by decreased serum high-density lipoprotein (HDL)-cholesterol, increased total triglycerides, very-low-density lipoprotein (VLDL)-triglycerides and VLDL-cholesterol levels and an elevated atherogenic index. The differences were more pronounced in the cases with serum parathyroid hormone levels in the normal range and were inversely correlated to the serum parathyroid hormone level. Parathyroidectomy, with or without additive hormone replacement therapy, normalized the dyslipidaemia. Five-year surveillance of pHPT without treatment was associated with a maintained increase in total triglycerides and the atherogenic index and a decrease in HDL-cholesterol levels. CONCLUSION: Proatherosclerotic dyslipidaemia characterizes mild pHPT and is effectively reversed by parathyroidectomy. As dyslipidaemia might contribute to the increased risk of cardiovascular diseases and death observed in pHPT, the findings favour operative intervention rather than conservative surveillance in mild, asymptomatic pHPT in postmenopausal females.     

Molecular Mechanisms of Inherited Ventricular Arrhythmias

Background: Inherited ventricular arrhythmias such as the long QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. The detailed pathogenetic mechanisms of inherited ventricular arrhythmias are still poorly understood because systematic investigations are difficult to perform due to low patient numbers and the lack of appropriate experimental models. However, recent advances in research and science have identified a genetic background for many of these diseases. Present Knowledge: In LQTS, various mutations in different genes encoding for cardiac potassium and sodium channel proteins have been identified ("channelopathy"), and initial progress in genotype-phenotype correlation is made. Mutations in the cardiac sodium channel gene have also been identified in a subset of patients with Brugada syndrome, whereas a genetic background has not yet been demonstrated in idiopathic VF and right ventricular outflow-tract tachycardia (RVO-VT). Very recently, mutations in the cardiac ryanodine receptor gene have been identified in CPVT and in a subgroup of patients with ARVC. Although several chromosomal loci were suggested, no other responsible genes or mutations have been found in autosomal dominant forms of ARVC. However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC. Future Perspectives: In the next years, significant progress in the genetic diagnosis pathophysiologic understanding of disease mechanisms, genotype-phenotype correlation, and the development of gene- or target-directed treatment strategies can be expected in the field of inherited ventricular arrhythmias. Conclusion: This review summarizes the current knowledge of the molecular mechanisms, including aspects of pathoanatomy, autonomic innervation, genetics, and genotype-phenotype correlations with their potential implications for diagnosis and treatment of inherited ventricular arrhythmias. Hintergrund: Angeborene ventrikuläre Arrhythmien wie QT-Syndrom (LQTS), Brugada-Syndrom, katecholamingerge polymorphe ventrikuläre Tachykardie (CPVT), idiopathisches Kammerflimmern sowie arrhythmogene rechtsventrikuläre Kardiomyopathie (ARVC) sind wesentliche Ursachen plötzlicher Herztodesfälle bei jungen Patienten. Die detaillierten pathogenetischen Mechanismen sind bislang nur in Anfängen aufgeklärt, da bei geringen Patientenzahlen und fehlenden Tiermodellen systematische Untersuchungen erschwert sind. Dennoch konnten jüngste Fortschritte in klinischer und experimenteller Forschung neue Erkenntnisse zum genetischen Hintergrund angeborener ventrikulärer Arrhythmien beitragen. Aktuelle Erkentnisse: Bei LQTS wurden in den letzten Jahren zahlreiche Mutationen in verschiedenen Genen nachgewiesen, die für Proteine kardialer Kalium- und Natriumkanäle kodieren ("Ionenkanalerkrankung"). Auch wurden erste Ergebnisse bei der Genotyp-Phänotyp-Korrelation erzielt. Mutationen im kardialen Natriumkanalgen wurden auch beim Brugada-Syndrom nachgewiesen, während bei Patienten mit idiopathischem Kammerflimmern und rechtsventrikulärer Ausflusstrakttachykardie bislang keine genetischen Veränderungen gefunden werden. Kürzlich konnten Mutationen im Gen des kardialen Ryanodinrezeptors bei Patienten mit CPVT und einer Untergruppe der ARVC nachgewiesen werden. Dagegen konnte bei anderen Formen autosomal-dominant vererbter ARVC trotz Lokalisation mehrerer chromosomaler Loci bislang kein Gendefekt identifiziert werden. Bei der rezessiv vererbten Naxos-Erkrankung, einer Sonderform der ARVC mit Koexpression von palmoplantarer Keratose, wurde unlängst eine Mutation im Plakoglobingen nachgewiesen, wodurch die potentielle Rolle genetischer Veränderungen in zytoskelettären Proteinen bei ARVC unterstrichen wird. Perspektiven: Auch in den kommenden Jahren sind entscheidende Fortschritte in der genetischen Diagnostik, dem Verständnis pathogenetischer Mechanismen, der Genotyp-Phänotyp-Korrelation und der Entwicklung von gentyporientierten Therapiestrategien bei angeborenen ventrikulären Arrythmien zu erwarten. Schlussfolgerung: Diese Übersicht fasst den aktuellen Wissensstand der molekularen Mechanismen zusammen und diskutiert dabei Aspekte von Pathoanatomie, autonomer Innervation, Genetik, und Genotyp-Phänotyp-Korrelation mit ihren potentiellen Implikationen für die Diagnostik und Therapie angeborener ventrikulärer Arrhythmien.     

Specific aspects of contemporary triathlon: implications for physiological analysis and performance

Triathlon competitions are performed over markedly different distances and under a variety of technical constraints. In 'standard-distance' triathlons involving 1.5km swim, 40km cycling and 10km running, a World Cup series as well as a World Championship race is available for 'elite' competitors. In contrast, 'age-group' triathletes may compete in 5-year age categories at a World Championship level, but not against the elite competitors. The difference between elite and age-group races is that during the cycle stage elite competitors may 'draft' or cycle in a sheltered position; age-group athletes complete the cycle stage as an individual time trial. Within triathlons there are a number of specific aspects that make the physiological demands different from the individual sports of swimming, cycling and running. The physiological demands of the cycle stage in elite races may also differ compared with the age-group format. This in turn may influence performance during the cycle leg and subsequent running stage. Wetsuit use and drafting during swimming (in both elite and age-group races) result in improved buoyancy and a reduction in frontal resistance, respectively. Both of these factors will result in improved performance and efficiency relative to normal pool-based swimming efforts. Overall cycling performance after swimming in a triathlon is not typically affected. However, it is possible that during the initial stages of the cycle leg the ability of an athlete to generate the high power outputs necessary for tactical position changes may be impeded. Drafting during cycling results in a reduction in frontal resistance and reduced energy cost at a given submaximal intensity. The reduced energy expenditure during the cycle stage results in an improvement in running, so an athlete may exercise at a higher percentage of maximal oxygen uptake. In elite triathlon races, the cycle courses offer specific physiological demands that may result in different fatigue responses when compared with standard time-trial courses. Furthermore, it is possible that different physical and physiological characteristics may make some athletes more suited to races where the cycle course is either flat or has undulating sections. An athlete's ability to perform running activity after cycling, during a triathlon, may be influenced by the pedalling frequency and also the physiological demands of the cycle stage. The technical features of elite and age-group triathlons together with the physiological demands of longer distance events should be considered in experimental design, training practice and also performance diagnosis of triathletes.     

MRI-guided thermal therapy of transplanted tumors in the canine prostate using a directional transurethral ultrasound applicator

PURPOSE: To evaluate MRI-based techniques for visual guidance, thermal monitoring, and assessment during transurethral ultrasound thermal therapy of implanted tumors in an in vivo canine prostate model. MATERIALS AND METHODS: Transmissible venereal tumors (TVT) were grown in the right lobe of the prostate in four dogs. High-temperature thermal therapy was selectively applied to the tumor-bearing lobe using a transurethral ultrasound applicator with a 180 degrees directional heating pattern. Temperature-sensitive MRI (MRTI) using a fast interleaved gradient-echo echo-planar (iGE-EPI) imaging sequence was used for cumulative thermal dose calculations in multiple image planes during the treatment. The results from MRTI-based dose maps and post-treatment MRI were compared to those from histologic analysis. RESULTS: MRTI monitoring in multiple planes across the prostate guided the use and control of a directive ultrasound applicator for the selective ablation of the sections of the prostate that contained implanted tumors. Findings in gadolinium enhanced MRI obtained immediately after thermal therapy slightly underestimated the size of tissue necrosis after treatment, as verified by histopathologic analysis. CONCLUSION: The use of multiplanar MRTI with a transurethral ultrasound applicator shows significant potential for selective thermal ablation of prostate tumor and tissue.     

Quantification of [<Superscript>123</Superscript>I]PE2I binding to dopamine transporters with SPET

The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with single-photon emission tomography (SPET). The aim of the present study was to describe a method for accurate quantification of binding data following a bolus injection of [(123)I]PE2I. Six healthy subjects (age 51+/-24 years) underwent xenon-133 SPET for quantification of regional CBF and [(123)I]PE2I SPET for quantification of DAT binding. rCBFs were within normal limits in all subjects. Fitting data to a two-tissue compartment model resulted in striatal K(1) values of 0.39+/-0.08 ml ml(-1) min(-1), equal to a first-pass extraction fraction of 0.72+/-0.13. Distribution volumes (DVs) were calculated using compartment analysis, area under the curve analysis and Logan analysis. Logan analysis is preferred since stable DV values were already obtained 120 min after [(123)I]PE2I injection. Mean striatal DV was 37.9+/-9.6 ml ml(-1) and mean occipital cortex DV was 5.5+/-0.7 ml ml(-1). In the absence of local pathology in a reference tissue, Logan analysis without blood sampling is an attractive method for accurate quantification of striatal [(123)I]PE2I binding. The distribution volume ratio (DVR) (6.6+/-1.4) was in good agreement with the DVR calculated with blood (6.7+/-1.4).     

A novel quantitative dual-isotope method for simultaneous ventilation and perfusion lung SPET

A quantitative dual-isotope single-photon emission tomography (SPET) technique for the assessment of lung ventilation (V) and perfusion (Q) using, respectively, technetium-99m labelled Technegas (140 keV) and indium-113m labelled macro-aggregated albumin (392 keV), is presented, validated and clinically tested in a healthy volunteer. In order to assess V, Q and V/Q distributions in quantitative terms, algorithms which correct for down scattering, photon scattering and attenuation, as well as an organ outline algorithm, were implemented. Scatter and down-scatter correction were made in the spatial domain by pixel-wise image subtraction of projection-dependent global scattering factors obtained from the energy domain. The attenuation correction was based on an iterative projection/back-projection method. All studies were made on a three-headed SPET system (Trionix) with medium-energy parallel-hole collimators. The set of input data for quantification was based on SPET acquisition of emission data in four separate energy windows, the associated cumulative energy spectra and transmission data. The attenuation correction routine as well as the edge detection algorithm utilized data from (99m)Tc transmission tomography. Attenuation data for (113m)In were obtained by linear scaling of the (99m)Tc attenuation maps. The correction algorithms were experimentally validated with a stack phantom system and applied on a healthy volunteer. The mean difference between the corrected SPET data of the dense stack lung phantom and those obtained from the corresponding scatter- and attenuation-"free" version was only 1.9% for (99m)Tc and 0.9% for (113m)In. The estimated fractional V/Q distribution in the 3-D lung phantom volume had its peak at V/Q=1, with a width (FWHM) of 0.31 due to noise, particularly in the (113m)In images, and to partial volume effects. For a healthy volunteer, the corresponding values were 0.9 and 0.35, respectively. This method allows accurate assessment of radionuclide distribution on a regional basis. For basic lung physiology and clinical practice, the method allows assessment of the global frequency functions of the V, Q and V/Q distributions.     

Clinical impact of diagnostic SPET investigations with a dopamine re-uptake ligand

The diagnosis of Parkinson's disease is based on clinical features with pathological verification. However, autopsy has been found to confirm a specialist diagnosis in only about 75% of cases. Especially early in the course of the disease, the clinical diagnosis can be difficult. Imaging of presynaptic dopamine transporters (DAT receptors) has provided a possible diagnostic probe in the evaluation of Parkinson's disease. The cocaine analogue [(123)I]-2-beta-carboxymethoxy-3-beta(4-iodophenyl)tropane ([(123)I]-beta-CIT) is one of several radioligands that have been developed for single-photon emission tomography (SPET). The purpose of this study was to evaluate the impact of [(123)I]-beta-CIT SPET on the diagnosis and clinical management of patients with a primary, tentative diagnosis of parkinsonism. We undertook a retrospective evaluation of the clinical records of 90 consecutive patients referred to [(123)I]-beta-CIT SPET from the neurological department, Bispebjerg Hospital. In 58 subjects the scans revealed altered tracer uptake consistent with Parkinson's disease, progressive supranuclear palsy and multiple system atrophy. A significant change in the management or treatment because of the scan was found in 25 patients (28%). The sensitivity of the examination was 97% and the specificity 83%. In conclusion, a significant clinical impact of DAT receptor SPET imaging was found. DAT receptor imaging is a useful diagnostic probe in patients with a possible diagnosis of parkinsonism.     

Early failures among 7,174 primary total knee replacements: a follow-up study from the Norwegian Arthroplasty Register 1994-2000

We studied primary total knee replacements (TKRs), reported to the Norwegian Arthroplasty Register, operated on between 1994 and 2000. A Cox multiple regression model was used to evaluate differences in survival among the prosthesis brands, their types of fixation, and whether or not the patella was resurfaced. In Norway in 1999, the incidence of knee prosthesis operations was 35 per 100,000 inhabitants. Cement was used as fixation in 87% of the knees, 10% were hybrid and 2% uncemented implants. Bicompartmental (not resurfaced patella) prostheses were used in 65% of the knees. With all revisions as endpoint, no statistically significant differences in the 5-year survival were found among the cemented tricompartmental prostheses brands: AGC 97% (n 279), Duracon 99% (n 101), Genesis I 95% (n 654), Kinemax 98% (n 213) and Tricon 96% (n 454). The bicompartmental LCS prostheses had a 5-year survival of 97% (n 476). The type of meniscal bearing in LCS knees had no effect on survival. Survival with revision for all causes as endpoint showed no differences among types of fixation, or bi- or tricompartmental prostheses. Pain alone was the commonest reason for revision of cemented bicompartmental prostheses. The risk of revision because of pain was 5.7 times higher (p < 0.001) in cemented bicompartmental prostheses than cemented tricompartmental ones, but the revisions mainly involved insertion of a patellar component. In tricompartmental prostheses the risk of revision because of infection was 2.5 times higher than in bicompartmental ones (p = 0.03). Young age (< 60) and the sequelae after a fracture increased the risk of revision. The 5-year survival of the 6 most used cemented tricompartmental knee prostheses brands varied between 95% and 99%, but the differences were not statistically significant. There were more revisions because of pain in bicompartmental than in tricompartmental knees. In tricompartmental knees, however, there were more revisions because of an infection. The relatively few patients with uncemented and hybrid implants showed no improvements in results compared to cemented knee prostheses.