Induction of arthritis in HLA-DR4-humanized and HLA-DQ8-humanized mice by human cartilage proteoglycan aggrecan but only in the presence of an appropriate (non-MHC) genetic background

OBJECTIVE: To determine whether the rheumatoid arthritis (RA)-predisposing class II molecules of the major histocompatibility complex (MHC) can present cartilage proteoglycan (PG) aggrecan, and if so, to determine the epitope repertoire of the human cartilage PG in HLA-transgenic mice and determine whether HLA-transgenic mice develop arthritis in response to immunization with human cartilage PG. METHODS: Mice transgenic for HLA-DR2.Ab(0), DR3.Ab(0), DR4.Ab(0), and DQ8.Ab(0), lacking their own (mouse) class II antigens (Ab(0)), on the original (arthritis-resistant) and the arthritis-susceptible BALB/c backgrounds, were immunized with human cartilage PG. The T cell epitope repertoire presented by these class II MHC alleles was determined using a synthetic peptide library (143 peptides of the core protein of human cartilage PG), and arthritis development was monitored and compared in wild-type and HLA-transgenic/congenic BALB/c mice. RESULTS: Mice of the 4 HLA-transgenic lines, either on the original mixed, arthritis-resistant background or DR4.Ab(0)- and DQ8.Ab(0)-transgenic/congenic mice on the arthritis-susceptible BALB/c genetic background, responded well to PG immunization (as assessed by T cell responses and antibody and cytokine production), and a number of T cell epitopes along the core protein of human cartilage PG were identified. DR4.Ab(0)- and DQ8.Ab(0)-transgenic mice immunized with human cartilage PG developed arthritis, but only when these class II MHC molecules were present on the arthritis-susceptible (BALB/c) genetic background. CONCLUSION: A number of human cartilage PG epitopes can be presented by HLA alleles that predispose to the development of RA, but the epitopes of the cartilage PG presented by HLA-DR4 or HLA-DQ8 can induce arthritis only in the presence of an appropriate genetic (non-MHC) background.     

Acute oliguric renal failure in HELLP syndrome: case report and review of literature

We describe a 32-year-old female with past medical history of preeclampsia, who presented at 29th week of gestation of her second pregnancy with abdominal pain, emesis, and diarrhea. Initial evaluation revealed hypertension, placental abruption, and intrauterine fetal death. After spontaneous rupture of membranes, a stillborn fetus was delivered. The clinical course was complicated by seizures and acute kidney injury requiring hemodialysis. She also exhibited microangiopathic hemolytic anemia, thrombocytopenia, and elevated liver enzymes (consistent with HELLP syndrome). A biopsy showed acute renal cortical necrosis.     

Exercise is a potent stimulus for enhancing circulating DNase activity

Objectives

To elucidate cell free DNA (cfDNA) clearance kinetics following an acute bout of high intensity exercise by measuring circulating DNase activity reduction (AR).

Design and methods

Serum cfDNA concentration and DNase-AR were measured prior to and post (immediately post, 7 and 30 min post) an acute bout of rowing exercise until exhaustion.

Results

Serum cfDNA concentration was significantly (P ≤ .001) elevated immediately post (2.5-fold) and 7 min post exercise (2.3-fold) with a return close to baseline at 30 min post exercise (1.5-fold). The rise in cfDNA was accompanied by a concomitant, significant (P ≤ .001) decrease in serum DNase-AR from 15.1% prior to exercise to 3.1% AR at cessation of the exercise test and 7 min post exercise (3.9% AR). DNase-AR returned close to baseline at 30 min post exercise (5.2% AR).

Conclusions

A single bout of high intensity exercise is a potent stimulus for enhancing circulating DNase activity in healthy people. Acute exercise may therefore be considered as a non-pharmacological stimulus to trigger DNase activity.This finding may be relevant for pathological conditions associated with increased cfDNA concentrations like cystic fibrosis, where pharmacological recombinant human DNase (rhDNase) treatment has been successfully used to improve patients' health and physical function.     

Surgical treatment of superior mesenteric artery dissecting aneurysm and simultaneous celiac artery compression

Spontaneous dissections of visceral arteries are rare, but when they do occur, they most commonly involve the superior mesenteric artery (SMA). We present a case of intestinal ischemia caused by a spontaneous dissection of the SMA in a patient with simultaneous celiac artery occlusion. The patient was a 45-year-old woman who presented with intestinal angina of sudden onset. Arteriography revealed the classic findings of SMA dissection and occlusion of the celiac artery. The patient underwent repair of both visceral vessels and made a full recovery. The 18 previously reported cases of isolated, spontaneous dissection of the SMA are reviewed. No previous case has been associated with celiac compression syndrome. The reported experience with symptomatic dissections of the SMA would suggest that prompt surgical repair is indicated and yields excellent results.     

Determination of the125J-insulin-plasma complex by gel filtration

Summary The capacity of plasma proteins to bind insulin labelled with¹²⁵J has been studied by means of the gel-filtration method. Fractionation with Sephadex G-100 showed that only 10 % of the labelled insulin was bound by the plasma proteins of healthy subjects, pregnant females and untreated diabetes mellitus patients. A much higher percentage of insulin was bound by plasma proteins in patients who had previously been treated with beef insulin, while the degree of binding became extreme in insulin-resistant diabetics. Experiments made with Sephadex G-200 showed that, following short-term insulin therapy, the insulin-protein complex migrated with the globulins 19 S. After prolonged insulin therapy and in insulin-resistant cases most of the protein-bound labelled insulin was eluted with the globulins 7 S. The phenomenon, discussed in detail, is attributed to the action of beef insulin antibodies.

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Zusammenfassung Mittels der Gel-Filtration wurde die Fähigkeit der Plasmaproteine untersucht, das¹²⁵J markierte Insulin zu binden. Die Fraktionierung mittelsSephadex G-100 zeigte, dass nur 10 % des markierten Insulins durch die Plasmaproteine von gesunden Personen, Schwangeren und unbehandelten Diabetikern gebunden wurden. Ein weit grösserer Prozentsatz von Insulin wurde durch die Plasmaproteine von vorher mit Rinderinsulin behandelten Patienten gebunden, während das Bindungsausmass bei den insulin-resistenten Diabetikern stark zunahm. Untersuchungen mitSephadex G-200 zeigten, dass der Insulin-Protein-Komplex nach einer kurzen Insulin-Therapie mit den 19 S-Globulinen wanderte. Nach länger dauernder Insulin-Therapie und bei den Fällen mit Insulin-Resistenz wurde der Grossteil des an die Proteine gebundenen markierten Insulins mit den 7 S-Globulinen eluiert. Das in seinen Einzelheiten diskutierte Phänomen wird der Wirkung der Anti-Rinderinsulin-Antikörper zugeschrieben.

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Resumen La capacidad que poseen las proteínas para ligar la insulina marcada con¹²⁵J se estudió mediante el método de filtración engel. El fraccionamiento medianteSephadex G-100 demostró que solamente el 10 % de la insulina marcada estaba ligada por las proteínas plasmáticas de sujetos sanos, de mujeres embarazadas y de pacientes diabéticos no tratados. Un porcentaje de insulina notablemente superior estaba ligado por las proteínas plasmáticas en pacientes que anteriormente habían sido tratados con insulina bovina, mientras el grado de enlace se volvía muy elevado en los diabéticos resistentes a la insulina. Experimentos realizados conSephadex G-200 demostraron que después de un breve tratamiento insulínico, el complejo insulina-proteína migraba con las globulinas 19 S. Después de un prolongado tratamiento insulínico y en los casos resistentes a la insulina, la mayor parte de la insulina marcada con las proteínas resultaba eluida con las globulinas 7 S. El fenómeno, discutido detalladamente, se atribuye a la acción de los anticuerpos anti-insulina bovina.

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Resume Les AA. ont étudié la capacité des protéines plasmatiques de lier l'insuline¹²⁵J avec la méthode de filtration surgel. Le fractionnement parSephadex G-100 a démontré que seulement le 10 % de l'insuline marquée était lié par le protéines plasmatiques des sujets sains, des femmes gravides et des diabétiques non traités. Un pourcentage d'insuline beaucoup plus élevé était liée par les protéines plasmatiques dans des sujets que étaient traités precédemment avec de l'insuline bovine, tandis que le degrée de la liason était tres élevé dans les diabétiques insulino-résistants. De recherches avecSephadex G-200 ont demontré que, après une courte période d'insulinothérapie, le complexe insuline-protéine migrait avec les globulines 19 S. Après une insulinothérapie prolongée et dans les cas insulino-résistants la plus grande partie de l'insuline marquée liée aux protéines était élui avec les globulines 7 S. Le phénomène est attribué à l'action des anticorps anti-insuline bovine.

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Riassunto La capacità delle proteine plasmatiche di legare l'insulina marcata con¹²⁵J è stata studiata mediante il metodo di filtrazione sugel. Il frazionamento medianteSephadex G-100 ha dimostrato che soltanto il 10% dell'insulina marcata era legato dalle proteine plasmatiche di soggetti sani, di donne gravide e di pazienti diabetici non trattati. Una percentuale di insulina notevolmente superiore era legata dalle proteine plasmatiche in pazienti che erano stati precedentemente trattati con insulina bovina, mentre il grado di legame diveniva molto elevato nei diabetici insulino-resistenti. Esperimenti eseguiti conSephadex G-200 hanno dimostrato che, dopo una breve terapia insulinica, il complesso insulina-proteina migrava con le globuline 19 S. Dopo prolungata terapia insulinica e nei casi insulino-resistenti la maggior parte dell'insulina marcata legata alle proteine era eluita con le globuline 7 S. Il fenomeno, discusso nei particolari, è attribuito all'azione degli anticorpi anti-insulina bovina.

     

Regional variations in community consumption of antibiotics in Hungary, 1996-2003

AIMS: To study regional differences and identify determinants of antibiotic consumption in ambulatory care in Hungary. METHODS: Regional distribution-based antibiotic sales data were converted into a number of defined daily doses (DDD) per 1000 inhabitant-days. Correlations were assessed with the Spearman rank test. RESULTS: There were large and stable interregional differences in antibiotic consumption. They were associated with socio-economic determinants, e.g. the population receiving free access to medicines and receiving regular social assistance. CONCLUSIONS: More detailed studies are needed to better understand the determinants of antibiotic use in these specific patient populations and to identify additional determinants at regional level.     

Diagnosis and treatment outcome in primary aldosteronism based on a retrospective analysis of 187 cases

INTRODUCTION: Primary aldosteronism is the most common form of mineralocorticoid hypertension. The disease has been described by Jerome W. Conn in 1955; since that time there has been a great progress in the knowledge concerning the prevalence, diagnostics and treatment of the disease. AIMS: The authors retrospectively analyzed the efficacy of diagnostic procedures and the outcome of treatment by the analysis of data of 187 patients with primary aldosteronism examined between 1958 and 2004 at the 2nd Department of Medicine of Semmelweis University. METHODS: The efficacy of different methods used for the diagnosis, the frequency of the different subtypes of primary aldosteronism, as well as the surgical outcomes in patients with surgically treated subtypes of primary aldosteronism were studied. RESULTS: Aldosterone-producing adenoma was detected in more than two thirds of patients (n = 135), whereas idiopathic hyperaldosteronism was found in 46 patients. Other subtypes of primary hyperaldosteronism occurred less frequently (unilateral primary adrenocortical hyperplasia in 5 patients and adrenocortical carcinoma in one patient). For the diagnosis of familial hyperaldosteronism type I, molecular biological studies of the aldosterone-synthase/11beta-hydroxylase gene chimera were carried out in 30 patients but none of them showed the presence of the chimeric gene. When comparing the clinical parameters of patients with aldosterone-producing adenoma and idiopathic hyperaldosteronism, no significant differences were found in the time period between the diagnosis of hypertension and the diagnosis of primary aldosteronism, or in the systolic and diastolic blood pressure values. The mean of the lowest documented serum potassium concentration was slightly lower in patients with aldosterone-producing adenoma (2.8 +/- 0.1 mmol/l) compared to those with idiopathic hyperaldosteronism (3.1 +/- 0.2 mmol/l), but the difference was not significant. Normokalemic primary hyperaldosteronism was found in 7 cases. The ratio of plasma aldosterone concentration (ng/dl) to plasma renin activity (ng/ml/h) was above 20 in all patients with aldosterone-producing adenoma and in all but 5 cases with idiopathic hyperaldosteronism. To confirm the diagnosis and to differentiate the subtypes of primary aldosteronism, the postural test combined with furosemide administration was performed in the majority of patients. When cases showing an elevation of plasma cortisol level during the test were excluded, this test differentiated patients with aldosterone-producing adenoma from those with idiopathic hyperaldosteronism with a sensitivity of 69% and a specificity of 92%. In cases of adrenocortical adenomas not or not clearly detectable by radiological imaging techniques, as well as in cases with bilateral adrenocortical adenomas, selective adrenal vein sampling was performed (n = 55). All but 4 patients with aldosterone-producing adenoma underwent adrenalectomy. Histology and postoperative hormone results confirmed the preoperative diagnosis in all operated patients. After surgery serum potassium concentration returned to normal in all patients showing low serum potassium levels before surgery. Also, the moderate to severe preoperative hypertension disappeared or improved after surgery. CONCLUSIONS: These observations are in contrast with the results of international studies which showed a high frequency of normokalemic primary aldosteronism and a more frequent occurrence of idiopathic hyperaldosteronism well treatable with aldosterone-antagonists. Therefore, it can be presumed that a significant number of primary aldosteronism cases that are not accompanied with severe hypokalemia remain undetected in Hungary.     

The role of biologic agents in the therapy of ankylosing spondylitis

Ankylosing spondylitis is a chronic, inflammatory rheumatic disease which etiology and pathogenesis are not yet fully understood. The inflammation involves the spine and also the peripheral joints might be affected in some cases resulting in a progressive ankylosis, restricted mobility, significant disability, loss of productivity and decreased quality of life. Gene technology based new drugs of the past decade, the biologic agents, offer an alternative opportunity for the treatment of ankylosing spondylitis in comparison with the previous drugs with doubtful efficiency. In Hungary infliximab and etanercept has been registered for ankylosing spondylitis. The aim of this study was to evaluate the efficacy of infliximab and etanercept by the available randomised controlled trials. A systematic search of the literature was performed from 01. 01. 2000 to 08. 31. 2005. and the relevant publications were analysed following the concepts of evidence based medicine. 7 double blind, randomised, placebo controlled trials were identified, three for infliximab (n = 389) and four for etanercept (n = 431). Although the inclusion criteria, the duration of the trials and the primary endpoints were different, the results confirm that both drugs significantly decrease symptoms and disease activity, and this effect is sustained during the therapy, nevertheless half of the patients did not achieve the standardised criteria of 50% decrease in disease activity. Both agents are well tolerated by patients. The outcomes of long-term therapy are reassuring by open extension studies of three years. Guidelines for biologic therapy has been developed in Hungary determining the target patient group, the conditions of the therapy and also an arthritis centre network has been established. Though individual admission is feasible, biologic drugs are not under reimbursement in Hungary. High drug costs makes the implementation of this new therapeutic opportunity difficult in the daily medical practice.