Adipose thyrotrophin receptor expression is elevated in Graves' and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo.

The thyrotrophin receptor (TSHR) provides an autoantigenic link between the thyroid and orbit in Graves' (GD) and thyroid eye diseases (TED). We measured TSHR transcripts in different fat depots to determine whether TSHR expression levels are influenced by the autoimmune/inflammatory process and/or thyroid hormone status, using quantitative real-time PCR. Nine intact or fractionated adipose samples, from patients with GD and/or TED, were analysed ex vivo. Eight expressed the TSHR, at levels approaching the thyroid, and one was at the limit of detection. Thirteen/fifteen orbital and abdominal fat samples from patients free of GD and TED, measured ex vivo, were negative for TSHR transcripts and two were at the limit of detection. All preadipocyte samples induced to differentiate in vitro expressed the TSHR. To investigate the influence of thyroid hormone status on adipose TSHR expression, we induced hyper- and hypothyroidism in BALBc mice by administering tri-iodothyronine and propylthiouracil respectively. In euthyroid animals, whole fat samples were at the limit of detection and were not altered by thyroid hormone status. The results show that adipose TSHR expression ex vivo indicates adipogenesis in progress in vivo and is associated with the autoimmune/inflammatory process in GD and TED but is not restricted to the orbit or influenced by thyroid hormone status.

Detection of electrocardiographically imperceptible ventricular pre-excitation by phase imaging.

The sequence of ventricular contraction was studied by radionuclide phase imaging in 25 patients with Wolff-Parkinson-White syndrome. The studies were performed when no signs of precontraction were present in the electrocardiogram; in these cases pre-excitation was either intermittent or suppressable by injection of ajmaline. In 11 of the 16 patients with free wall accessory pathways, precontraction could be detected in spite of electrocardiographically absent pre-excitation. Discrete precontraction was seen also in 2 of the 9 patients with paraseptal accessory pathways. We conclude that antegrade conduction through the accessory pathway does not need to be completely blocked if signs of pre-excitation are absent on the electrocardiogram, and that phase imaging is, at least in some patients (especially those with free wall accessory pathways), a more sensitive technique for detection of pre-excitation (precontraction) than the electrocardiogram.

Controlled multicentre comparison of captopril versus lisinopril in the treatment of mild-to-moderate arterial hypertension.

The antihypertensive efficacy and safety of lisinopril (L), a novel ACE inhibitor, were compared to those of captopril (C), the familiar drug of the same class, in a multicentre controlled trial. The study included 91 mild-to-moderate, middle-aged hypertensives of both genders, 46 of which were randomized to C and 45 to L. After a two-week placebo period the examinees were receiving either L o.d. in increasing dosage of 10, 20, or 40 mg per day (amount necessary to achieve normotension), or C b.i.d. in a corresponding daily dose of 25, 50, or 100 mg. During the eight-week formal part of the trial, L decreased the systolic blood pressure from the initial values by an average of 14.9%, and the diastolic pressure by some 15.2%. The same parameters were lowered on C by 11.2%, and 11.7%, respectively. The mean arterial pressure from an initial average of 125.5 mmHg was lowered to 110.9 mmHg on C (11.6% reduction, p < 0.01), and from 125.3 mmHg to 108.2 mmHg on L (13.6% reduction, p < 0.01). Although the L effects were more pronounced, the observed between-group differences did not reach the level of statistical significance, except for the achievement of normotension, which disclosed the superiority of L (p < 0.05). The tolerability of both drugs was good and only one examinee had to be excluded because of side-effects (proteinuria). It is concluded that both ACEIs under study showed comparable efficacy and safety, L being marginally more potent and longer acting.

[Comparison of captopril and lisinopril in the treatment of mild and moderate hypertension]. / Usporedba kaptoprila i lizinoprila u lijecenju blage i umjerene arterijske hipertenzije.

The antihypertensive efficacy and safety of lisinopril (L), a novel ACE inhibitor, was compared to captopril (C), the known and already approved drug in our country in a multicenter double-blind Yugoslav trial. The study included 91 mild-to-moderate hypertensive patients of both sexes. Forty-six patients were randomized to receive captopril and 45 lisinopril. After a 2 week placebo, the examinees were administered either L in increasing dose of 10, 20, or 40 mg per day (amount necessary to achieve normotension), or C in a dosage of 25, 50, or 100 mg per day. During the 8 week formal trial L decreased the systolic blood pressure by an average of 14.9% from the initial values, and the diastolic pressure by some 15.2%. The same parameters were lowered on C by 11.2%, and 11.7%, respectively. Although the L effects were more pronounced, the observed differences did not reach the level of statistical significance (except for the dose-to-normotension relationship which was significantly better in the L group). It is concluded that both ACEIs under study showed comparable efficacy and tolerability, L being marginally more potent, and longer acting.

[Comparison of amlodipine and the nifedipine retard preparation in the treatment of arterial hypertension]. / Usporedba amlodipina i retard pripravaka nifedipina u lijecenju arterijske hipertenzije.

The efficacy and acceptability of amlodipine (5-10 mg o.d.) and sustained-release nifedipine (20-40 mg b.i.d.) were compared in a multicenter, double-blind clinical trial. After a two-week placebo period, 71 essential hypertensives of both sexes, aged 51.7 +/- 8.5 years, having diastolic blood pressure of 95-114 mmHg were randomly allocated to either amlodipine 5 mg once daily (group A) or nifedipine 20 mg twice daily (group B). With respect to the blood pressure response, the initial dose was doubled after two weeks. No significant differences in blood pressures recorded at baseline and at the end of the placebo period were demonstrated. A significant reduction in both systolic and diastolic blood pressures in the supine position was observed already two days after the start of treatment. In the group A it decreased from 163.2 +/- 21.4/102.7 +/- 8.5 to 155.7 +/- 20.7/98.2 +/- 8.9 mm Hg (p < 0.05) and in the group B from 160.5 +/- 16.2/100.5 +/- 12.2 to 152.2 +/- 17.0/95.4 +/- 9.5 mm Hg (p < 0.05). The similar changes of blood pressure were observed in the standing position, as well. At the end of the study, the overall reduction of the supine diastolic blood pressure was 12.5% in the group A versus 5.2% in the group B (p < 0.05). In the standing position, amlodipine decreased diastolic blood pressure by 8.8% and nifedipine by 6.4% (p < 0.05). Furthermore, amlodipine decreased the standing diastolic blood pressure to a greater extent (8.8% versus 6.4%; p < 0.05) than nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiographic evidence of coronary artery ectasia: our experience.

The purpose of this angiographic study was to make a review of patients with coronary artery ectasia (CAE) and to compare the average coronary artery diameters of proximal, middle and distal segments of the following three groups of coronary arteries: Group E (ectatic segments in patients with CAE and ischaemic heart disease), Group E-n (presumably normal segments in the same group of patients) and Group N (normal coronary arteries of control patients). It was found that distal segments of all three coronary arteries and the middle segment of the circumflex artery in Group E-n were significantly narrower than the corresponding segments in Group N (p = 0.001 or less than 0.05 respectively), which suggested the arteriosclerotic origin of both, CAE and distal coronary artery involvement.

The value of echocardiography in assessing the severity of mitral stenosis.

In a group of 24 patients having pure mitral stenosis, the relation between the echo parameters of the mitral valve and pressures in the pulmonary circulation was studied. On the basis of the authors' results, it was concluded that the sensitivity of one-dimensional echocardiography for the assessment of the severity of mitral stenosis can be further improved by measuring not only the widely accepted parameters, such as the diastolic closing velocity and the motion amplitude of the AML, but also by taking into account the echodiameter of the mitral orifice. Besides, careful observation of the motion pattern of the PML might be of use for distinguishing between a mild and moderate degree of mitral stenosis.

Regulation of immune response to SRBC: suppressor cell activity induced by soluble fraction of antigen.

Water soluble fraction (SF) of SRBC was obtained by hypotonic lysis and ultracentrifugation. SF was found to induce very weak SRBC-specific antibody response in mice. Pretreatment with SF accelerated direct PFC response to SRBC and accelerated and suppressed indirect PFC response. Spleen cells from mice treated with SF exhibited enhanced response to SRBC after transfer in irradiated recipients. The transfer of spleen cells from mice treated with SF to normal non-irradiated mice markedly suppressed the recipients' PFC responses to SRBC. The observed suppressive effect is interpreted as a consequence of suppressor cell activity.

Conduction disturbances in the Kearns-Sayre syndrome.

The Kearns-Sayre syndrome is an uncommon disease, characterized by the triad of external ophthalmoplegia, retinitis pigmentosa, and heart block. Cardiac manifestations of this syndrome in a 31-year-old man are presented. Electrocardiogram revealed intermittent left bundle branch block and right bundle branch block with left anterior hemiblock. His bundle recording disclosed a prolonged HV interval. Clinical features of the syndrome are discussed and other published cases reviewed.

Brown adipose tissue and immunity. Effect of neonatal adipectomy on humoral and cellular immune reactions in the rat.

This work concerns the involvement of brown adipose tissue in the immune system ofthe rat. Wistar rats were thymectomized, adipectomized (surgical extirpation of the interscapular brown adipose tissue), thymectomized and adipectomized, and sham-operatedat birth, only 8-week-old females being employed in the experiment. The production of antibody to bovine werum albumin (BSA) and sheep red blood cells (SRBC), delayed skin reactions to BSA, rejection of thyroid allograft implanted under the kidney capsule, and development of experimental allergic encephalomyelitis were investigated. Neonatal adipectomy did not affect the production of anti-BSA and anti-SRBC antibodies. On the other hand, delayed skin reactions to BSA, rejection of thyroid allograft, and incidence and severity of allergic encephalomyelitis were much more pronounced in adipectomized animals. It has been postulated that the immune function of brown adipose tissue is an expression of the secretory activity of the tissue. Since the immunosuppressive effect of neonatal thymectomy on demyelinating disease was neutralized by neonatal adipectomy, and vice versa, and since thymectomy rendered ineffective the immunopotentiating influence of adipectomy on this disease, as demonstrated in thymo-adipectomized rats, it was concluded that the brown adipose tissue is a naturalantagonist of the thymus in cell-mediated immunity. This paper also describes the extra thymuses which were situated in the vicinity of the thyroid and parathyroid lobes of23.2 per cent of rats.

The bioavailability of oral nifedipine formulations: a statistical and simulation approach.

The bioequivalence of three oral forms of nifedipine was assessed in a triple crossover study on 12 healthy volunteers. Single 10 mg dose was given and ten blood samples were drawn during the first 8 h after administration. Highly sensitive gas chromatographic method was used for the nifedipine assay. Pharmacokinetic parameters which describe bioavailability and general kinetic behaviour of the drug (AUC, Cmax, tmax, beta, MRT) were calculated from individual plasma profiles. They were subjected to statistical analysis (paired t-test, Hauck's inverted t-test, and Westlake's method of confidence intervals). Analogue-hybrid simulation and identification was used to generate plasma profiles of nifedipine after single and multiple dosing. Averaged plasma concentrations were used for this purpose. The three formulations studied were bioequivalent in terms of the rate of absorption. The simulation proved to be an efficient tool to substitute in vivo multiple dosing studies for assessment of bioavailability. The specific statistical methods should be preferred in bioequivalence data evaluation due to their greater power and inclusion of extraneous bioequivalence limits interval. Despite the differences among the formulations studied, each one of them should be viewed according to its intended clinical use.

Bioavailability of piroxicam: oral and rectal multiple application in humans.

The aim of the work is to evaluate the bioequivalence of piroxicam administered orally and rectally in 20 mg dose every 24 hours. The corresponding "in vivo" study was undertaken and plasma samples were collected during the ninth dosing interval. HPLC method was used for piroxicam plasma concentrations determination. AUC and C were calculated and the obtained data were statistically analyzed. Analog-hybrid simulation was used to confirm additionally the similarity between the discussed formulations. No significant differences were observed using paired t-test and two-way analysis of variance while the methods of Hauck and Westlake, looking strictly, gave nonbioequivalence. Simulated response of one compartment model is suitable for "in vivo" data in both cases. Measured and simulated average steady state concentrations are equal and in complete accordance with those given in literature. Finally it can be concluded that oral and rectal application are bioequivalent in the sense of expected clinical effects.

Pericardial mesothelioma.

The case of a 44-year old man, never exposed to asbestos, who died from a pericardial mesothelioma is described. The diagnosis was made by surgical examination. Two weak transient episodes of amelioration, the first accomplished with pronison administration and the other one by radiotherapy, were registered.

Release of RANTES, MIP-1 alpha, and MCP-1 into asthmatic airways following endobronchial allergen challenge.

We have investigated the presence of regulated on activation, normal T-cell expressed and probably secreted (RANTES), macrophage inflammatory peptide-1 alpha (MIP-1 alpha), and macrophage chemotactic peptide (MCP-1) in the bronchoalveolar lavage fluid (BALF) obtained from normal (n = 7) and stable asthmatic subjects (n = 8), and studied their kinetic release into asthmatic airways following endobronchial allergen challenge (n = 18). Measurements of RANTES, MIP-1 alpha, and MCP-1 in 10 times (10x) concentrated BALF showed that these three chemokines were present in both normal controls and stable asthmatic patients, but no significant difference between the two groups was found in the levels of the three chemokines. However, at 4 h after allergen challenge, BALF levels of RANTES, MIP-1 alpha, and MCP-1 were significantly increased in fluid obtained from the allergen-challenge site when compared with the saline-challenge control site (median: 175 pg/ml versus 11.5 pg/ml, 258 pg/ml versus 88 pg/ml, and 900 pg/ml versus 450 pg/ml, respectively). At 24 h, levels of the three chemokines returned to baseline values. To investigate whether cells in BALF obtained 4 h after allergen exposure release chemokines, they were cultured for 24 h. BALF cells from the allergen site released more RANTES and MCP-1 than those from the saline site, but released similar amounts of MIP-1 alpha. These findings suggest that RANTES, MIP-1 alpha, and MCP-1 may regulate cell trafficking in asthma in response to allergen exposure.

Localization of accessory pathways in Wolff-Parkinson-White syndrome by phase imaging.

Phase image analysis of blood pool scintigrams was performed in 6 patients with Wolff-Parkinson-White (WPW) syndrome to determine the relationship of phase changes and abnormalities of atrioventricular conduction. The site of preexcitation was located by invasive endocardial mapping. The phase advance generally correlated with the electrophysiologically determined location of the accessory pathway. Factors which increase or decrease the amount of preexcitation also increased or decreased the advance of mean phase angles. Phase imaging is a useful noninvasive means for tentative location of accessory pathways in WPW syndrome.

Immunogenetic analysis of the heavy chain variable regions of IgE from patients allergic to peanuts.

Peanuts are one of the most allergenic of the foods, and hypersensitivity responses to peanut allergens can be fatal. Although the nature of the antigenic components of peanuts is being defined at the molecular level, there is little information on the induced IgE antibodies, which are central to the allergic reaction. Recognition sites of IgE antibody molecules arise from the variable regions of heavy and light chains (VH and VL). By using nested polymerase chain reactions with specific primers for the available repertoire of VH genes, together with primers in the constant epsilon region, we have amplified VH sequences of IgE from blood lymphocytes of two patients with peanut allergy. After cloning and sequencing the products, we found a predominance of VH1 family use in both patients, which was not found in control IgM-specific primers. The IgE VH sequences were highly somatically mutated, but in only six of 17 cases was there clear evidence for clustering of amino acids indicative of antigen selection. Previous results from patients with allergy to house dust mites have indicated predominance of VH5 use and little evidence for antigen selection. Although results from two patients allergic to peanuts must be regarded as preliminary, they do suggest that the IgE response to peanuts may have a different VH bias, with a similar mutational pattern.