Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation.

AIM: The spectrum of histological alterations, namely atrial amyloidosis, in the right and left atria of patients with chronic persistent atrial fibrillation (AF) and rheumatic heart disease is not completely known. METHODS AND RESULTS: One hundred and twenty-eight atrial appendages (66 left and 62 right), obtained from 72 patients with rheumatic valve disease and chronic AF undergoing cardiac surgery for valve replacement or repair and AF treatment were histologically evaluated for the presence of amyloid deposits. One hundred and four specimens of left and right auricles from 52 patients in sinus rhythm with severe chronic heart failure undergoing heart transplant were also analyzed (controls). Amyloid was found in 33 (46%) valvular patients with chronic persistent AF and in 6 (12%) controls. Amyloid was related to the presence and duration of AF, was more frequently found in left atrial samples and was independent of age. On stepwise logistic regression analysis, AF duration and female gender were independently related to amyloid deposition. CONCLUSIONS: Patients with long-standing AF and rheumatic heart disease have a very high prevalence of atrial amyloidosis. Amyloid deposition is more frequent in left than in right atrial appendage and correlates with AF duration and female gender. Amyloid deposition could constitute an additional histological feature in the structural remodeling of atria during long-standing AF, at least in rheumatic valve disease. Persistence of AF might play a pivotal role in promoting amyloid deposition.     

Retrospective analysis of the association of nodular goiter with primary and secondary hyperparathyroidism

BACKGROUND: The association of hyperparathyroidism (HPT) with thyroid disease has long been known, but the mechanisms underlying such an association have not yet been clarified. OBJECTIVE: To elucidate the main factors determining this combination of endocrine diseases, in a retrospective multicenter study. METHODS: We retrospectively reviewed all patients referred for parathyroid scintigraphy in the period 1990-1999. A total of 487 patients in the age range 17-65 years were selected for the analysis (339 women and 148 men); group A included 241 patients with primary and group B 246 patients with secondary HPT. RESULTS: A total of 124/241 patients in group A (51.5%), but only 92/246 patients in group B (38.2%) had thyroid disorders (notably nodular goiter) associated with HPT (P=0.0035). Thyroid disorders were evenly distributed throughout the entire 17-65 years age range in group A, but 17-40-year-old patients in group B had significantly fewer thyroid disorders than the older patients of the same group (15.5% compared with 43.3%, P<0.002), as expected in a general population. In patients with primary HPT there was no difference in the prevalence of thyroid disease between women and men, whereas the ratio of women to men in secondary HPT patients with thyroid disease was about 3:1. CONCLUSIONS: These results demonstrate an increased prevalence of nodular goiter in patients with primary rather than secondary HPT, and are consistent with a possible role of increased endogenous calcium concentrations (a hallmark of primary, but not of secondary, HPT) as a goitrogenic factor in patients with HPT.     

Percutaneous balloon catheter closure of a patent foramen ovale in a patient with pulmonary disease,profound hypoxemia,and normal right heart pressures

Right-to-left intracardiac shunting across a patent foramen ovale (PFO) has been reported in patients with pulmonary embolism, right ventricular (RV) infarction, positive pressure ventilation with positive end-expiratory pressure, heart failure with left ventricular assist devices, cardiac tamponade, and unilateral diaphragmatic paralysis. The primary driving force for these shunts is a reduction in the compliance of the pulmonary bed or right ventricle; right atrial pressure is usually elevated and pulmonary hypertension is frequently present. Significant shunting and hypoxemia are unusual in the absence of these diseases. We encountered a patient with normal pulmonary pressures, severe hypoxemia, pulmonary disease, and intracardiac shunting across a PFO in whom it was difficult to determine how great a role intracardiac shunting was playing in his hypoxemia. To assess this, we performed percutaneous balloon catheter occlusion of the PFO, using transthoracic echocardiography with contrast to confirm closure of the PFO. Therapeutic balloon occlusion has been reported in severe hypoxemia due to shunting across a PFO in a patient with RV infarction. Our case is unique, however, in two respects. First, this patient had normal right-sided cardiac pressures and normal RV function and, thus, no obvious driving force for a significant right-to-left shunt. Second, transthoracic echocardiography with contrast was used before and after balloon inflation to confirm closure of the PFO. This technique helped to answer the important clinical question of whether surgical closure of the PFO in this patient with both lung disease and intracardiac shunting would significantly improve his oxygenation.     

Immunohistochemical characterization of a 183 KD myeloid-specific-DNA- binding protein in B5 fixed, paraffin-embedded tissues, and bone marrow aspirates by monoclonal antibody BM-1

A monoclonal antibody, designated BM-1, which is reactive in B5 formalin-fixed, paraffin-embedded tissues, has been generated against a cytoplasmic and nuclear antigen expressed in human myeloid precursor cells and derived leukemias. Using the avidin-biotin-complex immunoperoxidase procedure, BM-1 was found to stain selectively myeloid precursor cells in normal bone marrow and mature granulocytes in the blood. In a screen of 26 normal adult and fetal human organs fixed in B5 formalin, BM-1 was negative in all nonhematopoietic tissues with the exception of tissue granulocytes and scattered cells in the peripheral cortex of the thymus. Likewise a screen of 30 solid tumor cell lines including a spectrum of carcinomas, sarcomas, and neural-derived tumors was negative. BM-1 was also negative with 21 T and B cell lymphomas and 11 Hodgkin's disease tumors. A preliminary study of tumors of the hematopoietic system revealed that BM-1 was reactive with M2 and M3 acute myelogenous leukemias (AML), chronic myelogenous leukemias (CML) and myelomonocytic leukemias, and granulocytic sarcomas. M1, M4, M5, and M6 AML clot preparations were negative in this study, indicating that BM-1 may have a role in the histopathologic diagnosis of myelogenous leukemia. Myeloid leukemic cell lines HL-60, ML-2, KG1, and TPH-1-O showed BM-1 nuclear and/or cytoplasmic reactivity in a subpopulation of cells, but erythroid and lymphoid leukemias and all lymphoma cell lines were negative. Immunoperoxidase studies of a panel of fetal tissues showed BM-1 positive cells in the peripheral cortex of the thymus and portal myelopoietic regions of the liver at 18 weeks gestation. Finally, DNA-cellulose and solid phase radioimmunoassay (RIA) techniques developed in our laboratory demonstrate that the BM-1 antigenic domain is reactive only after binding to eukaryotic but not prokaryotic single- or double-stranded DNA. Immunoblot techniques using a DNA-cellulose purified protein sample revealed that BM-1 recognizes a 183 kD protein. These studies indicate that BM-1 is recognizing a myeloid-specific antigen that, because of its DNA binding characteristics, may have an important role in the differentiation of myeloid cells at the molecular level.     

The influence of aminotransferase levels on liver stiffness assessed by Acoustic Radiation Force Impulse Elastography: A retrospective multicentre study

BackgroundAcoustic Radiation Force Impulse Elastography is a new method for non-invasive evaluation of liver fibrosis.AimTo evaluate the impact of elevated alanine aminotransferase levels on liver stiffness assessment by Acoustic Radiation Force Impulse Elastography.MethodsA multicentre retrospective study including 1242 patients with chronic liver disease, who underwent liver biopsy and Acoustic Radiation Force Impulse. Transient Elastography was also performed in 512 patients.ResultsThe best Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis was 1.29 m/s in cases with normal alanine aminotransferase levels and 1.44 m/s in patients with alanine aminotransferase levels > 5× the upper limit of normal. The best cut-off for predicting liver cirrhosis were 1.59 and 1.75 m/s, respectively.Acoustic Radiation Force Impulse cut-off for predicting significant fibrosis and cirrhosis were relatively similar in patients with normal alanine aminotransferase and in those with alanine aminotransferase levels between 1.1 and 5× the upper limit of normal: 1.29 m/s vs. 1.36 m/s and 1.59 m/s vs. 1.57 m/s, respectively.For predicting cirrhosis, the Transient Elastography cut-offs were significantly higher in patients with alanine aminotransferase levels between 1.1 and 5× the upper limit of normal compared to those with normal alanine aminotransferase: 12.3 kPa vs. 9.1 kPa.ConclusionLiver stiffness values assessed by Acoustic Radiation Force Impulse and Transient Elastography are influenced by high aminotransferase levels. Transient Elastography was also influenced by moderately elevated aminotransferase levels.     

Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion.

Regional chemotherapy allows further exploitation of the steep dose response curve of most chemotherapeutic agents, while systemic toxicity remains tolerable. We investigated the difference in maximally tolerated dose, pharmacokinetics and antitumour effect comparing administration of melphalan as a bolus in isolated liver perfusion (ILP) or via hepatic artery infusion (HAI). For these in vivo studies an experimental model for liver metastases in male WAG/Ola rats is obtained by subcapsular inoculation of CC531 rat colon carcinoma cells. In this system, ILP allowed administration of a two times higher dose than HAI (12 mg kg-1 vs 6 mg kg-1). In both treatment modalities systemic toxicity (leukopenia) was dose limiting. No hepatic toxicity was observed. Bolus administration of the maximally tolerated doses of melphalan in HAI (6 mg kg-1) and ILP (12 mg kg-1) resulted in four times higher concentrations in both liver and tumour tissue of the ILP treated rats. However, the ratio of mean drug concentration in liver vs tumour tissue appeared to be 1.5 times that found for HAI. In the range of the in tumour tissue measured melphalan concentrations the CC531 cells showed a steep dose response relationship in vitro. Whereas HAI resulted in significant tumour growth delay, complete remissions were observed in 90% of the rats treated with ILP. This study shows that with 12 mg kg-1 melphalan in ILP highly effective drug concentrations are achieved in CC531 tumour tissue; although the melphalan concentration in liver tissue shows an even higher increase than in tumour tissue, hepatic toxicity is negligible in this dose range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Guidelines for international collaborative research

OBJECTIVE: As the global village becomes a reality, there is an increasing need to conduct international collaborative studies in family practice. A workshop at the WONCA meeting in Hong Kong used international attendees to produce a set of guidelines for international research. METHODS: At the workshop four completed international projects, each using a different strategy, were presented so that common themes might become apparent. The themes were then discussed and guidelines emerged from the process. RESULTS: Seven guidelines emerged for consideration before embarking on an international collaborative research project in family medicine. The guidelines deal with the characteristics of the research question and the importance of communication. The need for simple, brief methods of data collection, funding and pilot testing were identified. CONCLUSION: The question must be relevant to all participants to maintain interest and measurement tools must be validated to understand the impact of cultural differences in understanding.      

Pharmacological stimuli decreasing nucleus accumbens dopamine can act as positive reinforcers but have a low addictive potential

Opioid peptides, through μ and δ receptors, play an important part in reward. In contrast, the role of κ receptors is more controversial. We examined the possible positive reinforcing effects of a selective κ agonist, RU 51599, by studying intravenous self‐administration in the rat. The effect of RU 51599 on dopamine release in the nucleus accumbens was also studied, as opioids and dopamine seem to interact in the mediation of reward. The behavioural and dopaminergic effects of RU 51599 were compared with those of the μ agonist heroin. Rats self‐administered both RU 51599 (6.5, 20 and 60 μg/inj) and heroin (30 μg/inj) at low ratio requirement. When the ratio requirement, i.e. the number of responses necessary to receive one drug infusion, was increased, self‐administration of RU 51599 rapidly extinguished, whereas self‐administration of heroin was maintained. Intravenous infusion of RU 51599 (100, 200 and 400 μg) dose‐dependently decreased (25, 30 and 40%, respectively) extracellular concentrations of dopamine, as measured by means of microdialysis in freely moving rats. In contrast, heroin increased accumbens dopamine (130% over baseline). These results indicate that κ receptors, similarly to μ ones, can mediate positive reinforcing effects of opioid peptides. However, the strength of the reinforcement is very low for κ receptors. This suggests that changes in accumbens dopamine do not correlate with the capacity of a stimulus to induce reward or aversion. In contrast, a parallel seems to exist between an increase in accumbens dopamine and the drive to reach or obtain a positive reinforcer.