Giant Retroperitoneal Myelolipoma: An Unusual Diagnostic GI Challenge-Case Report and Review of the Literature.

INTRODUCTION: Myelolipomas are rare, benign neoplasms usually arising from the retroperitoneum. They represent an unusual diagnostic challenge due to their vague GI symptoms. We present a case of an 81-year-old patient complaining of severe dyspepsia. An abdominal CT scan and a fine needle biopsy lead to a diagnosis of giant retroperitoneal myelolipoma. A complete surgical resection was performed; no evidence of recurrent tumor was noted after 10 months. AREAS COVERED: Giant myelolipomas are very rare lesions. Clinical diagnosis of myelolipomas can be problematic due to their indefinite symptoms. CT scan and fine needle biopsy can be useful to reach a diagnosis, although they cannot be used to exclude malignancy in giant lesions. Surgery is the principal treatment if the tumor is symptomatic or > 7 cm. Follow-up is not mandatory due to the lack of any example of recurrence described in literature. EXPERT COMMENTARY: Despite the size of the neoplasms, since most of the complaints are vague, patients with this diagnosis should be considered among patients with unexplained gastrointestinal symptoms. Since malignancy cannot be excluded based on preoperative and intraoperative biopsy, an aggressive surgical approach is essential.

Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy.

OBJECTIVES: To assess the prevalence of dystrophin defects in dilated cardiomyopathy (DCM) in male patients and to formulate investigation strategies for their identification. BACKGROUND: Dystrophin defects presenting with predominant or exclusive cardiac involvement may be clinically indistinguishable from "idiopathic" DCM. Diagnosis may be missed, unless specifically investigated. METHODS: Clinical and biochemical evaluation, right ventricular endomyocardial biopsy (EMB), light and electron microscopic and immunohistochemical studies of biopsy samples, six multiplex and two single polymerase chain reactions for 38 exons and automated sequencing of exon 9 and muscle promoter-exon 1 were undertaken in 201 consecutive male patients presenting with DCM, with (n = 14) and without (n = 187) increased serum creatine phosphokinase (sCPK). RESULTS: Dystrophin defects were identified in 13 of the 201 patients (6.5%, age 16-50). Family history was positive in four patients. Serum CPK levels were increased in 11 of 13 patients. Light microscopy examination of EMB was uninformative; ultrastructural study showed multiple membrane defects. Dystrophin immunostain was abnormal. Eight patients, all older than 20, had deletions affecting midrod domain, normal or mildly increased CPK and better outcome than the five remaining cases all younger than 20, with more than five-fold increase of sCPK. Two of these latter had proximal and rod-domain deletions. Sisters of two patients were diagnosed as noncarriers with microsatellite analysis. CONCLUSIONS: Although the overall prevalence of dystrophin defects in our consecutive DCM male series is low (6.5%), immunohistochemical and molecular studies are essential to identify protein and gene defects; screening studies are justified to define prevalence, clinical profile and genotype-phenotype correlation.

The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA(Leu(CUN)) and is associated with dilated cardiomyopathy.

Mitochondrial DNA (mtDNA) mutations have been causally linked with cardiomyopathies, both dilated (DCM) and hypertrophic. We identified the T12297C mutation in the mtDNA-tRNA(Leu(CUN)) of a 36-year-old male patient diagnosed with DCM. The mutation was heteroplasmic, with high amount (88%) of mutant DNA in the myocardium, and was absent in normal (n = 120) and disease (n = 150) controls. It affects a highly conserved nucleotide (adjacent to the anticodon triplet) that allows the phospho-ribose backbone to turn and form the loop. The potential pathological role of T12297C mutation is further supported by its recent identification in another unrelated Italian family with DCM associated with endocardial fibroelastosis. In the variable loop of the same tRNA, our patient also carried the A12308G transition that is debated as pathological mutation or neutral polymorphism in progressive external ophthalmoplegia: the two defects could exert a synergistic effect on the tRNA structure and function. The endomyocardial biopsy study showed abnormal ring-like mitochondria and occasional cytochrome c oxydase negative myocytes. Overall, the heteroplasmy, the highly conserved position of the mutated nucleotide, the absence of the mutation in large series of diseased and normal controls, and the cardiac mitochondrial changes support a causative link of the mutation with the disease.

Human cytomegalovirus early infection, acute rejection, and major histocompatibility class II expression in transplanted lung. Molecular, immunocytochemical, and histopathologic investigations.

The present study aimed to investigate the relationship between acute rejection and human cytomegalovirus (HCMV) infection, as well as the coexpression of HLA-DR and immediate-early (IE) viral antigens, in 143 transbronchial biopsies and bronchoalveolar lavage fluids of 32 lung transplant recipients. We investigated the occurrence of morphologically overt viral infection with conventional histopathology, the expression of IE antigens with single labeling immunohistochemistry, the coexpression of IE antigens and HLA-DR molecules with double labeling techniques, and the presence of viral IE genes with polymerase chain reaction. Histopathologic study showed overt viral infections (12.6%) in 18 of the 143 biopsies; 8 were in a context of pneumonia and 10 were localizations without surrounding inflammatory cells; immunohistochemistry showed IE viral antigen expression in 31 (21.67%); PCR detected viral IE genes in 73/143 lavage fluids and biopsies (51%). The double labeling immunohistochemical technique showed that most IE antigen-expressing, noncytopathic cells were either HLA-DR negative in areas without infiltrates, or HLA-DR positive in those areas where inflammatory infiltrates were consistent, in the absence of viral cytopathy, with acute rejection. The results indicate that, in transplanted lung, the frequency of morphologically occult HCMV infection (as detected by immunohistochemically and/or PCR) is much higher than that of morphologically overt viral infection. The occurrence of inflammatory infiltrates (consistent with acute rejection) around morphologically occult infected cells and the possible lack of inflammation around both early- and late-infected cells suggest that in biopsies with occult infection the infiltrates should be attributed to allograft reaction. This conclusion would be in keeping with the coexpression of HLA-DR and HCMV IE in infiltrate-rich biopsies that are consistent with acute rejection, as well as with the absence of HLA-DR expression in IE antigen-positive cells in infiltrate-free-areas.

Expression of natriuretic peptide in ventricular myocardium of failing human hearts and its correlation with the severity of clinical and hemodynamic impairment.

Atrial natriuretic peptide (ANP) was immunohistochemically investigated in (1) right ventricular endomyocardial biopsy specimens from 87 apparently healthy donor hearts taken from victims of cerebral accidents; (2) 1 normal heart not suitable for transplantation (HBsAg carrier); (3) right ventricular endomyocardial biopsy specimens from 151 patients with dilated cardiomyopathy (DC); and (4) 57 explanted hearts, 26 with DC and 31 with ischemic heart disease. No ANP immunoreactivity was found in normal ventricles. Failing hearts showed ventricular positivity in 31% of the DC biopsy series, in 61% of the left ventricles, and in 30% of the right ventricles of the explanted heart series. An endoepicardial gradient was observed, because ANP positivity was greater and more extensive in the subendocardial layers. Ultrastructural studies were performed on biopsy specimens from 10 normal hearts and 132 DC biopsy samples. No ANP-storing granules were found in biopsy samples of normal ventricles, whereas ANP granules were seen in 15 of 132 (11.4%) DC cases. In parallel immunoblotting, investigation showed the same 13 kDa band protein in 1 normal atrium as well as in 8 failing atria and ventricles. ANP immunoreactivity was positively correlated with higher New York Heart Association functional classes as well as with higher left ventricular end-diastolic pressure (p less than 0.005), end-diastolic volume (p less than 0.005) and end-diastolic volume index (p less than 0.005). In conclusion, apparently healthy ventricles do not show ANP immunoreactivity, whereas failing ventricles do. ANP expression seems to be independent of the underlying disease, but positively related to the clinical status and the degree of left ventricular impairment and dilatation.

Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes: a morphologic, immunohistochemical, and biochemical study.

We investigated incidence, severity, and distribution of coronary atherosclerosis, acute thrombosis, and plaque fissuring in ischemic heart disease (both unstable-acute syndromes and chronic ischemia) and in nonischemic controls. We also studied the structural, immunohistochemical, and biochemical profile of plaques, with and without thrombus, including morphometry, immunophenotyping of inflammatory infiltrates, cytokine presence, and ultrastructural features. Critical coronary stenosis was almost the rule in both acute and chronic ischemic series (greater than 90%) whereas it reached 50% in control subjects. Thrombosis was principally characteristic of unstable-acute ischemic syndromes (unstable angina, 32%; acute myocardial infarction, 52%; cardiac sudden death, 26%) but was also found in chronic ischemia (stable angina, 12%; ischemic cardiomyopathy, 14%) and in control subjects (4%). Plaque fissuring without thrombus occurred in low percentages in lipid-rich, severe eccentric plaques in most series. Major differences were found between pultaceous-rich versus fibrous plaques rather than between plaques with or without thrombus. Pultaceous-rich plaques were frequent in sites of critical stenosis, thrombosis, and ulceration. Inflammatory infiltrates, i.e., T cells, macrophages, and a few beta cells, mostly occurred in lipid-rich, plaques unrelated to thrombus. In adventitia, infiltrates were a common finding unrelated to any syndrome. Necrotizing cytokines such as alpha-TNF were immunohistochemically detected in macrophages, smooth muscle, and intimal cells and detected by immunoblotting in 67% of pultaceous-rich plaques, either with or without thrombus. Immune response mediators such as IL-2 were also expressed in analogous plaques but in a minor percentage (50%-40%). Media were extensively damaged in severely diseased vessels with and without thrombus. Ultrastructural study showed that the fibrous cap was either highly cellular or densely fibrillar. Intimal injury with collagen exposure was often associated with platelet adhesion, whereas foamy cell exposure was not. In conclusion, investigated parameters were essentially similar in plaques, both with and without thrombus, whereas major differences were found between pultaceous-rich and fibrous plaques. Since platelets adhere to exposed collagen and not to foam cells, the type of exposed substrates could play a major role in thrombosis.

Expression of proliferating cell markers in normal and diseased human hearts.

Proliferating cell nuclear antigen (PCNA) myocyte expression and histopathologic features related to its occurrence were investigated in normal and diseased hearts of adult humans using both immunohistochemical and Western blotting techniques. Ki67 Western blotting was also performed in the same samples used for PCNA blotting. Two hundred seventy-one endomyocardial biopsies, and 15 adult, 1 embryonic and 2 fetal hearts were studied. The biopsies were from normal donor hearts (n = 71), patients with cardiomyopathy and myocarditis (n = 64), and patients with transplantation with (n = 106) and without (n = 30) acute rejection of any grade. The 15 hearts were from 1 heart donor, and from patients with cardiomyopathy (n = 5), valvular heart disease (n = 2), ischemic heart disease (n = 4), amyloidosis (n = 1) and transplantation with acute rejection (n = 2). The PCNA labeling index was plotted against myocyte hypertrophy, inflammatory infiltrates and binucleation index. The PCNA labeling index ranged from 2 to 9% in embryonic and fetal hearts. PCNA was expressed by 1 to 2% of myocyte nuclei in 12% of normal heart biopsies, 1 to 5% of myocyte nuclei in 28% of cardiomyopathy and myocarditis biopsies, and by up to 8% of myocyte nuclei in 53% of biopsies of patients with transplantation, independently of the presence and degree of acute rejection. In the latter biopsies and in myocarditis, some inflammatory cells also showed PCNA expression. PCNA positive myocytes were both mono- and binucleated, and there was no correlation between binucleation and PCNA labeling indexes. Ki67 and PCNA blotting confirmed immunohistochemical results.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphologic changes induced by acetylcholine infusion in normal and atherosclerotic coronary arteries.

Low doses of acetylcholine induce "endothelium-dependent" dilatation in normal coronary arteries and constriction of diseased vessels. This study investigated morphologic changes induced by perfusion of normal and diseased coronary arteries with low and high doses of acetylcholine. Vessels were excised from a series of beating hearts explanted at transplantation for idiopathic dilated cardiomyopathy and coronary artery disease. Coronary arteries from other explanted hearts, perfused with saline solution under similar conditions were taken as controls. Samples were studied using conventional histopathologic and immunohistochemical methods. Coronary arteries were grouped according to presence or absence of histologically detectable structural modifications of any type and extent. Low doses of acetylcholine induced changes in all but 1 structurally diseased coronary artery, whereas no change was induced in any but 1 histologically normal coronary artery. High doses of acetylcholine induced contraction changes in both normal and diseased vessels. Changes observed in the wall of the contracted vessels were: (1) endothelial cell contraction with protruding nuclei and detachment of their intercellular junctions with exposure of subjacent collagen to flow, (2) contraction of plaque smooth muscle cells, (3) formation of cushions protruding into vessel lumens causing blunt microchannels. Contraction in both intimal and plaque cells occurred even in diseased vessel segments with intimal denudation. These effects seemed to be dose-dependent in structurally normal vessels because low doses of acetylcholine did not produce any morphologically detectable changes in histologically normal coronary arteries, while low doses of acetylcholine induced similar reactions in vessels affected by both atherosclerosis and subintimal fibrocellular thickening.

Search for Coxsackievirus B3 RNA in idiopathic dilated cardiomyopathy using gene amplification by polymerase chain reaction.

A polymerase chain reaction (PCR) amplification assay was developed to detect Coxsackievirus B3 ribonucleic acid (RNA) in blood and myocardial tissue of explanted hearts from 40 patients who underwent cardiac transplantation and in 1 normal heart. Twenty-one patients were affected by idiopathic dilated cardiomyopathy of different duration and 19 by coronary artery disease. Coxsackievirus B3 in vitro infected Vero cells and cells infected by related human enteroviruses (Coxsackievirus B2, B4, and poliovirus 1) were used as reaction controls. PCR was performed using 4 pairs of primers homologous to Coxsackie-virus B3 sequences. Three sets were located in regions of the genome conserved at nucleotide level between several enterovirus species (replicase gene, 5' noncoding region), while one was located in a Coxsackievirus B3-specific region (VP1 gene). Total RNA was prepared by acid guanidinium isothiocyanate extraction from tissue stored frozen at -80 degrees C. One microgram of total RNA was retrotranscribed with either antisense primer or with random hexanucleotide primers and then subjected to 40 cycles of amplification. PCR products were separated by electrophoresis on a 10% polyacrylamide gel, electrotransferred to a nylon membrane and then hybridized to oligonucleotide probes specific for the coxsackievirus B3 genome radiolabeled with radioactive isotope of phosphorous. All pairs of primers yielded specific amplification products when tested on Coxsackievirus B3-infected Vero cells, with a sensitivity of 1 infected cell out of 10(5) to 10(6) cells starting from 1 microgram total RNA. Primer sets for regions of Coxsackievirus B3 genome highly conserved between related enteroviral species gave positive amplification also when challenged with RNA from cells infected by Coxsackievirus B2, B4 and poliovirus 1.

Enteroviral RNA and virus-like particles in the skeletal muscle of patients with idiopathic dilated cardiomyopathy.

The role of chronic viral infection in the etiopathogenesis of idiopathic dilated cardiomyopathy (IDC) has generated considerable research. Enteroviruses were the favorite candidates as etiologic agents of IDC. However, enteroviruses were rarely demonstrated in affected hearts. We investigated whether enteroviral infection persists in the heart and in extracardiac sites, particularly in skeletal muscle, in patients with IDC. Blood and myocardial and skeletal muscle samples were collected at cardiac transplantation from 31 IDC patients, 24 non-IDC heart disease patients, and 3 heart donors. Samples underwent ultrastructural studies and ribonucleic acid (RNA) extraction. RNA was reverse-transcribed, and 2 nested fragments (bps 179 and 126) were amplified in the highly conserved 5' noncoding region of enteroviral genomic RNA. Enteroviral RNA was found in the skeletal muscle of 12 cases, whereas only 4 hearts (2 of which with positive skeletal muscle) were positive. Of the 24 controls, 2 were positive (1 muscle and heart, 1 muscle only). Automated sequencing confirmed the enteroviral nature of the amplified products. Ultrastructural study showed enterovirus-like particles in 4 of the enterovirus-positive muscles, and myopathic changes in all enterovirus-positive cases. Skeletal muscle hosts chronic enteroviral infection in more than one third of patients with sporadic IDC. Two hypotheses may explain this link. Myocardial damage may derive directly from recurrent subclinical heart infections caused by enteroviruses harbored in skeletal muscle. Alternatively, enterovirus-related myopathy may trigger an autoimmune response to antigens shared by muscle and myocardium. Further studies are needed to assess the importance of these, non-mutually exclusive mechanisms in IDC pathogenesis.

Frequency and characteristics of coronary thrombosis in the epicardial coronary arteries after cardiac transplantation.

We investigated at autopsy or at retransplantation the frequency and characteristics of coronary thrombosis in 76 cardiac allografts: 37 in place for < or = 2 months (early) and 39 in place >2 to 99 months (late). The 76 allografts were inserted in 69 patients: a single 1 in 56 patients and 2 allografts in 13 patients, 7 of whom subsequently died and had an autopsy. An average of 140 sections from 70 5-mm-long segments of 8 epicardial coronary arteries were examined from each of the 76 allografts with both hematoxylin-eosin and Movat pentachrome stains. Thrombus was found in only 1 coronary artery (3%) (the right one) of the 37 early allografts, and in 24 of 39 late allografts (61%). Of the latter 39 grafts, 29 (79%) had allograft vascular disease (AVD) and 24 (83%) of them had coronary thrombosis. Of the 312 epicardial coronary arteries (4 major and 4 minor) examined in the 39 late cases, 66 arteries (21%) contained thrombus. Of the 24 late cases with thrombus in at least 1 artery, thrombus was present in 66 (34%) of the 192 epicardial coronary arteries examined: in 6 of the 8 arteries in 3 patients; in 5 arteries in 2 patients; in 4 arteries in 1 patient; in 3 arteries in 5 patients; in 2 arteries in 6 patients, and in a single artery in 7 patients. In all 66 arteries with thrombus (24 patients) the thrombus was longer than 5 mm. The thrombus in the late cases was entirely nonocclusive (mural) in 51 (77%) of the 66 epicardial coronary arteries containing thrombus and entirely occlusive in 10 arteries (15%). It consisted exclusively of multiluminal channels in 6 arteries (9%) and combinations in 1 artery (2%). Acute myocardial infarcts were present in 3 patients, all of whom had occlusive thrombi. In all 10 arteries with occlusive thrombi, the thrombus was larger than the underlying plaque and no occlusive thrombi were located over ulcerated plaques. These observations demonstrate that thrombus is common in epicardial coronary arteries >2 months after cardiac transplantation.

Comparison of coronary lesions obtained by directional coronary atherectomy in unstable angina, stable angina, and restenosis after either atherectomy or angioplasty.

The present study investigated the incidence of the histopathologic lesions and of growth factor expression in a consecutive series of directional coronary atherectomy (DCA) samples from 40 unstable angina pectoris patients without prior acute myocardial infarction and compared the findings with those obtained in DCA samples from 18 patients with stable angina without previous infarction and 18 patients with restenosis. We investigated coronary thrombosis, neointimal hyperplasia, and inflammation. For unstable angina, we correlated the angiographic Ambrose plaque subtypes with the histopathologic findings. The immunophenotype of plaque cells and the growth factor expression were assessed with specific antibodies for cell characterization and for the expression of basic fibroblast and platelet-derived AA and AB growth factors and receptors. The incidence of coronary thrombosis was 35% in patients with unstable angina, 17% in those with stable angina, and 11% in patients with restenosis. Neointimal hyperplasia was found in 38% of unstable angina cases, in 17% of stable angina cases, and in 83% of restenosis cases. Inflammation without thrombus or accelerated progression occurred in 20% of unstable angina and 6% of stable angina samples. In 52% of unstable angina cases, inflammation coexisted with thrombosis and/or neointimal hyperplasia. In the unstable angina group, 71% of the plaques with thrombus had a corresponding angiographic pattern of complicated lesions. The growth factor expression, reported as percentage of cells immunostaining with different growth factor antibodies, was highest in restenosis, followed by unstable angina and stable angina lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Histopathologic and molecular profile of human cytomegalovirus infections in patients with heart transplants.

From November 1985 to December 1990, 2,552 endomyocardial biopsy specimens from 209 heart transplant patients were studied. Forty-four (21%) patients developed 45 episodes of major human cytomegalovirus infection (HCMV). Human cytomegalovirus infection was primary in 13 of 44 patients. Thirty-one patients developed episodes of recurrent major infection. One patient had both primary and recurrent infections. Conventional histopathologic and immunohistochemical study, in situ hybridization, and polymerase chain reaction were used to diagnose HCMV myocardial involvement on corresponding endomyocardial biopsy specimens performed during infection. Conventional morphologic study showed typical viral inclusion bodies in four biopsy specimens. Two cases had myocyte HCMV localization with necrotizing myocarditis, whereas two had endothelial cell involvement without any inflammatory reaction. In these four biopsy specimens, immunohistochemistry showed a higher number of infected cells than that recognized by conventional histopathologic study. In situ hybridization detected infected cells with no evidence of cytopathic effect. Polymerase chain reaction gave HCMV amplification products in two additional biopsy specimens otherwise interpreted as moderate and mild rejection, respectively. Therefore, 6 biopsies showed HCMV myocardial involvement (6 of 45; 13.3%): all were from patients with primary HCMV infection (6 of 13; 46%). None of 32 major recurrent infections showed any myocardial involvement. In conclusion, our study is the first to demonstrate that myocardial HCMV involvement preferentially occurs in primary infection and HCMV endothelial localization can be free from inflammatory reaction, whereas HCMV myocyte localization leads to necrotizing myocarditis. Polymerase chain reaction has a higher diagnostic sensitivity than in situ hybridization. However, polymerase chain reaction findings of HCMV DNA on otherwise negative endomyocardial biopsy specimens remains of questionable significance because polymerase chain reaction-positive biopsy samples do not necessarily indicate tissue infection. It is impossible to determine whether amplified sequences derive from circulating leukocytes or from tissue cells.

Cytogenetic studies in venous tissue from patients with varicose veins.

Cytogenetic investigation of primary cell cultures from fragments of varicose veins of seven patients with familial varicosity and seven patients with the sporadic type revealed the presence of metaphases with structural abnormalities, clonal trisomies of chromosomes 7, 12, and 18, and monosomy of chromosome 14 only in cases with the familial type, while the sporadic cases had no similar chromosome aberrations. The immunophenotypical results are consistent with fibroblast lineage of the cultured cells. These results suggest that karyotypic variations in familial varicose vein tissue cultures could in some way be associated either with the genotypic constitution responsible for the familial type or a longer duration of disease on average than those with sporadic varicosities.

Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure.

OBJECTIVE: To investigate the possible coexistence of mitochondrial DNA (mtDNA) mutations in patients with beta myosin heavy chain (beta MHC) linked hypertrophic cardiomyopathy (HCM) who develop congestive heart failure. DESIGN: Molecular analysis of beta MHC and mtDNA gene defects in patients with HCM. SETTING: Cardiovascular molecular diagnostic and heart transplantation reference centre in north Italy. PATIENTS: Four patients with HCM who underwent heart transplantation for end stage heart failure, and after pedigree analysis of 60 relatives, eight additional affected patients and 27 unaffected relatives. A total of 111 unrelated healthy adult volunteers served as controls. Disease controls included an additional 27 patients with HCM and 102 with dilated cardiomyopathy. INTERVENTION: Molecular analysis of DNA from myocardial and skeletal muscle tissue and from peripheral blood specimens. MAIN OUTCOME MEASURES: Screening for mutations in beta MHC (exons 3-23) and mtDNA tRNA (n = 22) genes with denaturing gradient gel electrophoresis or single strand conformational polymorphism followed by automated DNA sequencing. RESULTS: One proband (kindred A) (plus seven affected relatives) had arginine 249 glutamine (Arg249Gln) beta MHC and heteroplasmic mtDNA tRNAIle A4300G mutations. Another unrelated patient (kindred B) with sporadic HCM had identical mutations. The remaining two patients (kindred C), a mother and son, had a novel beta MHC mutation (lysine 450 glutamic acid) (Lys450Glu) and a heteroplasmic missense (T9957C, phenylalanine (Phe)-->leucine (Leu)) mtDNA mutation in subunit III of the cytochrome C oxidase gene. The amount of mutant mtDNA was higher in the myocardium than in skeletal muscle or peripheral blood and in affected patients than in asymptomatic relatives. Mutations were absent in the controls. Pathological and biochemical characteristics of patients with mutations Arg249Gln plus A4300G (kindreds A and B) were identical, but different from those of the two patients with Lys450Glu plus T9957C(Phe-->Leu) mutations (kindred C). Cytochrome C oxidase activity and histoenzymatic staining were severely decreased in the two patients in kindreds A and B, but were unaffected in the two in kindred C. CONCLUSIONS: beta MHC gene and mtDNA mutations may coexist in patients with HCM and end stage congestive heart failure. Although beta MHC gene mutations seem to be the true determinants of HCM, both mtDNA mutations in these patients have known prerequisites for pathogenicity. Coexistence of other genetic abnormalities in beta MHC linked HCM, such as mtDNA mutations, may contribute to variable phenotypic expression and explain the heterogeneous behaviour of HCM.

Coronary thrombosis in non-cardiac death.

BACKGROUND: Coronary thrombosis is the major cause of acute myocardial ischaemia but can be, albeit rarely, clinically silent. We investigated a series of autopsy hearts from hospitalized patients who died from non-cardiac causes, to detect and study coronary thrombosis. METHODS: The series consisted of 132 autopsy cases (81 men and 51 women, age range 32-39 years, mean 63 +/- 14), in whom cause of death was confirmed as extracardiac. Major epicardial coronary arteries were isolated from the hearts and routinely processed for histopathological study. We evaluated the presence of coronary atherosclerosis and thrombosis. Plaque size was histologically graded with low magnification lenses. RESULTS: Coronary atherosclerosis, which was found in 110 hearts, caused critical stenosis or occlusion of at least one major vessel in 55 (41.6%) cases. Coronary thrombosis was found in 10 vessels from nine different hearts. One coronary tree presented two thrombi in two different vessels. Thrombi were mural in all but one vessel. We did not observe either deep sub-thrombotic ulceration or atheromatous material mixed with thrombus. Deep thrombus layers often presented organizing features. There was no correlation between thrombosis and degree of vessel stenosis, which was only mildly increased by thrombus. Plaque rupture without thrombus was found in five coronary arteries of five different cases. CONCLUSIONS: Coronary thrombus may overlay the intima of a diseased vessel independently of plaque type and severity. Moreover, thrombosis is more frequent than expected, although it is rare when compared with the spread of coronary atherosclerosis. It may represent a plaque progression mechanism in the natural history of coronary atherosclerosis.

Localization of brain and atrial natriuretic peptide in human and porcine heart.

We have compared the localization of brain and atrial natriuretic peptide-like immunoreactivity in human and porcine hearts, using immunohistochemical techniques at both the light and ultrastructural level and specific antisera to amino-(cardiodilatin) and carboxy-terminal regions of the atrial natriuretic precursor molecule and to brain natriuretic peptide. Atrial myocardial cells in human fetal, normal adult and failing explanted hearts, displayed immunoreactivity for both brain and atrial natriuretic peptide-like sequences. At the subcellular level, brain natriuretic peptide-, cardiodilatin- and alpha-atrial natriuretic peptide-like immunoreactivity were co-localized to secretory granules in atrial myocardial cells. Immunoreactivity was also detected in the left (64%) and right ventricular free walls (23%) of 22 failing explanted hearts, but not in donor cardiac tissues. A gradient of natriuretic peptide immunostaining was observed across ventricular free walls and immunoreactivity for both natriuretic peptide sequences co-localized to secretory granules in a subpopulation of myocardial cells, concentrated in subendocardial regions of the ventricular walls. Brain and atrial natriuretic peptide-like immunoreactivity were also demonstrated in porcine atrial myocardium and cells of the ventricular conduction system. The parallel distribution of cardiac brain and atrial natriuretic peptide-like immunoreactivity suggests a dual regulation and co-storage of the natriuretic peptides in human and porcine hearts.

Central precocious puberty: clinical and imaging aspects.

We review briefly the definition of central precocious puberty (CPP), and discuss early puberty and very early puberty. The association of hypothalamic hamartoma and empty sella with CPP is described. The contribution of new imaging techniques - CT, MRI and ultrasound in the differential diagnosis of CPP is discussed.

A double-blind trial of four medications to treat severe premenstrual syndrome.

OBJECTIVE: To determine the efficacy of fluoxetine (10 mg), alprazolam, propanolol and pyridoxine in the treatment of severe premenstrual syndrome (PMS). METHOD: One-hundred and twenty women were divided into four groups of 30 patients. Patients were submitted to a randomized, double-blind, placebo-controlled treatment and were given 3 months of placebo and 3 months of active drug. The active drug was pyridoxine (300 mg/day) in group 1; alprazolam (0.75 mg/day) in group 2; fluoxetine (10 mg/day) in group 3; and propanolol (20 mg/day and 40 mg during the menstrual period) in group 4. RESULTS: Fluoxetine in 10-mg doses obtained a mean reduction of 65.4% in symptoms, followed by propanolol (58.7%), alprazolam (55.6%), pyridoxine (45.3%) and placebo (39.4-46.1%). CONCLUSION: Fluoxetine in 10-mg doses presented the best results for treating premenstrual syndrome.