Histopathology of familial versus nonfamilial dilated cardiomyopathy

Idiopathic dilated cardiomyopathy is most likely a heterogenous group of diseases characterized by ventricular dilatation and dysfunction. Approximately 20% of patients with idiopathic dilated cardiomyopathy have familial disease, which may be inapparent by review of the family history alone. It has been suggested that histopathologic features, particularly the presence of bizarrely shaped mitochondria, may be useful in distinguishing familial from nonfamilial disease.

We investigated 57 patients with dilated cardiomyopathy, 13 familial and 43nonfamilial or indeterminate. Pathologic examination of right endomyocardial biopsy specimens showed no significant differences between the familial, nonfamilial, or indeterminate groups by light microscopy or electron microscopy. We conclude that the distinction between familial and nonfamilial dilated cardiomyopathy cannot be made by histopathologic examination in most cases.     

家族聚集性HBV相关慢加急性肝衰竭患者临床特点分析

目的 分析家族聚集性乙型肝炎患者发生慢加急性肝衰竭的临床特点,为指导防治乙型肝炎患者相关慢加急性肝衰竭提供依据.方法 选取解放军三○二医院住院的HBV相关慢加急性肝衰竭患者275例,根据其流行病学特点,分成家族聚集性及非家族聚集性组,对比两组临床及检验指标特点.结果 275例患者中有家族聚集性患者为93例（33.82％）,与慢性乙型肝炎患者中家族聚集性比例38.3％差异无统计学意义.在HBV相关慢加急性肝衰竭患者中两组平均年龄分别为45.98岁及43.61岁（P＞0.05）;有家族聚集性患者中肝硬化比例更高（73.91％vs 58.24％,P＜0.05）;转归稍差（62.37％ vs 70.33％）,但差异无统计学意义.两组患者胆红素最高值及凝血酶原活动度最低值均无统计学差异,但丙氨酸转移酶差异有统计学意义,非家族聚集性组比有家族聚集性组ALT更高,平均为407.80U/L及256.45U/L（P＜0.05）.结论 在慢性HBV感染患者中,慢加急性肝衰竭的发生率与是否具有家族聚集性无明显相关,但家族聚集性HBV相关慢加急性肝衰竭患者中肝硬化比例更高.     

Psychological factors of familial alcoholism in American Indians and caucasians

Previous studies have reported on the familial transmission of alcoholism and its psychological concomitants. To date, investigators have not studied the familial factor and its relationship to transmission/risk in a group of American Indians (doubly at risk for alcoholism). In two related studies, we have assessed psychological adjustment and drinking behavior of (1) a group of Indians with one or more first-degree alcoholic relatives and a group of Indians without a history of familial alcoholism; and (2) Indians with a history of familial alcoholism compared to Caucasians with a history of familial alcoholism. Results indicate no psychological functioning differences between familial and nonfamilial Indians. However, the familial Indian group reported a style of drinking that more closely resembled that of an alcoholic group. Looking at these data cross-culturally, there are differences between Indians and Caucasians on psychological adjustment, as well as drinking behavior. These differences are present in spite of a shared familial history of alcoholism.     

Ultraviolet-induced formation of micronuclei and sister chromatid exchange in cultured fibroblasts of patients with cutaneous malignant melanoma

Genetically enhanced sensitivity to ultraviolet (UV) radiation may play an important role in the development of cutaneous malignant melanoma (CMM). This was studied in cultured fibroblasts of 26 CMM patients and controls by micronucleus (MN) test and sister chromatid exchange (SCE) after UV irradiation (375 J/m2). Sister chromatid exchange and MN formation were used as parameters to detect the UV-induced genotoxic damage in the individual cell strains. We found that the UV-induced level of MN was significantly increased in CMM patients (p = 0.0005), being most pronounced in the familial cases (p = 0.0001). Ultraviolet-induced SCE was also elevated in CMM patients (p = 0.001), but there was no difference between familial and nonfamilial cases. The present findings indicate that genetic predisposition contributes to the development of CMM in a subset of CMM patients and may be due to an enhanced susceptibility to UV light.     

Elastin and collagen in the aortic wall: changes in the Marfan syndrome and annuloaortic ectasia

Elastin and collagen concentrations were determined in intimal-medial samples of ascending aortas from healthy controls of different ages and from 20 patients with annuloaortic ectasia (AAE). Five patients had the Marfan syndrome. In controls the highest elastin concentrations (estimated from desmosine concentrations or insoluble residues after hot-alkali extraction) were found in children. During aging until 60 years, elastin concentration decreased when determined by the hot-alkali extraction method while desmosine concentration changed less. Aorta samples from the Marfan-syndrome patients showed a great variation of elastin concentration from total lack to normal values. Samples from the other AAE patients could be divided into two groups. One contained clearly less elastin and more collagen than the controls whereas in the other group this difference was less marked. Histological examination of the aortic wall of the first group also showed marked fibrosis accompanied by severe elastin fragmentation and acellularity. From the 15 non-Marfan patients 14 were men. By means of clinical examination these patients could also be divided into "familial" and "nonfamilial" groups, because increased diameter of the aortic root was found in relatives of almost half of the patients. However, there were no differences in elastin and collagen concentrations between the familial and nonfamilial cases. As well, no correlation was found between biochemical findings and diameters of the aortic roots. These results point to altered elastin and/or collagen metabolism in the aortic wall of AAE patients.     

ATP13A2 variability in Parkinson disease

Recessively inherited mutations in ATP13A2 result in Kufor‐Rakeb syndrome (KRS), whereas genetic variability and elevated ATP13A2 expression have been implicated in Parkinson disease (PD). Given this background, ATP13A2 was comprehensively assessed to support or refute its contribution to PD. Sequencing of ATP13A2 exons and intron‐exon boundaries was performed in 89 probands with familial parkinsonism from Tunisia. The segregation of mutations with parkinsonism was subsequently assessed within pedigrees. The frequency of genetic variants and evidence for association was also examined in 240 patients with nonfamilial PD and 372 healthy controls. ATP13A2 mRNA expression was also quantified in brain tissues from 38 patients with nonfamilial PD and 38 healthy subjects from the United States. Sequencing analysis revealed 37 new variants; seven missense, six silent, and 24 that were noncoding. However, no single ATP13A2 mutation segregated with familial parkinsonism in either a dominant or recessive manner. Four markers showed marginal association with nonfamilial PD, prior to correction for multiple testing. ATP13A2 mRNA expression was marginally decreased in PD brains compared with tissue from control subjects. In conclusion, neither ATP13A2 genetic variability nor quantitative gene expression in brain appears to contribute to familial parkinsonism or nonfamilial PD. Hum Mutat 0, 1–5, 2008. © 2008 Wiley‐Liss, Inc.     

Galectin-3 and Ki-67 expression in multiglandular parathyroid lesions

Hyperplastic and neoplastic parathyroid lesions may present overlapping morphologic features, and several markers have been proposed to distinguish benign from malignant growths. Recently, it was reported that galectin-3 is a useful marker of malignancy in uniglandular parathyroid diseases. To investigate galectin-3 and Ki-67 immunoexpression in parathyroid hyperplastic disease, 63 multiglandular lesions (13 primary, 40 secondary, and 10 tertiary hyperplasia cases) were analyzed and compared with 45 control cases of parathyroid adenomas and 24 carcinomas. Our data showed that hyperplastic lesions responsible for primary nonfamilial or tertiary hyperparathyroidism, as well as parathyroid adenomas, were negative for galectin-3, as opposed to carcinomas. In addition, secondary and familial primary hyperplasia cases were surprisingly positive for galectin-3 in approximately two thirds of cases. All hyperplastic lesions (positive or negative for galectin-3) had a low Ki-67 index. Based on these findings, secondary hyperplasia has a low proliferative potential but an unexplained galectin-3 reactivity, which reduces its diagnostic role in differentiating benign from malignant nodules in the context of multiglandular parathyroid diseases.     

The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy.

BACKGROUND. Dilated cardiomyopathy is characterized by an increase in ventricular size and impairment of ventricular function. Most cases are believed to be sporadic, and familial dilated cardiomyopathy is usually considered to be a rare and distinct disorder. We studied the proportion of cases of idiopathic dilated cardiomyopathy that were familial in a large sequential series of patients whose first-degree relatives were investigated regardless of whether these relatives had cardiac symptoms. METHODS. We studied relatives of 59 index patients with idiopathic dilated cardiomyopathy of obtaining a family history and performing a physical examination, electrocardiography, and two-dimensional, M-mode, and Doppler echocardiography. A total of 315 relatives were examined. RESULTS. Eighteen relatives from 12 families were shown to have dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3 percent) had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2 percent) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8 percent) who were studied separately. CONCLUSIONS. Dilated cardiomyopathy was found to be familial in at least one in five of the patients in this study, a considerably higher percentage than in previous reports. This finding has important implications for family screening and provides direction for further investigation into the causes and natural history of dilated cardiomyopathy.     

Neuroimaging and neurogenetics of epilepsy in humans

In the past decade, several genetic mutations have been associated with different forms of familial focal and generalized epilepsies. Most of these genes encode ion-channel subunits. Based on neurophysiological in vitro and in vivo animal studies, substantial progress has been made in understanding the functional consequences of gene defects associated with epilepsies. However, the knowledge transition from animal studies to patients carrying a mutation, or even suffering from a nonfamilial form of epilepsy, is very limited. This review will illustrate how neuroimaging studies in humans may help to bridge the gap between genotype and phenotype. We will be presenting examples of familial focal (autosomal dominant nocturnal frontal lobe epilepsy), idiopathic generalized epilepsies (severe myoclonic epilepsy of infancy). Such studies will help to better understand functional consequences of genetic alterations and may contribute to a better phenotype characterization.     

Immunohistochemical study of cerebral amyloid angiopathy. II. Enhancement of immunostaining using formic acid pretreatment of tissue sections.

Cerebral amyloid angiopathy (CAA) is a biochemically heterogeneous entity most commonly associated with stroke syndromes, Alzheimer's disease (AD), Down's syndrome, and miscellaneous neurologic conditions. The authors have applied and extended (using formic acid pretreatment of histologic sections) an immunocytochemical technique that used antibody to a synthetic 28-amino acid peptide representing a segment of the AD amyloid precursor, to study CAA and related parenchymal amyloid deposits in brain tissues originally derived from: 1) patients with CAA with or without typical clinicopathologic features of AD, cerebral hemorrhage, and infarcts; 2) a young boy with angiocentric brain amyloid; 3) patients with familial (Icelandic, Dutch) forms of cerebral hemorrhage caused by CAA; and 4) Japanese patients with nonfamilial CAA-related brain hemorrhage, sometimes associated with histopathology characteristic of AD. Formic acid pretreatment of sections resulted in markedly enhanced staining of senile plaque core and microvascular, especially capillary, amyloid, and some apparent staining of the neuritic component of senile plaques. Perivascular halos of immunoreactive material were observed frequently. Neurofibrillary tangles were not immunolabeled, nor were blood vessels or any parenchymal components within cerebral white matter. CAA in Japanese patients with nonfamilial encephalic hemorrhages appeared immunocytochemically identical to AD-related CAA. Arterioles in brains that had severe CAA frequently showed significant stenosis of their lumina by nonamyloid hyaline or cellular material.     

Molecular classification of parathyroid neoplasia by gene expression profiling

The current classification of sporadic parathyroid neoplasia, specifically the distinction of adenoma from multiple gland neoplasia (double adenoma and nonfamilial primary hyperplasia) is problematic and results in a relatively high rate of clinical error. Oligonucleotide microarrays (Affymetrix U133A) were used to evaluate parathyroid samples from 61 patients; 35 adenomas, 10 nonfamilial multiple gland neoplasia, 3 familial primary hyperplasia, 8 renal-induced hyperplasia, and 5 from patients without parathyroid disease (normals). A multiclass comparison using supervised clustering identified distinct gene signatures for each class of parathyroid samples. We developed a predictor model that correctly identified 34 of 35 cases of adenoma, 9 of 10 cases of nonfamilial multiple gland neoplasia, and identified a minimum set of 11 genes for the distinction of adenoma versus multiple gland neoplasia. All methods of unsupervised clustering showed two related but different types of parathyroid adenomas that we have arbitrarily designated as type 1 and type 2 adenomas. Multiple gland parathyroid neoplasia, which represents either synchronous or asynchronous autonomous growth in two, three, or all four parathyroid glands, is a distinct molecular entity and does not represent the molecular pathogenesis of adenoma occurring in multiple glands.     

Familial isolated noncompaction of ventricular myocardium

We report a family in which two male sibs were affected with isolated noncompaction of ventricular myocardium (INVM). The familial occurrence of INVM suggests a genetic basis. We review the literature of familial and nonfamilial cases and discuss the inheritance pattern of INVM. Received: August 26, 1998 / Accepted: October 16, 1998     

Glomerular morphometry II: familial and nonfamilial haematuria

Differential glomerular cell counts and measurements of glomerular diameter were made in 13 children with Alport's syndrome (AS), four with benign familial haematuria (BFH) and 15 with nonfamilial haematuria (NFH). Mesangial cellularity was increased in the six cases of NFH with diffuse mesangial deposits of IgA (IgA+). In AS, IgA+ and -NFH, epithelial cellularity decreased with age while glomerular diameter increased. In AS mesangial and endothelial cellularity also decreased with age. These findings support the view that AS, IgA + and -NFH are three distinct entities. BFH, although similar in several respects to IgA–NFH, should nevertheless be retained as a separate category by virtue of its familial incidence of haematuria.     

No evidence of increased chromosomal aberrations and micronuclei in lymphocytes from nonfamilial thyroid cancer patients prior to radiotherapy

The relationship between the presence of high frequencies of chromosomal aberrations in peripheral lymphocytes and predisposition to cancer has been suggested for some cancer diseases. In nonfamilial thyroid cancer, the few reports available are equivocal. The aim of this study was to assess the possible chromosomal instability in peripheral blood lymphocytes from 22 patients suffering from nonfamilial thyroid cancer. For this purpose, 2 classic cytogenetic assays, the chromosomal aberrations assay and cytokinesis-blocked micronucleus assay, were chosen. The frequency of chromosomal aberrations excluding gaps (%) was 1.68 +/- 1.39 (mean value +/- SD) for the patients group versus 2.20 +/- 1.87 for the control group. The frequency of binucleated lymphocytes with micronuclei ( per thousand) was 5.41 +/- 3.51 (mean value +/- SD) for the patients group versus 5.37 +/- 3.21 for the control group. The results obtained revealed no significant differences between both groups. The present study reinforces the idea that constitutional chromosomal instability in peripheral blood lymphocytes is not visible in nonfamilial thyroid carcinomas.     

Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN 1-associated pancreatic endocrine tumors.

Pancreatic endocrine tumors occur sporadically and as part of the multiple endocrine neoplasia type 1 (MEN 1) and von Hippel-Lindau (VHL) syndromes. The MEN1 locus on 11q13 and a candidate tumor suppressor locus on 3p are known to be hemi- or homozygously mutated in a subset of these tumors. Chromosome arm 18q harbors the SMAD4/DPC4 tumor suppressor gene that is frequently deleted and inactivated in tumors of the exocrine pancreas. We have analyzed 22 nonfamilial and 16 MEN 1-associated pancreatic endocrine tumors for loss of heterozygosity (LOH) at 3p, 11q13, and 18q. LOH at 3p was revealed in 45% and 36% of tumors from 31 patients with nonfamilial and MEN 1-associated disease, respectively. The corresponding proportions for 11q13 were 55% and 91%, and for 18q 27% and 25%, respectively. A striking relation between LOH at 11q13 and 3p and a malignant phenotype was found for the nonfamilial tumors. None of the six benign tumors (all of them insulinomas) had allelic loss at 3p or 11q13, whereas 92% (P < 0.01) of the malignant tumors (including malignant insulinomas) had such deletions. Besides the 11q13 abnormality, more than half of the MEN 1-associated tumors had additional genetic lesions affecting 3p or 18q. LOH analysis of several tumors from two MEN 1 patients suggested different clonal origin of the lesions. Sequencing of the SMAD4/DPC4 gene did not identify mutations in coding regions or at exon/intron boundaries in tumors with LOH at 18q. The data indicate involvement of tumor suppressor genes on 3p and 18q, in addition to the MEN1 gene at 11q13, in the tumorigenesis of both nonfamilial and MEN 1-associated pancreatic endocrine tumors.     

Paternal age and sporadic schizophrenia: evidence for de novo mutations

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.     

Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data.

Forty-one patients with adrenal cortical tumors were evaluated retrospectively for the presence of histologic and non-histologic features associated with malignant behavior. The patients who survived operation were followed at least five years. The association of these features with subsequent metastasis was examined by both parametric and nonparametric statistical methods. Twelve criteria were statistically significant in predicting subsequent metastasis. The most significant of these were: clinical evidence of weight loss, broad fibrous bands traversing the tumor, a diffuse growth pattern, vascular invasion, tumor cell necrosis, and tumor mass. The tendency toward metastasis for each tumor was expressed in indices that correlated well with diagnoses made by conventional histologic means, but were more accurate in predicting subsequent clinical behavior than nonquantitative methods of evaluation.     

C-Cell hyperplasia and medullary thyroid microcarcinoma

Since the discovery of the thyroid C-cell, considerable progress has been made regarding its origin, function, and pathology. In this article an attempt is made to summarize and update our knowledge about physiologic or reactive C-cell hyperplasia, neoplastic C-cell hyperplasia (medullary carcinoma in situ), and medullary microcarcinoma. Seldom recognized preoperatively, physiologic C-cell hyperplasia is associated with inflammatory, metabolic, and neoplastic thyroid disorders as well as with hypercalcemia. However, the pathogenesis is still unclear. Although physiologic C-cell hyperplasia may progress to medullary carcinoma, the full malignant potential is unknown. Problems related to the definition of physiologic C-cell hyperplasia are discussed. Immunohistochemistry and quantitative analysis are required for the diagnosis. By contrast, C-cell hyperplasia associated with MEN II syndromes or familial medullary carcinoma can be diagnosed preoperatively in asymptomatic children or adolescents by the detection of germline mutations of the RET protooncogene. Morphologic and genetic abnormalities support the idea that C-cells in the familial form of C-cell hyperplasia are neoplastic and can be recognized with conventional stains. Therefore, the number of C-cells is irrelevant for the diagnosis. Medullary microcarcinoma is a neoplasm that measures < 1 cm. The sporadic variant is usually an incidental microscopic finding, whereas the familial form can be diagnosed by genetic testing. Its morphologic features and biologic behavior differ from those of larger medullary carcinomas. The frequency of medullary microcarcinoma will probably increase with the use of genetic testing.     

颌骨牙源性钙化囊肿病变性质的探讨

目的：明确所谓牙源性钙化囊肿（calcifying odontogenic cyst,COC)各临床病理亚型的特点及其病变性能。方法：回顾分析21例被笼统诊断为COC病例资料,通过对临床、X线、病理、治疗及预后特点的综合分析,将本组病例分为囊肿、良性肿瘤和恶性肿瘤3类病损进行观察。结果：囊肿组16例（男性9例、女性7例）,10－19岁为高发年龄,前磨牙区好发,随访13例患者无复发。良性肿瘤组4例,临床病理表现各异,其中2例表现为所谓实性型COC,1例为COC伴发成釉细胞瘤,1例为COC伴发牙源性纤维黏液瘤;这组病例均发生于下颌,其中2例有多次复发史。恶性肿瘤组1例,肿瘤呈实性,除表现某些COC特点外,具有显著的组织学恶性特点。结论：以往被笼统归类为COC的病变可表现囊肿,良性肿瘤或恶性肿瘤等多种病理和行为特点,因此其命名和分类应作相应修改,临床治疗也应区别对待。     

Correlation of histologic architectural and cytoplasmic features with nuclear atypia in atypical (dysplastic) nevomelanocytic nevi

The dysplastic nevus in nonfamilial melanoma is a clinicopathologic entity consistently demonstrating an eightfold or greater association with malignant melanoma. The present report quantifies the relationship between nuclear atypia and 16 architectural and cytoplasmic features in 153 pigmented nevi removed from a similar number of patients with newly diagnosed nonfamilial melanoma. All lesions were evaluated by one dermatopathologist, and most lesions were reviewed by a second dermatopathologist. Nuclear atypia of nevomelanocytes was defined as at least three of the following: nuclear enlargement, pleomorphism, hyperchromatism, and prominent nucleoli easily observed throughout each lesion. Seventeen percent of the total nevi had such atypia. On univariate analysis, 11 parameters (lentiginous hyperplasia of the epidermis, basal melanocytic hyperplasia, junctional nest disarray, fusion [bridging] of theques, suprabasal melanocytes, lymphoid response, prominent vascularity, fibroplasia, abundant cytoplasm, "dusty" cytoplasm, and large melanin granules) showed an association with nuclear atypia (P less than .05). However, on multivariate analysis only five parameters continued to be important: basal melanocytic hyperplasia, junctional nest disarray, melanophages (inverse correlation), prominent vascularity, and large melanin granules. These data support the idea that multiple histopathologic characteristics, correlating objectively with nuclear atypia, are important for the diagnosis of dysplastic nevi. In our view, the minimal essential histologic criteria for dysplastic nevi based on these findings include nuclear atypia and abnormal patterns of intraepidermal nevomelanocytic proliferation (ie, basal melanocytic hyperplasia and/or junctional nest disarray).