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PubMed2006

beta3-adrenoceptors in the cardiovascular system: putative roles in human pathologies.

The sympathetic nervous system is central for the neurohumoral regulation of the cardiovascular system and is largely involved in many cardiovascular diseases affecting millions of people around the world. It is classically admitted that beta-adrenoceptors (beta-AR) of the beta1 and beta2 subtypes mediate the effects of catecholamines on the force of contraction of cardiac muscle, and on the relaxation of vascular smooth muscle. However, the molecular characterization in 1989 of a third beta-AR subtype, beta3, and later its identification in human heart has changed the classically admitted paradigm on the regulation of heart function by the beta-adrenergic system. In blood vessels, beta3-AR, like beta1 and beta2, produced a relaxation. But at the present time, the physiological role of beta3-AR is not clearly identified. Thus, the purpose of this review is to summarize the pharmacological and molecular evidence supporting the functional roles of beta3-AR in cardiovascular tissues of various species, including humans. In addition, this review discusses the potential role of beta3-AR in several cardiovascular diseases and emphasizes their putative involvement as new therapeutic targets.

Amino Acid Sequence↗

PubMed2006

Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants.

Histologic variants of idiopathic focal segmental glomerulosclerosis (FSGS) may have prognostic value. A recent working classification system has distinguished five FSGS variants. We evaluated a cohort of adult patients with biopsy-proven FSGS diagnosed between March 1982 and July 2001 to determine if subtypes were associated with renal outcome. Renal biopsies were reviewed by two pathologists. Demographic and clinical data were obtained from charts. Outcomes were partial and complete remission of the nephrotic syndrome, and renal failure. The frequency of FSGS variants was: 3% cellular (N=6), 11% collapsing (N=22), 17% tip lesion (N=34), 26% perihilar (N=52), and 42% not otherwise specified (NOS) (N=83). Collapsing FSGS affected younger and more often black patients. Black race was uncommon in tip variant. Collapsing and tip variants had higher proteinuria and lower serum albumin than perihilar and NOS variants. Better renal function and less severe tubulointerstitial injury were observed in patients with tip variant. These patients were more likely to receive steroids and more often achieved complete remission (50%). After a median follow-up of 1.8 years, 23% of patients were on dialysis and 28% had renal failure. Collapsing FSGS had worse 1-year (74%) and 3-year (33%) renal survival compared to other variants (overall cohort renal survival at 1 and 3 years: 86 and 67%). Different histologic variants of FSGS have substantial differences in clinical features at the time of biopsy diagnosis and substantial differences in renal outcomes.

Adult↗

PubMed2003

Differential role of melanocortin receptor subtypes in cachexia.

Animals and humans respond to starvation with a complex neuroendocrine response that ultimately leads to an increase in appetite, a sparing of lean body mass (LBM) and burning of fat, and an overall decrease in basal metabolic rate. In contrast, cachexia is a pathological state of malnutrition associated with many infections and chronic diseases, wherein appetite is diminished concomitant with an increase in metabolic rate, and a relative wasting of LBM. In previous studies, we demonstrated that anorexia and weight loss in mouse cachexia models induced by lipopolysaccharide (LPS) administration and by tumor growth are ameliorated by central melanocortin-4 (MC4) receptor (MC4-R) blockade. In contrast to the results seen with MC4 blockade, melanocortin-3 (MC3) receptor knockout (MC3-RKO) mice show illness-induced anorexia and weight loss with LPS administration and with cytokine administration, and they have similar decreases in mobility. Both MC3-RKOs and MC4-RKOs have an intact corticosterone response and fever with LPS injection. In tumor models, we show that MC4-RKO mice resist the loss of LBM brought about by tumor growth, whereas MC3-RKO animals show enhanced tissue wasting. These data underscore the importance of central melanocortin signaling in weight homeostasis and demonstrate differential effects of MC3-R and MC4-R blockade on the development of cachexia.

Animals↗

PubMed1999

A subtype of sporadic prion disease mimicking fatal familial insomnia.

OBJECTIVE: To establish a variant of sporadic prion disease as the sporadic form of fatal familial insomnia (FFI). BACKGROUND: FFI is a recently described prion disease characterized clinically by severe sleep impairment, dysautonomia, and motor signs, and pathologically by atrophy of thalamic nuclei, especially the medial dorsal and anterior ventral, and of the inferior olive. FFI is linked to the D178N mutation coupled with the methionine codon at position 129 in the prion protein gene (PRNP). It is also identified by the properties of the abnormal prion protein (PrP(Sc)), which has the relative molecular mass of 19 kDa, corresponding to the so-called type 2, and a marked underrepresentation of the unglycosylated form relative to the diglycosylated and monoglycosylated forms. METHODS: Clinical, pathologic, PrP(Sc), and PRNP data from 5 subjects with a sporadic prion disease phenotypically similar to FFI were collected and analyzed. RESULTS: All 5 subjects had a disease clinically similar and histopathologically virtually identical to FFI. PrP(Sc) type 2 was present in all subjects in amount and distribution similar to those of FFI. However, the PrP(Sc) did not show the striking underrepresentation of the unglycosylated isoform of the protein that is characteristic of FFI. Moreover, none of the subjects had the D178N PRNP mutation but all were homozygous for methionine at codon 129. CONCLUSION: This condition is likely to represent the sporadic form of FFI and the term "sporadic fatal insomnia" is proposed.

Adult↗

PubMed1999

Molecular pathology of colorectal cancer.

The identification of several types of familial colorectal cancer has led to the discovery of some of the genes involved in these diseases. It was subsequently shown that somatic mutations of these genes (APC, mismatch repair genes, TP53, KRAS, and DCC) also occur in sporadic colorectal cancer. Gradually, this molecular information is being incorporated into the standard histopathological analysis of colorectal cancer and can be used for the characterization of primary tumors. Although attempts have been made to use molecular parameters to better define dysplasia grades, differentiate between adenoma and carcinoma, and subtype carcinomas, histological parameters remain the standard for the classification of primary tumors. Nonetheless, molecular parameters may help define subgroups of colorectal carcinoma differing in prognosis and requiring individualized treatment regimens. Interesting possibilities are predicting the response to chemotherapy or radiotherapy at a molecular level and the search for metastasis by looking for molecular markers in lymph nodes or circulating blood. Other pathological tests being developed include the detection of KRAS, TP53, or APC mutations in stool and plasma. Such approaches will have a significant impact on the clinical management of colorectal cancer.

Adenoma↗

PubMed1993

[Lysosomal storage disease: a group of genetic neurodegenerative disorders].

Lysosomal storage disease is a group of neurometabolic diseases mainly occurring in infancy and childhood. They were first recognized as new diseases on the basis of unique clinical manifestations or pathological findings, and then the stage of biochemical analysis of storage material and enzyme assays in tissues and cells from patients followed. Recent technological development has enabled us to look further into the molecular genetic basis of these inherited diseases. Protein analysis revealed intracellular events of the mutant enzyme molecule responsible for the pathogenesis of a disease, and more detailed information has been obtained about the mutant gene and its product. Clinical manifestations are not always uniform for a single disease with mutations in the same gene. Clinical subtypes have been proposed for many lysosomal diseases. At present, the molecular and metabolic basis of each phenotypic expression is not clear, although common mutations have been found for specific clinical forms in some diseases. In this article, the current status of lysosomal disease research was summarized, particularly focusing on molecular pathology and molecular diagnosis. Finally future prospects for pathogenetic analysis of neural dysfunction and possible gene therapy were briefly discussed.

Child↗

PubMed2001

Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart.

The sympathetic and parasympathetic nervous system play a powerful role in controlling cardiac function by activating adrenergic and muscarinic receptors. In the human heart there exist alpha1-, beta1- and beta2-adrenoceptors and M2-muscarinic receptors and possibly also (prejunctional) alpha2-adrenoceptors. Beta1- and beta2-adrenoceptors are quite evenly distributed in the human heart while M2-receptors are heterogeneously distributed (more receptors in atria than in ventricles). Stimulation of beta1- and beta2-adrenoceptors causes increases in heart rate and force of contraction while stimulation of M2-receptors decreases heart rate (directly in atria) and force of contraction (indirectly in ventricles). Pathological situations (such as heart failure) or pharmacological interventions (for example, beta-blocker treatment) can alter the distribution of beta1- and beta2-adrenoceptors in the human heart, while M2-receptors are only marginally affected. On the other hand, relatively little is known on distribution and functional role of alpha1- and alpha2-adrenoceptor subtypes in the human heart.

Heart↗

PubMed1992

Clinico-pathological correlations in Parkinson's disease.

Based on comparative clinical and morphometric studies in 45 autopsy cases of Parkinson's disease (PD), 27 clinically presenting with akinesia and rigidity (AR-type), 18 with predominant resting tremor (T-type), the neurobiological basis of the major clinical subtypes in PD is discussed. The AR-type showed higher neuronal losses in locus coeruleus (LC) and in medial and lateral parts of substantia nigra (SNM, SNL), suggesting lesion patterns different from the T-type. More severe cell loss in the serotonergic dorsal raphe nucleus was observed in PD patients with depression than in non-depressed ones. Demented PD subjects showed higher cell loss in SNM than non-demented ones indicating dysfunction of the mesocortical dopamine system, and significantly more severe Alzheimer lesions in isocortex and hippocampus. These and other recent data from the literature indicate that some major clinical features of PD are related to lesions of distinct neuronal systems.

Aged↗

PubMed1988

The Non-Hodgkin Lymphoma Pathologic Classification Project. Long-term follow-up of 1153 patients with non-Hodgkin lymphomas.

STUDY OBJECTIVE: To document the long-term prognosis of patients with non-Hodgkin lymphoma treated between 1971 and 1975 and to determine how the prognosis varies by histologic subtype and stage. SETTING: Three cancer referral centers in the United States and one center in Italy. PATIENTS: A consecutive sample of 1153 previously untreated patients with non-Hodgkin lymphoma. At the time of analysis, 71% of the patients had died and the median follow-up for patients still alive was 11.2 years. MEASUREMENTS AND MAIN RESULTS: The 10-year survival proportions were 45% (CI, 40% to 50%); 26% (CI, 22% to 30%); and 23% (CI, 18% to 30%) for patients with low-, intermediate-, and high-grade lymphomas, respectively. Patients with intermediate- and high-grade lymphomas were curable, but this was not apparent for patients with advanced stage low-grade lymphomas. For the low-grade follicular small cleaved and follicular mixed lymphomas, the Ann Arbor staging system distinguished the prognosis of patients with stage I disease from those with more extensive involvement. For the diffuse large cell and immunoblastic lymphomas, the Ann Arbor staging system distinguished long-term prognosis for patients with stage I disease from patients with stage II disease and those with more disseminated involvement. CONCLUSIONS: The probability of long-term survival for unselected patients with non-Hodgkin lymphoma can be substantial. Long-term prognosis depends on the histologic subtype of the tumor and the extent of dissemination. The Working Formulation for non-Hodgkin lymphomas is a simple and useful nomenclature for selecting treatment and reporting results. The Ann Arbor staging system is a useful but imperfect prognostic indicator.

Bone Marrow↗

PubMed2005

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications.

Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of high-grade, highly proliferating, estrogen receptor- and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor- and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma.

BRCA1 Protein↗

PubMed2001

Atrioventricular septal defects: possible etiologic differences between complete and partial defects.

BACKGROUND: Recent advances in clinical, pathological, and genetic aspects of atrioventricular septal defects (AVSD) have set the stage for epidemiologic investigations into possible risk factors. Previous analyses of the total case group of AVSD included complete and partial subtypes without analysis of the subsets. METHODS: To address the question of possible morphogenetic heterogeneity of AVSD, the Baltimore-Washington Infant Study data on live-born cases and controls (1981-1989) was reanalyzed for potential environmental and genetic risk-factor associations in complete AVSD (n = 213), with separate comparisons to the atrial (n = 75) and the ventricular (n = 32) forms of partial AVSD. RESULTS: Complete and ventricular forms of AVSD had a similar proportion of isolated cases (12.2% and 15.6%, respectively, without associated extracardiac anomalies) and high rates of Down syndrome, whereas the atrial form of partial AVSD included 55% isolated cases. Trisomy 18 occurred in 22% of infants with the ventricular form, compared with <2% in the other AVSD groups. Analysis of potential risk factors revealed further distinctions. Complete AVSD as an isolated cardiac defect was strongly associated with maternal diabetes (odds ratio [OR] = 20.6; 95% confidence interval [CI] =5.6-76.4) and also with antitussive use (OR = 8.8; CI = 1.2-48.2); there were no strong associations other than maternal age among Down syndrome infants with this type of heart defect. Isolated cases with the atrial type of partial AVSD were associated with a family history of heart defects (OR = 6.2; CI = 1.4-24.4) and with paternal occupational exposures to ionizing radiation (OR = 5.1; CI = 1.4-27.4), but no risk factors were associated with Down syndrome. There were no significant associations of any risk factors in the numerically small subsets of isolated and Down syndrome cases with the ventricular form of partial AVSD. CONCLUSIONS: These results indicate a similar risk profile of complete AVSD and the ventricular type of partial AVSD, with a possible subset of the latter due to trisomy 18. Maternal diabetes constituted a potentially preventable risk factor for the most severe, complete form of AVSD.

Adult↗

PubMed1999

Multiple developmental roles of VEGF suggested by a LacZ-tagged allele.

Vascular endothelial growth factor (VEGF) is an angiogenic factor and a potent stimulator of microvascular permeability. It is a mitogen specific for endothelial cells. The expression of VEGF and its two receptors, Flk-1 and Flt-1, is pivotal for the proper formation of blood vessels in embryogenesis as shown by gene-targeting experiments. Interestingly, the loss of even a single allele of VEGF led to embryonic lethality between day E9.5 and day E10.5 in the mouse. To assess the role of VEGF during embryonic development we decided to tag VEGF expression with LacZ, by inserting an IRES (internal ribosome entry site)-LacZ reporter cassette into the 3' untranslated region of the gene. This alteration enabled us to monitor VEGF expression throughout embryonic development at single-cell resolution. beta-Galactosidase expression from the altered VEGF locus was first observed prior to gastrulation and was detectable at all stages of vascular development in the embryo. Later, the specific cellular distribution and the level of VEGF expression indicated its pleiotropic role in development. High expression levels seemed to be associated with vasculogenesis and permeability, whereas lower levels were associated with angiogenesis and cell migration. In addition, we found VEGF expression in a subtype of endothelial cells present in the endocardium. We believe that the LacZ-tagged allele we have generated offers a precise means of detecting VEGF expression under a variety of physiological and pathological conditions.

Alleles↗

PubMed1997

Papillary serous and clear cell type lead to poor prognosis of endometrial carcinoma in black women.

OBJECTIVE: To investigate the significance of race and histologic type as prognostic factors in endometrial carcinoma. METHODS: We conducted a retrospective review of the medical records of all patients diagnosed with endometrial cancer from 1982 to 1995. Patients' clinical and pathologic characteristics were analyzed. RESULTS: The sample consisted of 401 patients, 59.9% (N = 229) were blacks and 40.1% (N = 153) were non-blacks. The mean age was 63.7 +/- 11.6 years. The histologic subtypes of endometrial carcinoma included 346 endometrioid (86.3%), 42 papillary serous (10.5%), and 13 clear cell (3.2%) adenocarcinomas. We found 79% of endometrioid adenocarcinomas were stage I or II compared to 26% of papillary serous tumors and 58% of clear cell carcinomas (P < 0.01). Eighty-eight percent of patients with papillary serous and 77% of patients with clear cell cancers were black (P < 0.01). Within each stage, patients were treated similarly irrespective of cell type or race. Five-year survival for endometrioid, papillary serous and clear cell adenocarcinomas was 69, 18, and 25%, respectively (P < 0.01). Black women had poorer 5-year survival (56%) than non-black women (71%). In multivariate analyses using age, stage, race, and histology, only stage and histology were independent risk factors for survival. CONCLUSIONS: Patients with papillary serous and clear cell endometrial cancer were more likely to be black, present at an advanced stage of disease, and have poor survival compared to patients with endometrioid adenocarcinoma. This may help to explain the poorer survival reported in blacks with endometrial cancer.

Adenocarcinoma, Clear Cell↗

PubMed2007

[Intravascular lymphoma causing acute abdomen].

A 65-year old man presented with acute abdominal pain and fever. The initial diagnosis was small bowel gangrene. Pathology revealed small to large abdominal vessels obliterated by cells of intravascular B-cell-lymphoma (IVL). Visceral IVL involvement is common at autopsy but rarely reported in patients with acute abdomen. The subtype of diffuse large B-cell lymphoma is a rare and aggressive malignancy, which in typical cases is characterized by cephalic or cutaneous manifestation. Few cases showed involvement of large vessels which in combination to fibrin thrombi may lead to infarction of the organ involved. Thus IVL should be considered in cases of ischemic diseases with fever of unknown origin.

Abdomen, Acute↗

PubMed1993

Neuroendocrine differentiation as a prognostic factor in non-small cell lung cancer.

The prognostic value of clinical and pathological factors in 97 patients with non-small cell lung cancer (NSCLC), were analyzed through immunohistochemical methods. The impact on response rate and survival of age, Karnofsky performance status (PS), sex, NSCLC subtype and grade, extent of disease, objective chemotherapy response, LDH values, metastatic sites involved and immunohistochemical markers of neuroendocrine differentiation (neuron specific enolase (NSE), synaptophysin (Sy 38), chromogranin (Chr A) and Leu-7) were analyzed. Median age was 61 years and seven patients were women. Histologically, 58 had squamous cell carcinoma, 28 adenocarcinoma and 11 large cell undifferentiated carcinoma. One patient had Stage II, 35 Stage IIIa, 19 Stage IIIb and 42 Stage IV. Six patients achieved complete response, 18 partial response, 34 stable disease and 39 progressive disease. NSE was negative in 54.3% of cases as was Sy 38 (77.4%), Chr A (97.8%) and Leu-7 (95.8%). We have found correlation between neuroendocrine differentiation and absence of P-Glycoprotein expression; patients included in this subset had a higher response rate but no evidence of longer survival. The univariate analysis showed that four parameters had significant adverse effect on survival: non-responders, poor PS, abnormal LDH value and absence of NSE expression. Multivariate analysis showed that the best combination of independent prognostic factors in predicting survival was: PS and NSE expression by immunohistochemical methods.

Adult↗

PubMed1997

The prognostic importance of peritoneal involvement in colonic cancer: a prospective evaluation.

BACKGROUND & AIMS: Prognostic parameters specific to the colon have been somewhat neglected compared with the rectum. This study was instituted to assess the influence of local peritoneal involvement (LPI) on pelvic and intraperitoneal recurrence and prognosis in an unselected, prospective series of colonic cancer resections. METHODS: Meticulous examination of 412 resections included evaluation of the relation of the tumor to the peritoneal surface. Histological assessment was as follows: 1, peritoneal involvement absent (81 resections, 20%); 2, inflammatory reaction with tumor close but not present at the surface (89 resections, 22%); 3, peritoneal surface unequivocally infiltrated (112 resections, 27%); and 4, peritoneal involvement with ulceration and tumor cells lying apparently free in the peritoneum (130 resections, 32%). RESULTS: LPI showed strong independent prognostic influence in both curative surgery groups and in all patients. In multivariate analysis in curative surgery, LPI was the most powerful prognostic indicator. It was significantly associated with palliative surgery, extent of local spread, and mucinous subtype and predicted cases with subsequent intraperitoneal recurrence and/or persistence. CONCLUSIONS: LPI is a common event in colonic cancer and is a consistent predictor of subsequent intraperitoneal recurrence. It is an important independent pathological prognostic parameter and may supersede other parameters in current usage in colonic cancer prognosis.

Adult↗

PubMed1996

HIV-associated Hodgkin's disease. Biologic and clinical aspects.

The incidence of HD appears to have increased in HIV-infected individuals, with HIV-seropositive intravenous drug users most likely to develop the disorder. All groups at risk for HIV, however, may develop HD. The pathologic spectrum of HD in the setting of HIV infection is distinct from that seen in "de novo" HD in the United States, with the majority of patients diagnosed with the mixed cellularity subtype, as opposed to the more usual occurrence of nodular sclerosis in "de novo" disease. The presence of fibrohistiocytic stromal cells within involved tissues is also a distinct characteristic of HIV-associated HD. Epstein-Barr viral genome has been detected within tumor cell nuclei, and it may be involved in the pathogenesis of disease. Clinically, patients often present with systemic "B" symptoms and widely disseminated extranodal disease, seen in 75% to 90%. Bone marrow is involved in 40% to 50% of cases at diagnosis. Complete remission may be achieved in approximately 50% of patients after use of combination chemotherapy, but median survival is short, in the range of 12 to 18 months. Death is often due to bacterial or opportunistic infection (or both), often occurring in the setting of chemotherapy-induced neutropenia.

AIDS-Related Complex↗

PubMedDate not supplied

CT features of calcifications in abdominal malignant fibrous histiocytoma.

The purpose of this study was to describe the computed tomographic (CT) features of intralesional calcifications in abdominal malignant fibrous histiocytomas (MFH). Forty-three pathologically proven abdominal MFH with preoperative CT were retrospectively reviewed, of which seven tumors with intralesional calcifications were studied with pathohistologic correlation. All seven calcified abdominal MFH belonged to the storiform-pleomorphic subtype with peripherally located calcifications that appeared as either lumpy (three cases) or ringlike (four cases), which were due to the presence of variable amounts of osseous (six cases) and chondroid metaplasia (two cases). About 16% of abdominal MFH, especially the storiform-pleomorphic subtype, exhibited metaplastic calcifications which were characteristically located at the periphery of the tumor and appeared as either lumpy or ringlike on CT.

Abdominal Neoplasms↗