[Incidental finding of a cardiac paraganglioma]. / Zufallsbefund eines kardialen Paraganglioms.

Cardiac paragangliomas are extremely rare neoplasms with an incidence of 1% of all cardiac tumors and can be completely asymptomatic, therefore, diagnosis is difficult. This article reports the case of an 18-year-old man with a heart murmur detected during a routine physical examination. Echocardiography revealed a heart tumor measuring 7 cm in size in the right atrium. Due to the tumor size and the threat of tricuspid valve insufficiency, tumor resection was performed. The histopathological examination revealed a cardiac paraganglioma with positive reactions of the tumor cells for chromogranin A, synaptophysin and CD56. Differentiating a primary cardiac paraganglioma from other more common cardiac tumors and particularly from metastases of neuroendocrine neoplasms from other locations is essential not only for the further clinical treatment but also for the prognosis of the patient.

Smell in cystic fibrosis.

In cystic fibrosis (CF), the most frequent life threatening inherited disease in Caucasians, sinonasal mucosa is regularly affected by defective mucociliary clearance. This facilitates pathogen colonization into CF airways and causes frequent symptoms of rhinosinusitis, including an impaired sense of smell. Despite probable effects on nutrition and overall health, CF-rhinosinusitis is little understood: CF-associated smelling deficiencies reported in literature vary between 12 and 71 %. The aim of this study was to assess olfactory and gustatory function in relation to sinonasal symptoms and sinonasal colonization, and lung function and nutrition. Thirty-five CF patients of different ages were compared to 35 age-matched healthy controls. Olfactory function was assessed by 'Sniffin'Sticks', gustatory qualities by "Taste-strips", and symptoms by sino-nasal outcome test 20 (SNOT-20). Normosmia was found in 62.8 % of healthy controls but only in 28.6 % of CF patients. In contrast the majority of CF patients exhibited a smell loss; almost 62.9 % of them were hyposmic, and 8.6 % functionally anosmic. Importantly, reduced olfactory function only affected odor thresholds, which were significantly increased in CF, not odor identification. This suggests that the olfactory dysfunction in CF results from the olfactory periphery due to either problems in conduction and/or a functional lesion due to the inflammatory process. SNOT-20 scores increased continuously from normosmic to hyposmic and anosmic CF patients (means 7.2/11.1/28.3 points). Neither sinonasal pathogen colonization, gender, pulmonary function, nor allergy or sinonasal surgery appeared to have significant effects on olfactory function and taste. Olfactory disorders are considerably more frequent in CF patients than in age-matched healthy controls. Assessing these parameters within CF-routine care should be considered because of their importance to nutrition and, thus, overall therapy outcome.

Intrapericardial giant lipoma displacing the heart.

Despite their benign character, intrapericardial lipomas can cause life-threatening complications by rapid growth. This paper presents a case of an intrapericardial lipoma in an almost asymptomatic 41-year-old female patient only suffering from mild dyspnoea on exertion. The tumour was found incidentally by chest X-ray. Echocardiographic examination and a CT scan of the thorax revealed a 16 × 14 × 12 cm lipomatous tumour mass highly suspective of a lipoma. Histological examination of excised tumour specimens confirmed the diagnosis of a lipoma. The patient is currently asymptomatic and has not presented with evidence of recurrence at the 6-month followup.

Two malignant tumours in the anterior mediastinum positive for CD5.

To our knowledge, the simultaneous involvement of the anterior mediastinum by a thymic carcinoma and a B-cell chronic lymphocytic leukaemia has not been reported previously. The authors describe the case of a 62-year-old man, suffering from severe bronchitis. Chest x-ray and CT scan showed a mediastinal tumour, resected short-time after diagnosis. First, standard based histological examination revealed a thymic carcinoma admixed by a dense lymphatic infiltrate. Additional immunohistochemical staining for CD5-labelled epithelial thymic carcinoma cells as well as neoplastic B cells and led in combination with blood tests to confirm the diagnosis of the composite occurrence of a thymic carcinoma and a B-cell chronic lymphocytic leukaemia.

Connective tissue changes in a mouse model of vein graft disease.

AIM: The extracellular matrix plays an important physiological role in the architecture of the vascular wall. In arterialized vein grafts severe early changes, such as thrombosis and neointimal hyperplasia occur. Paclitaxel is in clinical use as antiproliferative coating of coronary stents. We aimed to investigate the early connective tissue changes in arterialized vein grafts and the influence of perivascular paclitaxel treatment in an in vivo model. METHODS: C57 black mice underwent interposition of the vena cava into the carotid artery. Neointimal hyperplasia, thrombosis, acid mucopolysaccharides (Alcian), collagen fibers (trichrome Masson), elastic fibers, and apoptosis rate (TUNEL) were quantified in paclitaxel treated veins and controls. RESULTS: In both, controls and paclitaxel treated vein grafts acid mucopolysaccharides and elastic fibers were found predominantly in the neointima, whereas collagen fibers were found mainly in the media and adventitia. At 4 weeks postoperatively the neointimal thickness in controls was 52 (13-130) microm, whereas in 0.6 mg/mL l paclitaxel treated veins it was 103 (43-318) microm (P=0.094). At 8 weeks postoperatively paclitaxel treated veins showed a significantly increased neointimal thickness of 136 (87-199) microm compared with 79 (62-146) microm in controls (P=0.032). There was no difference in apoptosis rate between the two groups (P=NS). Even with the lowest concentration of 0.008 mg/mL paclitaxel veins showed a neointimal thickness of 67 (46-205) microm at 4 weeks postoperatively (P=NS vs controls). CONCLUSION: Early vein graft disease is characterised by an accumulation of acid mucopolysaccharides and elastic fibers in the thickened neointima. Paclitaxel treatment increases the neointimal hyperplasia in mouse vein grafts in vivo.

QT prolongation due to aortic aneurysm rupture and amiodarone in a patient with a H558R polymorphism in the cardiac sodium channel gene SCN5A.

The duration of the QT interval is influenced by many pathologic processes and drugs. We report a 74-year-old man who was admitted after syncope. His electrocardiogram (ECG) showed a QT interval of 0.44 s (QTc 0.53 s). After 10 h a ruptured abdominal aortic aneurysm was diagnosed and the patient underwent implantation of an aorto-bi-iliac Y-prosthesis. After surgery QT interval normalized. Under therapy with amiodarone, given because of atrial fibrillation, QT prolongation occurred again and disappeared after discontinuation of amiodarone. The postoperative course was complicated by critical illness polyneuropathy and plexopathy. Whereas amiodarone is a well recognized cause of QT prolongation, aortic aneurysm rupture has not been described previously. Vegetative mechanisms and sudden decrease of cardiac afterload due to the ruptured aneurysm may have altered myocardial repolarisation and thus prolonged QT interval duration. In conclusion in a patient with syncope and QT prolongation, extracardiac causes like rupture or an aortic aneurysm have to be included into the differential diagnosis.

The occurrence of malolactic fermentation in brandy base wine and its influence on brandy quality.

AIMS: In this study we determined the extent to which lactic acid bacteria (LAB) occurred in brandy base wines, their ability to catalyse the malolactic fermentation (MLF) and the effect of MLF on the quality of the base wine and the brandy distillate. METHODS AND RESULTS: Lactic acid bacteria were isolated and enumerated from grape juice, experimental and commercially produced brandy base wines. Spontaneous MLF occurred in approximately 50% of the commercial base wines. The occurrence of MLF had an influence on the quality of the base wines and the resulting distillates. In samples where MLF occurred there was a loss of fruitiness and in the intensity of aroma. Volatile compounds like iso-amyl acetate, ethyl acetate, ethyl caproate, 2-phenethyl acetate and hexyl acetate decreased in samples having undergone MLF, while ethyl lactate, acetic acid and diethyl succinate increased in the same samples. CONCLUSIONS: Spontaneous malolactic fermentation does occur in commercial brandy base wines and it has an influence on base wine and brandy quality. SIGNIFICANCE AND IMPACT OF THE STUDY: This study showed that MLF influences the quality of the base wine and the resulting distillate and with this in mind commercial base wine producers should be able to produce brandy of higher quality.

Marketing to America's youth: evidence from corporate documents.

OBJECTIVE: To evaluate the claim that the tobacco industry does not market its products to youth. DESIGN: The data for this study come from tobacco industry documents collected from the tobacco industry's document websites, presently linked at http://www.tobaccoarchives.com. The websites were searched using "request for production" (RFP) codes, specified keyword searches, and serendipitous terms identified in document citations found with RFP and keyword searches. RESULTS: Industry documents show that the cigarette manufacturers carefully monitored the smoking habits of teenagers over the past several decades. Candid quotes from industry executives refer to youth as a source of sales and as fundamental to the survival of the tobacco industry. The documents reveal that the features of cigarette brands (that is, use of filters, low tar, bland taste, etc), packaging (that is, size, colour and design), and advertising (that is, media placements and themes and imagery) were developed specifically to appeal to new smokers (that is, teenagers). Evidence also indicates that relevant youth oriented marketing documents may have been destroyed and that the language used in some of the more recent documents may have been sanitised to cover up efforts to market to youth. CONCLUSIONS: The tobacco industry's internal documents reveal an undeniable interest in marketing cigarettes to underage smokers. The industry's marketing approaches run counter to and predicate methods for tobacco prevention: (1) keep the price of the product high; (2) keep product placements and advertising away from schools and other areas with a high volume of youth traffic; (3) make cigarette advertising (that is, themes and visual images) unappealing to youth; (4) make product packaging unappealing to youth; and (5) design the product so it is not easy to inhale.

Regulation of MCP-3 and BRCA2 mRNA expression levels by beta(1) integrins.

The integrin cytoplasmic domain has been shown to modulate several cellular functions, including cell proliferation, adhesion, migration, and intracellular signaling. The beta(1) integrin subunits beta(1C) and beta(1A), which contain variant cytoplasmic domains, differentially affect cancer and normal cell functions. To identify target genes selectively regulated by these beta(1) cytoplasmic variants, stable cell transfectants expressing either beta(1A) or beta(1C) under the control of a doxycycline-inducible promoter were obtained using murine beta(1)-deficient GD25 cells. Screening of 1176 murine cDNAs using first-strand cDNA of mRNA isolated from either beta(1C)- or beta(1A)-expressing cells showed a striking differential expression of few genes. The differential expression of two genes, MCP-3 and BRCA2 (monocyte chemoattractant protein-3 and breast cancer susceptibility gene 2, respectively), whose products are involved, respectively, in chemotaxis and embryonic proliferation, was confirmed by Northern blot analysis. Increased MCP-3 and decreased BRCA2 mRNA levels in cells expressing beta(1C) compared to those in cells expressing beta(1A) were observed. Since beta(1C) and beta(1A) stable cell transfectants showed comparable adhesion to fibronectin, upregulation of MCP-3 and downregulation of BRCA2 mRNA levels did not appear to be due to a differential ability of the beta(1C) cells to adhere to the beta(1) ligand fibronectin. Overall, our data show that beta(1) integrin cytoplasmic domain variants control expression of downstream target genes in a differential manner without affecting cell adhesion.

A phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma.

BACKGROUND: Unresectable adenocarcinomas of the biliary tree have a very poor prognosis. No good chemotherapeutic regimen is available. Irinotecan has not yet been fully tested in this disease. We evaluated its activity in unresectable bile duct cancers. PATIENTS AND METHODS: Twenty-five consecutive eligible patients at our two institutions were treated with irinotecan at a starting dose of 125 mg/m2. A cycle consisted of once-a-week treatments for four consecutive weeks, followed by two weeks of rest. All patients were required to have histologically confirmed diagnosis, clinically documented metastatic or unresectable carcinoma and measurable disease. Patients were evaluated for response, toxicity, and survival. RESULTS: A total of 83 cycles of therapy were delivered. Two patients had a partial response (8%; 95% confidence interval (CI): 0%-18%) and ten additional patients had stable disease for at least two months (40%; 95% CI: 20.8%-59.2%). The therapy was well tolerated, with moderate myelosuppression and diarrhea as the main toxicities. The overall median survival was 10 months. CONCLUSIONS: Irinotecan has minimal activity in biliary tree carcinomas, but is well tolerated with appropriate supportive care, and produces occasional objective responses.

A phase II study of irinotecan in patients with advanced hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma has a poor prognosis. In a Phase II clinical trial, two academic centers assessed irinotecan, a topoisomerase-1 inhibitor with broad spectrum clinical activity, in patients who had advanced hepatocellular cancer. METHODS: Patients who had had up to one prior chemotherapy regimen were eligible. Bidimensionally measurable disease, a good performance status, and adequate major organ function were required. At a starting dose of 125 mg/m2, irinotecan was administered weekly for 4 weeks followed by a 2 week break, which constituted 1 treatment cycle. Patients were restaged radiologically after two cycles of therapy. Dose attenuations were made as indicated for toxicity. RESULTS: Fourteen patients were enrolled over a 10-week period in 1997. There were ten males and four females. The median age was 58 years (range, 38-74 yrs). The Eastern Cooperative Oncology Group median performance status was 1 (range, 0-1). Two patients had prior chemotherapy (14%), and 1 patient (7%) had had radiation. A total of 30 cycles of therapy were delivered (median, 1; range, 1-6). Considerable toxicity was observed, mostly neutropenia, diarrhea, nausea, vomiting, and fatigue. All patients required at least one dose attenuation for toxicity. One partial response (7%; confidence interval, 0-20%) was noted to last 7 months. One patient had transient stable disease, and all others (86%) had progression of disease as their best response. CONCLUSIONS: Irinotecan had modest activity in advanced hepatocellular cancer. Toxicity was substantial, presumably reflecting impaired underlying liver function or poor ability to metabolize and eliminate the drug. The current study indicated that continued new therapy assessment is warranted for this disease.

Differential role of beta(1C) and beta(1A) integrin cytoplasmic variants in modulating focal adhesion kinase, protein kinase B/AKT, and Ras/Mitogen-activated protein kinase pathways.

The integrin cytoplasmic domain modulates cell proliferation, adhesion, migration, and intracellular signaling. The beta(1) integrin subunits, beta(1C) and beta(1A), that contain variant cytoplasmic domains differentially affect cell proliferation; beta(1C) inhibits proliferation, whereas beta(1A) promotes it. We investigated the ability of beta(1C) and beta(1A) to modulate integrin-mediated signaling events that affect cell proliferation and survival in Chinese hamster ovary stable cell lines expressing either human beta(1C) or human beta(1A). The different cytodomains of either beta(1C) or beta(1A) did not affect either association with the endogenous alpha(2), alpha(V), and alpha(5) subunits or cell adhesion to fibronectin or TS2/16, a mAb to human beta(1). Upon engagement of endogenous and exogenous integrins by fibronectin, cells expressing beta(1C) showed significantly inhibited extracellular signal-regulated kinase (ERK) 2 activation compared with beta(1A) stable cell lines. In contrast, focal adhesion kinase phosphorylation and Protein Kinase B/AKT activity were not affected. Selective engagement of the exogenously expressed beta(1C) by TS2/16 led to stimulation of Protein Kinase B/AKT phosphorylation but not of ERK2 activation; in contrast, beta(1A) engagement induced activation of both proteins. We show that Ras activation was strongly reduced in beta(1C) stable cell lines in response to fibronectin adhesion and that expression of constitutively active Ras, Ras 61 (L), rescued beta(1C)-mediated down-regulation of ERK2 activation. Inhibition of cell proliferation in beta(1C) stable cell lines was attributable to an inhibitory effect of beta(1C) on the Ras/MAP kinase pathway because expression of activated MAPK kinase rescued beta(1C) antiproliferative effect. These findings show that the beta(1C) variant, by means of a unique signaling mechanism, selectively inhibits the MAP kinase pathway by preventing Ras activation without affecting either survival signals stimulated by integrins or cellular interactions with the extracellular matrix. These findings highlight a role for beta(1)-specific cytodomain sequences in maintaining an intracellular balance of proliferation and survival signals.

Expression and function of sialoadhesin in rat alveolar macrophages.

Alveolar macrophages (Amφ) represent an immunologically distinct sub-population within the reticuloendothelial system. Phagocytosis and possibly antigen presentation by Amφ are essential components of specific and innate primary immune defence processes against inhaled material. The mφ-restricted sheep erythrocyte receptor sialoadhesin (Sn) is a member of the immunglobulin superfamily and binds specifically to sialic acid-containing structures such as selectins and was originally identified as the sheep erythrocyte receptor (SER) responsible for sialic acid-dependent binding of native sheep erythrocytes (SE) to resident murine bone marrow macrophages in rosetting assays. Sn expression has been demonstrated on murine and rat mφ in lymphatic organs and is recognised by the monoclonal antibody (mAb) ED3 in the rat. In addition, sialic acid-dependent receptor (SAR) activities that mediate rosette formation of alveolar, peritoneal, splenic and bone marrow-resident rat mφ with SE pretreated with gangliosides and SER-like activities between native SE and trypsinised Amφ, have been described. The binding activities of both SAR and Sn show similar characteristics suggesting that these molecules are closely structurally related or identical. To clarify the relationship between Sn, SAR and SER-like activities, the binding of mAb ED3 to isolated rat Amφ was investigated by flow cytometry and rosetting assays. It is demonstrated that rat Amφ express Sn and evidence is provided that SAR and SER-like activities are mediated by Sn.

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors.

PURPOSE: In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS: To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS: Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION: The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.

Techniques for a structural analysis of dermatoscopic imagery.

Techniques were developed for automated detection and characterization of dermatoscopic structures, including the pigment network and brown globules. These techniques incorporate algorithms for grayscale shape extraction based on differential geometry developed by Steger, a snake algorithm, and a modification of the region competition strategy of Zhu and Yuille. A novel approach was developed for global segmentation of pigmented lesions, based on stabilized inverse diffusion equations. Procedures for detection of air bubbles and hairs in dermatoscopic images are also reported.

Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors.

PURPOSE: To determine the maximum-tolerable dose (MTD) of fluorouracil (5FU) when given with fixed doses of leucovorin and irinotecan (CPT-11), to define the dose-limiting toxicities of this combination, and to evaluate the effect of 5FU on the pharmacokinetics of CPT-11. PATIENTS AND METHODS: CPT-11, leucovorin, and 5FU were administered in repeated 6-week cycles that consisted of weekly treatment with all three drugs for 4 consecutive weeks followed by a 2-week break. On day 1 of treatment, CPT-11 alone was given by 90-minute infusion, and pharmacokinetic sampling was performed over 24 hours. Leucovorin and 5FU were administered by brief intravenous injection on day 2. On days 8, 15, and 22, CPT-11 infusion was immediately followed by leucovorin and then 5FU. A second 24-hour pharmacokinetic sampling was performed on day 8, which permitted comparison of the pharmacokinetics of CPT-11 with and without 5FU. For the second 6-week cycle, leucovorin was administered first, followed by 5FU and then CPT-11, and a third pharmacokinetic sampling was performed. RESULTS: Forty-two patients were entered onto this trial. The CPT-11 dose was initially fixed at 100 mg/m2. Leucovorin was fixed at 20 mg/m2. 5FU doses of 210, 265, 340, 425, and 500 mg/m2 were studied. When the 500-mg/m2 dose of 5FU was found to be tolerable, this was then maintained and CPT-11 was escalated to 125 and then 150 mg/m2. This final CPT-11 dose exceeded the MTD. Neutropenia was the major dose-limiting toxicity. Diarrhea was common, but was rarely dose-limiting. Coadministration of 5FU had no substantial effect on the pharmacokinetics of CPT-11 or SN-38. Among the 38 patients with colorectal cancer, six partial responses (PRs) were seen in this predominantly 5FU-refractory patient population. CONCLUSION: 5FU does not substantially affect the metabolism of CPT-11 to its active metabolite, SN-38. The combination of CPT-11125 mg/m2, 5FU 500 mg/m2, and leucovorin 20 mg/m2 is feasible and tolerable on this schedule.

Maturation of collagen fibrils in the corneal stroma results in masking of tyrosine-rich region of type V procollagen.

PURPOSE: To determine the molecular form of type V procollagen in collagen fibrils in mammalian corneal stromas. METHODS: The presence of the tyrosine-rich region in the NH2-propeptide of type V procollagen in collagen fibrils was examined in human, bovine, and mouse corneas and human corneal fibroblast cultures by immunofluorescence microscopy and immunoblot analysis using a polyclonal antibody specific for this region. The antibody was generated using a glutathione S-transferase-fusion peptide. RESULTS: The tyrosine-rich region was detected readily in frozen sections of 5- to 6-month-old mouse corneal stromas without the need for any unmasking techniques, indicating that this domain is exposed on the surface of striated collagen fibrils. In contrast, frozen sections of adult human and bovine corneas did not label with the polyclonal sera to the tyrosine-rich region. Immunoblot analysis of bacterial collagenase digests of human and bovine corneas, however, indicated that peptide fragments containing the tyrosine-rich region of type V procollagen and of the expected molecular weight of 70 to 85 kDa were present. Further immunofluorescence microscopic studies and immunoblot analysis of mouse corneas at different ages and of collagen fibrils formed in human corneal fibroblast cultures over time indicated that, initially, the tyrosine-rich region of type V procollagen could be detected in all these collagen fibrils; however, as the age of the mouse and the culture increased, the ability to detect this region decreased. CONCLUSIONS: These results suggest that, in vivo, the tyrosine-rich region of type V procollagen is retained on type V procollagen molecules within mammalian collagen fibrils from corneal stromas and that this region becomes masked as collagen fibrils mature or the species ages.

Contrasting resources in disturbed and non-disturbed family systems.

Previous research has shown that problems in family functioning and psychological disturbances in children are closely related. To increase understanding of this complex interaction the present review sets out to make explicit certain aspects of the relationship between child psychopathology and the quality of family life. The usefulness of the concept of resources for analysing major aspects of family functioning (contextual, intra-familial and extra-familial) is discussed within a systems framework and is then applied to a wide range of empirical studies which relate important features of family functioning to disturbed behaviour in children. It is found that interpersonal conflict in the lives of parents before marriage may severely constrain their own psychological development. When the psychological effects of such early disadvantage are amplified by marital conflict other family members are also affected. The notion of resources requires such disabilities to be assessed as well as directing attention to non-family interactions which offer compensating supports.