Biomedical subjects

H F Otto

Publications and source records attributed to H F Otto.

At least 19 recordsLinked to original sources

PubMed2005

Right ventricular expression of extracellular matrix proteins, matrix-metalloproteinases, and their inhibitors over a period of 3 years after heart transplantation.

Fibrillar collagens I and III, nonfibrillar collagen IV, and the glycoproteins fibronectin and laminin, are elements of the myocardial extracellular matrix (ECM). Alterations in the normal concentrations and ratios of these elements may reflect remodeling in response to physiologic stress. In the case of patients' post-heart transplantation (HTx), specific patterns of alteration may herald myocardial dysfunction. Right ventricular biopsies were taken from the same 28 HTx patients before implantation and 1 week, 2 weeks, and 1, 2, and 3 years after HTx. The above-noted five ECM proteins, six matrix metalloproteinases (MMPs) and two of their tissue inhibitors (TIMPs) were detected by immunohistochemistry and scored as cells per square millimeter or semiquantitatively. The total connective tissue fibers were detected by connective tissue stain and morphometry. Variations in these ECM components were followed in the same patient cohort over 3 years. In summary, during the first 2 weeks after HTx, a predominant increase in connective tissue occurred. Increases in MMP-8 and MMP-9 were found. By 3 years after transplantation, there was a decrease of connective tissue fibers and a significant reduction of all ECM components and an increase in MMPs and TIMPs. These findings may reflect a pattern of remodeling specific to the transplanted heart.

Adolescent↗

PubMed2005

Extracellular matrix proteins and matrix metalloproteinases differ between various right and left ventricular sites in end-stage cardiomyopathies.

This study was undertaken to investigate whether there might be differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), depending on their specific sites within the heart. We investigated 33 explanted human hearts, 15 with dilated cardiomyopathy (DCM) and 18 with ischemic cardiomyopathy (ICM). Transmural samples from the right ventricle, the interventricular septum and the left ventricle, either from near the apex or from near the base were taken from every heart. Frozen sections were processed for connective tissue staining and immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities of laminin in ICM as well as of fibronectin and collagen types I and IV in DCM showed significant differences between right and left ventricular sites. The volume densities of matrix proteins usually did not reveal significant differences among the three left ventricular sites tested in both DCM and ICM. MMPs partly showed differences between the right and the left ventricular myocardium. These results suggest that the distributions of ECM proteins and MMPs differ between the two ventricles in both end-stage DCM and ICM. This gives rise to the hypothesis that a specific pattern of ECM degradation exists in the right and left ventricular myocardium.

Cardiomyopathy, Dilated↗

PubMed2005

[Ambulatory management of hepatitis B before and after liver transplantation].

HISTORY AND CLINICAL FINDINGS: A 48-year-old patient from Pakistan was referred with scleral icterus, ascites and lower limb edema. DIAGNOSIS: The patient was suffering from post-hepatitis liver cirrhosis, CHILD stage B, with underlying chronic hepatitis B and C coinfection. TREATMENT AND COURSE: One year after diagnosis, orthotopic liver transplantation (OLT) was performed. To avoid recurrence of the hepatitis B in the transplant, the patient was given a treatment with lamivudine preoperatively. A prophylaxis with a combination of lamivudine and hepatitis B immunoglobulin peri- and postoperatively has been given for more than 5 years. CONCLUSION: The use of lamivudine and hepatitis B immunoglobulin improves transplant survival in patients who have undergone OLT on the basis of post-hepatitis liver cirrhosis secondary to chronic hepatitis B. Costs are reduced by administering the hepatitis B immunoglobulin intramuscularly and by managing the preoperative and aftercare of the patient on an outpatient basis.

Ambulatory Care↗

PubMed2004

[Anorectal melanoma. A rare and highly malignant tumor entity of the anal canal].

Anorectal melanomas represent a very small group of mucosal melanoma with unknown etiology and poor prognosis. In view of their location, a history of sun exposure is not likely to have had an impact on their development. Recent epidemiologic data indicate a bimodal age distribution. To date there is no information whether an infection with the human papilloma virus plays a role in the tumorigenesis of anorectal melanoma. The lesions can be misdiagnosed as hemorrhoids on clinical examination. On histological examination amelanotic types have been misdiagnosed as lymphoma, sarcoma,and undifferentiated carcinoma. Useful immunohistochemical markers are S 100 protein, HMB-45, Melan A, and MiTF (microphthalmia-transcription-factor). Therapy includes local excision or abdominoperineal resection followed by optional inguinal and parailiac lymph node dissection, and consecutive chemo- and immunotherapy. The poor long-term prognosis of anorectal melanomas correlates with their advanced tumor size and depth of infiltration at diagnosis. The overall 5-year survival rates range between <5 and 22% in different series.

Anus Neoplasms↗

PubMed2004

[Secondary malignant melanoma of the gallbladder. A contribution to the differential diagnosis of pigmented lesions of the gallbladder].

The history of gallbladder involvement by a malignant melanoma in a 65-year-old woman is reported. The gallbladder, clinically resected for cholecystitis, harboured a polypoid dark pigmented tumour. The tumour was identified as a malignant melanoma immunohistochemically by positive reactions for gp100 (HMB45), melan A, and MiTF. Clinically, the patient was treated for cutaneous malignant melanoma by local excision 10 years earlier. The literature of pigmented lesions of the gallbladder is reviewed. In conclusion, the most important differential diagnosis of pigmented lesions of the gallbladder is the secondary gallbladder melanoma.

Aged↗

PubMed2004

Mutational activation of the RAS-RAF-MAPK and the Wnt pathway in small intestinal adenocarcinomas.

BACKGROUND: Adenocarcinomas of the small and the large intestine share risk factors and morphological features but both tumor types seem to follow different genetic pathways. The aim of this study on small intestinal carcinomas was to analyze alternative mechanisms of activation of pathways that are typically affected in colorectal cancer. METHODS: Twenty-one sporadic carcinomas were investigated for mutations in KRAS, BRAF, the beta-catenin gene CTNNB1, and the mutational cluster region of APC. Immunohistochemical analysis was performed with a monoclonal antibody for beta-catenin, the transcriptionally active downstream component of wnt signaling. RESULTS: Oncogene mutations were found in 13 (62%) small intestinal adenocarcinomas. Twelve tumors displayed a KRAS mutation, and a novel BRAF mutation at codon 603/604 was seen in one carcinoma without KRAS mutation. One tumor harbored a CTNNB1 mutation consisting of an insertion of 247 nucleotides deriving from chromosome 9. APC mutations were identified in 2 tumors. Immunohistochemistry demonstrated nuclear accumulation of beta-catenin in 5 carcinomas. These carcinomas included the tumor with a CTNNB1 mutation but not those with APC mutations. CONCLUSIONS: Our data show frequent activation of the RAS-RAF-MAPK pathway through mutations of either KRAS or, infrequently, BRAF. Activation of the wnt pathway through accumulation of beta-catenin may have a role in a subset of small intestinal adenocarcinomas but in contrast to colorectal carcinoma, accumulation of beta-catenin is generally not caused by inactivating APC or activating CTNNB1 mutations.

Adenocarcinoma↗

PubMed2003

[Gastrointestinal stromal tumors. A morphologic and molecular genetic independent tumor entity with new therapeutic perspectives].

Recent morphological and molecular genetic findings have greatly expanded our understanding of gastrointestinal stromal tumors (GISTs). GISTs are now defined by their overexpression of CD117 (KIT), the receptor for the stem cell factor, and can thus be discriminated from smooth muscle tumors. Cytogenetically, GISTs are characterized even in early lesions by frequent entire or partial loss of the chromosomes 14 and 22 and terminal deletions of the chromosomal arm 1p. During tumor progression further chromosomal imbalances accumulate. Following the first report on activating KIT mutations in GISTs, several studies have addressed the role of wild-type and mutant KIT in GISTs and demonstrated activating KIT mutations in the majority of cases. Moreover, KIT tyrosine phosphorylation is even present in KIT mutation-negative GISTs, implicating KIT activation as a central event in the pathogenesis of GISTs. Imatinib (STI571/Glivec) is a selective inhibitor of BCR/ABL, PDGFR and KIT receptor-tyrosine kinases. First therapeutic applications of imatinib in patients with progressive GISTs have yielded promising results. This review focuses on the morphological and molecular findings in GISTs which have opened up a new therapeutic perspective.

Antigens, CD↗

PubMed2003

Distinct expression of calnexin in major human salivary glands.

Calnexin (Cnx) has been characterized as a membrane-bound protein that transiently interacts in a unique chaperone system with newly synthesized glycoproteins in order to allow the establishment of their proper tertiary and, in most cases, quarternary structures. The aim of the study was to identify and to locate the expression of Cnx in the three major salivary glands of humans by different methods. Strong expression of Cnx protein and mRNA were generally found in serous salivary secretory units. With regard to mucous secretory units, expression of Cnx was only detectable at a low level in mucous acinar cells of sublingual glands, but not of submandibular glands. Expression of Cnx was always preserved in the surface epithelium of intralobar and interlobular duct segments. In addition, expression of Cnx was detected in sebaceous glands of parotid tissues, with a distribution pattern resembling that seen in sebaceous glands of the normal skin. In conclusion, production of saliva is associated with the expression of Cnx. Synthesis of molecules in mucous secretory units is not necessarily associated with a strong Cnx expression, whereas synthesis in serous secretory units apparently is. The tissue-specific Cnx expression is also paralleled by the observation that the secretions produced by the major salivary glands differ in their composition and amount.

Blotting, Western↗

PubMed2002

The index of pulmonary vascular disease in children with congenital heart disease: relationship to clinical and haemodynamic findings.

OBJECTIVE: We asked whether a scoring system [index of pulmonary vascular disease (IPVD)] that quantifies the individual pulmonary vascular pathology would relate to postoperative survival in patients with congenital heart disease and pulmonary hypertension (PH). METHODS: Lung biopsy specimens from 28 patients at a median age of 6 months (1 month to 21 years) were analysed qualitatively and morphometrically. The IPVD and other morphometric parameters were related to haemodynamic findings and survival. RESULTS: Mean pulmonary artery pressure (PAP) was 44 mmHg (15-72 mmHg), and the resistance to pulmonary perfusion was 5 U x m(2) (0.9-14 U x m(2)). There were three early (in-hospital) and three late deaths during the follow-up period of 2.5 years (6 months to 7 years). Incipient plexiform lesions were observed in one infant with trisomy 21 and complete atrioventricular septal defect (cAVSD). An IPVD score above the upper critical limit (>2.2) was not observed during the first year of life. On discriminant analysis, morphometric parameters could not predict mortality ( P=0.08). CONCLUSIONS: The IPVD is not helpful to predict surgical mortality during the first year of life. Patients with trisomy 21 and cAVSD may show advanced pulmonary vascular disease in infancy.

Child↗

PubMed2002

[Carcinoma cuniculatum of the oral cavity. A contribution to the differential diagnosis of potentially malignant papillary lesions of mouth mucosa].

Although carcinoma cuniculatum clinically appears to be malignant, histological evaluation often results in a false diagnosis of a benign papillomatous lesion or pseudoepitheliomatous hyperplasia, because the tumor usually displays a well differentiated tissue. In this report morphological and immunohistological features in a rare case of carcinoma cuniculatum of the oral cavity are described. Both clinical features and histomorphological evaluation must be taken into consideration when diagnosing the tumor.

Aged↗

PubMed2002

Expression of osteopontin (Eta-1) in Crohn disease of the terminal ileum.

BACKGROUND: The causes of Crohn disease (CD) are still regarded as unknown, but impaired mucosal immunoregulation with activation of T-helper-1 (Th-1) cytokine responses is probably involved and may contribute to the morphological changes. We investigated a possible role of osteopontin (Opn) in the pathogenesis of CD. This glycoprotein has been suggested to be involved in the generation of Th-1-type immune responses; moreover, it carries anti-inflammatory activities. METHODS: Ileal samples from CD patients--both actively inflamed and inactive areas as well as unaffected intestinal specimens from controls (normal ileum)--were investigated by Western blot analysis, immunohistochemistry and in situ hybridization. RESULTS: In normal gut, Opn was found to be regularly expressed by plasma cells (CD 38) and a subset of lamina propria mononuclear cells (MNC) as well as by intestinal epithelial cells (IEC). In active CD, immunohistochemistry and in situ hybridization analysis revealed a loss of Opn expression by IEC adjacent to ulcerative lesions, whereas especially plasma cells (CD 38) in the vicinity of such lesions were found to express the molecule. In addition, a slight overexpression of Opn protein was found in metaplastic crypts. However, quantitative analysis of total Opn protein in the ileal mucosa of CD patients did not reveal any difference vis-à-vis control tissues. CONCLUSIONS: The constitutive expression of Opn in normal gut indicates that it is involved in intestinal immune homeostasis. Downregulation of Opn expression in IEC might favour the disintegration of the epithelial barrier. The expression of Opn in lamina propria plasma cells could contribute to disease chronification, probably by affecting cell survival.

Adult↗

PubMed2001

Deleted in Malignant Brain Tumors 1 is a versatile mucin-like molecule likely to play a differential role in digestive tract cancer.

Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor gene for brain, lung, and digestive tract cancer. In particular, alterations of the gene and/or a loss of expression have been observed in gastric, colorectal, and esophageal carcinomas. Initial evidence has accumulated that DMBT1 may represent a multifunctional protein. Because the consequences of a loss of DMBT1 function may be different depending on its original function in a particular tissue, we wondered if it is appropriate to assume a uniform role for DMBT1 in digestive tract carcinomas. We hypothesized that a systematic characterization of DMBT1 in the human alimentary tract would be useful to improve the understanding of this molecule and its role in digestive tract carcinomas. Our data indicate that the expression pattern and subcellular distribution of DMBT1 in the human alimentary tract is reminiscent of epithelial mucins. Bovine gallbladder mucin is identified as the DMBT1 homologue in cattle. An elaborate alternative splicing may generate a great variety of DMBT1 isoforms. Monolayered epithelia display transcripts of 6 kb and larger, and generally show a lumenal secretion of DMBT1 indicating a role in mucosal protection. The esophagus is the only tissue displaying an additional smaller transcript of approximately 5 kb. The stratified squamous epithelium of the esophagus is the only epithelium showing a constitutive targeting of DMBT1 to the extracellular matrix (ECM) suggestive of a role in epithelial differentiation. Squamous cell carcinomas of the esophagus show an early loss of DMBT1 expression. In contrast, adenocarcinomas of the esophagus commonly maintain higher DMBT1 expression levels. However, presumably subsequent to a transition from the lumenal secretion to a targeting to the ECM, a loss of DMBT1 expression also takes place in adenocarcinomas. Regarding DMBT1 as a mucin-like molecule is a new perspective that is instructive for its functions and its role in cancer. We conclude that DMBT1 is likely to play a differential role in the genesis of digestive tract carcinomas. However, although DMBT1 originally has divergent functions in monolayered and multilayered epithelia, carcinogenesis possibly converges in a common pathway that requires an inactivation of its functions in the ECM.

Adenocarcinoma↗

PubMed2001

Splice donor site mutation in the lysosomal neuraminidase gene causing exon skipping and complete loss of enzyme activity in a sialidosis patient.

Sialidosis is a lysosomal storage disease caused by the deficiency of alpha-N-acetylneuraminidase (NEU1; sialidase), the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates. We have identified a homozygous transversion in the last intron (IVSE +1 G>C) in neu1 of a sialidosis patient. Sequencing of the truncated cDNA revealed an alternatively spliced neu1 transcript which lacks the complete sequence of exon 5. Skipping of exon 5 leads to a frameshift and results in a premature termination codon. This is the first description of an intronic point mutation causing a complete deficiency of the lysosomal neuraminidase activity.

Amino Acid Sequence↗

PubMed2001

Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

We have determined the frequency of 918 RET proto-oncogene mutations (ATG-->ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG-->ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild-type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow-up time. However, 918mt patients showed more aggressive development of distant metastases during follow-up (p = 0.032, Fisher's exact test) with decreased metastases-free survival (p < 0.005, log-rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log-rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow-up treatment.

Adult↗

PubMed2001

Anorectal melanomas do not harbour the Kaposi sarcoma-associated human herpesvirus type 8 DNA.

Anorectal melanomas are similar to cutaneous melanomas with regard to the mode of spread and to the immunophenotype. When compared with patients with cutaneous melanoma, those suffering from anorectal melanoma have a much worse outcome. The etiology of anorectal melanomas is as yet completely unknown. For anatomical reasons, ultra-violet (UV-B) radiation can not cause anorectal melanomas as in cutaneous tumours, that are associated with exposure of the skin to UV-B radiation. As the cytokine interleukin-6 (IL-6) is known to stimulate melanoma tumour cell proliferation and a functional homologue of human IL-6 has been identified recently in the HHV-8 genome, this tumorigenic virus might be involved in the pathogenesis of anorectal melanomas. Twelve formalin fixed and paraffin embedded primary anorectal melanomas from seven female and five male patients with a mean age at diagnosis of 71 years (range 38-88 years) were investigated for the presence of HHV-8 DNA. Using a specific and highly sensitive polymerase chain reaction protocol, this tumorigenic gamma-herpesvirus was not detectable in any tumour. This data indicates that HHV-8 is not involved in the development of anorectal melanomas.

Adult↗

PubMed2001

[Pathohistological findings in liver metastases].

Metastatic tumors are the most common malignancies of the liver. The frequency distribution of the primary tumor location site closely resembles the frequency distribution of primary cancers in general. Yet, due to the liver's filter function of the portal blood-stream, metastatic tumors of the gastrointestinal tract are overrepresented. Most metastatic tumors show a nodular growth pattern with a demarcation of the tumor by inflammatory or fibrous reactive tissue; a diffuse metastatic tumor spread within the sinusoids is uncommon. Metastatic liver tumors may be the first clinically detectable manifestation of an unknown primary tumor. In these cases, the histological and immunohistochemical pattern of the metastatic tumor cells may give a clue of the location of the corresponding primary tumor.

Adult↗

PubMed2001

[Pathology of liver cirrhosis and portal hypertension].

Cirrhosis is a late stage finding in chronic liver diseases of different aetiology. It is defined morphologically as a diffuse process with the presence of fibrosis and structurally abnormal nodules. The consequences of cirrhosis are both, mechanical and functional. The mechanical complications result from intra- and extrahepatic shunting of blood and portal hypertension while the functional relevance bases upon a failure of liver cells to perform their physiological role in metabolism, synthesis and secretion. Beside these complications that are directly linked to liver function cirrhosis in itself is a risk factor for hepatocellular carcinoma.

Carcinoma, Hepatocellular↗

PubMed2001

Ellis-van Creveld syndrome: a generalized dysplasia of enchondral ossification.

We report a 25-week fetus with lethal Ellis-van Creveld syndrome who was diagnosed prenatally from the US detection of a narrow chest, postaxial polydactyly of the hands, short acro-/mesomelic limbs and a ventricular septal defect. The postnatal radiographic features of the skeleton confirmed the diagnosis. Literature review of the histopathology of the physeal growth plate is contradictory, varying between retardation of the hypertrophic chondrocytes without disorganization and marked disorganization of the proliferating chondrocytes. We investigated numerous sites of the enchondral ossification and observed retardation of the physeal growth plate in all sites and retardation with pronounced disorganization of the physeal growth plate in the upper mesomelic bone segments only. These data support the concept that Ellis-van Creveld syndrome is mainly a generalized disorder of the maturation of enchondral ossification.

Adult↗