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Biomedical subjects

M P Manns

Publications and source records attributed to M P Manns.

At least 19 recordsLinked to original sources
PubMed2003

Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells.

Telomere shortening limits the regenerative capacity of primary cells in vitro by inducing cellular senescence characterized by a permanent growth arrest of cells with critically short telomeres. To test whether this in vitro model of cellular senescence applies to impaired organ regeneration induced by telomere shortening in vivo, we monitored liver regeneration after partial hepatectomy in telomerase-deficient mice. Our study shows that telomere shortening is heterogeneous at the cellular level and inhibits a subpopulation of cells with critically short telomeres from entering the cell cycle. This subpopulation of cells with impaired proliferative capacity shows senescence-associated beta-galactosidase activity, while organ regeneration is accomplished by cells with sufficient telomere reserves that are capable of additional rounds of cell division. This study provides experimental evidence for the existence of an in vivo process of cellular senescence induced by critical telomere shortening that has functional impact on organ regeneration.

Animals↗
PubMed2003

77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence for a genetic link.

Autoimmune hepatitis is a chronic immune-mediated disease characterized by a loss of tolerance against liver resident antigens. The genetic background of autoimmune hepatitis is considered to be polygenic. Here we analyzed the genetic association of the tyrosine phosphatase CD45 and autoimmune hepatitis. CD45 plays an important role in normal antigen receptor mediated signaling in T and B cells. A point mutation at nucleotide position 77 of the CD45 gene results in abnormal CD45 splicing. In this study a significantly higher frequency of the 77 C/G genotype was observed in 190 autoimmune hepatitis patients when compared to 210 healthy blood donors. Our data identify CD45 as a gene associated with AIH, and further substantiates the hypothesis that CD45 represents a modifier gene of human autoimmunity.

Confidence Intervals↗
PubMed2003

Increasing sensitivity of morphological diagnosis in hepatocellular carcinoma (HCC) by combination of cytological and fine-needle histological examination after ultrasound guided fine needle biopsy.

UNLABELLED: Increasing sensitivity of morphological diagnosis by combination of cytological and fine-needle histological examination after ultrasound guided fine needle biopsy in hepatocellular carcinoma (HCC). AIM: We investigated the factors which may affect the sensitivity of morphological diagnostics (cytology and fine-needle histology) in HCC after ultrasound guided biopsy. METHOD: In 62 patients, an ultrasound guided cytological (n = 62) and fine-needle histological (n = 45) biopsy was performed. In addition, the smears were investigated by cytophotometry (n = 62). RESULTS: Considering each method separately, the sensitivity of both cytological and histological diagnostics was about 80%. The sensitivity could be raised to 89% by combining the two methods. In seven patients, the HCC could not be primarily confirmed morphologically. In nine patients, the result of histological and cytological investigation was not congruent. With regard to the size of the biopsied lesion, tumor stage, cytophotometric finding and survival these 16 patients (group A) were compared with the 46 patients in whom the HCC could be primarily confirmed morphologically (group B). The statistical analysis did reveal a significantly lower percentage of tumors with diploid or tetraploid (euploid) cells in group B. Euploid tumors were significantly more highly differentiated. In patients with euploid tumors, the sensitivity of the cytological investigation was 67% and respectively 75% of the histological investigation. The sensitivity could be raised to 82% in this population by combining the two investigations. On the other hand in aneuploid tumors, the sensitivity could only be increased from 93% and 88% respectively to 97% by combining cytology and fine-needle histology. SUMMARY: Our investigations show that the sensitivity of morphological diagnostics can be raised especially in the highly differentiated HCC with a physiological DNA content by combination of cytological and fine-needle histological investigations.

Adult↗
PubMed2003

[Treatment of chronic hepatitis C with PEG-interferon alpha-2b and ribavirin: 24 weeks of therapy are sufficient for HCV genotype 2 and 3].

Patients with chronic hepatitis C infected with HCV genotype 2 and 3 can be successfully treated in more than 80 % of cases. It had been shown that a 24 week t.i.w. treatment period with standard interferon alpha and ribavirin is sufficient for these patients. However, the recent multicenter studies investigating the effect of pegylated interferons and ribavirin used a 48 week schedule for all patients irrespective of the HCV genotype. Thus, we prospectively investigated the efficacy of a 24 week treatment period with pegylated interferon alpha-2b (1.0-1.5 microg/kg o.i.w.) and ribavirin (1-1.2 g daily) in 54 patients with HCV-genotype 2 and 3 at two different sites. 29 patients were included in Herne (private practice) and 25 patients were treated in Hannover (Medical School). After the end of follow-up 46 (85%) patients showed a virological sustained response in the intent to treat analysis. Only four patients demonstrated a virological treatment failure (3 relapse, 1 breakthrough), two patients were non-compliant, and at each center therapy was stopped in one patient due to adverse events. There was no difference regarding treatment response between both sites, even though the patients in Herne were treated only with 1,0 microg/kg PEG-IFN alpha-2b, while patients in Hannover received 1,5 microg/kg PEG-IFN alpha-2b. In conclusion, the response rates of this study do not differ from the results of the 48 week treatment period of the recently published multicentre trials. Thus, we suggest treating all patients with HCV-genotype 2 and 3 for only 24 weeks when PEG-IFN alpha-2b is used in combination with ribavirin.

Adolescent↗
PubMed2003

A novel AIRE mutation in an APECED patient with candidiasis, adrenal failure, hepatitis, diabetes mellitus and osteosclerosis.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder, which is characterized by an immune-mediated destruction of endocrine tissues, chronic candidiasis and ectodermal disorders. In contrast to many other autoimmune diseases, APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE). We describe an APECED patient with severe deformities of the tibia with radiological signs of metaphyseal dysplasia in addition to candidiasis, hepatitis, diabetes mellitus and adrenal failure. In this patient, we identified a novel AIRE mutation in association with the C322fsX372 mutation in exon 8, which is frequently detected in Caucasian patients. The frame shift mutation G263fsX377 in exon 6 results in a protein lacking both PHD zinc-finger domains similar to the R257 X mutation. This novel mutation was not found in 50 German controls.

Adrenal Insufficiency↗
PubMed2003

Lupus-like panniculitis in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder, characterised by a loss of self-tolerance to endocrine tissues, chronic candidiasis and ectodermal disorders. APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE). We describe a 31-year-old APECED patient with non-traumatic, cutaneous ulcers on both forearms with features of a lupus-like panniculitis. On admission to the ICU in September 2001, the patient suffered from a ketoacidotic, hyperglycemic coma and adrenal crisis due to an Enterobacter-cloacae sepsis, originating from multiple, necrotising deep cutaneous ulcers. These ulcers spontaneously developed on both forearms, some of which were just emerging, full blown or healing with scars. Histological examination showed signs of a scarring panniculitis and vasculitis. Immunohistochemistry and direct immunofluorescence with characterisation of immunoglobulin and complement-factor binding pattern revealed features of a lupus-like panniculitis. Sequence analysis of all 14 exons of the AIRE gene revealed a R257 X mutation in exon 6 resulting in a nonsense mutation at codon 257 confirming the diagnosis of APECED. Oral treatment with 60 mg/day corticosteroids for two weeks led to complete resolution of all ulcers. In conclusion, mutations in the AIRE gene may provide the genetic background against which additional factors can initiate an autoimmune process. Here, autoimmune panniculitis appears to be an associated feature of the APECED syndrome. Our findings support the use of immunosuppressive therapy for autoimmune disease components of the APECED syndrome.

Adult↗
PubMed2003

Cost effectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C.

BACKGROUND: Peginterferon alpha-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. AIMS: To estimate the cost effectiveness of treatment with peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. METHODS: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. RESULTS: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon alpha-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11,800 euros and 6600 euros per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. CONCLUSIONS: Peginterferon alpha-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.

Adult↗
PubMed2003

Telomere shortening of epithelial cells characterises the adenoma-carcinoma transition of human colorectal cancer.

BACKGROUND: and aims: Chromosomal instability is one of the most consistent markers of sporadic colorectal cancer in humans. There is growing evidence that telomere shortening is one of the mechanisms leading to chromosomal instability and cancer initiation. METHODS: To test this hypothesis, the telomere length of colorectal epithelial cells and cells from connective tissue was determined at the adenoma-carcinoma transition at the cellular level by quantitative fluorescence in situ hybridisation. RESULTS: Our study showed that the telomere fluorescence intensity of epithelial cells was significantly weaker at the earliest morphologically definable stage of carcinoma-high grade dysplasia with minimal invasive growth-compared with the surrounding adenoma. In contrast, cells from connective tissue had a similar telomere signal intensity at the carcinoma stage compared with the adenoma, and in turn cells from connective tissue had overall significantly stronger telomere fluorescence signals compared with epithelial cells. CONCLUSIONS: These results demonstrate that short telomeres of epithelial cells characterise the adenoma-carcinoma transition during human colorectal carcinogenesis, suggesting that carcinomas arise from cells with critical short telomeres within the adenoma. Since the adenoma-carcinoma transition in colorectal cancer is characterised by an increase in chromosomal instability and anaphase bridges, our data support the hypothesis that short telomeres initiate colorectal cancer by induction of chromosomal instability.

Adenoma↗
PubMed2003

Acute CMV-colitis in a patient with a history of ulcerative colitis.

A symptomatic cytomegalovirus (CMV) infection usually occurs in patients with debilitating diseases, immunosuppression, transplantations and acquired immunodeficiency syndrome (AIDS). Gastrointestinal infections with CMV, especially colitis, are usually found in immunocompromised patients and rarely affect immunocompetent subjects. Here we report the case of a young female patient with a history of ulcerative colitis (UC) who presented with an acute attack of colitis caused by CMV infection. This was documented by the presence of CMV early antigen, antibodies and evidence of CMV in the colonic mucosa. After combined anti-inflammatory and antiviral treatment the patient recovered completely. As most attention is given to CMV-pathogeneity in immunocompromised patients, here we discuss the relationship to inflammatory bowel diseases.

Acute Disease↗
PubMed2002

[Helper cells, viral load, genetic factors, co-infections. Prognostic factors in HIV-1 infection].

The ideal time to initiate antiretroviral therapy in asymptomatic patients with chronic HIV infection remains to be defined. The most relevant laboratory parameter is the CD4 cell count. Therapy should be started before the CD4 cells drop below 200/microliter and the immune system becomes compromised. In contrast to past recommendations, viral load should not be used as a single laboratory parameter for initiation of antiretroviral therapy in asymptomatic untreated patients. The determination of genetic factors to assess the prognosis of HIV patients has not yet been incorporated into daily clinical practice. While co-infection with GBV-C is a prognostically favorable factor for the course of the HIV infection, replicative hepatitis C is associated with increased mortality.

AIDS-Related Opportunistic Infections↗