Search PubMed⌕ Search

Biomedical subjects

J Klempnauer

Publications and source records attributed to J Klempnauer.

At least 73 records · Page 4Linked to original sources
PubMed2000

Engineering of a glucose-responsive surrogate cell for insulin replacement therapy of experimental insulin-dependent diabetes.

Glucose responsiveness in the millimolar concentration range is a crucial requirement of a surrogate pancreatic beta cell for insulin replacement therapy of insulin-dependent diabetes. Novel insulin-secreting GK cell clones with millimolar glucose responsiveness were generated from an early-passage glucose-unresponsive RINm5F cell line. This line expressed constitutively both the K(ATP) channel and the GLUT2 glucose transporter; but it had a relative lack of glucokinase. Through overexpression of glucokinase, however, it was possible to generate glucose-responsive clones with a glucokinase-to-hexokinase ratio comparable to that of a normal pancreatic beta cell. This aim, on the other hand, was not achieved through overexpression of the GLUT2 glucose transporter. Raising the expression level of this glucose transporter into the range of rat liver, without correcting the glucokinase-to-hexokinase enzyme ratio, did not render the cells glucose responsive. These glucokinase-overexpressing RINm5F cells also stably maintained their molecular and insulin secretory characteristics in vivo. After implantation into streptozotocin diabetic immunodeficient rats, glucokinase-overexpressing cells retained their insulin responsiveness to physiological glucose stimulation under in vivo conditions. These cells represent a notable step toward the future bioengineering of a surrogate beta cell for insulin replacement therapy in insulin-dependent diabetes mellitus.

Animals↗
PubMed2000

Differentiation of multicentric origin from intra-organ metastatic spread of hepatocellular carcinomas by comparative genomic hybridization.

In hepatocellular carcinoma (HCC), multifocal growth may be due to intrahepatic metastatic spread or to the multicentric origin of clonal neoplasms. Although this issue is of potential clinical and prognostic importance, reliable differentiation cannot be achieved using clinical or morphological criteria alone. In this study, comparative genomic hybridization (CGH) was used to differentiate between metastatic spread and multicentric growth in two cases of HCC. In the first case, six carcinoma nodules were examined. The affected chromosomes and their pattern of aberrations were almost identical for all six nodules. In addition to aberrations of chromosomes 1, 4, 9, and 13, further aberrations were observed for chromosomes 2, 5, 7, and 17, which are less typical for HCC. These findings were seen as indicative of metastatic spread of the HCC. In the second case, 75% (3/4) of the nodules showed comparable aberration patterns involving chromosomes 1, 4, 8, 13, and 17, together with a number of further aberrations also not frequently seen in HCC including chromosomes 5, 7, 10, 12, 14, and 18. Chromosomes 4, 5, 8, 10, and 12 were also altered in the fourth nodule examined for this case, but they exhibited a unique aberration pattern. Additionally, gain of chromosome 15q was seen in only this fourth nodule. In the two cases examined, metastatic spread and multicentric origin of HCC could be differentiated by different patterns of karyotypic change. The CGH results were confirmed by fluorescence in situ hybridization (FISH). In conclusion, CGH facilitates the differentiation of multicentric growth from metastatic spread in HCC and appears to be superior to techniques previously used to resolve this clinically important diagnostic problem.

Adult↗
PubMed2000

[Hepatitis and liver transplantation].

Chronic hepatic dysfunction and acute liver failure due to viral hepatitis represent the most frequent indications for liver transplantation. Liver grafting is the only available life-saving intervention for most of these patients. Reinfection of the graft is still a central problem. In hepatitis B, reinfection frequently leads to cirrhosis with subsequent dysfunction of the graft. Prophylaxis of HBV reinfection with polyclonal human antibodies against HBsAg alone or in combination with the nucleoside analogue lamivudine is effective but costly. Reinfection in hepatitis C is a regular event in all patients and has a far better prognosis than HBV reinfection of the graft. Effective prophylaxis of HCV reinfection has still not been established and requires further studies. After HCV reinfection the prognosis of allograft survival is negatively affected; however, the 5-year survival rate in patients who have undergone liver transplantation for HCV-related liver disease is not lower than for other non-viral benign indications.

Hepatitis B, Chronic↗
PubMed2000

Familial papillary thyroid carcinoma: genetics, criteria for diagnosis, clinical features, and surgical treatment.

Hereditable predisposition to papillary thyroid carcinoma (PTC) and multinodular goiter (MNG) without evidence of an association with other malignancies as a distinct entity was recognized only recently. A meta-review of the literature on familial PTC (FPTC) was undertaken, and characteristics of families with frequent occurrence of PTC or MNG (or both) were summarized. A database on thyroid cancer patients maintained in our institution was searched for potential FPTC families. Clinical examinations were performed in 6 of 12 Hannover kindreds identified, and blood samples of all family members were collected for genetic analyses. Clinical presentations and histopathologic features of the FPTC cases were compiled. Based on the FPTC meta-review and own experience, predictive criteria to identify families at risk were developed: Exclusion criteria were previous radiation exposure and coincidence with neoplasia syndromes. Primary criteria for susceptibility to FPTC are (1) PTC in two or more first-degree relatives and (2) MNG in at least three first- or second-degree relatives of a PTC patient. Secondary criteria are diagnosis in a patient younger than 33 years, multifocal or bilateral PTC, organ-exceeding tumor growth (T4), metastasis (N1, M1), and familial accumulation of adolescent-onset thyroid disease. A hereditary predisposition to PTC is considered if both primary criteria or one primary criterion plus three secondary criteria are present. Family history-taking is recommended for all PTC patients to identify FPTC kindreds at risk. Blood relatives of FPTC index patients who harbor MNG should undergo thorough and regular clinical screening. Suspicious lesions should prompt early surgical intervention.

Adolescent↗
PubMed2000

Proximal versus distal gastric carcinoma--what are the differences?

BACKGROUND: The incidence of proximal gastric third carcinoma (PGC) has been rising in recent years. Classification and surgical therapy remain controversial. METHODS: Between May 1986 and October 1997, 532 patients were operated for primary gastric carcinoma. All patient data were analyzed retrospectively comparing findings in patients with PGC and those with distal gastric carcinoma (DGC). RESULTS: Two hundred fifty patients had a PGC, and 282 patients had a DGC. The rate of RO resections was 79.3% for PGC and 81.6% for DGC. In 93.9% of the patients with PGC total gastrectomy was performed; for DGC total gastrectomy was done in 74.5% of patients. Postoperative morbidity and mortality were 29.2% for PGC and 23.8% for DGC, and 3.2% for PGC and 3.5% for DGC, respectively. Patients with advanced tumor stages (stage III and IV) were more common in the PGC group (73.3% vs. 53.6% in DGC). After RO resection, the 5-year survival rate was 33.2% for PGC and 59.7% for DGC. CONCLUSIONS: There was no significant difference between the rates of RO resections for PGC and DGC. Total gastrectomy can be performed with low postoperative morbidity and mortality. PGC and DGC represent the same tumor entity, and prognosis is similar, but due to more advanced tumor stages, the long-term survival is worse for patients with PGC than for those with DGC. Left retroperitoneal lymphadenectomy may be indicated for PGC.

Adenocarcinoma↗
PubMed2000

Pancreatic metastasis of a pleuropulmonary blastoma in an adult.

Pleuropulmonary blastoma (PPB) is a rare dysontogenetic tumor that usually develops in the first decade of life and has been recognized as a distinct clinico-pathological entity different from the ordinary pulmonary blastoma of adulthood. Since the tumor grows aggressively and tends to metastasize early, physicians have to be aware of late onset of symptoms and uncommon manifestations. We report a case of PPB in a young adult and its recurrence in the pancreas after primary surgical treatment and adjuvant chemotherapy. Keeping in mind the moderate prognosis of PPB in children, accurate assessment and treatment of PPB require a team approach of oncology, radiology and surgery to establish new therapeutic guidelines in the future.

Adolescent↗
PubMed2000

Acute vascular rejection is associated with systemic complement activation in a pig-to-primate kidney xenograft model.

The introduction of h-DAF transgenic porcine organs into pre-clinical pig-to-primate discordant xenotransplantation has led to complete and reliable abrogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vascular rejection (AVR), with current treatment protocols being of only limited value. In a life-supporting model of pig-to-primate kidney transplantation, unmodified (n=8) or h-DAF-transgenic (n=9) porcine kidneys were transplanted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine and low-dose steroid immunosuppression. Longest recipient survival was 11 days in the control group and 68 days in the h-DAF transgenic group. Stable initial graft function with recipient survival >4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma complement levels were analyzed during ongoing AVR. Compared with baseline levels, a two-fold increase in C3a levels and a four-fold increase in sC5b-9 levels were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b-9 along with massive staining for recipient IgM immunoglobulins was detected in the xenografts on immunohistochemistry. We conclude that acute vascular xenograft rejection of porcine kidneys in cynomolgus monkeys is associated with classical pathway complement activation following binding of induced recipient anti-porcine antibodies. This complement activation can be observed despite membrane bound expression of human complement regulators in the porcine xenografts. Therefore, additional short-term fluid phase complement inhibition seems necessary for the future development of protocols designed for treatment of AVR in the pig-to-primate combination.

Acute Disease↗
PubMed2000

Common and epithelioid variants of hepatic angiomyolipoma exhibit clonal growth and share a distinctive immunophenotype.

Angiomyolipoma represents a rare liver tumor of uncertain histogenesis that is commonly considered a hamartoma. A series of 12 hepatic angiomyolipomas, including 3 samples of the epithelioid subtype, was analyzed for clonality using the human androgen receptor gene locus (HUMARA). Four of 6 informative cases revealed monoclonality. The polyclonal pattern in the 2 remaining cases was most probably caused by excessive infiltration of inflammatory cells. Monoclonality with an identical X-chromosomal inactivation pattern in all nodules was found in a multifocal recurrent tumor indicating a metastatic process. Despite the morphologic heterogeneity, all tumors displayed an identical immunohistochemical labeling pattern. It is concluded that different subtypes of hepatic angiomyolipoma exhibit a monoclonal and hence probably neoplastic growth and share an identical immunophenotype suitable for their identification even in small biopsy specimens. The epithelioid subtype may give rise to intrahepatic metastasis.

Adult↗
PubMed2000

[Perfusion parameters in MRI diagnosis of pancreas transplants].

PURPOSE: Evaluation of the role of perfusion parameters in the detection of circulatory disturbance and chronic rejection in patients after pancreas transplantation. MATERIALS AND METHODS: 70 examinations of 39 patients after pancreas transplantation were performed. Using a dynamic gadolinium-enhanced Turbo-FLASH-sequence, we evaluated the perfusion parameters in a group of patients with chronic rejection, with circulatory disturbance, and in a control group with normal organ function. RESULTS: There were statistically significant differences of the perfusion parameters in patients with chronic rejection and circulatory disturbance compared to the control group. CONCLUSION: Dynamic MRI can help detect patients with chronic rejection and circulatory disturbance and should therefore be part of the routine follow-up in patients after pancreas transplantation.

Adult↗
PubMed2000

Long-term experience after ex situ liver surgery.

BACKGROUND: Ex situ liver surgery allows liver resection and vascular reconstruction in patients who have liver tumors located at critical sites. Only a small series of studies about ex situ liver surgery is available in the literature. No long-term results have been published. METHODS: Twenty-four patients were considered for ex situ liver surgery because conventional liver surgery was considered impossible or too hazardous. The patient's ages were 51.3 +/- 7.5 years. Indications were various primary and secondary liver malignancies and benign liver tumors in 2 patients. RESULTS: In 22 of 24 patients, the ex situ liver resection and subsequent autotransplantation were performed. The anhepatic periods in these patients lasted for 5.6 +/- 1.1 hours. In the remaining 2 patients, autotransplantation was not possible and allogenic liver transplantation was performed 17 and 19 hours after hepatectomy. In 4 patients, liver failure occurred after autotransplantation and required transplantation. The confluens between hepatic veins and the inferior vena cava was reconstructed in 5 patients. Fifteen patients survived the postoperative period and were discharged after 36.5 +/- 16 days. The median survival time of 6 patients who had metastases of colonic carcinoma was 21 months. The 2 patients with benign liver disease are alive 9 and 5 years after ex situ surgery. CONCLUSIONS: Extended liver resections with difficult reconstructions of the hepatic venous confluens are feasible by ex situ liver surgery and subsequent autotransplantation. However, the early postoperative mortality rate is high, especially in patients with cholestatic livers. Early tumor recurrence remained the problem in these patients with extended local tumor spread. Ex situ liver surgery should only be performed in selected patients.

Adult↗
PubMed2000

A murine model of allogeneic adrenocortical cell transplantation: perspectives for the treatment of Addison's disease in humans.

BACKGROUND: Hormone substitution for the treatment of adrenocortical insufficiency (Addison's disease) does not adequately substitute the hormone peaks required in stress situations. Therefore, allogeneic transplantation of adrenal cortex could offer an intriguing alternative. METHODS: Major histocompatibility complex (MHC) class I transgenic mice were used for the implementation of an animal model of adrenocortical cell transplantation in adrenalectomized mice. K(b)-transgenic cells and allogeneic adrenocortical cells were cocultured in mixed lymphocyte cultures to examine the alloimmune response. Lymphocytes from T-cell receptor transgenic mice and normal allogeneic mice served as responder cells. The effect of corticosteroids secreted by adrenocortical cells was antagonized by the steroid receptor antagonist mifepristone (RU486). RESULTS: In vitro coculture experiments showed that MHC class I disparate adrenocortical cells failed to activate B10.BR and T-cell receptor transgenic lymph node cells. In the presence of mifepristone this inhibitory effect was antagonized, resulting in strong lymphocyte proliferation. Activation of B10.BR lymphocytes by K(b)-disparate spleen cells was also abolished in the presence of adrenocortical cells. This effect, however, could not be reversed by mifepristone. CONCLUSIONS: In vitro, the presence of adrenocortical cells potently suppressed allogeneic immune responses. This effect was only in part due to the secretion of corticosteroids, pointing to an additional immunomodulatory property of adrenocortical cells.

Addison Disease↗
PubMed2000

Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma.

BACKGROUND: The expression of RET/PTC chimeras was demonstrated in 10% to 20% of sporadic papillary thyroid carcinomas (PTCs), whereas rearrangements of NTRK1 were detected less frequently. Some investigators have hypothesized that RET/PTC activation is preferentially associated with slow-growing tumors of low malignancy in elderly patients; other studies support the contrary. METHODS: Expression analysis of RET and NTRK1 was performed by duplex reverse transcription-polymerase chain reaction in tumor tissues from 119 patients with PTC. Samples with suspected rearrangements were further analyzed for the expression of the hybrid messenger RNAs RET/PTC 1 to RET/PTC 7 and for known NTRK1 chimeras, respectively. RESULTS: Seventeen of 119 tumors (14.3%) revealed somatic rearrangements of RET; NTRK1-derived hybrids were demonstrated in 15 cases (12.6%). In patients with RET/PTC chimeras, a statistically not significant tendency towards younger age, lower recurrence rate, and improved survival was observed, despite increased incidence of lymph node metastasis. Cumulative survival analysis of NTRK1 rearrangement-positive individuals demonstrated a worse outcome when compared with patients with expression of RET hybrids (P =.055). CONCLUSIONS: The high incidence of yet uncharacterized NTRK1 hybrid mRNAs in our patient cohort leads to the speculation that activating chromosomal rearrangements of several tyrosine kinase receptors may be a common feature of PTCs and that the expression of distinct chimeras may potentially be of prognostic significance.

Carcinoma, Papillary↗
PubMed2000

Stromal sarcoma of the stomach: therapeutic considerations.

OBJECTIVE: To present our experience of the surgical treatment of primary gastric stromal sarcomas and to compare it with reported results. DESIGN: Retrospective study. SETTING: University hospital, Germany. SUBJECTS: 17 patients (13 men and 4 women, median age: 58 years) who were operated on for stromal sarcomas of the stomach from April 1987 to March 1999. MAIN OUTCOME MEASURES: Extent of resection, morbidity and mortality, histopathological features, survival. RESULTS: Stromal sarcomas made up 0.8% of all gastric malignancies. Abdominal pain and gastrointestinal bleeding were the main symptoms. 16/17 were resected succesfully. The main type of resection was total gastrectomy (n = 11, in 6 cases as extended gastrectomy), followed by wide local excision of the stomach wall (n = 4), and proximal gastrectomy (n = 1). Of all resections 10 were radical (R0) and 6 were palliative (R1/R2). 5 patients developed complications. One patient died postoperatively. Median tumour size was 70 mm (range 30-230). The serosa was penetrated in 11 cases, lymph node metastases were found in 3 patients, and distant metastases in 8. Overall median survival was 19 months (2-64) and 5 patients survived 5 years. After radical resection (n = 10) median survival was 39 months (2-64) and the above mentioned 5 patients survived 5 years. CONCLUSION: Stromal sarcomas of the stomach are rare, the resection rate is high and the type of resection varies with the extent of the tumour. Wide local excision may be sufficiently radical. Long-term results after radical resection seem to be better than those after gastric adenocarcinoma.

Adult↗