Andreas Hillenbrand

Sepsis induced changes of adipokines and cytokines - septic patients compared to morbidly obese patients

BackgroundHyperglycemia and insulin resistance frequently occur in critically ill and in morbidly obese (MO) patients. Both conditions are associated with altered serum levels of cytokines and adipokines. In addition, obesity related alterations in adipokine expression contribute to insulin resistance in metabolic syndrome. In this study we examined the serum adipocytokine profile in critically ill patients, MO patients, and healthy blood donors.Methods33 patients who fulfilled the clinical criteria for severe sepsis or septic shock (SP) were prospectively enrolled in this study. A multiplex analysis was performed to evaluate plasma levels of adiponectin, resistin, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha in 33 critically ill patients, 37 MO patients and 60 healthy blood donors (BD).ResultsIn SP, adiponectin was significantly lowered and resistin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha were significantly elevated compared to BD. Leptin levels were unchanged. In MO, adiponectin and IL-8 were significantly lowered, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, and IL-10 significantly elevated, whereas resistin was unaltered.In SP, adiponectin correlated negatively with BMI, SAPS II and SOFA scores, while resistin correlated positively with SAPS II and SOFA scores and leptin correlated positively with the BMI. Adiponectin was approximately equally diminished in SP and MO compared to BD. With the exception of active PAI-1, cytokine levels in SP were clearly higher compared to MO.ConclusionA comparable adipocytokine profile was determined in critically ill and MO patients. As in MO, SP showed reduced adiponectin levels and elevated MCP-1, active PAI-1, IL-1 alpha, IL-6, and IL-10 levels. Leptin is only elevated in MO, while resistin, IL-8, and TNF-alpha is only elevated in SP. As in MO patients, increased levels of proinflammatory cytokines and altered levels of adipokines may contribute to the development of insulin resistance in critically ill patients.

Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo

Background: Pancreatic ductal adenocarcinomas (PDACs) are highly resistant to treatment due to changes in various signalling pathways. CK1 isoforms play important regulatory roles in these pathways. Aims: We analysed the expression levels of CK1 delta and epsilon (CK1δ/∊) in pancreatic tumour cells in order to validate the effects of CK1 inhibition by 3-[2,4,6-(trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261) on their proliferation and sensitivity to anti-CD95 and gemcitabine. Methods: CK1δ/∊ expression levels were investigated by using western blotting and immunohistochemistry. Cell death was analysed by FACS analysis. Gene expression was assessed by real-time PCR and western blotting. The putative anti-tumoral effects of IC261 were tested in vivo in a subcutaneous mouse xenotransplantation model for pancreatic cancer. Results: We found that CK1δ/∊ are highly expressed in pancreatic tumour cell lines and in higher graded PDACs. Inhibition of CK1δ/∊ by IC261 reduced pancreatic tumour cell growth in vitro and in vivo. Moreover, IC261 decreased the expression levels of several anti-apoptotic proteins and sensitised cells to CD95-mediated apoptosis. However, IC261 did not enhance gemcitabine-mediated cell death either in vitro or in vivo. Conclusions: Targeting CK1 isoforms by IC261 influences both pancreatic tumour cell growth and apoptosis sensitivity in vitro and the growth of induced tumours in vivo, thus providing a promising new strategy for the treatment of pancreatic tumours.

Accurate preoperative localization of parathyroid adenomas with C-11 methionine PET/CT.

Background:Focused unilateral or minimally invasive parathyroidectomy for primary hyperparathyroidism (pHPT) depends on the successful preoperative localization of parathyroid adenomas. The aim of this prospective study was to determine the accuracy of C-11 methionine positron emission tomography/computed tomography (Met-PET/CT), a novel localization procedure for hyperfunctional parathyroid tissue. Methods:Preoperative Met-PET/CT scans of the neck and mediastinum of 102 patients undergoing parathyroidectomy for pHPT were preoperatively evaluated by a radiologist and a nuclear medicine physician and prospectively documented. The results of Met-PET/CT were compared with intraoperative and histopathological findings. Results:pHPT was caused by a single-gland adenoma in 97 patients, whereas 5 patients had multiglandular disease. Met-PET/CT correctly located a single-gland adenoma in 83 of 97 (86%) patients with pHPT (sensitivity 91%). The positive predictive value of Met-PET/CT in localizing a single-gland adenoma was 93%. Of the 5 patients with multiglandular disease, Met-PET/CT identified 2 hyperfunctioning parathyroid glands in 1 patient, 1 gland in 3 individuals, and was negative in the fifth patient (sensitivity 80%). A highly significant correlation was observed between true-positive findings and the size (mean = 1.81 ± 0.84 cm) and weight (mean = 1.50 ± 2.56 g) of parathyroid adenoma, whereas patients with false-negative findings had significantly smaller (mean = 1.09 ± 0.41 cm) and lighter (mean = 0.37 ± 0.29 g) glands (P < 0.001 and P = 0.001, respectively). Conclusions:This study demonstrates the high accuracy of Met-PET/CT in the preoperative localization of parathyroid adenomas in a large series of patients with pHPT.

Sepsis-Induced Adipokine Change with regard to Insulin Resistance.

Background. Assessment of white adipose tissue has changed in recent years, with WAT now being considered as an active endocrine organ, secreting a large number of bioactive mediators, so-called adipokines. Besides other functions, these adipokines are involved in inflammatory response thereby exhibiting predominantly proinflammatory or anti-inflammatory properties and contribute to insulin resistance. Methods. Comprehensive review of the literature of the role of adipokines relevant to critical care medicine using PubMed search. Results. Adiponectin—the prototype of an anti-inflammatory and insulin-sensitizing adipokine—is diminished in sepsis, while resistin—a protein with proinflammatory properties—is elevated. Plasminogen activator inhibitor-1, interleukin (IL)-1, IL-6, IL-8, and IL-10, and tumor-necrosis-factor-alpha mediate insulin resistance and are elevated in sepsis, while retinol-binding protein-4 concentrations are significantly reduced in sepsis. Chemerin displays potent anti-inflammatory and insulin-resistance properties, while monocyte chemotactic protein-1—increased in sepsis—contributes to macrophage infiltration in adipose tissue and insulin resistance. Conclusions. The expression of adipokines in humans is altered as well in obese as in septic patients with elevated levels of proinflammatory adipokines. Changes in adipokine levels in acute sepsis could contribute to insulin resistance. Consequently, in critically ill patients, these alterations underline a possible contribution of adipokines in the development of hyperglycemia.

Hyperhomocysteinemia and recurrent carotid stenosis

BackgroundHyperhomocysteinemia has been identified as a potential risk for atherosclerotic disease in epidemiologic studies. This study investigates the impact of elevated serum homocysteine on restenosis after carotid endarterectomy (CEA).MethodsIn a retrospective study, we compared fasting plasma homocysteine levels of 51 patients who developed restenosis during an eight year period after CEA with 45 patients who did not develop restenosis. Restenosis was defined as at least 50% stenosis and was assessed by applying a routine duplex scan follow up investigation. Patients with restenosis were divided into a group with early restenosis (between 3 and 18 months postoperative, a total of 39 patients) and late restenosis (19 and more months; a total of 12 patients).ResultsThe groups were controlled for age, sex, and risk factors such as diabetes, nicotine abuse, weight, hypertension, and hyperlipidemia. Patients with restenosis had a significant lower mean homocysteine level (9.11 μmol/L; range: 3.23 μmol/L to 26.49 μmol/L) compared to patients without restenosis (11.01 μmol/L; range: 5.09 μmol/L to 23.29 μmol/L; p = 0.03).Mean homocysteine level in patients with early restenosis was 8.88 μmol/L (range: 3.23–26.49 μmol/L) and 9.86 μmol/L (range 4.44–19.06 μmol/L) in late restenosis (p = 0.50).ConclusionThe finding suggests that high plasma homocysteine concentrations do not play a significant role in the development of restenosis following CEA.

Changed adipocytokine concentrations in colorectal tumor patients and morbidly obese patients compared to healthy controls

BackgroundObesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters.MethodsPlasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD).ResultsCompared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p<0.002) and grading (p=0.015) of rectal tumor patients.ConclusionsThe results suggest that both MO and CRC have low-grade inflammation as part of their etiology.

Frequency, symptoms and outcome of intestinal metastases of bronchopulmonary cancer. Case report and review of the literature

BackgroundWe report a new case of small bowel metastases from primary lung cancer. Such metastases are not exceptional, but their clinical manifestations are rare.Case presentationThe case involved a 56-year-old man with a squamous cell carcinoma of the lung (stage IV) that had been treated with chemotherapy. He presented fourteen months after diagnosis with an acute abdominal pain. Abdominal CT-scan demonstrated a perforated jejunum and he underwent emergency surgery. Postoperative pathologic analysis confirmed the diagnosis of metastatic pulmonary carcinoma. The patient was discharged after ten days, but died 8 weeks after surgery at home on tumor progression.ConclusionWe were able to find 58 documented similar cases in the literature. Most cases presented with bowel perforation or obstruction. Squamous cell carcinoma was the most common histological cell type followed by large cell carcinoma. Other metastases are often present, and the prognosis is mostly fatal at short term.

Sensitive and Specific Immunohistochemical Diagnosis of Human Alveolar Echinococcosis with the Monoclonal Antibody Em2G11

Background Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. Differential diagnosis with cystic echinococcosis (CE) caused by E. granulosus and AE is challenging. We aimed at improving diagnosis of AE on paraffin sections of infected human tissue by immunohistochemical testing of a specific antibody. Methodology/Principal Findings We have analysed 96 paraffin archived specimens, including 6 cutting needle biopsies and 3 fine needle aspirates, from patients with suspected AE or CE with the monoclonal antibody (mAb) Em2G11 specific for the Em2 antigen of E. multilocularis metacestodes. In human tissue, staining with mAb Em2G11 is highly specific for E. multilocularis metacestodes while no staining is detected in CE lesions. In addition, the antibody detects small particles of E. multilocularis (spems) of less than 1 µm outside the main lesion in necrotic tissue, liver sinusoids and lymphatic tissue most probably caused by shedding of parasitic material. The conventional histological diagnosis based on haematoxylin and eosin and PAS stainings were in accordance with the immunohistological diagnosis using mAb Em2G11 in 90 of 96 samples. In 6 samples conventional subtype diagnosis of echinococcosis had to be adjusted when revised by immunohistology with mAb Em2G11. Conclusions/Significance Immunohistochemistry with the mAb Em2G11 is a new, highly specific and sensitive diagnostic tool for AE. The staining of small particles of E. multilocularis (spems) outside the main lesion including immunocompetent tissue, such as lymph nodes, suggests a systemic effect on the host.

Anorectal amelanotic melanoma

Objective  Anorectal melanoma is a rare, highly malignant tumour with a poor 5 year survival of 10%. Most anorectal melanomas have gross and/or histologic pigmentation, however about 30% of anorectal melanomas are amelanotic.

Analysis of Cell Type-specific Expression of CK1ε in Various Tissues of Young Adult BALB/c Mice and in Mammary Tumors of SV40 T-Ag-transgenic Mice

Casein kinase 1 epsilon (CK1ε) is involved in various cellular processes, including cell growth, differentiation, and apoptosis, vesicle transport, and control of the circadian rhythm. Deregulation of CK1ε has been linked to neurodegenerative diseases and cancer. To better understand the cell type-specific functions of CK1ε, we determined its localization by immunhistochemistry in tissues of healthy, young adult BALB/c mice and in mammary tumors of SV40 T-antigen-transgenic mice. CK1ε expression was found to be highly regulated in normal tissues of endodermal, mesodermal, and ectodermal origin and in neoplastic tissue of mammary cancer. The data presented here give an overview of CK1ε reactivity in different organs under normal conditions and outline changes in its expression in mammary carcinomas. Our data suggest a cell/organ type-specific function of CK1ε and indicate that tumorigenic conversion of mammary glands in SV40 T-antigen-transgenic mice leads to downregulation of CK1ε. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.