Role of CD95-mediated adipocyte loss in autoimmune lipodystrophy

CONTEXT: Lipodystrophies are rare disorders characterized by the selective loss of adipose tissue. Metabolic complications increase in severity with the extent of fat loss. In some forms of acquired lipodystrophy, the loss of fat is suggested to be a result of autoimmune destruction of adipocytes. Here, the pathogenic mechanism is still poorly understood. OBJECTIVE: We have analyzed sc adipose tissue from a 5-yr-old girl with ongoing fat loss by immunohistochemistry. Using cultured human preadipocytes and adipocytes, we elucidated a possible mechanism leading to adipocyte loss in this patient. RESULTS: Analysis of adipose tissue samples of the patient with acquired lipodystrophy obtained from skin areas affected by panniculitis suggested that loss of adipocytes was mediated by CD95-induced apoptosis. Regression of adipose tissue was accompanied by lymphohistiocytic infiltration/inflammation and increased serum levels of inflammatory cytokines interferon-gamma and TNF-alpha. In vitro studies with human adipocytes demonstrated that interferon-gamma and TNF-alpha are able to up-regulate CD95 expression and enhance CD95-death-inducing signaling complex formation resulting in a robust sensitization for CD95-mediated apoptosis. CONCLUSION: We have identified here a possible mechanism responsible for the loss of adipocytes by apoptosis in autoimmune lipodystrophy.     

Toll-like 4 receptor variant, Asp299Gly, and reduced risk of hemorrhagic cystitis after hematopoietic stem cell transplantation

Hemorrhagic cystitis (HC) is a major cause of morbidity after hematopoietic stem cell transplantation. Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system and induces inflammation. Individuals with the single nucleotide polymorphisms Thr399Ile (rs4986791) or Asp299Gly (rs4986790) of TLR4 show diminished inflammatory responsiveness to endotoxins. The genotype of TLR4 was determined in 166 children who underwent allogeneic hematopoietic stem cell transplantation and in their donors. Asp299Gly was present in 21 patients (13%) and 24 donors (14%). Thr399Ile was found in 22 patients (13%) and 25 donors (15%). The incidence of HC was significantly lower in patients with Asp299Gly (0% vs 23%; P = .009) and in patients who underwent transplantation from a donor with Asp299Gly (4% vs 23%; P = .05). The trend was the same for Thr399Ile-donor positive (8% vs 22%; P = .17), recipient positive (9% vs 22%; P = .25), donor or recipient positive (8% vs 23%; P = .04). Multivariate analysis revealed age, conditioning with busulfan, and absence of Asp299Gly as independent risk factors for HC. In conclusion, the TLR4 Asp299Gly variant seems to confer protection against hemorrhagic cystitis. This study provides the first indication that the innate immune system through TLR4 signaling pathway plays a role in the pathogenesis of HC after hematopoietic stem cell transplantation.     

An inflammatory micro-environment promotes human adipocyte apoptosis

Obesity-associated macrophage infiltration into adipose tissue is responsible for both local and systemic inflammation. Recent findings suggest fat cell apoptosis as an initiator of macrophage recruitment. Here, we investigated the effects of an inflammatory micro-environment on fat cells using human THP-1 macrophages and SGBS adipocytes. Macrophage-secreted factors induced insulin resistance, inhibited insulin-stimulated Akt phosphorylation, and induced apoptosis of adipocytes. The apoptosis-inducing effect was even more pronounced in direct co-cultures of adipocytes and macrophages. Our data suggest a link between insulin resistance and apoptosis sensitivity. Accordingly, pharmacological and genetic inhibition of insulin signaling at the level of Akt2 sensitized adipocytes to apoptosis induction by macrophage-secreted factors. In conclusion, we describe here a novel interaction of macrophages and fat cells, i.e. induction of apoptosis. Our data suggest a feed-forward cycle in which macrophages further drive the inflammatory process by inducing insulin resistance and concomitant apoptosis of adipocytes.     

Intact apoptosis signaling in myeloid leukemia cells determines treatment outcome in childhood AML

Recently we reported that intact apoptosis signaling is indicative of favorable outcome in childhood acute lymphoblastic leukemia. Here we addressed this issue in 45 pediatric acute myeloid leukemia patients analyzing 2 core apoptogenic events: cytochrome c release and caspase-3 activation. In patients with good prognosis cytochrome c release was clearly found to be caspasedependent and correlated with activated caspase-3, indicating that activation of initiator or amplifier caspases such as caspase-8 together with an intact apoptosome function are elementary for favorable outcome. The functional integrity of this apoptogenic checkpoint is reflected by the parameter caspase-dependent cytochrome c-related activation of caspase-3 (CRAC(dep)). Patients with positive CRAC(dep) values (intact signaling) exhibited superior survival compared with CRAC(dep) negative patients (deficient signaling). Thus, the propensity to undergo apoptosis of leukemia cells is an important feature for favorable treatment outcome and may serve as an additional stratification tool for pediatric AML patients. This trial was registered at www.ClinicalTrials.gov as #NCT00111345.     

Posttraumatic stress,depression and anxiety among adult long-term survivors of cancer in adolescence

BackgroundTo determine the prevalence of posttraumatic stress, depression and anxiety in adults who have survived cancer (?5 years) diagnosed in adolescence, as compared to healthy controls.Patients and methodsSurvivors (n = 820) of cancer during adolescence (age M = 30.4 ± 6.0 years; M = 13.7 ± 6.0 years since diagnosis) and 1027 matched controls without history of cancer (age M = 31.5 ± 6.9 years) completed standardised questionnaires measuring posttraumatic stress, depression and anxiety. Additionally, sub-groups of 202 survivors and 140 controls with elevated scores received structured interviews to ascertain DSM-IV-diagnoses.ResultsA total of 22.4% of the survivors reported clinically relevant symptoms of posttraumatic stress, anxiety and/or depression compared to 14.0% of the controls (odds ratios [ORs] 1.77; 95% confidence interval [CI] 1.39–2.26). The odds of posttraumatic stress symptoms in male (OR 3.92, 95% CI 1.80–8.51) and female (OR 3.83, 95% CI 2.54–5.76) survivors were more than three times those in the controls. However, only female survivors reported symptoms of depression and anxiety significantly more often (respectively: OR 2.12, 95% CI 1.16–3.85; and OR 1.86, 95% CI 1.33–2.59) than the controls. A relevant subgroup of 24.3% of the survivors met DSM-IV criteria for at least one mental disorder compared to 15.3% of the controls.ConclusionSurvivors of cancer during adolescence show an elevated risk of presenting symptoms of posttraumatic stress, anxiety and/or depression during adulthood which is also reflected in a greater number of DSM-IV diagnoses when compared to controls. Comprehensive follow-up assessments should include the examination of possible psychological late effects of a cancer diagnosis in adolescence in order to identify survivors needing psychosocial interventions even years after the completion of successful medical treatment.     

Effectiveness of CT-guided percutaneous biopsies of the spine: an analysis of 202 examinations

RATIONALE AND OBJECTIVES: The study goal was to retrospectively evaluate the effectiveness of computed tomography (CT)-guided spinal biopsies. MATERIAL AND METHODS: Two hundred two CT-guided vertebral biopsies performed between May 1999 and June 2004 in 187 patients were retrospectively analyzed. Patient characteristics (age, sex, antibiotic therapy), technical parameters (depth and number of biopsies, needle approach), lesion features (spinal level, osteolysis, fluid collections, soft tissue tumor), and complications were documented. Furthermore, histopathological and microbiological diagnoses were considered. RESULTS: There were two focal hematomas in our study group (complication rate: 1%). Histopathological diagnosis was established in 74% of examinations with spondylitis (41% of cases) being most common. In spinal tumors (27% of cases), malignant lesions were found in 52 of 54 examinations (96%). Osteolysis was diagnosed in 98% of patients with spondylitis and in 87% of patients with tumors (P < .01). Spinal tumors were most commonly seen in the sacrum (53%, P < .001), whereas spondylitis typically occurred in the lumbar spine (55%, P = .001). Neither patient age nor sex, needle approach, needle depth, or vertebral abnormalities showed a significant impact on diagnostic accuracy. Microbiological tests were performed in 98 patients (49%); 62 of 98 patients (65%) received antibiotic therapy. In 12 of 62 patients (19%) with antibiotic therapy and in 9 of 36 patients (25%) without antibiotic treatment, microbiological tests were positive (P = .153). Staphylococcus aureus was found in 9 of 21 examinations (43%). CONCLUSIONS: CT-guided vertebral biopsy is a safe and effective procedure to establish final diagnosis in spinal lesions of unclear origin. Patient characteristics, lesions features, and technical considerations did not influence sample quality. In spondylitis, which was commonly caused by Staphylococcus aureus, microbiological yield was low regardless of antibiotic therapy.     

Benign solitary fibrous tumour of the thigh: morphological, chromosomal and differential diagnostic aspects

Solitary fibrous tumours (SFTs) are rare and usually benign neoplasms of mesenchymal origin that are often found in the visceral pleura (fibrous pleural tumour, FPT) or other serosal surfaces. They have also been found in soft tissues. We report the case of an SFT localised in the thigh of an 86-year-old woman. The tumour specimen was examined morphologically, immunohistochemically and molecular genetically, using comparative genomic hybridisation (CGH). The latter detects unbalanced chromosomal alterations in human neoplasms by competitive nucleic acid hybridisation and consecutive computer image analysis. The tumour consists of fibroblast-like cells, arranged in a typical "patternless pattern". Immunohistochemically, the tumour stained positively for vimentin, CD34, CD99, and focally for actin and desmin. No reaction occurred with keratin or S100 protein antibodies. CGH detected a single loss on chromosome 13q.     

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners

Objective  The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. Methods  A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. Results  There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. Conclusion  These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.