Changes in some components of the muscle lipids of three freshwater fish species under natural extreme cold and temperate conditions.

Fatty acid composition, conjugated linoleic acid and cholesterol contents in the muscles of three freshwater fish species (Barbus plebejus escherichi, Capoeta capoeta capoeta and Rutilus rutilus) were determined under natural extreme temperate (July) and cold (January) conditions. The aim of the study was to determine whether there were differences in these components of the muscle lipids among these three fish species under extreme natural conditions. Samples were analyzed using gas chromatography. Palmitic, oleic, docosahexaenoic and eicosapentaenoic acids were the predominant fatty acids in all fish in both months. The percentages of polyunsaturated fatty acids, n - 3 polyunsaturated fatty acids, n - 6 polyunsaturated fatty acids and eicosapentaenoic + docosahexaenoic acids in the muscle of B. plebejus escherichi and C. capoeta capoeta were significantly higher in January (P < 0.05) than in July. The ratio of n - 6 to n - 3 polyunsaturated fatty acids was lower than 0.60 in all fish species, with C. capoeta capoeta showing the lowest ratio in January (0.36). The levels of cholesterol and conjugated linoleic acid ranged from 103.46 to 150.10 mg/100 g oil and from 16.27 to 35.45 mg/100 g oil, respectively, for all samples in both months. There were no statistical differences in cholesterol levels among the three fish species in July and January. Conjugated linoleic acid contents were significantly higher in January in B. plebejus escherichi and C. capoeta capoeta. Of the three species tested, the extreme temperate and cold conditions affected B. plebejus escherichi the most.

Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity.

Thiazolidinediones (TZDs) are potent insulin-sensitizing compounds and high-affinity ligands for the transcription factor peroxisomal proliferator-activated receptor gamma. The mechanism through which TZDs improve insulin sensitivity, however, is not clear. In this study, we asked whether the ability of TZD to suppress and antagonize TNF alpha is an underlying mechanism for its molecular and physiological effects, using obese (ob/ob) mice lacking TNF alpha function. We found that the lipid-lowering effects of TZD are completely independent of TNF alpha suppression, and the insulin-sensitizing effects of TZD are partially independent. TZD treatment improved insulin sensitivity in ob/ob mice both with and without functional TNF alpha, albeit with different absolute potency. To characterize the potential interdependency of TZD- and TNF alpha-regulated pathways at the molecular level, we also performed four-way transcriptional profiling of white adipose tissue of TZD- and vehicle-treated ob/ob mice, with and without TNF alpha function. The majority of metabolic genes identified were regulated independent of the presence of TNF alpha, whereas most effects on inflammatory mediators were dependent on TNF alpha. This study demonstrates that the insulin-sensitizing action of TZD occurs partially through TNF-independent mechanisms, although a subset of the molecular effects of TZD treatment in adipose tissue depends on TNF alpha.

Role of the fatty acid binding protein mal1 in obesity and insulin resistance.

The metabolic syndrome is a cluster of metabolic and inflammatory abnormalities including obesity, insulin resistance, type 2 diabetes, hypertension, dyslipidemia, and atherosclerosis. The fatty acid binding proteins aP2 (fatty acid binding protein [FABP]-4) and mal1 (FABP5) are closely related and both are expressed in adipocytes. Previous studies in aP2-deficient mice have indicated a significant role for aP2 in obesity-related insulin resistance, type 2 diabetes, and atherosclerosis. However, the biological functions of mal1 are not known. Here, we report the generation of mice with targeted null mutations in the mal1 gene as well as transgenic mice overexpressing mal1 from the aP2 promoter/enhancer to address the role of this FABP in metabolic regulation in the presence or absence of obesity. To address the role of the second adipocyte FABP in metabolic regulation in the presence and deficiency of obesity, absence of mal1 resulted in increased systemic insulin sensitivity in two models of obesity and insulin resistance. Adipocytes isolated from mal1-deficient mice also exhibited enhanced insulin-stimulated glucose transport capacity. In contrast, mice expressing high levels of mal1 in adipose tissue display reduced systemic insulin sensitivity. Hence, our results demonstrate that mal1 modulates adipose tissue function and contributes to systemic glucose metabolism and constitutes a potential therapeutic target in insulin resistance.

A central role for JNK in obesity and insulin resistance.

Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.

Treatment outcome of adolescents with acute lymphoblastic leukemia.

Despite intensified chemotherapy, adolescents with acute lymphoblastic leukemia (ALL) still have lower rates of survival than younger children. The purpose of our study was to compare the treatment outcome and presenting clinical and laboratory features of adolescent and younger children with newly diagnosed ALL who were treated at our pediatric hematology department. Between April 1991 and February 2000, 42 children up to 18 years of age who were newly diagnosed with ALL and treated adequately with modified ALL Berlin-Frankfurt-Münster (BFM) 90 or 95 protocols were included in this study. The patients were examined in two groups according to their ages: the first group consisted of children who were <14 years old and the second group consisted of adolescents who were >14 years old. The median age of 42 patients was 6.5 years (range: 1-16.5 years); 26% of the patients were adolescents. The results of this study demonstrated that after a median observation time of 6 years the overall survival (OS) and event-free survival (EFS) of patients who were <14 and >14 years of age were 75% vs 49% and 70% vs 40%, respectively. When adolescent and younger patients were compared to each other according to gender, WBC count at administration, French-American-British (FAB) classification, immunophenotypes, risk groups, early deaths, and relapse rates, there were no statistically significant differences. Comparative data from other studies and data from this study indicate that adolescents with ALL still have shorter OS and EFS than younger children and a steady improvement in treatment outcome for adolescents with ALL over time suggests that more intensive therapy favorably influences prognosis.

Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity.

Tumor necrosis factor-alpha (TNF-alpha) is synthesized as a 26-kDa transmembrane protein (mTNF-alpha), which may present on the cell surface or be processed to release the 17-kDa soluble form (sTNF-alpha). Because regulation of this ectodomain shedding might be critical in the generation of systemic versus local cytokine responses, we examined the rate of mTNF-alpha processing in adipocytes and its regulation in obesity. Here, we demonstrate that the 26-kDa mTNF-alpha is present in adipose tissue and that its production is significantly increased in different rodent obesity models as well as in obese humans. There was no apparent deficiency in the level of the major TNF-alpha converting enzyme in adipose tissue to account for the excess amount of mTNF-alpha produced in obesity. However, experiments in cultured fat cells stably expressing TNF-alpha demonstrated a significantly decreased rate of TNF-alpha cleavage in differentiated adipocytes compared with preadipocytes. Thus, a decreased processing rate of mTNF-alpha in mature adipocytes combined with an increase in TNF-alpha production may be a potential mechanism resulting in elevated membrane-associated TNF-alpha in adipose tissue in obesity.

Exclusive action of transmembrane TNF alpha in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance.

Aberrant TNF alpha expression in adipocytes is a molecular mechanism by which insulin action is modulated in adipose tissue. While this might be a compensatory response to limit adipose expansion, neither the mechanisms underlying this local effect nor its systemic biological consequences have been studied. It is also not clear whether TNF alpha-induced insulin resistance in adipocyte alone is responsible for systemic insulin resistance in the absence of obesity. In a transgenic mouse model deficient in endogenous TNF alpha, we demonstrate that specific expression of the transmembrane TNF alpha (mTNF alpha) in adipocytes leads to decreased whole body adipose mass, and local, but not systemic insulin resistance. These data demonstrate that exclusive action of TNF alpha in adipose tissue strongly inhibits insulin action at this site and leads to reduced adiposity in mice. However, this isolated adipocyte insulin resistance in the context of reduced fat mass and/or the absence of obesity is insufficient to alter systemic glucose homeostasis.

Bleomycin-induced hyperpigmentation and hypersensitivity reactions to etoposide and vinblastine in a child with endodermal sinus tumor.

We report a pediatric case who developed bleomycin-induced hyperpigmentation and hypersensitivity reactions to both etoposide and vinblastine while receiving chemotherapy for germ cell tumor. Skin hyperpigmentation related to chemotherapeutic agents has been reported only rarely in pediatric patients. This patient developed a characteristic skin hyperpigmentation which was "flagellate" in appearance. Two features of the hyperpigmentation were noteworthy: development at a low cumulative dose of bleomycin and persistence after cessation of chemotherapy. Additive effect of cisplatinum-induced hyperpigmentation was suggested. Although hypersensitivity reactions to etoposide have been previously reported, hypersensitivity reactions to vinblastine are almost unknown. To our knowledge, this is the first report of hypersensitivity reaction to vinblastine in a child in English literature.

High-dose oral methylprednisolone therapy in childhood hemangiomas.

The authors report their experience with high-dose oral methylprednisolone therapy (HDMP) in 15 infants with complicated hemangiomas. The starting dose for methylprednisolone was 30 mg/kg/day for 5 days, then the dose was tapered gradually every 5 days to 20, 10, 5, 2.5, and finally to 1 mg/kg/day. Therapy was then stopped and the patients were followed. An initial response was evident in 12 patients. Nine out of 12 responders showed regrowth signs. After regrowth, 4 cases received prednisolone at doses between 1 to 5 mg/kg/day and 3 patients received a second course with HDMP as additional corticosteroid therapy. Overall, 9 out of 15 cases were responders; very good and good responses were obtained in 5, partial response in 4, and therapy failure in 5 cases. One child was not available for evaluation of response. A very rapid initial response was observed in subglottic and periocular hemangiomas. Side effects were not serious and resolved after discontinuation of treatment. Although the number of patients is small in this study, overall response rate with HDMP regimen seems not to be superior to the regimens that use lower doses (5 mg/kg/day), but it provides a high initial response rate and the duration of therapy is short. Therefore, it may be useful for treating hemangiomas that fail to respond with low doses, especially in centers with limited resources where other treatment modalities cannot be used at the moment.

Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.

The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe-/- mice with Ap2+/+ adipocytes and Ap2-/- macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.

Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.

Elevated levels of the hormone resistin, which is secreted by fat cells, are proposed to cause insulin resistance and to serve as a link between obesity and type 2 diabetes. In this report we show that resistin expression is significantly decreased in the white adipose tissue of several different models of obesity including the ob/ob, db/db, tub/tub, and KKA(y) mice compared with their lean counterparts. Furthermore, in response to several different classes of antidiabetic peroxisome proliferator-activated receptor gamma agonists, adipose tissue resistin expression is increased in both ob/ob mice and Zucker diabetic fatty rats. These data demonstrate that experimental obesity in rodents is associated with severely defective resistin expression, and decreases in resistin expression are not required for the antidiabetic actions of peroxisome proliferator-activated receptor gamma agonists.

A rare tumor of craniofacial bones in children: a pediatric chondroblastic osteosarcoma case with diagnostic and therapeutic problems.

Osteosarcoma of the cranial facial region is uncommon and only rarely involves the ethmoid or sphenoid bones. The authors report on an unusual case of a 17-year-old male presenting with chondroblastic osteosarcoma of the maxillary, ethmoid, and sphenoid sinuses who remains well and disease-free at 46 months. He was treated with anterior craniofacial resection followed by postoperative radiotherapy to the sight of the primary tumor. He did not receive chemotherapy because of emerging hepatitis-B infection and vasculitis. The literature on extragnathic craniofacial osteosarcomas is reviewed with particular emphasis on treatment options of this rare tumor.

Tc-99m MDP, thallium-201 chloride and Tc-99m MAG3 renal uptake in subacute and chronic radiation nephritis compared.

The authors present a comparison of the findings for thallium-201 (Tl-201), Tc-99m MAG3 and Tc-99m MDP in subacute and chronic radiation nephritis in a 9-yr-old boy who was treated by radiation therapy for alveolar rhabdomyosarcoma of the left chest wall by a radiation port that partially included the left kidney. Tl-201 imaging three and six months later showed a cortical defect in the left kidney due to radiation nephritis. Tc-99m MDP scan showed increased uptake on both occasions, but more marked in the subacute period than in the chronic period. Tc-99m MAG3 showed decreased concentration and increased cortical retention three months later. Six months after the radiation therapy, a cortical defect corresponding to the cortical area that showed increased parenchymal retention was more prominent in the Tc-99m MAG3 scan. In the present case, Tc-99m MDP, Tl-201 and Tc-99m MAG3 findings may provide useful information for understanding pathophysiological damage in the kidney after radiation.

Improved glucose and lipid metabolism in genetically obese mice lacking aP2.

Adipocyte fatty acid-binding protein, aP2, is a member of the intracellular fatty acid binding protein family. Previously, studies have shown increased insulin sensitivity in aP2-deficient mice with dietary obesity. Here, we asked whether aP2-related alterations in lipolytic response and insulin production are features of obesity-induced insulin resistance and investigated the effects of aP2-deficiency on glucose homeostasis and lipid metabolism in ob/ob mice, a model of extreme obesity. ob/ob mice homozygous for the aP2 null allele (ob/ ob-aP2-/-) became more obese than ob/ob mice as indicated by significantly increased body weight and fat pad size but unaltered body length. However, despite their extreme adiposity, ob/ob-aP2-/- animals were more insulin-sensitive compared with ob/ob controls, as demonstrated by significantly lower plasma glucose and insulin levels and better performance in both insulin and glucose tolerance tests. These animals also showed improvements in dyslipidemia and had lower plasma triglyceride and cholesterol levels. Lipolytic response to beta-adrenergic stimulation and lipolysis-associated insulin secretion was significantly reduced in ob/ob-aP2-/- mice. Interestingly, glucose-stimulated insulin secretion, while virtually abolished in ob/ob controls, was significantly improved in ob/ob-aP2-/- animals. There were no apparent morphological differences in the structure or size of the pancreatic islets between genotypes. Taken together, the data indicate that in obesity, aP2-deficiency not only improves peripheral insulin resistance but also preserves pancreatic beta cell function and has beneficial effects on lipid metabolism.

Tumor necrosis factor alpha mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity.

Severe quantitative and qualitative brown adipocyte defects are common in obesity. To investigate whether aberrant expression of tumor necrosis factor alpha (TNF-alpha) in obesity is involved in functional brown fat atrophy, we have studied genetically obese (ob/ob) mice with targeted null mutations in the genes encoding the two TNF receptors. The absence of both TNF receptors or p55 receptor alone resulted in a significant reduction in brown adipocyte apoptosis and an increase in beta(3)-adrenoreceptor and uncoupling protein-1 expression in obese mice. Increased numbers of multilocular functionally active brown adipocytes, and improved thermoregulation was also observed in obese animals lacking TNF-alpha function. These results indicate that TNF-alpha plays an important role in multiple aspects of brown adipose tissue biology and mediates the abnormalities that occur at this site in obesity.

A case with extraosseous Ewing's sarcoma: a late effect related to bone marrow transplantation for thalassemia or a component of a familial cancer syndrome?

Allogeneic bone marrow transplantation has proved to be a radical form of cure in patients with beta-thalassemia major who have a human leukocyte antigen identical donor. Although malignant neoplasms are serious late complications of bone marrow transplantation, very few reports describing the development of malignant tumors after allografting for thalassemia appeared in the literature. A case is presented here of extraosseous Ewing's sarcoma that developed 8 years after allogeneic bone marrow transplantation performed for beta-thalassemia major. The phenotypic features of the patient's family fulfill the criteria for Li-Fraumeni syndrome. The patient was treated with chemotherapy and radiotherapy and died with recurrent disease. To the authors' knowledge, this is the first case of extraosseous Ewing's sarcoma after bone marrow transplantation for thalassemia. The possible contribution of transplantation procedure and the genetic factors as well as the primary genetic hemoglobinopathy to the development of this malignant tumor are discussed.

Characterisation of receptor-specific TNFalpha functions in adipocyte cell lines lacking type 1 and 2 TNF receptors.

Tumour necrosis factor-alpha (TNFalpha) is a multifunctional cytokine that exerts a myriad of biological actions in numerous different tissues including adipocytes through its two distinct cell surface receptors. To address the role of each TNF receptor in the biological actions of TNFalpha in adipocytes, we have developed four new preadipocyte cell lines. These were established from wild type controls (TNFR1(+/+)R2(+/+)) and from mice lacking TNFR1 (TNFR1(-/-)), TNFR2 (TNFR2(-/-)) or both (TNFR1(-/-)R2(-/-)). All four new cell lines can fully differentiate to form mature adipocytes, under appropriate culture conditions, as judged by cell morphology, expression of multiple adipogenic markers and the ability to mediate agonist-stimulated lipolysis and insulin-stimulated glucose transport. In wild type (TNFR1(+/+)R2(+/+)) and TNFR2(-/-) adipocytes, TNFalpha stimulated lipolysis and inhibited insulin-stimulated glucose transport as well as insulin receptor autophosphorylation. In contrast, these activities were completely lost in the TNFR1(-/-)R2(-/-) and TNFR1(-/-) cells. Taken together, these studies demonstrate that TNFalpha-induced lipolysis, as well as inhibition of insulin-stimulated glucose transport are predominantly mediated by TNFR1 and that the presence of TNFR2 is not necessary for these functions. This new experimental system promises to be useful in dissecting the molecular pathways activated by each TNF receptor in mediating the biological functions of TNFalpha in differentiated adipocytes.

Upregulation of uncoupling protein 2 mRNA in genetic obesity: lack of an essential role for leptin, hyperphagia, increased tissue lipid content, and TNF-alpha.

Uncoupling protein 2 (UCP2) has been proposed to play a prominent role in the regulation of energy balance. UCP2 mRNA expression is upregulated in white adipose tissue (WAT) and liver, but is not altered in skeletal muscle in genetically obese ob/ob mice. The mechanisms involved in the upregulation of UCP2 in obesity have not been investigated. We have now examined the potential role of leptin, hyperphagia, increased tissue lipid content, and overexpression of tumor necrosis factor (TNF)-alpha in the upregulation of UCP2 mRNA expression in the liver and WAT in ob/ob mice. Treatment of ob/ob mice with leptin for 3 days significantly reduced their food intake but had no effect on the upregulation of UCP2 mRNA levels in the liver or WAT. To investigate the effect of feeding and higher tissue lipid content on the upregulation of UCP2 in liver and WAT, we compared UCP2 mRNA levels in ad-libitum fed and 72-h fasted control and ob/ob mice. In controls, fasting had no effect on UCP2 mRNA levels in liver, but increased UCP2 mRNA in WAT suggesting that the effects of fasting on UCP2 mRNA levels are tissue-specific. In ob/ob mice, fasting did not lower UCP2 mRNA levels in liver or WAT suggesting that the upregulation of UCP2 in ob/ob mice is not merely a direct consequence of increased food intake. 72-h fasting lowered hepatic total lipid content by 34% and 36% in control and ob/ob mice, respectively, without any corresponding decrease in hepatic UCP2 mRNA levels, suggesting that the enhanced UCP2 expression in the liver of ob/ob mice is not secondary to lipid accumulation in their livers. Although TNF-alpha has been shown to acutely increase UCP2 mRNA levels in liver and WAT, and is overexpressed in adipose tissue in obesity, deletion of the genes for both TNF receptors in ob/ob mice produces a further increase in UCP2 mRNA expression in liver and adipose tissue indicating a paradoxical inhibitory role. Taken together, these results suggest that the upregulation of UCP2 mRNA levels in the liver and WAT of ob/ob mice is not due to the lack of leptin, hyperphagia, increased tissue lipid content, or over-expression of TNF-alpha.