The role of p38 mitogen-activated protein kinase in serum-induced leukemia inhibitory factor secretion by bone marrow stromal cells from pediatric myelodysplastic syndromes

Stromal cells from pediatric myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) associated with MDS(MDS-AML) present high expression of leukemia inhibitor factor (LIF). We demonstrated using mitogen-activated protein kinase ( MAPK) inhibitors that in stromal cells from pediatric MDS and MDS-AML, p38MAPK was critical in serum-induced secretion of LIF. The serum induction of phosphorylated p38MAPK form was observed only in stromal cells from healthy children, whereas in MDS and MDS-AML basal levels were maintained suggesting constitutive p38MAPK activation. Our study suggested the possible importance in pediatric MDS of p38MAPK signaling pathway which may be a future therapeutic target. (C) 2009 Elsevier Ltd. All rights reserved.

Human leukemia inhibitory factor upregulates LDL receptors on liver cells and decreases serum cholesterol in the cholesterol-fed rabbit

In a previous study, we found that the cytokine (human) leukemia inhibitory factor (hLIF) significantly reduced plasma cholesterol levels and the accumulation of lipid in aortic tissues of cholesterol-fed rabbits after 4 weeks of treatment. The mechanisms by which this occurs were investigated in the present study. This involved examining the effect of hLIF on (1) the level of plasma cholesterol at different times throughout the 4-week treatment and diet period; (2) smooth muscle cell (SMC) and macrophage-derived foam cell formation in vitro; and (3) LDL receptor expression and uptake in the human hepatoma cell line HepG2. At time zero, an osmotic minipump (2-mL capacity; infusion rate, 2.5 mu L/h; 28 days) containing either hLIF (30 mu g.kg(-1).d(-1)) or saline was inserted into the peritoneal cavity of New Zealand White rabbits (N=24). Rabbits were divided into four groups of six animals each. Group 1 received a normal diet/saline; group 2, a normal diet/hLIF; group 3, a 1% cholesterol diet/saline; and group 4, a 1% cholesterol diet/hLIF. hLIF had no effect on the plasma lipids or artery wall of group 2 rabbits (normal diet). However, in group 4 rabbits, plasma cholesterol levels and the percent surface area of thoracic aorta covered by fatty streaks was decreased by approximate to 30% and 80%, respectively, throughout all stages of the 4-week treatment period. In vitro, hLIF failed to prevent lipoprotein uptake by either SMCs or macrophages (foam cell formation) when the cells were exposed to P-VLDL for 24 hours. In contrast, hLIF (100 ng/mL) added to cultured human hepatoma HepG2 cells induced a twofold or threefold increase in intracellular lipid accumulation in the medium containing 10% lipoprotein-deficient serum or 10% fetal calf serum, respectively. This was accompanied by a significant non-dose-dependent increase in LDL receptor expression in hLIF-treated HepG2 cells incubated with LDL (20 mu g/mL) when compared with controls (P

Inflammation and Biochemical Features of Bariatric Candidates: Does Gender Matter?

Background Accumulated fat is an accepted trigger of inflammation and metabolic syndrome but specific biochemical associations in males and females are still debated. In a prospective study, multiple variables were analyzed to search for gender-related correlations. Methods Bariatric candidates (n=94) were consecutively investigated. Age was 34.9 +/- 10.4 years (68.1% females) and body mass index (BMI) was 40.8 +/- 4.6 kg/m(2). Methods included anthropometrics, inflammatory indices (C-reactive protein (CRP), white blood cell count (WBC), ferritin) and general biochemical profile. Results Ferritin, but not CRP or WBC, was substantially more elevated in males. Serum albumin, uric acid, creatinine, and liver enzymes AST and ALT were also higher in men. Even after BMI was adjusted, all differences remained significant, and several, notably ferritin, withstood waist circumference control. Ferritin and CRP correlated with anthropometrics, glucose-related measurements, and liver enzymes, whereas WBC was only associated with triglycerides in females. Conclusions (1) Males displayed more severe inflammation according to ferritin profile, and also more signs of liver derangement; (2) all differences continued after BMI discrepancies were adjusted for, and ferritin was significant also after control of waist girth; (3) in both genders inflammatory markers often correlated with different anthropometrics, liver enzymes, and markers of glucose homeostasis; and (4) inflammatory and biochemical gender-related dissimilarities might have prognostic implications for cardiovascular risk and other comorbidities, and deserve additional studies.

IS SPLENECTOMY A DYSLIPIDEMIC INTERVENTION? EXPERIMENTAL RESPONSE OF SERUM LIPIDS TO DIFFERENT DIETS AND OPERATIONS

Spleen removal may be recommended during organ transplantation in ABO-incompatible recipients as well as for hypoperfusion of the grafted liver, besides conventional surgical indications, but elevation of serum lipids has been observed in certain contexts. Aiming to analyze the influence of two dietary regimens on lipid profile, an experimental study was conducted. Methods: Male Wistar rats (n = 86, 333.0 +/- 32.2 g) were divided in four groups: group 1: controls; group 2: sham operation; group 3: total splenectomy; group 4: subtotal splenectomy with upper pole preservation; subgroups A (cholesterol reducing chow) and B (cholesterol-rich mixture) were established, and diet was given during 90 days. Total cholesterol (Tchol), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and triglycerides were documented. Results: After total splenectomy, hyperlipidemia ensued with cholesterol-reducing chow. Tchol, LDL, VLDL, triglycerides, and HDL changed from 56.4 +/- 9.2, 24.6 +/- 4.7, 9.7 +/- 2.2, 48.6 +/- 11.1, and 22.4 +/- 4.3 mg/dL to 66.9 +/- 11.4, 29.9 +/- 5.9, 10.9 +/- 2.3, 54.3 +/- 11.4, and 26.1 +/- 5.1 mg/dL, respectively. Upper pole preservation inhibited abnormalities of Tchol, HDL, VLDL, and triglycerides, and LDL decreased (23.6 +/- 4.9 vs. 22.1 +/- 5.1, P = 0.002). Higher concentrations were triggered by splenectomy and cholesterol-enriched diet (Tchol 59.4 +/- 10.1 vs. 83.9 +/- 14.3 mg/dL, P = 0.000), and upper-pole preservation diminished without abolishing hyperlipidemia (Tchol 55.9 +/- 10.0 vs. 62.3 +/- 7.8, P = 0.002). Conclusions: After splenectomy, hyperlipidemia occurred with both diets. Preservation of the upper pole tended to correct dyslipidemia in modality A and to attenuate it in subgroup B. (c) 2008 Wiley-Liss, Inc. Microsurgery 29:154-160, 2009.

Increased Immunoglobulin G Anti-Paracoccidioides brasiliensis Serum Antibody Avidity as a Predictor of Favorable Posttherapeutic Evolution in Paracoccidioidomycosis

Paracoccidioidomycosis is endemic in Latin America, and ca. 80% of all cases occur in Brazil. Little is known about antibody avidity or the evolution of such avidity in the posttherapeutic period for the different clinical presentations of the disease. In the present study, we evaluated 53 patients with paracoccidioidomycosis and calculated the avidity index. Medium-and high-avidity antibodies were found in 79.5% of patients with chronic presentation (n = 39). Among patients with the acute form (n = 14), 57.1% of the antibodies presented low avidity. In the posttherapeutic period, there was a significant increase in antibody avidity in patients presenting with the chronic multifocal form. In our preliminary study, which needs to be confirmed using a larger number of samples, the optimized method for studying antibody avidity detected differences among the clinical presentations of the mycosis and indicated the value of the avidity index as a marker of posttherapeutic evolution of patients with a multifocal chronic form of the disease.

High serum follistatin levels in women with ovarian endometriosis

Follistatin is an activin-binding protein produced by several tissues, including endometrium and endometriotic implants. We aimed to quantify follistatin in patients with ovarian endometriosis and investigate its value as a diagnostic marker. Women undergoing laparoscopic excision of ovarian endometrioma (n = 52) or other benign ovarian cysts (n = 52) were studied, plus women with non-ovarian endometriosis (n = 11) and healthy controls (n = 27). Serum was collected from all subjects, and peritoneal and cystic fluid from a subset with endometrioma. Follistatin was measured by enzyme-linked immunosorbent assay. The diagnostic accuracy of follistatin to detect endometrioma was evaluated by receiver operating characteristic (ROC) curve and compared with cancer antigen (CA)-125. Serum follistatin was increased in women with ovarian endometrioma (2080 +/- 94 pg/ml) compared with controls (545 +/- 49 pg/ml, P < 0.001), other benign ovarian cysts (795 +/- 60 pg/ml, P < 0.001) or non-ovarian endometriosis (1271 +/- 115 pg/ml, P < 0.001). Cystic fluid showed a higher concentration of follistatin (9850 +/- 4461 pg/ml) than peritoneal fluid (1885 +/- 261 pg/ml, P < 0.001) and serum (P < 0.001). Follistatin levels detected 48/52 cases of endometrioma (92% sensitivity) at 1433 pg/ml cut-off, corresponding to 92% specificity. CA-125 detected only 44% of endometriomas with 90% specificity. ROC curve comparison showed follistatin was more accurate than CA-125 to discriminate women with endometrioma either from controls or women with other benign ovarian cysts (P < 0.0001). Serum follistatin is increased in women with endometriosis and allows clear distinction between endometrioma and other benign ovarian cysts. Follistatin has the sensitivity and specificity to become a useful clinical marker of ovarian endometrioma.

Acquisition of Serum Antibodies Reactive With Enterohemorrhagic Escherichia coli Virulence-Associated Factors by Healthy Brazilian Children and Adults

Background: Patients with hemorrhagic colitis or hemolytic uremic syndrome due to enterohemorrhagic Escherichia coli (EHEC) develop serum IgM and IgG response to lipopolysaccharide (LPS) and to virulence factors such as intimin. The small numbers of cases of diarrhea associated with EHEC strains in Brazil suggests a pre-existing immunity probably due to previous contact with diarrheagenic E. coli. Our aim was to evaluate the development of the serum antibody repertoire to EHEC virulence factors in Brazilian children and adults. Methods: Serum IgM and IgG antibodies were determined by enzyme-linked immunosorbent assay with LPS O111, LPS O26, and LPS O157 in 101 children between 2 months and 10 years of age and in 100 adult sera, by immunoblotting with protein membrane extracts and purified beta intimin; the ability of adult sera to neutralize Shiga toxin2 was also investigated. Results: Children older than 24 months had IgM concentrations reactive with the 3 LPS equivalent to those seen in the adult group, and significantly higher than the group of younger children (P < 0.05). Anti-O26 and anti-O157 LPS IgG concentrations were equivalent between the 2 groups of children and were significantly different from the adult group (P < 0.05). The anti-O111 LPS IgG levels in older children were intermediate between the younger group, and adults (P < 0.05). Immunoblotting revealed strong protein reactivity, including the conserved and variable regions of beta intimin and more than 50% of the adult samples neutralized Shiga toxin 2. Conclusions: Our results demonstrate an increasing anti-LPS and antiprotein antibody response with age, which could provide protection against EHEC infections.

Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression

Objectives. The aim of the present study is to investigate serum BDNF levels in older depressed patients as compared to healthy elderly controls. Methods. Twenty-nine elderly subjects with major depression and 42 healthy older adults were enrolled to this study. All depressed patients were antidepressant-free for at least 1 month prior clinical and laboratorial assessments. Serum BDNF levels were determined by sandwich ELISA. Results. BDNF levels were lower in elderly depressed patients as compared to controls (P = 0.034). Patients with late-onset depression had the lowest BDNF level (median 478.5, interquartile range 373.5-740.9 pg/l) when compared to early-onset depression (median 620.7, interquartile range 366.1-971.9 pg/l) and healthy controls (median 711.3, interquartile range 534.7-1181.0 pg/l) (P < 0.03). Conclusions. Reduced serum BDNF level may be a state marker of late-life depression in non-medicated elderly patients. Our findings provide further evidences that reduced neurotrophic support may have an important role in the physiopathology of late-life depression.

Body Mass Index Increase, Serum Leptin, Adiponectin, Neuropeptide Y and Lipid Levels during Treatment with Olanzapine and Haloperidol

Introduction: Body mass index (BMI) increase is an undesired effect associated with antipsychotics, and crucial for patients` global health and treatment compliance. We aimed to investigate the relation between BMI during olanzapine or halopericlol treatments and leptin, neuropeptide Y (NPY), adiponectin and lipid serum levels. Methods: In this 9-month, randomized and naturalist study, 34 male patients, 18 on olanzapine and 16 on haloperidol group were enrolled, all were under monotherapy. Patient outcome was evaluated with positive and negative syndrome scale (PANSS) at every 3-month period. In each visit, BMI, leptin, NPY, lipid, olanzapine or haloperidol levels were also monitored. Results and Discussion: Leptin levels positively correlated with BMI in olanzapine (r = 0.64, p < 0.001) and haloperidol (r = 0.73, p < 0.001) groups; only in olanzapine patients, the former also correlated with PANSS score (r = 0.54, p < 0.05). NPY levels negatively correlated with olanzapine levels (r = -0.65, p < 0.01). Adiponectin levels had not significantly varied. Conclusion: Antipsychotics probably interfere on leptin and NPY signalling ways and disturb these hormones in eating behaviour control.

Interleukin-1 beta Serum Levels is Increased in Antidepressant-Free Elderly Depressed Patients

Objective: To assess the serum levels of interleukin 1 beta (IL-1 beta) in elderly depressed patients in comparison with nondepressed healthy elderly subjects. Design: Cross-sectional study. Setting: Tertiary memory clinic. Participants: Twenty-three antidepressant-free elderly depressed patients and 44 nondepressed healthy elderly comparison group were enrolled to this study. Measurement: Serum IL-1 beta levels were determined with highly sensitive colorimetric sandwich enzyme-linked immunosorbent assay. Severity of the depressive episode was determined by scores on the Hamilton Depression Scale-21 item and cognitive performance by the scores on the Cambridge Cognition Examination, Mini Mental State Examination clock drawing test, and verbal fluency. Results: IL-1 beta serum levels were increased in elderly patients versus nondepressed elderly (t = 2.21, df = 65, p = 0.04). After categorizing elderly depressed subjects into late onset (LOD) versus early onset (EOD), patients with EOD had the highest IL-1 beta levels, when compared with nondepressed elderly patients and patients with LOD in analysis of variance (F = 4.9, df = 2, 64, p < 0.01). Conclusions: Late-life depression is associated with higher IL-1 beta levels suggesting that increased proinflammatory state may play a role in the physiopathology of depression in the elderly. The authors further show that this might be more prominent in those patients with EOD geriatric depression. (Am J Geriatr Psychiatry 2010; 18: 172-176)

Higher Serum sTNFR1 Level Predicts Conversion from Mild Cognitive Impairment to Alzheimer`s Disease

The activation of inflammatory cascades has been consistently demonstrated in the pathophysiology of Alzheimer`s disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor alpha (TNF-alpha) signaling system has a central role in this process. Recent evidence indicates that the abnormal production of inflammatory factors may accompany the progression from mild cognitive impairment (MCI) to dementia. We aimed to examine serum levels of TNF-alpha and its soluble receptors (sTNFR1 and sTNFR2) in patients with MCI and AD as compared to cognitively unimpaired elderly subjects. We further aimed to investigate whether abnormal levels of these cytokines predict the progression from MCI to AD upon follow-up. We utilized cross-sectional determination of serum levels of TNF-alpha, sTNFR1, and sTNFR2 (ELISA method) in a test group comprising 167 older adults (31 AD, 72 MCI, and 64 healthy controls), and longitudinal reassessment of clinical status after 18.9 +/- 10.0 months. At baseline, there were no statistically significant differences in serum TNF-alpha, sTNFR1, and sTNFR2 between patients with MCI and AD as compared to controls. Nevertheless, patients with MCI who progressed to AD had significantly higher serum sTNFR1 levels as opposed to patients who retained the diagnosis of MCI upon follow-up (p = 0.03). Cox regression analysis showed that high serum sTNFR1 levels predicted the conversion from MCI to AD (p = 0.003), whereas no significant differences were found with respect to serum levels of TNF-alpha and sTNFR2. Abnormal activation of TNF-alpha signaling system, represented by increased expression of sTNFR1, is associated with a higher risk of progression from MCI to AD.

Loxosceles venom-induced cytokine activation, hemolysis, and acute kidney injury

Herein, we describe a confirmed case of Loxosceles spider bite that illustrates the critical complications seen in loxoscelism, including skin necrosis, rhabdomyolysis, hemolysis, coagulopathy, acute kidney failure, and electrolyte disorders. Upon initial assessment, laboratory studies revealed the following: the white blood cell count was 29 400 WBCs/mm(3), hemoglobin was 9.2g/dL, and the platelet count was 218000cells/mm(3). Coagulation studies revealed the following: international normalized ratio, 1.83; activated partial-thromboplastin time, 62s; D-dimer, 600 ng/mL (normal range < 500 ng/mL); free protein S, 37% (normal range = 64-114%); protein C, negative; and antithrombin III, negative. Various serum levels were abnormal: urea, 110mg/dL; creatinine, 3.1 mg/dL; indirect bilirubin, 3.8 mg/dL; creatine kinase, 1631 U/L, lactate dehydrogenase, 6591 U/L; potassium 6.2mmol/L. Urine tests were positive for hemoglobin and bilirubin. In addition, concentrations of interleukin-6 and tumor necrosis factor-alpha were notably elevated in the serum. In conclusion, physicians must be alert to the possibility of loxoscelism when a patient presents with the clinical and laboratory findings described above, especially if the patient resides in an endemic area. Advances in our understanding of multiple pathways and mediators that orchestrate the response to Loxosceles venom might reveal new possibilities for the management of loxoscelism. (C) 2007 Elsevier Ltd. All rights reserved.

APOE polymorphism is associated with lipid profile, but not with arterial stiffness in the general population

Background: Cardiovascular diseases (CVD) are the main cause of death and disability in developed countries. In most cases, the progress of CVD is influenced by environmental factors and multifactorial inheritance. The purpose of this study was to investigate the association between APOE genotypes, cardiovascular risk factors, and a noninvasive measure of arterial stiffness in the Brazilian population. Methods: A total of 1493 urban Brazilian individuals were randomly selected from the general population of the Vitoria City Metropolitan area. Genetic analysis of the APOE polymorphism was conducted by PCR-RFLP and pulse wave velocity analyzed with a noninvasive automatic device. Results: Age, gender, body mass index, triglycerides, creatinine, uric acid, blood glucose, blood pressure phenotypes were no different between epsilon 2, epsilon 3 and epsilon 4 alleles. The epsilon 4 allele was associated with higher total-cholesterol (p < 0.001), LDL-C (p < 0.001), total-cholesterol/HDL-C ratio (p < 0.001), LDL/HDL-C ratio (p < 0.001), lower HDL-C values (p < 0.001) and higher risk to obesity (OR = 1.358, 95% CI = 1.019-1.811) and hyperuricemia (OR = 1.748, 95% CI = 1.170-2.611). Nevertheless, pulse wave velocity (p = 0.66) measures were no different between genotypes. The significant association between APOE genotypes and lipid levels persisted after a 5-year follow-up interval, but no interaction between time and genotype was observed for lipids longitudinal behavior. Conclusion: The epsilon 4 allele of the APOE gene is associated with a worse lipid profile in the Brazilian urban population. In our relatively young sample, the observed effect of APOE genotype on lipid levels was not translated into significant effects in arterial wall stiffness.

Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment

Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer`s disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2 +/- 210.5; 581.9 +/- 379.4; and 777.5 +/- 467.8 pg/l respectively; P < 0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8 +/- 463.0; stable MCI, 724.0 +/- 343.4; P = 0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR = 3.0 CI(95%) [1.2-7.8], P = 0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR = 4.4 CI(95%) [1.6-12.1], P = 0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.