Anti-oxidized low-density lipoprotein (oxLDL) antibody levels are not related to increasing circulating oxLDL concentrations during the course of pregnancy

To address the question of whether the high levels of oxidative modified low-density lipoproteins (oxLDL) in pregnancy are opposed by an appropriate humoral autoimmune response providing anti-oxLDL autoantibodies in maternal serum of healthy women throughout gestation.

Effect of pregnancy and birth on the course of myasthenia gravis before or after transsternal radical thymectomy

OBJECTIVE: Myasthenia gravis (MG) affects women at childbearing age. Therefore, the question arises if these patients should become pregnant and if thymectomy has a positive effect on the course of MG in pregnant patients. METHODS: Fifteen pregnancies had been followed retrospectively. All patients underwent transsternal radical thymectomy for MG. The course of MG in the period before, during, and after the pregnancy was scored according to Ossermann's classification. The effect of thymectomy on delivery and on the newborns was evaluated. RESULTS: Patients were divided in two groups: pregnancies before (group I, n=8) and after (group II, n=7) thymectomy. During pregnancy, in group I, one deterioration was observed and in seven patients the disease was unchanged. In group II, one deterioration, five unchanged courses, and one improvement were observed. In the postpartum period, in group I, seven patients did not change and one improved. In group II, two deteriorations, three unchanged courses, and two improvements were observed. Before pregnancy, group II patients were in a better Ossermann stage in comparison with those in group I. Eight of the 12 deliveries were spontaneous (three abortus). Myasthenic symptoms were observed in two newborns in group I. CONCLUSION: Our data suggest that MG is not prohibitive to have children. The course of MG after transsternal radical thymectomy is often ameliorated. A better MG-stage, reached after thymectomy, before pregnancy seems to be correlated with a better course during pregnancy.

Therapeutic protein transduction of mammalian cells and mice by nucleic acid-free lentiviral nanoparticles

The straightforward production and dose-controlled administration of protein therapeutics remain major challenges for the biopharmaceutical manufacturing and gene therapy communities. Transgenes linked to HIV-1-derived vpr and pol-based protease cleavage (PC) sequences were co-produced as chimeric fusion proteins in a lentivirus production setting, encapsidated and processed to fusion peptide-free native protein in pseudotyped lentivirions for intracellular delivery and therapeutic action in target cells. Devoid of viral genome sequences, protein-transducing nanoparticles (PTNs) enabled transient and dose-dependent delivery of therapeutic proteins at functional quantities into a variety of mammalian cells in the absence of host chromosome modifications. PTNs delivering Manihot esculenta linamarase into rodent or human, tumor cell lines and spheroids mediated hydrolysis of the innocuous natural prodrug linamarin to cyanide and resulted in efficient cell killing. Following linamarin injection into nude mice, linamarase-transducing nanoparticles impacted solid tumor development through the bystander effect of cyanide.

Exhaustion is associated with reduced habituation of free cortisol responses to repeated acute psychosocial stress

We investigated the association between exhaustion and the habituation of free cortisol responses to repeated stress exposure. The study comprised 25 healthy male subjects (38-59 years) who were confronted three times with the Trier Social Stress Test. Mean cortisol responses showed the well-known general habituation effect. A two-way interaction day by exhaustion (p<0.05) indicated that mean cortisol responses vary across stress sessions depending on the extent of exhaustion. Linear regression revealed a negative dose-response relationship between exhaustion and the degree of habituation (p<0.02). We identified 19 individuals showing a response habituation (negative slope) and 6 individuals showing a response sensitization over the three sessions (positive slope) with the latter reporting higher exhaustion scores. It might be hypothesized that impaired habituation to repeated exposure to the same stressor could reflect a state of increased vulnerability for allostatic load. Absence of normal habituation might be one potential mechanism how exhaustion relates to increased disease vulnerability.

Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons may be at increased risk for developing type 2 diabetes mellitus because of viral coinfection and adverse effects of treatment. METHODS: We studied associations of new-onset diabetes mellitus with hepatitis B virus and hepatitis C virus coinfections and antiretroviral therapy in participants in the Swiss HIV Cohort Study, using Poisson regression. RESULTS: A total of 123 of 6513 persons experienced diabetes mellitus during 27,798 person-years of follow-up (PYFU), resulting in an incidence of 4.4 cases per 1000 PYFU (95% confidence interval [CI], 3.7-5.3 cases per 1000 PYFU). An increased incidence rate ratio (IRR) was found for male subjects (IRR, 2.5; 95% CI, 1.5-4.2), older age (IRR for subjects >60 years old, 4.3; 95% CI, 2.3-8.2), black (IRR, 2.1; 95% CI, 1.1-4.0) and Asian (IRR, 4.9; 95% CI, 2.2-10.9) ethnicity, Centers for Disease Control and Prevention disease stage C (IRR, 1.6; 95% CI, 1.04-2.4), and obesity (IRR, 4.7; 95% CI, 3.1-7.0), but results for hepatitis C virus infection or active hepatitis B virus infection were inconclusive. Strong associations were found for current treatment with nucleoside reverse-transcriptase inhibitors (IRR, 2.22; 95% CI, 1.11-4.45), nucleoside reverse-transcriptase inhibitors plus protease inhibitors (IRR, 2.48; 95% CI, 1.42-4.31), and nucleoside reverse-transcriptase inhibitors plus protease inhibitors and nonnucleoside reverse-transcriptase inhibitors (IRR, 3.25; 95% CI, 1.59-6.67) but were not found for treatment with nucleoside reverse-transcriptase inhibitors plus nonnucleoside reverse-transcriptase inhibitors (IRR, 1.47; 95% CI, 0.77-2.82). CONCLUSIONS: In addition to traditional risk factors, current treatment with protease inhibitor- and nucleoside reverse-transcriptase inhibitor-containing regimens was associated with the risk of developing type 2 diabetes mellitus. Our study did not find a significant association between viral hepatitis infection and risk of incident diabetes.

Impaired protein stability of 11beta-hydroxysteroid dehydrogenase type 2: a novel mechanism of apparent mineralocorticoid excess

Apparent mineralocorticoid excess (AME) is a severe form of hypertension that is caused by impaired activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts biologically active cortisol into inactive cortisone. Mutations in HSD11B2 result in cortisol-induced activation of mineralocorticoid receptors and cause hypertension with hypokalemia, metabolic alkalosis, and suppressed circulating renin and aldosterone concentrations. This study uncovered the first patient with AME who was described in the literature, identified the genetic defect in HSD11B2, and provided evidence for a novel mechanism of reduced 11beta-HSD2 activity. This study identified a cluster of amino acids (335 to 339) in the C-terminus of 11beta-HSD2 that are essential for protein stability. The cluster includes Tyr(338), which is mutated in the index patient, and Arg(335) and Arg(337), previously reported to be mutated in hypertensive patients. It was found that wild-type 11beta-HSD2 is a relatively stable enzyme with a half-life of 21 h, whereas that of Tyr(338)His and Arg(337)His was 3 and 4 h, respectively. Enzymatic activity of Tyr(338)His was partially retained at 26 degrees C or in the presence of the chemical chaperones glycerol and dexamethasone, indicating thermodynamic instability and misfolding. The results provide evidence that the degradation of both misfolded mutant Tyr(338)His and wild-type 11beta-HSD2 occurs through the proteasome pathway. Therefore, impaired 11beta-HSD2 protein stability rather than reduced gene expression or loss of catalytic activity seems to be responsible for the development of hypertension in some individuals with AME.

Deficiency of mannose-binding lectin-associated serine protease-2 associated with increased risk of fever and neutropenia in pediatric cancer patients

BACKGROUND: Mannose-binding lectin-associated serine protease-2 (MASP-2) is an essential component of the lectin pathway of complement activation. MASP-2 deficiency is common because of genetic polymorphisms, but its impact on susceptibility to infection is largely unknown. The aim of the present study was to determine whether children with cancer and MASP-2 deficiency develop more frequent or more severe episodes of fever and severe chemotherapy-induced neutropenia (FN). METHODS: Serum MASP-2 was measured by enzyme-linked immunosorbent assay at the time of diagnosis in children treated with chemotherapy for cancer. Association of FN episodes with MASP-2 concentration was analyzed using Poisson regression accounting for chemotherapy intensity and duration. RESULTS: Median MASP-2 in 94 children was 527 ng/mL (interquartile range, 367-686). Nine (10%) children had MASP-2 deficiency (<200 ng/mL). During a cumulative chemotherapy exposure time of 82 years, 177 FN episodes were recorded. MASP-2 deficient children had a significantly increased risk of developing FN (multivariate risk ratio, 2.08; 95% confidence interval, 1.31-3.21; P = 0.002), translating into significantly prolonged cumulative duration of hospitalization and of intravenous antimicrobial therapy. They experienced significantly more episodes of FN without a microbiologically defined etiology, and there was a trend toward more frequent episodes of FN with bacteremia. CONCLUSION: In this study, MASP-2 deficiency was associated with an increased risk of FN in children treated with chemotherapy for cancer. MASP-2 deficiency represents a novel risk factor for chemotherapy-related infections.

High-molecular weight adiponectin is independently associated with the extent of coronary artery disease in men

OBJECTIVE: Adiponectin has anti-atherogenic properties and low circulating adiponectin has been linked to coronary atherosclerosis. Yet, there is considerable evidence that the high-molecular weight (HMW) complex of adiponectin is the major active form of this adipokine. We therefore investigated whether HMW adiponectin is associated with the extent of coronary artery disease (CAD) in men. RESEARCH DESIGN AND METHODS: Associations among CAD, HMW adiponectin and the HMW/total-adiponectin ratio were assessed in 240 male patients undergoing elective coronary angiography. Total adiponectin and HMW adiponectin was measured by enzyme-linked immunosorbent assay and serum levels were correlated with defined coronary scores and established cardiovascular risk factors. RESULTS: We found significant inverse correlations between angiographic scores and HMW adiponectin [Extent Score (ES): r=-0.39; Gensini Score (GS): r=-0.35; and Severity Score (SS): r=-0.40, all P<0.001], and the HMW/total-adiponectin ratio (ES: r=-0.49; GS: r=-0.46; SS: r=-0.46; all P<0.001). Multivariable regression analyses revealed that HMW adiponectin and the HMW/total-adiponectin ratio were significantly associated with the extent of CAD (both P<0.001). ROC analyses demonstrated that the predictive value of HMW adiponectin and the HMW/total-adiponectin ratio for the extent of coronary atherosclerosis significantly exceeded that of total adiponectin (P<0.001, P=0.010, respectively). CONCLUSIONS: HMW adiponectin and the HMW/total-adiponectin ratio inversely correlate with the extent of CAD. HMW adiponectin in particular seems to be a better marker for CAD extent than total adiponectin.

Gene and protein expression of galectin-3 and galectin-9 in experimental pneumococcal meningitis

Inflammation of the subarachnoid and ventricular space contributes to the development of brain damage i.e. cortical necrosis and hippocampal apoptosis in pneumococcal meningitis (PM). Galectin-3 and -9 are known pro-inflammatory mediators and regulators of apoptosis. Here, the gene and protein expression profile for both galectins was assessed in the disease progression of PM. The mRNA of Lgals3 and Lgals9 increased continuously in the cortex and in the hippocampus from 22 h to 44 h after infection. At 44 h after infection, mRNA levels of Lgals9 in the hippocampus were 7-fold and those of Lgals3 were 30-fold higher than in uninfected controls (P<0.01). Galectin-9 protein did not change, but galectin-3 significantly increased in cortex and hippocampus with the duration of PM. Galectin-3 was localized to polymorphonuclear neutrophils, microglia, monocytes and macrophages, suggesting an involvement of galectin-3 in the neuroinflammatory processes leading to brain damage in PM.

Hypothetical mortality risk associated with spiral tomography of the maxilla and mandible prior to endosseous implant treatment

Radiation dose delivered from the SCANORA radiography unit during the cross-sectional mode for dentotangential projections was determined. With regard to oral implantology, patient situations of an edentulous maxilla and mandible as well as a single tooth gap in regions 16 and 46 were simulated. Radiation doses were measured between 0.2 and 22.5 mGy to organs and tissues in the head and neck region when the complete maxilla or mandible was examined. When examining a single tooth gap, only 8% to 40% of that radiation dose was generally observed. Based on these results, the mortality risk was estimated according to a calculation model recommended by the Committee on the Biological Effects of Ionizing Radiations. The mortality risk ranged from 31.4 x 10(-6) for 20-year-old men to 4.8 x 10(-6) for 65-year-old women when cross-sectional imaging of the complete maxilla was performed. The values decreased by 70% when a single tooth gap in the molar region of the maxilla was radiographed. The figures for the mortality risk for examinations of the complete mandible were similar to those for the complete maxilla, but the mortality risk decreased by 80% if only a single tooth gap in the molar region of the mandible was examined. Calculations according to the International Commission on Radiological Protection carried out for comparison did not reveal the decrease of the mortality risk with age and resulted in a higher risk value in comparison to the group of 35-year old individuals in calculations according to the Committee on the Biological Effects of Ionizing Radiations.

Prognosis in pediatric hematologic malignancies is associated with serum concentration of mannose-binding lectin-associated serine protease-2 (MASP-2)

BACKGROUND: Mannose-binding lectin (MBL) and MBL-associated serine protease-2 (MASP-2) are key components of the lectin pathway of complement activation. Their serum concentrations show a wide interindividual variability. This study investigated whether the concentration of MBL and MASP-2 is associated with prognosis in pediatric patients with cancer. METHODS: In this retrospective multicenter study, MBL and MASP-2 were measured by commercially available ELISA in frozen remnants of serum taken at diagnosis. Associations of overall survival (OS) and event-free survival (EFS) with MBL and MASP-2 were assessed by multivariate Cox regression accounting for prognostically relevant clinical variables. RESULTS: In the 372 patients studied, median serum concentration of MBL was 2,808 microg/L (range, 2-10,060) and 391 microg/L (46-2,771) for MASP-2. The estimated 4-year EFS was 0.60 (OS, 0.78). In the entire, heterogeneous sample, MBL and MASP-2 were not significantly associated with OS or EFS. In patients with hematologic malignancies, however, higher MASP-2 was associated with better EFS in a significant and clinically relevant way (hazard ratio per tenfold increase (HR), 0.22; 95% CI, 0.09-0.54; P = 0.001). This was due to patients with lymphoma (HR, 0.11; 95% CI, 0.03-0.47; P = 0.003), but less for those with acute leukemia (HR, 0.35; 95% CI, 0.11-1.15; P = 0.083). CONCLUSION: In this study, higher MASP-2 was associated with better EFS in pediatric patients with hematologic malignancies, especially lymphoma. Whether MASP-2 is an independent prognostic factor affecting risk stratification and anticancer therapy needs to be assessed in prospective, disease-specific studies.