Mannose-binding lectin engagement with late apoptotic and necrotic cells

The serum opsonin mannose-binding lectin (MBL) has been shown to be involved in the handling of apoptotic cells. However, at what stage in the process this happens and whether this mediates activation of complement is unknown. Cells rendered apoptotic or necrotic were incubated with purified MBL/MBL-associated serine protease (MASP) complexes and assessed by flow cytometry and fluorescence microscopy. MBL bound specifically to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells. Binding of MBL could be inhibited by EDTA as well as with an antibody against the CRD region. Addition of C1q, another serum opsonin involved in the handling of apoptotic cells, prior to MBL partly inhibited MBL binding to apoptotic cells and vice versa. MBL/MASP could initiate deposition of purified complement C4 on the target cells. However, addition of MBL/MASP to whole serum deficient for both C1q and MBL did not enhance deposition of C4, but MBL enhanced phagocytosis of apoptotic cells by macrophages. These results demonstrate that MBL interacts with structures exposed on cells rendered late apoptotic or necrotic and facilitates uptake by macrophages. Thus, MBL may promote non-inflammatory sequestration of dying host cells.     

Characterization of familial non-BRCA1/2 breast tumors by loss of heterozygosity and immunophenotyping.

PURPOSE: Since the identification of BRCA1 and BRCA2, there has been no major breast cancer susceptibility gene discovered by linkage analysis in breast cancer families. This has been attributed to the heterogeneous genetic basis for the families under study. Recent studies have indicated that breast tumors arising in women carrying a BRCA1 mutation have distinct histopathologic, immunophenotypic, and genetic features. To a lesser extent, this is also true for breast tumors from BRCA2 carriers. This indicates that it might be possible to decrease the genetic heterogeneity among families in which BRCA1 and BRCA2 have been excluded with high certainty (BRCAx families) if distinct subgroups of BRCAx-related breast tumors could be identified. EXPERIMENTAL DESIGN: Loss of heterozygosity (LOH) analysis with at least one marker per chromosomal arm (65 markers) was used to characterize 100 breast tumors derived from 92 patients from 42 selected BRCAx families. In addition, the immunophenotype of 10 markers was compared with that of 31 BRCA1- and 21 BRCA2-related breast tumors. RESULTS AND CONCLUSIONS: The BRCAx-related tumors were characterized by more frequent LOH at 22q relative to sporadic breast cancer (P < 0.02), and differed significantly from BRCA1- and BRCA2-related tumors in their positivity for Bcl2. However, cluster analyses of the combined data (LOH and immunohistochemistry) did not result in subgroups that would allow meaningful subclassification of the families. On chromosomes 2, 3, 6, 12, 13, 21, and 22, we found markers at which LOH occurred significantly more frequent among the tumors from patients belonging to a single family than expected on the basis of overall LOH frequencies. Nonetheless, linkage analysis with markers for the corresponding regions on chromosomes 12, 21, and 22 did not reveal significant logarithm of the odds.     

Meningitis Caused by the Live Varicella Vaccine Virus: Metagenomic Next Generation Sequencing,Immunology Exome Sequencing and Cytokine Multiplex Profiling

Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3–4 weeks before onset of vaccine meningitis may be a risk factor in some cases.     

Intestinal Absorption of Lipids Using a Pancreatic Enzyme-Free Nutritional Supplement in Patients with Cystic Fibrosis: A Randomized,Double-Blind,Crossover Pilot Trial

Nutritional supplements for patients with exocrine pancreatic insufficiency (EPI) typically utilize pancreatic enzyme replacement therapy (PERT) which is associated with gastrointestinal side effects. We evaluated serum triglyceride levels in patients with cystic fibrosis following consumption of an enzyme-modified oil oral nutritional supplement (EMO-ONS) versus a standard triacylglycerol-based ONS product (TAG-ONS) used concomitantly with PERT and patient tolerability between the two approaches. Ten subjects with CF and EPI taking PERT were enrolled in a single-center, double-blind, cross-over proof of concept trial. Five subjects randomized to Arm 1 were administered a PERT placebo and EMO-ONS and 5 subjects in Arm 2 were administered TAG-ONS+PERT. After 4 to 14 days, subjects received the opposite ONS. Serum triglyceride levels were measured at baseline and hourly for 6 h. Following the above, subjects were randomly assigned to receive 2 daily servings of EMO-ONS+PERT placebo or TAG-ONS+PERT at home for 7-days, self-reporting gastrointestinal symptoms daily. Mean change in peak serum triglyceride levels were similar for both groups (EMO-ONS = 41.9 ± 46.7 mg/dL vs. TAG-ONS+PERT = 46.4 ± 44.1 mg/L; p = 0.85). There was no difference in mean ratio of the serum triglyceride AUC between the two groups (p = 0.58) or self-reported gastrointestinal tolerance. EMO-based products may provide a PERT-free alternative to traditional ONS products in patients with cystic fibrosis.     

Bilateral cornual abscess after endometrial ablation following Essure sterilization

Endometrial ablation is used extensively to treat dysfunctional bleeding. Since the introduction of Essure tubal sterilization, this permanent contraception method has been widely used. Both endometrial ablation and Essure sterilization are procedures reported to have only a few complications. We describe a serious infectious complication shortly after an endometrial ablation in a patient with Essure microinserts in situ. To our knowledge, this complication has not been reported before in patients with Essure microinserts in situ. We suggest administering prophylactic antibiotics before endometrial ablation in women with Essure microinserts in situ.     

Quality based social insurance coverage and payment of the application of a high cost medical therapy: the case of spinal cord stimulation for chronic non-oncologic pain in The Netherlands

This article describes a project in which a national continuous quality improvement system and a payment scheme were explicitly linked, while introducing an expensive treatment (Spinal Cord Stimulation (SCS)) in the social health insurance benefit package, in The Netherlands. By linking a national CQI system and a payment scheme in a conditional financing policy a steering instrument for future control of the quality of neuromodulation treatment through SCS is created.     

Adequacy of family history taking in ovarian cancer patients: a population-based study

The aim of this study was to evaluate the adequacy of family history taking in epithelial ovarian cancer (EOC) patients and to identify factors that determine adequacy. Furthermore, the validity of family history taking was assessed by comparison with self-administered questionnaires. Medical records of all 1,112 EOC patients registered by the nation-wide cancer registry and diagnosed in eleven Dutch hospitals between 1996 and 2006 were reviewed. Adequate family history taking was defined as a written notification of the presence or absence of relatives with breast or ovarian cancer. Factors that were correlated with family history taking were identified using univariable and multivariable logistic regression.?147 patients filled in a postal questionnaire. An adequate family history was taken in 41% of all cases. Younger age, an academic hospital and having undergone surgery and/or chemotherapy were associated with adequate family history taking. The comparison with self-administered questionnaires showed a disagreement in 64% mainly due to missing data in medical records. Documentation on family history is either absent or inadequate in the medical records in the majority of EOC patients. These data urge for better uptake of hereditary cancer risk assessment. Different strategies for this assessment like improved family history taking and genetic testing in EOC patients should be explored.     

Parental reports of adverse events following simultaneously given dT-IPV and MMR vaccines in healthy 9-year-old children

In the Netherlands, children at 9 years of age receive a booster dT-IPV together with their second measles, mumps, and rubella (MMR) vaccination within the national immunization program. Safety is monitored continuously by enhanced passive surveillance. This population-based study was conducted to obtain more information on adverse events after vaccination at 9 years of age. Questionnaires on local and systemic reactions were distributed 1 and 3 weeks after vaccination, respectively, to parents of 1,250 healthy children who received their MMR and diphtheria, tetanus, and inactivated poliovirus injection (dT-IPV) vaccination as scheduled. Response to the quesionnaires was 57.0% and 46.5%, respectively. Local reactions occurred in 86.5% of the children within 7 days after vaccination, more often at the dT-IPV (83.4%) than at the MMR site (32.7%). Pain was the most reported symptom (80.8% at the dT-IPV site; 29.1% at the MMR site). Systemic events occurred in 33.4% children within 7 days after vaccination, with headache as the most frequently reported (20.8%). Systemic events occurred in 20.8% children 8–21 days after vaccination. Children with local reactions at only the dT-IPV site had significantly more systemic events (19.3%) than those without local reactions (3.4%, p < 0.01). Such difference was not found for the MMR site. No serious adverse events were reported. Medical intervention was applied to 133 children (130 used analgesics and for three children the GP was consulted by phone). In conclusion, the frequency of reported local reactions is high, especially at the dT-IPV site, but all symptoms were transient. However, the use of reduced antigen content vaccines in association with the occurrence of adverse events is meaningful to explore. Furthermore, the overall rates are useful for monitoring variations in adverse events rates in the general population.