Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130

The retinoblastoma gene family consists of three genes: RB, p107, and p130. While loss of pRB causes retinoblastoma in humans and pituitary gland tumors in mice, tumorigenesis in other tissues may be suppressed by p107 and p130. To test this hypothesis, we have generated chimeric mice from embryonic stem cells carrying compound loss-of-function mutations in the Rb gene family. We found that Rb/p107- and Rb/p130-deficient mice were highly cancer prone. We conclude that in a variety of tissues tumor development by loss of pRB is suppressed by its homologs p107 and p130. The redundancy of the retinoblastoma proteins in vivo is reflected by the behavior of Rb-family-defective mouse embryonic fibroblasts in vitro.     

Adolescents'' opinions about genetic risk information, prenatal diagnosis, and pregnancy termination

Advances in genetics create increasing possibilities of diagnosing and preventing genetic disease. In most countries, the community is poorly informed about the role of genetic factors in human disease and about genetic testing and its social, emotional, and ethical implications. School education about genetics may improve this situation. Students are, of course, the adults of the future and the potential users of the new genetic tests. To gain further insight into the perception of genetic risk of adolescents and their perception of the new genetic techniques and as a starting point for setting up an adequate information campaign in Flanders, we assessed the opinions and beliefs of students with regard to health, genetic diseases, genetic risk, and genetic testing.

A standardised interview and questionnaire were administered within the scope of the two yearly medical check up of 166 fifth grade students. They were randomly selected from the group of all fifth grade high school students in seven different schools.

This paper focuses on the attitudes of adolescents towards obtaining genetic information, towards prenatal diagnosis and pregnancy termination. Adolescents in Flanders are interested in being informed about genetic risks and genetic diseases and in making use of prenatal diagnosis because they want to make informed reproductive decisions in the future and to be emotionally prepared for the birth of an affected child. They adopt a critical attitude towards pregnancy termination. The association between these attitudes and several relevant factors was investigated. This showed significant correlations between some attitudes and general health related prevention, perceived burden of genetic diseases, the importance of the value “own health”, the perceived role of society, and the regularity of religious practice. Some points for special attention were formulated with regard to information campaigns for adolescents.

     

IgG anti-tetanus toxoid antibody synthesis by human bone marrow. I. Two distinct populations of marrow B cells and functional differences between marrow and peripheral blood B cells

This investigation uses a system for inducing and detecting anti-tetanus toxoid antibody (anti-TT) synthesis to study specific antibody (Ab) synthesis by bone marrow mononuclear cells (MC). We measured the amounts of anti-TT secreted and the number of B cells secreting antibody (Ab). The ELISA plaque detects single B cells secreting specific Ab. The results show that (1) spontaneous anti-TT secretion by MC is higher than spontaneous anti-TT secretion by peripheral blood lymphocytes (PBL) using an ELISA plaque (P<0.01); (2) spontaneous anti-TT production by MC correlated with the serum anti-TT titers as measured by an ELISA (r=0.75,P=0.005); (3) two types of marrow B cells were identified—one that spontaneously secretes anti-TT and another that produces anti-TT after TT-stimulation; (4) the frequency of anti-TT-secreting B cells is higher in MC than in PBL; (5) the amount of Ab secreted per marrow B cell is not different from that secreted by a peripheral B cell; and (6) marrow B cells could be induced to produce anti-TTin vitro up to 10 months without added cytokines. These results show that bone marrow is a major repository for differentiated B cells that spontaneously produce Abs to maintain circulating Abs titers and for memory B cells that can be induced to produce specific Ab.     

Placental inflammation and perinatal transmission of HIV-1

The effect of placental membrane inflammation on mother-to-child transmission (MTCT) of HIV-1 is reported. Placentas from HIV-1-infected women were examined as part of a perinatal HIV-1 project in Mombasa, Kenya. Polymerase chain reaction analysis was used to test for HIV-1 in the infants at birth and at 6 weeks. The maternal HIV-1 seroprevalence was 13.3% (298 of 2,235). The overall rate of MTCT of HIV-1 was 25.4%; polymerase chain reaction analysis revealed that of the 201 infants 6.0% (12) were already HIV-1-positive at birth (intrauterine transmission) and 19.4% (39) were infected during the peripartum period or in early neonatal life (perinatal transmission). The prevalence of acute chorioamnionitis was 8.8%, that of deciduitis was 10.8%, and that of villitis was 1.6%. Acute chorioamnionitis was independently associated with peripartum HIV-1 transmission but not with in utero MTCT (17.9% vs. 6.7%, respectively; adjusted odds ratio, 3.9; 95% confidence interval, 1.2-12.5; p =.025). Other correlates of perinatal MTCT were presence of HIV in the genital tract and in the baby's oral cavity and a high maternal viral load in peripheral blood. The adjusted population attributable fraction of 12.8% (95% confidence interval, 1.5%-22.8%) indicated that approximately 3% of MTCT could be prevented if acute chorioamnionitis was eliminated. We suggest that further research on the role of antimicrobial treatment in the prevention of chorioamnionitis and the reduction of peripartum MTCT needs to be performed.     

Vital signs of the systemic inflammatory response syndrome in adult patients with acute infections presenting in out-of-hours primary care: A cross-sectional study

BackgroundSigns of the systemic inflammatory response syndrome (SIRS) – fever (or hypothermia), tachycardia and tachypnoea – are used in the hospital setting to identify patients with possible sepsis.ObjectivesTo determine how frequently abnormalities in the vital signs of SIRS are present in adult out-of-hours (OOH) primary care patients with suspected infections and assess the association with acute hospital referral.MethodsWe conducted a cross-sectional study at the OOH GP cooperative in Nijmegen, the Netherlands, between August and October 2015. GPs were instructed to record the body temperature, heart rate and respiratory rate of all patients with suspected acute infections. Vital signs of SIRS, other relevant signs and symptoms, and referral state were extracted from the electronic registration system of the OOH GP cooperative retrospectively. Logistic regression analysis was used to evaluate the association between clinical signs and hospital referral.ResultsA total of 558 patients with suspected infections were included. At least two SIRS vital signs were abnormal in 35/409 (8.6%) of the clinic consultations and 60/149 (40.3%) of the home visits. Referral rate increased from 13% when no SIRS vital sign was abnormal to 68% when all three SIRS vital signs were abnormal. Independent associations for referral were found for decreased oxygen saturation, hypotension and rapid illness progression, but not for individual SIRS vital signs.ConclusionAlthough patients with abnormal vital signs of SIRS were referred more often, decreased oxygen saturation, hypotension and rapid illness progression seem to be most important for GPs to guide further management.     

Structural spinal abnormalities on MRI and associations with weight status in a general pediatric population

BACKGROUND CONTEXTSeveral spinal abnormalities have been studied using magnetic resonance imaging (MRI). However, in children these studies were sparsely performed in general populations. Examining young children's spines is important since the shape of the bone is largely determined during the growth spurt. Furthermore, it is so far unknown if associations between weight status and spinal abnormalities, which are known for adolescents and adults, are already present in young children.PURPOSEWe aimed to present the prevalence of structural abnormalities in the prepubertal pediatric spine on MRI and their association with measures of the children's body weight and body composition.STUDY DESIGNCross-sectional study embedded in a prospective population-based birth cohort study.PATIENT SAMPLEFor this study, participants from the Generation R Study were selected based on the availability of MRI data of the lumbar spine and accelerometry data at the age of 9 years.OUTCOME MEASURESThe presence of structural abnormalities of intervertebral discs and vertebrae was scored on MRI. The body mass index-standard deviation [BMI-SD] score was calculated from objectively measured weight and height, and body composition measurements were obtained by a dual-energy X-ray absorptiometry scan.METHODSA semiquantitative scoring tool to assess the intervertebral discs and vertebrae of the lumbar spine on conventional MRI was designed for this purpose. Proportions of children with spinal abnormalities on at least one lumbar vertebral level were presented. Logistic regression was used to analyze associations between abnormalities and weight and body composition. We declare not to have any financial conflicts of interests.RESULTSWe included 559 children (median age of 9.88 years (interquartile range 6.74–10.02), 48.5% boys). Most frequently observed abnormalities of the intervertebral discs were abnormal signal intensity (24.9%), decreased or collapsed disc height (37.6%), disc bulging (73.3%), and abnormal nuclear shape (29.1%). Vertebral endplate irregularities and lumbosacral transitional vertebrae were seen in respectively 40% and 9.3% of the participants. Except for disc bulging, all abnormalities were predominantly present at the L5 level. Only the presence of endplate irregularities was associated with a higher body weight (BMI SD score (odds ratio [OR] 1.50 [95% confidence interval [CI] 1.21–1.86]) and BMI SD change (OR 1.48 [95% CI 1.07–2.03])) and increased body mass values in body composition measurements (% body fat (OR 1.05 [95% CI 1.02–1.09), fat mass index (OR 1.23 [95% CI 1.09–1.39]), and fat-free mass index (OR 1.30 [95% CI 1.06–1.59])) in adjusted analyses.CONCLUSIONSStructural spinal abnormalities, especially disc bulging, endplate irregularities, and an abnormal disc height, are already present in children aged 9 years from a Dutch population-based cohort. Of those abnormalities, endplate irregularities are associated with various weight and body composition measurements.     

Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma.

PURPOSE: The discovery of new ovarian cancer biomarkers that are suitable for early disease diagnosis and prognosis may ultimately lead to improved patient management and outcomes. PATIENTS AND METHODS: We measured, by immunoassay, human kallikrein 6 (hK6) concentration in serum of 97 apparently healthy women, 141 women with benign abdominal diseases, and 146 women with histologically proven primary ovarian carcinoma. We then calculated the diagnostic sensitivity and specificity of this test and examined the association of serum hK6 concentration with various clinicopathologic variables and patient survival. RESULTS: Serum hK6 concentration between normal and benign disease patients was not different (mean, 2.9 and 3.1 micro g/L, respectively). However, hK6 in presurgical serum of ovarian cancer patients was highly elevated (mean, 6.8 micro g/L; P <.001). Serum hK6 decreased after surgery (to a mean of 3.9 micro g/L) in 68% of patients. The diagnostic sensitivity of serum hK6 at 90% and 95% specificity is 52% and 47%, respectively, in the whole patient population. For early stage disease (stage I or II), sensitivity is approximately 21% to 26%. When combined with CA-125, at 90% specificity, sensitivity increases to 72% (for all patients) and to 42% in stage I or II disease. Serum hK6 concentration correlates moderately with CA-125 and is higher in patients with late-stage, higher-grade disease and in patients with serous histotype. Preoperative serum hK6 concentration is a powerful predictor of disease-free and overall survival in both univariate and multivariate analyses. CONCLUSIONS: Serum hK6 concentration seems to be a new biomarker for ovarian carcinoma and may have value for disease diagnosis and prognosis.