A model based safety architecture framework for Dutch high speed train lines

This paper presents a model-based safety architecture framework (MBSAF) for capturing and sharing architectural knowledge of safety cases of safetycritical systems of systems (SoS). Whilst architecture frameworks in the systems engineering domain consider safety often as dependent attribute, this study focusses specifically on sharing architectural knowledge of safety cases between stakeholders and managing safety in systems development. For this purpose, we adapt the A3 architecture overview (A3AO) tool. The application is shown though the case study of Dutch high speed train lines and shows how to derive requirements from various stakeholders by carrying out iterative validations of the A3AOs. The implemented technique consists of systems modeling language-based (SysML) diagrams. Outcomes of the assessment lead to guidelines for two A3AOs. This results in increasing and effective interaction between stakeholders, more overview for managing safety complexity, more insight into finding required safety information, and therefore; an increasing efficiency in safety engineerin

Cross-reactive broadly neutralizing antibodies: timing is everything

The recent surge of research into new broadly neutralizing antibodies in HIV-1 infection has recharged the field of HIV-1 vaccinology. In this review we discuss the currently known broadly neutralizing antibodies and focus on factors that may shape these antibodies in natural infection. We further discuss the role of these antibodies in the clinical course of the infection and consider immunological obstacles in inducing broadly neutralizing antibodies with a vaccine

Maternal death after oocyte donation at high maternal age: Case report

Background. The percentage of women giving birth after the age of 35 increased in many western countries. The number of women remaining childless also increased, mostly due to aging oocytes. The method of oocyte donation offers the possibility for infertile older women to become pregnant. Gestation after oocyte-donation-IVF, however, is not without risks for the mother, especially at advanced age. Case presentation. An infertile woman went abroad for oocyte-donation-IVF, since this treatment is not offered in The Netherlands after the age of 45. The first oocyte donation treatment resulted in multiple gestation, but was ended by induced abortion: the woman could not cope with the idea of being pregnant with twins. During the second pregnancy after oocyte donation, at the age of 50, she was mentally more stable. The pregnancy, again a multiple gestation, was uneventful until delivery. Immediately after delivery the woman had hypertension with nausea and vomiting. A few hours later she had an eclamptic fit. HELLP-syndrome was diagnosed. She died due to cerebral haemorrhage. Conclusion. In The Netherlands, the age limit for women receiving donor oocytes is 45 years and commercial oocyte donation is forbidden by law. In other countries there is no age limit, the reason why some women are going abroad to receive the treatment of their choice. Advanced age, IVF and twin pregnancy are all risk factors for pre-eclampsia, the leading cause of maternal death in The Netherlands. Patient autonomy is an important ethical principle, but doctors are also bound to the principle of 'not doing harm', and do have the right to refuse medical treatment such as IVF-treatment. The discussion whether women above 50 should have children is still not closed. If the decision is made to offer this treatment to a woman at advanced age, the doctor should counsel her intensively about the risks before treatment is started

In vitro replication capacity of HIV-2 variants from long-term aviremic individuals

To establish whether efficient suppression of virus replication in HIV-2-infected individuals is associated with low replicative capacity of HIV-2, replication kinetics of HIV-2 variants from long-term aviremic individuals was analyzed and compared with that of the relatively slow-replicating HIV-1 variants from asymptomatics and long-term nonprogressors (AS/LTNP). On average, HIV-2 from aviremic individuals had lower replication rates than HIV-1 variants from AS/LTNP in cells of 8 donors (0.45 log10 [range 0.14-0.77] vs. 0.58 log10 [range 0.32-0.99] pg RT/ml/day, P = 0.036). The relatively low replication rate of HIV-2 compared to HIV-1 variants was not related to different sensitivities to inhibition by CD8+ T cells or different degrees of infectivity. HIV-2 replication rates increased with progressive infection and with switch from CCR5 to CXCR4 usage. The relatively low replicative capacity of HIV-2 variants from aviremic individuals likely contributes to the low viral load and benign course of infection in these individuals

A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors

AbstractHere, we show that the β-chemokine receptor CKR-5 serves as a cofactor for M-tropic HIV viruses. Expression of CKR-5 with CD4 enables nonpermissive cells to form syncytia with cells expressing M-tropic, but not T-tropic, HIV-1 env proteins. Expression of CKR-5 and CD4 enables entry of a M-tropic, but not a T-tropic, virus strain. A dual-tropic primary HIV-1 isolate (89.6) utilizes both Fusin and CKR-5 as entry cofactors. Cells expressing the 89.6 env protein form syncytia with QT6 cells expressing CD4 and either Fusin or CKR-5. The β-chemokine receptors CKR-3 and CKR-2b support HIV-1 89.6 env-mediated syncytia formation but do not support fusion by any of the T-tropic or M-tropic strains tested. Our results suggest that the T-tropic viruses characteristic of disease progression may evolve from purely M-tropic viruses prevalent early in virus infection through changes in the env protein that enable the virus to use multiple entry cofactors

A study of circulating proteins associated with the pathophysiology of preeclampsia or gestational diabetes mellitus

A study of circulating proteins associated with the pathophysiology of preeclampsia or gestational diabetes mellitus.This study looked at the concentration of a number of proteins in the blood of pregnant women. The researchers were particularly interested in whether the proteins studied could play a role in the development of pregnancy complications, such as preeclampsia and gestational diabetes. ESM-1 and GBP-1, both proteins that are mainly produced by cells of the blood vessel wall and that also have effects on the blood vessel wall, differ in concentration in the blood of pregnant women compared to non-pregnant women. This is probably due to a mild inflammatory response during pregnancy. A difference was also found in the concentration of both proteins in the blood of a healthy pregnancy compared to a pregnancy with preeclampsia. Since ESM-1 seemed to be already different before the onset of preeclampsia, this protein could be involved in the onset of preeclampsia. The precise role of this protein remains to be determined. The protein sFRP4 in the blood of women who were early in pregnancy and later developed gestational diabetes was also examined. This protein, involved in the regulation of the body's sugar balance, was found in higher concentrations in women who would go on to develop gestational diabetes compared to women who would go on to have a healthy pregnancy. This higher concentration of sFRP4 inhibits insulin production by the pancreas, resulting in insulin deficiency and diabetes. Future research should investigate why the sFRP4 concentration is increased and what the exact role of this protein is

Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: A longitudinal analysis of rapid progressors and long-term asymptomatics.

To gain more insight into the role of HIV-1-specific cytotoxic T lymphocytes (CTL) in the pathogenesis of AIDS, we investigated temporal relations between HIV-1 Gag-specific precursor CTL (CTLp), HIV-1 viral load, CD4+ T cell counts, and T cell function. Six HIV-1-infected subjects, who were asymptomatic for more than 8 yr with CD4+ counts > 500 cells/mm3, were compared with six subjects who progressed to AIDS within 5 yr after HIV-1 seroconversion. In the long-term asymptomatics, persistent HIV-1 Gag-specific CTL responses and very low numbers of HIV-1-infected CD4+ T cells coincided with normal and stable CD4+ counts and preserved CD3 mAb-induced T cell reactivity for more than 8 yr. In five out of six rapid progressors Gag-specific CTLp were also detected. However, early in infection the number of circulating HIV-1-infected CD4+ T cells increased despite strong and mounting Gag-specific CTL responses. During subsequent clinical progression to AIDS, loss of Gag-specific CTLp coincided with precipitating CD4+ counts and severe deterioration of T cell function. The possible relationships of HIV-1 Gag-specific CTLp to disease progression are discussed