Immunisation coverage annual report, 2008

This, the 2nd annual immunisation coverage report, documents trends during 2008 for a range of standard measures derived from Australian Childhood Immunisation Register data, including overall coverage at standard age milestones and for individual vaccines included on the National Immunisation Program (NIP). Coverage by indigenous status and mapping by smaller geographic areas as well as trends in timeliness are also summarised according to standard templates. With respect to overall coverage, Immunise Australia Program targets have been reached for children at 12 and 24 months of age but not for children at 5 years of age. Coverage at 24 months of age exceeds that at 12 months of age, but as receipt of varicella vaccine at 18 months is excluded from calculations of 'fully immunised' this probably represents delayed immunisation, with some contribution from immunisation incentives. Similarly, the decrease in coverage estimates for immunisations due at 4 years of age from March 2008, is primarily due to changing the assessment age from 6 years to 5 years of age from December 2007. A number of individual vaccines on the NIP are not currently assessed for 'fully immunised' status or for eligibility for incentive payments. These include pneumococcal conjugate and meningococcal C conjugate vaccines for which coverage is comparable to vaccines which are assessed for 'fully immunised' status, and rotavirus and varicella vaccines for which coverage is lower. Coverage is also suboptimal for vaccines recommended for Indigenous children only (i.e. hepatitis A and pneumococcal polysaccharide vaccine) as previously reported for other vaccines for both children and adults. Delayed receipt of vaccines is an important issue for vaccines recommended for Indigenous children and has not improved among non-Indigenous children despite improvements in coverage at the 24-month milestone. Although Indigenous children in Australia have coverage levels that are similar to non-indigenous children at 24 months of age, the disparity in delayed vaccination between Indigenous and non-indigenous children, which is up to 18% for the 3rd dose of DTP, remains a challenge.     

Cannabinoid and planar cell polarity signaling converges to direct placentation

Directed trophoblast migration toward the maternal mesometrial pole is critical for placentation and pregnancy success. Trophoblasts replace maternal arterial endothelial cells to increase blood supply to the placenta. Inferior trophoblast invasion results in pregnancy complications including preeclampsia, intrauterine growth restriction, miscarriage, and preterm delivery. The maternal chemotactic factors that direct trophoblast migration and the mechanism by which trophoblasts respond to these factors are not clearly understood. Here, we show that invasive trophoblasts deficient in Vangl2, a core planar cell polarity (PCP) component, fail to invade in maternal decidua, and this deficiency results in middle-gestational fetal demise. Previously, we have shown that tightly regulated endocannabinoids via G protein–coupled cannabinoid receptor CB1 are critical to the invasion of trophoblasts called spiral artery trophoblast giant cells (SpA-TGCs). We find that CB1 directly interacts with VANGL2. Trophoblast stem cells devoid of Cnr1 and/or Vangl2 show compromised cell migration. To study roles of VANGL2 and CB1 in trophoblast invasion in vivo, we conditionally deleted Cnr1 (coding CB1) and Vangl2 in progenitors of SpA-TGCs using trophoblast-specific protein alpha (Tpbpa)-Cre. We observed that signaling mediated by VANGL2 and CB1 restrains trophoblasts from random migration by keeping small GTPases quiescent. Our results show that organized PCP in trophoblasts is indispensable for their directed movement and that CB1 exerts its function by direct interaction with membrane proteins other than its canonical G protein–coupled receptor role.

The placenta is a complex and highly vascularized organ that acts as an exchange platform for gases and nutrients between the maternal and fetal circulation (1, 2). Defects in placental development, therefore, have major consequences for the fetus and mother. Shallow trophoblast invasion results in pregnancy complications, including preeclampsia, intrauterine growth restriction, miscarriage, and preterm delivery. The outer epithelial layer of the blastocyst, termed trophectoderm, is the building block of the placenta in mice. Placental function is executed by differentiated trophoblast cells, originating from trophoblast stem (TS) cells. Factors regulating trophoblast invasion and the underlying mechanism are not clearly understood. We previously provided evidence for the role of cannabinoid signaling in placentation. Cannabinoids exert their effects via G protein–coupled cannabinoid receptors, CB1 and CB2.During the initial stages of placentation, fetal trophoblast cells are separated from the maternal decidual zone by a single layer of parietal trophoblast giant cells (P-TGCs). Notably, most trophoblast cells reside within the placenta throughout pregnancy. Two phenotypes of invasive trophoblasts breach the boundary and invade the maternal decidual zone. Cells crawling between decidual stromal cells are termed interstitial invasive glycogen trophoblast cells (GlyTs), whereas cells moving along uterine spiral arteries are called spiral artery TGCs (SpA-TGCs). During migration, SpA-TGCs replace maternal endothelial cells; their invasion into the maternal decidual zone is indispensable for normal placentation, as ablation of SpA-TGCs in mice results in embryonic death. The movement of interstitial GlyTs differs from that of SpA-TGCs. In interstitial invasion, GlyTs dissociate and display elements of an epithelial to mesenchymal transformation as they penetrate the decidual stroma. By contrast, invasive SpA-TGCs maintain connectivity and exhibit an epithelial to endothelial-like transformation to replace endothelial cells. The mechanism that regulates this directional cell movement of SpA-TGCs remains elusive.Cannabinoids can alter cell motility in a receptor-dependent or -independent manner (3–7). For example, the endocannabinoid 2-arachidonoylglycerol (2-AG) induces the migration of natural killer cells via CB2 (8). Activation of CB1 was reported to suppress prostate cell migration and induce growth cone collapse in developing GABAergic neurons (6, 9). In neurons, the stabilization of F-actin is diminished by CB1 agonists (10). Our current study focuses on Cnr1, since the expression of Cnr2 is not detectable in trophoblast cells (11). Considering transmembrane CB1 functions mainly through its coupling partners G_i or G_q (12) and their effectors cAMP and Ca²⁺, it is difficult to directly link CB1 and cell motility. Several reports have indicated CB1 influences activation of small GTPases and WAVE1 complex, which is known to be involved in actin nucleation (6, 7, 10). However, the mechanism by which CB1 regulates cell movement is still not clear. In addition, most of these studies, if not all, depended solely on pharmacological means to manipulate cannabinoid signaling. Given the inequity of agonists/antagonists’ specificity and efficacy, further studies using genetically modified cells or mouse models are necessary to preclude ambiguity.Using mice deficient in CB1 and CB2, we have shown that endocannabinoid signaling plays various roles in implantation chamber formation and trophoblast migration (11, 13). In the absence of CB1 and CB2, implantation chambers show abnormal epithelial projections. Interestingly, our recent study also reveals that mice with uterine deletion of Vangl2, a core planar cell polarity (PCP) component, show similar phenotypes during implantation. The PCP pathway is best known for its role in cell polarization at the plane of a sheet of cells, and recent data suggest that it plays a key role in directed cell migration during development (reviewed in ref. 14). VANGL2’s localization in the cell membrane promotes our hypothesis that cannabinoid receptors coupled with VANGL2 regulate cell movement.We found that VANGL2 physically associates with CB1, and deletion of either module compromises trophoblast cell migration in vitro. The in vitro data encourage us to study CB1 and VANGL2 interactions in vivo. VANGL2 is expressed in trophoblast cells located in the spongy layer where CB1 is also localized (13). Using a mouse line with Cre driven by Tpbpa (15), we deleted Vanlg2 and/or Cnr1 in trophoblast cells in this layer, where progenitor cells of invasive SpA-TGCs and GlyTs are located. We found that placentas deficient in spongy Vangl2 (Vangl2^f/fTpbpa^cre/+; Vangl2^d/d) are significantly compromised, resulting in termination of pregnancy of Vangl2^d/d fetuses. Overall, we show that VANGL2 coupled with CB1 directs SpA-TGC and GlyT migration, significantly affecting placentation. This study reveals that G protein-coupled receptor (GPCR) CB1 influences cell migration by coupling with core components in the PCP pathway, illuminating a previously unrecognized avenue for CB1’s regulation of cytoskeleton reorganization. More importantly, our data suggest that PCP signaling is critical to trophoblast invasion in the maternal–fetal interface, potentially explaining the long-standing question as to why trophoblasts invade toward the mesometrial pole. Shallow endovascular invasion is associated with preeclampsia, intrauterine growth restriction, and preterm birth, which impact a significant global population each year (16).     

Navigating cancer using online communities: a grounded theory of survivor and family experiences

Purpose

People affected by cancer often have unmet emotional and social support needs. Online cancer communities are a convenient channel for connecting cancer survivors, allowing them to support one another. However, it is unclear whether online community use makes a meaningful contribution to cancer survivorship, as little previous research has examined the experience of using contemporary cancer communities. We aimed to explore the experiences of visitors to online cancer communities.

Methods

Twenty-three in-depth interviews were conducted with online cancer community visitors, including cancer survivors (n = 18), family members (n = 2), and individuals who were both a survivor and family member (n = 3). Interviews were analysed using a grounded theory approach.

Results

A theory developed explaining how individuals ‘navigated’ the experience of cancer using online cancer communities. Online advice and information led participants on a ‘journey to become informed’. Online friendships normalised survivorship and cast participants on a ‘journey to recreate identity’. Participants navigated a ‘journey through different worlds’ as they discovered relevant and hidden communities.

Conclusions

This theory highlights virtual paths people affected by cancer can take to self-manage their experience of the disease. Online community experiences can be improved by promoting online evaluation skills and signposting visitors to bereavement support.

Implications for cancer survivors

Cancer survivors can benefit through both lurking and posting in online communities. However, individuals risk becoming distressed when they befriend individuals who may soon die. Additionally, people affected by rarer cancers can struggle to find shared experiences online and may need to look elsewhere for support.

     

Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors

The cardiovascular safety of COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has recently been called into question. The factors that predispose to adverse events by NSAIDs are unknown. Because patients with arthritis have decreased nitric oxide (NO) bioavailability, the in vivo effects of NSAIDs on murine vascular tone and platelet activity in the presence or absence of NO were examined. Here, we show that acute hypertensive and prothrombotic activities of the COX-2-selective inhibitor celecoxib are revealed only after in vivo inhibition of NO generation. The nonselective NSAID indomethacin was hypertensive but antithrombotic when NO was absent. In vitro myography of aortic rings confirmed that vasoconstriction required inhibition of both NOS and COX-2 and was abolished by supplementation with exogenous NO. These data indicate that NO suppresses vascular side effects of NSAIDs, suggesting that risk will be greatest in patients with impaired vascular function associated with decreased NO bioavailability.     

Outcomes of Multifetal Reduction: A Hospital-Based Study

Background

Higher-order multiple (HOM) pregnancies are associated with increased incidences of pregnancy complications mainly abortions, pre-eclampsia, preterm delivery and fetal death. Multifetal reduction (MFR) during first trimester and subsequent delivery of twins can reduce pregnancy associated morbidities. This study was conducted to evaluate the maternal and fetal outcomes of MFR procedure in patients with HOMs those managed in a tertiary care hospital.

Methods and Material

It was a prospective observational study carried out in a tertiary care military hospital, India, and all women with higher-order multiples (triplets or more) conceived spontaneously or after infertility treatment (ovulation induction, intra-uterine insemination, or in vitro fertilization) during the 3-year period from Jan 2014 to Dec 2016 were included for MFR. Demographic and clinical data, and obstetric and neonatal outcomes were tabulated.

Results

The study included 32 HOM pregnancies which underwent MFR. 16% patients had pre-eclampsia and 12% patients had gestational diabetes. The study had 2 pregnancy losses before 24 weeks period of gestation (POG). 70% patients underwent cesarean delivery with mean gestational age of 35.5 weeks. Average birth weight of newborn was 1820 gm and 80% of them required NICU admission.

Conclusion

Favorable pregnancy outcomes can be achieved after multifetal reductions during first trimester in higher-order multiples, but the procedure is not totally safe.

     

A Cytokine–Cytokine Interaction in the Assembly of Higher-Order Structure and Activation of the Interleukine-3:Receptor Complex

Interleukine-3 (IL-3) binds its receptor and initiates a cascade of signaling processes that regulate the proliferation and differentiation of hematopoietic cells. To understand the detailed mechanisms of IL-3 induced receptor activation, we generated a homology model of the IL-3:receptor complex based on the closely related crystal structure of the GM-CSF:receptor complex. Model-predicted interactions between IL-3 and its receptor are in excellent agreement with mutagenesis data, which validate the model and establish a detailed view of IL-3:receptor interaction. The homology structure reveals an IL-3:IL-3 interaction interface in a higher-order complex modeled after the dodecamer of the GM-CSF:receptor complex wherein an analogous GM-CSF:GM-CSF interface is also identified. This interface is mediated by a proline-rich hydrophobic motif (PPLPLL) of the AA′ loop that is highly exposed in the structure of isolated IL-3. Various experimental data suggest that this motif is required for IL-3 function through receptor-binding independent mechanisms. These observations are consistent with structure-function studies of the GM-CSF:receptor complex showing that formation of the higher-order cytokine:receptor complex is required for signaling. However, a key question not answered from previous studies is how cytokine binding facilitates the assembly of the higher-order complex. Our studies here reveal a potential cytokine–cytokine interaction that participates in the assembly of the dodecamer complex, thus linking cytokine binding to receptor activation.     

Posterior Reversible Encephalopathy Syndrome: Nitroglycerine a Friend or a Foe?

Posterior reversible encephalopathy syndrome (PRES) refers to a clinico-radiological entity with characteristic features on neuroimaging and rapid onset of nonspecific symptoms including headache, seizure, altered consciousness and visual disturbance. It is a neurotoxic state in response to the acute changes in blood pressure leading to vasogenic oedema. It is often but not always associated with hypertension. However, control blood pressure is one of the mainstays of management in such cases. Nitroglycerine (NTG) is a potent vasodilator and is one of the drugs for treatment of hypertensive emergencies. It is found to worsen the cerebral oedema in PRES which is considered due to failure of cerebral blood pressure autoregulation. Here, we report two such cases where patients with PRES deteriorated with NTG infusion. However, the neurological condition of the patients improved drastically the next day. NTG could have further enhanced vasodilation, thus aggravating developing PRES, after autoregulation was lost because of high blood pressure.