Raising the visibility of school nursing services.

In an attempt to raise the visibility and profile of the school nursing service in the London boroughs of Hounslow and Richmond, school nurses sought to hear from the voices of the young people with whom they work. Ten focus groups in secondary educational provisions were held in a bid to look at young people's accessibility to technological devices, where they would go if they had a health problem and which health topics they would like more information on. This paper examines both national and local data and demographics, and discusses findings from the focus groups run with local young people. The results collected from the focus groups emphasised that technology is a fundamental aspect of many young people's lives and that a large number of young people access the internet to source information about their personal health and wellbeing. The data suggests that the school nursing service could use technologies, such as an interactive app, to support the physical and emotional health of young people.

Evolution of sex-specific traits through changes in HOX-dependent doublesex expression.

Almost every animal lineage is characterized by unique sex-specific traits, implying that such traits are gained and lost frequently in evolution. However, the genetic mechanisms responsible for these changes are not understood. In Drosophila, the activity of the sex determination pathway is restricted to sexually dimorphic tissues, suggesting that spatial regulation of this pathway may contribute to the evolution of sex-specific traits. We examine the regulation and function of doublesex (dsx), the main transcriptional effector of the sex determination pathway, in the development and evolution of Drosophila sex combs. Sex combs are a recent evolutionary innovation and show dramatic diversity in the relatively few Drosophila species that have them. We show that dsx expression in the presumptive sex comb region is activated by the HOX gene Sex combs reduced (Scr), and that the male isoform of dsx up-regulates Scr so that both genes become expressed at high levels in this region in males but not in females. Precise spatial regulation of dsx is essential for defining sex comb position and morphology. Comparative analysis of Scr and dsx expression reveals a tight correlation between sex comb morphology and the expression patterns of both genes. In species that primitively lack sex combs, no dsx expression is observed in the homologous region, suggesting that the origin and diversification of this structure were linked to the gain of a new dsx expression domain. Two other, distantly related fly lineages that independently evolved novel male-specific structures show evolutionary gains of dsx expression in the corresponding tissues, where dsx may also be controlled by Scr. These findings suggest that changes in the spatial regulation of sex-determining genes are a key mechanism that enables the evolution of new sex-specific traits, contributing to some of the most dramatic examples of phenotypic diversification in nature.

Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier.

Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs are unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need to be delivered intrathecally to the central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, the oligonucleotide transport vehicle (OTV), to transport a tool ASO across the BBB in human TfR knockin (TfRmu/hu KI) mice and nonhuman primates. Intravenous injection and systemic delivery of OTV to TfRmu/hu KI mice resulted in sustained knockdown of the ASO target RNA, Malat1, across multiple mouse CNS regions and cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes. In addition, systemic delivery of OTV enabled Malat1 RNA knockdown in mouse quadriceps and cardiac muscles, which are difficult to target with oligonucleotides alone. Systemically delivered OTV enabled a more uniform ASO biodistribution profile in the CNS of TfRmu/hu KI mice and greater knockdown of Malat1 RNA compared with a bivalent, high-affinity TfR antibody. In cynomolgus macaques, an OTV directed against MALAT1 displayed robust ASO delivery to the primate CNS and enabled more uniform biodistribution and RNA target knockdown compared with intrathecal dosing of the same unconjugated ASO. Our data support systemically delivered OTV as a potential platform for delivering therapeutic ASOs across the BBB.

Dynamic, mating-induced gene expression changes in female head and brain tissues of Drosophila melanogaster.

BACKGROUND: Drosophila melanogaster females show changes in behavior and physiology after mating that are thought to maximize the number of progeny resulting from the most recent copulation. Sperm and seminal fluid proteins induce post-mating changes in females, however, very little is known about the resulting gene expression changes in female head and central nervous system tissues that contribute to the post-mating response. RESULTS: We determined the temporal gene expression changes in female head tissues 0-2, 24, 48 and 72 hours after mating. Females from each time point had a unique post-mating gene expression response, with 72 hours post-mating having the largest number of genes with significant changes in expression. At most time points, genes expressed in the head fat body that encode products involved in metabolism showed a marked change in expression. Additional analysis of gene expression changes in dissected brain tissues 24 hours post-mating revealed changes in transcript abundance of many genes, notably, the reduced transcript abundance of genes that encode ion channels. CONCLUSIONS: Substantial changes occur in the regulation of many genes in female head tissues after mating, which might underlie aspects of the female post-mating response. These results provide new insights into the physiological and metabolic changes that accompany changes in female behaviors.

Doublesex establishes sexual dimorphism in the Drosophila central nervous system in an isoform-dependent manner by directing cell number.

doublesex (dsx) encodes sex-specific transcription factors (DSX(F) in females and DSX(M) in males) that act at the bottom of the Drosophila somatic sex determination hierarchy. dsx, which is conserved among diverse taxa, is responsible for directing all aspects of Drosophila somatic sexual differentiation outside the nervous system. The role of dsx in the nervous system remainsminimally understood. Here, the mechanisms by which DSX acts to establish dimorphism in the central nervous system were examined. This study shows that the number of DSX-expressing cells in the central nervous system is sexually dimorphic during both pupal and adult stages. Additionally, the number of DSX-expressing cells depends on both the amount of DSX and the isoform present. One cluster of DSX-expressing neurons in the ventral nerve cord undergoes female-specific cell death that is DSX(F)-dependent. Another DSX-expressing cluster in the posterior brain undergoes more cell divisions in males than in females. Additionally, early in development, DSX(M) is present in a portion of the neural circuitry in which the male-specific product of fruitless (fru) is produced, in a region that has been shown to be critical for sex-specific behaviors. This study demonstrates that DSX(M) and FRU(M) expression patterns are established independent of each other in the regions of the central nervous system examined. In addition to the known role of dsx in establishing sexual dimorphism outside the central nervous system, the results demonstrate that DSX establishes sex-specific differences in neural circuitry by regulating the number of neurons using distinct mechanisms.

Somatic, germline and sex hierarchy regulated gene expression during Drosophila metamorphosis.

BACKGROUND: Drosophila melanogaster undergoes a complete metamorphosis, during which time the larval male and female forms transition into sexually dimorphic, reproductive adult forms. To understand this complex morphogenetic process at a molecular-genetic level, whole genome microarray analyses were performed. RESULTS: The temporal gene expression patterns during metamorphosis were determined for all predicted genes, in both somatic and germline tissues of males and females separately. Temporal changes in transcript abundance for genes of known functions were found to correlate with known developmental processes that occur during metamorphosis. We find that large numbers of genes are sex-differentially expressed in both male and female germline tissues, and relatively few are sex-differentially expressed in somatic tissues. The majority of genes with somatic, sex-differential expression were found to be expressed in a stage-specific manner, suggesting that they mediate discrete developmental events. The Sex-lethal paralog, CG3056, displays somatic, male-biased expression at several time points in metamorphosis. Gene expression downstream of the somatic, sex determination genes transformer and doublesex (dsx) was examined in two-day old pupae, which allowed for the identification of genes regulated as a consequence of the sex determination hierarchy. These include the homeotic gene abdominal A, which is more highly expressed in females as compared to males, as a consequence of dsx. For most genes regulated downstream of dsx during pupal development, the mode of regulation is distinct from that observed for the well-studied direct targets of DSX, Yolk protein 1 and 2. CONCLUSION: The data and analyses presented here provide a comprehensive assessment of gene expression during metamorphosis in each sex, in both somatic and germline tissues. Many of the genes that underlie critical developmental processes during metamorphosis, including sex-specific processes, have been identified. These results provide a framework for further functional studies on the regulation of sex-specific development.

Spontaneous Subdural Hematoma in Patient with Polycythemia Vera.

BACKGROUND: Polycythemia vera (PV) is a myeloproliferative disorder usually characterized by an increase tendency toward thromboembolic events. Spontaneous hemorrhage/bleeding in PV patients is seldom reported in neurosurgical literature. CASE DESCRIPTION: We report the case of a 76-year-old male with PV who developed a spontaneous subdural hematoma requiring surgical evacuation. He improved significantly after the resolution of brain compression and mass effect caused by the hematoma. CONCLUSIONS: Sporadic reports of hemorrhage within the central nervous system in the setting of PV exist and are attributed to microvascular thrombotic events with hemorrhagic conversion. Though rare, spontaneous central nervous system hemorrhage in the absence of vascular malformation or an inciting event such as trauma can occur in the setting of myeloproliferative disorders like PV.

The stability of leading-edge vortices to perturbations on samara-inspired rotors: a novel solution for gust resistance.

The stability of leading-edge vortices (LEVs) on a samara-inspired rotor during steady and unsteady gusty incoming flow was investigated experimentally using direct rotational speed measurements, as well as time-resolved particle image velocimetry (PIV). The blades of the samara-inspired rotor were designed to match the tip-speed ratio, the aspect ratio, and the distribution of the effective angle of attack of samara seeds to utilize LEVs similar to samara seeds. The flow around the blades of the samara-inspired rotor was compared to a reference rotor, which possesses a constant spanwise effective angle of attack, to investigate the influence of the samara-like spanwise effective angle-of-attack distribution on LEV stability. Furthermore, the unsteady performance of the samara-inspired rotor was compared to a generic low-inertia rotor that possesses blades with a constant effective angle of attack less than the stall angle. During steady rotation, the samara-inspired rotor exhibited a stably-attached LEV, while the reference rotor demonstrated unstable LEV shedding. Compared to a generic low-inertia rotor, the samara-inspired rotor demonstrated a relatively stable tip-speed ratio ([Formula: see text]) during the gust. Furthermore, the LEV remained stably-attached on the rotor's blades with a constant normalized circulation during the gust. Finally, the analysis of the LEV stability during the gust using the vorticity transport equation suggests that LEV stability is coupled with constant tip-speed ratio during gusts.

Changing the navigator's course: How the increasing rationalization of healthcare influences access for undocumented immigrants under the Affordable Care Act.

A number of researchers have shown that brokers (e.g., navigators and street-level bureaucrats) bridge access to healthcare services and information for immigrant patients through rich personal relationships and a mission of ethical care. An open question remains concerning how the increasing rationalization of healthcare over the past few decades influences brokerage for undocumented immigrant patients. Drawing from fieldwork and interviews conducted in California, as the Affordable Care Act (ACA) was implemented, I develop the concept of the "double-embedded-liaison." While other studies treat brokers as acting either as gatekeepers or patient representatives, this study explains how brokers simultaneously operate on multiple planes when new roles are added. I argue that with more formalization and scrutiny at health centers, the impact of brokerage is destabilized and, subsequently, diminished. Two consequences of the double-embedded-liaison brokerage form are: (1) some brokers become disillusioned and exit -resulting in the loss of valuable resources at the health centers, and (2) immigrants move away from the health centers that historically served them. In looking at brokers' simultaneous performance as gatekeepers and representatives, this research extends brokerage typologies and street-level bureaucracy arguments that largely treat brokerage in a mono-planar rather than in a bi-planar mode. Furthermore, in examining the risks and opportunities brokerage brings to addressing health disparities, the study provides insights into the effects of replacing the ACA or repealing it all together in the Post-Obama era.

Health Implications of an Immigration Raid: Findings from a Latino Community in the Midwestern United States.

Immigration raids exemplify the reach of immigration law enforcement into the lives of Latino community members, yet little research characterizes the health effects of these raids. We examined the health implications of an immigration raid that resulted in multiple arrests and deportations and occurred midway through a community survey of a Latino population. We used linear regression following principal axis factoring to examine the influence of raid timing on immigration enforcement stress and self-rated health. We controlled for age, sex, relationship status, years in the county in which the raid occurred, children in the home, and nativity. 325 participants completed the survey before the raid and 151 after. Completing the survey after the raid was associated with higher levels of immigration enforcement stress and lower self-rated health scores. Findings indicate the negative impact of immigration raids on Latino communities. Immigration discussions should include holistic assessments of health.

Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice.

Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.

Grassroots responsiveness to human rights abuse: history of the Washtenaw Interfaith Coalition for Immigrant Rights.

The purpose of this article is to discuss how a community agency based in Washtenaw County, the Washtenaw Interfaith Coalition for Immigration Rights (WICIR), emerged in response to increasing punitive immigration practices and human rights abuses toward the Latino community. The article discusses how WICIR is engaged in advocacy, community education on immigration issues, and political action toward a more humane immigration reform. Detailed examples of human rights abuses and the WICIR activities described in response to the abuses serve as illustrations of social work advocacy, education, and policy formulation that affect the general public, policymakers, and law enforcement officials.

Ecdysone receptor acts in fruitless- expressing neurons to mediate drosophila courtship behaviors.

In Drosophila melanogaster, fruitless (fru) encodes male-specific transcription factors (FRU(M); encoded by fru P1) required for courtship behaviors (reviewed in). However, downstream effectors of FRU(M) throughout development are largely unknown. During metamorphosis the nervous system is remodeled for adult function, the timing of which is coordinated by the steroid hormone 20-hydroxyecdysone (ecdysone) through the ecdysone receptor, a heterodimer of the nuclear receptors EcR (isoforms are EcR-A, EcR-B1, or EcR-B2) and Ultraspiracle (USP) (reviewed in). Here, we show that genes identified as regulated downstream of FRU(M) during metamorphosis are significantly overrepresented with genes known to be regulated in response to ecdysone or EcR. FRU(M) and EcR isoforms are coexpressed in neurons in the CNS during metamorphosis in an isoform-specific manner. Reduction of EcR-A levels in fru P1-expressing neurons of males caused a significant increase in male-male courtship activity and significant reduction in size of two antennal lobe glomeruli. Additional genes were identified that are regulated downstream of EcR-A in fru P1-expressing neurons. Thus, EcR-A is required in fru P1-expressing neurons for wild-type male courtship behaviors and the establishment of male-specific neuronal architecture.

Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A.

Transcription factor NF-kappaB plays a key regulatory role in the cellular response to pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF). In the absence of TNF, NF-kappaB is sequestered in the cytoplasm by inhibitory IkappaB proteins. Phosphorylation of IkappaBby the beta-catalytic subunit of IKK, a multicomponent IkappaB kinase, targets the inhibitor for proteolytic destruction and facilitates nuclear translocation of NF-kappaB. This pathway is initiated by TNF-dependent phosphorylation of T loop serines in IKKbeta, which greatly stimulates IkappaB kinase activity. Prior in vitro mixing experiments indicate that protein serine/threonine phosphatase 2A (PP2A) can dephosphorylate these T loop serines and inactivate IKK, suggesting a negative regulatory role for PP2A in IKK signaling. Here we provided several in vivo lines of evidence indicating that PP2A plays a positive rather than a negative role in the regulation of IKK. First, TNF-induced degradation of IkappaB is attenuated in cells treated with okadaic acid or fostriecin, two potent inhibitors of PP2A. Second, PP2A forms stable complexes with IKK in untransfected mammalian cells. This interaction is critically dependent on amino acid residues 121-179 of the IKKgamma regulatory subunit. Third, deletion of the PP2A-binding site in IKKgamma attenuates T loop phosphorylation and catalytic activation of IKKbeta in cells treated with TNF. Taken together, these data provide strong evidence that the formation of IKK.PP2A complexes is required for the proper induction of IkappaB kinase activity in vivo.

Manejo de la patología tiroídea: utilidad y limitaciones de la biopsia percutánea con aguja fina y de la biopsia rápida / Management of thyroid pathology: usefulness and limitations of percutaneous biopsy with fine needle and quick biopsy

Fine needle aspiration biopsy of the thyroid (FNAB) has become an accepted procedure for evaluation of the thyroid nodule, with 899 performed at the Lahey Clinic from 1981 to 1990. We examined them by medical record, pathology and cytology review, with follow up by chart or personal communication. Three hundred forty five came to surgery, of which 188 (34 percent) were malignant; the specificity of the aspirate was 97 percent, sensitivity 92 percent, with false negative of 8 percnt and false positive rate of 5 percent. In combination with frozen section, the fine needle aspirate result improved the accuracy of the intraoperative estimate of malignancy (p=0.03). When the aspiration was benign but the lesion was clinically suspicious, a cancer was found at surgery in 13 percent of cases. Of the patients observed for a minimum of 5 years, 1,3 percent developed a carcinoma. Both cases had a non diagnostic FNAB. None of the patients with a clinical and cytological benign lesion developed cancer. The complication rate of FNAB was 1.3 percent. FNAB is a helpful and low risk diagnostic procedure but it needs to be done and read appropriately and its result used within the clinical context. Each medical team needs to monitor their results (continued quality control)