IL-13 and IL-17A Activate ß1 Integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to Enhance Force Transmission in Airway Smooth Muscle.

Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although G-protein coupled receptor-mediated integrin activation has been extensively studied in non-adherent migratory cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent stationary cells such as airway smooth muscle. Here we show that two different asthmagenic cytokines, IL-13 and IL-17A, activate type I and IL-17 cytokine receptor families respectively, to enhance adhesion of muscle to the matrix. These cytokines also induce activation of ß1 integrins as detected by the conformation-specific antibody HUTS-4. Moreover, HUTS-4 binding is significantly increased in the smooth muscle of patients with asthma compared to healthy controls, suggesting a disease-relevant role for aberrant integrin activation. Indeed, we find integrin activation induced by a ß1 activating antibody, the divalent cation manganese, or the synthetic peptide ß1-CHAMP, dramatically enhances force transmission in collagen gels, mouse tracheal rings, and human bronchial rings even in the absence of cytokines. We further demonstrate that cytokine-induced activation of ß1 integrins is regulated by a common pathway of NF-κB-mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1γ-mediated synthesis of PIP2 resulting in ß1 integrin activation. Taken together, these data identify a previously unknown pathway by which type I and IL-17 cytokine receptor family stimulation induces functionally relevant ß1 integrin activation in adherent smooth muscle and help explain the exaggerated force transmission that characterizes chronic airways diseases such as asthma.

Integrin α2ß1 regulates collagen I tethering to modulate hyperresponsiveness in reactive airway disease models.

Severe asthma remains challenging to manage and has limited treatment options. We have previously shown that targeting smooth muscle integrin α5ß1 interaction with fibronectin can mitigate the effects of airway hyperresponsiveness by impairing force transmission. In this study, we show that another member of the integrin superfamily, integrin α2ß1, is present in airway smooth muscle and capable of regulating force transmission via cellular tethering to the matrix protein collagen I and, to a lesser degree, laminin-111. The addition of an inhibitor of integrin α2ß1 impaired IL-13-enhanced contraction in mouse tracheal rings and human bronchial rings and abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. We confirmed that this effect was not due to alterations in classic intracellular myosin light chain phosphorylation regulating muscle shortening. Although IL-13 did not affect surface expression of α2ß1, it did increase α2ß1-mediated adhesion and the level of expression of an activation-specific epitope on the ß1 subunit. We developed a method to simultaneously quantify airway narrowing and muscle shortening using 2-photon microscopy and demonstrated that inhibition of α2ß1 mitigated IL-13-enhanced airway narrowing without altering muscle shortening by impairing the tethering of muscle to the surrounding matrix. Our data identified cell matrix tethering as an attractive therapeutic target to mitigate the severity of airway contraction in asthma.

Dual antagonists of α5ß1/αvß1 integrin for airway hyperresponsiveness.

Inhibition of integrin α5ß1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5ß1 by backbone replacement of known αvß1 integrin inhibitors. These integrin α5ß1 inhibitors also retain the nanomolar potency against αvß1 integrin, which shows promise for developing dual integrin α5ß1/αvß1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin αvß3. We also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in ex vivo mouse tracheal ring assay. Results from this study will help guide further development of integrin α5ß1 inhibitors as potential novel asthma therapeutics.

G protein-regulated endocytic trafficking of adenylyl cyclase type 9.

GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires ß-arrestin but not Gs, AC9 traffic control requires Gs but not ß-arrestin. We also show that AC9, but not AC1, mediates cAMP production stimulated by endogenous receptor activation in endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in regulating the subcellular distribution of a relevant effector.

Cells sense changes in their chemical environment using proteins called receptors. These proteins often sit on the cell surface, detecting molecules outside the cell and relaying messages across the membrane to the cell interior. The largest family of receptors is formed of 'G protein-coupled receptors' (or GPCRs for short), so named because they relay messages through so-called G proteins, which then send information into the cell by interacting with other proteins called effectors. Next, the receptors leave the cell surface, travelling into the cell in compartments called endosomes. Researchers used to think that this switched the receptors off, stopping the signaling process, but it is now clear that this is not the case. Some receptors continue to signal from inside the cell, though the details of how this works are unclear. For signals to pass from a GPCR to a G protein to an effector, all three proteins need to be in the same place. This is certainly happening at the cell surface, but whether all three types of proteins come together inside endosomes is less clear. One way to find out is to look closely at the location of effector proteins when GPCRs are receiving signals. One well-studied effector of GPCR signaling is called adenylyl cyclase, a protein that makes a signal molecule called cAMP. Some G proteins switch adenylyl cyclase on, increasing cAMP production, while others switch it off. To find out how GPCRs send signals from inside endosomes, Lazar et al tracked adenylyl cyclase proteins inside human cells. This revealed that a type of adenylyl cyclase, known as adenylyl cyclase 9, follows receptors as they travel into the cell. Under the influence of active G proteins, activated adenylyl cyclase 9 left the cell surface and entered the endosomes. Once inside the cell, adenylyl cyclase 9 generated the signal molecule cAMP, allowing the receptors to send messages from inside the cell. Other types of adenylyl cyclase behaved differently. Adenylyl cyclase 1, for example, remained on the cell surface even after its receptors had left, and did not signal from inside the cell at all. Which cell behaviors are triggered from the membrane, and which are triggered from inside the cell is an important question in drug design. Understanding where effector proteins are active is a step towards finding the answers. This could help research into diseases of the heart, the liver and the lungs, all of which use adenylyl cyclase 9 to send signals.

Abortion service provision in South Asia: A comparative study of four countries.

OBJECTIVES: Nationally representative evidence on abortion service provision is scarce in South Asia. To inform improvements in service provision, this paper assesses the availability of facility-based postabortion services in Nepal, India (six states), Bangladesh and Pakistan, and legal abortion services in India and Nepal and Bangladesh (where the official term used is menstrual regulation or MR). STUDY DESIGN: The paper presents comparable indicators on three aspects of abortion service provision from representative surveys of public and private sector facilities, conducted over 2012-2015. Indicators cover three areas: (a) need for abortion-related care (total number of abortions and percent of abortions that are legal and the postabortion treatment rate); (b) availability and accessibility of facility-based abortion-related services (percent of facilities offering only one of the two services, percent which are public and percent located in rural areas); (c) quality of facility-based abortion care (percent of legal abortions using procedures not recommended by WHO and percent of women turned away when seeking abortion or MR services). RESULTS: The proportion of all abortions that are illegal ranges from 58% to almost 78% in the three countries where abortion is permitted under broad criteria. The annual treatment rate for abortion complications ranges from about 4 to 26 per 1000 women ages 15-49 across the countries and states covered. In India and Nepal, less than 40% of public sector facilities that are permitted to provide abortion services do so; in Bangladesh, the situation is somewhat better, at 53% providing MR. Across the six Indian states, 4-43% of facilities that offer abortion care are located in rural areas, disproportionately lower than the proportion of women living in rural areas (49-87%). About 30-60% of facilities offered only postabortion care and did not offer legal services in the three countries where legal services are permitted (with the sole exception of Tamil Nadu where this proportion was only 11%); of the remaining facilities, the large majority offered both services. Medication abortion is offered by the large majority of facilities that provide induced abortion and accounts for 40-45%, of facility-based abortions in Nepal and four of the states of India; in Assam and Bihar, this proportion was much lower (13% and 27% respectively). Invasive procedures that are not recommended by WHO are more widely used in India (up to 25-37% of facility-based abortions are D&C procedures; the large majority of this group are D&C, and a small proportion may be D&E, a WHO-recommended abortion procedure, that could not be separated out in this study because providers use the two labels interchangeably); by comparison, the proportion is much smaller in Nepal (5%). Between 22% to a little over half of facilities turned away some women who would otherwise be eligible for an abortion or MR procedure in Nepal, the six Indian states, and Bangladesh. CONCLUSIONS: There is an urgent need to increase access to abortion, MR and postabortion services, especially for rural women. Greater access to legal abortion/MR services in the three countries that permit these procedures would increase the proportion of abortions that are legal and safe, reduce morbidity and the need for facility-based treatment for complications. Broadening the legal criteria under which abortion is permitted in Pakistan, and implementing access under such broader criteria, is needed to achieve the same improvements in Pakistan. Ensuring that these services are of high quality and comprehensive-meeting WHO-recommended standards-is essential to protect women's reproductive health and rights. IMPLICATIONS: To improve access to abortion, MR and postabortion care in South Asia, all facilities (public and private) permitted to provide these services should do so, and should include medication abortion. Improvements in quality of care are critical: invasive procedures (D&C) should be eliminated through adherence to WHO's standards of safe abortion care and women seeking abortions should not be turned away because of providers' biases.

Providing quality abortion care: Findings from a study of six states in India.

OBJECTIVE: Although abortion has been legal in India since 1971, but very little research has been done so far on the issue of the quality of abortion services. To fill this gap, this paper examines whether the quality of abortion services provided in the country is in line with the WHO's recommendations. STUDY DESIGN: We analyse a cross-sectional health facilities survey conducted in six Indian states, representing different sociocultural and geographical regions, as part of a study done in 2015. MAIN OUTCOME MEASURES: Percentage of facilities offering different abortion methods, type of anaesthesia given, audio-visual privacy level, compliance with the law by obtaining woman's consent only, imposing the requirement of adopting a contraceptive method as a precondition to receive abortion. RESULTS: Except for the state of Madhya Pradesh, fewer than half of the facilities in the other states offer safe abortion services. Fewer than half of the facilities offer the WHO recommended manual vacuum aspiration method. Only 6-26% facilities across the states seek the woman's consent alone for providing abortion. About 8-26% facilities across the states also require that women adopt some method of contraception before receiving abortion. CONCLUSION: To provide comprehensive quality abortion care, India needs to expand the provider base by including doctors from the Ayurveda, Unani, Siddha, and Homeopathy streams as also nurses and auxiliary midwives after providing them necessary skills. Medical and nursing colleges and training institutions should expand their curriculum by offering an in-service short-term training on vacuum aspiration (VA) and medical methods of abortion.

A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion.

Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor ß (TGFß)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma. The fibrotic phenotype is thought to be regulated by changes in the ability of fibrillin-1 to mediate integrin binding. We characterized the ability of each RGD-binding integrin to mediate cell adhesion to fibrillin-1 or a disease-causing variant. Our data show that 7 of the 8 RGD-binding integrins can mediate adhesion to fibrillin-1. A single amino acid substitution responsible for SSS (W1570C) markedly inhibited adhesion mediated by integrins α5ß1, αvß5, and αvß6, partially inhibited adhesion mediated by αvß1, and did not inhibit adhesion mediated by α8ß1 or αIIbß3. Adhesion mediated by integrin αvß3 depended on the cell surface expression level. In the SSS mutant background, the presence of a cysteine residue in place of highly conserved tryptophan 1570 alters the conformation of the region containing the exposed RGD sequence within the same domain to differentially affect fibrillin's interactions with distinct RGD-binding integrins.

IL-17A Recruits Rab35 to IL-17R to Mediate PKCα-Dependent Stress Fiber Formation and Airway Smooth Muscle Contractility.

IL-17A is a critical proinflammatory cytokine for the pathogenesis of asthma including neutrophilic pulmonary inflammation and airway hyperresponsiveness. In this study, by cell type-specific deletion of IL-17R and adaptor Act1, we demonstrated that IL-17R/Act1 exerts a direct impact on the contraction of airway smooth muscle cells (ASMCs). Mechanistically, IL-17A induced the recruitment of Rab35 (a small monomeric GTPase) and DennD1C (guanine nucleotide exchange factor [GEF]) to the IL-17R/Act1 complex in ASMCs, resulting in activation of Rab35. Rab35 knockdown showed that IL-17A-induced Rab35 activation was essential for protein kinase Cα (PKCα) activation and phosphorylation of fascin at Ser39 in ASMCs, allowing F-actin to interact with myosin to form stress fibers and enhance the contraction induced by methacholine. PKCα inhibitor or Rab35 knockdown indeed substantially reduced IL-17A-induced stress fiber formation in ASMCs and attenuated IL-17A-enhanced, methacholine-induced contraction of airway smooth muscle. Taken together, these data indicate that IL-17A promotes airway smooth muscle contraction via direct recruitment of Rab35 to IL-17R, followed by PKCα activation and stress fiber formation.

The incidence of abortion and unintended pregnancy in India, 2015.

BACKGROUND: Reliable information on the incidence of induced abortion in India is lacking. Official statistics and national surveys provide incomplete coverage. Since the early 2000s, medication abortion has become increasingly available, improving the way women obtain abortions. The aim of this study was to estimate the national incidence of abortion and unintended pregnancy for 2015. METHODS: National abortion incidence was estimated through three separate components: abortions (medication and surgical) in facilities (including private sector, public sector, and non-governmental organisations [NGOs]); medication abortions outside facilities; and abortions outside of facilities and with methods other than medication abortion. Facility-based abortions were estimated from the 2015 Health Facilities Survey of 4001 public and private health facilities in six Indian states (Assam, Bihar, Gujarat, Madhya Pradesh, Tamil Nadu, and Uttar Pradesh) and from NGO clinic data. National medication abortion drug sales and distribution data were obtained from IMS Health and six principal NGOs (DKT International, Marie Stopes International, Population Services International, World Health Partners, Parivar Seva Santha, and Janani). We estimated the total number of abortions that are not medication abortions and are not obtained in a health facility setting through an indirect technique based on findings from community-based study findings in two states in 2009, with adjustments to account for the rapid increase in use of medication abortion since 2009. The total number of women of reproductive age and livebirth data were obtained from UN population data, and the proportion of births from unplanned pregnancies and data on contraceptive use and need were obtained from the 2015-16 National Family Health Survey-4. FINDINGS: We estimate that 15·6 million abortions (14·1 million-17·3 million) occurred in India in 2015. The abortion rate was 47·0 abortions (42·2-52·1) per 1000 women aged 15-49 years. 3·4 million abortions (22%) were obtained in health facilities, 11·5 million (73%) abortions were medication abortions done outside of health facilities, and 0·8 million (5%) abortions were done outside of health facilities using methods other than medication abortion. Overall, 12·7 million (81%) abortions were medication abortions, 2·2 million (14%) abortions were surgical, and 0·8 million (5%) abortions were done through other methods that were probably unsafe. We estimated 48·1 million pregnancies, a rate of 144·7 pregnancies per 1000 women aged 15-49 years, and a rate of 70·1 unintended pregnancies per 1000 women aged 15-49 years. Abortions accounted for one third of all pregnancies, and nearly half of pregnancies were unintended. INTERPRETATION: Health facilities can have a greater role in abortion service provision and provide quality care, including post-abortion contraception. Interventions are needed to expand access to abortion services through better equipping existing facilities, ensuring adequate and continuous supplies of medication abortion drugs, and by increasing the number of trained providers. In view of how many women rely on self-administration of medication abortion drugs, interventions are needed to provide women with accurate information on these drugs and follow-up care when needed. Research is needed to test interventions that improve knowledge and practice in providing medication abortion, and the Indian Government at the national and state level needs to prioritise improving policies and practice to increase access to comprehensive abortion care and quality contraceptive services that prevent unintended pregnancy. FUNDING: Government of UK Department for International Development (until 2015), the David and Lucile Packard Foundation, the John D. and Catherine T. MacArthur Foundation, and the Ford Foundation.

Contraceptive Failure in the United States: Estimates from the 2006-2010 National Survey of Family Growth.

CONTEXT: Contraceptive failure rates measure a woman's probability of becoming pregnant while using a contraceptive. Information about these rates enables couples to make informed contraceptive choices. Failure rates were last estimated for 2002, and social and economic changes that have occurred since then necessitate a reestimation. METHODS: To estimate failure rates for the most commonly used reversible methods in the United States, data from the 2006-2010 National Survey of Family Growth were used; some 15,728 contraceptive use intervals, contributed by 6,683 women, were analyzed. Data from the Guttmacher Institute's 2008 Abortion Patient Survey were used to adjust for abortion underreporting. Kaplan-Meier methods were used to estimate the associated single-decrement probability of failure by duration of use. Failure rates were compared with those from 1995 and 2002. RESULTS: Long-acting reversible contraceptives (the IUD and the implant) had the lowest failure rates of all methods (1%), while condoms and withdrawal carried the highest probabilities of failure (13% and 20%, respectively). However, the failure rate for the condom had declined significantly since 1995 (from 18%), as had the failure rate for all hormonal methods combined (from 8% to 6%). The failure rate for all reversible methods combined declined from 12% in 2002 to 10% in 2006-2010. CONCLUSIONS: These broad-based declines in failure rates reverse a long-term pattern of minimal change. Future research should explore what lies behind these trends, as well as possibilities for further improvements.

Targeting integrin α5ß1 ameliorates severe airway hyperresponsiveness in experimental asthma.

Treatment options are limited for severe asthma, and the need for additional therapies remains great. Previously, we demonstrated that integrin αvß6-deficient mice are protected from airway hyperresponsiveness, due in part to increased expression of the murine ortholog of human chymase. Here, we determined that chymase protects against cytokine-enhanced bronchoconstriction by cleaving fibronectin to impair tension transmission in airway smooth muscle (ASM). Additionally, we identified a pathway that can be therapeutically targeted to mitigate the effects of airway hyperresponsiveness. Administration of chymase to human bronchial rings abrogated IL-13-enhanced contraction, and this effect was not due to alterations in calcium homeostasis or myosin light chain phosphorylation. Rather, chymase cleaved fibronectin, inhibited ASM adhesion, and attenuated focal adhesion phosphorylation. Disruption of integrin ligation with an RGD-containing peptide abrogated IL-13-enhanced contraction, with no further effect from chymase. We identified α5ß1 as the primary fibronectin-binding integrin in ASM, and α5ß1-specific blockade inhibited focal adhesion phosphorylation and IL-13-enhanced contraction, with no additional effect from chymase. Delivery of an α5ß1 inhibitor into murine airways abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. Finally, α5ß1 blockade enhanced the effect of the bronchodilator isoproterenol on airway relaxation. Our data identify the α5ß1 integrin as a potential therapeutic target to mitigate the severity of airway contraction in asthma.

G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands.

The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications, but, if excessively propagated downstream, would introduce biologic noise compromising cognate ligand detection. We asked whether cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal. We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse ß-adrenoceptor agonists, isoproterenol and salmeterol. We show that both ligands generate an identical integrated response, and that this stereotyped output requires endocytosis. We further demonstrate that the endosomal ß2-adrenergic receptor signal confers uniformity on the downstream response because it is highly sensitive and saturable. Based on these findings, we propose that GPCR signaling from endosomes functions as a biologic noise filter to enhance reliability of cognate ligand detection.

Abortion Incidence and Unintended Pregnancy in Nepal.

CONTEXT: Although abortion has been legal under broad criteria in Nepal since 2002, a significant proportion of women continue to obtain illegal, unsafe abortions, and no national estimates exist of the incidence of safe and unsafe abortions. METHODS: Data were collected in 2014 from a nationally representative sample of 386 facilities that provide legal abortions or postabortion care and a survey of 134 health professionals knowledgeable about abortion service provision. Facility caseloads and indirect estimation techniques were used to calculate the national and regional incidence of legal and illegal abortion. National and regional levels of abortion complications and unintended pregnancy were also estimated. RESULTS: In 2014, women in Nepal had 323,100 abortions, of which 137,000 were legal, and 63,200 women were treated for abortion complications. The abortion rate was 42 per 1,000 women aged 15-49, and the abortion ratio was 56 per 100 live births. The abortion rate in the Central region (59 per 1,000) was substantially higher than the national average. Overall, 50% of pregnancies were unintended, and the unintended pregnancy rate was 68 per 1,000 women of reproductive age. CONCLUSIONS: Despite legalization of abortion and expansion of services in Nepal, unsafe abortion is still common and exacts a heavy toll on women. Programs and policies to reduce rates of unintended pregnancy and unsafe abortion, increase access to high-quality contraceptive care and expand safe abortion services are warranted.

The impact of Ghana's R3M programme on the provision of safe abortions and postabortion care.

In 2006, in response to the high maternal mortality, driven largely by unsafe abortions, the government of Ghana, in partnership with other organizations, launched the reducing maternal mortality and morbidity (R3M) programme in seven districts in Greater Accra, Ashanti and Eastern, to improve comprehensive abortion care services. This article examines whether this intervention made a difference to the provision of safe abortion services and postabortion care (PAC). We also examine the role played by provider attitudes and knowledge of the abortion law, on providers with clinical training in service provision. Primary data on health care providers in Ghana, collected using a quasi-experimental design, were analysed using propensity score weighting. Apart from the treatment group, the sample included two controls: (1) Districts in Accra, Ashanti and Eastern, not exposed to the treatment; and (2) Districts from distant Brong Ahafo, also not exposed to the treatment. The findings show that providers in the treatment group are nearly 16 times as likely to provide safe abortions compared with their peers in Brong Ahafo, and ∼2.5 times as likely compared with providers in the other control group. R3M providers were also different from their peers in providing PAC. Associations between provider attitudes and knowledge of the law on both outcomes were either non-significant or inconsistent including for providers with clinical knowledge of abortion provision. Provider confidence however is strongly associated with service provision. We conclude that the R3M programme is helping safe abortion provision, with the differences being greater with control groups that are geographically distant, perhaps owing to lower contamination from movement of providers between facilities. Increasing provider confidence is key to improving both safe abortion provision and PAC.

IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction.

The intracellular scaffold protein IQGAP1 supports protein complexes in conjunction with numerous binding partners involved in multiple cellular processes. Here, we determined that IQGAP1 modulates airway smooth muscle contractility. Compared with WT controls, at baseline as well as after immune sensitization and challenge, Iqgap1-/- mice had higher airway responsiveness. Tracheal rings from Iqgap1-/- mice generated greater agonist-induced contractile force, even after removal of the epithelium. RhoA, a regulator of airway smooth muscle contractility, was activated in airway smooth muscle lysates from Iqgap1-/- mice. Likewise, knockdown of IQGAP1 in primary human airway smooth muscle cells increased RhoA activity. Immunoprecipitation studies indicated that IQGAP1 binds to both RhoA and p190A-RhoGAP, a GTPase-activating protein that normally inhibits RhoA activation. Proximity ligation assays in primary airway human smooth muscle cells and mouse tracheal sections revealed colocalization of p190A-RhoGAP and RhoA; however, these proteins did not colocalize in IQGAP1 knockdown cells or in Iqgap1-/- trachea. Compared with healthy controls, human subjects with asthma had decreased IQGAP1 expression in airway biopsies. Together, these data demonstrate that IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP and RhoA, inactivating RhoA and suppressing airway smooth muscle contraction. Furthermore, our results suggest that IQGAP1 has the potential to modulate airway contraction severity in acute asthma.

The health system cost of post-abortion care in Uganda.

This article presents estimates based on the research conducted in 2010 of the cost to the Ugandan health system of providing post-abortion care (PAC), filling a gap in knowledge of the cost of unsafe abortion. Thirty-nine public and private health facilities were sampled representing three levels of health care, and data were collected on drugs, supplies, material, personnel time and out-of-pocket expenses. In addition, direct non-medical costs in the form of overhead and capital costs were also measured. Our results show that the average annual PAC cost per client, across five types of abortion complications, was $131. The total cost of PAC nationally, including direct non-medical costs, was estimated to be $13.9 million per year. Satisfying all demand for PAC would raise the national cost to $20.8 million per year. This shows that PAC consumes a substantial portion of the total expenditure in reproductive health in Uganda. Investing more resources in family planning programmes to prevent unwanted and mistimed pregnancies would help reduce health systems costs.

The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases.

Increased airway smooth muscle (ASM) contractility and the development of airway hyperresponsiveness (AHR) are cardinal features of asthma, but the signaling pathways that promote these changes are poorly understood. Tyrosine phosphorylation is tightly regulated by the opposing actions of protein tyrosine kinases and phosphatases, but little is known about whether tyrosine phosphatases influence AHR. Here, we demonstrate that genetic inactivation of receptor-like protein tyrosine phosphatase J (Ptprj), which encodes CD148, protected mice from the development of increased AHR in two different asthma models. Surprisingly, CD148 deficiency minimally affected the inflammatory response to allergen, but significantly altered baseline pulmonary resistance. Mice specifically lacking CD148 in smooth muscle had decreased AHR, and the frequency of calcium oscillations in CD148-deficient ASM was substantially attenuated, suggesting that signaling pathway alterations may underlie ASM contractility. Biochemical analysis of CD148-deficient ASM revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SRC family kinases (SFKs), implicating CD148 as a critical positive regulator of SFK signaling in ASM. The effect of CD148 deficiency on ASM contractility could be mimicked by treatment of both mouse trachea and human bronchi with specific SFK inhibitors. Our studies identify CD148 and the SFKs it regulates in ASM as potential targets for the treatment of AHR.

Documenting the individual- and household-level cost of unsafe abortion in Uganda.

CONTEXT: Although Uganda has a restrictive abortion law, illegal abortions performed under dangerous conditions are common. Data are lacking, however, on the economic impact of postabortion complications on women and their households. METHODS: Data from a 2011-2012 survey of 1,338 women who received postabortion care at 27 Ugandan health facilities were used to assess the economic consequences of unsafe abortion and subsequent treatment. Information was obtained on treatment costs and on the impact of abortion complications on children in the household, on the productivity of the respondent and other household members, and on changes in their economic circumstances. RESULTS: Most women reported that their unsafe abortion had had one or more adverse effects, including loss of productivity (73%), negative consequences for their children (60%) and deterioration in economic circumstances (34%). Women who had spent one or more nights in a facility receiving postabortion care were more likely than those who had not needed an overnight stay to experience these three consequences (odds ratios, 1.6-2.8), and women who had incurred higher postabortion care expenses were more likely than those with lower expenses to report deterioration in economic circumstances (1.6). Wealthier women were less likely than the poorest women to report that their children had suffered negative consequences (0.4-0.5). CONCLUSIONS: The impact of complications of unsafe abortion and the expense of treating them are substantial for Ugandan women and their households. Strategies to reduce the number of unsafe procedures, such as by expanding access to contraceptives to prevent unintended pregnancies, are urgently needed.

Factors associated with abortion-seeking and obtaining a safe abortion in Ghana.

Although Ghana's abortion law is fairly liberal, unsafe abortion and its consequences remain among the largest contributors to maternal mortality in the country. This study analyzes data from the 2007 Ghana Maternal Health Survey to identify the sociodemographic profiles of women who seek to induce abortion and those who are able to obtain safe abortion services. We hypothesize that women who have access to safe abortion will not be distributed randomly across different social groups in Ghana; rather, access will be influenced by social and economic factors. The results confirm this hypothesis and reveal that the women who are most vulnerable to unsafe abortions are younger, poorer, and lack partner support. The study concludes with policy recommendations for improving access to safe abortion for all subgroups of women, especially the most vulnerable.

The αvß6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells.

Allergic asthma is the most common form of asthma, affecting more than 10 million Americans. Although it is clear that mast cells have a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo remain to be elucidated. Here we report that mice lacking αvß6 integrin are protected from exaggerated airway narrowing in a model of allergic asthma. Expression microarrays of the airway epithelium revealed mast cell proteases among the most prominent differentially expressed genes, with expression of mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in WT mice and expression of mMCP-4, -5, and -6 increased at baseline in ß6-deficient mice. These findings were most likely explained by loss of TGF-ß activation, since the epithelial integrin αvß6 is a critical activator of latent TGF-ß, and in vitro-differentiated mast cells showed TGF-ß-dependent expression of mMCP-1 and suppression of mMCP-4 and -6. In vitro, mMCP-1 increased contractility of murine tracheal rings, an effect that depended on intact airway epithelium, whereas mMCP-4 inhibited IL-13-induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-ß by the αvß6 integrin regulates airway responsiveness by modulating mast cell protease expression and that these proteases and their proteolytic substrates could be novel targets for improved treatment of allergic asthma.