Kisspeptin treatment induces gonadotropic responses and rescues ovulation in a subset of preclinical models and women with polycystic ovary syndrome.

STUDY QUESTION: Can kisspeptin treatment induce gonadotrophin responses and ovulation in preclinical models and anovulatory women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Kisspeptin administration in some anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. WHAT IS KNOWN ALREADY: PCOS is a prevalent, heterogeneous endocrine disorder, characterized by ovulatory dysfunction, hyperandrogenism and deregulated gonadotrophin secretion, in need of improved therapeutic options. Kisspeptins (encoded by Kiss1) are master regulators of the reproductive axis, acting mainly at GnRH neurons, with kisspeptins being an essential drive for gonadotrophin-driven ovarian follicular maturation and ovulation. Altered Kiss1 expression has been found in rodent models of PCOS, although the eventual pathophysiological role of kisspeptins in PCOS remains unknown. STUDY DESIGN, SIZE, DURATION: Gonadotrophin and ovarian/ovulatory responses to kisspeptin-54 (KP-54) were evaluated in three preclinical models of PCOS, generated by androgen exposures at different developmental windows, and a pilot exploratory cohort of anovulatory women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three models of PCOS were generated by exposure of female rats to androgens at different periods of development: PNA (prenatal androgenization; N = 20), NeNA (neonatal androgenization; N = 20) and PWA (post-weaning androgenization; N = 20). At adulthood (postnatal day 100), rats were subjected to daily treatments with a bolus of KP-54 (100 µg/kg, s.c.) or vehicle for 11 days (N = 10 per model and treatment). On Days 1, 4, 7 and 11, LH and FSH responses were assessed at different time-points within 4 h after KP-54 injection, while ovarian responses, in terms of follicular maturation and ovulation, were measured at the end of the treatment. In addition, hormonal (gonadotrophin, estrogen and inhibin B) and ovulatory responses to repeated KP-54 administration, at doses of 6.4-12.8 nmol/kg, s.c. bd for 21 days, were evaluated in a pilot cohort of anovulatory women (N = 12) diagnosed with PCOS, according to the Rotterdam criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Deregulated reproductive indices were detected in all PCOS models: PNA, NeNA and PWA. Yet, anovulation was observed only in NeNA and PWA rats. However, while anovulatory NeNA rats displayed significant LH and FSH responses to KP-54 (P < 0.05), which rescued ovulation, PWA rats showed blunted LH secretion after repeated KP-54 injection and failed to ovulate. In women with PCOS, KP-54 resulted in a small rise in LH (P < 0.05), with an equivalent elevation in serum estradiol levels (P < 0.05). Two women showed growth of a dominant follicle with subsequent ovulation, one woman displayed follicle growth but not ovulation and desensitization was observed in another patient. No follicular response was detected in the other women. LIMITATIONS, REASONS FOR CAUTION: While three different preclinical PCOS models were used in order to capture the heterogeneity of clinical presentations of the syndrome, it must be noted that rat models recapitulate many but not all the features of this condition. Additionally, our pilot study was intended as proof of principle, and the number of participants is low, but the convergent findings in preclinical and clinical studies reinforce the validity of our conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our first-in-rodent and -human studies demonstrate that KP-54 administration in anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. As our rat models likely reflect the diversity of PCOS phenotypes, our results argue for the need of personalized management of anovulatory dysfunction in women with PCOS, some of whom may benefit from kisspeptin-based treatments. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research agreements between Ferring Research Institute and the Universities of Cordoba and Edinburgh. K.S. was supported by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative (STMTI). Some of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. M.T.-S. is a member of CIBER Fisiopatología de la Obesidad y Nutrición, which is an initiative of Instituto de Salud Carlos III. Dr Mannaerts is an employee of Ferring International PharmaScience Center (Copenhagen, Denmark), and Drs Qi, van Duin and Kohout are employees of the Ferring Research Institute (San Diego, USA). Dr Anderson and Dr Tena-Sempere were recipients of a grant support from the Ferring Research Institute, and Dr Anderson has undertaken consultancy work and received speaker fees outside this study from Merck, IBSA, Roche Diagnostics, NeRRe Therapeutics and Sojournix Inc. Dr Skorupskaite was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A. The other authors have no competing interest.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Trends in overweight among women differ by occupational class: results from 33 low- and middle-income countries in the period 1992-2009.

OBJECTIVE: There has been an increase in overweight among women in low- and middle-income countries but whether these trends differ for women in different occupations is unknown. We examined trends by occupational class among women from 33 low- and middle-income countries in four regions. DESIGN: Cross-national study with repeated cross-sectional demographic health surveys. SUBJECTS: Height and weight were assessed at least twice between 1992 and 2009 in 248,925 women aged 25-49 years. Interviews were conducted to assess occupational class, age, place of residence, educational level, household wealth index, parity, age at first birth and breastfeeding. We used logistic and linear regression analyses to assess the annual percent change in overweight (body mass index >25 kg m(-2)) by occupational class. RESULTS: The prevalence of overweight ranged from 2.2% in Nepal in 1992-1997 to 75% in Egypt in 2004-2009. In all the four regions, women working in agriculture had consistently lower prevalence of overweight, while women from professional, technical, managerial as well as clerical occupational classes had higher prevalence. Although the prevalence of overweight increased in all the occupational classes in most regions, women working in agriculture and production experienced the largest increase in overweight over the study period, while women in higher occupational classes experienced smaller increases. To illustrate, overweight increased annually by 0.5% in Latin America and the Caribbean and by 0.7% in Sub-Saharan Africa among women from professional, technical and managerial classes, as compared with 2.8% and 3.7%, respectively, among women in agriculture. CONCLUSION: The prevalence of overweight has increased in most low- and middle-income countries, but women working in agriculture and production have experienced larger increases than women in higher occupational classes.

The differential impact of the financial crisis on health in Ireland and Greece: a quasi-experimental approach.

OBJECTIVES: Greece and Ireland suffered an economic recession of similar magnitude, but whether their health has deteriorated as a result has not yet been well established. STUDY DESIGN: Based on five waves (2006-2010) of the European Union Statistics of Income and Living Conditions (EU-SILC) survey a (DID) approach was implemented that compared trends in self-rated health in Greece and Ireland before and after the crisis with trends in a 'control' population (Poland) that did not experience a recession and had health trends comparable to both countries before the crisis. METHODS: Logistic regression using a (DID) approach. RESULTS: A simple examination of trends suggests that there was no significant change in health in Greece or Ireland following the onset of the financial crisis. However, DID estimates that incorporated a control population suggest an increase in the prevalence of poor self-rated health in Greece (OR = 1.216; CI = 1.11-1.32). Effects were most pronounced for older individuals and those living in high-density areas, but effects in Greece were overwhelmingly consistent in different population sub-groups. In contrast, DID estimates revealed no effect of the financial crisis on the prevalence of poor self-rated health in Ireland (OR = 0.97; CI = 0.81-1.16). CONCLUSIONS: DID estimates suggest that the financial crisis led to higher prevalence of reporting poor health in Greece but not in Ireland. Although the research design does not allow the authors to directly assess the role of specific policies, contextual factors including policy responses may have contributed to the different effect of the crisis on the health of the two countries.

Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination.

Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination.

Health equity and health system strengthening - Time for a WHO re-think.

The pursuit of health equity is foundational to the global health enterprise. But while moral concerns over health inequities can galvanise political commitment, how such concerns can or should translate into practice remains less clear. This paper reviews evolving ways that equity goals have featured in key World Health Organization (WHO)-related policy documents, before discussing the heuristic value and empirical traction that the concept of equity can bring to the health system strengthening (HSS) agenda. We argue that while health equity is often presented as the overarching goal of HSS, in practice this is typically circumscribed to the provision of healthcare services. Although healthcare equity is important, we suggest that this narrow focus risks losing sight of the structural political, social and economic drivers of health and health inequities, as well as the broader contexts of care and complex socio-political mechanisms through which health systems are strengthened. Drawing on new lines of empirical inquiry, we propose that broadening the equity lens for HSS -offers exciting opportunities to put health systems at the heart of a more ambitious equity agenda in global health.

Cash transfers and the mental health of young people: Evidence from South Africa's child support grant.

This study examines the longitudinal impact of the South African Child Support Grant (CSG) on risk for depression and life satisfaction among young people (15-19 years). We analysed data from the last three waves of the National Income Dynamics Study (NIDS), a nationally representative panel survey that took place every two years from 2008 to 2017. We used an instrumental variable (IV) approach that exploits multiple changes in age eligibility from 1998 to 2012. Depressive symptoms were assessed using an 8-item version of the Centre for Epidemiological Studies Depression Scale; participants who scored above 8 were considered at risk for depression. Life satisfaction was rated on a scale of 1 ('very dissatisfied') to 10 ('very satisfied'); participants who scored 8 or above were classified as satisfied. We also examined impacts on educational deficit (≥2 years behind) and not being in education, employment or training (NEET) as secondary outcomes, as these are also important for mental health. Age eligibility strongly predicted CSG receipt at Wave 3. In instrumental variable models, CSG receipt did not influence the risk for depression (ß = 0.10, SE = 0.10, p = 0.316), nor life satisfaction (ß = -0.07, SE = 0.09, p = 0.420) at Wave 3, nor at Waves 4 or 5. Some improvements in educational deficit were observed at Wave 3 among CSG beneficiaries compared to non-beneficiaries. These results were robust to multiple specifications. CSG receipt did not improve the psychological wellbeing of adolescents and young adults, nor did it improve their education or employment outcomes. Our findings highlight the need to identify alternative social policies that address the root causes of youth social disadvantage, in conjunction with targeted approaches to improve the mental health of young South Africans living in poverty.

Understanding the complex relationship between multidimensional poverty and depressive symptoms among young South Africans: A cross-sectional study.

BACKGROUND: We use the Global Multidimensional Poverty Index (MPI) to explore how different dimensions of poverty more directly linked to young people are associated with depressive symptoms among South African youth. METHODS: Data came from the 2017 wave of the nationally-representative National Income Dynamics Study (NIDS) in South Africa. We focused on a sample of 15-24-year-olds whose depressive symptoms were assessed using an adapted version of the 10-item Centre for Epidemiological Studies Depression Scale. We examine how individual dimensions and indicators of the MPI relate to depression, in comparison to more conventional measures, including household income, subjective social standing, overcrowding and personal assets. Cross-sectional analyses were adjusted for clustering to account for sampling design. RESULTS: The MPI index was not associated with probable depression (OR = 1.02, 95 % CI 0.81-1.29). Only lack of access to the labour market emerged as a key individual dimension associated with probable depression (OR = 5.29, 95 % CI 1.70-16.47), a relationship driven by an increased odds for those not in employment, education or training. Lack of household assets, living in an informal dwelling and lower perceived social standing were also associated with increased odds for depression. No gender differences were noted. LIMITATIONS: The study is cross-sectional and not suitable to examine the causal nature of the association between multidimensional poverty and depression. CONCLUSIONS: Poverty dimensions that measure youth's access to employment or training have a strong association with depression. Further research is needed to assess whether improved access to employment or training contributes to improving mental health among young South Africans.

Waning and boosting of functional humoral immunity to SARS-CoV-2.

Since the emergence of the SARS-CoV-2 virus, we have witnessed a revolution in vaccine development with the rapid emergence and deployment of both traditional and novel vaccine platforms. The inactivated CoronaVac vaccine and the mRNA-based Pfizer/BNT162b2 vaccine are among the most widely distributed vaccines, both demonstrating high, albeit variable, vaccine effectiveness against severe COVID-19 over time. Beyond the ability of the vaccines to generate neutralizing antibodies, antibodies can attenuate disease via their ability to recruit the cytotoxic and opsinophagocytic functions of the immune response. However, whether Fc-effector functions are induced differentially, wane with different kinetics, and are boostable, remains unknown. Here, using systems serology, we profiled the Fc-effector profiles induced by the CoronaVac and BNT162b2 vaccines, over time. Despite the significantly higher antibody functional responses induced by the BNT162b2 vaccine, CoronaVac responses waned more slowly, albeit still found at levels below those present in the systemic circulation of BNT162b2 immunized individuals. However, mRNA boosting of the CoronaVac vaccine responses resulted in the induction of significantly higher peak antibody functional responses with increased humoral breadth, including to Omicron. Collectively, the data presented here point to striking differences in vaccine platform-induced functional humoral immune responses, that wane with different kinetics, and can be functionally rescued and expanded with boosting.

Entamoeba histolytica: expression and localization of Gal/GalNAc lectin in virulent and non-virulent variants from HM1:IMSS strain.

We have purified Gal/GalNAc lectin from Entamoeba histolytica by electroelution. The purified protein was used to immunize rabbits and obtain polyclonal IgG's anti-lectin. These antibodies were used as tools to analyze the expression and localization of the amoebic lectin in both virulent (vEh) and non-virulent (nvEh) variants of axenically cultured HM1:IMSS strain. vEh is able to induce liver abscesses in hamsters, whereas nvEh has lost this ability. In vitro, amoebic trophozoites from both variants equally express this protein as shown by densitometric analysis of the corresponding band in Western blots from lysates. In both types of trophozoites, the pattern of distribution of the lectin was mainly on the surface. We have also compared by immunohistochemistry the presence and distribution of lectin in the in vivo liver lesions produced in hamsters. In order to prolong the survival of nvEh to analyze both variants in an in vivo model, hamsters inoculated with nvEh were treated with methyl prednisolone. Our results suggest that the Gal/GalNAc lectin is equally expressed in both nvEh and vEh.

Optimization of a MALDI-Imaging protocol for studying adipose tissue-associated disorders.

Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) is increasingly recognized for its potential in the discovery of novel biomarkers directly from tissue sections. However, there are no MALDI IMS studies as yet on the adipose tissue, a lipid-enriched tissue that plays a pivotal role in the development of obesity-associated disorders. Herein, we aimed at developing an optimized method for analyzing adipose tissue lipid composition under both physiological and pathological conditions by MALDI IMS. Our studies showed an exacerbated lipid delocalization from adipose tissue sections when conventional strategies were applied. However, our optimized method using conductive-tape sampling and 2,5-dihydroxybenzoic acid (DHB) as a matrix, preserved the anatomical organization and minimized lipid diffusion from sample sections. This method enabled the identification of a total of 625 down-regulated and 328 up-regulated m/z values in the adipose tissue from a rat model of extreme obesity as compared to lean animals. Combination of MALDI IMS and liquid chromatography (LC)-MS/MS data identified 44 differentially expressed lipid species between lean and obese animals, including phospholipids and sphingomyelins. Among the lipids identified, SM(d18:0_18:2), PE(P-16:0_20:0), and PC(O-16:0_16:1) showed a differential spatial distribution in the adipose tissue of lean vs. obese animals. In sum, our method provides a valuable new tool for research on adipose tissue that may pave the way for the identification of novel biomarkers of obesity and metabolic disease.

Automated peritoneal dialysis as a lifesaving therapy in an emergency room: report of four cases.

The present article describes four cases of patients with chronic kidney disease who arrived at the emergency room in critical condition, needing acute dialysis for severe hyperkalemia and metabolic acidosis. These four patients were treated acutely with automated peritoneal dialysis (APD) using a Tenckhoff catheter placed percutaneously at the bedside in the emergency room. All patients were discharged in good condition and with APD as their chronic renal replacement therapy (RRT). APD is a RRT, that may be considered a frontline acute therapy option for renal failure patients in an emergency room. Coordinated teamwork between emergency and nephrology medical and nursing staff is the key to a successful outcome in these life threatening situations.

Oral vaccine based on a surface immunogenic protein mixed with alum promotes a decrease in Streptococcus agalactiae vaginal colonization in a mouse model.

The Surface Immunogenic Protein (SIP) of Group B Streptococcus (GBS) had been described as a good target for vaccine development. To date, SIP has been reported as a highly conserved protein, and in a mouse model it induces protection against lethal GBS challenge. Also, similar effects have been described by intranasal immunization with a SIP-based vaccine. In this study, we show the immune response induced by an oral SIP-based vaccine formulated on alum in a mouse model. Our vaccine can reduce vaginal GBS colonization and induce specific SIP-antibodies with opsonophagocytosis activities against GBS. Moreover, we observed the activation of T-cells producing IFN-γ, TNF-α, IL-10, IL-2, and increased expression of the transcription factor T-bet, suggesting a Th1-type humoral response. The oral SIP-based vaccine is a novel alternative in the development of a vaccine against GBS.

Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty.

BACKGROUND: Puberty is a complex developmental event, controlled by sophisticated regulatory networks that integrate peripheral and internal cues and impinge at the brain centers driving the reproductive axis. The tempo of puberty is genetically determined but is also sensitive to numerous modifiers, from metabolic and sex steroid signals to environmental factors. Recent epidemiological evidence suggests that the onset of puberty is advancing in humans, through as yet unknown mechanisms. In fact, while much knowledge has been gleaned recently on the mechanisms responsible for the control of mammalian puberty, fundamental questions regarding the intimate molecular and neuroendocrine pathways responsible for the precise timing of puberty and its deviations remain unsolved. OBJECTIVE AND RATIONALE: By combining data from suitable model species and humans, we aim to provide a comprehensive summary of our current understanding of the neuroendocrine mechanisms governing puberty, with particular focus on its central regulatory pathways, underlying molecular basis and mechanisms for metabolic control. SEARCH METHODS: A comprehensive MEDLINE search of articles published mostly from 2003 to 2017 has been carried out. Data from cellular and animal models (including our own results) as well as clinical studies focusing on the pathophysiology of puberty in mammals were considered and cross-referenced with terms related with central neuroendocrine mechanisms, metabolic control and epigenetic/miRNA regulation. OUTCOMES: Studies conducted during the last decade have revealed the essential role of novel central neuroendocrine pathways in the control of puberty, with a prominent role of kisspeptins in the precise regulation of the pubertal activation of GnRH neurosecretory activity. In addition, different transmitters, including neurokinin-B (NKB) and, possibly, melanocortins, have been shown to interplay with kisspeptins in tuning puberty onset. Alike, recent studies have documented the role of epigenetic mechanisms, involving mainly modulation of repressors that target kisspeptins and NKB pathways, as well as microRNAs and the related binding protein, Lin28B, in the central control of puberty. These novel pathways provide the molecular and neuroendocrine basis for the modulation of puberty by different endogenous and environmental cues, including nutritional and metabolic factors, such as leptin, ghrelin and insulin, which are known to play an important role in pubertal timing. WIDER IMPLICATIONS: Despite recent advancements, our understanding of the basis of mammalian puberty remains incomplete. Complete elucidation of the novel neuropeptidergic and molecular mechanisms summarized in this review will not only expand our knowledge of the intimate mechanisms responsible for puberty onset in humans, but might also provide new tools and targets for better prevention and management of pubertal deviations in the clinical setting.

Disparities in stroke preventive care in general practice did not explain socioeconomic disparities in stroke.

OBJECTIVE: To assess socioeconomic disparities in stroke incidence and in the quality of preventive care for stroke in the Netherlands. STUDY DESIGN AND SETTINGS: A total of 190,664 patients who registered in 96 general practices were followed up for 12 months. Data were collected on diagnoses, referrals, prescriptions, and diagnostic procedures. Hazard ratios (HR) were calculated to assess the association between educational level and stroke incidence. Multilevel logistic regression was used to assess socioeconomic disparities in the quality of preventive care for stroke precursors. RESULTS: Lower educational level was associated with higher incidence of stroke in men (HR=1.36, 95% CI=1.06-1.74) but not in women. Among both men and women, there were socioeconomic disparities in the prevalence of hypertension, hypercholesterolemia, diabetes, angina pectoris, heart failure, and peripheral artery disease. Lower educated hypercholesterolemia patients under medication were less likely to be prescribed statins (odds ratio=0.62, 95% CI=0.42-0.91). However, for other precursors of stroke, there were no major disparities in the quality of preventive care. CONCLUSION: There are socioeconomic disparities in stroke incidence among men but not among women. Socioeconomic differences in factors such as hypertension and diabetes are likely to contribute to stroke disparities. However, general practitioners (GPs) provide care of a similar quality to patients from different socioeconomic groups.

Role of COX-2-derived PGE2 on vascular stiffness and function in hypertension.

BACKGROUND AND PURPOSE: Prostanoids derived from COX-2 and EP receptors are involved in vascular remodelling in different cardiovascular pathologies. This study evaluates the contribution of COX-2 and EP1 receptors to vascular remodelling and function in hypertension. EXPERIMENTAL APPROACH: Spontaneously hypertensive rats (SHR) and angiotensin II (AngII)-infused (1.44 mg · kg(-1) · day(-1), 2 weeks) mice were treated with the COX-2 inhibitor celecoxib (25 mg · kg(-1) · day(-1) i.p) or with the EP1 receptor antagonist SC19220 (10 mg · kg(-1) · day(-1) i.p.). COX-2(-/-) mice with or without AngII infusion were also used. KEY RESULTS: Celecoxib and SC19220 treatment did not modify the altered lumen diameter and wall : lumen ratio in mesenteric resistance arteries from SHR-infused and/or AngII-infused animals. However, both treatments and COX-2 deficiency decreased the augmented vascular stiffness in vessels from hypertensive animals. This was accompanied by diminished vascular collagen deposition, normalization of altered elastin structure and decreased connective tissue growth factor and plasminogen activator inhibitor-1 gene expression. COX-2 deficiency and SC19220 treatment diminished the increased vasoconstrictor responses and endothelial dysfunction induced by AngII infusion. Hypertensive animals showed increased mPGES-1 expression and PGE2 production in vascular tissue, normalized by celecoxib. Celecoxib treatment also decreased AngII-induced macrophage infiltration and TNF-α expression. Macrophage conditioned media (MCM) increased COX-2 and collagen type I expression in vascular smooth muscle cells; the latter was reduced by celecoxib treatment. CONCLUSIONS AND IMPLICATIONS: COX-2 and EP1 receptors participate in the increased extracellular matrix deposition and vascular stiffness, the impaired vascular function and inflammation in hypertension. Targeting PGE2 receptors might have benefits in hypertension-associated vascular damage.

HuR mediates the synergistic effects of angiotensin II and IL-1ß on vascular COX-2 expression and cell migration.

BACKGROUND AND PURPOSE: Angiotensin II (AngII) and IL-1ß are involved in cardiovascular diseases through the induction of inflammatory pathways. HuR is an adenylate- and uridylate-rich element (ARE)-binding protein involved in the mRNA stabilization of many genes. This study investigated the contribution of HuR to the increased expression of COX-2 induced by AngII and IL-1ß and its consequences on VSMC migration and remodelling. EXPERIMENTAL APPROACH: Rat and human VSMCs were stimulated with AngII (0.1 µM) and/or IL-1ß (10 ng · mL(-1)). Mice were infused with AngII or subjected to carotid artery ligation. mRNA and protein levels were assayed by quantitative PCR, Western blot, immunohistochemistry and immunofluorescence. Cell migration was measured by wound healing and transwell assays. KEY RESULTS: In VSMCs, AngII potentiated COX-2 and tenascin-C expressions and cell migration induced by IL-1ß. This effect of AngII on IL-1ß-induced COX-2 expression was accompanied by increased COX-2 3' untranslated region reporter activity and mRNA stability, mediated through cytoplasmic HuR translocation and COX-2 mRNA binding. These effects were blocked by ERK1/2 and HuR inhibitors. VSMC migration was reduced by blockade of ERK1/2, HuR, COX-2, TXAS, TP and EP receptors. HuR, COX-2, mPGES-1 and TXAS expressions were increased in AngII-infused mouse aortas and in carotid-ligated arteries. AngII-induced tenascin-C expression and vascular remodelling were abolished by celecoxib and by mPGES-1 deletion. CONCLUSIONS AND IMPLICATIONS: The synergistic induction of COX-2 by AngII and IL-1ß in VSMCs involves HuR through an ERK1/2-dependent mechanism. The HuR/COX-2 axis participates in cell migration and vascular damage. HuR might be a novel target to modulate vascular remodelling.

Human carcinogenesis and bracken fern: a review of the evidence.

The complex taxon embraced in the Pteridium genus, popularly known as bracken fern and notorious weeds in many parts of the world, is one of the few vascular plants known to induce cancer naturally in animals. It has been known for long to be acutely toxic to livestock and sublethal chronic oral feeding of bracken fronds leads to cancerous lesions in the urinary bladder, or bovine enzootic haematuria (BEH) and ileum of cattle. Bracken poisoning has been attributed chiefly to ptaquiloside, a norsesqui-terpene which is also a potent carcinogen inducing various malignancies in laboratory animals. It is capable of alkylating uncoiled DNAbases at key proto-oncogenes of selected organs. Some human populations also eat young bracken shoots and epidemiological studies in Japan and Brazil have shown a close association between bracken consumption and cancers of the upper alimentary tract. In addition, other studies reveal that the mere presence of bracken swards represents a greater risk to die of gastric adenocarcinoma for people who live more than 20 years in such areas or are exposed in childhood. This work reviews the bracken-cancer connections established by in vitro and in vivo experiments and epidemiological studies in various parts of the world, and provides insights into the possible bridges for bracken carcinogens to reach the human diet. Also, specific points where more research is needed are highlighted.

The ventilatory response to arm elevation of patients with chronic obstructive pulmonary disease.

Although arm activity is poorly tolerated by patients with COPD, the ventilatory response to arm elevation alone is not well understood. We therefore studied the ventilatory response to arm elevation using a customized arm support sling to eliminate the effect of an increase in metabolic activity that might be attributable to independent arm elevation and used leg exercise to increase metabolic activity. During arm elevation at rest, there was a significant decrease in vital capacity (180 ml) and a small decrease in functional residual capacity (120 ml) as measured by body plethysmography. Minute ventilation was unchanged. When supported arm elevation (SAE) was compared with the control arm position (CAP), minute ventilation was unchanged although the pattern of breathing became more rapid and shallow (mean +/- SD, SAE vs CAP: fb = 17.9 +/- 5.3 vs 16.2 +/- 4.8 breaths.min-1; VT = 533 +/- 126 vs 579 +/- 142 ml; p < 0.05). During steady-state leg exercise, the increase in VO2, VCO2 and VE did not differ between SAE and CAP; however, both fb and VT changed toward a more rapid, shallow pattern of breathing (SAE vs CAP: fb = 24.3 +/- 3.0 vs 22.8 +/- 3.5 breaths.min-1; VT = 990 +/- 293 vs 1,081 +/- 309 ml; p < 0.05). During unsupported arm elevation VO2, VCO2, and VE, and fb were significantly greater than during the CAP. Approaches that train arm muscles and strategies that either support arm muscles or allow for frequent rests during upper arm activity may improve the endurance and the quality of life for COPD patients.

Effect of external chest wall oscillation on gas exchange in healthy subjects.

Effective gas exchange can be maintained in animals without the need for endotracheal intubation using external chest wall oscillation (ECWO). The clinical application of this technique has been limited by equipment which was either impractical or uncomfortable. We evaluated a prototype of a new oscillator in which an oscillatory profile of negative and positive pressure was imposed on a negative baseline pressure within a cuirass. In seven healthy subjects, we identified an oscillatory cuirass pressure that could effectively ventilate but would not result in severe hypocapnia over 5 min. We then measured the influence of changing the frequency of oscillation (fo) on PaCO2 and spontaneous ventilation. Lastly, we evaluated the capability of this prototype to achieve targeted changes in chamber pressure. Subjects were ventilated with an inspiratory chamber pressure of -20 +/- 4 cm H2O, an expiratory chamber pressure of 5 cm H2O and an inspiratory-expiratory ratio of 1:1 at 9 oscillatory frequencies (fo: 1 to 5 Hz at 0.5-Hz increments). Each subject was ventilated for 5 min with consecutive periods of ECWO being separated from each other by 10 min of unassisted breathing. Oscillatory tidal volume (Vo) was sampled and PaCO2 was determined from the expired carbon dioxide concentration (FECO2) measured at the mouth. The change in PaCO2 (delta PaCO2) was the difference in PaCO2 immediately before and after ECWO. We found that delta PaCO2 and Vo were inversely related to fo. At 1 Hz the delta PaCO2 was -13 +/- 1 mm Hg and Vo was 344 +/- 34 mL in the absence of spontaneous breathing (fb = 0). At 3 Hz and above, at the chamber pressures used, the delta PaCO2 was small (-1 to -2 mm Hg) and the Vo was less than the predicted dead space. Subjects breathed spontaneously but at a frequency below that of their resting fb. With this prototype, chamber pressure changes up to 30 cm H2O could be accurately achieved at 1, 2.5, and 4 Hz. In conclusion, ECWO can provide effective ventilation among healthy adults in the presence or absence of spontaneous breathing, and further studies are warranted to explore its effectiveness in a variety of clinical circumstances.