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.

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.

Trends in overweight by educational level in 33 low- and middle-income countries: the role of parity, age at first birth and breastfeeding.

This study examined trends in overweight among women of reproductive age by educational level in 33 low- and middle-income countries, and estimated the contribution of parity, age at first birth and breastfeeding to these trends. We used repeated cross-sectional Demographic Health Surveys of 255,828 women aged 25-49 years interviewed between 1992 and 2009. We applied logistic regression to model overweight (>25 kg m(-2) ) as a function of education, reproductive variables and time period by country and region. The prevalence of overweight ranged from 3.4% in South and Southeast Asia to 73.7% in North Africa West/Central Asia during the study period. The association between education and overweight differed across regions. In North Africa West/Central Asia and Latin American, lower education was associated with higher overweight prevalence, while the inverse was true in South/Southeast Asia and Sub-Saharan Africa. In all regions, there was a consistent pattern of increasing overweight trends across all educational groups. Older age at first birth, longer breastfeeding and lower parity were associated with less overweight, for differences by educational level in overweight prevalence and trends.

Consenso chileno de manejo de fármacos antiepilépticos en algunos síndromes electro-clínicos y otras epilepsias en niños y adolescentes / Chilean consensus on the use of antiepileptic drugs in electro-clinical syndromes

Por iniciativa de tres instituciones: Liga Chilena contra la Epilepsia (LICHE), Sociedad de Epileptología de Chile (SOCEPCHI) y Sociedad de Psiquiatría y Neurología de la Infancia y Adolescencia (SOPNIA) de Chile, se constituye un comité de trabajo que convoca a un consenso de uso de fármacos antiepilépticos (FAEs) en un grupo de 16 Síndromes electro-clínicos y otras Epilepsias en niños y adolescentes. Cuarenta y dos médicos neuropediatras especialistas en Epilepsias de todas las regiones de Chile, participaron en la discusión y realizaron una propuesta de tratamiento farmacológico para cada cuadro. El comité de trabajo realizó un análisis exhaustivo y discusión de los documentos, para finalmente concluir en una recomendación de tratamiento para cada cuadro. Este consenso es una guía práctica de orientación para ayudar a las decisiones de tratamiento en situaciones clínicas concretas. Su objetivo final es ofrecer una mejor calidad de atención a los niños y adolescentes con epilepsias, a través de decisiones fundadas que contribuyan a disminuir la variabilidad de las decisiones terapéuticas.

Committed by three institutions: Liga Chilena contra la Epilepsia (LICHE), Sociedad de Epileptología de Chile (SOCEPCHI) y Sociedad de Psiquiatría y Neurología de la Infancia y Adolescencia (SOPNIA) de Chile, a 6-member working committee called for a meeting of 42 Chilean pediatric epileptologists from all over the country, with the aim of reaching a consensus on the use of antiepileptic drugs in 16 selected children and adolescents electro-clinical syndromes and epilepsies. These treatment proposals were analyzed and fully discussed by the working committee, ending in an antiepileptic drug treatment recommendation guideline for each condition. This consensus is a practical guideline to be used in specific clinical situations, which aims to support treatment decision making. Its main purpose is to offer the best evidence based treatments to our children and adolescents patients with epilepsy, thus contributing to diminish variability in therapeutic decisions.

Childhood and adulthood socioeconomic position and the hospital-based incidence of hip fractures after 13 years of follow-up: the role of health behaviours.

BACKGROUND: To investigate the association between childhood and adulthood socioeconomic position and the hospital-based incidence of hip fractures, and the contribution of health behaviours to these socioeconomic disparities. METHODS: Baseline (1991) information about socioeconomic position in childhood and adulthood, behavioural factors (alcohol consumption, smoking, physical inactivity, coffee consumption) and body height of 25-74-year-old participants (n=18 810) were linked to hospital admissions for hip fractures (ICD9 code 820-821) over a follow-up period of almost 13 years. RESULTS: During follow-up 192 hip fractures resulted in hospital admission. Childhood socioeconomic position was not associated with the incidence of hip fractures. Adjusted for body height, a lower educational level and being in a lower income proxy group were associated with an increased probability of hip fractures (HR=1.88, 95% CI 1.00 to 3.53 in the lowest education group; HR=2.39, 95% 1.46 to 3.92 in the lowest income group). Very excessive alcohol consumption, smoking and physical inactivity were associated with an increased probability of hip fractures, and contributed (10-31%) to socioeconomic disparities in hip fractures. CONCLUSIONS: The higher prevalence of unhealthy behaviour in lower socioeconomic groups in adulthood contributes moderately to socioeconomic disparities in incidence of hip fractures later in life.

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.

Cysteine proteinase activity is required for survival of the parasite in experimental acute amoebic liver abscesses in hamsters.

Axenic trophozoites of Entamoeba histolytica strain HM1-IMSS grown in vitro in the presence of E-64, a potent irreversible inhibitor of cysteine proteinases, preserved their viability, their rate of replication, their resistance to complement, their haemolytic capacity and their ability to destroy target cells, despite complete inhibition of total cysteine proteinase activity. On the other hand, their erythrophagocytic capacity and their ability to decrease TER of MDCK cells was partially decreased. The same trophozoites injected into the portal vein of hamsters receiving a maintaining dose of E-64 failed to cause tissue damage and were rapidly eliminated. Our results suggest that amoebic cysteine proteinase activity is not required for amoebic functions in in vitro conditions, but that it becomes necessary for survival of trophozoites in in vivo conditions, whatever other role (if any) it may play in the parasite's virulence.

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.

Diagnóstico endoscópico de la enfermedad celíaca en pacientes sin sospecha clínica: 4 casos / Endoscopic diagnosis of unsuspected celiac disease: 4 cases

Presentamos cuatro pacientes en los que durante una endoscopía alta se encontraron alteraciones de la mucosa duodenal que hicieron sospechar la presencia de una enfermedad celíaca y cuyo estudio histológico confirmó una atrofia subtotal/total de las vellosidades. Es importante que el endoscopista tenga presente el aspecto que puede presentar la mucosa duodenal en la enfermedad celíaca y que ante su hallazgo, proceda a tomar las biopsias intestinales correspondientes. Esto perimitirá el diagnóstico de esta compleja enfermedad en un buen número de pacientes en los que no existía sospecha clínica. Se incluyen fotos endoscópicas de dos casos característicos

Possible association between gastric cancer and bracken fern in Venezuela: an epidemiologic study.

To explore a possible connection between specific environmental factors that might explain the high rates of stomach cancer in people living in the highlands of western Venezuela, an epidemiologic study was conducted in 2 regions of contrasting topography. The regions embrace 3 Andean states, Mérida, Táchira and Trujillo, and the vicinal lowland surrounding the Maracaibo lake basin of Zulia State. Statistical sanitary records from 1986 to 1996 comprising 5.5 million people in the study area indicated that age-sex-adjusted gastric cancer death rate per 100,000 people (DR) was up to 3.64 times higher in highland than lowland areas, although total cancer-related DRs were comparable in both regions. DRs of other less frequent cancers from the upper alimentary tract [esophagous (1.18/0.99) and mouth-throat (1.39/2.64)] showed comparable values in both regions as well as colorectal, breast, and uterus-cervix cancers, suggesting that the stomach cancer DRs were related to geographically determined factors. Comparison of some nutrition issues, incidence of Helicobacter pylori infection in selected areas, the discovery of the bracken carcinogen ptaquiloside in milk from bracken-fed cows, the prevalence of this plant in mountain cattle households and pasturelands and the rates of bracken-evoked bovine enzootic hematuria led us to conclude that consumption of ptaquiloside-contaminated milk may contribute to human gastric cancer in the Andean states of Venezuela.

Neurocisticercosis / Neurocysticercosis

La neurocisticercosis es la parasitosis del sistema nervioso central (SNC) producida por la forma larval de la taenia solium. En 1950 Parnolus encontró un cisticerco en el cuerpo calloso, pero sólo en 1985 Kuchen Meister asoció afección con la taenia solium. La forma muscular fue descubierta por primera vez por Priets en 1926 y subsecuentemente también la comunicaron M Gill, Jacob y Mathews. En Estados Unidos la neurocisticercosis se describió por primera vez en 1927 por Walter Dandy

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.

[Weber-Christian disease]. / Enfermedad de Weber-Christian.

A fourteen month old infant was admitted for evaluation because of continuous high fever and an indurated nodular lesion at the left thigh of one month course. After admittance painful inflammatory subcutaneous nodules appeared in the face and trunk, these were accompanied by enlarged cervical lymph nodes and hepatomegaly. Histological evaluation of the skin biopsy showed destruction of subcutaneous tissue, foamy cells, vasculitis and polymorphonuclear leukocyte infiltration; histiocytic proliferation in the lymph nodes and steatosis in the liver biopsy. Osteoarticular infection, cellulitis, sepsis, tuberculosis, collagen disease, and malignancies of hematologic origin were all ruled out. Response to treatment with prednisone was excellent and the patient has been asymptomatic along a one year follow up period.