A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.16-17/10/Newlife - The Charity for Disabled Children FS/13/32/30069/BHF_/British Heart Foundation/United Kingdom 72160007/Chile's National Commission for Scientific and Technological Research MR/K011154/1/MRC_/Medical Research Council/United Kingdom WT_/Wellcome Trust/United Kingdompre-prin

Variability of systemic and oro-dental phenotype in two families with non-lethal Raine syndrome with FAM20C mutations

Background: Raine syndrome (RS) is a rare autosomal recessive bone dysplasia typified by osteosclerosis and dysmorphic facies due to FAM20C mutations. Initially reported as lethal in infancy, survival is possible into adulthood. We describe the molecular analysis and clinical phenotypes of five individuals from two consanguineous Brazilian families with attenuated Raine Syndrome with previously unreported features. Methods: The medical and dental clinical records were reviewed. Extracted deciduous and permanent teeth as well as oral soft tissues were analysed. Whole exome sequencing was undertaken and FAM20C cDNA sequenced in family 1. Results: Family 1 included 3 siblings with hypoplastic Amelogenesis Imperfecta (AI) (inherited abnormal dental enamel formation). Mild facial dysmorphism was noted in the absence of other obvious skeletal or growth abnormalities. A mild hypophosphataemia and soft tissue ectopic mineralization were present. A homozygous FAM20C donor splice site mutation (c.784 + 5 g > c) was identified which led to abnormal cDNA sequence. Family 2 included 2 siblings with hypoplastic AI and tooth dentine abnormalities as part of a more obvious syndrome with facial dysmorphism. There was hypophosphataemia, soft tissue ectopic mineralization, but no osteosclerosis. A homozygous missense mutation in FAM20C (c.1487C > T; p.P496L) was identified. Conclusions: The clinical phenotype of non-lethal Raine Syndrome is more variable, including between affected siblings, than previously described and an adverse impact on bone growth and health may not be a prominent feature. By contrast, a profound failure of dental enamel formation leading to a distinctive hypoplastic AI in all teeth should alert clinicians to the possibility of FAM20C mutations

Socioeconomic and physical distance to the maternity hospital as predictors for place of delivery: an observation study from Nepal

BACKGROUND: Although the debate on the safety and women's right of choice to a home delivery vs. hospital delivery continues in the developed countries, an undesirable outcome of home delivery, such as high maternal and perinatal mortality, is documented in developing countries. The objective was to study whether socio-economic factors, distance to maternity hospital, ethnicity, type and size of family, obstetric history and antenatal care received in present pregnancy affected the choice between home and hospital delivery in a developing country. METHODS: This cross-sectional study was done during June, 2001 to January 2002 in an administratively and geographically well-defined territory with a population of 88,547, stretching from urban to adjacent rural part of Kathmandu and Dhading Districts of Nepal with maximum of 5 hrs of distance from Maternity hospital. There were no intermediate level of private or government hospital or maternity homes in the study area. Interviews were carried out on 308 women who delivered within 45 days of the date of the interview with a pre-tested structured questionnaire. RESULTS: A distance of more than one hour to the maternity hospital (OR = 7.9), low amenity score status (OR = 4.4), low education (OR = 2.9), multi-parity (OR = 2.4), and not seeking antenatal care in the present pregnancy (OR = 4.6) were statistically significantly associated with an increased risk of home delivery. Ethnicity, obstetric history, age of mother, ritual observance of menarche, type and size of family and who is head of household were not statistically significantly associated with the place of delivery. CONCLUSIONS: The socio-economic standing of the household was a stronger predictor of place of delivery compared to ethnicity, the internal family structure such as type and size of family, head of household, or observation of ritual days by the mother of an important event like menarche. The results suggested that mothers, who were in the low-socio-economic scale, delivered at home more frequently in a developing country like Nepal

Ibero-American Consensus on Low- and No-Calorie Sweeteners: Safety, Nutritional Aspects and Benefits in Food and Beverages

International scientific experts in food, nutrition, dietetics, endocrinology, physical activity, paediatrics, nursing, toxicology and public health met in Lisbon on 2-4 July 2017 to develop a Consensus on the use of low- and no-calorie sweeteners (LNCS) as substitutes for sugars and other caloric sweeteners. LNCS are food additives that are broadly used as sugar substitutes to sweeten foods and beverages with the addition of fewer or no calories. They are also used in medicines, health-care products, such as toothpaste, and food supplements. The goal of this Consensus was to provide a useful, evidence-based, point of reference to assist in efforts to reduce free sugars consumption in line with current international public health recommendations. Participating experts in the Lisbon Consensus analysed and evaluated the evidence in relation to the role of LNCS in food safety, their regulation and the nutritional and dietary aspects of their use in foods and beverages. The conclusions of this Consensus were: (1) LNCS are some of the most extensively evaluated dietary constituents, and their safety has been reviewed and confirmed by regulatory bodies globally including the World Health Organisation, the US Food and Drug Administration and the European Food Safety Authority; (2) Consumer education, which is based on the most robust scientific evidence and regulatory processes, on the use of products containing LNCS should be strengthened in a comprehensive and objective way; (3) The use of LNCS in weight reduction programmes that involve replacing caloric sweeteners with LNCS in the context of structured diet plans may favour sustainable weight reduction. Furthermore, their use in diabetes management programmes may contribute to a better glycaemic control in patients, albeit with modest results. LNCS also provide dental health benefits when used in place of free sugars; (4) It is proposed that foods and beverages with LNCS could be included in dietary guidelines as alternative options to products sweetened with free sugars; (5) Continued education of health professionals is required, since they are a key source of information on issues related to food and health for both the general population and patients. With this in mind, the publication of position statements and consensus documents in the academic literature are extremely desirable

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

PURPOSE: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. METHODS: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. RESULTS: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. CONCLUSION: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1

Ibero-American Consensus on Low- and No-Calorie Sweeteners : Safety, Nutritional Aspects and Benefits in Food and Beverages

International scientific experts in food, nutrition, dietetics, endocrinology, physical activity, paediatrics, nursing, toxicology and public health met in Lisbon on 2\u207b4 July 2017 to develop a Consensus on the use of low- and no-calorie sweeteners (LNCS) as substitutes for sugars and other caloric sweeteners. LNCS are food additives that are broadly used as sugar substitutes to sweeten foods and beverages with the addition of fewer or no calories. They are also used in medicines, health-care products, such as toothpaste, and food supplements. The goal of this Consensus was to provide a useful, evidence-based, point of reference to assist in efforts to reduce free sugars consumption in line with current international public health recommendations. Participating experts in the Lisbon Consensus analysed and evaluated the evidence in relation to the role of LNCS in food safety, their regulation and the nutritional and dietary aspects of their use in foods and beverages. The conclusions of this Consensus were: (1) LNCS are some of the most extensively evaluated dietary constituents, and their safety has been reviewed and confirmed by regulatory bodies globally including the World Health Organisation, the US Food and Drug Administration and the European Food Safety Authority; (2) Consumer education, which is based on the most robust scientific evidence and regulatory processes, on the use of products containing LNCS should be strengthened in a comprehensive and objective way; (3) The use of LNCS in weight reduction programmes that involve replacing caloric sweeteners with LNCS in the context of structured diet plans may favour sustainable weight reduction. Furthermore, their use in diabetes management programmes may contribute to a better glycaemic control in patients, albeit with modest results. LNCS also provide dental health benefits when used in place of free sugars; (4) It is proposed that foods and beverages with LNCS could be included in dietary guidelines as alternative options to products sweetened with free sugars; (5) Continued education of health professionals is required, since they are a key source of information on issues related to food and health for both the general population and patients. With this in mind, the publication of position statements and consensus documents in the academic literature are extremely desirable

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Pros And Cons Of Vaginal Rings For Contraceptive Hormone Delivery

The capacity of the vaginal epithelium to absorb hormonal steroids and the ability of silicone elastomers to release these hormones at an almost constant rate form the basis for the use of synthetic rubber vaginal rings for therapeutic purposes. The first prototypes were made for contraception purposes but were later used for hormone replacement therapy (HRT) and, more recently, for the release of antiviral drugs. We have limited this article to contraceptive vaginal rings (CVRs), as their use in HRT was recently extensively reviewed and there are no publications on microbicide-delivering vaginal rings, available to date. Numerous models of CVRs have been studied, but only two have reached the market: NuvaRing® that releases ethinylestradiol and etonogestrel; and Progering® that releases progesterone, for use in lactating women. The main advantages of CVRs are: their effectiveness (similar or slightly better than the pill); ease of use, negating the need to remember a daily routine; the user's ability to control initiation and discontinuation; the nearly constant release rate allowing for lower doses; and, the good cycle control with the combined ring. It was expected that the CVRs would also allow avoidance of the first-pass effect on liver metabolism, but that hypothesis has not yet been confirmed. The main disadvantages are related to the mode of delivery: vaginal insertion may be unpleasant for some women; ring expulsion is not uncommon; the ring may be felt during coitus and be unpleasant for some partners; and, it may cause vaginal discharge and complaints. Although one ring model was associated with disruption of the vaginal mucosa, other studies with different models have not shown conclusive evidence that the ring causes vaginal lesions. CVRs are new methods of hormonal contraception that are likely to be used by many women, particularly in countries where there is greater cultural acceptance of women touching their own genitals. © 2004 Adis Data Information BV. All rights reserved.24241250Ballagh, S.A., Vaginal ring hormone delivery systems in contraception and menopause (2001) Clin. Obstet. Gynecol., 44 (1), pp. 106-113Dezarnaulds, G., Fraser, I., Vaginal ring delivery of hormone replacement therapy: A review (2002) Expert. Opin. Pharmacother., 4 (1), pp. 201-212MacPherson, K., Device gives women possible shield against AIDS (2003) Alliance Microbicidal Dev. Wkly. News Digest, 4 (10), pp. 1-3. , Jul 25Shulman, L.P., Advances in female hormonal contraception (2003) Treat. Endocrinol., 2 (4), pp. 247-256Mishell, D.R., Lumkin, M.E., Contraceptive effect of varying dosages of progestogen in silastic vaginal rings (1970) Fertil. Steril., 21, pp. 99-103Dziuk, P.J., Cook, B., Passage of steroids through silicone rubber (1966) Endocrinology, 78, pp. 208-211Greenblatt, R.B., The physiologic effectiveness of progesterone vaginal suppositories (1954) J. Clin. Endocrinol. Metab., 14, pp. 1564-1567Widholm, O., Vartiainen, E., The absorption of conjugated estrogens and sodium estrone sulfate from the vagina (1974) Ann. Chir. Gyneacol. Fenn., 63, pp. 186-190Mishell, D.R., Moore, D.E., Roy, S., Clinical performance and endocrine profile with contraceptive vaginal rings containing a combination of estradiol and d-norgestrel (1978) Am. J. Obstet. Gynecol., 130 (1), pp. 55-62Toivonen, J., Lahteenmaki, P., Luukkainen, T., Pituitary and gonadal function during the use of norgestrel-estradiol vaginal rings (1978) Contraception, 18 (3), pp. 201-211. , SepJackanicz, T.M., Levonorgestrel and estradiol release from an improved contraceptive vaginal ring (1981) Contraception, 24 (4), pp. 323-339Sivin, I., Mishell Jr., D., Victor, A., A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings: I. Use effectiveness: An international comparative trial (1981) Contraception, 24 (4), pp. 341-358. , OctSivin, I., Mishell Jr., D., Victor, A., A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings: II. Subjective and objective measures of effects: An international comparative trial (1981) Contraception, 24 (4), pp. 359-376. , OctSivin, I., Mishell Jr., D., Victor, A., A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings: III. Menstrual patterns: An international comparative trial (1981) Contraception, 24 (4), pp. 377-392. , OctAhren, T., Lithell, H., Victor, A., Comparison of the metabolic effects of two hormonal contraceptive methods: An oral formulation and a vaginal ring: II. Serum lipoproteins and apolipoproteins (1981) Contraception, 24 (4), pp. 471-478. , OctRobertson, D.N., Alvarez, F., Sivin, I., Lipoprotein patterns in women in Santo Domingo using a levonorgestrel/estradiol contraceptive ring (1981) Contraception, 24 (4), pp. 469-480. , OctRoy, S., Krauss, R.M., Mishell Jr., D.R., The effect on lipids and lipoproteins of a contraceptive vaginal ring containing levonorgestrel and estradiol (1981) Contraception, 24 (4), pp. 429-449. , OctAdams, M.R., Clarkson, T.B., Koritnik, D.R., Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques (1987) Fertil. Steril., 47 (6), pp. 1010-1018Ballagh, S., Mishell, D., Jackanicz, T., Dose-finding study of a contraceptive ring releasing norethindrone acetate/ethinyl estradiol (1994) Contraception, 50, pp. 535-549Ballagh, S.A., Mishell Jr., D.R., Lacarra, M., A contraceptive vaginal ring releasing norethindrone acetate and ethinyl estradiol (1994) Contraception, 50, pp. 517-533Weisberg, E., Fraser, I.S., Lacarra, M., Effect of different insertion regimens on side effects with a combination contraceptive vaginal ring (1997) Contraception, 56, pp. 233-239Weisberg, E., Fraser, I.S., Mishell Jr., D.R., A comparative study of two contraceptive vaginal rings releasing norethindrone acetate and differing doses of ethinyl estradiol (1999) Contraception, 59, pp. 305-310Weisberg, E., Fraser, I.S., Lacarra, M., Efficacy, bleeding patterns, and side effects of a 1-year contraceptive vaginal ring (1999) Contraception, 59 (5), pp. 311-318. , MayAlvarez-Sanchez, F., Brache, V., Jackanicz, T., Evaluation of four different contraceptive vaginal rings: Steroid serum levels, luteal activity, bleeding control and lipid profiles (1992) Contraception, 46, pp. 387-398Laurikka-Routti, M., Haukkamaa, M., Heikinheimo, O., A contraceptive vaginal ring releasing EE and the progestin ST1435: Bleeding control, serum steroid concentrations, serum lipids and serum chemistry (1990) Contraception, 42, pp. 111-120Sivin, I., Mishell, D.R., Alvarez, F., Contraceptive vaginal rings releasing Nestorone® and ethynylestradiol: A one-year dose finding trial Contraception, , In pressApter, D., Cacciatore, B., Stenman, U.H., Clinical performance and endocrine profiles of contraceptive vaginal rings releasing 3-keto-desogestrel and ethinylestradiol (1990) Contraception, 42 (3), pp. 285-295. , SepOlsson, S.E., Odlind, V., Contraception with a vaginal ring releasing 3-keto-desogestrel and ethinylestradiol (1990) Contraception, 42 (5), pp. 563-572. , NovTimmer, C.J., Apter, D., Voortman, G., Pharmacokinetics of 3-keto-desogestrel and ethinylestradiol released from different types of contraceptive vaginal rings (1990) Contraception, 42 (6), pp. 629-642. , DecKirkman, R.J., Bounds, W., Colliver, D., Practical experience in the UK with an oestrogen/progestogen contraceptive vaginal ring (1992) Br. J. Fam. Plann., 18 (1), pp. 12-15. , AprSchindeler, A.E., The 3-keto-desogestrel/ethinylestradiol ring: A new parenteral form of hormonal contraception (1993) Eur. J. Obstet. Gynecol. Reprod. Biol., 49 (1-2), pp. 13-14Roumen, F.J., Apter, D., Mulders, T.M., Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl estradiol (2001) Hum. Reprod., 16 (3), pp. 469-475Dieben, T.O., Roumen, F.J., Apter, D., Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring (2002) Obstet. Gynecol., 100 (3), pp. 585-593. , SepDiaz, S., Jackanicz, T.M., Herreros, C., Fertility regulation in nursing women: VIII. 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IVBrache, V., Alvarez-Sanchez, F., Faundes, A., Progestin-only contraceptive rings (2000) Steroids, 65, pp. 687-769Brache, V., Mishell, D.R., Lahteenmaki, P., Ovarian function during use of vaginal rings delivering three different doses of NES (2001) Contraception, 63, pp. 257-261Massai, R., Diaz, S., Jackanicz, T., Vaginal rings for contraception in lactating women (2000) Steroids, 65, pp. 703-707Sahota, J., Barnes, P.M., Mansfield, E., Initial UK experience of the levonorgestrel-releasing contraceptive intravaginal ring (1999) Adv. Contracept., 15 (4), pp. 313-324Rosenberg, M., Waugh, M.S., Causes and consequences of oral contraceptive non-compliance (1999) Am. J. Obstet. Gynecol., 180, pp. 276-279Novak, A., de la Loge, C., Abetz, L., The combined contraceptive vaginal ring, NuvaRing®: An international study of user acceptability (2003) Contraception, 67, pp. 187-194Weisberg, E., Fraser, I.S., Mishell Jr., D.R., The acceptability of a combined oestrogen/progestogen contraceptive vaginal ring (1995) Contraception, 51 (1), pp. 39-44. , JanFaundes, A., Hardy, E.E., Reyes, Q., Acceptability of the contraceptive vaginal ring by rural and urban population in two Latin American countries (1981) Contraception, 24 (4), pp. 393-414. , OctLandgren, B.M., Johannisson, E., Masironi, B., Pharmacokinetics and pharmacodynamic investigation with vaginal devices releasing levonorgestrel at a constant near zero order rate (1982) Contraception, 29 (6), pp. 567-585Jackson, R., Newton, J.R., The in vivo release characteristics of a multi-compartment vaginal ring releasing 3-keto-desogetrel (1989) Contraception, 40 (5), pp. 615-621Timmer, C.J., Mulders, T.M., Pharmacokinetics of etonorgestrel and ethynil estradiol released from a combined contraceptive vaginal ring (2000) Clin. 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Steril., 75 (1), pp. 200-202http://www.nuvaring.com/Authfiles/Images/309_76063.pdf, Available from URLSalas, V.L.B., A feminilidade: Uma revisão da fala fálica (1990), Porto Alegre: Artes MédicasRome, E., Reame, N., Sanford, W., Understanding our bodies: Sexual anatomy, reproduction, and the menstrual cycle (1998) Boston Women's Health Book Collective: Our Bodies, Ourselves for the New Century, pp. 269-287. , New York: Simon and Schuster IncRosenbaum, L., Sanford, W., Jacobs, J.Z., Sexuality (1998) Boston Women's Health Book Collective: Our Bodies, Ourselves for the New Century, pp. 229-267. , New York: Simon and Schuster IncHardy, E., Padua, K.S., Hebling, E.S., Women's preferences for vaginal antimicrobial contraceptives: V. 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Plann., 14 (11), pp. 284-290Roy, S., Wilkins, J., Mishell Jr., D.R., The effect of a contraceptive vaginal ring and oral contraceptives on the vaginal flora (1981) Contraception, 24 (4), pp. 481-491. , OctDavies, G.C., Fenf, L.X., Newton, J.R., The effects of a combined contraceptive vaginal ring releasing ethinylestradiol and 3-ketodesogestrel on vaginal flora (1992) Contraception, 45 (5), pp. 511-518. , MayBounds, W., Szarewski, A., Lowe, D., Preliminary report of unexpected local reactions to a progestogen-releasing contraceptive vaginal ring (1993) Eur. J. Obstet. Gynecol. Reprod. Biol., 48 (2), pp. 123-125. , FebWeisberg, E., Fraser, I.S., Baker, J., A randomized comparison of the effects on vaginal and cervical epithelium of a placebo vaginal ring with non-use of a ring (2000) Contraception, 62 (2), pp. 83-89Fraser, I.S., Lacarra, M., Mishell Jr., D.R., Vaginal epithelial surface appearances in women using vaginal rings for contraception (2000) Contraception, 61 (2), pp. 131-138. , FebFraser, I.S., Lahteenmaki, P., Elomaa, K., Variations in vaginal epithelial surface appearance determined by colposcopic inspections in healthy, sexually active women (1999) Hum. Reprod., 14 (8), pp. 1974-1978Gallo, M.F., Grimes, D.A., Schulz, K.F., Skin patch and vaginal ring versus combined oral contraceptives for contraception (2003) The Cochrane Collaboration, (1). , Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. Oxford: Oxford Update Softwar