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Objective: To report a case of a patient with Turner syndrome (TS) mosaicism and polycystic ovarian syndrome (PCOS), who underwent successful ovarian stimulation, oocyte retrieval, and cryopreservation. Design: Case report. Subjects: A female patient with mosaic TS (45,X [24%]/46,XX [76%]) and a paternally inherited balanced reciprocal translocation t(2:6) diagnosed with PCOS. Interventions: Controlled ovarian stimulation, oocyte retrieval, and cryopreservation. Main outcome measures: Successful oocyte retrieval and cryopreservation. Results: We report an interesting case of a patient with TS mosaicism 45,X [24%]/46,XX [76%] and a paternally inherited t(2:6) balanced reciprocal translocation, who was diagnosed with PCOS on the basis of oligomenorrhea and ultrasound polycystic ovary morphology (antral follicle count of 17 and >20, left and right ovaries, respectively), underwent 2 cycles of ovarian stimulation, oocyte retrieval, and cryopreservation, resulting in 19 cryopreserved oocytes. Conclusions: Our case highlights the importance of early counseling regarding fertility options in patients with mosaic TS and the need for careful monitoring of ovarian reserve during this process, which could be done by measuring the anti-müllerian hormone or antral follicle count. It also underscores the possibility of women with mosaic TS being affected by PCOS.
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Neglected tropical diseases caused by kinetoplastid parasites (Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp.) place a significant health and economic burden on developing nations worldwide. Current therapies are largely outdated, inadequate, and face mounting drug resistance from the causative parasites. Thus, there is an urgent need for drug discovery and development. Target-led drug discovery approaches have focused on the identification of parasite enzymes catalyzing essential biochemical processes, which significantly differ from equivalent proteins found in humans, thereby providing potentially exploitable therapeutic windows. One such target is ribose 5-phosphate isomerase B (RpiB), an enzyme involved in the nonoxidative branch of the pentose phosphate pathway, which catalyzes the interconversion of d-ribose 5-phosphate and d-ribulose 5-phosphate. Although protozoan RpiB has been the focus of numerous targeted studies, compounds capable of selectively inhibiting this parasite enzyme have not been identified. Here, we present the results of a fragment library screening against Leishmania infantum RpiB (LiRpiB), performed using thermal shift analysis. Hit fragments were shown to be effective inhibitors of LiRpiB in activity assays, and several fragments were capable of selectively inhibiting parasite growth in vitro. These results support the identification of LiRpiB as a validated therapeutic target. The X-ray crystal structure of apo LiRpiB was also solved, permitting docking studies to assess how hit fragments might interact with LiRpiB to inhibit its activity. Overall, this work will guide structure-based development of LiRpiB inhibitors as antileishmanial agents.
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Leishmania infantum , Preparações Farmacêuticas , Sequência de Aminoácidos , Humanos , RibosemonofosfatosRESUMO
Leishmaniases are neglected tropical diseases. The treatment of leishmaniasis relies exclusively on chemotherapy including amphotericin B (AmB), miltefosine (hexadecylphosphocholine), and pentamidine. Besides the fact that these molecules are harmful for patients, little is known about the impact of such antileishmanial drugs on primary human cells in relation to immune function. The present study demonstrates that all antileishmanial drugs inhibit CD4 and CD8 T cell proliferation at the doses that are not related to increased cell death. Our results highlight that antileishmanial drugs have an impact on monocytes by altering the expression of IL-12 induced by LPS, whereas only AmB induced IL-10 secretion; both cytokines are essential in regulating Th1 cell-mediated immunity. Interestingly, IL-12 and anti-IL-10 Abs improved T cell proliferation inhibited by AmB. Furthermore, our results show that in contrast to hexadecylphosphocholine and pentamidine, AmB induced gene expression of the inflammasome pathway. Thus, AmB induced IL-1ß and IL-18 secretions, which are reduced by specific inhibitors of caspase activation (Q-VD) and NLRP3 activation (MCC950). Our results reveal previously underestimated effects of antileishmanial drugs on primary human cells.
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Antiparasitários/farmacologia , Inflamassomos/efeitos dos fármacos , Interleucina-12/metabolismo , Leishmania/genética , Leishmaniose/tratamento farmacológico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-10/metabolismo , Leishmania/metabolismo , Leishmaniose/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
SUMMARY: Hypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea. LEARNING POINTS: IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both. Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH. IHH is associated with a wide spectrum of clinical manifestations. IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.
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The de novo crystal structure of the Leishmania infantum Silent Information Regulator 2 related protein 1 (LiSir2rp1) has been solved at 1.99Å in complex with an acetyl-lysine peptide substrate. The structure is broadly commensurate with Hst2/SIRT2 proteins of yeast and human origin, reproducing many of the structural features common to these sirtuin deacetylases, including the characteristic small zinc-binding domain, and the larger Rossmann-fold domain involved in NAD+-binding interactions. The two domains are linked via a cofactor binding loop ordered in open conformation. The peptide substrate binds to the LiSir2rp1 protein via a cleft formed between the small and large domains, with the acetyl-lysine side chain inserting further into the resultant hydrophobic tunnel. Crystals were obtained only with recombinant LiSir2rp1 possessing an extensive internal deletion of a proteolytically-sensitive region unique to the sirtuins of kinetoplastid origin. Deletion of 51 internal amino acids (P253-E303) from LiSir2rp1 did not appear to alter peptide substrate interactions in deacetylation assays, but was indispensable to obtain crystals. Removal of this potentially flexible region, that otherwise extends from the classical structural elements of the Rossmann-fold, specifically the ß8-ß9 connector, appears to result in lower accumulation of the protein when expressed from episomal vectors in L. infantum SIR2rp1 single knockout promastigotes. The biological function of the large serine-rich insertion in kinetoplastid/trypanosomatid sirtuins, highlighted as a disordered region with strong potential for post-translational modification, remains unknown but may confer additional cellular functions that are distinct from their human counterparts. These unique molecular features, along with the resolution of the first kinetoplastid sirtuin deacetylase structure, present novel opportunities for drug design against a protein target previously established as essential to parasite survival and proliferation.
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Histona Desacetilases do Grupo III/química , Histona Desacetilases do Grupo III/metabolismo , Leishmania infantum/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Modelos Moleculares , Peptídeos/metabolismo , Ligação Proteica , Estrutura Secundária de Proteína , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismoRESUMO
Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.
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Antiprotozoários/metabolismo , Doença de Chagas/parasitologia , Inibidores Enzimáticos/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Niacinamida/metabolismo , Quinolonas/metabolismo , Espermina/análogos & derivados , Espermina/metabolismo , Resultado do TratamentoRESUMO
In this article, the four coordinators of neglected tropical disease (NTD) drug development projects funded under the European Commission (EC) Framework Programme 7 argue that the EC should reassess their funding strategy to cover the steps necessary to translate a lead compound into a drug candidate for testing in clinical trials, and suggest ways in which this might be achieved.
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Descoberta de Drogas/tendências , Doenças Negligenciadas , Saúde Pública/tendências , Medicina Tropical , Descoberta de Drogas/economia , Descoberta de Drogas/normas , União Europeia , Humanos , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/economia , Saúde Pública/economia , Saúde Pública/normas , Medicina Tropical/economiaRESUMO
Chronic low back pain (CLBP) is one of the most common medical conditions, ranking as the greatest contributor to global disability and accounting for huge societal costs based on the Global Burden of Disease 2010 study. Large genetic and -omics studies provide a promising avenue for the screening, development and validation of biomarkers useful for personalized diagnosis and treatment (precision medicine). Multicentre studies are needed for such an effort, and a standardized and homogeneous approach is vital for recruitment of large numbers of participants among different centres (clinical and laboratories) to obtain robust and reproducible results. To date, no validated standard operating procedures (SOPs) for genetic/-omics studies in chronic pain have been developed. In this study, we validated an SOP model that will be used in the multicentre (5 centres) retrospective "PainOmics" study, funded by the European Community in the 7th Framework Programme, which aims to develop new biomarkers for CLBP through three different -omics approaches: genomics, glycomics and activomics. The SOPs describe the specific procedures for (1) blood collection, (2) sample processing and storage, (3) shipping details and (4) cross-check testing and validation before assays that all the centres involved in the study have to follow. Multivariate analysis revealed the absolute specificity and homogeneity of the samples collected by the five centres for all genetics, glycomics and activomics analyses. The SOPs used in our multicenter study have been validated. Hence, they could represent an innovative tool for the correct management and collection of reliable samples in other large-omics-based multicenter studies.
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Análise Química do Sangue/normas , Coleta de Amostras Sanguíneas/normas , Dor Crônica/genética , Dor Crônica/metabolismo , Dor Lombar/genética , Dor Lombar/metabolismo , Área Sob a Curva , Austrália , Biomarcadores/sangue , Carboxipeptidases/sangue , Dor Crônica/sangue , Europa (Continente) , Humanos , Dor Lombar/sangue , Análise Multivariada , Polissacarídeos/sangue , Curva ROC , Estudos Retrospectivos , Estados UnidosRESUMO
INTRODUCTION: Chronic low back pain (CLBP) produces considerable direct costs as well as indirect burdens for society, industry and health systems. CLBP is characterised by heterogeneity, inclusion of several pain syndromes, different underlying molecular pathologies and interaction with psychosocial factors that leads to a range of clinical manifestations. There is still much to understand in the underlying pathological processes and the non-psychosocial factors which account for differences in outcomes. Biomarkers that may be objectively used for diagnosis and personalised, targeted and cost-effective treatment are still lacking. Therefore, any data that may be obtained at the '-omics' level (glycomics, Activomics and genome-wide association studies-GWAS) may be helpful to use as dynamic biomarkers for elucidating CLBP pathogenesis and may ultimately provide prognostic information too. By means of a retrospective, observational, case-cohort, multicentre study, we aim to investigate new promising biomarkers potentially able to solve some of the issues related to CLBP. METHODS AND ANALYSIS: The study follows a two-phase, 1:2 case-control model. A total of 12â 000 individuals (4000 cases and 8000 controls) will be enrolled; clinical data will be registered, with particular attention to pain characteristics and outcomes of pain treatments. Blood samples will be collected to perform -omics studies. The primary objective is to recognise genetic variants associated with CLBP; secondary objectives are to study glycomics and Activomics profiles associated with CLBP. ETHICS AND DISSEMINATION: The study is part of the PainOMICS project funded by European Community in the Seventh Framework Programme. The study has been approved from competent ethical bodies and copies of approvals were provided to the European Commission before starting the study. Results of the study will be reviewed by the Scientific Board and Ethical Committee of the PainOMICS Consortium. The scientific results will be disseminated through peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02037789; Pre-results.
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Biomarcadores/metabolismo , Dor Crônica/genética , Estudo de Associação Genômica Ampla , Glicômica , Dor Lombar/genética , Estudos de Casos e Controles , Dor Crônica/sangue , Dor Crônica/epidemiologia , Dor Crônica/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Dor Lombar/sangue , Dor Lombar/epidemiologia , Dor Lombar/fisiopatologia , Masculino , Medição da Dor , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Current treatments for African trypanosomiasis are either toxic, costly, difficult to administer, or prone to elicit resistance. This study evaluated the activity of bisnaphthalimidopropyl (BNIP) derivatives againstTrypanosoma brucei BNIPDiaminobutane (BNIPDabut), the most active of these compounds, showedin vitroinhibition in the single-unit nanomolar range, similar to the activity in the reference drug pentamidine, and presented low toxicity and adequate metabolic stability. Additionally, using a murine model of acute infection and live imaging, a significant decrease in parasite load in BNIPDabut-treated mice was observed. However, cure was not achieved. BNIPDabut constitutes a new scaffold for antitrypanosomal drugs that deserves further consideration.
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Naftalimidas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Linhagem Celular , Estabilidade de Medicamentos , Feminino , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Naftalimidas/síntese química , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Carga Parasitária , Pentamidina/farmacologia , Cultura Primária de Células , Relação Estrutura-Atividade , Análise de Sobrevida , Tripanossomicidas/síntese química , Trypanosoma brucei brucei/crescimento & desenvolvimento , Trypanosoma brucei brucei/metabolismo , Tripanossomíase Africana/mortalidade , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/patologiaRESUMO
STUDY OBJECTIVE: To identify current clinical services and training available across Europe within pediatric and adolescent gynecology (PAG) and establish the extent to which PAG services meet current European Board and College of Obstetrics and Gynecology (EBCOG) standards. DESIGN: Quantitative and qualitative questionnaire. SETTING: European countries that are members of the EBCOG and the European Association of Pediatric and Adolescent Gynecology. PARTICIPANTS: Thirty-six countries that were approached beginning in September 2013; data were obtained from 27 countries. INTERVENTIONS: Questionnaires with 28 stems were sent to clinical leaders in 36 European countries. MAIN OUTCOME MEASURES: National society, national standards, legislation for female genital mutilation, protocols for transition to adult services, human papilloma virus vaccination programs, sex and contraception education, safeguarding, clinical leads for PAG, delivery of PAG services, and training available for PAG. RESULTS: Of 36 countries, 27 responded. Seventy-seven percent had a national PAG society but only 44% had national standards in PAG. There was agreement that PAG cases should be multidisciplinary but not all have clinical networks in place to facilitate this. Human papilloma virus programs are available in some European countries and not all have legislation against female genital mutilation. A significant proportion of cases continue to be seen in adult gynecology clinics as opposed to designated PAG clinics with only 41% with processes to transfer patients into adult care. CONCLUSION: In this article we provide a framework to explore areas for improvement within PAG services and training across Europe. The EBCOG standards of care are not being adhered to in many countries because processes and clinical networks are not in place to facilitate them.
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Medicina do Adolescente/normas , Ginecologia/normas , Pediatria/normas , Padrão de Cuidado/estatística & dados numéricos , Adolescente , Medicina do Adolescente/educação , Medicina do Adolescente/métodos , Adulto , Europa (Continente) , Feminino , Ginecologia/educação , Ginecologia/métodos , Humanos , Pediatria/educação , Pediatria/métodos , Gravidez , Pesquisa Qualitativa , Inquéritos e QuestionáriosRESUMO
A 41-year-old nulliparous woman, with a medical history of unexplained infertility and multiple in vitro fertilisation (IVF) cycles with immunosuppressive therapy, was admitted to our tertiary obstetrics unit with sepsis at 18 weeks of pregnancy with dichorionic diamniotic twins. Candida glabrata was grown from her blood cultures, then subsequently from the liquor and placentae. She was treated with intravenous ambisome (amphotericin), but unfortunately, the infection resulted in the rupture of her membranes, preterm labour and the demise of her twins. She delivered both twins at 23 weeks, 3 days apart. The antifungal agent was changed to high-dose fluconazole after delivery for 2 weeks and she is now well. Women undergoing IVF-embryo transfer with immunomodulation therapy have a potential risk of developing candidal chorioamnionitis and sepsis.
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Candida glabrata , Candidemia/complicações , Transferência Embrionária , Fertilização in vitro , Ruptura Prematura de Membranas Fetais/microbiologia , Terapia de Imunossupressão/efeitos adversos , Complicações Infecciosas na Gravidez/microbiologia , Adulto , Feminino , Humanos , Gravidez , Gravidez de Gêmeos , Nascimento Prematuro/microbiologia , NatimortoRESUMO
Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.
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Síndrome de Resistência a Andrógenos , Síndrome de Resistência a Andrógenos/classificação , Síndrome de Resistência a Andrógenos/diagnóstico , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/terapia , Androgênios/fisiologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Mutação , Dedos de Zinco/genéticaRESUMO
Capture-recapture (C-RC) using four data sources, one of which accounted for 81% of captured injectors, and multiple indicator methods (MIM) were used to obtain national, regional and local estimates of the prevalence of injecting drug use among opiate and/or crack cocaine users in England. Persons aged 15 to 64 years, in contact with health and/or criminal justice services during 2005/2006, and known to be using opiates and/or crack cocaine and injecting drugs were included in the C-RC analysis. The MIM analysis included indicators relating to drug treatment, drug-related deaths, population density and drug offences.There were an estimated 130,000 opiate and/or crack cocaine users who injected drugs in 2005/06 (95% confidence interval 125,800 to 137,000), corresponding to 3.9 per thousand of the population aged 15 to 64 years (95% confidence interval 3.8-4.1). Regional variation in the prevalence of injecting was evident, ranging from 6.1 per thousand of the population aged 15 to 64 years in Yorkshire and the Humber (95% confidence interval 5.6 to 6.6) to 2.3 per thousand in the East of England (95% confidence interval 1.8 to 2.9). Application of gender and age-group distributions for treated injecting drug users (IDUs) to the prevalence estimates suggested that there were 97,200 male injectors (95% confidence interval 94,000 to 102,500) and 63,600 female injectors aged 25 to 34 years (95% confidence interval 61,500 to 67,000).The prevalence estimates provide a basis from which numbers of current IDUs infected with hepatitis C virus (HCV) can be approximated.
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Abuso de Substâncias por Via Intravenosa/epidemiologia , Adolescente , Adulto , Intervalos de Confiança , Estudos Transversais , Coleta de Dados/métodos , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Adulto JovemRESUMO
OBJECTIVE: We investigated the effects of normal variations in maternal glycemia on birth size and other birth outcomes. RESEARCH DESIGN AND METHODS: Women in two unselected birth cohorts, one retrospective (n = 3,158) and one prospective (n = 668), underwent an oral glucose challenge at 28 weeks of gestation. In the retrospective study, glycemia was linked to routine birth records. In the prospective study, offspring adiposity was assessed by skinfold thickness from birth to age 24 months. RESULTS: In the retrospective study, within the nondiabetic range (2.1-7.8 mmol/l), each 1 mmol/l rise in the mother's 60-min glucose level was associated with a (mean +/- SEM) 2.1 +/- 0.8% (P = 0.006) rise in absolute risk of assisted vaginal delivery, a 3.4 +/- 0.8% (P < 0.0001) rise in emergency cesarean delivery, a 3.1 +/- 0.7% (P < 0.0001) rise in elective cesarean delivery, and a 46 +/- 8 g (P < 0.0001) increase in offspring birth weight. In the prospective study, fetal macrosomia (birth weight >90th centile) was independently related to the mother's fasting glucose (odds ratio 2.61 per +1 mmol/l [95% CI 1.15-5.93]) and prepregnancy BMI (1.10 per +1 kg/m(2) [1.04-1.18]). The mother's higher fasting glycemia (P = 0.004), lower insulin sensitivity (P = 0.01), and lower insulin secretion (P = 0.02) were independently related to greater offspring adiposity at birth. During postnatal follow-up, the correlation between the mother's glycemia and offspring adiposity disappeared by 3 months, whereas prepregnancy BMI was associated with offspring adiposity that was only apparent at 12 and 24 months (both P < 0.05). CONCLUSIONS: Prepregnancy BMI, pregnancy glycemia, insulin sensitivity, and insulin secretion all contribute to offspring adiposity and macrosomia and may be separate targets for intervention to optimize birth outcomes and later offspring health.
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Peso ao Nascer , Glicemia/metabolismo , Índice de Massa Corporal , Resultado da Gravidez , Adiposidade , Feminino , Humanos , Recém-Nascido , Razão de Chances , Gravidez , Estudos Prospectivos , Estudos RetrospectivosRESUMO
AIM: The aim of the study was to explore the different ways in which doctors have learned to teach and train. INTRODUCTION: There is no coherent theory of medical teacher development. Doctors are experts in what they teach; most have had little or no training in how they teach. Research has mostly concentrated on the acquisition and improvement of pedagogical skills by attendance at formal, generally short courses. These may have limited impact. METHODS: We carried out semistructured interviews with 10 experienced medical teachers. A review of the literature had suggested areas to explore. Interviews were transcribed and coded and thematic analysis and grounded theory used as the framework for qualitative analysis. RESULTS: Four areas were identified as important in teacher development: acquisition of educational knowledge and skills; modelling and practice of teaching skills; encouragement and motivation of teachers, and constraints on teaching and learning. DISCUSSION: The results suggest a model for teacher development that begins with doctors as learners, learning to learn and watching teachers teach. They then start to teach, acquiring and practising skills, and subsequently move on to reflect on their teaching. They can be encouraged to teach but may also be prevented from teaching. CONCLUSIONS: This inductive study proposes a model for medical teacher development that attempts to explain how doctors learn to teach and train. More research is needed to clarify the findings. There are implications for faculty development.