One of the most common global disorders is related to gastrointestinal system. Functional dyspepsia (FD) defined as upper abdominal pain and discomfort in the absence of organic ailments is a prevalent disease without any confirmed medication. The purpose of this study was to find gastric disorders which might be coincidental to FD based on traditional Persian medicine (TPM).We searched the main textbooks of TPM including Al-Havi (by Rhazes), Canon of medicine (by Avicenna), ZakhireKhawrazmshahi (by Ismail Jorjani), Moalijat-e Aghili and Makhzan Al-adviya (by Mohammad Hosein AghiliShirazi), and ExirAzam (by Hakim Azam Khan). Also, we searched Pubmed, Scopus, Science Direct, Medline, scientific information database (SID), Iranmedex and Google Scholar from 1980 to 1 August 2014 for dyspepsia, gastrointestinal disease, traditional Persian medicine, and gastric dystemperaments.There is no equivalent term for FD in traditional Persian medicine although similar signs and symptoms are visible in terms like simple cold dystemperament of stomach, indigestion, and digestion debility in TPM sources. Some treatments mentioned in TPM have shown promising results in the current experimental tests.Finding these similarities in complementary and alternative medicine (CAM) textbooks may lead to discovering new remedies for this widespread disease. Gastrointestinal diseases are very common in different populations, and many physicians spend a great deal of time and energy to treat these disorders carefully worldwide , called humoral medicine, as a famous medical school is based on four humors  , Canon of medicine (by Avicenna), ZakhireKhawrazmshahi (by Ismail Jorjani), Moalijat-e Aghili and Makhzan Al-adviya (by Mohammad Hosein AghiliShirazi), and ExirAzam (by Hakim Azam Khan) for gastric dystemperaments and treatments. Also, we searched Pubmed, Scopus, Science Direct, Medline, scientific information database (SID), Iranmedex, and Google Scholar from 1980 to 1 August 2014 for dyspepsia, gastrointestinal disease, traditional Persian medicine, and gastric dystemperaments. Those studies with randomized clinical trial or experimental methodology were included and reviewed by three authors. The aforementioned books were also reviewed focusing on GI system chapters by the same authors. The selected literature was discussed by all authors in several panel discussions and summarized for the manuscript draft.According to TPM principles, the stomach is one of the most important organs because it is the main route for food entrance and digestion  and the duodenum (Asna-ashar)   is the best remedy for all diseases. The diseases of the stomach as an individual organ and gastrointestinal tract in general, follow this rule. Tabi'at-e-modabbere (nature) or sober force of the body is considered the internal army of the body to maintain body health and defend the body in front of intrinsic and extrinsic harmful agents. Tabi'at-e-modabbere in TPM may partly be considered as an equivalent for the immune system and neuroendocrine system together  and prokinetics are good choices for empirical pharmacotherapy , radish (Raphinussativus L.), rocket (Eruka sativa), and marjoram (Origanummajorana L.) demonstrated anti-ulcer effect in experimental investigations  showed such an activity in wistar pylorus ligated rats , grape (Vitisvinifera), and nutmeg (Myristicafragrans), which have been advised in TPM resources, have been proven by modern investigations, liquorice (GlycyrrhizaGlabra), and black caraway (Niggella sativa) or compound medicinal plants like Jollab on the elimination of symptoms of FD in patients with promising results  modalities have multiple therapeutic options for relief of FD symptoms, and herbal medicines and natural products are of great importance Kav, 2009. Celery Cinnamomumzeylanicum) showed promising effects on the stomach in rats (AghiliShirazi, 2009The treatment of gastric temperaments either new or tenacious form is different from what is explained above in conventional medicine, although recommendations for changing dietary habits and life style in addition to promotion of the mental health are lookalike, and some are advised in new studies (Avicenna, 1988GI problems are among the most common diseases worldwide. Functional dyspepsia is a heterogeneous disorder with empirical treatments, and CAM practitioners are trying to put forward optimal remedies for it through well-designed researches. TPM school has its unique pathophysiology and therapies for GI diseases. Finding equivalent terminology for FD and reviewing the suggested medications may be so beneficial to fight this prevalent disorder. Promising results in this field trigger “the glimmers of hope” for future.The authors certify that there is no actual or potential conflict of interest in relation to this article.


AbstractZeugodacuscucurbitae (Coquillett), in the Afrotropical Region, including data on invasion history, distribution patterns, population genetics, host range, and interspecific competition. Although limited intraspecific variability has been observed within the region regarding the above mentioned aspects, there seems to be no indication that Zeugodacuscucurbitae represents a species complex. A checklist of all of the species included in Zeugodacus as recently proposed by This paper reviews all available information regarding the occurrence and biology of the melon fly,  Zeugodacuscucurbitae (Coquillett) is a major agricultural pest of Asian origin. Despite the vernacular English name and the species-group name, it is reported from a series of unrelated host families in addition to the vast host range within Cucurbitaceae , or not (in Bactrocera). Drew placed Zeugodacuscucurbitae in the subgenus Zeugodacus, first under Dacus following previous authors   cucurbitae for the melon fly, although most existing literature refer to it under the former combination, Bactrocera (Zeugodacus) cucurbitae.e Figure  was orig authors , and latctrocera . The subntation) . At leasistories . The molZeugodacus currently includes 192 species  populations found in Africa , while the basal scutellar seta can be rarely present . The crossband on r-m is not always distinct. However, these differences do not seem to reflect any particular pattern linked to cryptic PageBreakspeciation but rather phenotypic plasticity. Zeugodacuscucurbitae was not included in the list of the Asian species complexes defined by Zeugodacus species. Bactrocera of the Australasian and Oceanian regions, including Zeugodacuscucurbitae and 19 other Zeugodacus species, while Dacina including Zeugodacuscucurbitae.Contrary to other species like the rica see , there iDNA barcoding shows remarkably low intraspecific variability. A pilot study including COI barcodes of 44 specimens originating from 11 countries along the entire distribution range  revealed an average K2P genetic distance  of only Zeugodacuscucurbitae was originally described from the Hawaiian Islands, its presence there was the result of accidental human-mediated introduction  or whether it was already present for a much longer time. There are historical ties between the eastern coastal area of Africa  and the near East and Indian subcontinent that date back to 100 AD  as the most prevalent insect pest observed by farmers on tomatoes in Cameroon. No voucher specimens could be traced to any collections in order to confirm this record, and there is the possibility that it was based on a misidentification of another dacine attacking tomatoes. For example, Dacuspunctatifrons Karsch has been reported as a major pest of tomato in Cameroon  discovered it in Mali in cuelure traps and emerging from young pumpkins. Since the beginning of the 21st Century, several records of Zeugodacuscucurbitae from West and Central Africa became known  and the historical data of its occurrences in Africa and Hawaii, it is generally assumed that Zeugodacuscucurbitae originated in the Oriental Region and that its current distribution in Africa and in other parts of the world is the result of several invasion events  Asia and Hawaii, and (b) Sub Saharan Africa and La Réunion Island. The main differences between the African and all other samples suggested a bottleneck(s) following introduction, yet this model was not supported by the studies of Given the current geographic distribution of other ents see . The anaZeugodacuscucurbitae originated on the Indian Subcontinent and PageBreakPageBreakmight have expanded its range to South-East Asia and Hawaii on one hand and to Africa and the Indian Ocean islands on the other . Levels of genetic diversity and individual Bayesian assignments  seem to Zeugodacuscucurbitae. However, several of these hosts are considered doubtful because they were either based on casual observations (Zeugodacuscucurbitae in Africa (including Indian Ocean islands) (Table rvations  or they rvations . De Meyes) Table .Cucurbitaceae. Cucumis spp. (in particular cucumber (Cucumissativus L.) and melon (Cucumismelo L.)) and Momordica spp. (in particular Momordicacftrifoliata Hook. f. and bitter gourd (Momordicacharantia L.)) were the preferential hosts both in West and East African studies  Standl. yielded very low numbers in West and East Africa but more than 100 specimens/kg in Réunion. These examples are, however, based on too limited a number of samples to draw definite conclusions, and it is not clear what are all of contributing causes of these differences in infestation rates. Seasonal differences (Mangiferaindica L.), PageBreakPageBreakcitrus (Citrus spp.) or carambola (Averrhoacarambola L.), can have regulatory implications for export of particular commodities. On the other hand, other polyphagous fruit fly species in Africa, such as Bactroceradorsalis, Ceratitiscapitata (Wiedemann) or Ceratitisrosa Karsch, which attack these commercial non-cucurbit hosts, are rarely encountered in Cucurbitaceae , Dacusvertebratus Bezzi, Dacusfrontalis Becker, and Dacuspunctatifrons. All these species have a large geographic overlap with Zeugodacuscucurbitae  Matsum. and Nakai (and Momordicacharantia to a lesser extent). A pilot study exploring genetic differentiation between 42 Tanzanian Zeugodacuscucurbitae specimens PageBreakPageBreakreared from different cucurbit hosts  and genotyped at 19 microsatellite loci did not suggest the occurrence of possible host races ) infested a range of 16 cucurbit species  and two biotic ones  are the main screening factors for species-dominance in La Réunion. Among the 16 cucurbit hosts, Dacusciliatus dominated in the cultivated hosts Citrulluscolocynthis (L.) Schrader, Cyclantherapedata (L.) Schrader, Secchiumedule (Jacq.) Sw., and several cultivars of Cucumismelo and Cucurbitapepo L., which were cultivated above the altitudinal limit of Zeugodacuscucurbitae (600m during the cold season and up to 1200 meters during the hot season). Zeugodacuscucurbitae dominated on wild species such as Cocciniagrandis (L.) Voigt., Cucumisanguria L., Lagenariasphaerica (Sond.) Naudin, Momordicacharantia, and also cultivated ones such as Citrulluslanatus, Cucumismelo, Cucumissativus, Curcubitapepo, Luffaacutangula (L.) Roxb., Luffacylindrica M. Roem., Momordica sp., and Trichosanthescucumerina L. , three species , with al niche . It has al niche  and thatt Africa , with Ze Réunion , at leas Réunion . This coZeugodacuscucurbitae. Earlier studies in Hawaii have shown that it is a species that is mainly found in warmer areas and that its abundance declines with increasing rainfall and increasing elevation  are the result of local expansions of already established African populations or of one or more introductions from non-African sources. Regardless differences in host range reported across African populations there is no evidence supporting the existence of genetically isolated host races with specific feeding preferences and the observed host range variability seems more to be related to factors such as interspecific competition, host availability, and ecological niche partitioning. Although our study focused on the African populations, there is no indication that the situation might differ across the distribution of Zeugodacuscucurbitae.Morphologically and genetically


The aim of the present review is twofold: (i) providing an overview of recent applied and fundamental studies investigating the effects of MI practice (MIP) on motor learning; and (ii) detangling applied and fundamental findings in support of a sleep contribution to motor consolidation after MIP. We conclude with an integrative approach of online and offline learning resulting from intense MIP in healthy participants, and underline research avenues in the motor learning/clinical domains.There is now compelling evidence that motor imagery (MI) promotes motor learning. While MI has been shown to influence the early stages of the learning process, recent data revealed that sleep also contributes to the consolidation of the memory trace. How such “ This was thought to provide a reliable corpus to convey both the development and current trends in the field. Only interventions targeting the acquisition/improvement of motor skills were included in the pool of “motor learning” MIP articles. A related—yet distinct—research topic, since the pioneering contribution by Cornwall et al. (Motor imagery (MI) is the mental representation of an action without engaging its actual execution. MI practice (MIP) refers to the repetitive use of MI to improve performance . Surprisingly, they did not consider the potential delayed performance gains consecutive to MIP, in other words the MIP effects on offline learning. The present review was therefore designed to provide a comprehensive overview of motor learning after MIP in healthy participants in relation to both online and offline processes.Motor learning is classically defined as a change in motor behavior resulting from practice. Accordingly, motor learning is quantified in terms of performance improvements before and after a practice intervention in longitudinal research designs. When the practice intervention involves multiple sessions within a span of several days/weeks, the cumulated effects on performance are evaluated to attest motor learning. These can be summarized as Centre pillar of applied sport psychology”  Motor learning and Performance; (ii) Motivation, Self-confidence and Anxiety; (iii) Strategies and Problem-solving; and (iv) Injury Rehabilitation. Overall, particular attention has been paid to the effect of cost-effective MIP interventions in enhancing online learning, MIP improving both quantitative and qualitative aspects of the motor performance . Overall, there is accumulated evidence that MIP contributes to achieve a greater level of sporting performance  motor learning experiments attesting MIP efficacy ; and (ii) functional brain imaging findings supporting the functional equivalence principle. Accordingly, MI and physical practice of the corresponding action engage both overlapping neural networks and comparable patterns of connectivity between brain motor system regions  reinforcement of brain activity within motor system regions  preservation of functional equivalence between MI and physical practice after motor learning  were later replicated in several experiments  from data measured in healthy participants. Particularly, Volz et al.  could be prolonged, the intention to act would become progressively a MI of the same action (…). Actions which fail or which are cancelled at the last moment may be situations where a non-conscious program is transformed into a conscious image”  A type of implicit learning wherein a stimulus prompts a change in behavior”  the neurophysiological underpinnings of the individual predispositions to benefit from MIP; (ii) the relationship between MI ability and MIP effects on motor performance, assessed at behavioral and/or neurophysiological level; and (iii) the efficacy of combined MIP intervention  will have strong practical implications.Historically, applied and fundamental MIP findings in healthy participants frequently provided a scientific rationale preceding clinical applications. Prompted by insights from Warner and McNeill  see als, the numFDR, UD, SD, ES, CD, JD, CC and AG contributed to the conceptual background of the review and to the preparation of the manuscript . FDR, AG, UD, CC and JD wrote the article. FDR, UD, SD, ES, CD, JD, CC and AG all read and commented the article throughout the writing. They also reviewed the final article before submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Rhizoma Coptidis (Huang Lian in Chinese pinyin) is among the most widely used traditional Chinese herbal medicines and has a profound history of more than 2000 years of being used as a therapeutic herb. The antidiabetic effects of Rhizoma Coptidis have been extensively investigated in animal experiments and clinical trials and its efficacy as a promising antihyperglycemic agent has been widely discussed. In the meantime, findings from modern pharmacological studies have contributed the majority of its bioactivities to berberine, the isoquinoline alkaloids component of the herb, and a number of experiments testing the antidiabetic effects of berberine have been initiated. Therefore, we conducted a review of the current evidence profile of the antihyperglycemic effects of Rhizoma Coptidis as well as its main component berberine and the possible mechanism of actions, in order to summarize research evidence in this area and identify future research directions. Diabetes mellitus refers to a metabolic disorder of multiple etiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from disturbed insulin secretion, insulin action, or both . There aAccording to the WHO diabetes fact sheets, 347 million people in the world have diabetes [ Coptis chinensis Franch, Coptis deltoidea C. Y. Cheng et Hsiao or Coptis teeta Wall. As first recorded in Shennong's Materia Medica in the eastern Han dynasty (25–220 AD), the herbal medicine has been prescribed by Chinese herbalists for a variety of illnesses and conditions for more than 2000 years. According to traditional beliefs, Rhizoma Coptidis is cold in nature and bitter in taste and enters the heart, spleen, stomach, liver, gallbladder, and large intestine meridians. It has the function of clearing heat, drying dampness, and purging fire toxins [Rhizoma Coptidis (Huang Lian) is the dried rhizome ofdynasty 2–220 AD, dynasty 2–220 AD,  Miscellaneous Records of Famous Physicians, compiled around 510 AD, Rhizoma Coptidis was first described as an agent for the wasting syndrome [ Newly Revised Materia Medica compiled during the Tang dynasty (618–907 AD), it was noted that “Huang lian grown in west China is bulky, bitter and good for treating the wasting syndrome” [ Formulas from Benevolent Sages found that Rhizoma Coptidis was among the top ten most frequently used medicinal herbs in formulas designated for the wasting syndrome [ Puji Fang Prescriptions for Universal Relief, completed around 1406 AD in the Ming dynasty, contained Rhizoma Coptidis [ Compendium of Materia Medica, published in the same dynasty, it recorded that “Huang lian, steamed with wine, is used for treating emaciation, thirst and excessive excretion of urine” [As early as the Wei and Jin dynasties in the Chinese history 220–589 AD), Rhizoma Coptidis was described as a therapeutic agent for patients suffering from the wasting syndrome. In dynasties that followed, numerous records had been kept in a series of herbal classics of the medicinal use of Rhizoma Coptidis for the wasting syndrome, either alone or combined with other herbs in a formula. This proved the prevalence of the use of Rhizoma Coptidis since ancient times and formed the empirical evidence base for its antidiabetic effects. For example, in thesyndrome . In the ty 618–90 AD, it w9 AD, RhiModern pharmacological research identified the major chemical constituents of Rhizoma Coptidis to be alkaloids including berberine, coptisine, worenine, palmatine, jatrorrhizine, and epiberberine , 11. AmoIn view of this, a comprehensive review of the relevant literatures on the antihyperglycemic effects of Rhizoma Coptidis (or berberine) and the mechanism of actions was conducted. The aim of this study is to give a summary of the existing evidence.In January 2013 two reviewers (Hui Wang and Wei Mu) searched the following Chinese-language electronic databases: Chinese Biomedical Literature Database , Chinese Journal Full-Text Database , Weipu Journal Database , and Wanfang Data (1990–2013), and three English-language databases: PubMed, EMBASE (1989–2013), and the Cochrane Library. The search terms included “huang lian,” “Coptis,” “berberine,” “hypoglycemic,” “diabetes,” and “xiaoke” in English or Chinese. These terms were searched as free text in the title or the abstract.Two reviewers Hui Wang and Wei Mu screened citations identified from electronic searches and retrieved the full texts of relevant studies. Then they summarized records in ancient medical books and the findings of systematic reviews and pharmacological studies on the antihyperglycemic effects of berberine, Rhizoma Coptidis extracts, and other Rhizoma Coptidis-containing agents.Two systematic reviews on the antihyperglycemic effects of berberine were identified. In the first study authored by Dong et al. , a totalDrawn upon the above research findings, the isoquinoline-type alkaloid berberine has beneficial effects for blood glucose control in the treatment of type 2 diabetic patients and exhibits efficacy comparable with that of conventional oral hypoglycaemics. No significant statistical difference in the incidence of adverse events was observed between groups. However, the evidence is inconclusive because clinical trials included in the two systematic reviews were of low methodological quality. Therefore, the antihyperglycemic effects of berberine warrant further examination and more rigorously controlled, methodologically sound, and scientifically designed RCTs need to be conducted.A number of animal experiments investigating the antihyperglycemic effects of Rhizoma Coptidis, berberine, or herbal prescriptions in which Rhizoma Coptidis plays a dominant role were identified through electronic searches and careful screening. A summary of the experimental models used and the antidiabetic mechanism of berberine observed in these studies were presented in β-cells, enhancement of insulin sensitivity, suppression of gluconeogenesis in the liver, promotion of glucose disposal in the periphery, and inhibition of aldose reductase [Findings from previous researches showed that the insulin-stimulated glucose uptake by target tissues such as adipocytes and skeletal muscles involved a series of signaling transduction cascades starting from insulin receptor (InsR) via insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI-3K) and leading to the translocation of glucose transporter (GLUT4) . From theductase –61. The eductase –76.In addition to the above findings, results from a few studies –89 invesAccording to traditional beliefs, Chinese herbal remedy helps recover inner peace and tranquility in the human body with its multiple active constituents taking effects through various mechanisms and pathways. Therefore, the use of Chinese herbal medicines for diabetes treatment or for the prevention of diabetes complications might be generally considered good for the patients' general well-being, apart from their effectiveness and safety.The existing evidence profile of the antihyperglycemic effects of Rhizoma Coptidis includes both textual records in ancient herbal classics and findings from animal experiments and systematic reviews of RCTs. Modern research uniformly focuses on berberine, whereas the pharmacological actions of other active ingredients of Rhizoma Coptidis, of single herb remedy, and of Rhizoma Coptidis-dominant couplet medicines and Rhizoma Coptidis-containing patent drug still remain to be investigated.As was summarized in this review, the antihyperglycemic effects of Rhizoma Coptidis may rely upon drug actions on a variety of targets via multiple pathways. Many animal experiments , 78–89 hFurthermore, there were other issues to consider before Rhizoma Coptidis can be put into extensive clinical use. For instance, the most appropriate drug form and dosage, dose-effect relationship, and drug-drug interactions should be made clear through a series of pharmacological experiments and long-term clinical observations. Also, whether the antihyperglycemic effect is best exerted synergically in a prescription or independently as an active component remains to be investigated. Besides, the possible antidiabetic effects of the other chemical ingredients of Rhizoma Coptidis and the interactions among its various components, as well as the long-term health benefits of its use in diabetic patients, are all problems that need to be addressed in future research.


Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified) classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for the underlying cause. Increased availability of medical options has expanded the choice for women and many will no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, as well as address the management of AUB in order to achieve improved quality of life.Abnormal uterine bleeding (AUB) is a common and debilitating condition with high direct and indirect costs. AUB frequently co-exists with fibroids, but the relationship between the two remains incompletely understood and in many women the identification of fibroids may be incidental to a menstrual bleeding complaint. A structured approach for establishing the cause using the Fédération International de Gynécologie et d'Obstétrique (FIGO) PALM-COEIN ( •The FIGO ‘PALM COEIN’ classification of AUB is considered in this review•Mechanisms by which fibroids contribute to AUB are elucidated.•A structured approach to management of the patient with fibroids and AUB is proposed. Abnormal uterine bleeding (AUB) is a significant clinical entity. AUB and its sub group, heavy menstrual bleeding (HMB), are common conditions affecting 14–25% of women of reproductive age Fibroids (leiomyoma) represent the most common tumour of women; by the age of 50, almost 70% of white women and >80% of black women will have developed at least one fibroid As women increasingly defer pregnancy, fertility preservation is critical and newer medical options offer genuine effective relief for both AUB and other symptoms associated with fibroids. This review addresses the causes of AUB and approach to assessment and general principles of management of the pre-menopausal woman with fibroids.AUB was redefined by Fédération International de Gynécologie et d'Obstétrique (FIGO) in 2009 by the FIGO Menstrual Disorders Group (FMDG) Chronic AUB was defined as ‘bleeding from the uterine corpus that is abnormal in volume, regularity and/or timing that has been present for the majority of the last 6 months’ With regard to volume, however, both the Royal College of Obstetricians and Gynaecologists (RCOG) and American College of Obstetricians and Gynecologists (ACOG) prefer the patient-centred definition of HMB, ‘excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life’ Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified Once bleeding is defined as being abnormal, the acronym PALM-COEIN is now being increasingly used for categorising causes: Depending on the site, leiomyoma (fibroids) are further subdivided into submucosal (SM) and other (O) and then into nine tertiary categories adapted from the Wamsteker classification The relationship between AUB and fibroids remains incompletely understood. The obvious paradox is that many women have fibroids but also have entirely normal bleeding patterns. Fibroids are also highly prevalent in women presenting with AUB.Previous postulated theories include an increased endometrial surface area and the presence of fragile and engorged vasculature in the perimyoma environment Matrix metalloproteinase (MMP) 2 and 11 levels are increased in fibroids (with MMP 1 and 3 unchanged) There is alteration of plasminogen modulators and this may impact on endometrial haemostasis and repair In women with fibroids, alterations in the blood plasma levels of circulating interleukin (IL)-13, IL-17 and IL-10 have been reported With regard to the location of fibroids, it was previously thought that those women with SM fibroids, particularly with those distorting the cavity, were more likely to present with HMB The PALM-COEIN classification system accepts that women may have more than one underlying aetiology and also that often in the case of structural abnormalities, many women may in fact be asymptomatic.Endometrial polyps are epithelial proliferations arising from the endometrial stroma and glands. The majority are asymptomatic. The contribution of polyps to AUB varies widely ranging from 3.7% to 65% The relationship between adenomyosis and AUB remains unclear Endometrial cancer is the most common gynaecological malignancy in the western world. Historically, endometrial cancer has rarely occurred in premenopausal women; however, with increasing obesity and rising prevalence of the metabolic syndrome, the endocrine-driven subset of endometrial malignancy has markedly increased in frequency. Between 1992–1994 and 2009–2011, the European age-standardised rates of uterine cancer in the UK have increased by 48% The diagnosis of cervical cancer should be considered, particularly with persistent intermenstrual bleeding, and rarely ovarian cancer may present with AUB.Uterine sarcoma have been reported as rare  Interestingly, the previously held view was that a rapidly enlarging uterus would raise the suspicion for malignancy. This is now no longer held to be true as benign fibroids can grow rapidly and sarcomas grow slowly If malignancy or premalignancy is found along with AUB classification, the pathology should be described and staged utilising the appropriate WHO/FIGO systems Coagulopathies are reported to affect 13% If 1, 2 or 3 see  is ascerAnticoagulant and antiplatelet therapy hitherto has been considered as a part of ‘AUB-C’ (rather than AUB-I). Compression caused by a large fibroid uterus may lead to venous thromboembolism (VTE). Bleeding previously deemed as AUB-L may be exacerbated by subsequent anticoagulation and presents additional management challenges.Anovulatory cycles may contribute to AUB by unopposed oestrogen effects on the endometrium causing marked proliferation and thickening resulting in HMB along with an altered frequency of menstruation. This is observed at the extremes of reproductive age; however, impact on the HPO axis along with endocrinopathies is also present. The latter include polycystic ovarian syndrome (PCOS), hyperprolactinaemia, hypothyroidism as well as factors such as obesity, anorexia, weight loss, mental stress and extreme exercise. Typically, women in this group have menstrual cycles that fall out with 38 days or have a variation of >21 days. Drugs that affect dopamine levels, with their attendant effects on the HPO axis, also currently fall under this category rather than AUB-I. In women with fibroids, the co-existing ovulatory dysfunction may exacerbate menstrual loss.The FIGO AUB classification system is a dynamic system with feedback and contemporary debate informing future revisions AUB that occurs in the context of a structurally normal uterus with regular menstrual cycles without evidence of coagulopathy is likely to have an underlying endometrial cause. Endometrial function in the context of menstruation and its disorders is still not fully understood and remains an area of active scientific enquiry, particularly the complexities of the sequence of events triggered by progesterone withdrawal (due to demise of the corpus luteum in the absence of pregnancy). Hypoxia, inflammation, haemostasis and angiogenesis all play crucial roles in the shedding and subsequent scarless repair of the functional upper layer of the endometrium. Perturbation of local glucocorticoid metabolism, aberrant prostaglandin synthesis and excessive plasminogen (resulting in premature clot lysis) have all been implicated in AUB AUB-E may be implicated in many women with AUB, but a lack of clinically available specific tests or biomarkers means that practical testing for such disorders is not yet feasible. As such, diagnosis depends on careful history taking and exclusion of other contributors. The high prevalence of potential endometrial dysfunction means that it is highly likely that those with AUB-L will often have an element of AUB-E contributing to increased/aberrant menstrual blood loss with its attendant implication for therapy.Iatrogenic causes of AUB include exogenous therapy than may lead to unscheduled endometrial bleeding. This is typically associated with continuous oestrogen or progestin therapy (systemic or intrauterine delivery routes) or those interventions that act on ovarian steroid release such as gonadotropin-releasing hormone (GnRH) agonists and aromatase inhibitors. Selective oestrogen receptor modulators (SERMs) and more rarely selective progesterone receptor modulators (SPRMs) may cause AUB through direct action on the endometrium.The use of an intrauterine device (IUD) may cause a low-grade endometritis which may also contribute to AUB.It is inevitable that there will be pathologies that are either rare or poorly defined that do not easily fit within the categories described earlier. Examples include arteriovenous malformations, endometrial pseudoaneurysms, myometrial hypertrophy and chronic endometritis (not precipitated by an IUD). All of these can co-exist with AUB-L.The planned regular review of the FIGO PALM-COEIN classification system every 3–5 years through FIGO As described earlier, all of the other causes of AUB may co-exist with fibroids. As such, it is crucial when a patient with known or suspected fibroids presents with AUB, she is appropriately assessed for the presence of other aetiologies. Misdiagnosis will have an impact on treatment options and efficacy, and in the event of undiagnosed coagulopathy, render surgical intervention disproportionately hazardous.As part of structured history, factors such as co-morbidities, polypharmacy, body mass index (BMI), previous surgery and most crucially fertility desire and impact of pressure symptoms must be assessed as these significantly affect treatment approach. A structured approach is shown in An accurate menstrual history and associated symptoms will identify a likely AUB-O cause. As described earlier, a structured screen for coagulopathies will identify 90% of those women with disorders of systemic haemostasis . HistoryCombined history and examination will suggest possible AUB-P/-A/-L and should be confirmed with subsequent imaging. TV-USS remains the most acceptable and validated first-line investigation. The increasing use of saline infusion ultrasonography (SIS) and selected hysteroscopy will improve sensitivity and specificity for diagnosis of polyps and SM fibroids MRI plays a role in selected patients with AUB and fibroids, also in the assessment of suitability for uterine artery embolisation (UAE). As previously discussed, it is relatively poor at providing reassurance of the absence of sarcomatous change.In the UK, NICE recommend endometrial sampling in women with persistent inter-menstrual bleeding or aged ≥45 years with treatment failure Management of AUB-L should address fertility desire, impact of pressure symptoms, co-morbidities, and any other AUB contributors. Treatment should be individualised. No one-size-fits-all approaches are available with regard to initial and subsequent treatment options, and there is a relative paucity of large robust clinical trials providing head-to-head data rather to placebo.In those with other underlying AUB causes co-existing with fibroids, targeted treatment of these may ameliorate bleeding, and in the absence of pressure symptoms or sub-mucosal myoma-related infertility, all the treatments may be required. Specific treatments for other causes are shown in Otherwise, treatment should be tailored depending on the impact of related symptoms, fertility requirements and cavity distortion . It shouIn AUB, in the absence of pressure symptoms, medical treatment may be more appropriate, particularly when fertility preservation is required. Tranexamic acid and NSAIDs (e.g. mefenamic acid) remain the only fully non-contraceptive medical options The current Cochrane review for the SPRMs is limited to mifepristone With regard to interventional radiological  and surgical options, the anticipated outputs of the FEMME study •A structured approach for using the PALM-COEIN framework should be developed to ensure that important contributors apart from fibroids are not missed.•In particular, coagulopathies should be verbally screened for in all patients presenting with AUB, given their high prevalence in this population and implications for management.•In view of the rapid increase in endometrial cancer, clinical judgment regarding endometrial sampling should be considered in younger women with AUB with risk factors for EIN and malignancy.•Treatment should be individualised encompassing impact of pressure symptoms, desire for retention of fertility, contraceptive needs and impact of symptoms on quality of life.•Imaging for fibroids, in particular, modality for diagnosis of adenomyosis and for discriminating between fibroids and leiomyosarcoma.•Increased evidence base for long-term medical treatments for management of AUB in the context of fibroids, with particular emphasis on quality of life.•Improved evidence for interventional treatments for AUB in the context of fibroids.AUB is a common and debilitating condition with high direct and indirect costs. Symptoms of AUB frequently co-exist with fibroids, but the relationship between AUB and fibroids remains incompletely understood. In many women, fibroids may be an incidental innocent bystander in the underlying aetiology of a menstrual bleeding complaint. A structured approach to establishing the cause using the FIGO PALM-COEIN classification system will facilitate accurate diagnosis and inform treatment options. The classification system, however, still lacks effective biomarkers for ‘AUB-E’. Office hysteroscopy and the increasingly sophisticated imaging will assist provision of robust evidence for the underlying cause. The increased availability of medical options has expanded the choice for women. Many will no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, as well as address the management of their AUB in order to achieve improved quality of life.LW has no conflict of interest. HODC has clinical research support for laboratory consumables and staff from Bayer Pharma AG and provides consultancy advice  for Bayer Pharma AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.


Uteroplacental tissue plays a key role in substance exchanges between maternal and fetal circulation, and, therefore, in the growth and development of fetuses. In this study, proteomics and western blotting were applied to investigate the changes of proteome in the placenta and endometrium of normal and intrauterine growth restriction (IUGR) porcine fetuses during mid to late pregnancy . Our results showed that proteins participating in cell structure, energy metabolism, stress response, cell turnover, as well as transport and metabolism of nutrients were differentially expressed in placenta and endometrium between normal and IUGR fetuses. Analysis of functions of these proteins suggests reductions in ATP production and nutrients transport, increases in oxidative stress and apoptosis, and impairment of cell metabolism in IUGR fetuses. Collectively, our findings aid in understanding of the mechanisms responsible for uteroplacental dysfunction in IUGR fetus, and are expected to provide new strategies to reduce fetal growth restriction in pigs and other mammals. Intrauterine growth restriction (IUGR) commonly occurs in both human and livestock species  and impaPlacental transport of nutrients is a key determinant of fetal intrauterine growth . The endThis experiment was approved by China Agricultural University Animal Care and Use Committee (No. 20080106–1). All surgery was performed under anesthesia with halothane, and all efforts were made to minimize discomfort.-1) formulated to meet or exceed nutrient requirements according to the National Research Council (2012). At d 60, 90 and 110 of gestation, 8 gilts were randomly selected and exsanguinated after induction of anesthesia with halothane 17]. PARKes (ROS) . The incHsps are molecular chaperones that control protein folding and protect cells and tissues from being damaged in adverse environmental conditions. Previous studies have indicated that Hsp70s and Hsp90s are strongly up-regulated by heat stress, oxidative stress, and toxic chemicals  and 21]21]. At tC3 plays a central role in activation of the complement system , contribEfficiency of substrate transport in uteroplacental tissues is crucial for fetal intrauterine growth by supplying nutrients from mother to fetus and by eliminating fetal metabolic wastes . PreviouAnother important finding of this study is that abundances of proteins related to substrate transport, including ALB, AFP and APOA1, were down regulated in IUGR fetuses. ALB acts as a carrier of various substances, including lipid soluble molecules and certain minerals , in the blood circulation. ALB present in placental and endometrial tissues is derived from fetal and maternal circulation, respectively. AFP, produced by the yolk sac and the liver during fetal development, is considered to be the fetal form of ALB. The decreased levels of ALB and AFB in uteroplacental tissues may reduce substance exchanges between maternal and fetal circulation, contributing to the impairment of nutrient uptake and waste elimination in IUGR fetuses. APOA1, a major component of high-density lipoproteins, mainly participates in reverse transport of cholesterol from tissues back to the liver for excretion and plays an important role in cholesterol efflux from tissues. The decreased expression of APOA1 probably can result in higher levels of cholesterol in the IUGR placenta, which can result in more extensive stress in IUGR fetuses.Blood flow is a major determinant of uteoplacental function and fetal growth. Angiogenesis in the placental vasculature during pregnancy is necessary for increasing uteroplacental blood flow and, therefore, the supply of nutrients from maternal to fetal circulation . SeveralThe altered expression of several proteins related to amino acid metabolism in the IUGR endometrium could further aid in explanation of our previous findings of decreased concentrations of amino acids in the IUGR umbilical cord . ASS1 isTo fulfill the metabolic demands of the growing fetuses, placenta and endometrium undergo dramatic morphological and histological changes during pregnancy, including active cell proliferation and extensive cell differentiation . StresseProgrammed cell death is a fundamental process for maintaining homeostasis in multi-cellular organisms and involves highly regulated processes, including pro-apoptotic and anti-apoptotic signal pathways. CTSZ is a lysosomal cysteine protease to hydrolyze proteins and have a vital role in mammalian cellular apoptosis, while CTSB is thought to play a key role in protecting cells against leaking of proteases from lysosomes during apoptosis. Enhanced expression of proteinase CTSZ, may imply higher apoptosis levels in the IUGR placenta, whereas enhanced expression of protease inhibitor CSTB may be related to protective reactions against apoptosis. In the endometrium, we found that 3 members of serpins , all of which are capable of inhibiting proteases to control proteolytic cascades and mediate apoptosis processes as caspase inhibitors by preventing apoptosis in mammalian cells , 43, werFourteen proteins related to cell morphology and twelve proteins related to cell motility were differentially expressed in placentae and endometria between IUGR and NBW fetuses. Actin is a globular multi-functional protein that forms microfilaments of cytoskeleton and is essential for maintenance of cell shape and mobility. Several isoforms of actin were altered in IUGR, including ACTB (down-regulated in the IUGR placenta and endometrium); ACTN4, Macf1 (down-regulated in the IUGR endometrium); and ACTG (up-regulated in the IUGR endometrium). Besides, EZR, MRLC2, MLC-2A, MSN, GEL, and CCT2, which interact with actin to regulate cellular morphology, were differentially expressed between IUGR and NBW placentae. Similar results were obtained for ARP3 in the endometrium. In addition, both TUBA1B and TUBA1C, which are cytoskeleton microtubule elements, were differentially expressed in the placenta and endometrium. Furthermore, KRT7 and KRT8 were up regulated in the IUGR placenta, whereas CK19 was increased at D90, but deceased at D110 of gestation. Altered expression of these proteins related to actin, tublin and keratin could result in an abnormal change of cytoskeleton in the placenta and endometrium of IUGR fetuses.Annexins provide a membrane scaffold and link to fibrinolysis, coagulation, inflammation and apoptosis. Reductions in two members of annexins (ANX4 and ANX8) may result in placental structural abnormality and dysfunction in IUGR fetuses. This novel finding provides another line of evidence for impaired utero-placental development in the IUGR conceptus.All the nutrients provided to fetuses during pregnancy are transported from maternal circulation through uteroplacenta tissue. Therefore, sufficient development of both placenta and endometrium  is very important for substance exchange between maternal and fetal circulation, and plays a key role in fetal growth and development. In order to fulfil substance transport between mother and fetus, the utero-placenta needs (1) energy and transporters; (2) an established vascular system. Results of the current work reveal that expression of several proteins related to energy metabolism, transportation, and vasculargenesis was reduced in IUGR placenta and endometrium, which could lead to inadequate energy provision and insufficient nutrient transport. Such utero-placental dysfunction could be a factor contributing to IUGR. Additionally, based on our proteomics data, we suggest that increased oxidative stress and apoptosis in IUGR placenta and endometrium, which can compromise utero-placental function, is another factor for the development of IUGR. Collectively, these findings have important implications for both human health and animal production to reduce the occurrence of IUGR fetuses.S1 File(PDF)Click here for additional data file.S2 File(DOCX)Click here for additional data file.


EHP, investigators describe results from DEMOCOPHES, the demonstration project that proved the feasibility of a harmonized approach across 17 EU nations.The Consortium to Perform Human Biomonitoring on a European Scale (COPHES) was launched to collect population-representative data on environmental exposures for the European Union (EU) as a whole. In this issue of This type of human biomonitoring can be used to track exposure trends and potential impacts of environmental regulations. For example, ongoing biomonitoring by the German Environmental Survey (GerES) suggests that a 1992 recommendation against the use of amalgam fillings in children and women of child-bearing age may have contributed to decreasing urinary mercury levels in that country’s population.For the current study, researchers analyzed hair and urine samples from 1,844 mother–child pairs recruited from 17 countries. Half the participants lived in rural areas, and half lived in urban areas. All were healthy with no known metabolic disturbances. Samples yielded information on exposures to mercury, cadmium, nicotine, and several phthalates found in personal care products and food packaging. To help ensure validity and transferability of results, researchers developed harmonized protocols and quality controls for chemical and data analyses.As with the U.S. National Health and Nutrition Examination Survey, exposures were associated with known lifestyle and diet predictors, and biomarkers for children closely matched those of their mothers. “This overall pattern provides confidence that the effort to validly collect and analyze these samples and companion exposure information was successful,” says Lesa Aylward, a toxicologist at Summit Toxicology LLP, who was not involved with the study.The vast majority of biomarker concentrations were below health-based guidance values set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the German Human Biomonitoring Commission, as well as published values from independent scientists. Eastern, southern, and (to a lesser extent) western European countries clustered together based on similar biomarker patterns, differences that Schoeters says are probably related to lifestyle factors, environmental conditions, and possibly regulation.,,Levels of metabolites of di(2-ethylhexyl) phthalate (DEHP) indicated ubiquitous exposure to this compound even though its use is restricted in the EU.n-butyl phthalate and DEHP metabolites, but these differences were less dramatic.For monoisobutyl phthalate, average European values in both mothers and children were 3–4 times higher than those observed in the United States. Compared with the United States, Europeans on average had lower biomarker concentrations of monobenzyl phthalate and monoethyl phthalate, and higher concentrations of mono-Hair mercury concentrations increased with reported consumption of fish and shellfish. Concentrations were 35% higher for children and 30% for mothers living in urban areas, the only result in this study that showed differences between residents of urban and rural areas. Hair mercury was highest among children living in Spain and Portugal, whose average concentrations were 6 and 7 times higher, respectively, than the European average. The proportion of participants whose mercury levels exceeded the JECFA/WHO provisional threshold value differed considerably by country, with no participants exceeding the threshold in most northern and central European countries and up to 33% of mothers exceeding the threshold in countries with high fish consumption.Concentrations of cotinine (a metabolite of nicotine) varied widely by country, with levels lowest in countries with the strongest anti-smoking legislation.“The study is a step towards European reference values,” says coauthor Ludwine Casteleyn, a researcher at the University of Leuven Center for Human Genetics in Belgium. “Currently European countries, together with the European Commission, are exploring the possibilities for a more sustainable system that should be able to support environmental health policy, at a European and a national level.”


Global energy demand is increasing as greenhouse gas driven climate change progresses, making renewable energy sources critical to future sustainable power provision. Land-based wind and solar electricity generation technologies are rapidly expanding, yet our understanding of their operational effects on biological carbon cycling in hosting ecosystems is limited. Wind turbines and photovoltaic panels can significantly change local ground-level climate by a magnitude that could affect the fundamental plant–soil processes that govern carbon dynamics. We believe that understanding the possible effects of changes in ground-level microclimates on these phenomena is crucial to reducing uncertainty of the true renewable energy carbon cost and to maximize beneficial effects. In this Opinions article, we examine the potential for the microclimatic effects of these land-based renewable energy sources to alter plant–soil carbon cycling, hypothesize likely effects and identify critical knowledge gaps for future carbon research. From 20ed EPIA, . Consequed EPIA, .et al., et al., et al., et al., et al., et al., While there is some understanding of the environmental impacts of LBRs  and nitrous oxide (N2O)] concentration profiles in the near-surface boundary layer. In addition, large-scale modelling predicts that rainfall could be enhanced by wind farms due to reduced movement of drier air  and exchange between the land surface and atmosphere Fig. . The ins2, CH4 and N2O and productivity  to C-rich environments (e.g. blanket peatlands of Scotland), in heavily managed  and relatively unmanaged systems (e.g. deserts). Soil is recognized as the largest single store of terrestrial organic C, containing more C than vegetation and the atmosphere combined Swift, . BiologiIn the following sections we summarize the potential effects of microclimatic change caused by LBR on key processes in the terrestrial C cycle and hypothesize the likely implications on productivity, soil C and GHG emissions. We first discuss direct effects, changes in temperature, soil moisture and radiation, on plant–soil C cycling. Then, we discuss indirect effects mediated through changes in plant and microbial communities and describe some of the likely interactive effects.2 and CH4 , determines the amount of energy available for photosynthesis . Atmospheric CO2 concentrations affect plant productivity and decomposition processes, with higher CO2 concentrations commonly stimulating higher rates  and local climate, as well as the type and intensity of management .et al., 4 fluxes . The potential to increase C benefits from ground-level changes in microclimate needs to be examined, and placed in the broader context of the full C costs of electricity produced by LBRs; we argue that there is much scope to maximize beneficial effects.in situ; (iii) controlled environment studies examining the interactive effects of diurnal, seasonal and annual microclimatic controls on plant–soil C cycling; and (iv) modelling that uses mechanistic understanding from field and laboratory studies to upscale, and forecast effects of LBR-induced microclimates on C cycling and greenhouse gas emissions across the globe. Given the dominance of temperature on plant–soil C cycling, it is crucial that new experiments and models examine LBR effects on this parameter. However, the effects of other abiotic and biotic factors that are affected by LBR, and their interactions, also need to be resolved, across the full range of hosting systems.To determine the long-term operational impacts of LBR on plant and soil C, and allow generalization and prediction of effects across the globe, we strongly advocate the investigation of LBR-induced microclimatic effects under different atmospheric conditions, across a range of ecosystems occurring in different climatic zones. Furthermore, understanding and modelling needs to be developed to account for the range of wind farm and solar park designs and consequently designs optimized for energy production and plant–soil C cycling. Therefore, we call for an increase in research effort in this emerging field and propose specific research priorities should be (i) field assessment of the effects of LBR on the local climate, especially solar parks for which there is no evidence, with potential for remote sensing to provide data at a larger scale; (ii) field experiments in carbon relevant hosting ecosystems to examine the effects of LBR-induced microclimates on plant–soil C cycling Land use change for LBR is global, widespread and predicted to increase. Understanding of microclimatic effects is growing, but currently incomplete, and subsequent effects on plant–soil C cycling, GHG emissions and soil C stocks are unknown. We urge the scientific community to embrace this research area and work across disciplines, including plant–soil ecology, terrestrial biogeochemistry and atmospheric science, to ensure we are on the path to truly sustainable energy provision.


The vast majority of eukaryotic organisms reproduce sexually, yet the nature of the sexual system and the mechanism of sex determination often vary remarkably, even among closely related species. Some species of animals and plants change sex across their lifespan, some contain hermaphrodites as well as males and females, some determine sex with highly differentiated chromosomes, while others determine sex according to their environment. Testing evolutionary hypotheses regarding the causes and consequences of this diversity requires interspecific data placed in a phylogenetic context. Such comparative studies have been hampered by the lack of accessible data listing sexual systems and sex determination mechanisms across the eukaryotic tree of life. Here, we describe a database developed to facilitate access to sexual system and sex chromosome information, with data on sexual systems from 11,038 plant, 705 fish, 173 amphibian, 593 non-avian reptilian, 195 avian, 479 mammalian, and 11,556 invertebrate species. These data are suitable for in depth comparative analyses of the factors influencing the evolution of sexual systems as well as analyses of the impact of sexual system on, e.g., species ranges, invasiveness, or extinction risk.Sexual reproduction is a nearly universal feature of eukaryotes, yet a remarkable diversity of sexual systems and sex determining (SD) mechanisms exists. The sexual system of a lineage has important evolutionary and ecological implications, affecting the levels of genetic variation maintained, the degree of inbreeding, the rate of adaptation to novel environments, as well as having longer-term consequences for the formation of new species and the risk of extinction. However, we know little about why and how different sexual systems have evolved. In order to remedy this knowledge gap, the Tree of Sex consortium, a working group of the National Evolutionary Synthesis Center (NESCent), has compiled existing information on sexual systems and sex determination mechanisms, focusing particularly on groups of plants and animals exhibiting variation. In addition to sexual system and mechanism of sex determination , we have endeavored to make our database comprehensive, representing nearly all known data about the sexual traits compiled. For plants, the database includes 382 genera , although we concentrated our data collection on 77 clades (primarily genera), which were known to be variable for sexual system. For these 77 clades, the database has high coverage of the available information, enabling users to address questions about the impact of sexual system on evolutionary and ecological processes. Many genera of plants and invertebrates, however, remain poorly covered in the current database. For vertebrates, our coverage has focused on species with information about the mechanism of sex determination. Do hermaphrodites diversify more rapidly than species with separate sexes (dioecy)? Information in the database, coupled with phylogenetic information, is being used to determine the impact of dioecy on speciation and extinction rates across multiple genera of plants.Does environmental sex determination place species at heightened risk of extinction, especially in the face of a changing climate? The database allows us to measure the impact of environmental versus genetic sex determination on extinction risk in both turtles and squamates (lizards plus snakes) and to compare extinction risks among groups with different climatic histories.Are some sexual systems more transient than others? By mapping changes in sexual systems to the tree of life, we are assessing whether some transitions are more likely to happen than others .Does the mechanism of sex determination affect genomic evolution? The data are being used to assess which taxa are most likely to undergo fusions between autosomes and sex chromosomes to test ideas about the drivers of fusion events.What factors influence loss of Y chromosomes? In some taxa, Y chromosomes are readily lost, while in others they persist; we have explored the tempo and mode of Y chromosome loss1.Does sociality affect the evolution of chromosome number? Eusocial lifestyles may create selection pressure for increased recombination and indirectly increase the number of chromosomes; we are performing a comparative analysis to test this hypothesis.The Tree of Sex database facilitates comparative analyses exploring hypotheses about the evolutionary factors driving transitions among sexual systems. Examples of the type of questions that are being addressed using the database are: By synthesizing existing data on sexual systems, the database will allow biologists to identify the evolutionary and ecological processes that underlie the remarkable diversity in sexual systems across the tree of eukaryotic life. The database will also facilitate rapid identification of suitable taxonomic groups that contain variation in traits of interest for future studies of sexual systems and sex determination.Sexual system, karyotype, genome size, ploidy, and life history data were collated from taxonomic accounts, books on flora and fauna, online scientific databases, and the primary scientific literature (sources from the literature were preferred when available). For each species and trait, state values and data sources were entered in the database. In cases where within-species variation in a trait was documented, variants were included in the database, except where noted as ‘rare.’ A notes field in the database for each species allows additional information, such as taxonomic uncertainty or rare variants, to be listed. We avoided using generic information about higher-level taxa  to inform the trait states of a species, unless the source explicitly listed the species when describing the characteristics of the higher-level taxon.2–112–112–112–112–112–112–112–112–112–11, online databases12, review papers14, and primary research papers. If different values were identified for a particular trait in a given species, multiple entries with the different values are provided for that species.Data for fish, non-avian reptiles, amphibians, mammals, and birds were compiled from literature searches. Birds appear to be uniform with respect to their sex determination system and were only included if they had specific karyotypic information to distinguish between ZW or complex ZW  systems. Sources included books with karyotype information15). For each group in our database we performed literature searches using order and family names in conjunction with the terms: karyotype, cytotaxonomy, cytogenetic, parthenogenesis, haplodiploidy, polyploidy, sex chromosomes and chromosome number. To the extent possible, we reconciled historical karyotype data with currently accepted taxonomy.We performed an extensive literature search using Google Scholar and Web of Science and compiled ~12,000 entries across all orders of hexapods as well as mites. The invertebrate data are drawn from approximately 453 published records including primary research papers, review papers and previous compilations in books. We also incorporated additional data from existing databases  had at least 15 species, (b) were thought to have at least three dioecious species and three non-dioecious species according to Renner and Ricklefs16, and (c) have sufficient sequence information in GenBank for phylogenetic analyses based on NCBI taxonomy19. Species names were checked against The Plant List (Version 1.1)20. For each of these clades, we gathered data on sexual system, life history, growth form, woodiness and chromosome numbers from four main sources: (1) searching through monographs and local floras , (2) detailed search of the primary literature (454 papers), (3) additional online sources , and (4) consulting with experts with knowledge of the group in question. Finally, we included the extensive information on reproductive traits in parasitic plants from Bellot and Renner22 and on woodiness from Zanne et al.24The dataset focused on 77 angiosperm clades (primarily at the genus level) exhibiting inter-specific variation in sexual systems to allow species-level analysis of sexual diversity. Genera were chosen from the list containing species with separate sexes compiled by Renner and RicklefsThe database files  in csv format were uploaded to Dryad (Data Citation 1). Separate files are available for thevertebrate, invertebrate, and plant data. Additional notes about the data and pers. comm. filesare in this Dryad record as a zip file. Taxonomic information is provided to ensure unique species identity of each record .25within the Tree of Sex project (Data Citation 2). TraitDBis a searchable MySQL-based database, custom built by NESCent, which allows authorizedadministrators to upload additional data and delete incorrect records. Contributors ofadditional data should go to treeofsex.org for file configuration information.The trait data were also uploaded to TraitDBAutomated data entries were manually curated to ensure validity. Sub-samples of the records were checked by a different author from the data collector. For the invertebrate and plant data sets, custom scripts were written to identify potentially inconsistent entries . All records that appeared to be inconsistent were checked against the original sources to confirm that the entries represent either true trait variation or variation in expert opinion. The on-line database may also be expanded and corrected, as new information becomes available.26 for use in comparative analyses, e.g., using ape27, diversitree28, GraPhlAn29  and from TraitDB. These data may be imported into RHow to cite this article: The Tree of Sex Consortium. Tree of Sex: A database of sexual systems. Sci. Data 1:140015 doi: 10.1038/sdata.2014.15 (2014).


Effective interventions to promote maternal health and address obstetric complications exist, however 800 women die every day during pregnancy and childbirth from largely preventable causes and more than 90 % of these deaths occur in low and middle income countries (LMIC). In 2014, the Maternal Health Task Force consulted 26 global maternal health researchers to identify persistent and critical knowledge gaps to be filled to reduce maternal morbidity and mortality and improve maternal health. The vision of maternal health articulated was comprehensive and priorities for knowledge generation encompassed improving the availability, accessibility, acceptability, and quality of institutional labor and delivery services and other effective interventions, such as contraception and safe abortion services. Respondents emphasized the need for health systems research to identify models that can deliver what is known to be effective to prevent and treat the main causes of maternal death at scale in different contexts and to sustain coverage and quality over time. Researchers also emphasized the development of tools to measure quality of care and promote ongoing quality improvement at the facility, district, and national level. Knowledge generation to improve distribution and retention of healthcare workers, facilitate task shifting, develop and evaluate training models to improve “hands-on” skills and promote evidence-based practice, and increase managerial capacity at different levels of the health system were also prioritized. Interviewees noted that attitudes, behavior, and power relationships between health professionals and within institutions must be transformed to achieve coverage of high-quality maternal health services in LMIC. The increasing burden of non-communicable diseases, urbanization, and the persistence of social and economic inequality were identified as emerging challenges that require knowledge generation to improve health system responses and evaluate progress. Respondents emphasized evaluating effectiveness, feasibility, and equity impacts of health system interventions. A prominent role for implementation science, evidence for policy advocacy, and interdisciplinary collaboration were identified as critical areas for knowledge generation to improve maternal health in the post-2015 era.The online version of this article (doi:10.1186/s12978-015-0044-5) contains supplementary material, which is available to authorized users. We as researchers need to change that conversation.”While respondents were not specifically asked about research methods, the urgent need for well-designed implementation research and evaluation was a recurrent theme. Insistence on the importance of re-orientating knowledge generation was summed up by the respondent who stated: ““research as advocacy, research for political argumentation” to advance implementation of what works, particularly for controversial topics . National demonstration projects and estimates of costs, lives saved, and disabilities averted were mentioned as promising evidence to support policy advocacy.Respondents stressed the need to think strategically about the relationships between knowledge generation and policy advocacy as we move into the post-2015 era. They identified policymakers’ lack of knowledge about public health and maternal health as critical barriers to the development of evidence-informed policy and allocation of funds for maternal health. Proposed solutions included providing basic public health education to policymakers, increasing the research capacity of national Ministries of Health, and engaging policymakers in the development and implementation of maternal health research. Further, respondents emphasized the need for “I am a pre-eclampsia-ologist, there are postpartum hemorrhage-ologists—everyone is an ologist, we need maternal health-ologists to pull it all together.” Respondents also made emphatic and repeated calls for interdisciplinary research, particularly the need to collaborate with social scientists.Finally, the need to overcome disciplinary siloes within maternal health was frequently mentioned. Respondents identified that going beyond narrowly defined areas of specialization would advance maternal health: The global maternal health researchers consulted by the Maternal Health Task Force placed high priority on implementation research to improve the delivery of existing evidence-based maternal health interventions, echoing the results of a recently published international survey on priorities for maternal and perinatal health research . The vis


Delgado et al.), modulating immune response, lowering concentration of cholesterol in blood , and exerting antioxidant activity. The mechanisms underlying the health effects of probiotic bacteria raise great interest among researchers. Modulation of the host gut microbiome represents an intriguing mechanism and is the subject of two research articles  published in this Research Topic. In detail, reutericyclin, a broad spectrum antimicrobial compound produced by Lactobacillus reuteri during feed fermentation, increased the abundance of Dialister and Mitsuokella, two Firmicutes genera that are gut commensals in weanling pigs . Senan et al. reported that differences in gut microbiome composition  affected the response of geriatric individuals to Lassi, a fermented milk containing a cholesterol-lowering strain of Lactobacillus helveticus.Notwithstanding the European Food Safety Authority (EFSA) did not approve any health claims for probiotic foods [including terms such as “probiotic,” “active bacteria”; European Commission (EC), in vitro” and “in vivo.” The use of omics approaches is going to flank the traditional assays, thus probably speeding up research progress in the field of probiotics in the near future. For instance, sequencing of genomes will allow to rapidly detect and discard candidate probiotic microorganisms possessing genes coding for antibiotic resistance or virulence factors . In this regard, an excellent example is provided in this Research Topic by Balzaretti et al. which performed comparative genome analysis of four strains of Lactobacillus paracasei in order to select the two best probiotic strains for oral usage. Anyway, in vivo approaches will keep on being unreplaceable, given the variability of host response to probiotics as affected by genotype, age, diet, variations in human environmental exposure, and composition of gut microbiome .Evaluation assays of probiotic potential are traditionally classified in two groups: “Akkermansia muciniphila and Faecalibacterium prausnitzii ; (ii) non-dairy food items  as carriers of probiotic bacteria ; (iii) health effects of microbial metabolites ; and (iv) probiotic interventions on livestock indirectly benefiting human health .Besides the understanding of the mechanisms underlying probiotic activities and studies dealing with interactions between probiotic microorganisms and gut microbiome, other future perspectives about microorganisms for functional food are: (i) novel putative probiotic bacteria, such as FM resumed some of the contributions published in this research topic and wrote the Editorial. MD settled the structure of and reviewed the Editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The revised World Health Organization’s International Health Regulations (2005) request a timely and all-hazard approach towards surveillance, especially at the subnational level. We discuss three questions of syndromic surveillance application in the European context for assessing public health emergencies of international concern: (i) can syndromic surveillance support countries, especially the subnational level, to meet the International Health Regulations (2005) core surveillance capacity requirements, (ii) are European syndromic surveillance systems comparable to enable cross-border surveillance, and (iii) at which administrative level should syndromic surveillance best be applied?Despite the ongoing criticism on the usefulness of syndromic surveillance which is related to its clinically nonspecific output, we demonstrate that it was a suitable supplement for timely assessment of the impact of three different public health emergencies affecting Europe. Subnational syndromic surveillance analysis in some cases proved to be of advantage for detecting an event earlier compared to national level analysis. However, in many cases, syndromic surveillance did not detect local events with only a small number of cases.The European Commission envisions comparability of surveillance output to enable cross-border surveillance. Evaluated against European infectious disease case definitions, syndromic surveillance can contribute to identify cases that might fulfil the clinical case definition but the approach is too unspecific to comply to complete clinical definitions. Syndromic surveillance results still seem feasible for comparable cross-border surveillance as similarly defined syndromes are analysed.We suggest a new model of implementing syndromic surveillance at the subnational level. In this model, syndromic surveillance systems are fine-tuned to their local context and integrated into the existing subnational surveillance and reporting structure. By enhancing population coverage, events covering several jurisdictions can be identified at higher levels. However, the setup of decentralised and locally adjusted syndromic surveillance systems is more complex compared to the setup of one national or local system.We conclude that syndromic surveillance if implemented with large population coverage at the subnational level can help detect and assess the local and regional effect of different types of public health emergencies in a timely manner as required by the International Health Regulations (2005). Europe faces different health threats which are arising from infectious disease outbreaks, natural disasters or man-made events. The variety of potential health threats led the World Health Organization (WHO) to adjust their International Health Regulations (IHR 2005)). The IHR (2005) now follow an all-hazard approach, focusing on an “illness or medical condition, irrespective of origin or source, that presents or could present significant harm to humans” . Detecti005). TheFor the European Union (EU), comparability of surveillance results in the form of comparable case definitions, data formats and diagnostic codes is of high value to enable cross-border monitoring of events. EU member states, however, are very diverse and adopting comparative case definitions based on similar data sources is difficult to achieve . The newWe understand the subnational level in this paper as primary level, e.g., county, and intermediate level, e.g., province, of the public health response in a country according to the IHR (2005) . The subBut how can the subnational level be equipped with the means to detect different types of events or related health effects in a timely fashion? Local intelligence in the form of professionals reporting on events, e.g., in schools, or health care institutions, are the cornerstone of detecting the onset of events at the local level, as shown for example, during the 2009 A/H1N1 pandemic ,9. StillAccording to a recent definition by the European project Triple S-AGE, syndromic surveillance augments traditional surveillance systems by providing clinically nonspecific but (near) real-time information on the public health impact of events, gained from existing and if possible automatically generated data that were originally not collected for surveillance purposes . The TriTimeliness, flexibility and cost-effectiveness are considered to be the major strengths of syndromic surveillance which could make it a suitable solution for gaining timely information on different kinds of health threats as required by the IHR (2005) . Its majHow can syndromic surveillance be used to support European countries to meet the IHR (2005) requirements for the core capacity of immediate detection, assessment and reporting of different kinds of  Public Health Emergencies of International Concern (PHEIC), especially at the subnational level?How comparable are syndromic surveillance systems to enable cross-border surveillance in Europe referring to case definitions, data formats and diagnostic coding systems?What are strengths and weaknesses of different implementation models for subnational syndromic surveillance in Europe?Below, we discuss the following questions around the usefulness of syndromic surveillance in the light of the IHR (2005) implementation in Europe:In the following, we explore three European public health emergencies during which syndromic surveillance was applied, the 2009 A/H1N1 influenza pandemic, the volcanic ash plume which covered Europe in 2010, and the O104:H4 gastrointestinal outbreak in 2011. The pandemic was declared a PHEIC in the framework of the IHR (2005) while the other two events were reported to WHO by member states as potential PHEIC. We analyse the contribution of syndromic surveillance in the three cases in terms of timeliness, added value of subnational level application and flexibility in terms of an all-hazard approach.a, we identified seven additional systemsb, for which no details were retrievable and they were not included in further analysis  OR pandemic[Title/Abstract]) AND “syndromic surveillance”[Title/Abstract]. The search string for Google Scholar was: H1N1 OR pandemic AND “syndromic surveillance”. The review of Google Scholar hits stopped after 10 pages of hits which did not provide any new relevant content. We checked references of selected full-text articles for further relevant publications.bThe additional identified systems were the SurSauUD emergency department and general practitioner house calls surveillance systems in France, the national emergency department surveillance system and the Lazio emergency department surveillance system in Italy, the South Holland South general practitioner pandemic surveillance system in the Netherlands, the PIPeR general practitioner pandemic surveillance system in Scotland, the general practitioner out-of-hours surveillance system in Ireland, and the general practitioner surveillance system in Wales.


We tested the hypothesis that there is a topographical sympathetic activation in rats submitted to experimental cirrhosis. Baseline renal (rSNA) and splanchnic (sSNA) sympathetic nerve activities were evaluated in anesthetized rats. In addition, we evaluated main arterial pressure (MAP), heart rate (HR), and baroreceptor reflex sensitivity (BRS). Cirrhotic Wistar rats were obtained by bile duct ligation (BDL). MAP and HR were measured in conscious rats, and cardiac BRS was assessed by changes in blood pressure induced by increasing doses of phenylephrine or sodium nitroprusside. The BRS and baseline for the control of sSNA and rSNA were also evaluated in urethane-anesthetized rats. Cirrhotic rats had increased baseline sSNA , but no baseline changes in the rSNA compared to controls. These data were accompanied by increased splanchnic BRS (p<0.05) and decreased cardiac (p<0.05) and renal BRS (p<0.05). Furthermore, BDL rats had reduced basal MAP  accompanied by increased HR . Our data have shown topographical sympathetic activation in rats submitted to experimental cirrhosis. The BDL group had increased baseline sSNA, independent of dysfunction in the BRS and no changes in baseline rSNA. However, an impairment of rSNA and HR control by arterial baroreceptor was noted. We suggest that arterial baroreceptor impairment of rSNA and HR is an early marker of cardiovascular dysfunction related to liver cirrhosis and probably a major mechanism leading to sympathoexcitation in decompensated phase. The cardiovascular autonomic dysfunction is well established in cirrhosis of different etiologies, with the degree of sympathetic activation strongly associated with the disease severity and poor prognosis , 2. IncrAbnormal cardiovascular homeostasis is also manifested by blunted responsiveness of blood vessels and attenuated reflexes such as the arterial baroreceptors , 17, 18.Male Wistar rats weighing 200 to 250 g obtained from the Federal University of São Paulo were housed in group cages (n = 5) in a room with controlled temperature, a 12:12h light-dark cycle and free access to water and food. Experiments followed the Guiding Principles in the Care and Use of Animals of the American Physiological Society and were approved by the Institutional Review Board of the Federal University of Sao Paulo (protocol 1095/10).The rats were distributed into two experimental groups: control and bile duct ligation (BDL). The present study was divided into two independent series of experiments. In the first series, the hepatic function was assessed in the two groups of rats. In the second series of experiments, the cardiovascular parameters: mean arterial pressure (MAP), heart rate (HR), and arterial baroreceptor reflex control of HR were assessed in conscious rats. At least 24h after that, the same group of rats was slowly anesthetized with urethane   to avoid any change in MAP, and the basaline splanchnic (sSNA) and renal sympathetic nerve activity (rSNA) were recorded. The baroreceptor function for the control of sSNA and rSNA were also evaluated.Cirrhosis was induced in the rats by the bile duct-ligation rat model, a well-established model of cirrhosis, portal hypertension, hemodynamic and pharmacological studies –31. AnimThe liver function parameters, alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were measured by colorimetric assay employing commercial kits .For intravenous injection of drugs and direct arterial pressure recording, the rats were anesthetized with ketamine and xylazine  and catheterized with femoral venous and arterial catheters. Following ≥24h of surgical recovery, MAP and HR were recorded in conscious rats using an analog-digital board that communicated with the PowerLab software . Subsequently, pressor doses of phenylephrine  and depressor doses of sodium nitroprusside  (Sigma-Aldrich) were acutely administered to induce a blood pressure increase or decrease and reflex bradycardia or tachycardia, respectively. The vasoactive drugs were administered with ≥5 min intervals between doses, until blood pressure returned to baseline. Values of matching MAP variations (ΔMAP from 20 to 55 mmHg) with reflex HR (ΔHR) response were separately plotted for each vasoactive drug to create linear regression curves of baroreceptor function for each group, and their slopes (beats/min/mmHg) were compared to test changes in the baroreceptor reflex sensitivity.Rats were slowly anesthetized with urethane . For the renal sympathetic nerve activity (rSNA) and splanchnic sympathetic nerve activity (sSNA) recordings, the left renal and splanchnic nerve were retroperitoneally exposed, placed on bipolar silver electrodes and once the conditions for nerve recording was established, the nerve and electrode were covered with paraffin oil. The signal from the renal nerve was displayed on an oscilloscope , and the nerve activity was amplified , filtered by a band-pass filter , and collected. Data analysis was then performed using the PowerLab data acquisition system . At the end of the experiments, the background noise level of SNA was determined following hexamethonium bromide administration  (Sigma-Aldrich). The sSNA and rSNA were rectified online, integrated from the raw data obtained for each heart period, and expressed as volts-seconds (V.s). In addition, the neural activity was analyzed offline using the appropriate software . For this purpose, the raw nerve signal was passed through a spike discriminator  to remove background noise. The total nerve activity expressed in spikes per second (spikes/s) was then computed from the time at which nerve activity changed from the basal value to when it returned to the basal value. The baseline sSNA and rSNA are expressed as spikes per second (spikes/s) over a period of 60s. The mean values obtained were compared to the mean values determined before each test, as reported previously . Only thResults were expressed as mean ± standard error of the mean (SEM). Data were evaluated by unpaired Student’s t-test using Graph-Pad Prism . The level of statistical significance was defined as P<0.05.Under baseline conditions, HR was significantly higher and MAP significantly lower in the cirrhotic rats compared to control rats .The BRS was attenuated in conscious cirrhotic rats .BDL group had higher baseline sSNA than control . However, no difference was found between control and BDL groups in baseline rSNA , as shown in The major new findings of the present study were 1) the preferential increase in sSNA in BDL rats, but not in rSNA, 2) the enhanced BRS for sSNA and decreased for HR and rSNA. The autonomic changes in BDL rats were accompanied by a significant drop in MAP and increased HR.Four weeks after BDL, the rats had confirmed liver cirrhosis characterized by elevated serum transaminases levels and hepatomegaly, but without ascites. The reduced MAP observed in cirrhotic rats was probably a result of systemic vasodilation that leads to low systemic vascular resistance as a consequence of a combination of overproduction of circulating vasodilators, vasodilators of intestinal or systemic origin, vasodilators that escape degradation in the diseased liver or bypass the liver through portosystemic collaterals, reduced resistance to vasoconstrictors and increased sensitivity to vasodilators , 36.The autonomic dysfunction, characterized by a sympathovagal imbalance is probably a cause of elevated basal HR in BDL rats, considering that increased cardiac SNA, accompanied by decreased vagal activity was described in cirrhosis . IncreasThe present study confirmed the increased sSNA by directly recording the splanchnic nerve activity. However, the baseline rSNA was not changed by BDL. These data is consistent with Henriksen et al. 1989) that found elevated norepinephrine in the liver and intestine, but no in renal vein from preascitic cirrhotic patients, suggesting specific sympathetic hypertonia to splanchnic territory in this phase . However9 that foDespite the fact that the topographical sympathetic change is organized in BDL rats is not well established, several brain regions have been implicated in the generation of differential sympathetic outflow to distinct cardiovascular targets , 45, 46,A large number of chemo and mechanic receptor are present in the liver that sense ions, nutrients and blood flow and send signals to the brain . Our hypThe efferent SNA control by arterial baroreceptors also presented topographic differences in BDL group. Cardiac e renal BRS were reduced and splanchnic BRS was increased. Several studies described impairment of cardiac and renal BRS in patients as well as in experimental models of cirrhosis , 23, 24.Despite the fact that components of the renin-angiotensin system (RAS) were not measured in the present study, there is an inverse relationship between the BRS and RAS in liver disease, which may be involved in reducing the BRS , decreasThere is substantial evidence that the RAS is deeply involved in the impaired baroreflex function in animals or patients with cirrhosis and that the reflex control of circulation may be partially restored by blockade of RAS , 66. We However, the splanchnic sympathoexcitation in BDL rats was independent of arterial baroreceptor reflex dysfunction. Considering that the splanchnic vascular bed receives 25% to 30% of the total cardiac output and has a major role in blood storage , an incrAlthough we did not investigate the venous congestion in BDL rats, we believe that increased sSNA activity is a compensatory mechanism to reduce venous congestion in liver disease, and mobilize blood volume from splanchnic region to other body tissues. In conclusion, our data have shown topographical sympathetic activation in rats submitted to experimental cirrhosis.The BDL group had increased baseline sSNA, independent of arterial baroreceptor reflex dysfunction and no changes in baseline rSNA, although impairment of rSNA and HR control by arterial baroreceptor was found. The changes are probably organized by central nuclei of the brain related to autonomic cardiovascular control. However, the mechanisms underlying increased SNA and BRS dysfunction in cirrhosis is still not well understood.New studies in late decompensate cirrhosis would be important to further our understanding regarding the evolution of autonomic and kidney dysfunction as well as the relationship of increased sympathetic drive to splanchnic territory and portal hypertension. The reno-renal and the hepato-renal reflex assessing during cirrhosis development and how they interact with the arterial baroreceptor reflex could contribute to elucidate the mechanisms leading to autonomic dysfunction in cirrhosis.