Developmental programming of reproduction and fertility: what is the evidence?

The concept of the foetal/developmental origins of adult disease has been around for ~20 years and from the original epidemiological studies in human populations much more evidence has accumulated from the many studies in animal models. The majority of these have focused upon the role of early dietary intake before conception, through gestation and/or lactation and subsequent interactions with the postnatal environment, e.g. dietary and physical activity exposures. Whilst a number of theoretical models have been proposed to place the experimental data into a biological context, the underlying phenomena remain the same; developmental deficits (of single (micro) nutrients) during critical or sensitive periods of tissue growth alter the developmental pathway to ultimately constrain later functional capacity when the individual is adult. Ageing, without exception, exacerbates any programmed sequelae. Thus, adult phenotypes that have been relatively easy to characterise (e.g. blood pressure, insulin sensitivity, body fat mass) have received most attention in the literature. To date, relatively few studies have considered the effect of differential early environmental exposures on reproductive function and fecundity in predominantly mono-ovular species such as the sheep, cow and human. The available evidence suggests that prenatal insults, undernutrition for example, have little effect on lifetime reproductive capacity despite subtle effects on the hypothalamic-pituitary-gonadal axis and gonadal progenitor cell complement. The postnatal environment is clearly important, however, since neonatal/adolescent growth acceleration (itself not independent from prenatal experience) has been shown to significantly influence fecundity in farm animals. The present paper will expand these interesting areas of investigation and review the available evidence regarding developmental programming of reproduction and fertility. However, it appears there is little strong evidence to indicate that offspring fertility and reproductive senescence in the human and in farm animal species are overtly affected by prenatal nutrient exposure. Nevertheless, it is clear that the developing gonad is sensitive to its immediate environment but more detailed investigation is required to specifically test the long-term consequences of nutritional perturbations during pregnancy on adult reproductive well-being.     

Impact of global warming on viral diseases: what is the evidence?

Global warming is believed to induce a gradual climate change. Hence, it was predicted that tropical insects might expand their habitats thereby transmitting pathogens to humans. Although this concept is a conclusive presumption, clear evidence is still lacking--at least for viral diseases. Epidemiological data indicate that seasonality of many diseases is further influenced by strong single weather events, interannual climate phenomena, and anthropogenic factors. So far, emergence of new diseases was unlinked to global warming. Re-emergence and dispersion of diseases was correlated with translocation of pathogen-infected vectors or hosts. Coupled ocean/atmosphere circulations and 'global change' that also includes shifting of demographic, social, and economical conditions are important drivers of viral disease variability whereas global warming at best contributes.     

Value of anti-infective chemoprophylaxis in primary systemic vasculitis: what is the evidence?

Although infections are a major concern in patients with primary systemic vasculitis, actual knowledge about risk factors and evidence concerning the use of anti-infective prophylaxis from clinical trials are scarce. The use of high dose glucocorticoids and cyclophosphamide pose a definite risk for infections. Bacterial infections are among the most frequent causes of death, with Staphylococcus aureus being the most common isolate. Concerning viral infections, cytomegalovirus and varicella-zoster virus reactivation represent the most frequent complications. The only prophylactic measure that is widely accepted is trimethoprim/sulfamethoxazole to avoid Pneumocystis jiroveci pneumonia in small vessel vasculitis patients with generalised disease receiving therapy for induction of remission.     

Coxiella burnetii: what is the reality?

After the Second World War, in Italy Q Fever or Coxiellosis has been shown a significant relevance, a recrudescence with an epidemic state for over ten years. Later, the infectious disease occurred as endemic since the 80s, the outbreaks were just isolated. Workflows analysis of some authors has demonstrated the spread out of the infection throughout Italian herds with a prevalence ranging from 1.2 per cent to 10 per cent. Our survey carried out throughout Campania area in cattle has shown a real positivity over 14 per cent performing the IFAT for the detection of IgG antibodies for Coxiella burnetii. Therefore, it has been so important to stress the influence of cattle farming management in stables as a real risk of Coxiellosis. For example, the Relative Risk (RR) has been registrated about 6.84 (2.18相似文献   

Cardiac adrenoceptors at low temperature: what is the experimental evidence for the adrenoceptor interconversion hypothesis?

Isolated heart preparations of frog and rat were used to test the validity of the adrenoceptor interconversion hypothesis. This hypothesis claims that low temperature converts the inotropic beta-adrenoceptors in isolated frog and rat heart to alpha-adrenoceptors. The present results do not support the adrenoceptor interconversion hypothesis. In the isolated frog ventricle, lowering the temperature from 24 C to 14 C did not significantly alter the inotropic potency of the sympathomimetic drugs isoprenaline, epinephrine, and phenylephrine and did not reduce the potency of the beta-adrenoceptor blocking drug propranolol as an epinephrine antagonist. In the isolated rat left atrium, lowering the temperature from 31 C to 17-19 C did not significantly change the inotropic potency of isoprenaline, norepinephrine and phenylephrine, did not diminish the potency of propranolol, and did not increase the potency of the alpha-adrenoceptor blocking drug phentolamine.--Benfey, B. G. Cardiac adrenoceptors at low temperature; what is the experimental evidence for the adrenoceptor interconversion hypothesis?     

Sex and death: what is the connection?

A cost of reproduction, where lifespan and fecundity are negatively correlated, is of widespread occurrence. Mutations in insulin/IGF signaling (IIS) pathways and dietary restriction (DR) can extend lifespan in model organisms but do not always reduce fecundity, suggesting that the link between lifespan and fecundity is not inevitable. Understanding the molecular basis of the cost of reproduction will be informed by elucidation of the mechanisms by which DR and IIS affect these two traits.     

Mosquito transgenesis: what is the fitness cost?

The generation of transgenic mosquitoes with a minimal fitness load is a prerequisite for the success of strategies for controlling mosquito-borne diseases using transgenic insects. It is important to assemble as much information as possible on this subject because realistic estimates of transgene fitness costs are essential for modeling and planning release strategies. Transgenic mosquitoes must have minimal fitness costs, because such costs would reduce the effectiveness of the genetic drive mechanisms that are used to introduce the transgenes into field mosquito populations. Several factors affect fitness of transgenic mosquitoes, including the potential negative effect of transgene products and insertional mutagenesis. Studies to assess fitness of transgenic mosquitoes in the field (as opposed to the laboratory) are still needed.     

Autophagy and apoptosis: what is the connection?

The therapeutic potential of autophagy for the treatment cancer and other diseases is beset by paradoxes stemming from the complexity of the interactions between the apoptotic and autophagic machinery. The simplest question of how autophagy acts as both a protector and executioner of cell death remains the subject of substantial controversy. Elucidating the molecular interactions between the processes will help us understand how autophagy can modulate cell death, whether autophagy is truly a cell death mechanism, and how these functions are regulated. We suggest that, despite many connections between autophagy and apoptosis, a strong causal relationship wherein one process controls the other, has not been demonstrated adequately. Knowing when and how to modulate autophagy therapeutically depends on understanding these connections.     

Bilateral fetal uropathy: what is the outlook?

OBJECTIVE--To assess the morbidity and mortality associated with a prenatal diagnosis of bilateral fetal uropathy. DESIGN--Retrospective study. SETTING--Departments of radiology, paediatric surgery, obstetrics, and pathology in two teaching hospitals that serve as referral centres for the Yorkshire region. PATIENTS--126 Cases of fetal uropathy were referred either prenatally or postnatally from hospitals in Yorkshire between August 1982 and December 1987. The disease was bilateral in 54 cases and unilateral in 72 cases. In 14 cases bilateral fetal uropathy was associated with coexistent disease. INTERVENTIONS--All cases were managed individually by an obstetrician after discussion with the radiologists and paediatric surgeons. Babies who survived were treated prophylactically with antibiotics after delivery and were operated on if appropriate. END POINT--Assessment of prognosis for long term renal function for each baby referred between August 1982 and December 1987: follow up ranged from six months to five years. MEASUREMENTS AND MAIN RESULTS--Of the 54 fetuses with bilateral fetal uropathy, 13 were terminated as the prenatal findings of ultrasonography were considered to be incompatible with long term survival. Ten of the liveborn babies died, five of renal or pulmonary insufficiency, or both, and five of associated congenital anomalies. Thirty one infants survived to follow up; four of these had serious coexistent disease and two had impaired renal function. Thus the overall mortality was 43% and the morbidity rate 19%. The renal anomaly was associated with other serious disease in 14 cases (26%) compared with two (3%) of the 72 cases of unilateral fetal uropathy. All but two of the 27 infants with isolated bilateral urinary tract disease had excellent prospects for survival. CONCLUSION--Although bilateral fetal uropathy is associated with a high morbidity rate and mortality, careful prenatal assessment can help to identify fetuses with a poor prognosis. The outlook for a fetus with isolated renal disease if treated promptly after delivery is excellent and compares favourably with that reported after prenatal surgical intervention.     

Phosphatidylserine receptors: what is the new RAGE?

The identification of RAGE as a phophatidylserine receptor—in this issue of EMBO reports by He et al—adds to the range of molecules that can sense this ‘eat-me'' signal, and suggests new potential therapeutic opportunities.EMBO Rep (2011) advance online publication. doi:10.1038/embor.2011.28The recognition of apoptotic cells by phagocytes is a complex, yet highly orchestrated event. Many receptors have been identified that recognize phosphatidylserine (PS; Fig 1)—which is exposed on early apoptotic cells—leading to downstream signalling and apoptotic cell engulfment. In a paper published this month in EMBO reports, the receptor for advanced glycation end-products (RAGE) is described as a new PS receptor on alveolar macrophages that participates in the clearance of apoptotic cells (He et al, 2011).…[RAGE] is described as a new phosphatidylserine receptor on alveolar macrophages that participates in the clearance of apoptotic cellsOpen in a separate windowFigure 1Phosphatidylserine-dependent apoptotic cell recognition.Schematic of the known PS receptors and downstream signalling to Rac. Dashed lines indicate unknown signalling mechanisms. PS, phosphatidylserine; RAGE, receptor for advanced glycation end-products; sRAGE, soluble RAGE.More than 200 billion cells undergo apoptosis every day in a human body, yet few apoptotic cells are detected in healthy tissue (Ravichandran, 2010). Apoptotic cells are generated during development, as part of normal homeostatic turnover and in disease states. The efficient clearance of apoptotic cells is crucial to prevent them from becoming secondarily necrotic, thereby limiting the immune response to apoptotic cell-derived self-antigens (Green et al, 2009). Disruptions to the clearance of apoptotic cells are linked to several diseases including atherosclerosis, chronic inflammation and autoimmunity (Elliott & Ravichandran, 2010).More than 200 billion cells undergo apoptosis every day in a human body, yet few apoptotic cells are detected in healthy tissueApoptotic cell engulfment can be divided into several steps. The first is the release of ‘find-me'' signals—such as triphosphate nucleotides (ATP and UTP), sphingosine-1-phosphate (S1P), lysophosphatidylcholine (LPC) and the chemokine CX₃CL1—by apoptotic cells (Ravichandran, 2010). Then, phagocytes sense the find-me signals and migrate toward the apoptotic cell. When they are in close proximity, recognition is mediated by the interaction between engulfment receptors on phagocytes and ligands, known as ‘eat-me'' signals, that are expressed on the dying cells (Ravichandran, 2010). The best-studied eat-me signal is PS, which is flipped from the inner leaflet to the outer leaflet of the plasma membrane during early apoptosis. Many receptors have been linked to the recognition of the exposed PS on apoptotic cells, and they are discussed below. The recognition of an apoptotic cell results in a downstream signalling cascade that leads to cytoskeletal rearrangement of the phagocytic membrane and subsequent engulfment of the apoptotic cell. Once the corpse is internalized, the phagocyte must process and digest the cellular contents.The exposure of PS on the outer leaflet of the membrane is the most-characteristic marker of an apoptotic cell. Phagocytes can recognize PS directly through receptors such as Bai1, TIM-4 and stabilin 2, or through soluble bridging molecules that bind to both PS and specific phagocyte receptors. For example, bridging molecules MFG-E8 and Gas6 interact with α_Vβ_3/5 and MER on the phagocytic membrane, respectively. Other eat-me signals and the molecules that bind to them have been characterized: thrombospondin is recognized by the vitronectin receptor, calreticulin by LRP1, oxidized LDL by scavenger receptors, ICAM3 might bind to CD14 and altered sugars bind to lectins (Lauber et al, 2004). Not all receptors need to be engaged for engulfment to occur, and different cell types have different receptor-expression levels.In a paper published this month in EMBO reports, the Yamamoto team identify RAGE as a new type of PS receptor on macrophages (He et al, 2011). There are two functional forms of RAGE, an abundant full-length transmembrane form that can initiate signalling through its intracellular tail, and a soluble isoform (sRAGE) that acts as a decoy receptor. RAGE is characteristically regarded as a pro-inflammatory receptor and has a variety of ligands, including advanced glycation end-products (AGEs) and many other damage-associated molecular patterns (DAMPs; Sims et al, 2010). One ligand in particular—high-mobility group protein B1 (HMGB1)—is released by cells undergoing necrosis and has been shown to bind to RAGE and induce inflammation (Sims et al, 2010). Therefore, RAGE might function during pro-inflammatory conditions and—as proposed by He and colleagues—during the anti-inflammatory process of apoptotic cell clearance. RAGE is mainly expressed in the lungs, but levels of it quickly increase at sites of inflammation, mostly on inflammatory and epithelial cells. Given the multitude of RAGE ligands and its inducible expression levels, RAGE is implicated in a variety of inflammation-related pathological states such as neurological and pulmonary disorders, vascular disease, cancer and diabetes (Sims et al, 2010).He and colleagues suggest that RAGE is a PS receptor during apoptotic cell engulfment in alveolar macrophages (He et al, 2011). Furthermore, sRAGE—which can bind to PS and apoptotic thymocytes—acts as a decoy and inhibits RAGE recognition of PS. By using PS liposomes as an artificial apoptotic target, the authors find RAGE in areas of the membrane in which a pseudopod forms to engulf a PS liposome. Additionally, sRAGE can compete with transmembrane RAGE to block the recognition of PS by the phagocyte and subsequently decrease the engulfment of apoptotic cells. Under homeostatic conditions, alveolar macrophages isolated from RAGE-deficient mice have defects in phagocytosis of apoptotic thymocytes. In a model of lung injury induced by lipopolysaccharide administration, RAGE-deficient mice accumulate neutrophils in the alveolar space and RAGE-deficient macrophages have defects in neutrophil engulfment. Previous works have implicated RAGE expression and/or upregulation in inflammatory conditions. In fact, genetic deletion of RAGE in mice can result in attenuated atherosclerosis, resistance to septic shock and reduced diabetic kidney disease (Ramasamy et al, 2010). Apoptotic cell clearance is generally an immunologically silent process and, therefore, if RAGE significantly contributes to engulfment, RAGE-deficient mice would be expected to have defects in cell clearance, leading to enhanced inflammation and disease. However, this does not seem to be the case. Thus, future studies should examine cell-type specific deletions of RAGE to clarify its apparently contradictory role in cell clearance and inflammation in these diseases.Given that several modes of PS recognition have been identified (Ravichandran, 2010), there must be some redundancy. The way in which RAGE contributes to this scenario remains to be investigated. Analysis of the expression levels of each PS receptor on different cell types will also help to define their relative importance in individual cells. As RAGE is highly expressed in the lung, it would be interesting to analyse its contribution to apoptotic cell engulfment in this tissue, in comparison with the other PS receptors. Furthermore, RAGE is induced by inflammation, suggesting that it is probably important during disease states to facilitate engulfment and reduce inflammation in the microenvironment.Another interesting question that remains is how RAGE signals to the phagocyte for engulfment. RAGE signalling results in pro-inflammatory cytokine production through activation of NF-κB (Yan et al, 1994), which seems to be different from the production of anti-inflammatory cytokines—such as IL-10 and TGFβ—by phagocytes during cell engulfment. However, as several RAGE ligands exist, the way in which they bind to RAGE could result in differential signalling. RAGE has also been shown to interact with mouse Dia1, leading to downstream activation of Rac1 and Cdc42, and cell migration (Hudson et al, 2008). Now, He and colleagues suggest that RAGE signals to Rac1 through Dia1 in the context of apoptotic cell clearance, as RAGE-deficient macrophages have decreased Rac1 activity in response to PS-liposome engulfment. Two evolutionarily conserved Rac-dependent pathways have been identified to mediate corpse internalization. Engagement of some engulfment receptors such as Bai1, results in Rac activation through the ELMO–Dock180–CrkII complex. ELMO and Dock180 mediate the exchange of GDP to GTP on Rac, whereas CrkII has been proposed to function as an adaptor protein. Another pathway involves signalling from the engulfment receptor LRP1 or stabilin 2, leading to Rac activation through the engulfment adaptor protein (GULP). Additional work is necessary to determine whether RAGE–mDia1 signalling constitutes a third intracellular signalling pathway for cell engulfment.Another interesting question that remains is how RAGE signals to the phagocyte for engulfmentThe study from the Yamamoto team identifies RAGE as a new PS-recognition molecule implicated in apoptotic cell-clearance in the lung. As each new receptor is identified, we are reminded of the redundancy and cell-type-specific expression of PS receptors. Defects in apoptotic cell-clearance lead to a variety of inflammatory diseases, including cardiovascular and autoimmune diseases. This study could also open an interesting therapeutic avenue; if sRAGE blocks the recognition of PS by RAGE and other PS receptors, it might be beneficial as a therapy by enhancing cell clearance and decreasing the severity of cell-clearance-associated diseases.