An increasing number of studies show that besides the inherited genetic architecture , various environmental factors significantly contribute to the etiology of rheumatoid arthritis. Epigenetic factors react to external stimuli and form bridges between the environment and the genetic information-harboring DNA. Epigenetic mechanisms are implicated in the final interpretation of the encoded genetic information by regulating gene expression, and alterations in their profile influence the activity of the immune system. Overall, epigenetic mechanisms further increase the well-known complexity of rheumatoid arthritis by providing additional subtle contributions to rheumatoid arthritis susceptibility. Although there are controversies regarding the involvement of epigenetic and genetic factors in rheumatoid arthritis etiology, it is becoming obvious that the two systems (genetic and epigenetic) interact with each other and are ultimately responsible for rheumatoid arthritis development. Here, epigenetic factors and mechanisms involved in rheumatoid arthritis are reviewed and new, potential therapeutic targets are discussed. More than 10 years after the completion of the human genome sequencing project , we stilIn this commentary, we will first introduce the basic epigenetic mechanisms and then discuss the results of RA-related epigenetic studies. Finally, we will provide a brief description of epigenetic factor-based future therapeutics in RA.Ab ovo, each cell of the body inherits the same genetic information. What makes each cell unique is that, during ontogenesis, different sets of genes are turned on and off. Epigenetic mechanisms establish the proper nuclear milieu for cell-specific gene expression and are responsible for the cellular memory, that is, keeping and transmitting cell-specific gene expression patterns to daughter cells. Epigenetic factors can deposit, interpret and eliminate epigenetic information and, in this sense, they can be divided into distinct functional groups: epigenetic ‘writers’ or enzymes that modify DNA and histones; epigenetic ‘readers’ with specific protein domains that recognize DNA or histone marks; and epigenetic ‘erasers’ that can delete the existing signals to make room for new modifications  and associated with gene silencing . DNA metHistone acetylation and methylation exert their effects on gene expression by regulating the accessibility of DNA for transcription factors. As a general rule, modifications decrease the compactness of chromatin structure and promote gene expression Figure B 14]. H. H14]. HUnlike genomic DNA , epigenetic signals  are highly dynamic and show cell type-specific patterns. Each type of cell has its own characteristic epigenome profile with unique gene expression patterns; therefore, studies must be highly specific regarding the investigated cell type.CXCL12 gene [Early studies found widespread DNA hypomethylation in RA synovial fibroblasts, including hypomethylation of the promoter of the L12 gene  and the L12 gene  that areL12 gene . Most ofL12 gene . AnotherL12 gene , ultimatA genome-wide DNA methylation profiling study in peripheral blood mononuclear cells reported differentially methylated regions in the major histocompatibility complex loci that make a significant contribution to the genetic risk of developing RA . Our groIn addition to Aurora kinases, several members of the HAT family are also significantly upregulated in arthritic mice and patients with RA, with the gene encoding Esco2 showing the strongest increase in expression. Esco2 is thought to be required for the establishment of sister chromatid cohesion and it also couples cohesion and DNA replication to ensure that only sister chromatids are paired together ,24. BecaKDM6B, a histone methyltransferase responsible for eliminating a repressive epigenetic signal , is involved in macrophage activation [SETD6 gene, which encodes a known negative regulator of NF-κB, leads to runaway activity of this transcription factor [As described earlier, many of the epigenome modifiers can directly or indirectly affect the activity of NF-κB, a master regulator of the transcription of inflammation-related genes. With regard to autoimmune or inflammatory diseases such as RA, the emerging consensus is that epigenetic factors (enzymes) supporting repressive signals are downregulated, whereas those that promote transcription are upregulated. A combination of these activities in immune cells ultimately results in the strengthening of pro-inflammatory pathways and the weakening of anti-inflammatory mechanisms. For example, disease-linked expression of n factor .The results of epigenetic studies in RA raise the question whether the reported epigenetic alterations play a causative role or are the consequences of other pathologic processes that take place in RA. To answer this question, there is a need for further epigenome-wide studies on all types of cells involved in RA, exploration of a larger repertoire of epigenetic signals, and investigation of the epigenetic landscape at different phases of arthritis. It is possible that significant advances will be achieved in the near future because the technologies and model systems, including genome and epigenome-wide analysis tools  and animal models, are readily available.Information from RA-associated epigenetic studies can be useful for diagnostic and therapeutic purposes because investigation of the epigenetic landscape can provide both potential biomarkers and therapeutic targets. There have been numerous clinical trials involving patients with cancer that have tested such inhibitors as therapeutics against malignancies . AlthougMGMT and MLH1) can result in inactivation of cellular mechanisms responsible for keeping the genetic mutation rate low [A common outcome of genetic and epigenetic mutations is that both ultimately lead to aberrant gene expression. The mechanisms by which genetic mutations affect gene expression are well known, including shorter or longer deletions, insertions, inversions, translocations, or single nucleotide changes within transcription factor binding sites. Mutations hitting genes that encode epigenetic regulators may result in aberrant expression or functional impairment of the affected epigenetic factors -33. The rate low ,35 or inrate low ,37. DNA rate low ,39.Alteration in epigenetic mechanisms can trigger genetic mutations and genetic mutations in epigenetic regulators can lead to an altered epigenetic profile. Therefore, genetics and epigenetics can be considered two sides of the same coin, as has been established in the field of cancer research . It is vACA: anacardic acid; GWAS: genome-wide association studies; HATs: histone acetyltranferases; HDACs: histone deacetylases; NF-κB: nuclear factor-kappaB; PGIA: proteoglycan-induced arthritis; RA: rheumatoid arthritis.The authors declare that they have no competing interests.All authors contributed to the manuscript. TAR wrote the first draft and all other authors amended the manuscript. All authors read and approved the final manuscript.TTG and KM are Professors at Rush University Medical Center, and founding members of the Section of the Molecular Medicine. They have been studying immunological aspects of rheumatoid arthritis and ankylosing spondylitis in patients and corresponding animal models for more than three decades. They first described cartilage proteoglycan/aggrecan-induced arthritis (PGIA) and spondylitis (PGISpA) in genetically susceptible mice, and this pioneering work was honored by the Carol Nachman Price. TAR is an Assistant Professor at Rush University Medical Center. He is an expert in disease-associated epigenetic modifications of DNA and histones in cancer, and most recently, in rheumatoid arthritis.


The integrity and function of neurons depend on their continuous interactions with glial cells. In the peripheral nervous system glial functions are exerted by Schwann cells (SCs). SCs sense synaptic and extrasynaptic manifestations of action potential propagation and adapt their physiology to support neuronal activity. We review here existing literature data on extrasynaptic bidirectional axon-SC communication, focusing particularly on neuronal activity implications. To shed light on underlying mechanisms, we conduct a thorough analysis of microarray data from SC-rich mouse sciatic nerve at different developmental stages and in neuropathic models. We identify molecules that are potentially involved in SC detection of neuronal activity signals inducing subsequent glial responses. We further suggest that alterations in the activity-dependent axon-SC crosstalk impact on peripheral neuropathies. Together with previously reported data, these observations open new perspectives for deciphering glial mechanisms of neuronal function support. Neurons generate and propagate action potentials (APs) over long distances along their axons. Their functional and structural integrity depend on their partnership with adjacent glial cells. Glia confers trophic and metabolic support, regulates neuronal structure, insulates axons, controls the neuronal environment and has immunoprotective role. In the peripheral nervous system (PNS) the majority of these functions are exerted by Schwann cells (SCs) , via paracrine signaling, and by physical coupling, for instance through adhesion molecules or gap junctions (GJs). Indications exist for the utilization of all three means in activity-dependent interactions among PNS neurons and glia.+ (NaV) and K+ (KV) channels, and propagate autoregeneratively along axons. In non-myelinated fibers APs travel successively through ion channels expressed all along the axons  and juxtaparanodal  regions, and conduction is saltatory , via vesicular pathways  Figure  Butterm. The exp2+ transients that develop subsequently to ES of myelinated and unmyelinated fibers , ex vivo (nerve preparations) and/or in vitro (SC cultures), using biochemical and functional approaches , and ligand-gated  ion channels, and of GPCRs   -currents and T-type CaV depend on axonal firing  or indirect (by conferring metabolic support) impact on axonal activity.+ and K+ ions tend to accumulate in the axoplasm and in the periaxonal space respectively. Maintenance of neuronal excitability requires maintenance of ion homeostasis and fast restoration of the axonal resting potential. Both nmSC and mSCs contribute to it by buffering extracellular K+ ions, mainly through the activity of Na+/K+ pumps and KV channels , metabolic  or genetic  diseases, and injury.2+ overload  also occurs after injury , which have defective lipid biosynthesis and exhibit PNS hypomyelination and progressive demyelination, respectively, and the Pmp22 total KO, which lacks the myelin protein PMP22 and is a model of Hereditary Neuropathy with Liability to Pressure Palsy  have demonstrated that myelin impairments affect neural influx conduction and axonal excitability through different mechanisms, including decreased electrical isolation of the axolemma, the exposure, redistribution or abnormal expression of voltage-gated ion channels, and the potential change from saltatory to continuous conduction Brismar, . AberranAxonal dysfunctions in pathologies and animal models with impaired SCs may also occur secondary to or without myelin abnormalities  and vesicle trafficking, and for genes encoding potential SC exosome or other vesicular cargo (Lopez-Verrilli and Court, To investigate whether glia-to-axon support mechanisms are affected in our in vitro ES via conventional electrodes or microelectrode array platforms could be used to investigate the neuronal activity dependence and relevance of SC molecules and signaling pathways (Kanagasabapathi et al., Neuronal activity plays a central role in the extrasynaptic communication between peripheral axons and SCs. SCs express proteins that allow them to detect signals produced by firing axons. Our microarray data indicate that the list of SC activity sensors may be more extensive than currently known, thus providing indications for novel axonal activity signals. Detection of those signals permits SCs to adjust their physiology, so as to sufficiently support and control neuronal activity. Although this reciprocal interaction is constantly required to sustain the PNS function, it becomes particularly critical in transitional periods, during development or under pathology-induced stress. By identifying SC activity sensor- and neuronal support-genes that are regulated during development and/or PNS disease, we attempt to shed light on mechanisms mobilized by SCs to cover the altered needs and increased requirements of the challenged nervous system. More questions, however, arise, especially regarding the potential contribution of neuronal activity signals to these regulations, their nature, the downstream signaling pathways mediating SC responses, and the role of the latter in the maintenance of neuronal integrity and the regulation of axonal function. Characterization of respective mechanisms can be facilitated by implementation of recently developed microfluidic compartmentalized cell culture technologies that enable cell-specific analyses and application of advanced microscopy techniques (Taylor et al., Chrysanthi Samara and Olivier Poirot, concept and design, data analysis, and interpretation, manuscript writing; Enric Domènech-Estévez, manuscript writing; Roman Chrast, concept, and design, final approval of manuscript, financial support.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.


GOAT structure and activity appears to be conserved from fish to man. Since the acyl modification is critical for most of the biological actions of ghrelin, especially metabolic functions, GOAT emerged as a very important molecule of interest. The research on GOAT is on the rise, and several important results reiterating its significance have been reported. Notable among these discoveries are the identification of GOAT tissue expression patterns, effects on insulin secretion, blood glucose levels, feeding, body weight, and metabolism. Several attempts have been made to design and test synthetic compounds that can modulate endogenous GOAT, which could turn beneficial in favorably regulating whole body energy homeostasis. This paper will focus to provide an update on recent advances in GOAT research and its broader implications in the regulation of energy balance.Ghrelin O-acyl transferase (GOAT) is a recently identified enzyme responsible for the unique  Ghrelin is a gut hormone discovered in 1999 by Dr. Kojima and colleagues in the laboratory of Dr. Kangawa . Since iYang et al.  first idMeanwhile, Gutierrez et al.  performein vitro studies by Ohgusu and colleagues [More recent lleagues  found thlleagues  proposedin situ hybridization and immunohistochemistry that found GOAT mRNA expression in ghrelin immunopositive cells and neighboring cells within the gastric mucosa. Together, these results indicate that the primary source of GOAT is gastrointestinal cells that are positive for ghrelin. Stengel et al. [The discoverers of GOAT found highest levels of GOAT mRNA expression in the stomach and intestine followed by the testis of mice  and the l et al.  for the l et al. . This suIn agreement with the original studies, An et al.  found abad libitum fed rats. These results indicate that malnutrition and leptin are two regulatory factors that determine GOAT mRNA expression. In contrast, fasting for 12, 24, or 36 hours caused a significant reduction in stomach GOAT mRNA in mice [ad libitum fed leptin deficient ob/ob mice compared to wild-type controls [To date, two lines of evidences are available indicating the involvement of GOAT in regulating energy homeostasis. The first set of data is originated from GOAT mRNA expression studies during various metabolic states. The second type of results arises from studies directly testing the effects of GOAT by perturbing the endogenous GOAT. Chronic food deprivation for 21 days resulted in a significant increase in ghrelin mRNA expression in the gastric mucosa of rats and a corresponding increase in GOAT mRNA in the same tissue . Intrape in mice . No diffcontrols . Meanwhicontrols  found thad libitum feeding on regular or high-fat diets showed no difference in the metabolic phenotype, calorie-restricted GOAT knockout mice lost more weight and had low blood glucose levels compared to wild-type controls. The adverse effects of GOAT absence on glucose levels were reversed upon exogenous administration of acylated ghrelin or growth hormone administration. Overall, the outcome of this genetic approach highlights the significance of GOAT in acylating ghrelin and regulating the role of ghrelin on energy balance. It is important to consider the possibility of GOAT modulating peptides other than ghrelin. Therefore, whatever effects resulting from GOAT alterations are possibly not exclusively due to the absence of acylated ghrelin, as other metabolically relevant peptides could be affected due to the absence of GOAT. A new review [The importance of GOAT on metabolism was further elucidated using GOAT knockout mice, which lack acyl ghrelin in their circulation. These mice have normal body weight compared to wild-type control mice, but they gained significantly less weight and had reduced fat mass when fed on a high-fat diet for eight weeks . The enrw review  is now a2). It was also reported that a modified ghrelin fragment with the third serine replaced with an octanoylated diaminopropionic acid could enhance the GOAT inhibitory activity to 45-fold. Such inhibitors could therefore be used to attenuate active ghrelin and its effects on metabolism.Modulating GOAT activity could potentially affect biological actions of ghrelin and this aspect could be targeted to design pharmacological approaches to regulate energy intake and body weight. A successful attempt in this direction was made when Yang et al.  discoverin vivo in mice fed with medium chain fatty acid rich food. In addition, daily administration of GO-CoA-Tat prevented body weight gain in mice fed on a high-fat diet. GOAT inhibition in pancreatic beta cells using the GO-CoA-Tat caused a significant increase in glucose-stimulated insulin secretion, suggesting an inhibitory role for ghrelin in this process. Similar increases in glucose-induced insulin secretion were also found in mice treated with the GOAT antagonist. The expression of mRNA encoding UCP2, a potent inhibitor of insulin secretion, was suppressed 20-fold in GO-CoA-Tat-treated islets. In agreement with these islet effects, An et al. [in vitro. In addition, it was also determined that the mammalian target of rapamycin (mTOR) regulates transcription and translation of GOAT. Inhibition of mTOR signaling using rapamycin significantly increased GOAT mRNA in INS-1 cells in a concentration and time dependent manner. Similarly, intraperitoneal injection of rapamycin that reduced mTOR increased GOAT mRNA expression in the pancreas of C57BL/6 mice. In contrast, leucine, an activator of mTOR, attenuated GOAT mRNA expression in mice pancreas. Overexpressing tuberculosis sclerosis complex 1 and 2 (TSC1 and TSC2), the negative regulators of mTOR action, increased GOAT activity in INS-1 cells. Together, these results provide further evidence for an important role for the endogenous GOAT on glucose homeostasis and insulin secretion, and intracellular mechanisms that mediate these effects.In this regard, other GOAT-specific antagonists have also been designed and functionally characterized . GO-CoA-n et al.  reportedCurrently, GOAT is the only known enzyme that is capable in acylating ghrelin. It is now clear that GOAT is a critical component in making bioactive ghrelin, and thus mediating the physiological functions of ghrelin. Within a short period since its discovery, enough strong evidence have been collected to support a clear and very important role for GOAT in metabolic physiology. GOAT expression is tissue specific, is modulated by a number of factors, and appears to vary among organisms. It is especially interesting that GOAT is regulated by the metabolic status of animals. Whether GOAT expression is altered in metabolic pathophysiology in humans remain unknown. Another fascinating discovery is the development of GOAT inhibitors and its success in preventing weight gain, stimulating insulin secretion and reducing blood glucose levels. If these findings are translatable, inhibition of endogenous GOAT using specific inhibitors could emerge as potential treatment or preventative strategy for diabetes. Similarly, tweaking GOAT biology may reap rewards in the march towards curbing overweight and obesity. While several interesting results have been obtained to date, GOAT research is still in its infancy, and future studies hold the key to further our understanding of this protein and enhancing its utilization for the benefit of humans.


This investigation examines differences in cognitive profiles in subjects with major depressive disorder (MDD) and generalized anxiety disorder (GAD).Data were used from subjects with current MDD (n = 655), GAD (n = 107) and comorbid MDD/GAD (n = 266) diagnosis from the Netherlands Study of Depression and Anxiety (NESDA). The Composite Interview Diagnostic Instrument was used to diagnose MDD and GAD. Cognitive profiles were measured using the Leiden Index of Depression Sensitivity, the Anxiety Sensitivity Index, and the Penn State Worry Questionnaire.Results showed that differences in cognitive profiles between single MDD and single GAD subjects were present: scores on hopelessness/suicidality and rumination were significantly higher in MDD than GAD, whereas anxiety sensitivity for physical concerns and pathological worry were higher in GAD than MDD. The cognitive profile of comorbid MDD/GAD showed more extreme depression cognitions compared to single disorders, and a similar anxiety profile compared to single GAD subjects.Despite the commonalities in cognitive profiles in MDD and GAD, there are differences suggesting that MDD and GAD have disorder-specific cognitive profiles. Findings of this investigation give support for models like the cognitive content-specificity model and the tripartite model and could provide useful handles for treatment focus. Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly comorbid disorders -3. AccorDespite the commonalities between MDD and GAD there are also distinguishing factors. Some research, for instance, gave indications that there are differences in cognitive profiles -12. A nuSo overall there are suggestions for an overlapping shared latent structure behind GAD and MDD as well as for distinct underlying cognitive vulnerabilities as described in e.g. the tripartite and cognitive content-specificity models. Research on depression and anxiety cognitions across MDD and GAD shows inconsistent findings. A meta-analysis of Naragon-Gainey  showed tA better understanding of cognitive profiles in MDD and GAD is important for making accurate diagnostic decisions, and would indicate whether treatment approaches developed for MDD might be relevant for GAD and vice versa. Furthermore, it might highlight effective points of intervention for comorbid anxiety and depression symptoms. Little is known about differences and commonalities in cognitive profiles between comorbid MDD/GAD (having both a MDD and a GAD diagnosis) and MDD and GAD, but research indicated that a comorbid MDD/GAD diagnosis shows more severe cognitive problems than a single MDD or GAD diagnosis .Consequently, the extent to which underlying cognitive profiles across GAD and MDD are similar or distinct remains rather unclear. The present study will examine differences in cognitive profiles in three cognitive constructs: cognitive reactivity to sad mood, anxiety sensitivity and pathological worry. Cognitive reactivity to sad mood is defined as the extent to which dysfunctional schemas are activated when mood decreases,  and has The Netherlands Study of Depression and Anxiety (NESDA) is a naturalistic cohort study to examine the long-term course and consequences of depressive and anxiety disorders. A detailed description of the design and sampling is provided elsewhere . In shorThe Composite Interview Diagnostic Instrument (CIDI version 2.1)  was usedThe Leiden Index of Depression Sensitivity (LEIDS-R), the Anxiety Sensitivity Index (ASI) and the Penn State Worry Questionnaire (PSWQ) were used to examine cognitive profiles in MDD and GAD.The Leiden Index of Depression Sensitivity (LEIDS-R) -45 is a Anxiety Sensitivity Index (ASI)  is a 16-The Penn State Worry Questionnaire (PSWQ)  is origiCovariates included age, gender, years of education attained, current (6-month recency) comorbid social phobia and comorbid panic disorder.Statistical analyses were conducted with SPSS Version 20.0 . Chi-square statistics for categorical and analyses of variance for continuous variables were used to compare characteristics across MDD, GAD and comorbid MDD/GAD. Logistic regression analyses determined whether cognitive vulnerability differed significantly between MDD and GAD and whether comorbid MDD/GAD differed from the single disorders. Analyses were corrected for covariates age, gender, years of education attained, current comorbid social phobia, and current comorbid panic disorder. Effect sizes were measured by calculating Cohen’s d .The baseline characteristics of the respondents are summarized in Table Table Logistic regression analysis was used to determine whether cognitive vulnerability differed significantly between MDD, GAD, and comorbid MDD/GAD Tables  and 4. AFor MDD versus comorbid MDD/GAD Table  hopelessWhen comparing GAD and comorbid MDD/GAD Table , hopelesThe aim of this investigation was to examine cognitive profiles in MDD and GAD, and to examine whether cognitive profiles differentiate between these disorders. Furthermore, we wanted to investigate if the cognitive profile of comorbid MDD/GAD is more comparable with MDD or with GAD. The results showed that there are differences in depression and anxiety cognitions in MDD and GAD, although differences showed moderate effect sizes. Furthermore, most subscales showed similar results for MDD and GAD. Previous research is inconsistent about these findings. For example, in a meta-analysis Beck & Perkins  showed tOur results showed that rumination is more prominent in MDD whereas worry is more prominent in GAD. Although our findings are much in line with previous studies, -57 the aWe found higher scores on hopelessness/suicidality in MDD compared to GAD. Previous research reported that hopelessness is a stronger indicator of depression than anxiety, and may distinguish individuals with MDD from those with GAD ,21,25. SAnother finding in our study was that physical concerns are more prominent in GAD compared to MDD, but cognitive and social concerns do not differ between GAD and MDD. Anxiety sensitivity refers to the fear of anxiety symptoms because of beliefs about their perceived harmful physical, social, or cognitive consequences . Most ofThe cognitive profile of comorbid MDD/GAD showed more extreme depression cognitions than both single disorders, and a comparable anxiety profile compared to GAD. These results may suggest that comorbidity between MDD and GAD denotes a more severe illness since previous research showed that severity is strongly related to comorbidity . As mentThis study has several strengths. The large sample size, including well diagnosed subjects with affective and anxiety disorders allows in-depth analyses of the cognitive profiles of subjects with MDD and GAD. Subjects were recruited in both primary care and specialized mental health care increasing the generalizability of our findings to standard clinical settings.Limitations of this study should be acknowledged as well. First, the cross-sectional study design precludes any causal interpretations regarding the cognitive profiles in MDD and GAD, and longitudinal studies are necessary to address such questions. Second, GAD was not the only anxiety disorder present and we did not exclude subjects with other anxiety disorders. However, analyses were corrected for comorbid panic disorder and social phobia and comorbidity patterns were not different across single MDD and single GAD groups. Subjects were excluded when they had a clinically primary diagnosis of severe other psychiatric disorders such as psychotic, obsessive compulsive, bipolar or severe addiction disorder. However, some other conditions may have been present which were not further assessed, such as posttraumatic stress disorder, specific phobia, personality disorder or eating disorder. Consequently, we could not examine the full range of comorbidity among GAD and MDD in more detail. Third, the group sizes differed substantially: the GAD group was smaller compared to the MDD group, which indicates that statistical significance was harder to obtain for the single GAD group comparisons. However, when examining the results of the study, this does not seem to have affected the conclusions of the paper. Finally, a selection has been made among the available measurements of depression and anxiety cognitions. It would have been interesting to include intolerance of uncertainty, which is discussed broadly because of the possible high influence on the different paths leading to MDD and GAD ,29.The classification of MDD and GAD was under scrutiny in the process leading to DSM-5 and there has been a number of calls to reclassify GAD in the same category as MDD (‘the distress disorders’). Early GAD definitions suffered considerably from low reliability and poor validity. However, worry became the essential feature of GAD in DSM-III-R . DSM-IV The results of this study demonstrate that subjects with MDD and GAD have disorder-specific cognitive profiles, despite commonalities in other aspects. Specific depression cognitions, such as rumination, hopelessness, and suicidality, are more prominent in MDD whereas specific anxiety cognitions, such as physical concerns and pathological worry, are more prominent in GAD. These findings suggest that both MDD and GAD have specific features and may support a separate classification of MDD and GAD. Furthermore, the cognitive profile of comorbid MDD/GAD showed more extreme depression cognitions than both single disorders, and a comparable anxiety profile compared to GAD. The findings of this investigation give support for models like the cognitive content-specificity model and the tripartite model and could provide useful handles for treatment focus.The authors declare that they have no competing interests.SH participated in the design of the study, performed and interpreted the statistical analyses and wrote the manuscript. CL interpreted the statistical analyses and has critically revised the manuscript. JS, AB, FH and RdG have critically revised the manuscript. BP is the principal investigator of the NESDA study, and participated in the design of the study and revising the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/14/96/prepub


Currently available antidepressants used to treat major depressive disorder (MDD) unfortunately often take weeks to months to achieve their full effects, commonly resulting in considerable morbidity and increased risk for suicidal behavior. Our lack of understanding of the precise cellular underpinnings of this illness and of the mechanism of action of existing effective pharmacological treatments is a large part of the reason that therapies with a more rapid onset of antidepressant action (ROAA) have not been developed. Other issues that need to be addressed include heterogeneous clinical concepts and statistical models to measure rapid antidepressant effects. This review describes the timing of onset of antidepressant effects for various therapies used to treat MDD. While several agents produce earlier improvement of depressive symptoms (defined as occurring within one week), the response rate associated with such agents can be quite variable. These agents include both currently available antidepressants as well as other pharmacological and non-pharmacological interventions. Considerably fewer treatments are associated with ROAA, defined as occurring within several hours or one day. Treatment strategies for MDD whose sustained antidepressant effects manifest within hours or even a few days would have an enormous impact on public health.  Major depressive disorder (MDD) is a severe, recurrent, and disabling medical illness, that is highly prevalent worldwide and that is associated with a significant negative impact on productivity and quality of life. In this context, clinical improvement during the first month of treatment with antidepressants is a critical component for achieving long-term stability . HoweverNotably, this lag in onset of antidepressant action is associated with negative consequences. Jick and colleagues described an increased risk of suicidal behavior during the first month of antidepressant treatment, particularly during the first nine days; this risk was similar regardless of the chemical class of antidepressant  . It is iDelayed onset of antidepressant effects can also be associated with psychosocial losses. Depressive episodes limit quality of life by limiting the ability of individuals to function socially and occupationally, thus impairing the skills needed to work, to create and maintain relationships, and to function and be productive across multiple domains ,10. ConsPresently, any discussion of the timing of antidepressant effects associated with either traditional antidepressants or novel therapeutic agents is hampered by the lack of any consistent definition for the terms “early improvement of depressive symptoms” or “rapid onset of antidepressant effects” (ROAA). For the purposes of this review, we define “early improvement of depressive symptoms” as improvement that occurs within one week; however, response rates associated with such agents, including traditional antidepressants from diverse classes, are quite variable (see below). In contrast, agents with ROAA induce significant response rates within a few hours or one day; as we discuss later, considerably fewer agents are associated with ROAA. Current definitions of response/remission were developed to detect improvement occurring only after several weeks; thus, whether the same definition could or should apply when defining a response that occurs within a few hours or even a few days is still unclear. In fact, most of the findings regarding the early therapeutic effects of currently available antidepressants were drawn from post-hoc analyses and meta-analyses of clinical trials that were not specifically designed to detect the speed of onset of improvement in depressive symptoms, thus presenting several limitations when attempting to assess this parameter .Treatment response has been widely characterized as a 50% decrease in Hamilton Depression Rating Scale (HAM-D) score compared to baseline. The definition of remission varies considerably from study to study, but at least one widely-used definition describes remission as a HAM-D score lower than 8 ,14. In cThe stringency of current criteria for evaluating rapid antidepressant effects and the lack of standard procedures for measuring it clearly demonstrate the need to assess currently-used depression rating scales according to different validity paradigms potentially associated with an earlier improvement in depressive symptoms . For insAs noted previously, for the purpose of this review we define ROAA agents as those that induce significant response rates within a few hours or one day of administration. To date, only a few such agents have been definitively identified. They include thyrotropin releasing hormone (TRH), ketamine, and sleep deprivation (SD). Several other agents associated with earlier improvement of depressive symptoms are also being investigated. In this review, we define earlier improvement of depressive symptoms as those that occur within one week, though the response rate associated with such agents can be quite variable. Such agents, reviewed below, include both currently available antidepressants , olanzapine-fluoxetine combination (OFC), intravenous administration of standard antidepressants (ISA), and mirtazapine) as well as other pharmacological and non-pharmacological interventions (electroconvulsive therapy (ECT), pindolol, stimulants, hypothalamic pituitary adrenal (HPA) axis inhibitors, repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), and the NR2B subunit-selective antagonist .Our ability to develop newer, faster-acting, and more effective antidepressants has been hampered by the fact that the biological aspects involved in the first weeks of antidepressant treatment are still poorly understood. In the last few decades, the monoaminergic hypothesis of depression has been considered a useful neurobiological model for explaining the delayed onset of antidepressant response associated with these agents. According to this hypothesis, a reliable and sustained antidepressant response can only occur after two to three weeks of treatment with standard antidepressants ,19. HymaHere, we begin by reviewing studies that more precisely examine the timing of onset of currently available antidepressants, regardless of class. Some studies have suggested that for currently available antidepressants, the average time for onset of antidepressant action is 13 days, but when considering full response criteria, this period goes up to 20 days ,23. To s However, these findings have been questioned by several investigators who demonstrated that early improvement (defined as improvement occurring in the first two weeks) is a real antidepressant effect, and not secondary to placebo response; furthermore, this early improvement potentially predicted subsequent positive long-term outcome. For instance, a recent meta-analysis found that patients using currently available antidepressants had a significantly higher rate of sustained clinical response beginning at Week 1 or 2, compared to individuals receiving placebo . AnotherNevertheless, some limitations are present in any discussion of this topic. For instance, when evaluating mean time to response or remission, current antidepressants may show a latency period longer than two weeks. Second, most of the studies pooled in the meta-analyses were not specifically designed to detect rapid antidepressant effects because of the reduced frequency of early assessments as well as the statistical methods used. Finally, available depression rating scales and sub-scales for evaluating early improvement possess limited validity when measuring score changes and differences between real antidepressant and placebo effects for those assessments conducted earlier than a week after treatment onset; obviously, this would affect investigators’ ability to assess improvement that occurs within hours or days. Finally, and as noted previously, the field currently has no clear or standard definition of ROAA compared with “early” or “earlier” improvement of depressive symptoms. Because depression is a multi-faceted disorder, some investigators have suggested that any measure used to evaluate early improvement should include subscales measuring cognitive, vegetative, and emotional dimensions ,27,28. Ietc.). Recently, the same investigators proposed a direct connection between antidepressant-induced neural and behavioral changes  and the prediction of clinical outcome based on early response [This approach has, as yet, not been widely adopted. Only the studies performed by Katz and colleagues have systematically investigated individual depressive dimension changes associated with different antidepressants, or addressed the methodological limitations of previous studies assessing earlier improvement of depressive symptoms  [Mirtazapine is an αiewed in ). Simila[vs. 6%) . Recent [vs. 6%) . In cont[vs. 6%) . Overall[vs. 6%) ,25.ECT has been considered the most effective and rapid-acting long-term somatic treatment in psychiatry . Some st1A autoreceptors in the dorsal raphe nucleus subsequent to an initial increase in serotonin levels [1a blocker pindolol led to only a modest (19%) occupancy of the 5-HT1a autoreceptor [1A autoreceptors directly influences brain serotonergic function.Augmenting serotonergic central metabolism is believed to play a central role in the therapeutic effects of diverse antidepressants . As noten levels . A PET sreceptor . In healreceptor , suggest1A autoreceptors and regulate serotonergic neuronal firing rates [Since the first placebo-controlled trial showing a faster onset of antidepressant action using pindolol as an add-on treatment to SSRIs, more than fifteen trials have been performed . A recenng rates . InteresAnecdotal data suggest that stimulants may shorten the latency period for antidepressant response. For instance, early reports noted an earlier onset of antidepressant effects with the stimulant benzedrine . MethylpIn recent years, several drugs that target the HPA axis have been investigated for their potential antidepressant properties. Consistent evidence exists that both MDD and bipolar disorder are associated with HPA axis dysfunction. Specifically, depressed patients show increased levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol compared to normal controls, which purportedly normalize after antidepressant response. CRH receptor antagonists, glucocorticoid receptor (GR) antagonists, and steroid synthesis inhibitors are the three major classes of these compounds being investigated in the treatment of mood disorders. The non-selective GR antagonist mifepristone RU-486) was associated with antidepressant and antipsychotic effects in psychotic depression . In a si was assoIn preclinical studies, altered CRF1 receptor activity critically regulated depressive-like behaviors. As a result, diverse nonpeptide CRF1 receptor antagonists have also recently been tested preclinically as potential antidepressant agents (reviewed in ), includAnother recent, double-blind, placebo-controlled trial investigated the antidepressant effects of add-on treatment (nefazadone or fluvoxamine) with metyrapone, a steroid synthesis inhibitor, in hastening antidepressant response . SurvivarTMS is a non-invasive tool that has recently been used to treat MDD. The precise biological mechanisms involved in its mechanism of antidepressant action have yet to be elucidated ,96. RumiDBS is a surgical treatment involving the implantation of a medical device that sends electrical impulses to specific parts of the brain. It is approved as a treatment for Parkinson’s disease and dystonia, and is also routinely used to treat chronic pain. In patients with treatment-resistant MDD, DBS reduced elevated activity in the subgenual cingulated cortex (Cg25). Although clinical response was not directly assessed, symptoms of depression were noted to improve within a short period of time . After aFollowing the promising findings obtained with ketamine (see below), the potential rapid antidepressant efficacy of the NR2B subunit-selective antagonist CP-101,606 was investigated [The tripeptide TRH modulates serotonergic, dopaminergic, and glutamatergic transmission in cortical and limbic areas ,103,104.In addition to route of TRH administration, the timing of TRH administration also seems to be a key issue in studying its antidepressant properties. For instance, nocturnal intravenous TRH induced rapid clinical response within 24 hours of administration  in patieN-methyl-D-aspartate (NMDA) antagonist ketamine induced a rapid (within two hours) and sustained (one to two weeks) antidepressant effect in patients with treatment-resistant MDD [Recently, Zarate and colleagues showed that a single infusion with the tant MDD . Previoutant MDD . The rantant MDD . More thInterestingly, ketamine also significantly reduced suicidal ideation in individuals with treatment-resistant MDD ,115. The1A autoreceptors after total SD [Sleep deprivation (SD) has consistently been shown to induce rapid, dramatic, but transitory antidepressant effects in depressed patients that usually last until recovery sleep takes place . Studiestotal SD . Recent Interestingly, the potential activation of plasticity-induced pathways during SD appears to be predominantly mediated by the activation of noradrenergic projections in the locus coeruleus. One night of SD has been demonstrated to stimulate hippocampal neurogenesis, but opposite effects have also been described ,124. PhaHigh rates of relapse (around 80%) are common following sleep recovery ,126. ThuThis model seems to be useful and reliable for studying specific validity paradigms related to the neurobiological basis of depressive episodes, but its putative long-term antidepressant effects—either as monotherapy or as an add-on strategy—have not yet been demonstrated. Currently available antidepressant medications all exhibit a delayed onset of antidepressant response, resulting in considerable morbidity, disruption to personal, professional, family, and social life, and elevated suicide risk. Any antidepressant treatment that shifts the time frame of response from weeks to a few hours would undoubtedly revolutionize the care of the millions of individuals who suffer from MDD. Most current approaches for examining early or rapid improvement in depressive symptoms have focused on weekly evaluation. As a result, the field of psychiatry lacks any consistent definition of “earlier” improvement in depressive symptoms or ROAA. In this review, we have defined the former as occurring within one week of administration, and the latter as occurring within hours or one day of administration. In this respect, the recent studies conducted with sleep deprivation, ketamine, and TRH provide direct evidence that ROAA in a few hours is possible. Therefore, any new paradigm to evaluate ROAA must include the evaluation of antidepressant efficacy occurring within hours or days of first administration. In this context, future studies focusing on the onset of antidepressant effects should address three major issues: 1) the time necessary for antidepressants to induce a significantly greater therapeutic effect  compared to placebo, and the potential association of this effect with other outcomes such as response and remission; 2) the timing of improvement in individual depressive symptoms and constructs, given that some specific symptoms or groups of symptoms (clusters) may remit faster than others depending on the class of antidepressant used; and 3) elucidating the relationship between early improvement and long-term effect, which is critical for confirming any agent’s potential ability to affect long-term outcome. Also, it should be pointed out that many substances are capable of inducing transitory euphoria and hyperactivity limited to the half-life of the compound administered, but these effects cannot be characterized as improving core depressive symptoms. As the search for treatments for MDD continues, it is crucial to change the way we understand and conduct drug development. As with other areas of medicine, our gradual understanding of the pathophysiology of MDD and the mechanism of action of currently available antidepressants indicates that an antidepressant response that occurs within hours is now an obtainable goal. As this review has highlighted, there is direct evidence that such a rapid response is possible. Therefore, instead of developing treatments that take weeks to induce response, the next generation of antidepressants should aim to resolve symptoms within hours, thereby alleviating much of the suffering associated with MDD.


Conceptually, stem cells can act directly to myelinate axons or indirectly through different mechanisms to promote endogenous repair; importantly these two mechanisms of action are not mutually exclusive. We propose that discovery of novel methods to invoke or enhance remyelination in MS may be the most effective therapeutic strategy to limit axonal damage and instigate restoration of structure and function in this debilitating condition. Human stem cell derived neurons and glia, including patient specific cells derived through reprogramming, provide an unprecedented experimental system to model MS “in a dish” as well as enable high-throughput drug discovery. Finally, we speculate upon the potential role for stem cell based therapies in MS.Multiple Sclerosis (MS) is an inflammatory demyelinating neurodegenerative disorder of the brain and spinal cord that causes significant disability in young adults. Although the precise aetiopathogenesis of MS remains unresolved, its pathological hallmarks include inflammation, demyelination, axonal injury (acute and chronic), astrogliosis and variable remyelination. Despite major recent advances in therapeutics for the early stage of the disease there are currently no disease modifying treatments for the progressive stage of disease, whose pathological substrate is axonal degeneration. This represents the great and unmet clinical need in MS. Against this background, human stem cells offer promise both to improve understanding of disease mechanism(s) through  Multiple Sclerosis (MS) is a chronic inflammatory and progressive demyelinating disorder of the central nervous system that causes significant morbidity. It has a prevalence of 1.2 per 1000 and a lifetime risk of 1 in 400 [MS is the prototypic immune-mediated demyelinating disease characterized pathologically by mult-focal and multi-phasic inflammatory demyelinating lesions of the central neuraxis. Blood-brain barrier breakdown and subsequent (multi-) focal inflammation typically leads to clinical disability in the form of discrete relapses. In addition to targeting a particular neural cell type , MS additionally exhibits regional bias with particular sites of predilection, including the optic nerves, periventricular white matter, cerebellum and corpus callosum. Most MS patients develop progressive and permanent neurological deficit after 10–15 years of disease activity. Axonal loss and progressive brain atrophy are histologically and radiologically conspicuous features of MS –6, and cIn vivo studies demonstrate that these two processes are intricately coupled, and suggest that remyelination will serve to protect axons [The major therapeutic goal in MS is neuroprotection; two important components of this goal are the promotion of remyelination  and the ct axons –13 in adct axons ,15. Althct axons ,17, its ct axons ,19. UnfoFollowing an episode of demyelination, sodium channels  redistribute as a compensatory mechanism thus allowing conduction to be maintained ,21 . The repopulation of demyelinated areas by adult OPCs is robust [i.e., repeated / continuous disease activity), this may well contribute to remyelination failure [Why remyelination fails in some lesions but not others is unknown . Some ofs robust , suggests robust . It has  failure ,47. A fa failure  and is s failure  or aberr failure . Differe failure –54. The  failure ; age rel failure ,57. Chan failure ,59, as h failure –62. Addi failure  and gene failure .Pathological studies from patients with early and aggressive multiple sclerosis have proven to be a valuable resource for understanding early pathological events ,66, inclDetailed pathological analyses of more chronic progressive MS cases have also yielded valuable insights including an association of progressive disease with insoluble tau accumulation ,68, not in vivo  to these co-culture models can be utilized to gain further insight into the molecular pathogenesis of MS as previously described [in vitro myelination co-culture systems will facilitate the discovery of novel therapeutics in a more focused and clinically relevant manner. Such approaches will complement existing and indispensible in-vivo model systems.Against this background, the isolation of human embryonic stem cells (hESCs)  and subsescribed –30,99. SA stem cell is defined as having the ability to both self-renew and generate specialised cell types. The differentiation of a stem cell to a specialized cell type is often simplified to a series of phenotypically defined populations, but in fact this is a continuum with multiple specific genetic steps (which may overlap). Human stem cells are of value as both an experimental resource (to study disease mechanisms and for drug discovery) and, potentially, a therapeutic strategy. Their ability to generate almost unlimited numbers of potentially clinical grade region-specific functional neuronal and glial populations while remaining karyotypically stable makes them a valuable resource.in vitro, responding predictably to developmental cues. Human ESCs (hESCs) were first isolated by Jamie Thompson’s laboratory in 1998 [A common taxonomy of stem cells is based on the developmental stage of isolation, which in turn determines the repertoire of specialised cell types they can generate (or their “potency”). Stem cells isolated from early stages of development possess greater potency than those from later in development. Embryonic stem cells (ESCs) are a type of pluripotent stem cell (PSC) that posses the greatest potency  in 1998  from the in 1998 –102. The in 1998 ,104.c-myc transcription factor. However, progress has since been made to improve efficiency and/or reduce the need for genetic manipulations [Initial attempts to derive pluripotent stem cells by different methods were largely inspired by early nuclear transfer experiments from Sirs John Gurdon and Ian Wilmut ,106. Theulations –110. Humulations ,111,112.in vitro human stem cell based systems can begin to capture this diversity [Human ESCs and iPSCs thus represent a powerful and unparalleled experimental opportunity to model neurodegenerative disease by virtue of their competence to respond to developmental signals permitting specification of functional neurons and glia. Thus far, directed differentiation has been achieved to various region-specific fates including human spinal cord, midbrain and forebrain neurons ,113,114.iversity ,90. Estaiversity .Human iPSCs offer an advantage over hESCs in enabling study of patient specific lines including disease-causing mutations from routine manipulation of readily available patient material ,116. TheCompared to ESCs, stem cells isolated at later developmental stages  possess restricted phenotypic potentials that are defined by both the tissue and the tissue sub-region from which they are isolated. Several studies have demonstrated that these cells cannot be readily directed towards a myelinating cell fate, a desirable attribute in demyelinating conditions such as MS –125. Givvs. non-cell autonomous mechanisms of disease is of considerable importance in this context, and can be directly addressed using a hPSC-based model system. One major challenge of using such an approach for the study of MS disease mechanisms is the difficulty of reliably generating oligodendrocytes from hPSCs [in vitro environment to model injury and repair in MS. Oligodendrocytes can then be used to myelinate neurons derived from the same hPSCs. Such myelination co-cultures can then be perturbed using injurious stimuli known to be relevant in MS in order to elucidate the precise mechanisms disrupting integrity of the neuron–oligodendrocyte interaction. Systematically and incrementally increasing the complexity of such co-culture systems will ultimately allow precise recapitulation and understanding of the key pathological phenomena in MS.The concept of cell autonomous om hPSCs , althougom hPSCs ,93,95. Iin vitro screening.Similar studies using rodent systems demonstrate the practical feasibility and conceptual value of such approaches; they have elegantly identified some of the mechanisms by which oligodendrocytes are neuroprotective ,30, inclvs. non-cell autonomous mechanisms of disease. The recent paradigm shift in motor neuron disease being (at least in part) an astrogliopathy [vs. non-cell autonomous mechanisms of oligodendrocyte injury and protection using similar strategies in co-culture paradigms . The emerging neuroprotective role of astrocytes is also both of great interest and potential relevance neurodegenerative disease [vs. anisotopic  co-culture paradigms. There is some evidence from using isotopic (midbrain) foetal astrocytes in co-culture with ESC derived midbrain dopaminergic neurons, which suggests that such experiments will be informative [The dynamic and evolving role of astrocytes in neurodegeneration and neuroprotection is another particularly relevant example of cell autonomous liopathy –133 high disease , althougormative .Broadly, stem cell therapy could work by two mechanisms, which are not mutually exclusive: (i) exogenous cell replacement and (ii) by enhancing endogenous repair.Once the desired cell type (OPC) has generated it must be rigorously characterized to qualify as a viable therapeutic candidate. The cells must have the robustness to survive and migrate through the pathological host milieu in order to myelinate denuded axons, exist is sufficient numbers, retain to capacity to proliferate and avoid immune rejection, while not causing tumor formation. Successful remyelination has been achieved experimentally in a range of animal models and using a variety of cell types. These have included embryonic- and adult-derived cells of the oligodendrocyte lineage, Schwann cells, olfactory ensheathing cells (OECs), and neural precursors (NPCs) and non-NPCs ,136–144.However, the translatability of these findings in acute monophasic rodent models to human MS, which is a relapsing-remitting chronic inflammatory condition, is less clear. Recognition of different lesion pathological phenotypes  also raiex vivo lineage commitment is of critical importance. This is illustrated by the demonstration in animal models (attempting to achieve exogenous remyelination) that mature oligodendrocytes are ineffective whereas oligodendrocyte progenitor cells (OPCs),  succeed and remyelinate [i.e., the degree of lineage commitment) and the effects of host environment on post-implantation lineage subspecification are thus critical if the promise of stem cells is to be realised in the clinical arena.Multiple specific genetic steps contribute to the transition from stem cell to a terminally differentiated state, raising the question of which specific point in the differentiation process provides cells best suited to the desired therapeutic goal. Successful therapeutic strategies require consideration of both (i) the pathogenic environment into which cells are to be deployed, and (ii) the desired therapeutic action . For example, an inflammatory environment has been shown to promote astrocyte specification from NPCs , whereasyelinate . These iOf these two strategies, promoting endogenous repair may prove more clinically realistic and practically feasible in the near future. Specifically, given that repopulation of MS plaques with functional OPCs is robust, the virtue of transplanting OPCs into such lesions is questionable and may be unnecessary. As endogenous remyelination can be extensive ,15 and rEx vivo pre-transplantation manipulation of stem cells is a possible strategy here; but it seems more intuitive to engage the abundant endogenous OPC population (possibly through exogenous stem cells). Against that background, a further noteworthy generic attribute of stem cells is the capacity to dynamically interact with the microenvironment they migrate to in a manner that may be beneficial to the host, or “therapeutic plasticity”. Promoting endogenous repair might also be achieved by transplanting engineered stem cells that secrete growth factors  or targh factor ) that exex-vivo manipulation to secrete growth factors as mentioned above. A recent clinical trial has confirmed that autologous MSCs can be safely administered intravenously in secondary progressive MS with some evidence to suggest structural, functional and physiological improvement following treatment consistent with neuroprotection [Stem cells can also be isolated from non-neural tissues throughout life . Although these cell populations do not reliably generate functional neural derivatives, their therapeutic potential arises from their biological properties through either the direct constitutive actions of the cells in question, such as immunomodulatory, or through their use as a vehicle following otection . It is lin vitro modeling of disease mechanisms and discovering new therapeutic strategies. Proof-of-concept studies have already demonstrated the practical feasibility of using both mouse and human in vitro iPSC model systems to elucidate both cell-autonomous and non-cell-autonomous mechanisms of neurodegeneration [Current therapeutic strategies for MS focus on symptomatic treatment and have only limited scope for arresting disease progression, let alone restoring structure and function where neurological deficit has accumulated. There is a large and unmet clinical need for new treatments in MS, particularly in the progressive phase. A key objective in terms of understanding the underlying molecular pathology, is to unravel the interrelationship of inflammation and axonal loss in MS; the key therapeutic objective to prevent axonal loss and limit demyelination. An intuitive strategy is to promote remyelination to achieve axonal protection. Recent advances in human stem cell biology have given rise to unprecedented experimental opportunities to study neurodegenerative disease using clinically relevant model systems, and patient-derived iPSCs now offer an unparalleled human system for neration –133. At


Vector control has substantially reduced Chagas disease (ChD) incidence. However, transmission by household-reinfesting triatomines persists, suggesting that entomological surveillance should play a crucial role in the long-term interruption of transmission. Yet, infestation foci become smaller and harder to detect as vector control proceeds, and highly sensitive surveillance methods are needed. Community participation (CP) and vector-detection devices (VDDs) are both thought to enhance surveillance, but this remains to be thoroughly assessed.We searched Medline, Web of Knowledge, Scopus, LILACS, SciELO, the bibliographies of retrieved studies, and our own records. Data from studies describing vector control and/or surveillance interventions were extracted by two reviewers. Outcomes of primary interest included changes in infestation rates and the detection of infestation/reinfestation foci. Most results likely depended on study- and site-specific conditions, precluding meta-analysis, but we re-analysed data from studies comparing vector control and detection methods whenever possible. Results confirm that professional, insecticide-based vector control is highly effective, but also show that reinfestation by native triatomines is common and widespread across Latin America. Bug notification by householders (the simplest CP-based strategy) significantly boosts vector detection probabilities; in comparison, both active searches and VDDs perform poorly, although they might in some cases complement each other.CP should become a strategic component of ChD surveillance, but only professional insecticide spraying seems consistently effective at eliminating infestation foci. Involvement of stakeholders at all process stages, from planning to evaluation, would probably enhance such CP-based strategies. Blood-sucking triatomine bugs are the vectors of Chagas disease, a potentially fatal illness that affects millions in Latin America. With no vaccines available, prevention heavily depends on controlling household-infesting triatomines. Insecticide-spraying campaigns have effectively reduced incidence, but persistent household reinfestation can result in disease re-emergence. What, then, is the best strategy to keep houses free of triatomines and thus interrupt disease transmission in the long run? We reviewed published evidence to (i) assess the effectiveness of insecticide-based vector control, gauging the importance of reinfestation; (ii) compare the efficacy of programme-based  and community-based (with residents reporting suspect vectors found in their homes) surveillance strategies; and (iii) evaluate the performance of alternative vector-detection methods. The results confirm that insecticide-based vector control is highly effective, but also that persistent house reinfestation is a general trend across Latin America. Surveillance systems are significantly more effective when householders report suspect bugs than when programme staff search houses, either manually or using vector-detection devices. Our results clearly support the view that long-term vector surveillance will be necessary for sustained Chagas disease control – and that community participation can substantially contribute to this aim. Trypanosoma cruziChagas disease still imposes a heavy burden on most Latin American countries, with about 10–12 million people infected by This rapid overview shows why sustained Chagas disease control is believed to require some sort of longitudinal, long-term surveillance system capable of detecting and eliminating household infestation foci However, detecting the vectors can be difficult, particularly when only small populations occur within or around households. In fact, vector colonies are expected to become rarer and smaller as control programmes proceed, and managers are progressively less prone to fund costly active surveillance resulting in few detection events. A number of vector-detection devices have been designed in an attempt to enhance surveillance; most consist of boxes that triatomines can use as refuges or of paper sheets or calendars where the typical faecal streaks of the bugs can be identified Finally, and since the early vector control trials, there has been a perception that resident householders may have better chances of discovering bugs in their own homes than a visiting team searching the house for a few minutes every several months However, the effectiveness of these diverse strategies for Chagas disease vector surveillance, including community participation, has not been thoroughly and objectively assessed at the continental scale. With the aim of filling this gap, we systematically reviewed the published evidence on this issue, tackling specifically the following major questions: (i) How common and important is the phenomenon of house reinfestation by triatomine bugs after control interventions?; (ii) How effective are different vector surveillance strategies at detecting infestation/reinfestation foci?; (iii) To what extent have community participation and empowerment been effectively promoted?; and, finally, (iv) Can available strategic options be condensed in overarching recommendations for surveillance that apply across the highly diverse ecological and social-cultural settings where the problem is present?The review protocol is available upon request from the corresponding author. This review was carried out in the context of a collaborative project led by the Inter-American Development Bank, and was not formally registered. We searched Medline, ISI Web of Knowledge, Scopus, LILACS, and SciELO; the major query argument was “Triatomin* AND (Control OR Surveillance)”. Searches retrieved records from 1948 to 2009, including additional documents identified by searching bibliographies and in the authors' records. This search strategy aimed at recovering documents describing vector control interventions, with or without surveillance, so that post-control reinfestation trends could also be assessed. Only documents describing field interventions aimed at the control and/or surveillance of domestic Chagas disease vectors were included in the full review process. Descriptive (non-intervention) reports, results of research with laboratory or experimental vector populations, expert reviews, and opinion or commentary pieces were either excluded or used only for the introduction and/or discussion.Guide to Community Preventive Serviceswww.thecommunityguide.org) and including study quality indicators. FA-F revised data extraction results and resolved inconsistencies by re-checking the original documents. The following items were considered: (1) study classification ; (2) descriptive information, including (2.i) description of the intervention , (2.ii) study characteristics , (2.iii) results , and (2.iv) applicability in settings other than the actual study one ; and (3) study quality, including quality of descriptions, sampling , effect measurements, data analyses , and interpretation of results . Relevant references and other details deemed important were also recorded. The protocol required extracting detailed demographic data about intervention and control or indirectly affected populations. Such information was however absent from or incomplete in most studies; this, together with the fact that the outcomes of primary interest refer to households, not individual people, led us to exclude these items from the protocol during the course of the review.We were particularly interested in comparing strategies involving institutional  or participatory surveillance. We also compared alternative methods for vector detection, including active searches, vector-detection devices, and community participation. Major outcomes included household infestation/reinfestation indices  and vector detection rates. Inclusion/exclusion of documents was assessed independently by ARdA and FA-F, and discrepancies resolved by consensus. http://faculty.vassar.edu/lowry/VassarStats.html) and Microsoft Office Excel® spreadsheets were used for the analyses.The often important morphological, ecological and behavioural differences among triatomine bug species Database searches retrieved 1,342 candidate documents; elimination of duplicates yielded 858 unique records  in EngliThe spatial and ecological coverage of our review is represented in Collaborative efforts involving both academic institutions and official public health agencies were common (∼70% of studies), a typical historical trait of Chagas disease vector control Triatoma infestans populations T. infestans foci reappear quickly after spraying  and that standard deltamethrin application with manual sprayers performs better than more sophisticated techniques Since Carlos Chagas historic paper The ultimate measure of vector control effectiveness is the reduction of disease incidence. This is usually assessed through serological surveys For the purposes of our quantitative appraisal, we defined ‘community participation’ in Chagas disease vector surveillance as simply the involvement of local residents in reporting the presence of suspect bugs in their households. This narrow definition is justified by (i) the need to use some measure of effect size that is  comparable across studies, (ii) the fact that vector detection is the primary purpose of entomological surveillance, (iii) the fact than most ‘participatory’ experiences are limited to stimulating bug notification, and (iv) the principle of parsimony, whereby simpler approaches to surveillance, if they are shown to work, enjoy better chances of effectively translating into policy and practice. With a few exceptions, notification by residents performs obviously much better than active bug searches at detecting infestation foci, although the effect seems to be somewhat smaller in the peridomestic environment Conclusions and outlook) we provide methodological suggestions to this end.Several ‘passive’ vector surveillance methods have been devised and tested over the years. As defined here, they differ from the traditional, ‘active’ surveillance approach in that control programme agents do not search the whole residence to determine whether it is infested; instead, they rapidly check for bugs (or their traces) in a ‘detection device’. T. cruzi vectors In the long run, Chagas disease prevention will depend on keeping households free of T. cruzi, and that even the most notorious ‘primary’ vectors, T. infestans and Rhodnius prolixus, are native (and reinfest treated households) Entomological surveillance primarily aims at detecting (then eliminating) household infestation foci; it thus allows for monitoring reinfestation trends in areas under control But in order to attain these goals, vector detection must be as effective as possible, and the evidence we have reviewed shows that available vector-detection techniques all work far from perfectly. What would be, then, the best strategy to meet the permanent challenge of detecting reinfestation? Our appraisal yields strong support to the view that notification of suspect vectors by residents is the most sensitive among the several detection approaches tested to date – and that it is also probably the cheapest. Furthermore, the difference in performance seems to widen as vector population density declines, which is the typical situation in post-control settings.Such an austere ‘participatory’ strategy signals the minimum degree of community involvement required to effectively enhance surveillance: residents are just asked to report suspect insects found in their homes, and a response is mounted by professional staff, often related to decentralised health services This is not to say that more sophisticated approaches would not perhaps bring further benefits to people living under risk conditions. For instance, we found that most community-based experiences in Chagas disease vector surveillance are merely utilitarian, with little or no participation of the community in the design, planning, and evaluation of interventions. Effective involvement of all stakeholders along the whole process would no doubt foster true empowerment, and this could in itself result in improved health and living standards Finally, our review revealed that there is plenty of room for improvement of both methodological and reporting standards in the Chagas disease control/surveillance literature. In many cases, the results were reported incompletely and/or confusingly, sometimes precluding data extraction; in several instances, the data in the text, tables, and figures were incongruent. Indeed, just a few of the reviewed studies followed high-quality designs  and used sound analytical approaches, particularly in relation to the non-independence of observations; these reports tended to rely on small sample sizes and/or have limited spatial scope. Apart from the obvious need for using adequate design and analytical procedures, several guidelines for good reporting practices are readily available  are not bias-induced artefacts. We also note that our assessment focused on the initial stage of surveillance – the detection of infestation foci. The responses triggered by detection events, the monitoring of infestation trends, and the analysis and dissemination of epidemiological data are also essential components of disease surveillance Entomological surveillance is and will remain crucial to contain Chagas disease transmission; yet, the zoonotic nature of the parasite's life cycle implies that eradication is unfeasible It must finally be emphasised that, in practice, vector detection failures are unavoidable, particularly when bug population density is low Abstract S1Spanish and Portuguese translations of the abstract.(DOC)Click here for additional data file.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.List S193 documents submitted to full data extraction.(DOC)Click here for additional data file.List S227 documents used in partial quantitative assessments but not submitted to full data extraction.(DOC)Click here for additional data file.


Neural circuits distributed within the brainstem, hypothalamus, and limbic forebrain interact to control food intake and energy balance under normal day-to-day conditions, and in response to stressful conditions under which homeostasis is threatened. Experimental studies using rats and mice have generated a voluminous literature regarding the functional organization of circuits that inhibit food intake in response to satiety signals, and in response to stress. Although the central neural bases of satiation and stress-induced hypophagia often are studied and discussed as if they were distinct, we propose that both behavioral states are generated, at least in part, by recruitment of two separate but intermingled groups of caudal hindbrain neurons. One group comprises a subpopulation of noradrenergic (NA) neurons within the caudal nucleus of the solitary tract  that is immunopositive for prolactin-releasing peptide (PrRP). The second group comprises non-adrenergic neurons within the cNST and nearby reticular formation that synthesize glucagon-like peptide 1 (GLP-1). Axonal projections from PrRP and GLP-1 neurons target distributed brainstem and forebrain regions that shape behavioral, autonomic, and endocrine responses to actual or anticipated homeostatic challenge, including the challenge of food intake. Evidence reviewed in this article supports the view that hindbrain PrRP and GLP-1 neurons contribute importantly to satiation and stress-induced hypophagia by modulating the activity of caudal brainstem circuits that control food intake. Hindbrain PrRP and GLP-1 neurons also engage hypothalamic and limbic forebrain networks that drive parallel behavioral and endocrine functions related to food intake and homeostatic challenge, and modulate conditioned and motivational aspects of food intake. Factors that increase or decrease food intake do so by altering meal size, meal frequency, or both Smith, , 2000. SSatiation and satiety are normal, everyday processes. However, consuming a satiating meal can be stressful, especially if food intake occurs at an unusual  time, or if the meal is unusually large or calorically dense. Food intake presents an immediate physiological challenge to homeostasis Woods, , and thein vitro  neurons within the caudal nucleus of the solitary tract , a majority of which express prolactin-releasing peptide , and other regions of the pons, diencephalon, and telencephalon that are implicated in food intake and body energy balance Rinaman, . Direct Many reports cited in the present review leave open the possibility that functions ascribed to central signaling by PrRP and/or GLP-1 neurons include signaling from neurons located not within the cNST, but within the nearby medullary reticular formation. PrRP-positive neurons comprise a subset of the cVLM A1 NA cell group , the rate-limiting enzyme for dopamine synthesis, together with dopamine beta hydroxylase (DbH), the enzyme that converts dopamine to norepinephrine , where they form synaptic contacts with corticotropin releasing hormone (CRH)-positive neurons  or deprivation-induced food intake. By virtue of their synaptic inputs to CRH neurons, we hypothesize that PrRP and GLP-1 neurons may drive HPA axis responses to food intake, because PrRP and GLP-1 neurons drive HPA axis responses to some  experimental stressors  adult rats that are killed during the first few hours of the light cycle. Under such conditions, identified PrRP and NA neurons rarely express cFos in rats or mice  of small meals each day, with ∼80% of daily food intake occurring nocturnally, and the largest meals predictably consumed near the beginning and end of the dark phase of the photoperiod  receptors. However, central administration of a monoclonal anti-PrRP antibody in rats was reported to increase meal size but not meal frequency, and to increase total food intake compared to the effects of a control antibody , a specific GLP-1R antagonist. Daily intraventricular administration of Ex-9 produces daily increases in food intake compared to intake by rats after vehicle administration , and acute handling for central or systemic drug injection. Such manipulations are themselves likely to promote some degree of stress-induced hypophagia, such that “baseline” food intake measured in animals after central or systemic vehicle treatment may be less than intake that would be observed under non-manipulated conditions. Accordingly, the ability of centrally administered Ex-9 or anti-PrRP antibody to increase food intake could be interpreted as evidence that central GLP-1 or PrRP signaling attenuates stress-induced hypophagia. Some experiments have attempted to address this issue by pre-exposing animals to experimental handling and drug infusion conditions in order to habituate them to the potentially stressful aspects of those conditions. However, results in “habituated” animals rarely are compared to results obtained in non-manipulated animals, making it unclear whether or how the habituation procedure affected results. It will be important for future studies to include additional comparative data from non-manipulated controls.To better understand the role of endogenous GLP-1 signaling in satiation and long-term energy balance, one research group used a knockdown strategy in which short hairpin RNA was microinjected into the cNTS of adult rats to suppress endogenous PPG expression; this produced a significant and long-lasting increase in daily food intake and body weight compared to control rats -deficient mice display hyperphagia under ad lib feeding conditions, but not in a one-time 16 h fasting/re-feeding protocol , promote the release of proinflammatory cytokines, elevate plasma levels of ACTH and corticosterone (Sapolsky et al., One of the most commonly used models of cognitive stress is physical restraint, which activates the HPA axis and suppresses food intake (Rybkin et al., Stress affects both food intake and energy balance, and food intake can itself be stressful Woods, . For theThe 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.


Diabetes mellitus is one of the most common chronic global diseases affecting children and adolescents in both the developed and developing nations. The major types of diabetes mellitus are type 1 and type 2, the former arising from inadequate production of insulin due to pancreatic β-cell dysfunction, and the latter from reduced sensitivity to insulin in the target tissues and/or inadequate insulin secretion. Sustained hyperglycaemia is a common result of uncontrolled diabetes and, over time, can damage the heart, eyes, kidneys and nerves, mainly through deteriorating blood vessels supplying the organs. Microvascular (retinopathy and nephropathy) and macrovascular (atherosclerotic) disorders are the leading causes of morbidity and mortality in diabetic patients. Therefore, emphasis on diabetes care and management is on optimal blood glucose control to avert these adverse outcomes.Studies have demonstrated that diabetic nephropathy is associated with increased cardiovascular mortality. In general, about one in three patients with diabetes develops end-stage renal disease (ESRD) which proceeds to diabetic nephropathy (DN), the principal cause of significant morbidity and mortality in diabetes. Hypertension, a well-established major risk factor for cardiovascular disease contributes to ESRD in diabetes. Clinical evidence suggests that there is no effective treatment for diabetic nephropathy and prevention of the progression of diabetic nephropathy. However, biomedical evidence indicates that some plant extracts have beneficial effects on certain processes associated with reduced renal function in diabetes mellitus. On the other hand, other plant extracts may be hazardous in diabetes, as reports indicate impairment of renal function. This article outlines therapeutic and pharmacological evidence supporting the potential of some medicinal plants to control or compensate for diabetes-associated complications, with particular emphasis on kidney function and hypertension. Diabetes mellitus is a global disease affecting both the developed and developing nations. Epidemiological data suggest that at least one in 20 deaths are attributable to diabetes and related complications, a proportion which increases to at least one in 10 deaths in adults aged 35 to 64 years.3The principal causes of mortality in type 1 and 2 diabetes patients are disorders grouped as microvascular (retinopathy and nephropathy) and macrovascular (atherosclerotic) complications.8Conventional diabetes therapy using blood glucose-lowering agents such as sulphonylureas, insulin therapy, α-glucosidase inhibitors, peroxisome proliferator gamma (PPAR-γ) agonists and biguanides has limitations. For instance, insulin therapy does not achieve glycaemic control in patients with insulin resistance, and oral hypoglycaemic agents may lose their efficacy after prolonged use. Previous studies elsewhere suggest that insulin is not only ineffective in preventing type 1 diabetes in patients at risk of developing this condition, but it can also cause cardiovascular disease.Traditional herbal medicine is used by many rural African communities to treat a range of diseases, including diabetes. Anecdotal evidence suggests that diabetic complications are less common in rural populations, attributable to either the beneficial effect of plant medicines or to the fact that other risk factors that aggravate diabetes in the urban context are less prevalent in rural situations. The World Health Organisation not only encourages the use of plant medicines, but also recommended scientific evaluation of the hypoglycaemic properties of plant extracts.Research summarised in a recent reviewThe focus of this article is to evaluate current evidence on plant extracts used for the management of hypertension and kidney disease in diabetes. The beneficial as well as deleterious effects of medicinal plants in both conditions are discussed based on reports on plants frequently used in the southern Africa setting. Herein, a medicinal plant is defined as any plant which provides health-promoting characteristics, temporary relief or has curative properties.Diabetic complications, which include damage to large and small blood vessels, can lead to coronary heart disease, stroke and hypertension, the latter being a well-established major risk factor for cardiovascular disease that contributes to end-stage renal disease (ESRD). Reduction of blood pressure (BP) is therefore an efficient way of preventing or slowing the progression of ESRD. Conventionally, reno-protection is achieved through reduction in BP with antihypertensive regimens.28The major antihypertensive drug classes widely used include thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers, central sympatholytic agents, calcium channel antagonists and other vasodilators. However, some antihypertensive agents, for example, thiazide diuretics and β-blockers deleteriously influence glycaemic control.29To date, the most effective treatments for diabetic nephropathy (DN) are the antihypertensive drugs, particularly those that target the renin–angiotensin system (RAS) such as ACE inhibitors, angiotensin-1 receptor antagonists, or their combination.8For these reasons, novel anti-diabetic therapeutic agents that supplement, substitute or complement the existing modern medications to ameliorate renal function in diabetes constitute novel therapeutic strategies for diabetes. Evidence from biomedical literature suggests that some plant extracts have protective effects against cardiovascular disease in diabetes.Helichrysum ceres S Moore [Asteraceae] to treat kidney and cardio-respiratory disorders.H ceres leaf extract in anaesthetised male Sprague-Dawley rats could in part be attributed to the extract’s natriuretic and diuretic properties.H ceres ethanolic leaf extract’s hypotensive effects were elicited in part by the direct relaxant effects on cardiac and vascular smooth muscles.H ceres leaf extract elicited potent negative inotropic and chronotropic effects in vivo and exhibited vasorelaxant effects in vascular tissue preparations.Several plant extracts with potential therapeutic properties for the treatment of hypertension and complications such as coronary heart disease, angina, arrhythmias and congestive heart failure have been identified.Ekebergia capensis Sparrm (Meliaceae) leaf extract prevented the development of hypertension in weanling genetically hypertensive Dahl salt-sensitive (DSS) rats, which develop hypertension as they age.in vivo reduction in blood pressure by the extract occurred without significant alterations in the heart rate, suggesting that the in vitro cardiovascular effects of the extract significantly contributed to the hypotensive effects. Indeed, studies showed that the hypotensive effect of E capensis leaf extract was in part mediated via modulation of total peripheral resistance of the vascular smooth muscles, as evidenced by the extract’s elicited dose-dependent vasorelaxations in endothelium-intact and endothelium-denuded aortic ring preparations. It should be noted that lanoxin, one of the cardiac glycosides found in a number of plants, has specific effects on the myocardium.We also reported that Sustained hyperglycaemia is the main cause of the changes in kidney function in diabetes mellitus. Hyperglycaemia leads to the increased formation of advanced glycation end-products (AGEs), oxidative stress, activation of the polyol pathway and hexosamine flux, causing inflammation and renal damage.41Irrespective of all the other structural and functional changes, the mesangial alterations appear to be the main cause of declining renal function in experimental diabetic animal models.The accumulation of AGEs can be prevented by antioxidants such as flavonoids or by preventing the glucose-dependent formation of intermediate products . Indeed, blocking or deleting AGEs’ receptor (RAGE) in experimental animals reversed atherosclerosis.48et al.Galega officinalis) may be useful in the prevention of the development of AGEs. The Panax quinquefolium (Linnaeus) [Araliaceae] extracts, a phyto-oestrogen derived from Vitis vinifera (Linnaeus) [Vitaceae] (resveratrol), curcumin from Curcuma longa (Linnaeus) [Zingiberaceae] and glycosides from Stelechocarpus cauliflorus (RE Fr) [Annonaceae] have also been reported to inhibit formation of AGEs or RAGE.56Tanaka Renal disease is a common and often severe complication of diabetes, with the majority of patients with 18 years’ duration showing signs of diabetic renal involvement.World Health Organisation data report age-standardised death rate for diabetics in South Africa is 85 per 100 000 compared with 18 in the USA and six per 100 000 in the UK.14DN progresses through five well-defined stages.ESRD is managed in developed countries by renal replacement therapy (RRT), such as dialysis and transplantation. In developing countries, however, kidney failure rates are double those in the West because access to RRT is severely limited by its high cost to patients.12Current conventional diabetes therapy using blood glucose-lowering medications has limitations in averting renal complications. Progression towards ESRD may be slowed in part by strict control of blood sugar levels and blood pressure, a reduction in dietary protein intake and inhibition of the renin–angiotensin system. Consequently, drug developmental strategy should target these metabolic pathways for the prevention of progression to ESRD, which proceeds to DN.Many patients of sub-Saharan Africa however cannot afford these expensive drugs. Hence there is an urgent need to find affordable treatments which are effective in slowing the progression of DN.Ethno-medicinal plants have traditionally been used for the treatment of diabetes and its complications. In fact, current pre-clinical and clinical studies have demonstrated that many have beneficial effects on some processes associated with reduced renal function in experimental animals.Our research has established the therapeutic and pharmacological properties of a number of ethno-botanical herbs traditionally used in the management of diabetes mellitus by African communities.Hypoxis hemerocallidea corm aqueous extract (APE) had hypoglycaemic effects, they may have deleterious effects on kidney function. Gondwe et al. found that APE increased renal fluid output and electrolyte retention, and reduced glomerular filtration rate,Opuntia megacantha leaf extract, which had hypoglycaemic effects, reversed the inability of the kidney to excrete Na+ in STZ diabetes mellitus, suggesting that this plant may be beneficial.17Investigations from our laboratory have also examined whether herbal extracts could lower blood pressure or improve the impaired renal and cardiovascular functions often seen in diabetes. The results suggest that while some extracts such as Sclerocarya birrea [(A Rich) Hochst] [Anachardiaceae], Persea americana (Miller) [Lauraceae], Ficus thonningii (Blume) [Moraceae] and Helichrysium ceres had reno-protective effects We undertook a systematic survey of medicinal plants used by rural communities in South Africa and have identified several species with beneficial effects in the prevention of renal complications in diabetes mellitus. These effects were observed with both crude extracts and bioactive compounds isolated from antidiabetic plants. In particular, we showed that plants such as S cordatum-derived oleanolic acid caused increased renal Na+ excretion in STZ-induced diabetic rats, which was mediated by an improvement in glomerular filtration rate Subsequently, we isolated oleanolic acid as the bioactive compound and have shown that it possesses reno-protective effects in experimental diabetes mellitus. Therefore Corni fructus has shown reno-protection in experimental diabetes through a reduction in the production of AGEs.1 and the endothelin-1 receptor A (ETRA).65There are various mechanisms by which reno-protection may be achieved, including modulation of AGEs, of the polyol pathway, and of the PKC pathway, and anti-oxidative properties. For example, morroniside isolated from Available evidence suggests that some herbal extracts interfere with the concentrating and diluting mechanisms of tubular transport processes in the proximal and distal tubules and/or on other components of tubular cell membranes. Therefore we speculate that oleanolic acid influences renal fluid and electrolyte handling by altering the structural integrity and function of tubular epithelial cells to affect reabsorption and secretion.Modification of risk factors in diabetes has an impressive impact on morbidity and mortality in diabetic patients. An overview of some of some medicinal plants currently used in diabetic hypertension and kidney disease, together with the possible mechanism(s) is summarised in Table 1.We describe the therapeutic and pharmacological evidence in support of some of the medicinal plant extracts used in the management of hypertension and kidney disease in diabetes mellitus. Some of these medicinal plant extracts are a potential source of anti-diabetic drugs because of their therapeutic efficacy and anti-diabetic mechanisms reported in experimental animals. However, at present, the cellular/molecular mechanisms of action of these plant extracts remain to be established.Future research directed at the identification of active components is the only viable option for supporting the efficacy claims for all herbs. In the absence of such standardisation, health practitioners and consumers alike should remain optimistic but wary. Research funding to investigate potentially beneficial effects of medicinal plants is critically important for optimal patient care and safety.


Normally at birth, the human infant gut is sterile, but it becomes fully colonized within a few days with bacteria from the mother and the environment  in human subjects both during pregnancy or in the neonatal period. Probiotic trials thus far have failed to show a consistent preventive effect . Fallani compared neonatal fecal samples from Sweden, Scotland, Germany, Italy, and Spain. Bifidobacterium genus was predominant , followed by Bacteroides (11.4%) and Enterobacteria  the establishment of a stable flora is delayed  during late pregnancy promotes a Bifidobacteria profile of infant gut microbiota, similar to that of a healthy breastfed infant. Microbial diversity in neonatal gut microbiota was not influenced by this probiotic administration at 1 week postpartum , whereas after long-term follow-up at 2 years, there were less Lactobacilli/Enterococci and Clostridia in feces in the probiotic group than in the placebo group (Rinne et al., Altered gut colonization could lead to obesity in later life. Germ-free mice are protected against developing diet-induced obesity. The gut microbiota affects expression of secreted proteins in the gut, which modulate lipid metabolism in peripheral organs and is a source of pro-inflammatory molecules that augment adipose inflammation and macrophage recruitment by signaling through the innate immune system Bäckhed, . An intrL. rhamnosus administration that at 3 months IgG-secreting cells in breastfed infants supplemented with probiotics was higher (Rinne et al., Rinne showed in another randomized trial of neonatal In conclusion, we infer that many observations indicate the significance of bacterial neonatal colonization of the gut. A tighter control of factors influencing this phenomenon is warranted if results of preventive or therapeutic measures, or effects of maternal, or perinatal conditions is to be identified.