Background. This paper aimed to identify condition-specific patient-reported outcome measures used in clinical trials among people with wrist osteoarthritis and summarise empirical peer-reviewed evidence supporting their reliability, validity, and responsiveness to change. Methods. A systematic review of randomised controlled trials among people with wrist osteoarthritis was undertaken. Studies reporting reliability, validity, or responsiveness were identified using a systematic reverse citation trail audit procedure. Psychometric properties of the instruments were examined against predefined criteria and summarised. Results. Thirteen clinical trials met inclusion criteria. The most common patient-reported outcome was the disabilities of the arm, shoulder, and hand questionnaire (DASH). The DASH, the Michigan Hand Outcomes Questionnaire (MHQ), the Patient Evaluation Measure (PEM), and the Patient-Reported Wrist Evaluation (PRWE) had evidence supporting their reliability, validity, and responsiveness. A post-hoc review of excluded studies revealed the AUSCAN Osteoarthritis Hand Index as another suitable instrument that had favourable reliability, validity, and responsiveness. Conclusions. The DASH, MHQ, and AUSCAN Osteoarthritis Hand Index instruments were supported by the most favourable empirical evidence for validity, reliability, and responsiveness. The PEM and PRWE also had favourable empirical evidence reported for these elements. Further psychometric testing of these instruments among people with wrist osteoarthritis is warranted. Wrist osteoarthritis is a common condition treated by upper limb orthopaedic teams . ClinicaThe use of patient-reported outcomes as primary measures in clinical trials has become increasingly popular over recent decades . There aThe use of condition-specific instruments has great potential for evaluating domains of physical functioning and health-related quality of life commonly affected by a specific pathology or body region dysfunction . ConditiThe selection of patient-reported outcomes for use in clinical trials should be informed by empirical research supporting several key instrument properties . It is cPrior critical analyses examining the psychometric or clinimetric properties of outcome measures with relevance to orthopaedic upper limb patients have been undertaken , 40, 41.The specific aims of this paper are therefore threefold: first, to identify which condition-specific patient-reported outcome measures have been used during randomised controlled trials among people with wrist osteoarthritis; second, to examine whether these instruments are supported by peer-reviewed published empirical data reporting their reliability, validity, or responsiveness, third, to discuss priorities for future research to improve the quality of condition-specific patient-reported outcomes for use in clinical trials. A systematic review of condition-specific patient-reported outcome measures used in randomised trials among people with wrist osteoarthritis was undertaken.Searches were performed in Medline, National Institutes of Health online database, PubMed, and CINAHL from the earliest records until the date of the search (January 2012). Search terms included combinations of terms  and (“arthritis” or “osteoarthritis”) and . These terms were used as keywords and expanded Medical Subject Headings (MESH) terms to search all text. A conventional four-stage screening approach to identify studies meeting the inclusion and exclusion criteria was undertaken by two researchers . A thirdManuscripts reporting randomised clinical trials among adults with wrist osteoarthritis were included. This included samples with arthritis affecting any joint adjacent to the carpal bones . Studies that included participants with osteoarthritis of other  joints in the hand or elsewhere in the body were excluded. Studies among clinical groups with other inflammatory arthritis such as rheumatoid arthritis or juvenile arthritis were excluded. Manuscripts that did not specify the type of arthritis present in their sample were also excluded. There were no exclusion criteria based on the intervention type or length of follow-up within the trial as these factors were not under consideration in this paper. The population, interventions, and all outcome measures used in each of the included studies were summarised and tabulated . ConditiA summary of the elements of validity, reliability, and responsiveness that have been reported for each of the instruments were then tabulated . PsychomThe searches returned a total of 1014 hits . This inA total of 9 condition-specific patient-reported outcomes were used across the included clinical trials . The mosA concise summary of manuscripts reporting the reliability, validity, and responsiveness of each of the 9 instruments is outlined in This investigation has identified 9 condition-specific patient-reported outcomes reported across 13 clinical trials amongst patients with wrist osteoarthritis . EmpiricFew investigations of validity, reliability, and responsiveness of these instruments included patients with osteoarthritis . The finThe selection of a patient-reported outcome for use in a clinical trial should be informed by several factors in addition to the measurement properties of the instrument . Not allThe findings of favourable empirical psychometric data for the condition-specific patient-reported outcomes  reportedThe systematic audit trail approach to identify potential empirical evidence to support or refute the use of the patient-reported outcomes identified in this paper may be considered both a strength and weakness of this systematic review. A strength as it offers a systematic, albeit time consuming, method to identify studies that have reported elements of validity, reliability, and responsiveness. On the other hand, this citation trail audit would not have identified non-peer reviewed or unpublished sources of data reporting these attributes. However, this approach suited the aim of this investigation to review only published peer-reviewed reports of this information. A limitation to the extrapolation of study findings is that study designs other than randomised controlled trials were excluded. This approach was the most appropriate for addressing the research question at hand that dealt specifically with identifying instruments that have been used in clinical trial environments. However, instruments used in other contexts (such as population-based surveys) were not included in the scope of this review. Findings from this investigation have several key implications for future research. Future clinical trials should consider the reliability, validity, and responsiveness of patient-reported outcomes under consideration for inclusion in clinical trial assessments. The DASH, MHQ, PEM, PRWE, and AUSCAN Osteoarthritis Hand Index all have published peer-reviewed empirical evidence available to inform this decision. Future research involving the other instruments reported in this investigation  should cThis investigation identified a range of condition-specific patient-reported outcome measures that have been used in clinical trials amongst patients with wrist osteoarthritis. The DASH was the most commonly used instrument across these clinical trials. The DASH and MHQ both had consistent favourable findings across all elements of validity, reliability, and responsiveness under consideration. However, the PEM and PRWE also generally had favourable empirical evidence reported for elements of validity, reliability, and responsiveness. The AUSCAN Osteoarthritis Hand Index was not used among trials meeting the strict inclusion criteria. However, it was identified as another suitable instrument with favourable reliability, validity, and responsiveness and is also worthy of consideration for future clinical trials among people with wrist osteoarthritis.


Psychosocial stress is a contributing factor to cardiovascular disease.11The complex pattern of responding to stress is influenced by individual differences, such as coping style, race and ethnicity, genetic make-up, background stress, and lifestyle habits, which should be taken into account when interpreting results. For example, a unique interplay between cardiac and vascular responses in urban black AfricansThere are, however, marked ethnic differences in cardiovascular responses or reactivity (CVR) that may in part be explained by psychosocial factors. Black AfricansMental and chronic psychosocial stress triggers sympathetic nervous system (SNS) hyperactivity and has been shown to be associated with increased vascular responsiveness, pressure overload, hypertension and myocardial ischaemic risk.The concept of coping style or strategies implies that humans have a differential capacity to adapt to the same environmental conditions. When attended to and appraised in certain ways, a coordinated set of responses involving behavioural and physiological systems is triggered.4It is difficult to fully elucidate if an enhanced stress response is dependent on the appraisal of the stressor, and if mental stress evokes the same stress response pattern in groups of different ethnicity. What is however evident from animal studies is that stress and re-exposure illicit different mono-aminergic  responses in cortical and sub-cortical (e.g. hippocampus) brain regions, resulting in behavioural changes, and which have their origin in altered functioning of the hypothalamic–pituitary–adrenal stress axis. Appraisal or detection of stressful stimuli at conscious and subconscious levels involves the thalamus, sensory and prefrontal cortex. Reciprocal connections exist with several sub-cortical pathways, determining autonomic and emotional responses through the hypothalamus and amygdala.5Animal studies indicate that while acute stress significantly elevates nor-adrenalin levels, especially in the hippocampus, a significant attenuation is experienced following re-experience. Interestingly, this does not occur in the frontal cortex, suggesting that subsequent behavioural changes following re-stress are driven by adrenergic-mediated changes in the hippocampus, such as deficits in cognition. The latter will compromise stress coping and stress responsiveness and in this way ultimately compromise central and peripheral cardiovascular response mechanisms. Hence a sensitisation of defensive pathways may occur, with α-adrenergic vascular pathways gaining influence. Consequently, the risk for established essential hypertension in high-demand situations may increase.5It has also been shown that peripheral vascular adrenergic hyperactivity contributes to human hypertensionet al.5Overall, subjects maintain their characteristic response tendencies  across mental tasks but it was also shown that when the task was long enough, certain individuals shifted from cardiac to vascular responders. This could support the findings of Malan Biol Psych 2010) and predispose these individuals to greater cardiovascular risk. Clearly, our understanding of these interactions is critical for the development of recommendations for early prevention of hypertension and the metabolic syndrome in urbanised Africans.Implementing Future studies are, however, required to establish if stress responses to behaviourally induced stressors could prospectively predict hard clinical CVD endpoints, such as myocardial infarction and cardiovascular death. Laboratory-induced responses are relatively stable within an individual and consistent across time, although the responses might not always be reflective of everyday life. Therefore, future work is required that examines not only a battery of laboratory measures but also the associations of ambulatory responses to real-life stress in relation to risk of CVD.The first well-controlled psycho-physiological study in Africa, the SABPA I study (Sympathetic activity and Ambulatory Blood Pressure study on Africans) was conducted in 2008/2009. It is an example of such a study where genetic polymorphisms, adrenergic, pro-inflammatory, prothrombic, blood pressure, heart rate variability (HRV), ischaemic events, oxidative stress, and stress hormone responses to acute mental stress were evaluated in urban teachers from South Africa. In addition, the study will incorporate ambulatory measures during the normal working day. Preliminary findings from SABPA I indicated that the prevalence of HIV/AIDS in the black SABPA teachers was only 9%, opposed to the overwhelmingly increased hypertension prevalence rates in the black teachers . This implies that CVD risk attributable to other risk factors apart from the inflammatory status contributed to their overall health profile, and risk factors should be broadened without concentrating on only the HIV/AIDS factor. Data from the SABPA I and SABPA II follow-up (2011/2012) studies will therefore provide an estimate of the health/disease burden attributable to established and emerging risk factors for CVD, metabolic syndrome, psychological distress and progression of subclinical atherosclerosis.Future studies should examine whether non-pharmacological interventions that reduce SNS hyper-responsiveness, such as physical activity and/or active relaxation breathing techniques could lessen sympathetic drive and increase vagal outflow.


Moreover, several studies have tried to identify physiological conditions, such as early menarche, late menopause, age of first pregnancy, and number of pregnancies, prolonged lactation, and obesity, that may all affect sex steroids availability/exposure and modulate cancer risk. Another series of studies have identified germline polymorphisms, which are linked to the modulation of cancer risk through the genetic control of serum hormone levels or target tissue responses  may elicit both canonical genomic effects and MISS, a member of the seven-transmembrane G protein-coupled receptor family, GPER, may also mediate both rapid and transcriptional events in response to estrogens, especially in cancer cells . GPER isOverwhelming evidence now indicates that both obesity and type 2 diabetes mellitus (T2DM) are associated with up to two to threefold increased risk for various malignancies . InsulinAlthough the degree of insulin resistance has a genetic basis, it is greatly modulated by diet and lifestyle. In fact, the rising occurrence of obesity and T2DM in western countries, and in the developing world, is causally associated with changing diet and lifestyle. Therefore, insulin resistance has become a major preventable cancer risk factor .In this context, it is increasingly recognized that a variety of chronic drug therapies, including oncologic treatments may cause or worsen insulin resistance. Whether they affect cancer risk or cause resistance to oncologic treatment should be addressed by future studies.For instance, antipsychotic drugs can induce weight gain, insulin resistance, and other components of the metabolic syndrome . Some anMoreover, anti-androgen and anti-estrogen therapies may be associated with worsening of insulin resistance. Anti-androgen therapy, besides being associated with well-established complications of male hypogonadism, is also associated with the development or worsening of insulin resistance and T2DM . A subtlDevelopment of insulin resistance is a major side effect of cancer target therapy with IGF-IR blocking agents and may contribute to the dismal results of clinical trials employing these agents .Development of insulin resistance in the course of cancer treatment should be now considered a factor that may significantly interfere with efficacy of treatment itself. We need, however, a new strategy to predict the individual risk of insulin resistant patients, including those receiving chronic therapies with drugs that worsen insulin resistance, not only in terms of metabolic complications, but also in terms of cancer risk or cancer resistance to therapy. The use of large-scale omics analyses  may perhaps help to identify such new strategies.Antidiabetic drugs may modulate insulin sensitivity and/or circulating insulin levels. Insulin sensitizers, like metformin are associated with decreasing insulin levels, while administration of insulin secretion modulators or of exogenous insulin is often associated with non-physiological circulating insulin levels. Insulin analogs, which are now widely used in diabetes therapy, may elicit biased insulin effects at cellular levels . EpidemiAccumulating evidence indicate that hormones secreted by non-classical endocrine organs may affect cancer risk through both direct and indirect mechanisms. Indirect mechanisms often act through the modulation of insulin secretion and sensitivity, as well as sex hormones secretion and metabolism. Leptin and adiponectin are two adipokines extensively studied in relationship to cancer .Obesity is characterized by leptin resistance and increased leptin levels, and by reduced levels of circulating adiponectin. Receptors for both adipokines are present in cancer cells. Leptin may promote cancer both directly and by increasing aromatase expression and estrogen production . In contRecently, a complex relationship between bone metabolism with glucose metabolism and sex steroid metabolism has been found. For instance, an osteoblast secreted protein, osteocalcin, affects insulin production and sensitivity and testosterone production . MoreoveHow this complex interplay between various metabolic hormones can be integrated in the concept of hormone sensitive cancer is still undefined. Moreover, how and to what extent this network may be modulated by diet and lifestyle or by pharmacological interventions in order to reduce cancer risk is still an open question.l-thyroxine, a well-established therapy in the postoperative management of differentiated thyroid cancer. However, to exert its maximal mitogenic and protumorigenic effects, TSH requires concomitant ligand-activated tyrosine kinase receptor signaling  and non-classical (GPER) estrogen receptors, which may help explain why thyroid cancer is more frequent in females. Moreover, thyroid cancer cells and stem-like thyroid cells also overexpress the IR and IGF-IR , which mIntriguingly, the incidence of differentiated thyroid cancer is increasing more rapidly than that of other cancers in the United States  and in mThe increased awareness that hormones may modulate the risk and progression of most cancers poses the question of how hormone action fits into a general model of carcinogenesis. It is generally accepted that hormones may enhance the effects of mutagens or of spontaneous mutations by accelerating proliferation and inhibiting apoptosis of mutated cells . HoweverMost cancers appear “hormone sensitive” at least at some stages of their development and/or progression. It is clear now that the relevant hormones include also a typical metabolic hormone such as insulin, and possibly other metabolic hormones. We need better definitions, and better assessment of what hormone sensitivity means for individual cancer histotypes. This should bring about a consistent shift in our concept of “hormone sensitive” cancer, and has several relevant implications. New models of carcinogenesis should then incorporate mechanisms of hormonal action in cancer initiation and progression and should identify critical ages for hormonal carcinogenesis. As far as cancer treatment is concerned, the possibility exists that most cancer histotypes will be considered amenable to some form of hormone treatment in the near future.


Screening, brief intervention, and referral to treatment (SBIRT) dissemination has been presented as a way to change medical professionals’ attitudes toward adopting prevention practices for alcohol and other drug use. We evaluated the impact of SBIRT dissemination on attitudes related to preventive practices for alcohol consumption and on the moralization of alcohol and other drug use by primary care professionals (N = 123) in two Brazilian cities. Eighty-two participants received SBIRT training (intervention group), while 41 received no SBIRT training (control group). At baseline and three-month follow-up, both groups completed scales of beliefs and attitudes regarding SBIRT implementation and another scale about the moralization of tobacco, alcohol, marijuana, cocaine, and crack use. The intervention group showed an increase in the perception of obstacles to screening implementation at follow-up assessment (p < 0.05). Regarding moralization, the intervention group had lower moralization for crack consumption than controls at follow-up (p < 0.05). The other measures showed no significant differences. According to these results, SBIRT training and three months of practice supervision were not sufficient to promote changes in primary care professionals’ attitudes toward drug and alcohol screening or to reduce substance use moralization. These findings are relevant to research related to SBIRT dissemination, since merely learning SBIRT techniques without attitudinal changes and moralization reduction compromises the quality and effectiveness of those practices with regard to alcohol and other drug use.


Part 1 comments on the types of local anaesthetics (LAs); it provides a better understanding of the mechanisms of action of LAs, and their pharmacokinetics and toxicity. It reviews the newer LAs such as levobupivacaine, ropivacaine, and articaine, and examines the newer structurally different LAs. The addition of adjuvants such as adrenaline, bicarbonate, clonidine, and corticosteroids is explored. Comment is made on the delivery of topical LAs via bioadhesive plasters and gels and controlled-release local anaesthetic matrices. Encapulation matrices such as liposomes, microemulsions, microspheres and nanospheres, hydrogels and liquid polymers are discussed as well. New innovations pertaining to LA formulations have indeed led to prolonged action and to novel delivery approaches. Local anaesthetics (LAs) are used clinically for anaesthesia and analgesia either following surgery or for management of other acute and chronic pain conditions; they only last a few hours. Part 1 of this paper deals with the newer LAs, more recent LA formulations, a better understanding of the mechanisms of action of LAs, and their pharmacokinetics and toxicity.Local anaesthesia for a prolonged period of days is best provided using catheter techniques  with disLignocaine is perhaps most commonly used or known local anaesthetic agent; it is used either in local or regional anaesthesia, or in epidural or spinal blockade; it has a number of uses in anaesthesia and pain medicine. However, it is also given parenterally in the management of neuropathic pain states. EMLA, a eutectic mixture of lignocaine and prilocaine, is an effective topical anaesthetic in preventing pain associated with needle procedures .Local anaesthetics can be classified into two groups based on the nature of the link, namely, amides [–NH–CO–] and esters [–O–CO–] Figures  and 2. TThe ester group is weak bases, solubilised for injection as strong conjugate acidic hydrochloride salts pH 3–6); it includes cocaine, procaine, chloroprocaine, and amethocaine  3, 7]. –6; it in. –6; it Injectable local anaesthetics are subject to absorption; a large fraction of the injected drug is removed by the systemic circulation and distributed to distant organs according to their vascular density . Highly In recent years, levobupivacaine, the pure S (−) enantiomer of bupivacaine, emerged as a safer alternative for regional anaesthesia than its racemic parent . In commIn pharmacodynamic studies, levobupivacaine demonstrated less affinity and depressant effects on myocardial and central nervous vital centres and a superior pharmacokinetic profile . ClinicaThe incidence of adverse events with levobupivacaine was similar to that after bupivacaine in comparative trials. These include hypotension, nausea, postoperative pain, fever, vomiting, pruritus, back pain, headache, constipation, dizziness, and foetal distress . The earSurgical sensory block of similar characteristics and recovery over equal dose ranges of levobupivacaine and bupivacaine has been confirmed in surgical patients . The onsThe effective dose of epidural levobupivacaine for continuous postoperative analgesia approaches 15 mg/hour . The addμg) provides excellent prolonged sensory block with minimum motor blockade . Th. Th54]. Liposomes suffer lack of reliability and reproducibility during manufacture owing to oxidation and hydrolysis, which results in leaking of the encapsulated drug , 55. LipLiposomal formulations of various anaesthetics allow an increase in clinical efficacy in comparison with the plain drugs . RecentlLimitations of encapsulated local anaesthetic agents include neurotoxicity, myotoxicity, tachyphylaxis, motor block, and viscosity . Many foGrant et al.  describeα-, β-, and γ-cyclodextrins, comprising six to eight sugar units in the ring. This combined approach that simultaneously exploits the cyclodextrin solubilising power towards the drugs and the liposome carrier function through the skin has recently been demonstrated by using both classic [P < 0.05) improvement of the drug anaesthetic effect in terms of intensity and duration of action [The entrapment of hydrophobic drugs in the aqueous core of liposomes as soluble inclusion complexes with cyclodextrins has been proposed to avoid the use of organic solvents, giving rise to drug-in cyclodextrin-in liposome systems . The mai classic  and defo classic . The use classic . The comf action .Microemulsions have penetration-enhancing properties. Local anaesthetics encapsulated in microemulsions result in fast transdermal penetration and effect , 69. MicThe most commonly used micro- and nanoscale vehicles for drug encapsulation and delivery are microspheres and nanospheres. They are usually prepared from biodegradable synthetic hydrophobic materials such as homo- or copolymers of polylactic and polyglycolic acids .Microparticles are perfect for drug delivery as they remain at the depot site for long periods allowing slow prolonged release of the encapsulated drug . ParticlMore recently, a nanoliposphere has been developed that does not gelify and is suitable for injection , 71. WheHyaluronic acid is a nonimmunogenic naturally occurring mucopolysaccharide used as a viscous carrier solution to prolong LA action . HoweverSynthetic calcium-deficient apatites are structurally similar to biological apatites; they are chemical precursors of biphasic calcium phosphates. Biphasic calcium phosphates are mixtures of hydroxyapatite and beta-tricalcium phosphate and are widely used as bone substitutes in human surgery . In WistAs previously mentioned, the absorbable, controlled-release, local anaesthetic delivery system containing 16% (w/w) lignocaine (Xybrex) is capable of providing up to several days of reversible rat sciatic nerve block in a dose- (mass-) dependent fashion . Two setco-castor oil copolymer prolonged the in vivo effect to 96-hour sensory block [There are three types of polymers for encapsulation, namely, nondegradable polymers, synthetic polymers, natural biodegradables (that degrade to nontoxic products that are completely eliminated from the body), and drug-conjugated polymers (where a drug is attached to water-soluble polymer by a cleavable bond) . The drury block .Injectable polymers are simple and reliable to prepare; simple mixing combines the local anaesthetic. The main disadvantage is the prolonged time these polymer carriers dwell in the injection site, far beyond the time of the effect of the local anaesthetic agent . The safOne of the key areas of intense research is therefore to achieve an optimal and desirable controlled and sustained drug release from the use of biodegradable films. The buccal route has some unique compelling benefits making it worth trying; such benefits include avoiding first pass effect, easy accessibility, and better patient compliance. Adhesion of buccal adhesive drug delivery devices to mucosal membranes leads to an increased drug concentration gradient at the absorption site and therefore improved bioavailability of systemically delivered drugs . VariousA slow-release lignocaine sheet has been produced and has been used for sciatic nerve block in the rat model of postoperative pain. Single treatment of this controlled-release lignocaine inhibited hyperalgesia and c-fos expression in the spinal cord dorsal horn for one week without inducing inflammation of the sciatic nerve . BioadheLocal anaesthetics are widely used to manage acute, chronic, and cancer pain, for anaesthesia, and for diagnostic purposes. Local anaesthetics may have similar chemical structures, but differing pharmacokinetic properties and spectra of pharmacodynamic effects. This influences the selection of agents for use in various clinical situations . New inn


Although it is widely accepted that mitochondria play fundamental roles in the mechanisms of cellular and organismal aging and lifespan extension, some open questions remain concerning the requirements for aerobic energy production and the effect of the potentially hazardous reactive oxygen species (ROS) byproducts as well as their interplay with nutrition and caloric intake.Saccharomyces cerevisiae chronological life span (CLS) model of aging [We have recently revisited these questions using the of aging . CLS modof aging ,3. For Cof aging ,5. Howevof aging . StrainsAn essential question is why strains respiring below the threshold have a short CLS. First, aerobic energy production is required for the efficient function of anti stress systems, most needed during the diauxic shift and stationary phase. Furthermore, cells respiring below the threshold have altered metabolism of stored nutrients. Respiratory-deficient cells accumulate normal amounts of glycogen during growth, but they synthesize trehalose inefficiently. Both of these reserve carbohydrates are quickly consumed when the cells reach the stationary phase because, in the absence of respiration, yeast must rely on fermentation, which generates a 14-fold lower energetic yield. Glycogen and trehalose are virtually exhausted in respiratory-deficient cells by the end of their CLS, thus suggesting that starvation is an important factor limiting their survival. In support of this conclusion, trehalose supplementation of the growth media enhances the stress-resistance capacity of respiratory null strains and significantly extends their CLS.Another way in which mitochondrial respiration controls aging and longevity is through generation of ROS. Although mitochondrial ROS are known to limit the long-term survival of yeast cells during CLS and can have a detrimental effect during aging in higher eukaryotes, they can also act as signaling molecules with hormetic effects on longevity -8. For eIn conclusion, we have proposed a model Figure  in which


Arteriosclerotic vascular disease is the most common cause of death and a major cause of disability in the developed world. Adverse outcomes of arteriosclerotic vascular disease are related to consequences of tissue ischemia and necrosis affecting the heart, brain, limbs, and other organs. Collateral artery growth or arteriogenesis occurs naturally and can help restore perfusion to ischemic tissues. Understanding the mechanisms of collateral artery growth may provide therapeutic options for patients with ischemic vascular disease. In this review, we examine the evidence for a role of monocytes and macrophages in collateral arteriogenesis. Arteriosclerotic disease is the major cause of death, and a major cause of morbidity and healthcare expenditure in the developed world. The clinical consequences of arteriosclerotic diseases are primarily related to the acute and chronic effects of tissue ischemia and necrosis affecting particularly the heart, brain, and limbs. Revascularization strategies have been employed with the goal of restoring blood flow to the ischemic tissue. Approaches to restoring blood flow through occluded or highly narrowed vessels include thrombolytic therapy, percutaneous interventional procedures , and surgery .In situations of acute ischemia presenting as acute myocardial infarction, stroke or acute limb ischemia, emergent restoration of blood flow by pharmacological therapy (thrombolytic therapy) or percutaneous interventional procedures is essential for limiting tissue necrosis. However, the risk/benefit ratio of revascularization procedures often becomes less clear in situations of chronic ischemia. Furthermore, the above approaches may not always be feasible for patients with severe diffuse occlusive arterial disease and poor target vessels for grafting. The costs and potential short- and long-term complications of surgical and percutaneous interventional procedures are not always offset by the variable extent of the benefits. The risks associated with current revascularization approaches include acute thrombotic occlusion or gradual restenosis of stents, and occlusion of bypass grafts. While coronary artery bypass grafting using certain arterial conduits  have relatively high patency rates of 85–90% after 10 years, venous conduits  are patent only 55–70% of the time after 10 years and 50–60% after 15 or more years , who documented his findings on the occlusion of the external carotid artery of a buck, and its physiologic consequences. He observed that the animal’s ipsilateral antler became cool to touch and its arterial pulse became impalpable, as its blood supply was dependent on the ligated artery. However, when the animal was reexamined a week later, the temperature and arterial pulsations of the antler had normalized. On further examination, Hunter found that small branches of the artery above and below the ligature had enlarged, and through their anastomoses the blood supply was restored Murley, . Well ovde novo formation of a primary capillary plexus from mesenchymal-derived progenitor or stem cells , cellular proliferation and apoptosis in all layers of the developing vessel, alteration in physical dimensions , and finally, reversion of the vascular smooth muscle cells to a contractile phenotype. The extent of growth in diameter and wall thickness tends to be much greater in dogs and rabbits than in rodents  and adhesion molecules. The process is a continuum invoking bone marrow cell mobilization, monocyte emigration from bone marrow, chemotaxis, cell rolling along the endothelium, retention by adhesion, and transmigration through diapedesis  in human umbilical vein endothelial and bovine aortic endothelial cells  mice are deficient in colony-stimulating factor (CSF)-1, a growth factor that regulates the survival, proliferation, and differentiation of mononuclear phagocytic cells  mice exhibited delayed or reduced collateral artery development or perfusion recovery in several independent studies  with demonstrated importance in monocyte/macrophage recruitment. In studies using rabbit and porcine hind limb models of femoral artery ligation, Wolfgang Schaper and colleagues demonstrated that direct intraarterial infusion of MCP-1 led to an increase in collateral artery development in association with increased monocyte/macrophage accumulation around the growing collateral arteries  are probably the most well-studied chemokine receptors in monocytes/macrophages to date  animals have reported variable results in restoration of perfusion following hind limb ischemia  mediate the homeostatic functions of monocyte subsets, ranging from tissue and blood vessel patrolling , cell surface markers that have limited specificity in defining monocytes/macrophages. Furthermore, another study suggested that the CX3CR1–CX3CL1 interaction, which mediates recruitment of the Ly6Clo7/4lo subset of monocytes, corresponding to the human CD16+CD14lo “resident/patrolling” subset , which is known to be expressed by endothelial and vascular smooth muscle cells  that are normally kept at low levels by superoxide dismutase, catalase, and peroxidase at rest . When induced, macrophages release abundant amounts of nitric oxide in their antimicrobial defense against invading pathogens, generating damaging concentrations of reactive oxygen intermediates and peroxynitrite (ONOON-methyl-l-arginine-acetate or L-NNA), nitric oxide donors , –/–eNOS knockout and eNOS transgenic mice, and an exercise training animal model with acute arterial occlusion lysine  study of patients with peripheral artery disease did not show a difference between the intervention and control groups. As discussed above, activating macrophages (and angiogenesis) can worsen atherosclerosis, as shown in animal studies , and can trigger acute ischemic events .The therapeutic efficacy of macrophage-related therapies remains questionable. Data from clinical trials of GM-CSF and G-CSF suggested an increase in collateral-dependent flow; however, the largest (A better understanding of myeloid cells and their subsets in collateral arterial remodeling, and their involvement in atherogenesis, atherosclerotic plaque stability, and tissue resistance to ischemia, will be essential for the investigational field of “therapeutic arteriogenesis.”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.http://www.frontiersin.org/Vascular_Physiology/10.3389/fphys.2012.00353/abstractThe Supplementary Material for this article can be found online at


Globally, 11% of infants are born preterm. In adulthood, individuals born preterm are at increased risk of cardiovascular morbidity and mortality, but the mechanistic basis of this remains unknown. Clinically overt cardiovascular disease may be preceded by altered cardiac autonomic activity characterised by increased sympathetic activity and/or reduced parasympathetic activity. Thus, altered cardiac autonomic activity in survivors of preterm birth may underlie later cardiovascular risk.To investigate the impact of gestational age on cardiac autonomic activity in juvenile and adult sheep.Singleton-bearing ewes were randomised antenatally to spontaneous term birth  or corticosteroid induced preterm birth . Cardiac autonomic modulation was assessed using heart rate variability analysis in juvenile and adult offspring. Preterm birth in adult males was associated with altered sympatho-vagal modulation  and reduced parasympathetic modulation . Within the range of term birth, each one-day increment in gestational age was associated with a decrement in LFnu in juvenile females and with a decrement in LFnu and LF/HF ratio, but an increment in RMSSD and NN50 in adult females. Cardiac autonomic function in adult sheep is affected in a sex-specific manner by gestational age at birth, even within the term range. Altered cardiac autonomic function may contribute to increased later cardiovascular morbidity in those born preterm. As preterm birth rates and survival following preterm birth increase, it is becoming increasingly apparent that preterm birth is accompanied by later cardiovascular morbidity: increased blood pressure ,2, alterThe fetal autonomic nervous system increases in complexity as gestation advances, with reducing sympathetic and increasing parasympathetic activity . In the We hypothesized that gestation length at birth would alter autonomic balance in juvenile and adult sheep and that this might provide a mechanistic basis for increased cardiovascular morbidity in those born preterm. Ethics statement: Ethical approval for this study was obtained prospectively from the University of Auckland Animal Ethics Committee (AEC 628). Time-mated, singleton-bearing Romney ewes (n=133) were generated . At day PT ewes received 0.25mg/kg dexamethasone sodium phosphate  by intramuscular injection on days 135 and 136 with birth of the lamb on d137. TC ewes received no interventions during pregnancy. ® system  from standing, conscious sheep in a quiet, temperature and light-controlled  environment to which they had been extensively habituated. To control for any effect of diurnal variation in autonomic tone [At 5 months’ (juvenile) and 16 months’ (adult) corrected postnatal age, electrocardiograms (ECGs) were obtained using a PowerLabad libitum. Subcutaneous ECG needles  were placed on the sternum, over the left scapula and the left flank and secured in place with adhesive [Animals were studied while housed in metabolic crates to which they were also well habituated, with standard sheep pellets and water available adhesive . After aadhesive . These fadhesive , reflectadhesive . ECGs weAs cardiovascular disease risk is known to be different between the sexes, males and females were analysed separately using JMP v. 8 . Non-parametric data were log transformed prior to analysis. Data were analysed by factorial ANOVA with Tukey post hoc correction. Associations between continuous variables were examined by regression analysis within each birth group, in same sex animals. Multivariate regression models were adjusted for the effect of: birthweight z-score (birthweight - mean birthweight for gestation and sex / SD of mean birthweight for gestation and sex), age and weight (juveniles) or weight-for-length (weight (kg) / crown-rump length (m)) in adults as a better measure of soft tissue mass relative to skeletal growth. Measures of length were not available for juvenile sheep. At birth, but not in juvenile or adult life, same-sex PT lambs were smaller and lighter than TC lambs . In males, PT sheep had altered indices of sympatho-vagal modulation as juveniles and adults, with reduced indices of parasympathetic modulation in adulthood, but no difference in heart rate at either age . In femaTC sheep had a gestational age range of 142-156 days . In females, each one-day increment in gestational age was associated in juveniles with a decrement in LFnu and in adulthood with a decrement in LFnu and LF/HF ratio, but an increment in RMSSD and NN50 . Our data demonstrate that both preterm birth and gestation length within the term range result in sex-specific effects on autonomic balance in juvenile and adult sheep, with reduced gestation length associated with altered sympatho-vagal balance. Although HRV does not represent direct measurements of autonomic nerve activity, it is a sensitive technique for estimation of overall autonomic balance and is predictive of cardiovascular morbidity. Tonic elevation of sympathetic activity and / or parasympathetic withdrawal may precede development of clinically overt hypertension ,21 and cGestational age and preterm corticosteroid exposure both may be implicated in early postnatal autonomic function and separation of the two factors is challenging. Steroid-naïve preterm birth in experimental animals is associated with significant mortality  and, in per se is unlikely to be the sole mediator of the differences in HRV between preterm- and term-born sheep. Preterm birth in lambs is not accompanied by the increase in HR, BP and renal sympathetic nerve activity observed in term-born lambs unless the ewe receives antenatal corticosteroid treatment . Howeverin situ to control for the effect of variation in oestrous cycling between animals. The impact of gestational age at birth on age-related changes in sex hormones was not assessed in this study, but may be one mechanism through which gestational age modifies later sympatho-vagal balance. Further studies are needed to define the interaction between normal cyclical changes in sex hormones in animals born preterm on modulation of autonomic tone. It is also possible that in our female sheep the differences in baseline heart rate masked differences in HRV [The emergence of sexually dimorphic HRV characteristics is congruent with the sex-specific differences in manifestation of cardiovascular disease . Sexualls in HRV . HoweverOur data describe the effect of gestational age and preterm birth in singleton animals only. In humans, although preterm birth is common in twins and higher order multiples, singletons account for approximately 75% of the preterm population . DiffereFinally, the large number of animals studied is a strength of this study but also limited us to the use of a tethered ECG system with relatively short ECG recordings compared to those that can be acquired through a telemetric system. Future studies will include ECG recordings throughout a 24 hour period and also blood pressure recordings to better define the low frequency modulation of HRV and better characterise the contribution of the sympathetic nervous system to overall autonomic balance. Despite these limitations, we believe that these data represent a novel insight into a late autonomic dysfunction arising from preterm birth. Preterm birth in sheep results in altered sympatho-vagal modulation of autonomic activity in adulthood in a sex-specific manner. This may contribute to the emergence of adult cardiovascular morbidity in humans born preterm.


We hypothesize that the unique properties of modified MSC may enable MSC to serve as an unconventional but innovative, vaccine platform. Such a platform would be capable of expressing hundreds of proteins, thereby generating a broad array of epitopes with correct post-translational processing, mimicking natural infection. By stimulating immunity to a combination of epitopes, it may be possible to develop prophylactic and even therapeutic vaccines to tackle major health problems including those of non-microbial and microbial origin, including cancer, or an infectious disease like HIV, where traditional vaccination approaches have failed.Vaccines are the most efficient and cost-effective means of preventing infectious disease. However, traditional vaccine approaches have thus far failed to provide protection against human immunodeficiency virus (HIV), tuberculosis, malaria, and many other diseases. New approaches to vaccine development are needed to address some of these intractable problems. In this report, we review the literature identifying stimulatory effects of mesenchymal stem cells (MSC) on immune responses and explore the potential for MSC as a novel, universal vaccination platform. MSC are unique bone marrow-derived multipotent progenitor cells that are presently being exploited as gene therapy vectors for a variety of conditions, including cancer and autoimmune diseases. Although MSC are predominantly known for anti-inflammatory properties during allogeneic MSC transplant, there is evidence that MSC can actually promote adaptive immunity under certain settings. MSC have also demonstrated some success in anti-cancer therapeutic vaccines and anti-microbial prophylactic vaccines, as we report, for the first time, the ability of modified MSC to express and secrete a viral antigen that stimulates antigen-specific antibody production  On the other hand, in carcinogenic situations there is an urgent need to develop therapies that promote the host immune system to target and destroy cancerous tumors and metastases. Mesenchymal stem cells (MSC) are unique bone marrow-derived multipotent progenitor cells that are presently being exploited as gene therapy vectors for a variety of conditions, including cancer and autoimmune diseases   that elicits an immune response that protects recipients from disease when they are exposed to the actual pathogen. In an ideal world a single vaccine would be able to target all major human pathogens (versatile), elicit strong protective immunity to these pathogens (robust) without inducing unwanted side-effects (safe), and still be fairly inexpensive to produce per dose (cost-effective). In the case of viruses or host-cell produced proteins, vaccine production that includes human post-translational processing, mimicking natural infection, will likely prove to be superior to bacterial or other expression systems.Traditional vaccine approaches have thus far failed to provide protection against human immunodeficiency virus (HIV), tuberculosis, malaria, and many other diseases, including dengue, herpes, and even the common cold. The reasons why traditional vaccine approaches have not been successful for these diseases are complex and varied. For example, HIV integrates functional proviral genomes into the DNA of host cells, thereby establishing latency or persistence. Once latency/persistence is established, it has not been possible to eradicate HIV, even with highly active antiretroviral therapy. Clearly, new approaches to vaccine development are needed to address HIV and other intractable vaccine challenges.in situ. Cellular vaccines use the direct transfer of pre-pulsed or transfected host cells  expressing or presenting the vaccine antigen. The advantage of these approaches is that vaccine antigens are produced in vivo and are readily available for immunological processing. Despite numerous reports of successful pre-clinical testing, both such approaches have hit stumbling blocks. DNA vaccination studies in humans show poor efficacy, which was linked to innate differences between mice and humans  to produce the vaccine antigen MSC are unique bone marrow-derived multipotent stem cells that are presently being exploited as gene therapy vectors for a variety of conditions, including cancer and autoimmune diseases , subcutaneous (SC) or intramuscular (IM) routes using either MSC-gp120 or purified gp120. Since transplanted MSC persist only for a few days at most in vivo  elicited undetectable humoral responses, similar to previous studies   molecules can become either anti- or pro-inflammatory, depending on the PAMP with which they are treated These studies support our hypothesis that MSC can be used to as a novel vaccination platform generating protective immunity. They also suggest mechanisms that may be involved during modified MSCs vaccination besides antigen delivery, including cytokine secretion and antigen presentation Figure . While nThe idea of MSC as a novel vaccine approach is clearly still in its infancy and many knowledge gaps exist before this strategy could ever be practically realized. In particular, while the potential for MSC as a delivery system is tremendous, in depth evaluation is needed into how many foreign or cancer antigens can be effectively expressed by MSC. It will also be important to perform a more detailed analysis on the impact of MSC vaccination responses on antigen-specific immunity, including humoral and cellular responses, induction of long-term memory, etc. As described above, it will be critical to establish the mechanism(s) whereby modified MSC promote vaccine immunity. While clearly MSC can effectively express and secrete vaccine antigens, these MSC might be more directly enhancing immune responses through antigen presentation and/or inflammatory cytokine expression, as seen in previous non-vaccination studies Table . It is pOne aspect of transfected MSC for vaccination is the difference in immunologic responses between stable-transfection strategies versus transient-transfection. Logic would indicate that a transient transfection might offer the best safety profile, without the worry of cell persistence, tumorigenicity etc. In addition, since MSC can have alternative immunomodulatory functions during inflammatory conditions and home to inflamed sites (at least when given intravenously), it will also be important to ascertain how effective an MSC vaccination will be when the host recipient is under any inflammatory disease setting. Therefore, a careful examination of the safety of MSC vaccination will also need to be evaluated.ex vivo for transient or stable transfection before in vivo administration, (3) ability to act as delivery vehicle/depot for antigen release over several days, and (4) initiation and possibly direct stimulation of antigen specific immune responses to these antigens in vivo.In summary, MSC have unique abilities that could enable their use as a novel vaccine delivery method. These include (1) protection from allogeneic host responses (GvHD), (2) ease of production attributes including ability to be expanded and modified Such a MSC platform is theoretically capable of expressing hundreds of proteins, thereby generating a broad array of epitopes with correct post-translational processing, mimicking natural infection. By stimulating immunity to a combination of epitopes, it may be possible to develop prophylactic and even therapeutic vaccines to major global health diseases, like HIV, where traditional vaccination approaches have failed. While modified MSC delivery is unconventional, their unique properties may indeed be able to serve as an innovative vaccine platform.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The metabolically connected triad of obesity, diabetes, and cardiovascular diseases is a major public health threat, and is expected to worsen due to the global shift toward energy-rich and sedentary living. Despite decades of intense research, a large part of the molecular pathogenesis behind complex metabolic diseases remains unknown. Recent advances in genetics, epigenomics, transcriptomics, proteomics and metabolomics enable us to obtain large-scale snapshots of the etiological processes in multiple disease-related cells, tissues and organs. These datasets provide us with an opportunity to go beyond conventional reductionist approaches and to pinpoint the specific perturbations in critical biological processes. In this review, we summarize systems biology methodologies such as functional genomics, causality inference, data-driven biological network construction, and higher-level integrative analyses that can produce novel mechanistic insights, identify disease biomarkers, and uncover potential therapeutic targets from a combination of omics datasets. Importantly, we also demonstrate the power of these approaches by application examples in obesity, diabetes, and cardiovascular diseases. As obesity (defined as body mass index (BMI) >30 kg/mDecades of research on MetDs show that obesity, T2D, and CVD are tightly linked and both genetic and environmental factors contribute to the susceptibility . At the The past two decades have witnessed major advances in omics technologies and genome-scale molecular data can now be obtained in diverse experimental and epidemiological settings. A large number of genetic, epigenetic, transcriptomic, proteomic and metabolomic studies of MetDs have already been conducted and numerous datasets at various molecular levels have become available. But collecting information is not enough. A key challenge for the research community is to integrate the sea of data into useful knowledge and insights. To address this critical need, various systems biology approaches have been developed over the past few years to organize the fragmented but valuable information into structures that collectively explain the observed biological phenomena.Traditional approaches focus on direct correlations between the molecular traits and the clinical diagnosis under investigation, but more advanced integrative or systems biology methodologies can help infer causality, disseminate the regulatory relationships among molecular traits, identify those biological processes or networks that are perturbed, and ultimately pinpoint the key regulatory genes and mechanisms of disease pathophysiology Fig. . In thisWhen a particular level of molecular data is generated, the most straightforward approach is to estimate the correlations between the molecular traits and clinical phenotypes. To simplify the discussion, we classify the molecular traits as either DNA, for which variation is typically captured by single nucleotide polymorphisms (SNPs), or intermediate molecular phenotypes (IMPs) that collectively represent the downstream layers such as the transcriptome, epigenome, proteome, or metabolome. Although studies on multiple types of IMPs have been fruitful in the past years –8, we mahttp://www.ncbi.nlm.nih.gov/geo/) and EMBL-EBI ArrayExpress Archive (http://www.ebi.ac.uk/arrayexpress/) a power house for large-scale systematic meta-analysis, or expression GWAS (eGWAS). It is plausible that disease-related genes exhibit persistent differential expression patterns across multiple studies, and that by scanning through a large data repository related to a given disease condition, these genes can be identified [The explosion of gene expression data has made central data repositories such as the NCBI Gene Expression Omnibus  has collected a total of 6598 SNPs for 677 unique human diseases or phenotypic traits from 1320 different publications. A number of loci have been associated with MetDs−56 for obesity, 48 for T2D, and 38 for CVD. Most of the genetic loci identified were never observed before the GWAS era and many of the candidate genes cannot be explained by current knowledge. For instance, from a recent GWAS of over 80,000 individuals, 13 out of the 23 significant genetic loci identified were novel and 17 appeared to contribute to CAD risk through mechanisms independent of traditional risk factors [In the past few years, human GWAS have achieved great success in uncovering novel genetic risk loci for hundreds of diseases or traits including MetDs and their risk phenotypes . GWAS exDespite the demonstrated power in uncovering novel genetic risk factors, GWAS have limitations. First, as SNP markers on GWAS genotyping panels are largely pre-selected tag SNPs rather than functional SNPs, the discovered loci may not directly represent the functional causal SNPs but may simply be proxies or in linkage disequilibrium with true causal genetic variations. Second, even if the SNP is causal itself, the exact functional consequences of the SNP and the genes affected are not directly identifiable, especially when the SNP is (as 40 % of the significant SNPs are) located in intergenic regions or within introns . The thiThe lack of explanatory and predictive power has cast severe criticisms and doubts on GWAS. That being said, GWAS provide first-hand information about the putative causal relationships between genetic variants and clinical diseases traits. In addition, much of the hidden heritability that could not pass the stringent genome-wide significance threshold may lie within the lower tier GWAS signals and can be brought back to light using more advanced integrative methodologies, as discussed later in the review.Once a genetic locus has been linked to a disease phenotype, the most intuitive step is to search for candidate genes in the neighborhood of the locus. However, tens to hundreds of genes may underlie each cQTL and a large proportion of the GWAS loci lie within intergenic regions, making it difficult to pinpoint the true underlying causal gene and mechanisms. Functional genomics aims to bridge the gap. In principle, genetic loci can impose disease risk via the products of the genome, that is, IMPs such as gene expression, microRNA, DNA methylation, protein levels and downstream metabolites. By linking genetic markers or SNPs to IMPs, functional consequences of genetic perturbations and mechanistic insights can be inferred.http://www.encodeproject.org/ENCODE/index.html) and Genotype-Tissue Expression  are likely to provide a comprehensive characterization of the full functional genome in the future. These iQTL/eQTL studies are able to establish the fundamental genetic regulatory architecture of IMPs, and thus serve as the basis for causality inference between genes and disease phenotypes.As summarized in our recent review articles , 35•, 36ULK3 are consistently associated with the intergenic CVD locus 15q24 across adipose, monocyte, liver, and blood [Based on the central dogma, heritable information flows from DNA to RNA, to proteins, and then to phenotypic traits. When cQTL and eQTL overlap, that is, a genetic locus or multiple genetic loci are in association with both disease phenotype and the expression levels of a gene, there is a higher probability that the gene associated with the disease-linked genetic loci is also the causal gene. Based on this principle, Meng et al. identified a significant overlap between the cQTL of aortic calcification and the eQTL for gene ABCC6 in a mouse F2 population and experimentally validated ABCC6 as the causal gene for the phenotype . The samnd blood •, thus rAs IMPs can be upstream , downstream , or independent of a disease phenotype, eQTL and cQTL overlap does not directly implicate causality. The three relationships can be formally tested via statistical and mathematical inference by using DNA or genetic variation information as the anchor Fig. . To thisAll the methodologies outlined above yield lists of molecular markers that are linked to disease development, but they offer little information on how genes and other IMPs are organized and how they operate together in complex biological systems. Networks have emerged as appealing tools to address this complexity; they depict the active agents in the systems as nodes, and their interactions as edges that connect the nodes. Notably, the edges can represent different types of relationships such as correlation, physical binding, biochemical reactions or transcriptional regulation, thereby transcending the boundaries of conventional statistics.http://www.hprd.org/), Biological General Repository for Interaction Datasets , and Ingenuity networks (www.ingenuity.com). These networks can capture literature-supported relationships but are far from being comprehensive and novel relationships or insights will not be covered. On the other hand, data-driven network reconstruction or reverse-engineering approaches systematically and objectively scan through and integrate all data points to uncover novel relationships among IMPs within a cell or a tissue, or even across tissues [Networks can be constructed based on curated knowledge (knowledge-driven) or computational modeling of large-scale genomic data (data-driven). Examples of knowledge-driven networks include protein-protein interaction (PPI) networks in the Human Protein Reference Database  , 55, BayWGCNA aims to identify the correlation patterns among IMPs (primarily gene expression traits) across samples involved in a study. The construction of co-expression network starts with a Pearson correlation matrix between all gene pairs, followed by transformation of the correlation matrix into an adjacency matrix , 55. TheIn contrast to simple clustering algorithms where genes are grouped based on the strength of pair-wise correlations, WGCNA searches for higher-level co-regulation structures. Importantly, the gene memberships of a module are determined not only by their direct correlations but also by the similarity in their relationships with the other genes , 73. TheNumerous studies have applied WGCNA to study the molecular mechanisms underlying MetDs or related phenotypes , 79–86. Although WGCNA is highly informative for deriving the overall organization of genes or other IMPs and for linking particular co-expression modules to disease phenotypes, the detailed relationships among genes within a module or between modules can be less descriptive. Graphical network modules such as BNs can provide more granular views of the interactions and directionalities between genes. BNs define a partitioned joint conditional probability distribution over all nodes (genes or other IMPs) in a network where the probability distribution of states of a node depends only on the states of its parent nodes . TherefoA number of studies in a variety of species have demonstrated that BNs can capture fundamental properties of molecular interactions in complex systems and can infer mechanisms , 89, 90.As shown in Table To harness the strengths of data-driven regulatory networks, the information from gene expression profiling, causality testing and GWAS can be overlaid onto co-expression networks and BNs to infer disease mechanisms and key regulatory genes. In a recent study, we identified a consistent differential gene signature comprised of ~1500 inflammation-related genes, termed inflammatome, from 12 tissue-specific gene expression profiling data of 11 different mouse and rat disease models of obesity, diabetes, atherosclerosis, respiratory diseases, autoimmune diseases, inflammation, aging, and sarcopenia •. This iIn order to explore the candidate causal genes and mechanisms behind GWAS, several novel functional genomics and network-driven methodologies have been recently developed. By integrating GWAS with functional genomics (primarily eQTLs or eSNPs), Zhong et al. found that eSNPs from T2D-related tissues such as liver and adipose tissues are more enriched for T2D risk SNPs •. FurtheSystems biology approaches that leverage genetic, tissue-specific IMP profiling data, and disease phenotypes have evolved rapidly in the past decade. Through their applications in various MetDs in both animal models and human populations, these highly integrative systems biology approaches have unveiled unprecedented insights into disease etiology and uncovered a large number of candidate novel genes, pathways, and subnetworks associated with MetDs. By far, inflammation and immune response related genes and processes have been the most consistent signal across tissue types, across studies, and across MetDs, and thus convincingly represent a key shared component of MetDs. The systems integration of tissue-specific molecular data also revealed many tissue- and disease-specific processes, such as liver-centric lipid metabolism and transport pathways for obesity and CVD; liver- and adipose-specific oxidative phosphorylation, fatty acid oxidation, PPAR signaling, fat cell differentiation for obesity, insulin resistance, and T2D; liver-specific glucagon signaling and islet-specific cell cycle regulation for T2D; and circadian rhythm and RNA splicing processes in brain for obesity and T2D.These findings highlight how tissue-specific gene networks and their cross-tissue interactions, rather than individual genes, mediate MetD etiology. It is therefore critical to shift from a traditional view of disease mechanisms as independent actions of individual genes to a network view, where a large number of genes coordinately define a particular network state in individual tissues and the interactions of gene networks in multiple tissues ultimately lead to MetD onset.Although proven predictive and informative, the existing systems biology methodologies are far from being comprehensive and accurate. Further refinement of existing methods and development of more advanced approaches are thus warranted. First of all, incorporation of next generation sequencing, DNA methylome, microRNA, metabolomics, and other types of data into the systems biology framework has become more pressing than ever, as such data are being rapidly generated and poured into data depositories in the past couple of years. Although some of the existing methodologies can be easily adapted for additional data types, innovative approaches guided by biological insights are still in great need. For instance, based on the regulatory relationships across data types, it is necessary to develop methodologies that leverage multiple levels of IMPs simultaneously to construct more sophisticated networks such as co-regulatory microRNA-gene-metabolite networks.Second, the involvement of multiple cell types, tissues, and organs in MetDs demands methodologies that explore cross-tissue interactions. As demonstrated elegantly in a recent study by Dutta et al., communications and signaling transductions across multiple critical tissues including heart muscle, sympathetic nervous system, bone marrow niches, and spleen are all involved in the enhanced inflammatory response after MI to induce atherosclerosis acceleration •. This tThird, most of the current methodologies capture static information that only represents snapshots of disease status at a given time. Dynamic models that take IMP data generated from time-course experiments are therefore needed to capture the dynamic nature of disease progression. All these different levels of technical and biological challenges have to be properly addressed in the future to allow a full dissemination of MetD etiology. Only when a comprehensive understanding is achieved, can effective diagnostic, preventative, and therapeutic strategies toward these disabling and deadly diseases become a reality.


Unravelling the molecular basis of malignancy is a challenging process of great priority, as cancer rates are increasing worldwide and because certain cancer types are still incurable. The urgent need for novel treatment modalities based upon recent discoveries at the genetic and epigenetic level necessitates a strong collaboration between researchers and clinicians to work toward a common aim: the control of the carcinogenic process in order to ultimately achieve a 100% cure rate.In the last 20 years, a myriad of discoveries at the molecular level have been accomplished, especially with the completion of the “Human Genome Project.” This special issue focuses on how senescence affects tumourigenesis and how novel senescence-related therapeutic approaches could be used to benefit tumour regression and eradication efforts.Mammalian cells have developed complex defence mechanisms, such as apoptosis, growth or cell cycle arrest, and senescence, to combat uncontrolled proliferation caused by external stimuli . Replicative senescence occurs when somatic cells spontaneously decline their growth rate in continuous culture due to an increasing number of population doublings, eventually terminating in a quiescent but viable state. Importantly, senescence has been observed in patients with premalignant tumours but has not been detected in malignant tumours. Clear evidence points to a crucial role of cellular senescence in counteracting malignant transformation. Therefore, in order to eradicate cancer, key molecules  and processes important in senescence could be targets for therapeutic intervention.The papers collected in this issue deal with the above-mentioned key senescence factors. All important oncogenes and tumour suppressor genes crucial in this process are shown. How and to what extent their targeting would be effective in cancer therapeutics is reviewed.Recently, a specific group of proteins called Sirtuins, which are part of an evolutionarily conserved family of NAD-dependent protein deacetylases/ADP-ribosyltransferases, have been identified as key components in senescence and aging. The relationship of Sirtuins with genomic instability and their influence on telomerase and tumourigenesis is discussed.DNA-damage response and its link with self-renewal and senescence are reviewed as determinant processes in which senescent cells may decide how their genetic backgrounds and protein statuses can promote or prevent carcinogenesis.MicroRNAs, short noncoding RNA molecules of ~22 nucleotides, are key post-transcriptional regulators of gene expression. MicroRNAs have an important role in tumour development, progression, chemosensitivity and cellular senescence. Decoding microRNA function is required for the development of novel therapies, such as restoring tumour suppressor-microRNAs and targeting onco-microRNAs with anti-miR technology. All of these approaches are extensively reviewed.Moreover, abundant evidence suggests that senescence plays an important role in aging. The paradoxical role of senescence as a protective mechanism against the eradication of cancer might be detrimental to the possible contribution of senescence to aging. The molecular regulation of senescence in cancer and aging is discussed.Overall, the potential of cellular senescence to be used as a target for anticancer therapy is a close reality in the clinical practice. In this issue, therapeutic strategies are fully considered, and their applications in each case are proposed.Matilde E. LLeonartMatilde E. LLeonartAmancio CarneroAmancio CarneroRosanna PaciucciRosanna PaciucciZhao-Qi WangZhao-Qi WangNoam ShomronNoam Shomron


MicroRNAs (miRNAs) are members of a large class of non–protein-coding RNA (ncRNA) molecules that represent a significant, but until recently unappreciated, layer of cellular regulation. Assessment of the generation and function of miRNAs suggests that these ncRNAs are vulnerable to interference from genetic, epigenetic, and environmental factors. A small but rapidly expanding body of studies using a variety of animal- and cell culture–based experimental models also has shown that miRNAs are important targets of alcohol during fetal development and that their dysregulation likely plays a significant role in the etiology of fetal alcohol spectrum disorders (FASD). Accordingly, an analysis of the regulation and function of these miRNAs may yield important clues to the management of FASD. MicroRNAs (miRNAs) are members of a vast, evolutionarily ancient, but poorly understood class of regulatory RNA molecules, termed non–protein-coding RNAs (ncRNAs). This means that in contrast to RNA molecules generated during gene expression , they are not used as templates for the synthesis of proteins. ncRNAs are encoded within the genomes of both eukaryotic and prokaryotic organisms and represent a novel layer of cell regulation and function that rivals the diversity and function of protein-coding mRNAs  and/or mediate its effects. Initial studies  exploredMaternal alcohol consumption during pregnancy can lead to a constellation of brain, face, cardiovascular, and skeletal defects of varying severity that collectively have been termed fetal alcohol spectrum disorders (FASD). At the extreme end of the spectrum of severity is fetal alcohol syndrome (FAS) , which iAlthough the facial characteristics seen in patients with FASD are the most obvious signs of fetal alcohol exposure, the most devastating consequences of prenatal alcohol exposure are brain defects that result in cognitive, affective, and motor deficits . TherefoCaenorhabditis elegans , first an mRNA copy of the corresponding DNA sequence is generated in a process called transcription. This mRNA molecule consists of three parts: a noncoding start region , the sequence actually containing the information for the encoded protein , and a noncoding tail region . miRNAs mainly act by binding to the 3′-untranslated region of their mRNA targets , althoug elegans , but sin elegans . miRNAs  elegans . miRNAs  elegans , and bra elegans .A normal transcription process, which is mediated by an enzyme called RNA-polymerase II, generates a longer primary transcript termed pri-miRNA. Like mRNA, the pri-miRNA transcripts can have certain modifications at their ends  and can be spliced . FurtherMost pri-miRNA transcripts are processed within the nucleus by a protein complex called the DiGeorge syndrome critical region-8 (Drosha/DGCR8) “microprocessor” complex to generate stem-loop structures termed pre-miRNAs that are approximately 70 nucleotides in length .The pre-miRNAs are moved from the nucleus to the cytoplasm by a chaperone protein called exportin-5 .Within the cytoplasm, a protein complex known as Dicer enzyme further processes pre-miRNAs into mature double-stranded miRNA molecules . This prOnce the Dicer complex is cut off to release the mature miRNA, one strand of the double-stranded molecule, termed the guide strand miRNA, preferentially attaches to another protein complex called RNA-induced silencing complex (RISC). This results in a microribonucleoprotein (miRNP) complex that can either destabilize mRNA transcripts or repress the next step of gene expression in protein-coding genes  . The secFinally, the mature miRNA can be degraded by an enzyme called 5′-3′ exoribonuclease (XRN2) .miRNAs are encoded within the genome either as independent genes or in gene clusters; however, they also can be encoded within intronsIn 2007, Other developmental ethanol exposure models also have indicated that ethanol alters the expression of several miRNAs. For example, Although the miRNAs identified by Finally, Guo and colleagues (2011) assessed the effects of chronic intermittent ethanol exposure on cultured neuronal cells obtained from mouse cerebral cortex at gestational day 15, which is equivalent to the middle of the second trimester. The investigators found that ethanol induced several miRNAs in these cells. Interestingly, a prolonged period of withdrawal following the ethanol exposure resulted in a more than fourfold increase in the number of significantly regulated miRNAs, suggesting that withdrawal itself also may have a significant damaging effect on neuronal maturation in the developing fetal brain. Although these data were obtained from a cell-culture model, the implications of maternal binge drinking–withdrawal cycles on fetal miRNAs and their control over neural differentiation need further investigation.Pregnant women who abuse ethanol also are likely to coabuse other drugs, such as nicotine . These oThe data cited above show that ethanol alters the expression of several miRNAs at different developmental stages and that these alterations have consequences for fetal neural development and behavior. miRNA dysregulation is likely to influence teratogenesis by destabilizing the mRNAs of individual genes or gene networks. However, emerging evidence indicates that miRNA function also can be altered at several stages in the miRNA biogenesis pathway. Although to date such alterations are poorly understood, they may have important implications for teratology. The following represent four intriguing possibilities.First, the presence of a 5′ cap and a 3′-polyA tail indicates that primary miRNA transcripts may have characteristics and function like regular mRNAs, and indeed evidence has been found for such a role . Althougwww.mirbase.org, miRBAse Release 19]), ethanol produced a more modest decrease in the expression of miR-9* . The ratio of miR-9 to miR-9* is important for development and teratogenesis because these two miRNAs work together to regulate two molecules controlling neuronal differentiation. Thus, miR-9 levels influence the levels of a neuronal differentiation inhibitor called RE1 silencing transcription factor/neuron-restrictive silencer factor (REST), whereas miR-9* regulates its cofactor, coREST (Second, until recently, the complementary miRNA* strands  were tho, coREST . Therefo, coREST , 2010. CThird, in humans, about 6 percent of mature miRNAs undergo editing by the enzyme adenosine deaminase , resultiFinally, emerging evidence indicates that some mature miRNAs are transported back to the nucleus, where they mediate the formation of heterochromatinDespite strong evidence that maternal alcohol consumption during pregnancy leads to harmful effects on the fetus, a significant number of women continue to report drinking even into the third trimester of pregnancy. Therefore, early detection and management of fetal alcohol exposure remains an urgent public health concern, as does the development of approaches to ameliorate or prevent ethanol’s detrimental effects. The identification of miRNAs as ethanol targets presents one hope for the development of novel therapeutic programs. miRNAs have coevolved with their mRNA targets to orchestrate development. It is possible that miRNA-like drugs may be used to mitigate the effects of fetal ethanol exposure on the development of specific organs. The challenge will be to identify tissue-specific miRNAs that can be used to reprogram development. In this context, miRNAs such as miR-9 make intriguing therapeutic targets because they are fairly specific to neuronal cells . Evidenc


The renin-angiotensin-aldosterone system (RAAS) plays a dominant role in the pathophysiology of hypertension, diabetes mellitus, chronic kidney disease and chronic heart failure. Therefore, drugs that block key components of the RAAS such as ACE inhibitors (ACEI) and angiotensin receptor blockers (ARBs) have gained wide clinical use for these indications. Despite progress, the morbidity and mortality of patients treated with ACEI or ARBs remain high. Aliskiren  is the first orally active inhibitor of renin approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg. Aliskiren is effective either as monotherapy or in combination with drugs from the other major classes. In this review we analyze and review the information already gained with Aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEIs and ARBs, their potential added value in combination with other RAAS modulators and other still unproven benefits in relation to prorenin and renin receptor biology. Hypertension is one of the most important risk factors for, and causes of, cardiovascular disease. The difficulty in achieving a normal blood pressure range in some patients makes the rate of cardiovascular disease high ,2,3. ForAliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro  ,5,6,7,8.Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics , ACE inhibitors (ramipril) and angiotensin receptor blockers , despite greater increases in the plasma renin concentration ,10,11. MHypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycaemic or lipid-lowering drugs. Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment ,13,16.Aliskiren is the first renin inhibitor to be licensed for use as an antihypertensive drug in both the United States and Europe. Opinions vary considerably concerning the future of aliskiren and renin inhibition. Some experts argue that renin inhibitors should only be prescribed when less expensive blockers of the renin-angiotensin system (RAS), with established effects on morbidity and mortality, are not tolerated or have failed to reduce blood pressure effectively. Others propose that because renin is a highly specific catalyst for the rate-limiting step of the RAS, renin inhibitors have the potential to supersede angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the preferred inhibitors of the cascade in patients with particular pathologies and/or genotypes . It has The evidence supporting the use of renin inhibitors to control hypertension, but limiting this use in patients with kidney disease progression even if ACE and ARB decrease cardiovascular risk in patients with chronic kidney disease. Renin-angiotensin-aldosterone system inhibition exerts a renoprotective effect independent of blood pressure reduction. Many studies using an end-point of proteinuria compared the effects of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker monotherapy with combination ACE/ARB therapy. Despite methodological limitations, most studies suggest that combination therapy provides a greater antiproteinuric effect than monotherapy, perhaps because of more prolonged and complete RAAS inhibition. COOPERATE and ONTARGET used more robust end-points to study renoprotective effects. In COOPERATE Study; combination therapy resulted in significantly longer times to doubling serum creatinine or developing end-stage renal disease than Trandolapril or losartan monotherapy. However, a secondary ONTARGET finding was that combination therapy significantly increased the risk for renal dysfunction compared with ramipril or telmisartan alone ,16,17,18versus existing RAAS antagonists in treating hypertension and target organ damage are under investigation. The antihypertensive efficacy of aliskiren monotherapy has been compared with that of other RAAS antagonists and combinations of aliskiren with these agents. Many studies have shown that aliskiren is equally effective as angiotensin receptor blockers and may be slightly more effective than angiotensin converting enzyme inhibitors in lowering blood pressure. In contrast to the other RAAS antagonists, aliskiren shuts down the entire downstream RAAS cascade. This results in greatly increased plasma renin concentration due to removal of angiotensin II-mediated feedback inhibition of renin release, which has raised concerns about whether direct renin inhibition adds anything to inhibition of downstream components of the RAAS cascade [24].The potential advantages and disadvantages of aliskiren therapy et al., that compared DRI to ramipril 10 mg conclude that aliskiren-based therapy produced sustained blood pressure (BP) and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted four weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug. Palatini et al. reported that aliskiren 300 mg provided a sustained BP-lowering effect beyond the 24-h dosing interval, with a significantly smaller loss of BP-lowering effect in the 24-48 h period after dose than irbesartan 300 mg or ramipril 10 mg .Till now aliskiren was added to valsartan in stage 2 hypertension in a recent report. This combination therapy provided significantly greater BP reductions over aliskiren or valsartan monotherapy. Also aliskiren was combined with losartan, with similar results. Finally, Freiberger Aliskiren has the potential to become the first orally active renin inhibitor that provides a true alternative to ACE-inhibitors and Ang II receptor antagonists in therapy for hypertension and other cardiovascular and renal diseases. As monotherapy, aliskiren now is reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated. Till now a large, formal, and prospective randomized study with major endpoints with aliskiren has not been completed Without such data, especially when alternative therapeies have such data, it is difficult to make a firm recommendation. Aliskiren is well on its way but falls short of this criterion until the navigator study is complete. In our opinion in the future it is possible that aliskiren could supplant ACE inhibitors and ARBs, because it was demonstrated more effective than ACE and ARB to reduce BP and to reduce PRA. Combination therapy with the direct renin inhibitor, aliskiren, and the angiotensin receptor blocker or ACE inhibitor has been shown to produce greater BP reductions than either agent alone in some double-blind study and it will represent the next future.


To the Editor: Usutu virus (USUV), a member of the Japanese encephalitis virus antigenic group, was first detected in 1959 in mosquitoes in South Africa (Turdus merula) in Italy  with central nervous system signs were recovered from a die-off of ≈10 birds at a hunting estate in southern Spain. A full necropsy was conducted on the 2 thrushes (which died shortly after capture), and samples were collected for virus detection and histopathologic examination. Total RNA was extracted from oral and cloacal swab specimens, from serum from a cardiac blood clot, and from heart, kidney, spleen, and brain tissues by using High Pure RNA Tissue Kit  and analyzed by generic flavivirus SYBR Green  real-time reverse transcription PCR (RT-PCR) and by a generic conventional nested flavivirus RT-PCR  showed a 96%–97% homology to published USUV sequences. Nucleotide sequence analysis revealed a higher homology to Northern European strains  than to a USUV strain isolated in South Africa (96% to SAAR-1776 [AY453412]). This finding was also supported by phylogenetic analysis of USUV strains , panel AHistologically, both birds had severe encephalitis characterized by congestion, neuronal and Purkinje cell necrosis, gliosis, satellitosis, neuronophagia, and endothelial cell swelling and vasculitis. Other lesions included multiorgan congestion, necrosis of renal tubular epithelium, and moderate hemosiderosis in the liver and spleen. Intravascular cross-sections of filarial parasites were detected in pulmonary capillaries. Antigen labeling was detected in neurons in the cerebral hemispheres and brain stem and in glia cells throughout the brain , panel BThe molecular genetic analysis, histopathologic examination, and immunohistochemical testing confirmed encephalitis caused by USUV in 2 migratory wintering song thrushes who died during a small mortality event in southern Spain. Phylogenetic analysis showed that the USUV strain infecting the diseased birds was more similar to USUV strains from Austria, Hungary, and Germany than to USUV strains isolated from mosquitoes in Spain  from Northern Europe, in addition to local endemicity and introduction from Africa, occurs, and that the zoonotic European USUV strain may be co-circulating with strains of African origin. At this time, it is not clear whether USUV strains of Spanish/African lineage differ in virulence for humans from strains from the European/African lineage. However, virus introduction by northern migrants, in combination with locally favorable conditions for vector populations, implies a risk for virus amplification and transmission and disease outbreaks in humans and horses outside the currently established mosquito-trapping period (May–October) of targeted flavivirus surveillance programs.


In 2011 driven by our growing concern regarding delivery of care related to infection control and the transmission of infections a hand hygiene project was initiated.Increase product accessibility at point of careImproved knowledge of hand hygiene and overall infection control processesIncrease in hand hygiene complianceA review of the following items was completed using the LEAN methodology, the 5 "Why”.System Change -Reviewed location of alcohol-based hand rub at point of care, reviewed accessibility of alcohol-based hand rub to Patients in wheelchair, reviewed accessibility to water soap and towels, reviewed accessibility to hand moisturizers, Interdisciplinary team involvement.- Training / Education -Family, Patients, staff, visitors, and outside contractors were trained on the moments of hand hygiene and correct procedures for hand rubbing and hand washing, Trained staff to complete hand hygiene observation audits, Staff reviews utilization of gloves, All staff watched a hand hygiene video.- Evaluation and feedback -Assessed staffs perception of hand hygiene – thru focused groups and surveys, Hand hygiene focused observation audits were completed prior to initiating the project and post implementation, Completed environmental Infection control audits to supplement infection control processes overall.- Reminders in the workplace -Poster were posted in public areas, audit results were posted in the quality board for all to see.- Institutional safety climate -Nurtured a culture of Patients safety, Implemented Patients hand hygiene champions on each floor, Involved Patients and Family council.- - Baseline hand observation audits were compiled and repeated every 3 months. Increase in hand hygiene from 67% to 96% (increase of 29%)- No outbreaks in 2011, 2012This project showed a benefit for the Patients, staff and the community at large.None declared


A vaccine adjuvant is a vaccine component that is used to enhance host immune responses to the antigens in the vaccine. While live attenuated vaccines without adjuvants often stimulate strong immune responses, they are difficult to be approved for human use due to potential safety concerns. Subunit vaccines  can purposely exclude possible allergens, toxins, and virulent molecular domains of a pathogen. The restriction of host immune responses to specified antigenic regions prevents autoimmune responses and increases vaccine safety. However, subunit vaccines do not typically induce strong immune responses. Therefore, the selection and usage of powerful vaccine adjuvants to enhance antigen-specific immune responses is critical to successful vaccine development.in vivo or cells in vitro for analysis of their induced immune responses and adverse effects. Overall, vaccine adjuvant informatics addresses scientific questions different from those associated with the whole vaccines or other vaccine components . Figure Intensive vaccine adjuvant research has been conducted and reported. As of January 11, 2014, a PubMed search of “vaccine and adjuvant” identified 35,000 articles published since 1948. Large amounts of high throughput gene expression datasets related to vaccine adjuvants are also publically available in centralized repositories, e.g., the NCBI Gene Expression Omnibus (GEO). These “big data” cannot be systematically analyzed without computational approaches. The specific field of developing and applying informatics tools for vaccine adjuvant research and development can be called “vaccine adjuvant informatics”. We have previously described the “vaccine informatics” that focuses on the development and application of bioinformatics methods for facilitating different aspects of preclinical vaccine research and development, clinical vaccine trials, and post-licensure vaccine safety and efficacy surveillance (http://www.violinet.org/vaxjo)  . Vaxjo sg/vaxjo) . Biologig/vaxjo) . Omics-bg/vaxjo)  and vaccg/vaxjo) .Informatics studies support basic and translational vaccine adjuvant research. Mechanistic understanding of how innate immunity is initiated and how it shapes adaptive B- and T-cell responses has significantly influenced the development of vaccine adjuvants. For example, as parts of innate immune system, the pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins, recognize the pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharide. Many TLR agonists have been developed as vaccine adjuvants to bind to TLRs, promoting the maturation of antigen presenting cells  and further induction of adaptive immune responses . HoweverMany new research areas have not been well studied but deserve intensive exploration. For example, it is likely that the immune responses induced by vaccine adjuvants and antigens can be different but cooperative. The mechanistic differences and similarities between vaccine adjuvant- and antigen-induced host responses and how these two types of responses interact have not been carefully studied. The addressing of these questions using a combination of Omics, literature mining, and informatics methods will likely lead to the development of new and better vaccine adjuvants and vaccines. In addition, rational vaccine adjuvant design needs to consider the factor of what infectious microbe or disease a vaccine is targeted for. Our Vaxjo data analysis has identified many possible correlations between infectious microbial agents targeted by vaccines and the adjuvants used in the vaccines . Out of In the exciting era of post-genomics and informatics, we also expect the advent of more advanced computational algorithms, easy-to-use software programs, and even theoretic breakthroughs that will provide researchers more capabilities to conduct vaccine adjuvant research and development.