Repetitive transcranial magnetic stimulation (rTMS) is a safe and painless method for stimulating cortical neurons. In neurological realm, rTMS has prevalently been applied to understand pathophysiological mechanisms underlying movement disorders. However, this tool has also the potential to be translated into a clinically applicable therapeutic use. Several available studies supported this hypothesis, but differences in protocols, clinical enrollment, and variability of rTMS effects across individuals complicate better understanding of efficient clinical protocols. The aim of this present review is to discuss to what extent the evidence provided by the therapeutic use of rTMS may be generalized. In particular, we attempted to define optimal cortical regions and stimulation protocols that have been demonstrated to maximize the effectiveness seen in the actual literature for the three most prevalent hyperkinetic movement disorders: Parkinson's disease (PD) with levodopa-induced dyskinesias (LIDs), essential tremor (ET) and dystonia. A total of 28 rTMS studies met our search criteria. Despite clinical and methodological differences, overall these studies demonstrated that therapeutic applications of rTMS to “normalize” pathologically decreased or increased levels of cortical activity have given moderate progress in patient's quality of life. Moreover, the present literature suggests that altered pathophysiology in hyperkinetic movement disorders establishes motor, premotor or cerebellar structures as candidate regions to reset cortico-subcortical pathways back to normal. Although rTMS has the potential to become a powerful tool for ameliorating the clinical outcome of hyperkinetic neurological patients, until now there is not a clear consensus on optimal protocols for these motor disorders. Well-controlled multicenter randomized clinical trials with high numbers of patients are urgently required. Alteration in dynamics of neural connectivity is the hallmark of motor and behavioral disease in humans. Brain connectivity affected by functional deficits will either produce exacerbated or reduced brain signal and thus the observed clinical symptomatology. In the motor domain, presence of hyperkinetic movement disorders is typically manifested as increased muscular activity that leads to involuntary and unwanted movements, abnormal postures or combination of both. These are present in several neurological disorders, such as essential tremor (ET), dystonia, and Parkinson's disease (PD). In contrast, hypokinetic movement disorders represent loss of vigor and movement that produces rigidity and the inability to initiate and terminate actions efficiently, present in bradykinesia or freezing of gait in PD. Current treatments are mainly pharmacological, but recently functional surgery has made progress in remediation of uncontrolled and unwanted motor disorders  or high frequency (>1 Hz), as well as single rTMS or multiple rTMS sessions. Generally, high frequency stimulation induces an increase in cortical excitability and low frequency stimulation causes a decrease in cortical excitability. To benefit plastic and long-term rTMS potentiation, multiple sessions tend to show stronger and cumulative effects in clinical and behavioral measures. An alternative use of rTMS is theta burst stimulation (TBS), consisting of short, repeated bursts of TMS pulses at 50 Hz , tremor, rigidity, and gait problems are cardinal motor signs in PD, greatly improved by treatments with dopamine replacement therapy. However, PD-related neurochemical changes are long-lasting and difficult to contrast by pharmacological interventions. For this reason, new treatment strategies have been proposed. rTMS has been studied as an intervention to ameliorate motor symptoms . The time-to-onset and severity of this motor complication show large individual variability thus limiting the long-term use of levodopa and clinical strategies aimed at reducing LIDs manifestation.in vivo that these abnormal neuronal firing patterns extended on the brain cortex mainly including the sensorimotor areas of the cortico-basal ganglia loop.In the last few years, a considerable effort has been made to understand the neurobiological basis of this motor complication. LIDs are classically ascribed to the degree of nigrostriatal neurodegeneration and striatal changes associated with chronic levodopa therapy  is to control/modulate the primary motor output pathway. Idiopathic PD is primarily a disorder of response initiation characterized by an excessive motor inhibition , whereas LIDs are clearly a clinical expression of disinhibition of movement. For this reason, the recent neuroimaging evidence strongly supports the idea that dysfunctions of the primary motor system in LIDs patients are related to that of motor inhibition pathway. However, it remains to be clarified why clinical beneficial effects are evident after rTMS over the cortical regions involved in the motor inhibition system (SMA and IFC), whereas brain stimulation on the primary motor cortex produced conflicting results  might be highly promising as therapeutical sites for treatment of LID. Otherwise, evidence provided by rTMS over the primary motor cortex requires further confirmation. Indeed, while in idiopathic PD a plethora of studies demonstrated the beneficial effects on motor symptoms after high-frequency stimulation of the primary motor cortex  is a solid factor of variability in the current literature. Most of the available literature reports low frequencies  prolonged sessions are possible, (ii) the use of low frequency rTMS i.e., 1 Hz), (iii) samples selection restricted to those patients refractory to regular medical treatment, and (iv) choosing the adequate target based on known cortical regions altered in pathophysiological models. Figure  Hz,  have not yet been applied in these disorders. Also, if rTMS protocols are used with patient samples grouped by disease onset and symptom type we may expand knowledge on patient-dependent states and how TMS may modulate differently at each disease stage or symptomatology.The reader should also note that in this review we neglected some other important hyperkinetic movement disorders such as, Huntington's disease and Tourette syndrome. With respect to Huntington's disease where the application of rTMS for therapeutic purpose is in its relative infancy (Berardelli and Suppa, To sum up, the current literature on therapeutic trials of rTMS in hyperkinetic movement disorders patients is still ambiguous, and there is need of well-controlled multicenter randomized clinical trials to define the most effective protocol. However, advancements in technology, as well as, in pathophysiological understanding will improve the effectiveness of this safe and potentially therapeutic option in hyperkinetic movement disorder patients.IO designed and wrote the manuscript. AC designed and wrote the manuscript. AQ wrote the manuscriptThe 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.


Neural activity was recorded while participants viewed a series of avatar male faces portraying positive, negative or neutral expressions. Significant gender differences were found in the left amygdala, where 23% (n = 15∕66) of neurons in men were significantly affected by facial emotion, vs. 8% (n = 6∕76) of neurons in women. A Fisher's exact test comparing the two ratios found a highly significant difference between the two (p < 0.01). These results show specific differences between genders at the single-neuron level in the human amygdala. These differences may reflect gender-based distinctions in evolved capacities for emotional processing and also demonstrate the importance of including subject gender as an independent factor in future studies of emotional processing by single neurons in the human amygdala.Well-documented differences in the psychology and behavior of men and women have spurred extensive exploration of gender's role within the brain, particularly regarding emotional processing. While neuroanatomical studies clearly show differences between the sexes, the functional effects of these differences are less understood. Neuroimaging studies have shown inconsistent locations and magnitudes of gender differences in brain hemodynamic responses to emotion. To better understand the neurophysiology of these gender differences, we analyzed recordings of single neuron activity in the human brain as subjects of both genders viewed emotional expressions. This study included recordings of single-neuron activity of 14  epileptic patients in four brain areas: amygdala (236 neurons), hippocampus ( Since gender is such an integral part of human identity, gender differences in the human brain have long been a source of interest and dissent amongst researchers. Anatomically, there are well-documented gender differences in relative volumes of neural structures including the frontal cortices, the hypothalamus, and the amygdala  at the Barrow Neurological Institute. Table Participants were presented with a set of 120 synthetic male faces which were originally designed to test the effects of race on the firing of human single neurons while also displaying varying emotional expressions. These faces were created using FaceGen Modeler  was included in the analysis. Trials in which participants responded early, pressed more than one identifying key, or failed to respond were eliminated from analyses. The elimination of error trials did not affect the reported results.We used surgical and recording methods which we have previously described in Valdez et al. . In briehttp://klustakwik.sourceforge.net). Post-sorting, each cluster was classified as either noise, multi-unit or single-unit activity per the criteria listed in Valdez et al.  with the open-source clustering program KlustaKwik . Image luminance and contrast were included as additional factors given their recently demonstrated effect on firing rate in the amygdala  for each neuron in the study to determine whether the addition of the affect stimuli factor improved goodness of fit  plots  but not in females (p = 0.28). A Fisher's Exact Test comparing these two ratios found the ratios to be significantly different between males and females (p = 0.013).Within the amygdala, we found this activity was highly lateralized, and differed measurably between men and women. Tables p-value distributions of tests of the effect of affect in male vs. female subjects. The distribution in the left amygdala  plots of the a Figure  demonstra Figure , and in a Figure , though p = 0.0054) and left amygdala (p = 0.0013).We next determined which categories of emotion  particular neurons were responding to using multinomial logistic regression (MLR). This regression determines whether a category of emotion can reliably be predicted based on changes of the firing of a neuron relative to background and provides a single test for each neuron which determines both that the response is different from background firing and provides information distinguishing between different emotions. The results of MLR analyses of the total and left amygdala are described in Tables As an additional test that neuronal responses to the three emotions differed from background firing, we tested whether the responses of neurons with a significant effect of emotion had responses which significantly differed from background firing, using the changes from background test . While inconsistencies within the neuroimaging literature have called into question whether the amygdala has greater activation under explicit or implicit experimental conditions (Habel et al., Although previous work utilizing non-invasive techniques to assess gender differences in hemodynamic responses to emotional stimuli has produced conflicting results (Sergerie et al., By using single-neuron recording to directly measure neural activity within the amygdala, we obtained results which suggest the opposite; namely, that neurons in amygdalae of men are more responsive to emotional stimuli than those in women. There are several possible explanations for the difference between our results and the bulk of those obtained via neuroimaging. Firstly, the relationship between the BOLD signal and underlying neural activity is still not well-understood (Sirotin and Das, Secondly, discrepancies within the neuroimaging literature have been attributed, amongst other factors, to variations in experiment design (Derntl et al., Both of these potential explanations suggest an interesting avenue for future research: how would single-neuron firing rates differ between men and women when viewing own-sex vs. opposite sex faces? If sample sizes permit, it may also prove intriguing to include additional subject variables which have been shown to influence BOLD signals in neuroimaging studies, including participant sexual preference (Perry et al., Intriguingly in this study, males were more accurate in identifying the emotion expressed on faces whereas women had shorter response times. While these differences did not correlate with neural firing on a trial-by-trial basis, the overall changes in neural firing suggest that the higher accuracy of males may be related to larger changes in neural firing which are present in the left amygdala of male subjects. We did not observe a specific neural firing rate correlate of the faster responses in females.Several limitations of this study should be noted. Firstly, the stimulus images in this study were designed to portray, as opposed to evoke, emotions. While these images were not designed to evoke emotion, it has been shown repeatedly that the viewing of emotional faces evokes the presented emotion in the participant, particularly with regards to “strong” emotions including happiness and sadness (Hess and Blairy, Secondly, due to the invasive nature of single-unit recording, participants could not be chosen at random. All subjects shared a common diagnosis of refractory epilepsy, and were thus neurologically distinct from the majority of the population. We are not aware, however, of any reports that epileptics process emotion in a fashion distinct from that of the general public, nor that it has been demonstrated that men and women with epilepsy have gender-linked differences in emotional responses unequal with those observed in healthy individuals.What is the potential cause of these gender based differences in neural responses to emotional faces? Given the limitations of this adventitous experimental design, we can speculate that these differences may reflect evolutionary differences accrued as a means of survival under respective selective pressures. Men have born the brunt of intergroup conflict dating back to hunter-gatherer societies (Van Vugt, Alternatively, the observed results may be due to differences in inter- vs. intra-sex male expression of empathy, an emotion whose neuronal network has been shown in imaging studies to include the amygdala (Völlm et al., In summary, our findings demonstrate emotional differences between men and women at the single neuron level, thereby illustrating the profound effect of gender on the human brain. This finding necessitates the inclusion of subject gender as a potential variable in single-unit recording studies, particularly those whose scopes include firing rates within the amygdala. Gender should also be a factor of interest in single-unit experiments which utilize emotional imagery or human expressions.MN analyzed data and created text and figures. PS Designed and conducted experiments and created text and figures. KS Performed patient surgeries. DT supervised patient safety and clinical compliance.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.


Acute kidney injury (AKI) is a frequent complication of the systemic inflammatory response syndrome (SIRS), which is triggered by many conditions in the intensive care unit, including different types of circulatory shock. One under-recognized characteristic of the SIRS-induced AKI is its avidity for sodium retention, with progressive decreases in urinary sodium concentration (NaU) and its fractional excretion (FENa). This phenomenon occurs in parallel with increases in serum creatinine, being only transitorily mitigated by diuretic use. In the present case, we report a situation of two consecutive shocks: the first shock is hemorrhagic in origin and then the second shock is a septic one in the same patient. The SIRS and AKI triggered by the first shock were not completely solved when the second shock occurred. This could be viewed as a persistent avid sodium-retaining state, which may be appreciated even during renal replacement therapy (in the absence of complete anuria) and that usually solves only after complete AKI and SIRS resolution. We suggest that decreases in NaU and FENa are major characteristics of SIRS-induced AKI, irrespective of the primary cause, and may serve as additional monitoring tools in its development and resolution.  Circulatory shock is a pathological condition resulting from the inadequate tissue perfusion and a mismatch between oxygen supply and demand. Systemic inflammatory response syndrome (SIRS) and subsequent multiple organ dysfunction are a frequent end-point of different types of circulatory shock.Acute kidney injury (AKI) is one of the most frequent organ dysfunctions in the course of SIRS and shock and carries high morbidity/mortality . The patWe have recently demonstrated that AKI development is associated with decreases in urinary sodium concentration (NaU)  and incrWe have also previously reported the NaU profile in the course of AKI secondary to septic shock . In thatKlebsiella pneumoniae in uroculture). Vasopressors were again required and new deterioration of renal function occurred  after being submitted to elective percutaneous lithotripsy, nephrostomy, and left double J stent due to a coraliform stone and recurrent previous urinary tract infections. No complications were reported during the surgical procedure. One hour after admission, the patient developed frank hematuria and bleeding through the nephrostomy tube, circulatory shock, and an abrupt fall of the hemoglobin level from 13 to 6 g/dL. After initial resuscitation with fluids, blood, and vasopressors, she was submitted to embolization of a distal branch of the left renal artery. A subsequent SIRS and multiple-organ dysfunction syndrome developed with abrupt increases in C-reactive protein CRP—, leukopeoccurred , but no occurred  and PCT.The above case can be divided in two fundamental parts: the first part (phase 1) that is related to the postoperative hemorrhagic shock and the second part (phase 2) in which the patient has developed a second shock due to a urinary tract infection. In phase 1, AKI developed and rapidly reached an AKIN stage 3  with theSince there was no complete anuria during CRRT, we continued to measure NaU and it remained decreasing daily even after RRT interruption. An increase in NaU may be observed between CRRT and conventional dialysis, but this was attributed again to diuretic use. The lowest NaU values were reached only after RRT was completely removed, suggesting a process that was not directly affected by RRT.If the increases in NaU due to diuretics were ignored , it may In the previous case , NaU staThe behavior of FENa reaffirms the avid sodium retention that was triggered by shock/SIRS . FENa vaSince FENa usually has a low range of variation (except after diuretic), we have proposed the evaluation of FEK  in the cCirculatory shocks, independently of their origin, trigger similar alterations in the urinary biochemical profile, particularly in NaU, FENa, and FEK. These alterations may precede increases in sCr and remain even after its normalization. Persistent AKI may have a persistent “prerenal” pattern in inflammatory states suggesting that decreases in GFR are followed by preserved global tubular capacity to avidly reabsorb sodium even in advanced stages of AKI. Significant increases in NaU in the absence of diuretics may be a sign not only of AKI resolution but also of SIRS resolution. However, further studies are required to better define the role of these urinary biochemical parameters in the context of SIRS generated by different types of shock.


This effect has been most extensively investigated for the tuberculosis vaccine strain Bacillus Calmette-Guérin (BCG). Epidemiological studies suggest that this vaccine is associated with a substantial reduction in overall child mortality that cannot be solely explained by prevention of the target disease but that it seems to rely on inducing resistance to other infections. Upon infection or vaccination, monocytes/macrophages can be functionally reprogrammed so as to display an enhanced defensive response against unrelated infections. Epigenetic modifications seem to play a key role in the induction of this “innate memory.” These findings are revolutionising our knowledge of the immune system, introducing the concept of memory also for mammalian innate immunity. Thus, vaccines are likely to nonspecifically affect the overall immunological status of individuals in a clinically relevant manner. As a consequence, future vaccine strategies ought to take into account the contribution of innate memory through appropriate design of formulations and administration scheduling.Recent findings in the field of immune memory have demonstrated that B and T cell mediated immunity following infections are enhanced by the so-called  Its effectiveness results in a reduction of mortality and an increase of life expectancy by the prevention of contagious diseases. A recent report shows that vaccines prevented more than 100 million cases of disease over the last century in the United States alone . Vaccinaresponse . Over 50response –9.In the last years, important discoveries changed the way of looking at the innate immune system. Features as specificity and memory, the main traits of the adaptive immune system, are now also considered to some extent for innate immunity.The discovery of Patter Recognition Receptors (PRRs) has introduced the concept of specificity in innate recognition, although not in the highly specific fashion characterising adaptive immune recognition. The existence of different classes of innate receptors , nucleotide-binding oligomerisation domain-like receptors (NLRs), and retinoic acid-inducible gene I (RIG-I) helicases) allows innate immune cells to identify different pathogenic microorganisms based on the recognition of pathogen-associated molecular patterns (PAMPs). The discovery of TLR and elucidation of their functions has led to the selection of a new class of adjuvants, that is, the TLR agonists –12.Revisited old knowledge on the repeated stimulation of the innate immune responses has reintroduced the old concept of innate immune memory , 14, redEvidence in both plants and invertebrates  indicates that phagocytes can respond much better to a challenge if they have been prestimulated with the same or with another agent . Thus, iThe concept of innate memory might help to develop new strategies of adjuvanticity in the near future.Generally, vaccines have antigen-specific protective effects, but they can also improve the resistance to other infectious diseases. This phenomenon of nonspecific memory induction may go both ways, as we will better describe later; that is, it can also result in decreased reactivity to an unrelated subsequent challenge. Accordingly, a vaccine is not only a preventive strategy that improves the immune response against a specific infection, but a “biological preparation that alters the resistance towards unrelated pathogens” . InteresThis review summarises the current knowledge and hypotheses on innate immune memory and its role on vaccine efficiency, focusing on mononuclear phagocytes as the main innate immune cells involved and on the role of innate immune memory on nonspecific immunity. We will also highlight which questions are still unanswered. Some vaccines have been associated with a high decrease in mortality that not only is accounted for by their specific effects against a certain pathogen, but also depends on the induction of a nonspecific protection against unrelated infections and pathogens . This no ex vivo stimulation up to 3 months after immunisation [γ-irradiated BCG vaccine. Considering that live BCG is detectable for up to 4 weeks at the challenge site [As already mentioned, the favourable nonspecific effects of vaccines are presumably mediated by both adaptive and innate immunity. A study on SCID mice (which are devoid of T and B cells) clearly shows BCG induced nonspecific protection against an unrelated pathogen, thereby underlining the crucial role of innate immune mechanisms in the BCG induced protection . Moreovenisation . Interesnisation . It shounge site , it is cnge site .A very interesting notion is that the innate memory is at least in part nonspecific, which implies that an improved defensive response can be obtained by prechallenging the host with  any kind of agents. This concept breaks the current dogma that innate immunity is a stable and nonvariable type of response, always the same at every challenge, as opposed to acquired immunity that “learns” after the first encounter and generates more rapid and more efficient responses upon subsequent challenges due to the presence of memory cells.+ NK cells of T and B cell-deficient mice develop nonspecific memory upon vaccination with structurally diverse antigens [The mechanisms underlying trained innate immunity have not been fully elucidated. Among the innate immune cells, the most active innate memory cells are monocytes/macrophages and NK cells. Both are cells with low turnover rates and thus more easily trainable compared, for instance, to terminally differentiated and short-lived neutrophils. In mice, memory NK cells mediate protection against viral infections in a T and B cell-independent manner, and memory properties apparently depend on a differential expression of the virus-specific LY49H receptor . Moreoveantigens . In humaantigens . Recentlantigens  and muriantigens  NK cellsIt is very interesting that monocytes/macrophages are able to develop different kinds of memory depending on the type of priming. Thus, monocytes/macrophages can develop a memory that leads them to be less reactive to some challenges  or to an enhanced response . These different ways depend on the nature of the first challenge. Both mild and severe stimulations with LPS trigger a strong reaction but, upon a second challenge, macrophages react much less because they aim at avoiding an excessive reaction to a minor challenge and the consequent risk of unwanted tissue damage . On the The question that arises from these observations is how can monocytes, which possess a relatively short half-life in circulation, be responsible for this long-term protection? A possible explanation is that a reservoir of epigenetically modified monocytes (memory monocytes) persists in the body, possibly located in the spleen, as hypothesized for NK cells. Alternatively, monocyte precursors could be “trained” directly in the bone marrow by the local microenvironment. The latter hypothesis is supported by a recent work that demonstrates how TLR2 stimulation of myeloid progenitor cells can influence the functional phenotype of the macrophages that develop from them . Thus, mβ-glucan requires a metabolic shift towards the high energy-producing type of aerobic glycolysis, which is referred to as the “Warburg effect” [α-dependent pathway [Other interesting aspects of trained memory are changes in metabolic processes, as already observed in macrophage polarisation . Recent  effect” . The swi pathway .dimCD16+, CD14+CD16−), a topic that has not yet been fully investigated [In addition to epigenetic and metabolic reprogramming, other putative mechanisms involved in establishing monocyte memory include the involvement of different monocyte subpopulations  possibly hold the potential of inducing innate memory and could thereby mediate long-term changes in host defense. Particular attention should be paid to potential variability of reaction depending on sex, ethnicity, and age.Adjuvants that are already in use and actBoosting innate defense mechanisms through trained memory induction seems particularly appealing for vulnerable populations that show impaired resistance to pathogens in general. However, boosted nonspecific immunity might also have beneficial outcomes on herd immunity in an average population against widespread diseases, such as the common cold.PAMPs that are able to robustly induce trained memory might also feature potential adjuvant capacity.Enhancing nonspecific effects induced by vaccination can affect the immune response to other routine immunisations, modulating the antibody titre and improving overall protective response, as seen for BCG vaccination .Sequence/timing and combination of vaccines against different pathogens are very important aspects of vaccination programmes. Importantly, detrimental nonspecific effects have been noted only when an inactivated vaccine was the most recent one . Thus, cInduction of trained immune memory might improve the induction of specific protection by low-efficiency vaccines.Nonspecific effects of established vaccines have to be further investigated in order to determine their potential in long-term innate immune memory.The memory-inducing capacity of a vaccine might depend on various factors  during the vaccine production process.Well-known vaccines with beneficial nonspecific effects could be (re)introduced in countries where they are not part of the immunisation schedule.Thus, the development of future vaccines should take into account not only pathogen-specific immunity but also the nonspecific effects mediated by innate memory. Several issues should be considered on the contribution of innate immune memory to vaccine formulations:The increased awareness of the properties of innate memory is changing our understanding of host defense and immunological memory and could lead to defining new classes of vaccines and adjuvants. Two major aspects have to be fully addressed, the in-depth identification of the molecular and cellular mechanisms involved and the duration of protection provided by innate memory, which is lifelong in plants and insects but not well evaluated in mammalian systems. Both epigenetic and metabolic reprogramming can be induced during establishment of innate memory. No information is however available on the possible cross-talk and cross-regulation between these events.Several questions are still open, concerning the epigenetic memory upon infection or vaccination. Does an epigenetic inheritance during myeloid cell linage division exist? Can epigenetic reprogramming be maintained during cell differentiation or upon reinfection? How long lasting are the memory reprogramming effects? Future studies will shed light on these open questions.A better understanding of innate memory mechanisms in general, and of those induced by licensed and candidate adjuvants and vaccines in particular, will help us to exploit in full the beneficial potential of vaccination and reduce all possible side effects.


Recent studies have revealed an inverse epidemiological correlation between Alzheimer’s disease (AD) and cancer − patients with AD show a reduced risk of cancer, while cancer survivors are less likely to develop AD. These late discoveries in human subjects call for explorative studies to unlock the underlying biological mechanism, but also may shed new light on conceptual interrogation of the principal pathogenic players in AD etiology.Here we hypothesize that this negative correlation reflects a rebalance of biosynthetic propensity between body systems under the two disease statuses. In normal condition the body cellular systems are maintained homeostatically under a balanced cell degenerative vs. surviving/regenerative propensities, determined by biosynthetic resources for anabolic processing. AD pathogenesis involves neurodegeneration but also aberrant regenerative, or reactive anabolic, burden, while cancer development is driving by uncontrolled proliferation inherent with excessive anabolic activity. The aberrant neural regenerative propensity in AD pathogenesis and the uncontrolled cellular proliferative propensity in cancer pathogeneses can manifest as competitive processes, which could result in the inverse epidemiological correlation seen among the elderly.The reduced prevalence of AD in cancer survivors may implicate a strong impact of aberrant neural regenerative burden in neurodegeneration. Further explorative studies into the inverse correlation between AD and cancer should include examinations of the proliferative propensity of tumor cells in AD models, and the development of AD-like neuropathology in cancer models as well as following anti-proliferative drug treatment. Alzheimer’s disease (AD) and cancer are major risk factors threatening human health and life especially in the elderly. AD is an age-dependent neurodegenerative disease, while the incidence of cancer is also dramatically increased with age. With the global population aging, AD and cancer become the leading causes of death in most societies across the globe ,2. A numThe reduced comorbidity of AD vs. cancer in the elderly is recognized fairly lately, for less than ten years. In 2005, Roe et al. reported prospective longitudinal data showing a reduced risk of developing cancer among participants with dementia of the Alzheimer-type (DAT), and a reduced risk of developing DAT among individuals with a history of cancer . A folloThe clinical phenotype of AD, largely manifested as cognitive decline, is most likely a result of neurodegeneration. Cerebral atrophy is evident macroscopically in AD, and strong evidence supports that dementia is best correlated to neuronal/synaptic degeneration and dysfunction –19. As dIt should be noted that neural regenerative burden is enhanced, and may be also important, in the development of AD. Many “morphoregulatory” molecules that play crucial role during brain development are upregulated in the brains of AD or even prodromal AD subjects –29. ThesIt is perhaps particularly worth noting that the hallmark lesions of AD, amyloid plaques and neurofibrillary tangles, are viewed by some as a part of host responses ,37. The While the molecular and cellular changes categorized above as anabolic events in AD pathogenesis may be activated to facilitate cell proliferation, survival and regeneration to compensate neuronal death, these events should not be generally regarded beneficial or neuronal protective, at least not over the entire disease course. As some of the cell surviving/regenerative responses  eventually yield toxic/detrimental effects on neuronal systems, neurodegenerative changes are exacerbated –27,54. SThe AD/cancer inverse correlation would imply that there exists a certain common biological process underlying a “mutual-competition” for the development of either AD or cancer. Based on this assumption, it appears that the maladapted neural regenerative propensity in AD pathogenesis better parallels or “matches” with the uncontrolled proliferative propensity in cancer development (see next section), given that cellular replication and regeneration/repair use the same anabolic/biosynthetic machinery.Cancer development involves complex biological deregulations in cellular and tissue systems . At the As major medical attention to cancer patients is life-saving, the extent of a potential rebalance in anabolic kinetics between tissue compartments, especially the effect thereof on brain metabolism and function, has scarcely been evaluated, therefore remains unclear to date. However, the brain receives 15-20% of the body’s blood supply, while it weighs about 2% of the total body mass. It is expectable that a dominated anabolic cellular processing inherent with tumorogenesis would very likely place a considerable or substantial deprivation effect on the biosynthetic activity in the brain given its great demand for and dependency on metabolic resource. Accordingly, such an effect would likely influence the aberrant regenerative propensity described above in the course of AD pathogenesis.Having analyzed the factors relevant to AD pathogenesis and cancer development, we propose the potential cellular and metabolic alterations that could underlie the inverse epidemiological association between AD and cancer seen among the elderly Figure . In the The biosynthetic resource referred above as the balance point includes the nutritional and bioenergetic systems supporting cellular processes in general. The nutritional components imply to substrates and catalytic elements  for molecular synthesis for such as nucleotides, proteins and lipids. Regarding bioenergetic metabolism, several review articles have discussed this topic in relevance to the inverse epidemiological correlation of cancer with AD and other neurodegenerative diseases ,66–68, tIn addition to the above proposed biological modification, the use of anti-tumor drugs perhaps should be also put into consideration, as a potential confounding factor, especially in the interpretation of the reduced comorbidity of AD among cancer survivors (since these patients would have or may be continuously received anti-proliferative treatments). In this regard, it is important to note that a recent large population-based cohort study has shown that the risk of developing AD, vascular dementia or other dementias is significantly lowered in patients receiving chemotherapy compared to those without chemotherapy, although chemotherapy can cause drug-induced dementia . FurtherAD has become a global healthcare crisis due to population aging, while no promising preventive and therapeutic strategies are currently available for this disease. The inverse association between AD and cancer discovered in human population-based studies deserves a great attention in disease biology and translational research. Additional epidemiological studies should be carried out to further confirm this relationship, with stratified analyses applied to determine whether this phenomenon links to different cancer types and the use of cancer drugs. Experimental studies should start to explore how AD conditions may influence tumorogenesis, and the cellular and molecular mechanism thereof. Vice versa, additional studies should be conducted to determine whether, and if so, how, condition of cancer or anti-cancer drugs modulate AD-type neuropathology. The concept raised in this work may be informative for additional clinical and explorative studies to unlock the biological basis underlying the novel inverse correlation between AD and cancer seen in humans. Our hypothesis has put together multiple pieces of information  that appear to be coherent in regard to the mutual-competitive nature of AD vs. cancer development. Obviously, much additional effort is needed to develop other conceptual models in order to fully unlock the mystery behind the AD/cancer inverse association.


Microeconomic evaluations of public health programmes such as immunisation typically only consider direct health benefits and medical cost savings. Broader economic benefits around childhood development, household behaviour, and macro-economic indicators are increasingly important, but the evidence linking immunization to such benefits is unclear.A conceptual framework of pathways between immunisation and its proposed broader economic benefits was developed through expert consultation. Relevant articles were obtained from previous reviews, snowballing, and expert consultation. Articles were associated with one of the pathways and quality assessed using modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria.We found 20 studies directly relevant to one or more pathways. Evidence of moderate quality from experimental and observational studies was found for benefits due to immunisation in improved childhood physical development, educational outcomes, and equity in distribution of health gains. Only modelling evidence or evidence outside the immunization field supports extrapolating these benefits to household economic behaviour and macro-economic indicators.Innovative use of experimental and observational study designs is needed to fill evidence gaps around key pathways between immunisation and many of its proposed economic benefits.The online version of this article (doi:10.1186/s12916-015-0446-9) contains supplementary material, which is available to authorized users. Investment in immunisation programmes in both developed and developing countries has dramatically increased over the past two decades . This isHowever, many cost-effectiveness studies only consider direct health benefits and medical cost savings, although some consider a few wider benefits such as indirect (herd) protection and care-related productivity gains. However, economists have argued that improvements in health lead to economic growth through longer-term mechanisms such as decreasing fertility, strengthening macroeconomic stability, and improving educational outcomes , 6. MoreTo address this gap, we constructed a conceptual framework that captures causal pathways linking vaccines to their proposed benefits and conducted a rapid review of the validity and strength of evidence behind each pathway. Our aim is to inform research into filling knowledge gaps in this area, as well as to strengthen evidence-based advocacy and decision making about vaccination.Two authors of this report (MJ and RH) facilitated expert consultations during vaccine meetings convened by the World Health Organization in Toronto (13–14 July 2011), Geneva (28–29 June 2012), Sydney (10–11 July 2013), and Bangkok Unexplained heterogeneity or inconsistency of results P <0.1)Imprecision of results Randomized controlled trials were given a default quality rating of ‘high’. They were downgraded by one level for any of the following that apply and by two levels for any factor regarded as severe, up to a maximum of three:Observational studies that were methodologically sound with no obvious bias were regarded as providing ‘high’ quality evidence for the existence of pathways being evaluated if they were able to demonstrate very large effects, ‘moderate’ quality evidence if the effect sizes were large, and ‘low’ quality evidence if there were small or no effects. Observational studies that were not methodologically sound were by default considered be ‘low’ quality evidence, regardless of effect size.Most studies reviewed were based around models rather than traditional epidemiological designs involving primary data collection. There are no GRADE criteria for quality assessment of modelling studies. In order to account for the existence of such studies as part of the evidence base, we expanded the categories of studies in GRADE to include modelling studies but kept them in a separate category from empirical studies. Table Figure After review and screening for duplications, 93 unique journal articles from the original reviews were included in the initial study. Of these, 23 were identified as being exempt from or not appropriate for evidence quality review for reasons such as being commentaries rather than analyses. Evidence quality grades for the remaining studies are shown in Table Evidence that immunization improves non-utility capabilities No experimental studies were reviewed that directly provided evidence of the impact of immunization on the physical development of children via reduced morbidity. A single observational study by Bloom et al. , found nOne randomised trial of moderate quality by Canning et al. , provideEvidence that immunization produces productivity gains via improvements in non-utility capabilities (strength of evidence = modelling)By improving human capital in the form of increased physical, cognitive, and educational skills of children, immunization may have an impact on future workforce productivity and hence labour income of households as well as overall economic growth. In one modelling study, Bloom et al.  proposedIn Bangladesh, Bishai et al.  found thTwo recent modelling studies also addressed the impact of rotavirus immunization programmes on equity. Rheingans et al.  modelledNo observational or experimental studies were found that provided direct evidence of interaction effects between immunization and other health interventions on economic outcomes. However, two modelling studies have explored the interaction between immunization and other health interventions from a cost-effectiveness perspective, showing mixed results. Jeuland et al.  examinedex ante valuations of vaccines that did not yet exist would match ex post valuations in a future context. Further, while they provide evidence that significant private economic benefits exist to households, it is not possible to distinguish among the various pathways that may contribute to those benefits.Several observational studies –32 used Two mechanisms have been proposed by which immunization may reduce household financial vulnerability: firstly, through overall changes in labour earnings or savings behaviour, and secondly by reducing the risk from specific health shocks. None of the reviewed studies provided direct empirical evidence for either of these pathways. However, Verguet et al.  has propIf labour income rises, all else equal, we expect that households will be able to increase consumption, savings, and investment in human capital (such as education). Even in the absence of evidence for longer-term increases in labour income due to improved human capital, we would expect changes in immediate household consumption, savings, and investment because of increased disposable income as a result of reduced health expenditure and lost wages. However, no experimental, observational, or modelling studies were found that directly examine the effect of immunization on changes to household consumption, saving, or investment behaviour.As the risk of childhood mortality and morbidity decreases and survival rates increase, households may also be expected to produce fewer children and invest more in their health . HoweverOne modelling study  considerNo empirical studies were found that estimated the effects of vaccination in mitigating the short-term macroeconomic consequences of an infectious disease outbreak. However, several modelling studies have examined the impact of vaccination  in the context of an influenza pandemic. Using a computable general equilibrium model, Smith et al.  estimateWe found no studies of any kind directly examining the impact that vaccination may have on long-term macro-economic indicators such as national income, growth, or foreign direct investment. However, outside the field of vaccination, there were several studies examining the relationship between improved health in general and such indicators. In a longitudinal cross-country study, Alsan et al.  found a We have developed a conceptual framework of the pathways between vaccines and their proposed benefits, and assessed the strength of evidence behind each pathway. Our framework builds on previous lists of benefits , 10, 11,We obtained mixed results from this assessment of the validity and strength of evidence behind conceptual pathways linking immunization programmes with their proposed benefits. There is indisputable evidence that vaccines bring ‘narrow’ benefits related to health outcomes, health care cost savings, and protection against productivity losses directly related to the illness episode at the level of individual vaccinees and at the community level via herd protection. There is also some limited experimental or at least observational evidence that vaccines bring wider benefits at the household level in the form of improved non-utility capabilities and equity in the distribution of health gains by wealth quintile . However, there is only modelling evidence to support extrapolating these benefits to meso-level household economic behaviour , as well as macro-level economic indicators  that might logically follow.To incorporate modelling evidence, we expanded the traditional GRADE criteria to include a category for such studies. There was a gradient in the robustness of evidence from the modelling studies we reviewed due to variation both in the quality of input data  and the way the data were handled . However, we did not attempt to assess the quality of modelling evidence. Although there do exist some frameworks for assessing the quality of mathematical models in health –44, nonede novo systematic review. Previous reviews also found that there were few studies examining many of the potential broader economic benefits of vaccination [Our objective was to conduct a rapid review of the literature in order to validate a conceptual framework that evolved out of a consultative process. Since several systematic and narrative reviews in the area had previously been carried out, we opted to conduct a review of existing reviews with additional expert consultation, rather than a cination –11. The One limitation is that we focused on the vaccine-specific literature only, and did not explore the wider literature on the relationship between health in general  and broader economic benefits. Since vaccines improve health, it may be reasonable to assume that the downstream relationship between health and its economic benefits also apply to vaccines. Herein, we have taken a conservative approach by ignoring any evidence relating to pathways in which immunization programmes were not the ultimate cause.Conversely, vaccines are only one component of health systems that contribute to economic benefits. For instance, recent modelling work found that vaccines only avert around 27 % of childhood diarrhoea and pneumonia deaths, so remaining mortality reductions come from other interventions such as nutrition, case management, and hygiene . The benAnother limitation is that our framework does not consider the special benefits of maternal vaccination, including improved maternal and child health outcomes following vaccines such as influenza. Further, our framework has focused on the broader economic benefits of vaccination. However, the broader economic costs of vaccination are also of increasing interest to decision making. These include costs related to addressing adverse effects following immunisation and vaccine hesitancy at a societal level.The absence of evidence from interventional studies to support many of the proposed pathways does not imply evidence for the absence of such relationships. Many vaccines have proven health and economic benefits and are being routinely used in most countries, so experimental designs that deny vaccines to a proportion of participants may be considered unethical. Furthermore, associations between interventions and long-term economic behaviour at the household or macroeconomic level are expensive and time-consuming to investigate experimentally. Conditions for well-controlled ‘natural’ experiments are also rare. Hence, the use of designs that would be considered robust in the medical literature may be less common in the economics literature. Similarly, assumptions about human behaviour  may be well-accepted in in the economics literature without the need for empirical justification, but this is not the case in the medical literature. This may explain the decrease in availability of experimental or even observational evidence as we move from health-related outcomes to economic outcomes at either the household or the macro-economic level.The present study highlights the importance of collecting data about such behaviour wherever possible in order to strengthen the evidence base behind the potential broader economic impacts of vaccination. For instance, some of the outcomes for which we did not find experimental evidence (such as household choices around consumption and savings) could be routinely incorporated into clinical effectiveness trials of vaccines or into standard demographic and health surveys, should suitable data collection instruments be developed. In the interim, innovative analyses of historical observational datasets may provide evidence that would be considered more robust than models whose assumptions are not driven by data. There is a need to design the requisite methods and initiate the relevant studies as soon as possible given the increasing importance of broader economic indicators of vaccine impact in informing investment decisions about vaccines.


The prevalence of overweight and obesity is high amongst healthcare professionals and there is growing interest in delivering weight loss interventions in the workplace. We conducted a systematic review to (i) examine the effectiveness of workplace-based diet and/or physical activity interventions aimed at healthcare professionals and to (ii) identify and describe key components of effective interventions. Seven electronic databases were systematically searched.Thirteen randomised controlled trials met the inclusion criteria, of which seven had data available for meta-analysis. Where meta-analysis was possible, studies were grouped according to length of follow-up (<12 months and ≥12 months) and behavioural target , with outcome data pooled using a weighted random effects model. Nine studies reported statistically significant (between-group) differences. Four studies reported being informed by a behaviour change theory. Meta-analysis of all trials reporting weight data demonstrated healthcare professionals allocated to dietary and physical activity interventions lost significantly more body weight  than controls up to 12 months follow up.Workplace diet and/or physical activity interventions targeting healthcare professionals are limited in number and are heterogeneous. To improve the evidence base, we recommend additional evaluations of theory-based interventions and adequate reporting of intervention content.The online version of this article (doi:10.1186/s40608-014-0023-3) contains supplementary material, which is available to authorized users. There is increasing recognition that healthcare professionals are role models for the public through their promotion of healthy lifestyle choices -4. DespiThe impact of overweight and obesity in healthcare professionals is significant and wide ranging negatively affecting not only the individual’s own health but also healthcare provider resources, service delivery and patient care . For insConsidering the high prevalence of overweight and obesity in healthcare professionals and the associated direct and indirect costs, there is a need for effective weight management interventions in this population group. In recent years, interest in using the workplace to deliver such interventions has grown . SeveralTo our knowledge, only one published systematic review has evaluated the possible effects of lifestyle interventions  delivered to healthcare professionals in the workplace . HoweverAs the healthcare workforce is a heterogeneous mix of professions it cannot be assumed that weight problems are confined to nurses. We, therefore, sought to undertake a formal systematic review of published RCTs which evaluated the effectiveness of workplace-based dietary and/or physical activity interventions targeting any healthcare professional group. In addition, our review sought to examine the theoretical underpinning and component parts of the identified interventions to facilitate an understanding of what works and why -24.The formal aims of the systematic review were to: 1) investigate the effectiveness of workplace-based dietary and/or physical activity interventions targeting any healthcare professional groups; 2) identify and describe key components of successful interventions, 3) identify theoretical models of behaviour change involved in effective interventions and 4) investigate whether intervention effectiveness is improved by the extent to which interventions are explicitly developed based on theory.The study was a systematic literature review of published studies. We considered ‘published’ studies to be manuscripts that appeared in peer-reviewed journals, dissertations, policy documents or reports. A formal protocol (available on request) was developed prior to undertaking the review and the conduct and reporting of this systematic review adhered to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Statement .Articles were eligible for inclusion if they described a randomised controlled trial (RCT) comparing a workplace-based diet and/or physical activity intervention with a comparator group and targeted healthcare professionals. Comparator groups could include no intervention, usual care, active control or a waiting list group. Studies were required to report at least one diet, physical activity or weight-related outcome. There were no restrictions on intervention content, intervention duration or follow-up period. No language restrictions were applied.Seven electronic databases were searched from database inception (through to July 2012); Medline, Embase, DARE, PsycINFO, CINAHL, SPORTDiscus and the Cochrane Central Register of Controlled Trials (CENTRAL). The electronic search strategy . Where relevant data was not available in the published reports, efforts were made to contact study authors, or to calculate them directly from other data available in the paper e.g. from confidence intervals or p-values. Remaining missing standard deviations from individual studies that could not be retrieved from the study authors or calculated were imputed according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions ,32. Whera priori that the effects of the intervention would likely be different over the shorter and longer term. We had further proposed a priori to investigate the effect, if any, within timeframes of behavioural target . A narrative synthesis was used to analyse the key findings and meta-analysis undertaken where data allowed – in this case, meta-analysis could be undertaken for body weight data.As per our pre-specified protocol, studies were grouped according to length of follow-up (<12 months and ≥12 months) as we postulated P <0.05. For the test of heterogeneity, we used Higgins I2. Values >50% were taken to indicate that there was substantial statistical heterogeneity across studies ) . Further −0.74]) .et al. excluded interventions aimed solely at overweight subjects as well as weight loss interventions a possible explanation could be that interventions aimed specifically at weight loss and/or where the targeted participants are overweight/obese may be more effective compared with interventions without a specific weight-related aim. Future research should investigate whether studies with specific weight-related aims produce greater weight loss than those without specific weight-related aims. Notwithstanding this, conclusions regarding the effectiveness of dietary and physical activity combined interventions on healthcare professional body weight are limited because of the small number of studies and small sample sizes. Therefore, these preliminary findings require confirmation by further RCTs with larger sample sizes.There are a number of possible explanations for these differences. One possible reason for the larger effect size observed in our meta-analysis is that healthcare professionals may be more amenable to behaviour change than the general population samples included in previous meta-analyses resulting in greater weight loss. For instance, Anderson et al. included studies focusing on varied occupational groups such as policemen and male employees working for a building maintenance company . FurtherThe findings of individual trials not included in the meta-analysis also merit mention. These trials demonstrated significant effects on a range of dietary intake outcomes such as reducing total fat and saturated fat intake and increasing fibre and fruit intake. Significant effects on physical activity outcomes were also reported. However, a variety of different methods were used across studies to measure dietary and physical activity behaviours, precluding cumulative analysis. For example, of the two studies measuring fruit intake ,48, one Two studies also conducted process evaluations ,53. ReasA key finding of this systematic review is that the majority of workplace dietary and physical interventions targeting healthcare professionals did not report their theoretical development. The use of theory to develop interventions, and adequate reporting of this, facilitates investigators in measuring and describing causal pathways through which targeted behaviour change occurs. Therefore, failure to report the theoretical underpinning of interventions hampers our understanding of the mechanisms involved in behaviour change . Only foMost of the interventions in this review were not reported in sufficient detail to allow analysis of specific individual intervention components. In other words, it was not possible to identify the ‘active ingredients’ in successful interventions as it was unclear what behavioural strategies or combination of behavioural strategies produced the most consistent effects for dietary and physical activity behaviour change and weight loss in healthcare professionals. Moreover, details of intervention characteristics such as intervention delivery source, delivery mode , and intervention contact time were not reported in detail, limiting this review’s capacity to elucidate their role in intervention effectiveness. There is emerging evidence that the active content of a control group can explain an intervention’s effects . For exarecommendations to Improve Reporting of the Content of Behaviour Change Interventions set out by the Workgroup for Intervention Development and Evaluation Research (WIDER) [et al. [Workplace dietary and physical activity interventions are complex and their implementation involves a number of detailed steps. It is possible that the complexity of these interventions coupled with journal word limit requirements could account for studies not being able to provide sufficient details on intervention and control group content. In order to address this, trial authors should consider reporting interventions in line with the  (WIDER)  and the  (WIDER) . Trial a (WIDER) . Moreove (WIDER) . This in [et al. .It is important to emphasise that, although the evidence regarding the effectiveness of dietary and/or physical activity interventions for changing weight, dietary and physical activity outcomes in healthcare professionals is currently limited, it does not mean that there is evidence of no effect from the interventions. Additionally, these interventions are unlikely to cause any harm. We therefore tentatively recommend such interventions may be beneficial in practice and should be offered to healthcare professionals. The potential number of healthcare professionals who may benefit from participation lends further support for this recommendation. Until further robust evidence is available, practitioners and decision-makers should continue to use current clinical practice guidelines, which outline various workplace intervention options and approaches.To our knowledge, this is the first review to examine the effects of workplace-based dietary and/or physical activity interventions in the wider healthcare professional population. As such, this review makes a valuable contribution to this area of research. We used explicit methods to code all intervention and control group components and reviewer errors and bias were minimised at the title and abstract screening, quality assessment and data extraction stages due to a minimum of two reviewers performing these tasks. Efforts were made to retrieve missing data through direct contact with authors. This review extends the evidence from a recent meta-analysis of interventions conducted across heterogeneous workplaces  and one Direct comparison between intervention components across studies and specific outcomes was difficult due to the disparate nature of interventions and the limited number of interventions reporting similar outcomes. It should be considered that publication bias may have impacted on the reporting of studies as relevant studies may not be published . The funOur review suggests workplace-based dietary and physical interventions may be potentially effective in reducing weight and changing the dietary and physical activity behaviours of healthcare professionals. However the available evidence base is limited with several important gaps identified which cause uncertainty in establishing what intervention content and characteristics contribute most to intervention effectiveness. As part of a research agenda to improve the interpretation of future interventions, further studies are required that: (i) publish comprehensive descriptive information on intervention content (ii) code effective intervention and control group components in workplace dietary and physical activity interventions targeted to healthcare professionals using a standardised taxonomy of BCTs and (iii) contain a minimum follow-up of 12 months in order to clarify the sustainability of intervention effects. Future interventions underpinned by psychological theory and providing details of how the selected theory is proposed to function within the intervention are also needed to enhance our understanding of the mechanisms behind intervention effects.


Diet induced obesity is associated with impaired mitochondrial function and dynamic behavior. Mitochondria are highly dynamic organelles and the balance in fusion/fission is strictly associated with their bioenergetics. Fusion processes are associated with the optimization of mitochondrial function, whereas fission processes are associated with the removal of damaged mitochondria. In diet-induced obesity, impaired mitochondrial function and increased fission processes were found in liver and skeletal muscle. Diverse dietary fat sources differently affect mitochondrial dynamics and bioenergetics. In contrast to saturated fatty acids, omega 3 polyunsaturated fatty acids induce fusion processes and improve mitochondrial function. Moreover, the pro-longevity effect of caloric restriction has been correlated with changes in mitochondrial dynamics leading to decreased cell oxidative injury. Noteworthy, emerging findings revealed an important role for mitochondrial dynamics within neuronal populations involved in central regulation of body energy balance. In conclusion, mitochondrial dynamic processes with their strict interconnection with mitochondrial bioenergetics are involved in energy balance and diet impact on metabolic tissues. Mitochondria are referred to as the “powerhouses” of the cell due to their prominent role in ATP production and cellular metabolism regulation. Together with their energetic role, mitochondria are very dynamic organelles that continuously divide, collide and fuse with other mitochondria. Therefore, their morphology is highly variable. It can shift between small round punctuated structures or reticulum networks of elongated mitochondria as a result of the balance between fusion and fission processes. Various work has been done to analyze the mechanism of this dynamic behavior and different proteins (a group of large ATPases) have been identified as being involved  accompanied by the presence of numerous small round mitochondria vs. control diet, as observed by electron microscopy  elicited hepatic fat accumulation and insulin resistance, which was parallel to impaired mitochondrial function, increased reactive oxygen species (ROS) production and a dysregulated expression profile of mitochondrial dynamics proteins  in both a rat liver cell-line and myoblasts , proteins related to mitochondrial fission  increased, but no changes were detected in proteins involved in mitochondrial fusion  (Khraiwesh et al., It is well known that in mammals the NPY/Agrp and POMC neurons within the arcuate nucleus of the hypothalamus regulate hunger and satiety. Recent works suggested that mitochondrial dynamics play an important role in these two neuronal populations, and that Mfn1 and Mfn2 are involved (reviewed in Nasrallah and Horvath, In all, these data suggested that mitochondrial dynamics, namely Mfn1 and Mfn2, in NPY/Agrp and POMC neurons may play a role in the central regulation of energy balance and in etiology of diet induced obesity.Mitochondrial function varies in accordance to cellular energetic needs and to nutrient supply. Noteworthy, a number of recent works have been focused on the importance of mitochondrial dynamic behavior in terms of fusion and fission processes in determining mitochondrial functionality in diverse diet conditions as well as in the central regulation of energy balance. Therefore, mitochondrial dynamic behavior contributes to bioenergetics physiological adaptation in response to the nutritional status Figure .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.


Consistent with this, protein synthesis inhibitors impair LTM for a variety of behavioral tasks when infused into the brain around the time of training or following memory retrieval, suggesting that protein synthesis is a critical step in LTM storage in the brain. However, evidence suggests that protein degradation mediated by the ubiquitin-proteasome system (UPS) may also be a critical regulator of LTM formation and stability following retrieval. This requirement for increased protein degradation has been shown in the same brain regions in which protein synthesis is required for LTM storage. Additionally, increases in the phosphorylation of proteins involved in translational control parallel increases in protein polyubiquitination and the increased demand for protein degradation is regulated by intracellular signaling molecules thought to regulate protein synthesis during LTM formation. In some cases inhibiting proteasome activity can rescue memory impairments that result from pharmacological blockade of protein synthesis, suggesting that protein degradation may control the requirement for protein synthesis during the memory storage process. Results such as these suggest that protein degradation and synthesis are both critical for LTM formation and may interact to properly “consolidate” and store memories in the brain. Here, we review the evidence implicating protein synthesis and degradation in LTM storage and highlight the areas of overlap between these two opposing processes. We also discuss evidence suggesting these two processes may interact to properly form and store memories. LTM storage likely requires a coordinated regulation between protein degradation and synthesis at multiple sites in the mammalian brain.Long-term memory (LTM) formation requires transient changes in the activity of intracellular signaling cascades that are thought to regulate new gene transcription and  The ubiquitin-proteasome system (UPS) is a complex network of different ubiquitin ligases and interconnected protein structures involved in the regulation of protein degradation in neurons. This system has been reviewed extensively by others Hegde, , but in in vitro  and two regulatory particles (19S)  formation and storage  and the object recognition paradigm. One of the most common rodent behavioral procedures is Pavlovian fear conditioning, in which a neutral conditional stimulus (CS) becomes associated with a noxious or aversive unconditional stimulus (UCS). As a result of this association, the CS can elicit an emotional response based on the memory of the UCS. A simple form of Pavlovian fear conditioning is contextual fear conditioning, in which rodents learn to fear the specific context or training environment in which the UCS occurred. Memories in this paradigm require an intact and active amygdala and hippocampus for their formation and long-term storage  by the E3 ligase Neuralized1 is critical for the consolidation of hippocampus dependent memories  dependent changes in CaMKII activity. As stated above, similar to protein degradation and synthesis, NMDAR activity at the time of training has been shown to be critical for the formation of different types of memories in various brain regions. NMDAR activity is thought to regulate the changes in protein synthesis necessary for LTM formation by altering the activity of a number of downstream signaling pathways (Johansen et al., in vitro relationship between NMDAR and ubiquitin-proteasome activity (Bingol and Schuman, in vitro (Djakovic et al., in vitro (Upadhya et al., In addition to overlapping with an increased need for protein degradation, recent evidence suggests that NMDAR and CAMKII activity can regulate UPS-mediated protein degradation during LTM in neurons (Jarome et al., in vitro (Banerjee et al., in vivo (Jarome et al., in vitro, suggesting that the proteasome could regulate protein synthesis during LTM formation through the removal of translational repressor proteins such as various RISC factors. However, it is currently unknown if the selective degradation of MOV10, or any RISC factor, is critical for memory formation in neurons. Nonetheless, studies such as these provide indirect evidence that protein degradation by the UPS could regulate protein synthesis during memory formation in the brain.A majority of the studies discussed here reveal a strong correlation between protein degradation and synthesis during LTM formation. This leads to one important question: Which comes first? While the exact relationship between protein degradation and synthesis during memory formation currently remains equivocal, the available evidence suggests that protein degradation likely regulates protein synthesis. For example, fear conditioning leads to an increase in polyubiquitinated proteins being targeted for degradation by the proteasome (Jarome et al., in vivo during memory formation. Collectively, the current evidence suggests that protein degradation may determine the requirement for protein synthesis during memory storage, though this relationship has never been directly proven.Some of the best evidence that protein degradation may be upstream of protein synthesis during memory storage comes from studies examining memory reconsolidation following retrieval. For example, inhibiting proteasome activity can prevent the memory impairments that normally result from post-retrieval blockade of protein synthesis in the hippocampus, amygdala, and nucleus accumbens (Lee et al., While it is currently not known if protein degradation regulates protein synthesis during memory formation, one recent study found that protein degradation regulates protein synthesis during LTP, a proposed cellular analog of memory (Dong et al., While the functional significance of the observed overlap between protein degradation and synthesis during LTM formation is unknown, it is possible that a coordinated balance between protein degradation and synthesis may be necessary for memory formation and storage in neurons (Jarome and Helmstetter, in vivo during memory formation as most times proteasome inhibitors are given alone and not in combination with protein synthesis inhibitors. Despite this, some studies suggest that an altered balance between protein degradation and synthesis cannot account for memory impairments following disruption of the UPS. For example, proteasome inhibitors infused into the amygdala result in similar memory impairments for a fear conditioning task as those produced by the broad spectrum protein synthesis inhibitor anisomycin and simultaneous infusion of both inhibitors does not rescue these impairments (Jarome et al., While the evidence discussed here suggests that protein degradation and protein synthesis may be interconnected processes necessary for memory formation and storage, an alternative theory is that these are actually opposing processes and that memory formation requires an appropriate balance between them. For example, both proteasome and protein synthesis inhibitors impair LTP when applied individually, but actually rescue these deficits when applied simultaneously (Fonseca et al., The studies reviewed here suggest a clear correlation between protein degradation and protein synthesis in LTM formation in the brain. However, we are currently far from understanding the exact relationship between these two opposing processes during in memory. As discussed above, the current evidence suggests that protein degradation and synthesis are both important regulators of LTM for auditory delay and trace fear conditioning, contextual fear conditioning, inhibitory avoidance, conditioned taste aversion, MWM, and object recognition memories and simultaneously occur in multiple brain regions including the amygdala, hippocampus, prefrontal cortex, and insular cortex. However, it is unknown if this relationship holds for all brain regions and behavioral tasks. For example, contextual and trace fear memories also require the retrosplinal cortex for their long-term storage (Kwapis et al., de novo protein synthesis. Finally, future studies should focus on identifying the non-proteolytic functions of the UPS during memory formation and storage. Currently, only two non-proteolytic roles for ubiquitin-proteasome activity exist (Pavlopoulos et al., Additionally, future studies should focus on how CaMKII signaling regulates increases in proteasome activity during memory formation and whether this occurs through Rpt6 phosphorylation. Considering that CaMKII is the only intracellular signaling molecule known to regulate protein degradation during LTM formation (Jarome et al., Here, we reviewed a number of studies suggesting that changes in protein degradation correlate with changes in protein synthesis during memory formation and storage in neurons. Additionally, we discussed evidence demonstrating that protein degradation is regulated by NMDAR activity and the intracellular signaling molecule CaMKII, two well-known regulators of memory formation that are thought to regulate protein synthesis, suggesting that protein degradation and synthesis may be linked through CaMKII signaling. Finally, we reviewed evidence demonstrating that protein degradation may be upstream of protein synthesis during LTM formation, suggesting that protein degradation may supersede protein synthesis during the memory consolidation process. Collectively, the studies outlined in this review suggest that protein degradation and protein synthesis are not likely two independent regulators of LTM formation but rather directly interact to modify active synapses and store memory for a variety of different behavioral tasks.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.


US and UK suicide prevention strategies suggest that bereavement by the suicide of a relative or friend is a risk factor for suicide. However, evidence is lacking that the risk exceeds that of any sudden bereavement, is specific to suicide, or applies to peer suicide. We conducted the first controlled UK-wide study to test the hypothesis that young adults bereaved by suicide have an increased risk of suicidal ideation and suicide attempt compared with young adults bereaved by other sudden deaths.National cross-sectional study.Staff and students at 37 UK higher educational institutions in 2010.3432 eligible respondents aged 18–40 exposed to sudden bereavement of a friend or relative after the age of 10.Bereavement by suicide (n=614), by sudden unnatural causes (n=712) and by sudden natural causes (n=2106).Incident suicidal ideation and suicide attempt.Adults bereaved by suicide had a higher probability of attempting suicide (adjusted OR (AOR)=1.65; 95% CI 1.12 to 2.42; p=0.012) than those bereaved by sudden natural causes. There was no such increased risk in adults bereaved by sudden unnatural causes. There were no group differences in probability of suicidal ideation. The effect of suicide bereavement was similar whether bereaved participants were blood-related to the deceased or not. The significant association between bereavement by suicide and suicide attempt became non-significant when adding perceived stigma . When compared with adults bereaved by sudden unnatural causes, those bereaved by suicide did not show significant differences in suicide attempt .Bereavement by suicide is a specific risk factor for suicide attempt among young bereaved adults, whether related to the deceased or not. Suicide risk assessment of young adults should involve screening for a history of suicide in blood relatives, non-blood relatives and friends. We conducted a large population-based national survey of young adults, using a precise sampling frame.We included exposures to the sudden death of any close contact, to describe the impact of suicide bereavement whether related to the deceased or not.Our primary outcomes were validated measures of self-reported suicidal ideation and suicide attempt occurring after the bereavement, adjusted for prebereavement suicidal behaviour and psychopathology.We compared bereavement by suicide with bereavement due to sudden natural causes, then separately compared those bereaved by suicide with those bereaved due to sudden unnatural death to measure the specific impact of suicide bereavement.Given the possibility of selection bias  and male non-response bias, the results of this study may be more generalisable to young bereaved women than men, and to the more highly educated.Suicide bereavement describes the period of grief, mourning and adjustment after a suicide death, that is experienced by family members, friends and any other contacts of the deceased affected by the loss.1International suicide prevention strategies have placed great emphasis on the provision of support for people bereaved by suicide,16Our objective was to design a study that could investigate whether there is a specific association between suicide bereavement and suicide attempt by making distinct comparisons between bereavement by suicide, unnatural causes and sudden natural causes. Use of routine clinical data was precluded because these record exposure only to mortality of first-degree relatives and cohabitees, and hospital presentations of self-harm. Conversely, survey methods permit ascertainment of exposure to all bereavements, and self-reported suicidality and self-harm, and are therefore a vital tool for investigating risk of suicidal events following suicide bereavement. We therefore undertook a population-based cross-sectional survey comparing the impact of specific modes of self-reported sudden bereavement on non-fatal suicide-related outcomes.Our primary hypothesis was that young adults in the UK who had been bereaved by suicide were at higher risk of suicidal thoughts and suicide attempts than those bereaved by other causes of sudden death. Collecting data on two control groups allowed us to address two research questions. First, comparison with adults bereaved by sudden natural causes of death took into account the sudden nature of the loss. Second, comparison with adults bereaved by sudden unnatural causes took into account the violent nature of the loss. Hypothesis 2 was that suicide bereavement would be a risk factor for four secondary clinical and occupational measures , reflecting policy concerns about the contribution of bereavement to workplace mental ill health and sickness absence.We invited all young adults working or studying at UK higher education institutions (HEIs) to participate in a closed, online study about sudden bereavement: the UCL Bereavement Study. We anticipated that using the email systems of large institutions would be the best means of accessing hard-to-reach groups, particularly those not normally accessing health services, and avoiding the biases associated with recruiting a help-seeking sample.All 164 HEIs in the UK in 2010 were invited to participate, following up non-responding HEIs to encourage broad socioeconomic and geographic representation. Over 20% of HEIs (37/164) agreed to take part, with a higher response (40%) from those classified as the more prestigious Russell Group of universities. This provided a sampling frame of 659 572 staff and students. All participants were invited to take part in a survey of ‘the impact of sudden bereavement on young adults’, with the aim of masking them to the specific study hypotheses. There was no accurate way of measuring response, as the denominator of bereaved people was not ascertainable using routine data or survey methods. The majority of participating HEIs agreed to send an individual email invitation with embedded survey link to each staff and student member. For reasons of sensitivity (recent staff/student deaths), 10 HEIs modified this strategy, for example, by emailing students only, using their weekly news digest email, or advertising via staff and student intranet.Inclusion criteria were as follows: people aged 18–40 who, since the age of 10, had experienced sudden bereavement of a close friend or relative. The 18–40 age range was defined to reflect an under-researched group of great policy interest.In the case of more than one exposure, we adopted a hierarchical approach favouring those bereaved by suicide, for whom we anticipated the lowest base rate. This group were classified as suicide bereaved regardless of other exposures. Those bereaved by more than one non-suicide sudden death were asked to relate their responses to whichever person they had felt closest to, with exposure status classified accordingly.We estimated that a minimum of 466 participants would be required in any one group  to detect a doubling of the UK community prevalence of lifetime suicide attempt (6.5%) in young adult samples.supplementary material) was designed in consultation with a group of young bereaved adults and bereavement counsellors, who identified important domains to cover in relation to the impact of bereavement, and was piloted with individuals accessing support from national bereavement support organisations. It elicited quantitative data on sociodemographic and clinical characteristics, including a personality disorder screen,The questionnaire Our four secondary measures were: postbereavement non-suicidal self-harm  using a standardised APMS measure242 tests  and one-way analysis of variance (continuous variables). We then used multivariable regression to estimate the strength of associations between suicide bereavement and outcomes. We fitted binary models using xtlogit commands in Stata,We summarised sample characteristics by exposure group, using χWe tested hypothesis 3, whether the effect of suicide bereavement was modified by kinship (blood-related vs non-blood-related), by adding an interaction term to all models. Hypothesis 4, whether stigma attenuated associations, was tested by including stigma scores in multivariable models.A series of a priori defined sensitivity analyses were conducted. These assessed the robustness of our main findings when using best-case and worst-case scenarios to impute missing values, and when applying more stringent inclusion criteria .Finally, we conducted a set of four post hoc analyses to describe probability estimates in those bereaved by the death of an older person; in a student-only sample; and in women (as the study was underpowered to add gender as an interaction term to models); and to ascertain whether exposure to more than one mode of sudden bereavement might attenuate associations .All analyses were conducted using Stata V.12 .A total of 5085 people of the 659 572 sampled responded to the questionnaire by clicking on the survey link, with 91% consenting to participate, and 68% (n=3432) fulfilling eligibility see . OverallThe sample was primarily female, white and blood-related to the deceased see . Of thos19In comparison with bereavement by sudden natural causes see , those bComparison between bereavement by sudden unnatural causes and the reference category of adults bereaved by sudden natural causes showed no evidence for any group differences.When directly compared with bereavement by sudden unnatural death, adults bereaved by suicide had a similar probability of postbereavement suicidal ideation and suicide attempt see . The proTests for an interaction between bereavement exposure and kinship to the deceased found that none of the significant or non-significant associations between suicide bereavement and adverse outcomes were modified by relatedness. This was the case even when excluding the 253 respondents who reported the death of a partner, ex-partner or non-blood relative, to describe associations in a group bereaved by peer death.Adding stigma scores to adjusted models for significant associations between suicide bereavement and adverse outcomes attenuated ORs, as predicted, with no evidence for group differences between those bereaved by suicide and those bereaved by sudden natural causes in postbereavement suicide attempt  or occupational drop-out , or between those bereaved by suicide and those bereaved by sudden unnatural causes in terms of poor social functioning .Main findings were unchanged after sensitivity analyses simulating worst-case and best-case scenarios for missing values, and after those simulating other potential biases, suggesting that any biases introduced had not resulted in an underestimation or overestimation of the risks.The magnitude and direction of the association between suicide bereavement and suicide attempt  were similar after excluding 769 participants bereaved by the death of someone aged over 60 , to exclude deaths that might be less unexpected. They were also unchanged when excluding 399 staff , and in a women-only sample . When compared with women bereaved by sudden unnatural causes, women bereaved by suicide had an increased probability of postbereavement suicide attempt , whereas in the full sample no association was found.When taking into account the higher prevalence of repeated exposure to sudden bereavement in the suicide bereaved group, ORs were attenuated and no significant findings remained. There was therefore no evidence of group differences between the suicide bereaved group and those bereaved by sudden natural causes in relation to postbereavement suicide attempt  or occupational drop-out , or between those bereaved by suicide and those bereaved by sudden unnatural causes in relation to poor social functioning .any sudden bereavement explains adverse outcomes. Our study supports a specific association between suicide bereavement and suicide-related outcomes, justifying the inclusion of people bereaved by suicide in national suicide prevention strategies. This study also provides the first evidence that blood relatedness to the deceased does not modify the association between suicide bereavement and suicide attempt, confirming that risk also applies to adults bereaved by peer suicide. Such findings must be interpreted in the context of a highly educated sample, in which exposure to violent losses may be lower than in a more nationally representative (but harder to recruit) sample.Our main finding was of a specific association between bereavement by suicide and subsequent suicide attempt among young adults who experience sudden bereavement. This was not attributable to prebereavement suicidality, despite higher rates of prebereavement psychopathology; a finding in keeping with the literatureThe absence of an association between suicide bereavement and suicidal ideation or depression is striking, as is the high prevalence of prebereavement and postbereavement suicidal ideation and depression in all three exposure groups. This may be explained by high baseline rates of depressive and suicidal thoughts among students,The clinical implications of these findings are that clinicians assessing suicide risk should inquire not only about a history of suicide in blood relatives, but also in friends and non-blood relatives. Employers should be aware of the impact of suicide bereavement on occupational functioning, and make adjustments to promote workplace mental health. The associations between suicide bereavement and adverse outcomes became non-significant when adding perceived stigma. This is an indicator that stigma might be a marker for motivational moderators of suicidality after a negative life event, such as reluctance to seek help, thwarted belongingness or perceived burdensomeness.Our study is of policy importance in specifying that friends as well as relatives warrant support after a suicide, addressing the vagueness of suicide prevention strategies on how extensively to offer support.This study's key strengths are its national population-based sample size, and ability to access those who do not normally participate in research. It is the largest scale survey conducted in any country comparing self-reported suicide-related outcomes in those bereaved by suicide and other mortality causes. Previous studies using national registries have achieved larger sample sizes, but under-recorded exposures and lacked self-reported outcomes such as untreated suicide attempts.Lack of information on response might be a considered a limitation, but no method permitted accurate estimation of the bereaved denominator. It is reasonable to assume that most non-responders had not been exposed to sudden bereavement, and that a minority were ineligible by age. Our hierarchical approach to classifying suicide exposure may have overestimated the effect of suicide bereavement due to clustering of violent bereavements, but we did not measure number of exposures to each type of bereavement. Our definition of non-suicidal self-harm followed that used for establishing UK population norms,Bereavement by suicide is a specific risk factor for suicide attempt when compared with bereavement due to sudden natural causes, whether blood-related to the deceased or not. As the association between suicide bereavement and suicide attempt is attenuated when taking into account perceived stigma, further investigation of the role of stigma and reduced help seeking is warranted. Such work will inform the development of acceptable interventions delivered after potentially traumatic losses. Our findings suggest that suicide risk assessment should extend screening for a family history of suicide to any history of suicide in non-blood relatives and friends. However, until we have evidence-based interventions for this group, the best ways of mitigating this risk of suicide attempt are unclear.