An essential function of the host response is to protect the organism against invading pathogens. At present, a multiplicity of mechanisms has been described on how the host sense and response to virus infections. Viruses are intracellular pathogens. Both RNA and DNA viruses have evolved mechanisms to evade host detection and to blunt both the host innate and adaptive immune responses. Considering viruses as pathogens with a relatively fast evolutionary rate, particularly RNA viruses, the result of host-virus coevolution depends on the rapid recognition and response by the host as well as on the evasion mechanism by the virus as a continuous struggle for escape/spread and immunity/clearance of virus from the host.Picornaviridae includes some of the most important RNA viruses for human and veterinary diseases as poliovirus, rhinovirus, and foot-and-mouth-disease virus, which comprised pioneer studies on the structural aspects of viral components. In their minireview, Cifuente and Moratorio summarize genetic variation mechanisms used by picornaviruses on structural changes involved in binding receptor and capsid antibody evasion of enteroviruses to ensure adaptation, spread and survival. The Paramyxoviridae family includes several important human RNA virus as Measles, Mumps, and RSV. In their article, Bakre et al. hypothesize that viral quasi-species enable RNA viruses to modulate host gene expression by regulating miRNA function via sequence complementarity or identity with the miRNA seed sites and consequently they test the hypothesis by analyzing Paramyxovirus transcripts that mimic or bind to host miRNAs by seed sequence and found that complex molecular interactions likely occurred at this host-virus interface. The human RSV (hRSV) belongs to the Pneumoviridae subfamily and is the leading cause of severe acute lower respiratory tract infections in humans at all ages and is the main cause of hospitalization due to pneumonia, asthma, and bronchiolitis in infants. Vaccine development against this pathogen has been delayed after the detrimental effects observed in children by vaccination with a formalin-inactivated hRSV preparation, which caused enhanced disease upon natural viral infection. In this issue, Acevedo et al., discuss the eventual role of Fcγ receptor-mediated immunity underlying such disease exacerbation and immune response mechanisms involved in reinfections. Respiratory viral infections are associated to IgA nephropathy (IgAN). Here, Hu et al., using a RSV-induced IgAN exacerbation mouse model demonstrates that RSV activates C5a-C5aR1 axis and modulates the Th1, Th17, and Treg balance. C5aR1 inhibition alters both kidney damage and Th1, Th17, and Treg cell dysfunction supporting that blocking the C5a-C5aR1 axis might be a potential therapy for RSV-induced IgAN. The Dengue virus (DENV), a member of the Flaviviridae family, causes 400 million infections each year. Whereas, primary dengue infection by any of the four serotypes is asymptomatic or mild, secondary infection with a heterotypic serotype is associated with hemorrhagic fever suggesting that pre-existing immunity to DENV play a role for enhanced secondary infections. Ripoll et al. carried out molecular simulations guided by previous in vitro experiments and structural studies to explore the role of antibody fine-specificity, viral conformation, and maturation state on antibody dependent enhancement in the context of primary and secondary DENV infections. The Influenza viruses belong to the Orthomyxoviridae family and are major pathogens that affect both humans and animals causing severe respiratory illness, including pneumonia. Neutrophils and macrophages play essential roles in the clearance of influenza virus from lungs, before the onset of virus specific immunity but their uncontrolled recruitment and activation contribute to acute lung injury. In this special issue, Rudd et al. study chemokine receptors expression in a murine model of influenza-induced pneumonia and reported a new set of chemokine receptors that modulates several biological functions of neutrophils. On the other hand, Tao et al. performed a comparative analysis of whole-transcriptome RNA expression between two influenza viruses and discuss how differently expressed genes may be involved in host response and evasion mechanisms. The Herpesviridae family includes very important human pathogens as the herpes simplex virus (HSV), associated with mucosal lesions and encephalitis. Tognarelli et al. review and update several mechanisms used by HSV that have been described to evade the host antiviral response. The epithelial surfaces of the human body contain complex communities of microorganisms collectively referred to as microbiota. Since the discovery that gut microbiome instruct host immunity, great attention has been directed to this interaction. In their minireview, Domínguez-Díaz et al., provides a general overview of the pro- and antiviral effects of the microbiota to prevent viruses entry into host cells or to help them to evade the host antiviral immunity. Regulation of RNA homeostasis is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with specific proteins in order to regulate their entire cycle, including mRNA localization, translation and degradation. The best characterized of such RNA-protein complexes are Stress Granules (SGs) and Processing Bodies (PBs), which are involved in RNA storage and RNA decay/storage, respectively, and are generally associated with repression of gene expression. Gaete-Argel et al. performed an exhaustive update about how viruses have evolved different mechanisms to counteract SGs and PBs assembly or to use them to his own benefit. Moreno-Altamirano et al. explore how viruses mimic, exploit, and/or interfere with host cell metabolic pathways and how, in doing so, they may evade immune responses. Programmed cell death protein (PD-1) and its ligands have received immense attention because of their role in the evasion of tumor cells from antitumor immunity. However, it has been less appreciated that the PD-1/PD-L1 axis also regulates antiviral immune responses and is therefore modulated by a number of viruses. Here, Schönrich and Raftery update and discuss the current literature regarding this important expanding field.In this Special Research Topics issue on the recent advances in Viral Evasion Mechanisms of the Host Response, we compiled a total of twelve research and review articles. The special issue includes five Original Research Articles, five Review Articles, and two Mini Review Articles. Meanwhile five articles were dedicated to viral general mechanisms, seven were specifically focused on picornavirus, respiratory syncytial virus (RSV), Dengue virus (DENV), herpes simplex virus (HSV), and Influenza virus (IAV). The family All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.SL is employed by Denka Life Innovation Research. The remaining 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.


With progress in genome-wide association studies of depression, from identifying zero hits in ~16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, understanding the genetic architecture of this debilitating condition no longer appears to be an impossible task. The pressing question now is whether recently discovered variants describe the etiology of a single disease entity. There are a myriad of ways to measure and operationalize depression severity, and major depressive disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders-5 can manifest in more than 10 000 ways based on symptom profiles alone. Variations in developmental timing, comorbidity and environmental contexts across individuals and samples further add to the heterogeneity. With big data increasingly enabling genomic discovery in psychiatry, it is more timely than ever to explicitly disentangle genetic contributions to what is likely ‘depressions’ rather than depression. Here, we introduce three sources of heterogeneity: operationalization, manifestation and etiology. We review recent efforts to identify depression subtypes using clinical and data-driven approaches, examine differences in genetic architecture of depression across contexts, and argue that heterogeneity in operationalizations of depression is likely a considerable source of inconsistency. Finally, we offer recommendations and considerations for the field going forward. Depression is a common, complex and debilitating condition with a lifetime prevalence of 20% worldwide. Whether it is one unitary construct, or better conceptualized as different and potentially overlapping disorders, has been the subject of vigorous debate over the past decades.A typical cohort used in genetic studies of depression includes cases with the same diagnosis. However, cases often differ in many respects including symptoms, number of episodes, comorbidities and disease course. This heterogeneity, often hidden and unexamined in genome-wide association studies (GWAS) cohorts, has been identified as one of the main roadblocks to successfully unraveling the genetic architecture of depression, as initial GWAS efforts were limited by both heterogeneity and low power ,2. In reHeterogeneity is irrelevant if depression reflects a single, specific disorder that carves nature at its joints , but worWe distinguish three sources of heterogeneity that impact genetic studies of depression, shown in construct definition and its measurement. The term ‘depression’ is an umbrella term that has been used to refer to, among others, depressive symptoms as a continuum and clinical depression as a category. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5)   offers a (DSM-5) ,12. Over (DSM-5) . Clinica (DSM-5) , and ref (DSM-5)  obfuscat (DSM-5) . In the symptoms, severity, developmental timing, comorbidities and physiology. DSM-5 criteria for MDD include diverse symptoms such as low mood, loss of interest, sleep disturbance, weight changes, psychomotor slowing/agitation and suicidal ideation. There are up to 10 377 unique ways to meet these diagnostic criteria  and external environments .Third, etiology, encompassing the diverse combination of Progress in the past years stems largely from genetics research studying heterogeneity in depression manifestations and etiology. Below, we review recent efforts to identify depression subtypes using clinical and data-driven approaches, examine differences in genetic architecture of depression across contexts, and discuss their promises and limitations. We argue that heterogeneity in operationalizations of depression cuts across these sections and is likely a considerable source of inconsistency.Subtypes of depression have been proposed based on clinical observations and data-driven approaches, and research has largely focused on comparing their genetic architectures and how well they can be predicted with existing polygenic risk scores (PRS).Decades of clinical experience and patients’ own accounts have led to clinical subtypes of MDD that are reflected in current DSM-5 specifiers such as atypical, melancholic and anxious depression. Subtypes have also been proposed based on developmental timing ,20, treaAs an example of a symptom-based clinical subtype, atypical depression is primarily characterized by hypersomnia and weight gain, as opposed to depression more typically characterized by insomnia and weight loss. Typical and atypical depression subtypes differ in heritabilities , with PRS for other psychiatric traits showing stronger associations with the typical than atypical subtype . ConversIn terms of developmental timing, genetic overlap between early and late-onset MDD has been shown to be only moderate . PRS froHowever, research into distinctions between subtypes, whether symptom- or timing-based, relies on data that is often not available. For example, The China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE), due to its strict enrollment criteria, is the only genetically informed cohort with a high proportion of cases presenting with melancholic depression ; no replA body of complementary research has emerged to identify depression subtypes using agnostic, data-driven methods. There is over half a century of literature characterising depression heterogeneity based on symptom data. There are two principled ways, reviewed extensively elsewhere . First, Despite these challenges, there are increasing efforts to recover latent dimensions and classes at the genetic level. Building on the identification of three genetic factors reflecting mood, psychomotor/cognitive and neurovegetative features of MDD using twin modeling , a recenOther data-driven approaches have been applied to physiological measures to identify etiologically meaningful subtypes. Variations of canonical correlation analysis (CCA) have characterized relationships between depressive symptoms and neuroimaging measures , and hieFinally, genetic data have been used to directly identify data-driven subtypes. For example, subsets of MDD cases in UKBiobank with distinct genetic risks for SCZ, high neuroticism and early age of menopause  were ideThis section reviews genetic investigations aiming to disentangle etiological heterogeneity across the contexts in which depression manifests. We also discuss challenges to these approaches, including measurement differences and ascertainment biases.N = 59 600) in the Million Veterans Program (MVP) in the USA with a meta-analysis of several depression cohorts of individuals with European ancestry , including MVP (N = 10 640) in the CONVERGE cohort to MDD of EUR in various cohorts from the Psychiatric Genomics Consortium      10 years ago .To summarize, we have identified three overarching sources of heterogeneity: operationalization, manifestations and etiology. The first pertains to heterogeneity in how we do science, the second and third to heterogeneity of the phenotype itself as well as its causes. Gaining a better understanding of how these three sources impact results in our field is a necessary (though not sufficient) step towards improving diagnostics and targeted treatments. From reviewing the literature, four lessons emerge.(1) Measure consistently: Inconsistent findings in subtype identification and their genetic architecture are inevitable if depression is not operationalized consistently. Overall, this calls for harmonizing assessments of depression across studies.(2) Measure more: Both theory- and data-driven approaches to disentangle the complex phenotype of depression rely on data, and even the most sophisticated statistical approaches cannot overcome missing input data. One crucial step forward is to assess a broader range of data—including individual depression symptoms and salient clinical characteristics such as age of onset, number of episodes and recurrence—and utilize them to study depression heterogeneity. Further, new types of data, including those from activity trackers in wearable technologies, text and voice through natural language processing, and longitudinal mood assessment by computerized adaptive screening questionnaires, may be helpful to identifying subtypes for genetic analysis.(3) Collaborate: Complex traits like depression cannot be understood in a mono-disciplinary vacuum, because they require, in addition to knowledge of quantitative genetics, a nuanced understanding of the phenotype under investigation. The goal to identify and validate depression subtypes therefore calls for collaborations with patients, clinicians, epidemiologists, statisticians, computer scientists, sociologists, anthropologists and many others.(4) Follow through: To make good on the promise of GWAS to deliver genetic insights that would improve diagnosis, treatment and prevention of depression in individuals with diverse etiological causes, we need to look beyond our findings of differences in genetic architecture and PRS associations. Fine-mapping using sequencing datasets may help identify candidate causal variants with heterogeneous effects on depression subtypes; integration of multi-omics data may point to the different tissues and biological pathways involved; single cell transcriptomics across developmental time points may lend spatial and temporal resolution; experimental designs in re-differentiated human induced pluripotent stem cells, organoids or model organisms may allow us to validate the biological relevance of effects we find and identify potential targets for drug interventions.Doing all of this, we may find that depression really consists of an entangled web of partly overlapping biopsychosocial constructs, with overlapping genetic contributions and underlying biological mechanisms. Perhaps now is the right time for us to take the bold next step and acknowledge the complex reality that the field is searching for the genetic architecture of ‘depressions’ rather than depression. This is a challenge, but simultaneously a great opportunity and offers a clear path forward towards embracing the heterogeneity of depressions in our theories, measures and methods.Conflict of Interest statement. The authors declare no conflicts of interest.National Institute of Mental Health (T32MH017119 to K.W.C.).


Hepatocellular carcinoma is one of few cancer types that continues to grow in incidence and mortality worldwide. With the alarming increase in diabetes and obesity rates, the higher rates of hepatocellular carcinoma are a result of underlying non-alcoholic fatty liver disease. Many have attributed disease progression to an excess consumption of fructose sugar. Fructose has known toxic effects on the liver, including increased fatty acid production, increased oxidative stress, and insulin resistance. These effects have been linked to non-alcoholic fatty liver (NAFLD) disease and a progression to non-alcoholic steatohepatitis (NASH). While the literature suggests fructose may enhance liver cancer progression, the precise mechanisms in which fructose induces tumor formation remains largely unclear. In this review, we summarize the current understanding of fructose metabolism in liver disease and liver tumor development. Furthermore, we consider the latest knowledge of cancer cell metabolism and speculate on additional mechanisms of fructose metabolism in hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is the fifth most common cancer and second leading cause of cancer-related deaths worldwide. East Asian countries suffer the greatest disease burden, with more than 40 in 100,000 people affected per year. This is attributed to the regional endemic infections of the hepatitis B virus (HBV) and hepatitis C virus (HCV) . HoweverThe major risk factors for HCC are HBV/HCV infections, aflatoxins, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and the inflammatory form of non-alcoholic steatohepatitis (NASH). Most HCC cases present with underlying cirrhosis, often due to viral infection or alcohol abuse. The epidemiology and associated risk factors of viral infection/alcoholic liver disease are well understood. In comparison, the link between NAFLD and the increased HCC incidence is less well described. Males and older individuals (>50 years) with NAFLD are at a greater risk of HCC development . AfricanCurrent treatment options for HCC therapy include surgical resection, liver transplantation, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), or medical treatment with sorafenib or regorafenib . Early-sThe development and progression of HCC is highly complex; thus, a deeper understanding of tumor pathogenesis will aid in future therapeutic advances. Recent research has investigated the role of dietary fructose in NAFLD and HCC progression. Excess fructose consumption is well established as a causative factor for developing insulin resistance and fatty liver, thus the rise in NAFLD/NASH cases progressing to HCC in developed countries may be attributed to Westernized diets. However, clinical evidence of fructose association with HCC is limited. This review will address fructose metabolism, the effects on liver and NAFLD pathogenesis, and how the metabolic fate of fructose may affect HCC development. The liver is the main metabolic hub for ingested carbohydrates and absorbs most of the circulating glucose from the blood. Circulating glucose is absorbed by hepatocytes via the glucose transporter type 2 (GLUT2) receptor. In the cytosol, glucokinase (GK) phosphorylates glucose to generate glucose-6-phosphate (G6P), which will either be converted to glycogen for energy storage or proceed through glycolysis for adenosine triphosphate (ATP) production ,18. G6P Fructose metabolism, however, has another fate within the liver. Fructose is absorbed principally by two GLUT transporter members, GLUT2 and GLUT5 . GLUT5 iFructose has been shown to increase the activity of proteins involved in lipogenesis, gluconeogenesis, and glycolysis. Transcription factors carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element binding protein-1 (SREBP-1) are potent inducers of lipogenesis by activating genes such as fatty acid synthase (FAS) and acetyl coA carboxylase (ACC) , and havFructose conversion to F1P occurs rapidly and is ATP-dependent, thus the ingestion of fructose results in ATP and intracellular phosphate depletion and increased intracellular adenosine monophosphate (AMP) ,38. ConsThe potential mechanisms of fatty liver development discussed above may also contribute to hepatic inflammation and consequently a progression to NASH. Fructose-induced accumulation of uric acid generates ROS both in hepatocytes and adipocytes , which iFurthermore, the cascade of inflammatory pathways induced by excess fructose consumption may also contribute to the activation of stress hormones involved in the hypothalamus–pituitary–adrenal (HPA) axis. In response to the fructose-induced inflammation in hepatocytes and adipocytes, the HPA axis is activated to synthesize immunosuppressors, such as glucocorticoids ,55. ThisIt has been well established through several animal and human studies that small intestine microbiome dysbiosis is associated with NAFLD/NASH development, as demonstrated by increased endotoxin levels and intestinal permeability . AlthougCurrent epidemiological studies show that the percentage of obese patients with NAFLD ranges from 30% to 75%, whereas NAFLD in non-obese patients shows a surprisingly high range of 5%–30%. The prevalence of NAFLD in the population varies substantially not only due to ethnical and environmental differences, but also due to the poor accuracy of ultrasounds while they are the most used method of diagnosing liver steatosis. Lean NAFLD cases have been characterized by visceral obesity and low or even absent hepatic insulin resistance (IR) . The devWhile the precise mechanisms in which NAFLD develops in non-obese patients has yet to be fully elucidated, dietary factors are likely to be a major contributor. One study has shown non-obese NAFLD patients to consume more than double the amount of sugar per day than the matched healthy controls, where nearly half of this sugar came from soft drinks . AdditioSome studies have shown small amounts of fructose in the presence of glucose can improve glucose uptake and decrease hyperglycemia in normal and diabetic subjects, particularly in states of exercise ,77,78,79Other short-term investigations in obese children have shown that restricting fructose consumption reduces liver fat, DNL, and improves insulin sensitivity ,89. In cHowever, considering that the majority of this clinical data was obtained over short time periods of 7–14 days, and the number of longer-term studies is limited, it remains unclear whether fructose alone is solely responsible for changes in fat metabolism and insulin levels in patients. Furthermore, there is a large range in the amount of fructose used in clinical studies varying from 20% to 35% of total energy requirements, either as weight-maintaining diets or hypercaloric diets ,84,85,90In healthy individuals, fructose circulates in the bloodstream at a significantly lower amount of just 5.5 μM in the fasted state, as compared to 4.5 mM for circulating glucose . HoweverSeveral meta-analyses display this controversy by indicating the large number of heterogenic studies that contribute to differences in fructose metabolism in healthy versus overweight patients. By example, a meta-analysis revealed that isocaloric diets supplemented with fructose over glucose showed no increase in postprandial triglycerides . HoweverIn contrast to the above, another meta-analysis identified fructose feeding to be positively associated with fasting blood sugar levels and increased triglycerides . HoweverThe progression of NASH to HCC is likely to be multifactorial, including factors such as oxidative stress and chronic inflammation leading to damaged hepatocytes and the stimulation of fibrosis, lipotoxicity, and genetic mutations. NASH is a major risk factor for HCC, with 4%–22% of HCC cases relating to underlying NAFLD and NASH . HoweverRegarding HCC, there are limited studies that have investigated the relationship of fructose consumption and HCC risk. Some studies have shown a positive association between glucose and the risk of HCC, where a sample of 147 and 250 respective HBV/HCV HCC patients with a high glycemic load had an increased overall risk (OR) of HCC compared to control  ,110. AnoSome animal studies have demonstrated that fructose containing diets increase the incidence of liver tumor growth. In one study, using the carcinogen diethylnitrosamine (DEN), mouse HCC was evaluated using diets that included (i) normal chow, (ii) high sucrose/high lard fat, (iii) high sucrose/high coconut oil fat, (iv) high sucrose/fructose and low fat, and (v) and high lard/low sugar. Healy and colleagues demonstrated a similar tumor incidence among male mice fed the above diets . HoweverIt is known that males are at a greater risk of attaining HCC. Therefore, using the above models, the same investigators observed that female mice had increased tumor incidence when fed the high sucrose/high lard fat, and high sucrose/fructose and low fat diets, compared to the high lard/low sugar and normal diets . Interes4) to induce fatty liver, fibrosis, and HCC [Another study evaluating DEN-treated rats on an eight-week diet of either high-fat, high-fructose, or normal chow reported somewhat controversial results. In this study, pre-cancerous cells were more prominent in the high-fructose compared to the high-fat diet . Liver o and HCC . CollectWhile there is limiting clinical evidence regarding the genetic changes associated with fructose exposure in HCC, there are several studies that imply reduced fructose metabolism in HCC. A recent study has demonstrated this in vitro, evident by a metabolic switch from KHK-C expression to predominant expression of KHK-A in HCC , which hTumor progression is dependent on acquired characteristics that allow the growth and development of cancerous cells, commonly known as the hallmarks of cancer . The halHowever, recently our understanding of cancer metabolism has shifted to a more dynamic view. This is termed the “reverse Warburg effect”, whereby anabolic cancer cells metabolically adapt to the tumor microenvironment and promote aerobic glycolysis in the neighboring stromal cells. The stromal cells produce lactate, fatty acids, amino acids, glutamine, and ketone bodies that are in turn used by the cancer cells to support growth ,134,135.According to these authors, integrating these observations with the current knowledge on fructose metabolism, results in a conflicting model of cancer development. The metabolic fate of fructose causes rapid depletion of ATP levels, increased cellular ROS, and increased gluconeogenesis. It could be expected that in HCC cancer cells that display the Warburg effect, a high fructose diet would not supply cancer cells with the appropriate fuel. The rapid conversion to F1P would be deleterious to proliferating cells due to ATP depletion, nucleotide degradation, and the accumulation of uric acid and ROS. As the Warburg effect encourages glycolysis, we would not expect much fructose to enter the PPP and promote nucleotide synthesis. It would be expected that the overload of ROS in association with depleted energy and nucleotides would lead to apoptosis. Additionally, as discussed in previous sections, the enzymes involved in fructose metabolism are thought to act as HCC tumor suppressors. Thus, it is conceivable that while fructose may contribute to NAFLD pathogenesis, HCC fed by fructose may lead to growth inhibition . AlthougTaking into account the current evidence, we suggest that fructose consumption more likely drives cancer cells into a metabolically stressed state, inducing the reverse Warburg effect to maintain cell growth and control the increase in cellular ROS. This is exemplified by the fact that fructose consumption has been shown to increase expression of FBP1 as well as increase enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the PPP . FurtherFructose metabolism has been implicated in the development and progression of NAFLD and NASH. Fructose metabolism in the liver bypasses the regulatory enzymes of glycolysis and is believed to result in increased lipogenesis, oxidative stress, and inflammation. Some studies have utilized high-fructose diets to study HCC development; however, it remains unclear how these models may translate to clinical NASH-HCC. Our current knowledge on traditional cancer metabolism and the genetic changes associated with HCC suggest that fructose as a fuel source may restrict tumor growth. However, while fructose may induce metabolic stress in cancer cells, it is likely that metabolic reprogramming will occur to allow continued tumor growth. A better understanding of the role of fructose in NAFLD-HCC development and the metabolic fates of fructose in cancer cells will allow for more specific drug therapies to be developed. Targeted treatment options are required to more effectively treat the increasing number of NAFLD-HCC cases arising in developed countries.


Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal dementia syndromes and Alzheimer's disease, but has not been studied and compared systematically in these diseases. We used a semi-structured caregiver survey to capture time-related behavioral alterations in 71 patients representing all major sporadic and genetic syndromes of frontotemporal dementia, in comparison to 28 patients with typical Alzheimer's disease and nine with logopenic aphasia, and 32 healthy older individuals. Survey items pertained to apparent difficulties ordering past personal events or estimating time intervals between events, temporal rigidity and clockwatching, and propensity to relive past events. We used a logistic regression model including diagnosis, age, gender, and disease severity as regressors to compare the proportions of individuals exhibiting each temporal awareness symptom between diagnostic groups. Gray matter associations of altered time awareness were assessed using voxel-based morphometry. All patient groups were significantly more prone to exhibit temporal awareness symptoms than healthy older individuals. Clinical syndromic signatures were identified. While patients with typical and logopenic Alzheimer's disease most frequently exhibited disturbed event ordering or interval estimation, patients with semantic dementia were most prone to temporal rigidity and clockwatching and those with behavioral variant frontotemporal dementia commonly exhibited all these temporal symptoms as well as a propensity to relive past events. On voxel-based morphometry, the tendency to relive past events was associated with relative preservation of a distributed left-sided temporo-parietal gray matter network including hippocampus. These findings reveal a rich and complex picture of disturbed temporal awareness in major dementia syndromes, with stratification of frontotemporal dementia syndromes from Alzheimer's disease. This is the first study to assess symptoms of altered temporal awareness across frontotemporal dementia syndromes and provides a motivation for future work directed to the development of validated clinical questionnaires, analysis of underlying neurobiological mechanisms and design of interventions. Our capacity to experience and calibrate the passage of time anchors us in the flux of sensory experience and allows us to track external events, conduct our daily affairs and most fundamentally, maintain a sense of self-continuity from past to future –3. Our aDistributed cortical and subcortical brain networks—including prefrontal and insular cortices , 10–14, This neural network paradigm provides a rationale for anticipating and understanding alterations of subjective temporal awareness accompanying neurodegenerative pathologies. These pathologies characteristically and selectively target the distributed neural networks implicated in temporal processing in the healthy brain –35. It fSeveral questionnaires and interview protocols have been developed to look at subjective time awareness in both healthy and clinical populations –39. NotaTemporal processing abnormalities have also been observed in FTD. This is a clinically and pathologically heterogeneous group of diseases , comprisHere we addressed the issue of temporal awareness in FTD in a cohort of patients representing all canonical syndromes of FTD , in relation to healthy older individuals and a cohort of patients with typical amnestic AD and its major, language-led variant phenotype, logopenic aphasia (LPA). We surveyed temporal behavioral alterations which we hypothesized on clinical grounds to be particularly pertinent to the target syndromes and to the timeframes of daily life and autobiographical experience. We did not set out in this first study to characterize temporal symptoms in detail. Rather, our principal objective here was to survey the kinds of altered temporal awareness that occur in FTD, to estimate the relative proportions of patients with different FTD syndromes exhibiting symptoms of altered temporal awareness and to explore possible differences with respect to typical and amnestic AD. We assessed structural neuroanatomical correlates of altered temporal awareness using voxel-based morphometry (VBM) of patients' brain magnetic resonance images.Based on clinical observations, we hypothesized that patients with AD syndromes  would exhibit particularly prominent disturbances of temporal interval estimation and event ordering. In contrast, we hypothesized that patients with FTD syndromes  would particularly exhibit reduced temporal flexibility and clockwatching. Based on available neuroimaging evidence in the healthy brain , 59–61, C9orf72, all bvFTD; seven MAPT, 6 bvFTD and 1 SD; seven GRN, 4 bvFTD and 3 PNFA). Brain MRI was consistent with the syndromic diagnosis in all patients and none had evidence of significant cerebrovascular burden. Cerebrospinal fluid profiles of tau and beta-amyloid1−42 were available for twelve patients with typical AD and six patients with LPA; each was consistent with underlying Alzheimer's pathology, based on local reference ranges . In all patients, the syndromic diagnosis was further corroborated by a comprehensive general neuropsychological assessment. We recorded the use of medications (antidepressants and neuroleptics) that could potentially affect time perception among the participant groups , twenty-eight patients with a typical memory-led syndrome of AD  and nine patients with LPA were recruited via a specialist cognitive disorders clinic. Thirty-two age-matched healthy individuals with no history of neurological or active psychiatric illness were recruited via the departmental research database. All patients fulfilled consensus diagnostic criteria for the relevant syndromic diagnosis –64 and at groups , 66. CliAll participants gave informed consent for their involvement in the study. Ethical approval was granted by the University College London and National Hospital for Neurology and Neurosurgery Joint Research Ethics Committees in accordance with Declaration of Helsinki.We surveyed the presence of behavioral symptoms suggesting an alteration of subjective temporal awareness . We sampPost-hoc tests of non-parametric continuous variables were performed using Dunn's test. For categorical variables, we used the chi-square test, or Fisher's exact test when expected counts were small.Clinical and behavioral data were analyzed using Stata version 14.0 software . Participant groups were compared using a one-way ANOVA for continuous variables satisfying normality criteria, or the non-parametric equivalent Kruskal-Wallis test if this was not the case. t-test or the Wilcoxon rank sum test for continuous variables, and the chi-square test for categorical variables. A statistical significance threshold p < 0.05 was accepted for all tests.Survey data were analyzed to determine the prevalence of changes in temporal awareness for each participant group. Temporal awareness symptoms were coded as 1 (present) or 0 (absent). Because for three of the five symptom items no healthy control participant exhibited the symptom, we did not build a logistic regression model to compare the prevalence of alterations on that item for all patient groups vs. the healthy control group. Instead, we performed a two-tailed Fisher's exact test for each item and corrected for multiple comparisons using the Benjamini-Yekutieli procedure . For eacwww.fil.ion.ucl.ac.uk/spm/software/spm12/), following an optimized protocol  and a further three  were inadequate on technical grounds. For each patient, a sagittal 3D magnetization-prepared rapid-gradient echo T1-weighted volumetric brain MR sequence  was acquired on a Siemens Prisma 3T MRI scanner using a 32-channel phased array head-coil. Pre-processing of brain images was performed using the New Segment and Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) toolboxes in SPM12  correction for multiple voxel-wise comparisons, separately within individual pre-specified neuroanatomical regions of interest. These regions were selected a priori based on functional neuroanatomical substrates of subjective time awareness identified in the healthy brain comprising anterior temporal lobe  (http://fsl.fmrib.ox.ax.uk/fsl/fslwiki/Atlases). The regions used are presented in Across the combined patient cohort, we ran a full factorial model to assess associations of regional gray matter volume with each temporal symptom. The model incorporated the five temporal symptom items , diagnosis as a five-level factor, as well as age, total intracranial volume, and MMSE score as nuisance covariates. Negative (inverse) associations with regional gray matter  were assessed for every symptom item; positive gray matter associations were additionally assessed for symptoms of temporal rigidity, clockwatching, and re-living the past, since these phenomena are likely chanisms . Statistal pole) , 79–81, al pole) , 82, paral pole) –17, 83 aal pole) , 20. RegF = 1.31; p = 0.2619], nor handedness (p = 0.885); but differed significantly in gender balance  and years of education ; the absolute difference was small, of the order of two years). Syndromic groups did not differ significantly in clinical illness duration . However, there was a significant difference in MMSE scores , attributable in a post hoc analysis to significantly higher scores in the bvFTD group compared with the LPA group (p = 0.012).Participant groups see  did not Data on the prevalence of temporal awareness alterations for all participant groups are summarized in Raw prevalence data  indicatep < 0.0001). In the logistic regression analysis comparing syndromic groups, there was a main effect of diagnosis for both confusion of temporal order  and interval estimation difficulties . Such disturbances were significantly more prevalent in the AD group than the SD group  and the PNFA group .Compared to healthy controls, the patient cohort overall had a significantly higher prevalence of confusion about ordering events in time and difficulty estimating intervals between events (both p < 0.001). There was a main effect of diagnosis for clockwatching  and temporal rigidity . Clockwatching was significantly more prevalent in the bvFTD and SD groups than the AD group . Temporal rigidity was significant more prevalent in the bvFTD, SD, and PNFA groups than the AD group .Compared to healthy controls, the patient cohort overall also had a significantly higher prevalence of increased temporal rigidity and clockwatching (both p < 0.001). However, while this symptom was more prevalent in the bvFTD and SD groups, the logistic regression analysis showed no significant main effect of diagnosis , precluding further comparisons between disease groups.Compared to healthy controls, patient groups overall were significantly more likely to re-live past events . No other significant associations between developing temporal awareness symptoms and general patient characteristics  were identified.MAPT mutations, contrasting with its low prevalence in association with C9orf72 and GRN mutations; no patients with GRN mutations were reported to have exhibited disturbances of temporal event ordering or interval estimation.Considering the small subgroup of patients with genetic mutations , symptomFWE < 0.05 within pre-specified anatomical regions of interest; statistical parametric maps are presented in Significant gray matter associations of altered time awareness across the patient cohort are summarized in Here we have demonstrated alterations of multiple dimensions of long-duration, subjective time awareness in canonical syndromes of FTD, referenced to syndromes of AD as well as healthy older individuals. Abnormalities of time awareness were exhibited by over half of patients with bvFTD and SD as well as typical amnestic AD and LPA, and by around a third of patients with PNFA. However, the pattern of abnormalities was not uniform over the patient cohort: syndromic groups showed separable  profiles of altered time awareness, in line with our prior clinical hypotheses. Patients with typical AD and LPA had particularly salient difficulties with ordering past events and placing events in time, without significant changes in other aspects of temporal behavior sampled here; the pattern of temporal symptoms was much more heterogeneous in the FTD cohort. The SD group had prominent temporal rigidity and clockwatching, while the bvFTD group exhibited predominant abnormalities of past event ordering and re-living past events. Profiles of altered temporal awareness differed significantly between AD and FTD disease groups when directly compared and although there was an overall correlation of abnormal past event ordering and interval estimation with worsening disease severity, syndromic profiles of altered temporal awareness were evident after taking background clinical characteristics  into account.Informed by previous work in the healthy brain –87, we pAcross the combined patient cohort, a tendency to re-live past events was associated with relative preservation of a distributed left-sided temporal, parietal, and hippocampal network. This is in line with an emerging picture of temporal processing and subjective temporal awareness derived from studies of the healthy brain. In particular, the parietal cortex has been implicated in reconstructing sequences of spatio-temporal events and their temporal ordering , 91, 92.The lack of gray matter associations of other symptoms of altered temporal awareness here is, at first sight, a little surprising. However, there are several factors that might potentially account for these results. Firstly, the neurobiological status of the temporal awareness “symptoms” we considered here are different between symptom categories. Re-living of past events depends to some extent on a neuroanatomical substrate that is at least partly preserved . It is therefore plausible that this substrate should be identified across syndromic groups, since it reflects the architecture of the healthy brain. On the other hand, we sampled other temporal symptoms that directly reflect the impact of neurodegenerative brain damage, which will have varied between syndromes and is therefore less likely to have a common neuroanatomical association across the patient cohort. In addition, it is possible that the neuroanatomical substrates of these other temporal symptoms are extensively distributed, widely variable between individuals or alternatively, highly convergent between symptom categories: any of these scenarios would have made neuroanatomical associations less liable to be identified using the VBM model we employed here. It is further plausible that at least some symptoms may arise from network connectivity changes that are not captured using VBM. Finally, the binarised symptom classification here may well have reduced scope to detect gray matter associations that might have been evident with a continuously distributed variable . It should be kept in mind that these factors are, to some extent, limitations imposed by the VBM technique itself  rather than specific to temporal processing per se.GRN mutations, whereas these were salient symptoms in patients with MAPT mutations. It may be relevant that MAPT mutations target the antero-mesial temporal lobes relatively selectively . The categories of temporal symptoms assessed in this first study were intentionally broad and qualitative, designed to capture a diverse range of phenomena. However, these symptom categories should be unpacked in further studies to quantify the frequency and severity of symptoms that patients experience and to capture the nature of their difficulties more precisely. For example, “difficulty” estimating the temporal intervals between events could mean simply that patients fail to take account of lapsed time or rather that they express unreasonable estimates of the relevant intervals. In turn, these processes might plausibly be affected differentially in different syndromes and diseases . Particularly with regard to symptoms suggesting disturbances of the mental timeline, it will be crucial to define how such disturbances relate to deficits of episodic memory and the detail with which particular events and their spatio-temporal context are encoded. It will also be important to acquire patients' own reports of time awareness, ideally in parallel with caregivers' perspectives. Certain aspects of temporal awareness  are intrinsically difficult to capture from second-person questionnaires but potentially highly illuminating in particular neurodegenerative syndromes . OuUnderstanding the neural mechanisms of altered temporal awareness associated with these neurodegenerative pathologies will require a detailed assessment of temporal perception , consideration of accompanying behavioral phenotypes [since altered emotional reactivity is very likely to impact on temporal behaviors ], and fuThis preliminary study calls attention to the significance of temporal awareness symptoms and pertinent neural network substrates across major dementia syndromes. The findings provide a rationale for a more systematic analysis of subjective time in neurodegenerative pathologies, with a view to developing validated clinical assessment tools, understanding underlying neurobiological mechanisms and designing management interventions.The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by University College London and National Hospital for Neurology and Neurosurgery Joint Research Ethics Committees. The patients/participants provided their written informed consent to participate in this study.CM and JW were responsible for the conception and design of the study. CM and HS carried out symptom survey data collection. LR, CG, KM, EB, and JR were responsible for recruitment, neuropsychology, and imaging data acquisition. M-CR-K was responsible for the analysis of the survey data and M-CR-K, CM, CH, RB, and JA for the voxel-based morphometry analysis. M-CR-K, CM, and JW were responsible for the interpretation of the data. M-CR-K and JW were responsible for drafting the manuscript. M-CR-K, CM, CH, and JW for revisiting it critically for important intellectual content. All authors read and approved the final manuscript.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.


Introduction: Osteoporotic fractures represent a major public health burden. The risk of fragility fractures in late adulthood is strongly impacted by peak bone mass acquisition by the third decade. Weight-bearing sporting activity may be beneficial to peak bone mass accrual, but previous studies have focused on elite sporting activity and have used dual energy X-ray absorptiometry as a measure of bone density. The authors performed a narrative systematic review of individual sports  and calcaneal quantitative ultrasound (cQUS) bone measures in young people.Methods: Multiple databases were systematically searched up until the 31st of March 2019. The authors included studies of participants' mean age (11–35 years), reporting any level of recreational sporting activity and cQUS measures as well as excluding elite/professional sporting physical activity. Studies (title and abstract) were screened independently by two reviewers, and a third reviewer resolved any discrepancies. STROBE guidelines were used to check the reporting of observational studies. The Newcastle–Ottawa Scale was used to assess the risk of bias of the studies included in the review. The systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO).Results: A search yielded 29,512 articles that considered relationships between bone density assessed by any technique and sporting activity. Duplicate and out of scope abstracts were removed. This left 424 papers that were screened by two reviewers; of these, six met the inclusion criteria, including assessment by cQUS. The authors identified papers where sports were considered, included soccer , swimming, cycling, gymnastics, dancing, badminton, basketball, fencing, wrestling, and judokas. Although study heterogeneity prohibited meta-analysis, all six included studies reported significant benefits of weight-bearing non-elite sports on cQUS outcomes.Conclusion: Our study found beneficial effects of non-elite sports participation on cQUS in adolescence and young adulthood, although further work is now indicated. Osteoporosis is a major international public health problem through its association with fragility fractures  and sporting activity. The effect of sporting activity varied according to sex; the skeletal sites and bone outcomes were measured as assessed by DXA and peripheral quantitative computed tomography (pQCT), which gives an estimate of volumetric bone density and other assessments of bone strength at relevant sites, including the calcaneus  proceeded until the 31st of March 2019 to source the relevant articles under review .Outcome: Any bone heel ultrasound measures, such as speed of sound (SOS)/velocity of sound (VOS), broadband ultrasonic attenuation (BUA), stiffness index (SI)/quantitative ultrasound index (QUI).PopulationInclusions: The age of study participants was mean age 11–35 inclusive. Both sexes were included. Participation in named sporting activity at a local or regional level.Exclusions: Those with long-term disease or health issues, such as physical/mental disability, that directly affect bone health through treatment, supplementation, or medication were excluded. Animal studies were excluded. Any participation in competition(s) at an elite or national level was also considered an exclusion, although typically elite sport is considered sport participation at a higher levels, such as at division I and professional levels  screened the abstracts and titles of relevant reports and articles in duplicate to determine whether these met the given criteria for inclusion in the systematic review. Any discrepancies were resolved through discussion or with a third reviewer (ED). Then, the reviewers independently screened the articles identified from the title and abstract screening to determine whether they met the inclusion criteria for the review, and a third reviewer's (ED) agreement was sought where appropriate. Where feasible, study authors were contacted by email for completeness and clarity. For those articles and reports meeting the inclusion criteria, their reference lists and bibliographies were screened for any additional relevant studies to be included in the systematic review.The review is reported using the guidelines Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement  guidelines were used to check the reporting of observational studies  as well as limited details of recruitment  had low bias with clear study designs. Additionally, confounding factors, such as diet and PA, were acknowledged, and a detailed dietary assessment was available, and face to face interviews for PA were also carried out  , Sahara Hologic (used in two studies), Heel ultrasound densitometer Paris (Norland), Contact Ultrasound Bone Analyser, and Lunar Achilles Insight  see . There wThe sports measured in this review included soccer, swimming, cycling, dancing, badminton, basketball, gymnastics, fencing, wrestling, and judokas. Lack of comparability of intensity of sports training and duration of involvement in regular sport made it hard to draw comparisons between studies. For example, in Vlachopoulos et al.'s study, athletic sports male participants at baseline had been engaged (≥3 h/week) in osteogenic (soccer) and/or non-osteogenic (swimming and cycling) sports for the previous 3 years or more  measurement for potential past sporting history and other physical activities (which may have impacted the bone measurements) was often lacking and was too heterogeneous to compare across the studies.Vlachopoulos et al.'s study of athletic sports compared osteogenic soccer against non-osteogenic sports (swimming and cycling) with a small control group of 14 active boys who did not participate in any sports  for more than 3 h per week or in the 3 years prior to the start of the study  and bone health, this may be reflective of the very small sample size and lower study power  of weight-bearing activity and bone health. While Mentzel et al.'s study did not observe strong correlations between increased weight-bearing activity in basketball  by exposing the skeleton to mechanical strain, provided that it is performed at a high enough frequency and high impact intensity (as evident in the studies that included swimmers or cyclists who had similar cQUS results to their comparative controls)  compared to non-weight bearing sports such as swimming and cycling. Sporting behaviors commencing in the early years is an opportunity to improve PBM potential and set in place other healthy long-term lifestyle behaviors. More studies, especially in young adults in their 20s and 30s, are now urgently required to examine this issue in greater detail with more clearly defined control groups.HP performed the searches. HP, LS, and ED reviewed the search results and extracted the data. HD provided advice and guidance regarding the systematic review methods. HP, ED, HD, PT-S, and LS edited the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.ED has received consulting fees from Pfizer and UCB. The remaining 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.


Atypical lymphocytic lobular panniculitis (ALLP) is a rare T-cell dyscrasia of the subcutaneous fat. It typically presents with indurated erythematous nodules on the lower extremities and often will have a relapsing and remitting course. The cause is unknown, but clinically and histopathologically it shares similarities to lupus panniculitis (LP) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). It generally has an indolent course, and may best be treated like indolent versions of SPTCL with systemic steroids and immunosuppressive medications. Atypical lymphocytic lobular panniculitis (ALLP) is a rare T-cell dyscrasia of subcutaneous fat initially described as indeterminate lymphocytic lobular panniculitis by Magro et al. in 2001 and later redesignated as ALLP [A 46-year-old female presented to the ambulatory dermatology clinic with a nine-year history of recurrent tender red nodules on bilateral legs and occasionally her thighs. The lesions would sometimes regress spontaneously, but would frequently recur at a nearby site. She did not note any triggers or remitting factors, and the lesions would not ulcerate. She was otherwise in good health and not on any medications. Her past medical history was only significant for a history of non-melanoma skin cancers excised in the past. She did not have any fevers, chills, night sweats, or constitutional symptoms, and she did not note any unintended weight loss. She also denied symptoms of chronic cough, headaches, weakness, or seizures. Physical examination revealed tender indurated red nodules on bilateral anterior and posterior aspects of her legs without overlying scale or ulceration Figure .The patient had several punch biopsies taken over the course of three years. Previous punch biopsies demonstrated a mildly to moderately dense infiltrate of small to medium sized lymphocytes predominantly around fat lobules with little to no atypia and variable rimming of lymphocytes around fat lobules. Another punch biopsy was obtained and findings were similar to previous biopsies. Histopathology showed an atypical lymphoid infiltrate in a predominately lobular pattern Figures -3. ImmunThis constellation of clinical, histologic, and laboratory findings were consistent with a diagnosis of atypical lymphocytic lobular panniculitis. The patient received short courses of prednisone and intralesional triamcinolone acetonide injections with temporary relief. Empiric trials of supersaturated potassium iodide and colchicine were not effective and not tolerated by the patient due to gastrointestinal side effects. The patient was started on hydroxychloroquine 200 mg once daily (3 mg/kg/d) for three months and underwent radiographic imaging. The patient had a normal computed tomography (CT) scan of her chest, abdomen, and pelvis. A full body positron emission tomography (PET)/CT scan and brain magnetic resonance imaging (MRI) detected an incidental benign mass in the left vertex of her brain that was excised and confirmed to be a benign meningioma. After resection of her meningioma, she discontinued her hydroxychloroquine and continued to experience episodes of ALLP with only intermittent intralesional triamcinolone acetonide injections to treat her ALLP recurrences.ALLP is a recently described entity that is thought to lie on a spectrum of cutaneous T-cell lymphoid dyscrasias--with lupus panniculitis (LP) on one end and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) on the other -3. In 20The clinical differential diagnosis of ALLP includes erythema nodosum, erythema induratum, nodular vasculitis, LP, pancreatic panniculitis, and SPTCL. Biopsy can often distinguish between these entities. Erythema nodosum presents primarily as a septal panniculitis; whereas, the others are primarily lobular panniculitides. Erythema induratum (or nodular vasculitis when not associated with tuberculosis) is usually associated with tuberculosis and will often show lobular or mixed septal and lobular panniculitis with prominent vasculitis on histopathology. Pancreatic panniculitis is usually identified by subcutaneous fat necrosis.Distinguishing between LP, ALLP, and SPTCL can be more difficult. All three entities favor the proximal extremities, buttocks, and trunk. LP and ALLP tend to have waxing and waning courses; whereas, SPTCL tends to be persistent and progressive. LP occurs in 1%-3% of patients with cutaneous lupus erythematosus . SPTCL pThese three entities are difficult to distinguish histologically as well. ALLP and SPTCL both exhibit an infiltrate of atypical lymphocytes in the dermis in an epidermotropic and eccrinotropic pattern, as well as plump rounded histiocytes in the interstitial reticular dermis. SPTCL exhibits a greater degree of lymphoid atypia, more extensive fat necrosis, and rimming of adipocytes by neoplastic T cells. Prominent erythrocyte phagocytosis by histiocytes and angiodestructive changes with luminal thrombosis are seen in SPTCL but not in ALLP . PhenotyClonal restriction is observed in both ALLP and SPTCL but not LP. Distinguishing characteristics of LP include prominent lymphoid germinal centers, hyalinosis of the fat lobule, prominent dermal and subcuticular mucin deposition, an interface dermatitis, and a positive lupus band on direct immunofluorescence .As a cutaneous lymphoma, SPTCL is included in the 2018 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of primary cutaneous lymphomas. ALLP, however, is not technically a lymphoma and not listed in the 2018 WHO-EORTC cutaneous lymphoma categorization system .The cause of ALLP is currently unknown, and a review of the literature failed to identify reports of ALLP associated with benign or malignant tumors. Purported triggers of ALLP in one case series include sinusitis, recurrent Streptococcal pharyngitis, and upper respiratory infections in four patients, but no identifiable trigger in the remaining eight patients. One patient had a remote history of non-Hodgkin’s lymphoma, but the other patients reported did not have a history of malignancy . Our patBoth LP and ALLP may respond to prednisone and hydroxychloroquine. There are reports of ALLP responding to systemic retinoids, alemtuzumab , and non-steroidal inflammatory drugs as well . HoweverIn conclusion, ALLP represents a rare T-cell dyscrasia of the subcutaneous fat with a chronic and relapsing course. The cause of ALLP is currently not known, but It shares clinical and histopathologic characteristics with LP and SPTCL and differentiation can often be difficult. ALLP’s indolent course may display similarities to the less aggressive variant of SPTCL, and similarly, therapy with systemic steroids and immunomodulatory or immunosuppressive medications such as hydroxychloroquine, methotrexate, and cyclosporine may be appropriate.


Acute kidney injury (AKI) is a heterogeneous syndrome characterized by a dramatic increase in serum creatinine. Mild AKI may merely be confined to kidney damage and resolve within days; however, severe AKI commonly involves extrarenal organ dysfunction and is associated with high mortality. There is no specific pharmaceutical treatment currently available that can reverse the course of this disease. Notably, mesenchymal stem cells (MSCs) show great promise for the management of AKI by targeting multiple pathophysiological pathways to facilitate tubular epithelial cell repair. It has been well established that the unique characteristics of MSCs make them ideal vectors for gene therapy. Thus, genetic modification has been attempted to achieve improved therapeutic outcomes in the management of AKI by overexpressing trophic cytokines or facilitating MSC delivery to renal tissues. The present article provides a comprehensive review of genetic modification strategies targeted at optimizing the therapeutic potential of MSCs in AKI. Acute kidney injury (AKI) is a multifactorial syndrome characterized by a sharp decline in renal function and is associated with high morbidity and mortality. AKI can be triggered by a variety of predisposing factors, including sepsis, nephrotoxic drugs, and cardiac surgery. AKI affects an estimated 2% of hospital inpatients and more than 40% of critically ill patients . NotablyThe pathophysiological mechanisms underlying AKI are complex and enigmatic . Damage Mesenchymal stem cell (MSC) therapy is considered to have great therapeutic promise for managing AKI and has shown beneficial therapeutic effects in a variety of animal models of AKI. Kale et al. showed that MSCs infused after renal ischemia migrated specifically to injured regions and resulted in improvements in renal function . MoreoveMSCs were first isolated from bone marrow by Friedenstein in the 1960s . SubsequIncreasing evidence has shown that the main mechanism of the action of MSCs in AKI is the paracrine secretion of bioactive molecules by MSCs rather than MSC transdifferentiation into renal-specific cells . InteresIn view of the promising results in different types of preclinical AKI models, several clinical trials have been performed to evaluate the safety and efficacy of MSC-based interventions for AKI patients. First, a phase 1 clinical trial was conducted to assess the safety and feasibility of allogeneic MSC administration to patients at high risk of AKI after open-heart surgery . PrelimiMoreover, Swaminathan et al. conducted a multicenter, randomized, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of allogeneic human MSC therapy for patients with AKI after cardiac surgery . A totalAKI is a multifactorial disease with high heterogeneity, which may mask the therapeutic effects of MSCs in certain subgroups of AKI patients. Therefore, additional large clinical trials in different types of AKI patients are urgently needed to shed light on the role of MSC therapy in the context of AKI. Several ongoing trials have been conducted to resolve these issues, and all registered trials on ClinicalTrials.gov regarding MSC therapy for patients with AKI are listed in The latest findings add to a growing body of evidence that the paracrine, homing, immunomodulatory, anti-inflammatory, and tissue repair properties of MSCs can be strengthened through genetic modification . It has Viral transduction is one of the most commonly used methods to deliver candidate genes to MSCs . Viral vNonviral gene transfer techniques commonly consist of physical and chemical methods . PhysicaTo achieve improved therapeutic outcomes in the management of AKI, genetic modification has been attempted to overexpress trophic cytokines or facilitate MSC delivery to renal tissues. A variety of target genes have been engineered for transfection into MSCs and applied in preclinical AKI models. These tested genes are summarized in CXC-chemokine receptor type 4 (CXCR4) is the receptor for stromal cell-derived factor-1 (SDF-1), and the SDF-1/CXCR4 axis has been shown to govern the migration of MSCs towards injured tissue in a variety of species and tissue types . SDF-1 wErythropoietin, a hemopoietic growth factor secreted mainly by the kidney, is a pleiotropic cytokine with tissue-protective and reparative properties. Mounting evidence shows that erythropoietin is a vital modulator that is involved in a variety of biological processes, including cellular mitogenesis, maturation, survival, DNA repair, and angiogenesis . In addiβ expression, thereby attenuating salt-induced renal fibrosis, as identified by reduced collagen deposition and renal fibrosis scores [Tissue kallikrein, a critical member of the kinin-releasing enzyme family, is a serine protease expressed in many cell types. Basic research has demonstrated that the kallikrein-kinin system (KKS) is implicated in the physiopathological mechanisms of cardiovascular disease and the inflammatory response . Notablys scores . Based os scores .Vascular endothelial growth factor (VEGF) is a proangiogenic cytokine that initiates the proliferation and migration of endothelial cells, thereby contributing to the generation and stabilization of new blood vessels . An inteHepatocyte growth factor (HGF) is generated by cells of mesodermal origins and primarily acts on epithelial and endothelial cells to produce a wide range of biological effects, including the promotion of cellular growth, the stimulation of cellular motility, and the induction of tissue regeneration . The cirNuclear factor E2-related factor 2 (Nrf2) is an important transcription factor that activates a range of antioxidant responsive element- (ARE-) driven genes, thereby contributing to the modulation of the cellular antioxidant defense system . In receKlotho is a membrane-bound protein that was originally identified as a suppressor of aging-related genes. Klotho is emerging as both a pharmaceutical agent and a highly promising biomarker for AKI . Prior aHeme oxygenase-1 (HO-1) is a rate-limiting enzyme that participates in heme breakdown, leading to the production of iron, biliverdin, and carbon monoxide. These degradation byproducts regulate a wide array of vital biological functions that involve anti-inflammation, antioxidation, and cellular protection . AccumulIn addition to genetic manipulation, another strategy which is aimed at enhancing the therapeutic potential of MSCs is to precondition MSCs in vitro. In particular, culturing MSCs under hypoxic conditions in vitro can enhance the secretion of trophic factors and their migratory capacity . Yu et aIt would take quite a long time to harvest enough gene-modified MSCs due to the relatively complex genetic transfection procedure. Notably, the study performed by Lee et al. showed that the levels of stress- and apoptosis-related genes in MSCs were markedly increased over time . Thus, tGenetic modification of MSCs represents a promising and effective approach to enhance the therapeutic potential of these cells for AKI treatment. However, among the multiple target genes listed in this review, it remains unknown which gene, after modification in MSCs, will achieve an ideal outcome for the management of AKI. With a more comprehensive understanding of the potential drawbacks and obstacles of genetically modified MSC therapy for AKI, additional efforts will be needed to address these issues prior to the use of MSC-based gene therapy to produce results that can be translated into clinical practice.


The endothelial glycocalyx comprises a complex layer of membrane-bound proteoglycans, secreted glycosaminoglycans, glycoproteins, glycolipids and bound plasma proteins such as albumin and antithrombin associated with the endothelial surface. The glycocalyx plays an important role in vascular homeostasis, regulating vascular permeability and cell adhesion, and acts as a mechanosensor for hemodynamic shear stresses; it also has antithrombotic and anti-inflammatory functions. Plasma proteins such as albumin are physiologically bound within the glycocalyx, thus contributing to stability of the layer. Albumin is the major determinant of plasma colloid osmotic pressure. In addition, albumin transports sphingosine-1-phosphate which has protective endothelial effects, acts as a free radical scavenger, and has immunomodulatory and anti-inflammatory effects. This review examines the physiological function of the endothelial glycocalyx and the role of human albumin in preserving glycocalyx integrity and the microcirculation. The endothelial glycocalyx is a complex carbohydrate-rich gel-like layer lining the luminal surface of blood vessels ; it funcThe term endothelial surface layer is sometimes used to describe the intimal surface of blood vessels comprising the endothelial glycocalyx and associated components derived from endothelial cells and plasma , 10. TheThe outermost layer of the microvasculature serves as a regulatory barrier of vascular permeability. It participates in mechanotransduction by sensing fluid shear forces and regulating the vascular tone. The endothelial glycocalyx, which has an important role in maintaining vascular homeostasis , also hais) and colloid osmotic pressure difference between plasma and the subglycocalyx (πp − πsg). This oncotic pressure difference explains the failure of the interstitial protein concentration to influence fluid movement [Starling’s original model of transvascular fluid exchange, which depends on a balance between hydrostatic and oncotic pressure gradients in semi-permeable capillaries, fails to explain the clinical responses observed after fluid resuscitation. A revised Starling model, first proposed by Levick and Michel  which inmovement , 17, 18.Under physiological conditions, the glycocalyx acts as a barrier against the shift of albumin and other circulating plasma components (mainly other proteins) across the endothelium , 21.Mechanical forces on endothelial cells generated by blood flow evoke biochemical responses that modulate endothelial structure and function through a process known as mechanotransduction. The glycocalyx acts as a cytoskeleton for endothelial cells. Mechanical distortion of ‘bush-like’ clusters of proteoglycans projecting from anchor points in the endothelial cell cytoskeleton generates forces which can deform the cytoskeleton. An associated increase in the expression of endothelial nitric oxide (NO) synthase catalyzes the production of NO, dilating vessels and reducing stress , 22, 23.The glycocalyx has a vasculo-protective role by repelling red blood cells and by physically inhibiting the interaction of endothelial cell adhesion molecules  with circulating platelets and leukocytes , 10.Several important anticoagulant mediators bind to GAGs located in the glycocalyx. These include antithrombin which binds via heparan sulfate to inhibit thrombin and activated factors IX and X; heparin cofactor II which is activated by dermatan sulfate; and tissue factor pathway inhibitor which binds via heparan sulfate to inhibit factors VIIa and Xa. Thrombomodulin, an endogenous anticoagulant produced by endothelial cells, interacts with thrombin to activate the protein C anticoagulant pathway .Glycocalyx binding of enzymes such as extracellular superoxide dismutase protects endothelial cells against oxidative stress from reactive oxygen species (ROS) while maintaining NO availability, thus preventing endothelial dysfunction , 24.Although albumin has a net negative charge, its amphoteric nature promotes tight binding to the glycocalyx with the net effect of reducing hydraulic conductivity across the vascular barrier, resisting glycocalyx degradation  and thereby contributing to maintenance of vascular integrity and normal capillary permeability, and facilitating transmission of shear stress , 23, 25.Under physiological conditions, the concentration of intravascular albumin is the major determinant of plasma colloid osmotic pressure .2−) and hydroxyl (•OH) radicals and reactive nitrogen species, e.g., peroxynitrite radicals. Albumin has an additional anti-oxidant effect through binding to free copper ions (Cu2+) which are known to accelerate the production of free radicals [Exposed thiol groups on the albumin molecule act as a scavenger for ROS such as superoxide  to the endothelial cell surface where it functions in maintaining normal vascular permeability . S1P proPost-translational modifications of human serum albumin include glycation, cysteinylation, S-nitrosylation, S-guanylation and S-transnitrosation which can affect the binding of some exogenous drugs . In addiGlycocalyx and endothelial cell damage, or endotheliopathy as it is known , occur iIschemia–reperfusion injury results in tissue damage following disruption of the glycocalyx . MicrovaGlycocalyx shedding is a feature of inflammation, trauma and sepsis, and is mediated by pro-inflammatory agents including tumor necrosis factor-α, C-reactive protein, adenosine, bradykinin, histamine, platelet-activating factor, and bacterial lipopolysaccharide. Glycocalyx shedding leads to increased vascular permeability, tissue edema and relative hypovolemia –43.Many features of endothelial dysfunction in sepsis are shared with aging and with numerous chronic diseases such as hypertension, dyslipidemia, diabetes mellitus (DM), cardiovascular disease (CVD), cerebrovascular disease, chronic kidney disease (CKD), chronic pulmonary disease, liver disease, and cancer. Common features include glycocalyx degradation and shedding; increased oxidative stress and systemic inflammation; intercellular junction disassembly, endothelial cell death and blood–tissue barrier disruption; enhanced leukocyte adhesion and extravasation; and induction of procoagulant and antifibrinolytic pathways .Endothelial glycocalyx shedding has been shown in rodent models of hemorrhagic shock, although the underlying mechanism is unknown –46. ReceEvidence from rodent models  and clinHigh-density lipoprotein cholesterol (HDL-C) may have a role as a causal contributor to sepsis survival , 53. Lowp < 0.05), despite infusion of a higher volume of crystalloids (median 1800 vs 1500 mL) [A direct comparison of the hemodynamic effects of resuscitation fluids showed that colloids significantly increased plasma volume, cardiac index, and central venous pressure compared with crystalloids (1500 mL) . This is1500 mL) . Fluid r1500 mL)  and, in 1500 mL) . A recen1500 mL) .As the type of fluid infused has an important effect on the glycocalyx, differences between albumin and crystalloids on glycocalyx function have been described.In in vivo experiments of anesthetized rats subjected to hemorrhagic shock followed by fluid resuscitation, administration of normal saline failed to restore endothelial glycocalyx thickness and plasma levels of syndecan-1 , leading to a marked increase in vascular permeability and leukocyte rolling/adhesion. In contrast, albumin stabilized permeability and leukocyte rolling/adhesion, effects which were comparable to fresh frozen plasma. Albumin partially restored endothelial glycocalyx thickness, and lowered plasma syndecan-1 to baseline levels .A recent review of commonly used resuscitation fluids for use in the critically ill highlighted the need to consider not only the oncotic properties of a fluid, but also its relative ability to protect and restore the endothelial glycocalyx. In this regard, evidence from observational and pre-clinical in vitro and in vivo studies indicates that albumin and fresh frozen plasma are superior to crystalloids and artificial colloids , althougBiomarkers of endothelial damage have been developed with most applied prognostically for conditions of systemic inflammation and sepsis , 62–71  reported that, compared with saline, albumin improved skin endothelial cell function, improving microcirculatory blood flow. These beneficial effects may be independent of the oncotic properties of albumin as neither cardiac output nor skin blood flow differed between albumin- and saline-treated patients [A recent study of patients with septic shock  imaging is a non-invasive method increasingly used to analyze the sublingual microcirculation. The technique visualizes erythrocytes within the microvasculature due to light emitted by a light emitting diode probe which is reflected by hemoglobin and detected by a SDF camera . Total vAccording to our clinical and scientific judgement, biomarkers of endothelial damage and/or evaluation of the sublingual microcirculation may have a role in identifying subgroups of patients at risk of morbidity and mortality.We consider that albumin should be used in accepted indications in which it has a proven positive risk:benefit balance, mainly in septic patients , for burn shock resuscitation and fluid maintenance, and in some cases of liver insufficiency. The benefits of albumin may relate to its ability to restore function to damaged glycocalyx, although further studies are required to confirm this relationship and identify thresholds for optimal benefit. The mechanism of action of these restorative effects also needs to be elucidated.As the lung and kidney are the organs most affected by septic shock, pre-clinical investigation of the effects of albumin on permeability disorders of these organs should be conducted. The development of non-invasive imaging-based analysis tools to assess changes in permeability, diameter, and blood flow of vessels in response to specific stimuli is beginning to benefit research in both pre-clinical and clinical areas. It is likely that patients’ response to albumin may differ depending on localization of the blood vessel under investigation.Detailed studies of the effect of albumin on oxidative stress are required and could be assessed using in vitro models , as these are more reproducible than pre-clinical animal studies.The main objective of clinical studies of albumin should not be to evaluate its effect on overall mortality, but rather on more specific endpoints such as organ dysfunction. Investigating the economic impact of albumin and its long-term consequences is also advised. Studies should accrue biological information, i.e., justification for the selected objectives. Smaller studies with homogeneous populations are preferred to large multicenter studies of patients with clinical heterogeneity.In summary, additional research needs to be conducted to clarify the role of albumin as a protector or restorer of damaged glycocalyx, with the aim of identifying clinical applications.Additional file 1: Table S1. Comparison of Starling’s original principle and the revised Starling equation and glycocalyx model. Adapted from [ted from .