It is the seventh CoV known to infect humans and causes damage to organs throughout the body, including lungs, throat, heart, liver, brain, kidneys and the intestines. Its variety of clinical presentations challenge all clinicians involved in cardiovascular management. The pandemic and its effects have produced, has killed, spared, and provoked a range of symptomatology afflicting adults and children. Advanced international centers are formulating relevant protocols for diagnosis, triage, isolation, and management of COVID-19 patients with cardiovascular complications: many of these are common sense precautions, but other management features have unconfirmed clinical value,2.For aspiring and struggling cardiac programs the immense shortage of even rudimentary equipment for testing, management, and intensive management severely limit their ability to follow such a routine. These cardiovascular teams fear an imminent deathblow to their programs as diversion of precious resources and funds from their programs takes place. For many, livelihoods have been upended and elective procedures suspended indefinitely; some are experiencing a reduction in pay to keep support staff and practices afloat while others have no revenue at allDifferential diagnosis:.This can be difficult because other organisms, such as the RNA virus (flavividirae) that causes yellow fever, also cause similar symptoms, signs and hemorrhagic changes. It is 40-50nm in width and is transmissible through filtered human serum. Covid-19 may behave similarly. Patients differ in their expression of antibodies and recent studies suggest a decrement in titers after one month. Responses to vaccine may also differ. We do not yet have an AB test that can confirm sustained immunity. Healthcare workers with adequate gloves, gowns and face masks may still have 3.4 times the risk of contracting the coronavirus compared to the general population, and support staff have an even greater risk of testing positive. Although nosocomial spread is relevant, person-toperson contact is more important type of transmissionChoices in therapeutic regimens are few and several clinical studies are underpowered to support widespread use; they are also expensive. Pricing for remdesivir has not yet been set. A recent.Chinese study of 393 patients who received 10 days treatment with remdesivir with no significant benefits. Angiotensin-Converting enzyme 2, (ACE2) molecules on the lung cells are the predominant focus of the Covid virus; such patients may suffer an associated cytokine storm syndrome and that lead to heart failure. Recovery may then depend on the role of cytotoxic T cells. Treatment with glucocorticoids and tocilizumab shows some promise in accelerating respiratory recovery, reducing in-hospital mortality and the likelihood of mechanical ventilation, but they may have deleterious side-effects of their own. Mother-fetus Covid transmission has been shown to occur without symptoms but this may have future clinical relevance to the performance and outcome of neonatal congenital surgery. More patients with COVID-19 infection on ventilators developed barotrauma than patients who required intubation for other reasons.This is a new pandemic: physicians who follow government guidelines in providing care in good faith during the public health emergency and in a reasonable time period, may not be adequately legally protected and the personal risk of ill-health among healthcare personnel is substantial. Adjustments to Consent forms may be required so that healthcare personnel’s risks are limitedPre-operative:,3.Evaluations must recognize the shared symptomatology among Covid disease presentations and those with cardiovascular disease: older age, diabetes, obesity, and hypertension may be worse. Low socio-economic status alone is a risk factor for total mortality independent of any other risk factors. A greater sensitivity to the issues faced by these patients is required. Lock-down, loss of job, spousal tensions and/or abuse, threat of dying on waiting list, threat of hospital closure, availability of essential medications, evolving mental health issues, fear of disease spread within the hospital, and operative outcome are especially tough burdens that are relevant to clinical management. In areas that are endemic for hemorrhagic diseases, uncertainty in diagnosis may occur. The Yellow fever virus’s ability at 40-50nm in width through with filtered human serum is worrying for our future use of blood products; Covid’s size ranges from 50-200nm. Use of blood products obtained by donation may therefore have uncertain deleterious consequencesBased on our current understanding the following measures are attainable and may prove helpful:A: Hospital precautions:Ensure essential personal protective equipment (PPE) items are well stocked before program growth develops.Have consistent policies for staff, patients and their relatives to follow.Share information on suspect patients with colleagues. When questioned, 12.1% of patients may not develop a fever at first evaluation, nor at admission, nor be symptomatic until several days post-operatively. They should be tested that day..In embracing telemedicine to patients and protect healthcare personnel, preoperative questionnaires can be dispensed to a cellphone, but paper manuscripts may also be required, as patients in poor regions may not have a computer or cellphone which may only be provided by their employerB: Pre-operative evaluation:Permit one significant relative in room who is also masked.The respiratory therapist (RT) and cardiologist should perform evaluations 7 days pre-operatively, and on admission, recommending that one significant relative assumes supportive role subsequently; both patient and relative self-isolate prior to next evaluation and/or procedure/surgery.including coagulation check, CoV-19 testing, temperature, CXR, respiratory and echo-cardiological assessments. Peri-operative echocardiography with pre- and post- comparisons may help demonstrate diffuse myocardial dyskinesia and pericarditis in Covid-suspected cases.The pre-admission assessment should include standard blood work Temperature check upon arrival; wear face-shield, only elevating the mask when listening so that personal, visual interaction is not lost and trust can develop. This is particularly important in children being prepared for surgery.Review and compare previous questionnaire.When possible, perform 6-minute walk test (children) and measured distance walking in older adults and monitor oxygen saturation .Dental assessment (modified) for valve presentations prior to hospital admission;Develop locally-relevant teaching protocols for peri-operative Covid-19 preventative measures including teaching of avoiding nosocomial causes.Neurological screening check; this needs to be thorough and similar in all patients;  . It may have value when used upon anesthetic induction nasally or painted intra-orally. It has better anti-viral activity than other antiseptics such as chlorhexidine.Povidone Iodine (PVP-I) an effective In view of the risk of viral transfer through standard filters surgical hemostasis, meticulous conservation of blood and avoidance of plasma use in a similar way to that applied for Jehovah’s Witness patients may produce more certain and favorable outcomes in patients in which Covid exposure is uncertain.Deciding which is emerging: Covid-caused pulmonary disease, or simply lung collapse following cardiac surgery. This may be difficult as more than 40% of patients may have no symptoms yet have levels of the virus similar to those who are clinically ill.Following reversal of heparinization, introduction of Aspirin or fractionated heparin (as is used for hip surgery) may reduce the incidence of future thrombo-embolism.Although expensive, Nitric Oxide may also help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication in epithelial cells.,6,8,9.Early discharge from the hospital may not be helpful if pulmonary and other symptoms persist: but if at risk patients are discharged early repeated tele-communications should be usedAs no intervention provides complete protection from infection, a combination of measures will be required, now and during the next pandemic wave. It is markedly so in healthcare deprived centers, where the usual struggle for having an open heart operation is currently worse while there is no robust evidence as to when this Covid-19 era will end.


Chronic kidney disease (CKD) is a global public health burden, needing comprehensive management for preventing and delaying the progression to advanced CKD. The role of nutritional therapy as a strategy to slow CKD progression and uremia has been recommended for more than a century. Although a consistent body of evidence suggest a benefit of protein restriction therapy, patients’ adherence and compliance have to be considered when prescribing nutritional therapy in advanced CKD patients. Therefore, these prescriptions need to be individualized since some patients may prefer to enjoy their food without restriction, despite knowing the potential importance of dietary therapy in reducing uremic manifestations, maintaining protein-energy status.  Proteins are highly complex, larges sized molecules, that are present in all living organisms being of great nutritional value and involved in the many chemical processes essential for life. Even the term “protein” suggests their importance, as this word is derived from the Greek prōteios, meaning “holding first place.” However, a high protein diet of animal origin, usually associated with Western dietary practices, is consistently associated with a small to moderate increased risk of premature mortality and deleterious effects for numerous chronic diseases, including CKD . A high consumption of proteins could be detrimental to kidney function through several mechanisms. First, it may induce vasodilation of afferent renal arterioles, glomerular hypertension, and hyperfiltration, which together accelerate the progression of pre-existing CKD. Second, increased consumption of red and processed meat is associated with an increased blood pressure (caused by the concomitant high intake of sodium chloride), metabolic acidosis, mitochondrial oxidative stress (triggered by saturated fats), DNA damage (caused by N-nitroso compounds), and increased accumulation of the end-products of protein catabolism  ,3. ThereIn contrast to meat-based diet, a diet rich in protein from plant sources may be beneficial, preventing heart disease and hypertension as well as delaying the progression of kidney disease. However, the optimal diet for CKD patients remains controversial, depending upon the estimated glomerular filtration rate (eGFR), type of kidney disease , and the presence of other comorbidities such as diabetes, hypertension, or heart failure. In this narrative review, we present a summary of the available published data on the impact of low-protein diets and dietary patterns on chronic kidney disease-related outcomes. A literature search was performed as appropriate for narrative reviews, including electronic databases of PubMed, Cochrane Library, and Google Scholar using a combination of the MESH terms: “CKD”, “nutrition”, and low protein diet”, “keto-analogues”, “Mediterranean diet, DASH diet”. All the articles published in the medical literature relevant to the queries were selected and evaluated for relevance to each of the domains selected for review.Low-protein diet (LPD) is a long-standing recommendation for CKD management, based on its potential protective effect on renal hemodynamic. Moreover, limiting protein intake from animal sources and shifting toward a vegetable protein sources is also associated with favourable effects, including reduction of uremic toxins and correction of metabolic acidosis, in addition to reduced phosphorus load with better control of metabolic bone disorder. These diets should be progressively installed to allow careful dietary monitoring and adequate adherence. Although such diets are not associated with wasting in carefully monitored research studies, on a routine basis, attention should be focused on energy intake, which may decrease over time and induce weight loss and wasting.2, randomized to a usual-protein diet or a LPD [Even if the results of studies that have examined protein restriction alone were variable, the balance of evidence suggests a benefit of CKD progression of moderate dietary protein restriction (0.6–0.8 g/kg/day) see . The laror a LPD . The resor a LPD . HoweverIn addition to these studies, two recent meta-analysis also showed conflicting effects of LPD on CKD progression in diabetic renal disease. The first one, including eleven randomized controlled trial failed to show any improvement of renal function by LPD in either type 1 or 2 diabetic nephropathy . More reA particular situation is represented by the CKD patients with nephrotic proteinuria, where the issue of protein restriction is controversial. A low protein diet coupled with reduced sodium intake may enhance the effects of angiotensin-modulation therapy in decreasing intraglomerular pressure and may also decrease proteinuria and slow the progression of kidney disease. However, concern exists that protein-restricted diets may increase the risk of protein malnutrition. Therefore, most nephrologists recommend no restrictions or only mild restriction in protein intake (0.8–1 g/kg daily), preferring more safer methods such as ACE inhibitors in order to decrease intraglomerular pressure in CKD ,8. Keto-analogues of amino acids (KAs) are nitrogen-free analogs of essential amino acids. Usually, in combination with either LPD (0.6–0.8 g/kg per day) or very-low-protein diets (VLPD) (0.3–0.4 g/kg per day), they allow a reduced intake of nitrogen while avoiding the deleterious consequences of inadequate dietary protein intake and malnourishment . 2. After 18 months of follow-up, significantly fewer patients from the KAs group reached the composite endpoint of >50 percent reduction in eGFR or initiation of renal replacement therapy as compared to the low protein diet group  [An important limitation of previous trials of protein restriction is that dietary trials have largely focused on restricting total protein rather than on the type of protein intake . Protein type may be more important for kidney disease progression than the total amount of protein intake, since the increasing intake of red and processed meat is associated with a significantly risk of GFR decline while a strong adherence to a diet characterized by high intake of fruits, vegetables, and low-fat dairy products is associated with a lower risk of CKD . The posctively) .Moreover, supplementation of a LPD/VLPD with KAs seems to have some advantages beyond kidney outcomes including preserved eGFR and declined proteinuria. Thus, in a recently published meta-analysis of seventeen RCTs with 1459 participants, KAs appears to provide more effectiveness in lowering blood pressure, nutritional outcomes including increased serum albumin and decreased serum cholesterol, and CKD-MBD parameters comprising diminished serum phosphate and reduced PTH level . These oThe most recent nutrition guidelines published in 2020 by the The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) recommend a LPD providing 0.55–0.60 g dietary protein/kg body weight/day, or a VLPD providing 0.28–0.43 g dietary protein/kg body weight/day with additional keto acid/amino acid analogs in CKD 3–5 who are metabolically stable to reduce risk for end-stage kidney disease (ESKD)/death (1 A) [Therefore it is of great importance to educate patients about the importance of dietary therapy with LPD/VLPD for the treatment of CKD and to supervise its inclusion in their eating habits. In clinical practice, the compliance with nutritional therapy is indirectly evaluated by dietary self-reporting questionnaires and interviews. Some other biologic like blood urea nitrogen, serum phosphate levels, or and daily urinary excretion of nitrogen are also indirect indicators of protein intake. Adherence to the prescriptions is linked to clinical conditions, sociodemographic factors, the educational level as well as psychological factors. Strategies to improve adherence for low protein diets include identifying and selecting the appropriate CKD candidates and intensive dietary counselling. An alternate graduate approach might be represented by the progressively reduction of the prescribed protein intake while maintaining an adequate energy status since undernutrition exacerbates the risk for malnutrition and wasting .Classically, the dietary measures in patients with advanced CKD mainly include a reduced sodium, phosphorus, and protein intake aiming to delay or postpone the onset of uremic toxicity that potentially may have cardio-vascular and renal toxic effects. The recommendation of a low-protein diet remains valid even for advanced stages of CKD aiming to enhance the conservative management of non-dialysis CKD patients especially those with contraindications to dialysis or those who chose to avoid or defer the renal replacement therapy . HoweverFor dialysis patients, evidence from observational studies indicates that LPD is associated with higher hospitalization rates and higher risk for mortality ,31. ThusPlant-based diets have been used with rising popularity in CKD. Plant base diet practically include all eating configurations with a great proportion of plant foods  and may or may not include minor/modest quantities of meat, fish, seafood, eggs, or diary. A vegan diet, the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet or healthy eating diet are all in line with the concept of plant based diet.DASH diet is a holistic eating pattern including legumes, whole grains vegetables, fruits, low-fat dairy products; moderate amounts of poultry, fish, and nuts; and low amounts of sodium, red/processed meats, and alcoholic and sweetened beverages. The traditional Mediterranean dietary pattern include a high ingesting of fruits, vegetables, bread and whole-grain cereals, potatoes, beans, nuts and seeds and extra virgin olive oil; low-to-moderate amounts of dairy products, fish and poultry and wine, during meals; sweets only occasionally and red meat less often, at special occasion. Healthy dietary patterns were commonly higher in fruit and vegetables, fish, legumes, cereals, whole grains, and fiber, and lower in red meat, salt, and refined sugars. These dietary patterns are linked with reduced cardiovascular events and death in healthy adults and those at high risk of cardiovascular disease. The impact of these patterns in CKD patients is still uncertain.Healthy dietary patterns were connected with the primary prevention of numerous major health conditions, including type 2 diabetes , hyperteA recent systematic review and meta-analysis reported an association between a healthy dietary pattern and incident CKD . EighteeThe relationship between DASH diet and the risk of incident CKD was evaluated in several studies, with varying findings. These studies are presented in p = 0.05), and no significant association in cross-sectional studies. Moreover, an important association was established between DASH dietary patterns and risk of CKD in the studies extracted DASH centered on nutrients , compared to the studies extracted DASH based on food groups .A recent systematic review and meta-analysis found a significant inverse association between DASH dietary patterns and the risk of developing CKD . Stratifn = 8467), was performed. Adherence to Mediterranean pattern by a one-point increment of MDS was associated with 10% lower risk of CKD.Superior adherence to the Mediterranean pattern could be also helpful on the prevention of CKD, but the studies in this regard are limited and more analyses to confirm these findings are necessary  see Tab. In a siIn a prospective study, adherence to modified Alternate Healthy Eating Index (close to DASH diet) was associated with 20% reduction in the incidence or progression of CKD between patients with diabetes after five years of follow-up . Other pDASH diet could also be protective for CKD progression. In a cross-sectional analysis of 2408 community-dwelling elderly participants from the Korean National Health and Nutrition Examination Survey, a high DASH score was related with low odds for CKD . The samA recent cross-sectional German study used a food frequency questionnaire (FFQ) in CKD patients and found that the Mediterranean pattern was associated with better GFR levels even after accounting for all possible confounders . In contIn a recent prospective cohort study including 2403 individuals with CKD from the Chronic Renal Insufficiency Cohort (CRIC) cohort, several diet scores were calculated from food frequency questionnaires; higher diet quality was consistently associated with lower risk of progression. The association between aMed and CKD progression was the strongest. The strong association in aMed may be due to the individual components included in the score.A systematic review that 1639 people with CKD did not find healthy dietary interventions  to influence ESRD, but were related with lower blood pressures and low-density lipoprotein cholesterol. Nevertheless, the quality of evidence was very low for ESRD  . n = 900), plant-based diets were linked with a 12% lower risk of decline in eGFR compared with meat-based diets [In the prospective observational Northern Manhattan Study , and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated from food frequency questionnaires. Higher diet quality based on each of the four dietary patterns evaluated was constantly related with lower risk of death.Similar results were provided by a recent meta-analysis of seven cohort studies, including 15,285 participants; it showed that a healthy dietary patterns were consistently associated with lower mortality . A previous (2017) review that incorporated 17 randomized clinical trials of 1639 people with CKD did not find a promising effect of the food-based dietary interventions  Diminished acid load—the incapacity of the kidney to excrete the daily dietary load acid predispose to the development of overt metabolic acidosis. It has already been shown that metabolic acidosis is associated with impaired insulin secretion, increased risk of hypertension, heart failure, muscle wasting, chronic inflammation, and progression of CKD and increased mortality . Metabol(2) Reduction in serum phosphate and a decreased urinary 24 h phosphorus excretion—The absorption of the phosphorus from plant sources is decreased (less than 30–40%) compared with phosphorus from animal sources (80%), due to the presence of phytate in plants, which causes phosphorus less bio accessible for gastrointestinal absorption. Additionally, animal-based food contains food additives, who can increase the amount of bioavailable phosphate by 7–100% . Small s(3) Reduction of metabolites resulting from gut bacteria that are linked with CKD and CV disease—It has already been presented that in CKD patients the gut microbiota is characterized by a disproportion between commensal bacteria, which are reduced and uremic toxins producing bacteria and pathobionts, which are augmented. The key modifiers of gut microbiota are the dietary habits . Animal (4) Anti-inflammatory and antioxidant effects: the dysbiotic gut microbiome augments pathobionts and increases intestinal barriers, promoting systemic inflammation and oxidative stress in CKD patients through the translocation of bacteria and bacterial products into the systemic circulation . ConsumpThere are numerous major concerns about these types of healthy diets in CKD patients. The most significant is clearly hyperkalemia. Recent data delivered by observational study do not establish an undoubted link between dietary potassium and circulating potassium levels in people with CKD, comprising those on hemodialysis . An imprHealthy dietary patterns higher in fruit and vegetables intake and lower in protein intake of animal origin may have potential benefits in slowing CKD progression, in postponing the onset of uremic toxicity in advanced stages of CKD and even in decreasing mortality. Protein-restricted diets have other important metabolic benefits including decreasing sodium intake and improving blood pressure control in patients with advanced CKD . HoweverThese potential benefits of these diets are sometimes counterbalanced by a poor patients’ adherence to these prescription. Thus, a personalized approach is mandatory in identifying and selecting the appropriate CKD candidates for nutritional therapy since some patients may prefer to enjoy their food without restriction, despite knowing the potential importance of dietary therapy in reducing uremic manifestations. Patients’ preference and compliance have to be considered when prescribing a low protein diet in advanced CKD patients in order to increase adherence. Therefore, in-depth education, nutritional education programs, and regular close monitoring by a renal dietician is mandatory for implementation of a low, or very low, protein diet in order to increase the adherence, and thus protect the kidneys.


Although adipose tissue metabolism in obesity has been widely studied, there is limited research on the anorexic state, where the endocrine system is disrupted by reduced adipose tissue mass and there are depot-specific changes in adipocyte type and function. Stress exposure at different stages of life can alter the balance between energy intake and expenditure and thereby contribute to the pathogenesis of anorexia nervosa. This review integrates information from human clinical trials to describe endocrine, genetic and epigenetic aspects of adipose tissue physiology in the anorexic condition. Changes in the hypothalamus-pituitary-thyroid, -adrenal, and -gonadal axes and their relationships to appetite regulation and adipocyte function are discussed. Because of the role of stress in triggering or magnifying anorexia, and the dynamic but also persistent nature of environmentally-induced epigenetic modifications, epigenetics is likely the link between stress and long-term changes in the endocrine system that disrupt homoeostatic food intake and adipose tissue metabolism. Herein, we focus on the adipocyte and changes in its function, including alterations reinforced by endocrine disturbance and dysfunctional adipokine regulation. This information is critical because of the poor understanding of anorexic pathophysiology, due to the lack of suitable research models, and the complexity of genetic and environmental interactions. There are two major types of adipose tissue – brown adipose tissue (BAT), responsible for non-shivering thermogenesis, and white adipose tissue (WAT), which is the primary site for energy storage . AdiposeObesity is associated with abnormal adipose tissue metabolism and function. Likewise, a lack of adipose tissue is associated with metabolic dysregulation. For instance, in lipodystrophy syndrome – a genetic or acquired disorder characterized by a lack of adipose tissue, patients have disproportionate hyperphagia, reproductive dysfunction, dyslipidemia, and insulin resistance, etc . In anorThis review focuses on the relationship between chronic stress and adipose tissue physiology in the anorexic state. We discuss genetic and epigenetic aspects of metabolic changes in adipose tissue and associated mechanisms, summarizing knowledge from human clinical trials and some animal models, with a focus on stress-induced epigenetic modifications that affect the endocrine system and adipose tissue physiology. Such information provides new insights for the direction of research in adipose tissue metabolism in the anorexic state.According to the Diagnostic and Statistical Manual of Mental Disorders, anorexia nervosa is defined as a restricted energy intake relative to the requirement due to the intense fear of weight gain even at a significantly low weight, where the body mass index (BMI) is below 18 in adults and the corresponding BMI percentile in children and adolescents . In the There are also BAT differences in AN patients. One study reported that adult female AN patients displayed no detectable BAT activity under 22–24 °C before or after weight regain but a lower resting metabolic rate compared to the healthy counterparts . Under cWhile substantial loss of adipose tissue in the trunk and extremity regions was reported in AN patients across different age groups, only a few studies distinguished between the loss of subcutaneous (sWAT) versus visceral adipose tissue (vWAT) in the trunk region. In adult female, AN subjects, the loss of vWAT contributed to less than 20%, while sWAT contributed to over 80% of the total loss of abdominal adipose tissue ,28. ConsAlthough research on abdominal and thigh fat in AN is limited, there is considerable focus on the marrow adipose tissue (MAT). In contrast to the reduced abdominal sWAT and vWAT as well as thigh fat and iMAT, there was increased MAT in the lumbar ,32,33, fServing as a key endocrine organ, WAT secretes over 700 confirmed and putative proteins , includiAdipose tissue function is directly impacted by changes in appetite regulation. In AN patients, food intake is substantially reduced, which triggers the release of ghrelin – an orexigenic peptide secreted from the hypothalamic arcuate nucleus (ARC) and stomach. Ghrelin acts on the growth hormone secretagogue receptor 1a in the hypothalamus and triggers the production of orexigenic peptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in the ARC to promote food intake  Figure . MeanwhiWhile changes in energy intake directly affect the function and mass of adipose tissue, in turn, changes in adipocyte abundance and consequently alterations in adipokine secretion, reciprocally affect appetite regulation, and directly impact other pathways that affect glucose homoeostasis and reproductive function. Leptin is an adipose-derived cytokine that is secreted in proportion to body fat mass. Like ghrelin, leptin is also a major regulator of appetite via receptor interactions in the ARC . With thIn addition to modulating the activity of hypothalamic appetite-regulatory neurons, leptin regulates kisspeptin neurons in the ARC . KisspepTestosterone enhances protein kinase A-mediated adipocyte lipolysis through upregulating the expression of β-adrenergic receptors . MeanwhiThere is also a direct effect of the stress response on the regulation of appetite and adipose tissue physiology. Chronic starvation activates the stress cascade, also known as the hypothalamus-pituitary-adrenal (HPA) axis, to further interfere with the hormonal regulation of ARC neuronal and adipocyte functions. One critical factor responsible for stress cascade activation is corticotropin-releasing factor (CRF), also referred to as corticotropin-releasing hormone. Upon starvation, increased CRF expression in the hypothalamic paraventricular nucleus (PVN) promotes the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary . ACTH thElevated cortisol suppresses the release of thyroid-stimulating hormone (TSH) from the anterior pituitary, which is also inhibited by ghrelin . TSH, thNPY-knockout mice displayed greater rates of lipolysis, fat mass loss and mortality during prolonged calorie restriction than wild-type healthy controls [It should be noted that there is limited knowledge on the regulation of lipolysis in AN. Although lipolysis can contribute to the energy requirement for maintenance under a negative energy balance state, in adult female AN patients, fasting plasma glycerol ,71 or frcontrols , suggestIn summary, although cause and effect relationships between stressors, reduced appetite, and metabolic disruptions in the anorexic state are unclear, there are obvious changes in major hormonal systems that exert effects on both appetite regulation and lipid mobilization in adipose tissue that eventually negatively impact other important physiological functions such as reproduction. In general, there is reduced activity of the HPT and HPG axes, coupled to increased activity of the HPA cascade, that interact to intensify hypothalamic anorexigenic pathways, a condition that is further exacerbated by reduced fat mass and dysregulation of adipocyte lipid metabolism and adipokine secretion.Based on family and twin studies, the symptoms/behaviours of AN are heritable, where genetic heritability explains about 46–72% of the eating behaviour (restrictive and binge-purging/vomiting) and 32–72% of the pathological attitudes , with higher heritability observed in post- than pre-pubertal twins . MoreoveZC3H10) and erb-b2 receptor tyrosine kinase ERBB3 [A recent genome-wide association study (GWAS) revealed one locus with genome-wide significance for a single variant on chromosome 12, which covers 6 genes including zinc finger CCCH-type containing 10  in AN than in healthy females [DGKG expression increases in the prefrontal cortex in response to chronic stress exposure [Transcriptomic analysis on cortical neurons differentiated from induced pluripotent stem cells revealed higher expression of the TSH receptor and diacylglycerol kinase gamma , DRD4, and adipose tissue regulatory gene LEP (encoding leptin) with AN, methylation status of these genes did not differ between AN and control subjects [Epigenetic modification refers to potentially heritable alterations in gene expression that occur without changes to the DNA sequence, including methylation, acetylation, phosphorylation, ubiquitination, and SUMOylation of the DNA or histone proteins . There asubjects . Epigenosubjects ,91, wherHDAC4 has been associated with serum oestrogen, fear, learning, appetite and body weight regulation as well as reward processing, etc., which share similar symptomatology with AN [HDAC4 resulted in lowered mRNA expression but higher lipogenic activity after long-term exercise intervention in healthy men [Although histone modifications have not been comprehensively studied in AN, histone deacetylase 4 (HDAC4) – an enzyme that facilitates the removal of acetyl groups from histones, is differentially methylated in AN and other eating disorders (reviewed in ). Altere with AN . In thiglthy men . These rin vitro and in the WAT of healthy lean rodents in vivo, and it also suppresses reward-driven but not hunger-driven food intake, indicating its essential role in maintaining energy homoeostasis. Therefore, hypermethylation of the oxytocin receptor gene may induce unbalanced energy homoeostasis together with other factors such as oestrogen, which eventually contribute to the pathogenesis of AN.A pilot study revealed that there was hypermethylation of several CpG sites in exon 1 and the MT2 region of the oxytocin receptor gene in the buccal cells of female AN patients compared to healthy controls, and the methylation level was inversely associated with BMI . CirculaLEP hypermethylation in only the male offspring regardless of the gestational stage of exposure [As described earlier, there is a high prevalence of AN in adolescent females that may be induced by external triggers, highlighting the importance of understanding how early-life stressors impact physiology later in life. Environmental factors include but are not limited to stress exposure , chemical exposure (e.g. pollutants and drugs/medications), and seasonal/biological rhythm, etc. Epigenetic modification is one major mechanism through which such factors contribute to the pathogenesis of AN. Stress-induced epigenetic changes in energy metabolism have been extensively studied . Female exposure . Similarexposure  and LDL exposure  levels dexposure , suggestCrf gene and consequently higher mRNA expression in the PVN [Crf gene in female adult rats, which was associated with decreased numbers of CRF-immunoreactive neurons in the PVN, whereas in males there were increased Crf mRNA-positive cells in the PVN, although both sexes had decreased body weights compared to non-stressed counterparts [As aforementioned, the HPA axis is activated by stimulation of hypothalamic CRF release. In adult mice, long-term social defeat stress exposure, which induces anhedonia, led to decreased DNA methylation in the promoter region of the  the PVN . Greater the PVN , where t the PVN . Meanwhi the PVN . In contterparts . Such a terparts .GR methylation in the promoter region [Glucocorticoid receptor (GR) activation by cortisol in the hypothalamus and pituitary provide negative feedback to the HPA axis, suppressing the stress response to restore homoeostasis . Maternar region  as well r region  of the or region , which mr region  and persr region . Indeed,r region .These symptoms are similar to those observed in AN patients, indicating that prenatal stress exposure plays a role in the pathogenesis of AN later in life. Although many of the studies that describe stress-induced changes in hormonal axes and metabolism do not focus on the AN condition, per se, they provide compelling evidence that chronic activation of the HPA axis induces changes that precede metabolic disorders, suggesting that a genetic predisposition to alterations in any of these pathways, might make an individual more susceptible to stress-induced AN. Although there are limitations in modelling this in a clinical setting, there are opportunities to develop animal models that recapitulate some of the features of AN and can be used to further define mechanisms and define molecular targets for pharmacotherapeutics.In summary, AN is characterized by a reduction in appetite and adipose tissue mass. Initially, lipid mobilization may increase to restore energy homoeostasis while with prolonged negative energy balance, this is reduced to preserve energy for vital functions to compensate for limited energy intake. Because adipose tissue is a critical endocrine organ that communicates with the rest of the body, including appetite-regulatory regions of the brain, to maintain energy homoeostasis, a reduction in its mass and change in adipocyte function may contribute to the endocrine disruptions that are present in AN, and lead to continued reinforcement of hypophagia and reduced metabolic rate. Traits associated with appetite regulation and lipid metabolism are heritable in AN. Epigenetic modifications may partially explain the differences in gene expression among adipose tissue depots in AN, although the environmentally sensitive nature of these marks makes it difficult to determine whether such modifications are the causes or consequences of AN.When considering the effects of stress-induced epigenetic modifications on energy homoeostasis, it should be noted that epigenetic modifications are very sensitive to the type and intensity of the stressors, and unlike experimental animals in which there is strict control of housing and diet, the human epigenome may also be affected by diverse factors such as lifestyle . Meanwhi


Clinicians should always suspect tuberculosis inpatients with chronic symptoms, especially in those with immunosuppression.Tuberculosis is one of the most common infections worldwide with particularlyhigh incidence rates in countries with unfavorable socioeconomic conditions andamong persons with impaired immune systems. While most patients with thisdisease will present with pulmonary tuberculosis, immunocompromised individualsalso commonly present with extrapulmonary manifestations. We report the case ofa 28-year More than two billion people worldwide are estimated to be infected with tuberculosis(TB), with the highest incidence rates observed in countries with unfavorablesocioeconomic conditionsAlthough pulmonary tuberculosis represents the great majority of cases,extrapulmonary tuberculosis (EPT) is seen in about 10% of all cases. Urogenitalinvolvement is the third most common form of EPT, just after lymph node and pleuralinvolvementThere is an increased incidence of TB in patients with end-stage renal disease (ESRD)compared to the general population. In absolute numbers, this observation isespecially important in areas where the disease is endemic as the presentation of TBin uremic patients is often unusual and insidiousHere we describe a patient with ESRD who developed urogenital and systemic symptoms,who was eventually diagnosed with EPT.The patient is a 28-year-old male student who is a known case of ESRD secondary topolycystic kidney disease and currently on maintenance hemodialysis who firstpresented to an Emergency Department in 2016 with a chief complaint of pain andswelling in the right testicle. Surgical drainage was performed which revealedabscess formation in the testicular pouch with preservation of the testis andepididymis. Intravenous antibiotics were administered after the completion ofdrainage. No information about material collection or culture results wereavailable. The patient then noted low-grade intermittent fever for almost two years, which wasthen followed by the development of an ulcerated lesion in the contralateral portionof the testicular pouch associated with purulent discharge . Other sLaboratory investigations showed negative results for HIV, hepatitis B, and hepatitisC. Urinalysis revealed pyuria and hematuria but without the presence of nitrites.Urine culture for common bacteria did not yield any growth. Serum measurement of thetumor markers beta-HCG, alpha-fetoprotein, and lactic dehydrogenase also yieldednormal results.A computed tomography scan of the chest and abdomen revealed minor pericardialeffusion and small calcifications scattered in the liver, pancreas, spleen, andprostate. The kidneys had diffusely increased volume due to the presence of cystsdisseminated in the parenchyma , thelar3 containing numerous nodular and cystic structures withirregular borders and signs of hypervascularization; such findings suggest thepresence of a chronic inflammatory or infectious process.On ultrasonography, the left testicle was found to be increased in size with a totalvolume of 32.5 cmMycobacterium tuberculosis (Mtb) while solid (LJ) and liquid(BACTEC MGIT 960 system) culture media showed growth of Mtb sensitive to first-lineanti-TB drugs.The tuberculin skin test was noted to be reactive, as demonstrated by a 12 mminduration after 48 hours, but acid-fast bacilli smear of the urine was negative.GeneXpert® MTB/RIF revealed the presence of Rifampicin-susceptibleAnti-TB treatment using rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), andethambutol (EMB) was then started with appropriate dose adjustments for creatinineclearance according to the Brazilian Guidelines for TB. The patient was monitoredevery month and a satisfactory outcome was eventually reached, as indicated by areduction in the size of the abdominal lymph node mass and testicular edema, totalcicatrization of the fistulous pathway in the scrotal sac, and the absence of feverstarting from the first month of treatment.However, during the third month of treatment, the patient developed painful nodulesin the left epididymis and noted other symptoms which, when taken together, werecompatible with retrograde ejaculation. Ultrasonography revealed a non-specificepididymal nodule while serum tumor markers for testicular neoplasms remainednegative.A multidisciplinary team approach was eventually used to manage the urogenitalcomplications that arose secondary to TB cicatrization that developed in thepatient. Full recovery was achieved after twelve months of TB treatment.M.tuberculosis, is determined by type 1 helper T-cell response and theproduction of interleukin (IL)-12, which increases the production of interferon(IFN)-ƴ. However, this mechanism is impaired in patients with chronic kidneydisease,The host response against intracellular pathogens, including ,Proposed reasons for this decrease in cellular immunity include a defect in thecostimulatory function of antigen-presenting cells, a persistent inflammatory statesecondary to uremia and dialysis, vitamin D deficiency, hyperparathyroidism, andmalnutrition,A negative tuberculin skin test, which occurs in 40-100% of cases of TB, can hamperthe diagnosis of this disease,,,The classic finding of sterile pyuria is neither sensitive nor specific fortuberculosis. However, persistence of this finding should increase the clinician’ssuspicion for TB,,,,There is no consensus regarding the treatment of TB in patients with renalimpairment. However, some authors recommend using the standard six-month treatmentregimen except in cases of meningeal, miliary or bone/joint tuberculosis. Othersexperts recommend a nine- or twelve-month-long regimen consisting of two months oftreatment with INH, RIF, PZA, and EMB, followed by treatment with RIF and INH forthe remaining monthsUrogenital TB should be suspected in all patients presenting with chronic orinsidious symptoms in any part of the genitourinary system, especially in thoseliving in areas endemic for the disease.


Varicella zoster virus (VZV) is a pathogenic human herpes virus which causes varicella as a primary infection, following which it becomes latent in peripheral autonomic, sensory, and cranial nerve ganglionic neurons from where it may reactivate after decades to cause herpes zoster. VZV reactivation may also cause a wide spectrum of neurological syndromes, in particular, acute encephalitis and vasculopathy. While there is potentially a large number of coding viral mutations that might predispose certain individuals to VZV infections, in practice, a variety of host factors are the main determinants of VZV infection, both disseminated and specifically affecting the nervous system. Host factors include increasing age with diminished cell-mediated immunity to VZV, several primary immunodeficiency syndromes, secondary immunodeficiency syndromes, and drug-induced immunosuppression. In some cases, the molecular immunological basis underlying the increased risk of VZV infections has been defined, in particular, the role of POL III mutations, but in other cases, the mechanisms have yet to be determined. The role of immunization in immunosuppressed individuals as well as its possible efficacy in preventing both generalized and CNS-specific infections will require further investigation to clarify in such patients. Varicella zoster virus (VZV) is a pathogenic and ubiquitous human alpha herpes virus which causes varicella (chickenpox) as a primary infection, usually, though not always, in children following which it may become latent in neurons in peripheral autonomic, sensory, and cranial nerve ganglionic neurons along the entire human neuroaxis , ischemic and hemorrhagic stroke, arterial dissection, transient ischemic attacks, ischemic cranial neuropathies, spinal cord infarction, and cerebral venous thrombosis  , this finding remains controversial and is the subject of ongoing investigation. Thus, Gilden et al.  first reSince zoster frequently affects the first division of the trigeminal nerve, VZV may also cause various types of eye disease, both neurological and primarily ophthalmological. Thus, zoster may cause oculomotor nerve and optic nerve lesions Kennedy  as well Finally, very rare cases have been described, in which VZV encephalitis triggers autoimmune NMDA receptor immunoreactivity/encephalitis, possibly through molecular mimicry or “altered self” or as a paraneoplastic phenomenon  when comparing two VZV from different geographic clades . Whether any detected SNPs confer important functionality in the VZV is certainly possible though not yet known for certain. But these possibilities do provide a feasible background for different VZV strains producing different clinical phenotypes in its human host. Support for this notion is suggested by finding mutations in the vaccine strain VZV that are more likely to cause complications of vaccination.It is possible that a particularly virulent strain of VZV may exert a clinically significant phenotype, and a recent study provided evidence that this may well be the case. When 11 VZV isolates from patients who had developed PHN were compared with 9 VZV isolates from non-PHN patients for their ability to produce different electrophysiological effects in the ND7/23-Nav1.8 neuroblastoma cell line, it was found that the PHN-associated viruses significantly increased sodium current amplitude in the cell line when compared with non-PHN VZV, wild-type (Dumas), or vaccine VZV strains  mouse models or post-mortem examination of human trigeminal ganglia are available. In this context, the study of human inborn errors of immunity conferring increased susceptibility to VZV has proven particularly valuable. It is clear that a prominent role is played by cellular immunity exerted by T cells and natural killer (NK) cells  have been shown to predispose to severe disseminated primary varicella, frequent and extensive zoster, varicella pneumonia, and in some cases CNS complications   issues related to its cell type specificity and redundancy, (ii) the specificity of POL III defects in VZV infection, (iii) its role in primary infection (primarily children) versus reactivation (primarily adults), (iv) its function in innate sensing versus priming of adaptive immunity, and (v) whether Pol III exerts its antiviral role by one  or whether several different mechanisms may be involved and in which cellular context.Previous studies have demonstrated high expression levels of POL III in PBMCs, whereas expression of other DNA sensors, such as cGMP-AMP synthase (cGAS), otherwise considered the dominant cytosolic DNA sensor, was relatively low in this cell population virus infections in the CNS. For instance, it is well established that defects of the TLR3 signaling pathway increase susceptibility to HSV encephalitis (HSE) , has been reported to be associated with progressive multifocal leukoencephalopathy (PML) caused by JC virus, and also increases the risk of VZV encephalitis and myelitis (Bourre et al. In addition to the specific examples mentioned above, several studies have reported an increased risk of VZV reactivation in patients with autoimmune conditions receiving various different immunosuppressive medications, including anti-TNFα treatment (Burmester et al. Within the group of more recently introduced immunosuppressive medications, the JAK inhibitors are relevant. These selective inhibitors of Janus kinases act to block JAK-STAT signaling downstream of the type I, II, and III IFN receptors. All JAKs play an important role in immune response and development, with JAK1 and JAK2 also involved in hematopoiesis. JAK1 is required for both type I and type II IFN signaling pathways, whereas JAK3 is essential for lymphocyte development and function Mogensen . JAK inhper se together with the immunosuppression exerted by the drug.Overall, VZV reactivation is more common in patients with rheumatoid arthritis and systemic lupus erythematosus, because of their inherently disturbed immune system (Forbes et al. Waning immunity occurring with increasing age is associated with a significantly increased risk of VZV reactivation, usually causing herpes zoster which may be accompanied by CSF pleocytosis and a degree of meningitis or, more rarely, encephalitis (Gilden et al. VZV infection can be largely prevented in the general population, since VZV vaccines that provide effective protection have been developed, including a live attenuated vaccine against varicella and a subunit vaccine for adults and the elderly against herpes zoster. However, a particular problem remains in individuals with severe PID, particularly in cases of profound cellular PID, in whom the live vaccine may pose a threat for serious disseminated VZV infection. More research is required to define more precisely the role of VZV immunization in immunosuppressed individuals. With increased clinical use of a wide variety of immunosuppressive drugs for an increasing number of clinical conditions, it seems very likely that the frequency and range of VZV infections, including those specifically affecting the central and peripheral nervous systems, will be reported. Host immune factors seem to be more important than intrinsic virological factors in predisposing susceptible individuals to VZV infections, but the specific molecular pathways involved in these remain to be elucidated in greater detail.


Growing evidence supports the link between genotype and patient outcome, portending a future of precision medicine in psychiatry.The diverse presentation of symptoms experienced by patients with schizophrenia is matched only by the complexity of the genetic architecture that underlies disease risk. To date, hundreds of rare6. No genetic test can yet match patients to the most appropriate drug; however, patients with rare disruptive variants in gene targets of antipsychotics7 and/or higher schizophrenia polygenic risk scores (PRS)8 tend to show less improvement with antipsychotic drug treatment. Although all current antipsychotics are antagonists of dopamine receptor signaling, and genetic variation at the dopamine D2 receptor may influence response to antipsychotic medications, the modest effect sizes at this locus have to date proven to be of limited clinical utility9. More promising, it is already possible to apply genetic markers to predict some adverse metabolic responses to antipsychotic treatment10.Clinicians still engage in a slow trial-and-error process with each patient, in order to identify the most efficacious drug(s) with the fewest side effects; critically, 30% of cases show little response to first-line antipsychotics13. Our expectation is that the predictive power of these circuit-based approaches will be further improved by considering patient genetics8 or imputed cell-type-specific gene expression15. An emerging platform involves reprogramming of patient somatic cells to human induced pluripotent stem cells (hiPSCs), in order to empirically test pharmacological response of patient-derived brain cells in vitro16. Even without understanding the complex interactions between multifaceted risk variants underlying each patient’s disease risk, researchers can systematically evaluate drug response in a donor and cell-type-specific manner. We hope that patient-specific phenotypic and/or transcriptomic drug screens will uncover novel drugs that act through mechanisms independent of dopamine biology. Most importantly, with an improved ability to predict which subset of patients will respond to which novel treatments, a successful drug need not be efficacious in all patients in order to be clinically useful.We foresee a not-too-distant future whereby a combination of patient genotype, brain imaging and biomarkers efficiently pairs patients to their ideal drug. Already it is possible to apply structural or functional brain measures to stratify patients based on the severity of disease and/or drug response17. Key candidate genes identified through such unbiased approaches can hint at points of convergence underlying schizophrenia risk that might represent novel therapeutic targets, or help to explain independent genetic mechanisms leading to disease. Resolving the causal variants underlying schizophrenia and treatment response should dramatically improve our ability to match patients to more effective treatments.Beyond drug response, hiPSC-based models allow for both targeted and large-scale functional validation of the growing list of variants thought to interact to contribute to schizophrenia risk. Rather than continuing to study disease risk variants one-at-a-time, CRISPR-based technologies can be applied to conduct forward genetic screens, simultaneously assessing the phenotypic impact of hundreds of genes in a single experiment. It is now possible to undertake large-scale studies of risk genes on neuronal gene expression and function, in either pooled or arrayed formatsThe complex heterogeneity of schizophrenia means that a single cure may not be found. New strategies to stratify etiologically complex patients, diagnosing high-risk individuals prior to psychosis onset, makes possible a future whereby we prevent, rather than treat, schizophrenia. Ultimately, tailoring interventions for each patient achieves the potential of precision medicine, treating schizophrenia with not one silver-bullet drug, but many.


There has been a growing interest in the potential of stem cell transplantation as therapy for pediatric brain injuries. Studies in pre-clinical models of pediatric brain injury such as Traumatic Brain Injury (TBI) and neonatal hypoxia-ischemia (HI) have contributed to our understanding of the roles of endogenous stem cells in repair processes and functional recovery following brain injury, and the effects of exogenous stem cell transplantation on recovery from brain injury. Although only a handful of studies have evaluated these effects in models of pediatric TBI, many studies have evaluated stem cell transplantation therapy in models of neonatal HI which has a considerable overlap of injury pathology with pediatric TBI. In this review, we have summarized data on the effects of stem cell treatments on histopathological and functional outcomes in models of pediatric brain injury. Importantly, we have outlined evidence supporting the potential for stem cell transplantation to mitigate pathology of pediatric TBI including neuroinflammation and white matter injury, and challenges that will need to be addressed to incorporate these therapies to improve functional outcomes following pediatric TBI. Traumatic brain injury (TBI) is the leading cause of death and disability among the pediatric population. In the United States, TBI affects half a million children under the age of 14 years old each year . HoweverTraumatic brain injury sustained during childhood can result in long-term visuomotor, cognitive, and behavioral symptoms that cause lifelong disability and impaired quality of life for survivors of childhood TBI. Pediatric TBI patients commonly exhibit impairments in visual perception, gross, and fine motor function –11, whicPediatric TBI has been studied using a variety of preclinical models, including controlled cortical impact (CCI), fluid-percussion injury (FPI), closed-head injury (CHI), weight-drop injury, and rotational injury in rodents of ages ranging from postnatal day 7–28 –33. ExpeThe major pathologic hallmarks of TBI in infants and children include cerebral edema, extra-axial and intraparenchymal hemorrhage, ventriculomegaly, and diffuse axonal injury (DAI) . ReductiPreclinical TBI studies have demonstrated diffuse damage in white matter tracts , 31, 44,Activation of inflammatory sequelae in both the acute and chronic post-injury phases occur following TBI in immature animals. Concentrations of pro-inflammatory cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor-alpha (TNF-α) are acutely and rapidly elevated in the injured brain  and can Preclinical evidence suggests that injury to the immature brain has robust effects on the proliferation of endogenous stem cell populations [reviewed in Niimi and Levison ]. MultipThe response of neural stem cells (NSCs) to neonatal HI is complex. In the early post-injury phase, increased mitotic activity in the subventricular zone (SVZ) is observed –55. HoweContusive TBI to the immature brain also found evidence of robust proliferation in response to injury , 61. In Despite the robust proliferative response of NSCs and NPs to pediatric brain injury, evidence suggests that most of the newly generated cells do not survive past 1–2 months , or predThe bone marrow niche is home to hematopoietic stem cells (HSCs) which are responsive to pediatric brain injuries and play a role in stem cell proliferation, mobilization, and migration. Several studies have found that neonatal HI mobilizes mesenchymal stromal cells (MSCs) in the peripheral blood which migrate to the location of the injured tissue where they can potentially aid in tissue repair and regeneration –69. In pA growing body of literature has accumulated supporting the potential of NSCs (either embryonic or adult) and/or MSCs  to treat the pathophysiology of TBI [reviewed by Mashkouri et al. ]. The seEvidence from adult animals suggests that cells grafted in the hostile environment of the injured brain often exhibit poor survival , 77. In in vitro studies using co-cultures of glial-restricted precursor cells (GRPs) with neonatal brain slices exposed to oxygen-glucose depravation, GRPs decreased tissue injury and cortical cell death without direct cell-cell contact suggesting that these effects were likely attributable to trophic support provided by the cells  and brain-derived neurotrophic factor (BDNF)  which prhe cells . Followihe cells , 80 and he cells . The admhe cells , 93, andhe cells . Moreovehe cells  and corphe cells , 94 as whe cells  comparedhe cells , 84, 94 he cells , 94, 95 he cells  in the iEfficacy of cell therapy needs to be documented via their effects on behavioral outcomes. Compared with vehicle-treated animals, MSC-administered animals exhibited improved motor function in the rotarod and beam walking tests between 2 and 4 weeks following brain injury , 92, 94.Bone-marrow derived MSCs (BM-MSCs) administered following adult TBI or neonatal HI demonstrate beneficial effects on white matter repair and regeneration , 97–99. Stem cells derived from umbilical cord blood demonstrate great therapeutic potential due to their ability to mitigate damage to the neurovascular unit following brain injury , 101. TrThe effectiveness of stem cell treatment combined with other pharmacotherapies in preclinical models of TBI is currently being established. These combination therapies may exhibit synergistic effects and result in greater neuroprotection relative to stem cell or pharmacological monotherapy , 105. MoAnti-inflammatory therapies such as minocycline show promise in adult TBI studies , althougAnother promising candidate for treatment of TBI is granulocyte-colony stimulating factor (G-CSF), which has an inherent capability to reduce brain edema and promote functional recovery following TBI. G-CSF also promotes neuroprotection of implanted stem cells  and recrMild hypothermia (HT) is currently the only therapy approved for the treatment of neonatal HI. Mild HT usually involves cooling the body to 32–35 degrees Celsius for 12–72 h within the first 6 h after HI . In clinInterestingly, there is recent evidence to suggest that hypoxic preconditioning could increase the therapeutic potential of stem cells , 115 andModifying stem cells to overexpress neurotrophic factors such as BDNF could maximize the inherent neurotrophic benefits of stem cell treatments in pediatric brain injuries , 118. BDin utero intravenous administration following global HI in ovine fetuses. In contrast to the previous study, they did not observe an effect of the exosome treatment on post-injury inflammation  microglia . During + microglThe immature brain is also particularly vulnerable to enhanced levels of pro-inflammatory cytokines and free radicals produced by microglia after brain injury due to the reduced antioxidant capacity of the developing brain as well as the vulnerability of OPCs within the white matter tracts , 130. ReThe effects of stem cell treatments in adolescent models of TBI have not been investigated, although transplantation of NSCs improved functional outcomes following global ischemia in adolescent rats . TBI durA promising therapeutic approach that would be well-suited for pediatric TBI patients is to target the survival of endogenous stem cells, as this would take advantage the robust proliferative capacity in the immature brain in response to TBI . This apAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Limitations include preponderance of cross-sectional data that precludes causal inferences, use of single measure or single-item assessments of loneliness, absence of testing bidirectionality, and small sample sizes.By 2050, it is estimated that about a fifth of the general population will be aged 65 years and older.The Lancet Public Health, Ziggi Ivan Santini and colleagues4 build on previous work by examining the bidirectional relations between depression or anxiety severity and social disconnectedness between 2005 and 2016, and the degree to which perceived isolation mediated those relationships. The authors tested these hypotheses in a large sample of 3005 community-dwelling adults aged 57 to 85 years in the National Social Life, Health, and Aging Project using random-intercept cross-lagged panel modelling.5 The analyses showed that social disconnectedness independently predicted depression and anxiety symptom severity (and vice versa). Additionally, self-perceived social isolation was found to mediate the link between social disconnectedness and depression and anxiety in both directions. For example, social disconnectedness predicted higher subsequent perceived isolation, which in turn predicted higher depression symptoms and anxiety symptoms . The random-intercept cross-lagged panel modelling approach, which adjusts for previous outcomes and between-person variation, permits the inference that these observed relations unfold within (as opposed to between) people, thus bringing us closer toward causal models. Moreover, the authors exemplified the best practices of longitudinal structural equation modelling by testing for measurement equivalence to verify that the latent constructs were assessed along the same scale at various timepoints (an often-neglected step).In 8 For instance, internet-delivered cognitive behaviourial therapy has been shown to enhance both the general impression and tangible indicators of social affiliation and support compared with waitlist controls.9 Similarly, establishing community volunteer outreach could also help in this regard, particularly for adults who are less mobile or more secluded.These findings can potentially inform public health and social policies. Brief evidence-based preventive interventions could plausibly be developed for older adults and implemented within multiple healthcare venues, religious or cultural organisations, and community centres. Such skills could help older adults form meaningful connections with others. Cognitive skills could help them to critically evaluate the degree to which their social support network fulfills their need for friendships and a sense of belonging. Relatedly, action-based strategies, such as establishing more frequent social contact with significant others or repairing strained relationships, might be important to deliver the best quality care. Randomised controlled trials examining the effects of cognitive behavioural based therapies, delivered online or in-person, have been shown to alleviate depression and anxiety symptoms while simultaneously decreasing loneliness.6These approaches can be implemented in geriatric and other clinical contexts, as well as welfare organisations that provide a range of meaningful and health-promoting social activities to older adults. Second, health-care providers can benefit from being mindful of the potentially scarring effects of untreated depressive and anxiety disorders in middle and late adulthood. Late-life affective disorders can trigger vicious cycles of social withdrawal, unhelpful self-referential thought patterns, and worsened psychiatric symptoms in the long term. Collectively, findings suggest that access to ageing or retirement communities that provide a sense of belonging and security is imperative for delivering high standards of mental health care to older adults.However, some study limitations deserve mention. It remains unclear if the results would be replicated if diagnostic or clinician rated measures (as opposed to self-report) were used; future replication efforts could thus administer multimodal diagnostic psychiatric instruments. In addition, although the prospective, observational design approximates causality by establishing temporal precedence and co-variation, no strong causal conclusions can be drawn because of the absence of experimental manipulation required for internal validity.10 Nonetheless, the study by Santini and colleagues is an important first step toward understanding the importance of social support for older adults in helping to prevent depression or anxiety.Finally, it is important to keep in mind that most psychological treatments targeting loneliness and related constructs to date were limited by small sample size, non-randomised controlled designs , absence of multiple-domain assessments of social disconnectedness, and use of an inactive no-treatment or waitlist comparison group. Accordingly, public health can benefit from future studies using a randomised controlled trial design with a bigger sample size, alongside a multiple-group factorial design to tease apart the treatments’ causal mechanisms. Further, an active control comparison group should be used to rule out regression to the mean, expectancy effects, and other confounders, to analyse factors that contribute to treatment effects on change in outcomes. For example, it might be worth examining if the remedying effect of cognitive behavioural treatments on social disconnectedness might be mediated or moderated by changes in allostatic load, immune functioning, lifestyle, or other putative variables.


Across metazoans, animal body structures and tissues exist in robust patterns that arise seemingly out of stochasticity of a few early cells in the embryo. These patterns ensure proper tissue form and function during early embryogenesis, development, homeostasis, and regeneration. Fundamental questions are how these patterns are generated and maintained during tissue homeostasis and regeneration. Though fascinating scientists for generations, these ideas remain poorly understood. Today, it is apparent that the Wnt/β-catenin pathway plays a central role in tissue patterning. Wnt proteins are small diffusible morphogens which are essential for cell type specification and patterning of tissues. In this review, we highlight several mechanisms described where the spatial properties of Wnt/β-catenin signaling are controlled, allowing them to work in combination with other diffusible molecules to control tissue patterning. We discuss examples of this self-patterning behavior during development and adult tissues’ maintenance. The combination of new physiological culture systems, mathematical approaches, and synthetic biology will continue to fuel discoveries about how tissues are patterned. These insights are critical for understanding the intricate interplay of core patterning signals and how they become disrupted in disease. Drosophila patterning and mouse tumor formation was discovered 40 years ago [The Wnt pathway is a highly conserved cell-to-cell signaling pathway, appearing in metazoans from sponges  to nematears ago , Wnt hasIn this review, we will focus on the canonical Wnt/β-catenin pathway as a tissue organizing and self-organizing factor during embryogenesis/development and regeneration/homeostasis. For more general reviews on patterning and self-organization, the reader should also consider References ,7,8. β-cIn the canonical Wnt/β-catenin pathway , cells nThe ability of a single cell to give rise to the complexity of a multicellular organism has fascinated scientists for generations. In 1892, Hans Dreisch separated sea urchin embryos at the 4-cell stage and discovered that all separated cells were able to differentiate into complete larvae ). This raised the question, what keeps the intact 4-cell embryo from giving rise to four complete larvae? Dreisch’s discovery was critical as it showed that a cell’s fate depends on the external (in this case inhibitory) signaling from proximity or contact with its neighbors. This was also a keystone discovery because it showed that early cells are autonomous units that contain all the information needed to self-organize themselves into complex functional tissues.Tissue self-organization is a key aspect of animal development and adult tissue homeostasis. We define self-organization as the process by which tissues can form patterns from an initial symmetrical or chaotic state. Self-organization can be driven by diffusible molecules, cell–cell or cell–substrate signaling, and mechanical forces. These triggers allow cells to “sense” their neighbors and environment to adjust proliferation, growth, differentiation, death, etc., accordingly, to insure robust and uniform development, regeneration, and homeostasis. Cell adhesion-based signaling is also essential to tissue organization. For example, the mechanosensing transcription factor YAP is required for the initial symmetry breaking events seen in organoids  and crypPlanarians [Tissue self-organizing events can be separated into two categories: embryogenesis/body development and homeostasis/regeneration . Developanarians .A clear example of adult tissue self-organization is the architecture of the mammalian intestinal crypts. Wnt signaling is critical for the establishment and maintenance of the regular periodic pattern of crypt invaginations lining the intestine. Crucially, this periodic pattern arises presumably from interactions of intestinal stem cells and their differentiated progeny . This waHow could patterns such as the repetitive intestinal crypts be autonomous to the crypt itself? To begin conceptualizing underlying mechanisms, we look back at pattern theory. How patterns in nature can arise from disorder has interested scientists for a long time. Famed mathematician and father of the computer, Alan Turing, was curious himself about the mechanisms underlying patterns found in nature. In 1952, in his only published work dealing with biological systems, he modeled how diffusible molecules (where he first coined the term “morphogen”) could lead to development of pattern formation from an initial random state. Notably, Turing showed through mathematical modeling that stationary polka dots, stripes, and wave patterns could be obtained from two molecules, an activator and its inhibitor, diffusing at different rates . SimilarRD models rely on critical diffusion properties of morphogens. In the past decade, many mechanisms have been discovered by which cells and tissues can propagate morphogen signals by means other than simple free diffusible molecules and Brownian motion. These other mechanisms include transport by motor proteins , mechaniDrosophila, limiting the morphogen diffusion by tethering has been used to uncouple the roles of short- and long-range morphogens such as Wnt [Across every multicellular organism, self-organization is present at strikingly different scales, from the subcellular mitotic spindle  to entirh as Wnt , and sugDrosophila embryo segmentation mutants [Xenopus laevis embryos showed that ectopic expression of Wnt1 mRNA was sufficient to induce the formation of a second body axis [A modern definition of a morphogen is a diffusible substance whose non-uniform distribution instructs tissue pattern formation and cell type specification. Wnts are classically defined as morphogens due to their clear function in tissue patterning and cell fate. Key components of the Wnt pathway were first identified in  mutants ,54, firsody axis . This suody axis . Many coody axis  as the mO-acetyltransferase porcupine (porcn) [Drosophila homolog of human Wnt, Wingless (Wg), was found within vesicle-like structures as well as in the spaces between cells, suggesting that that molecule acts in a paracrine signaling capacity [Xenopus axis formation [A highly conserved post-translational lipid modification that decreases its ability to diffuse long distances is essential for proper Wnt secretion. In order to leave the endoplasmic reticulum for eventual secretion, the Wnt protein must be mono-palmitoylated by the  (porcn) . Loss of (porcn)  and abno (porcn) . In earlcapacity . Since tcapacity . Other sormation . Wnt canormation . Wnt canormation ,41. In oormation . The conormation . These dDrosophila, acts across large distances in the development of the wing [Wg, the Wnt homolog in the wing , which rthe wing . Wg immothe wing , suggestthe wing ,68. Durithe wing . HoweverDrosophila [Studies of the embryo provide an ideal setting for examining the patterns which arise from stochasticity. The term “symmetry breaking” is commonly used to describe the first signs that tissue architecture is beginning to form, as seen during the formation of the intestinal crypt from a planar sheet of epithelium . Howeverosophila , Xenopusosophila , and murosophila ,47,74.In the developing embryo, Wnts are stemness-promoting activators. Other morphogens, such as BMPs, can act upon Wnts to establish the embryonic tissue patterning. In human embryos, BMP triggers a Wnt/Nodal positive feedback loop that initiates the development of the early germ layers . In XenoThe developing limb manages to accomplish the regular spacing and size of digits faithfully in many mammals. The bones of the hand show digitation well before the formation of fingers: what then controls the spatial patterning of the bones? This common yet remarkable three-dimensional (3D) patterning has been an active area of study to discover the critical regulators of tissue patterning during development. Using murine digit development as a patterning model, Raspopovic et al.  made an The regular spacing of mouse hair follicles  is lost, a self-organizing system will renew and repattern the damaged tissue. This plasticity provides a dynamic but controlled environment where cell fates are induced depending on need. Tissue level self-organization is critical in the process of regeneration where damaged tissue must reorganize itself robustly to reform functional tissue. Below, we highlight a few examples of the Wnt-driven tissue regeneration.Hydra has been an exceptional model to study regeneration of tissues as the head can be removed to induce regeneration [Hydra, during tissue regeneration, β-catenin and TCF transcription is upregulated within 30 min and Wnt protein expression is localized to the regenerating tips within an hour, and regeneration-deficient mutants lack Wnt signaling [Planarians (another useful model system due to their striking regeneration ability), the Wnt pathway antagonizes anterior development, as β-catenin knockdown animals which are damaged form multiple head structures at the regenerative sites, while APC knockdown results in multiple tails during regeneration [An early example of Wnt-dependent regeneration pathways comes from Cnidarian model systems. neration . This prignaling . In Planneration .Regularly patterned skin cells provide a useful tool for studying self-organization during development as well as during regeneration, as the patterning can be easily visualized in 2D. Zebrafish harbor symmetrically patterned sensory organs call neuromasts which are continuously renewed and can regenerate after damage. As in hair follicle placode formation , Wnt is Adult tissues will sustain some form of damage during an organism’s life, and therefore must maintain the ability to regenerate and re-organize lost tissue. The human gut is not only short lived but also has a remarkable ability to regenerate and self-organize after acute damage. Certain tissue cells types become short lived as they differentiate and serve their purpose, such as the absorptive and secretory cells within the gut. A robust self-organizing system exists within the gut as it can not only renew rapidly, but also can sense when specific cell types are depleted and replace them, such as during damage and regeneration. In humans and mice, regeneration of damaged tissue is dependent on canonical Wnt signaling, as Wnt drives the renewal of Lgr5+ stem cells which renew damaged cells in the intestine . A strikSelf-organization pathways are often dysregulated or hijacked during diseases of aberrant cellular growth such as cancers. Mutations in the Wnt pathway have long been associated with the disorganization seen during tumor progression. The first tool used by pathologists to diagnose cancer is the presence of dysplasia revealed as a lack of proper tissue patterning or superfluous cell growth. In many colon cancers, driver mutations are acquired sequentially, and common initial mutations driving dysplasia are nonsense mutations in APC, a negative regulator of the Wnt pathway . UncheckActivation of the Wnt/β-catenin is widely regarded as oncogenic in nature, yet recent studies have shown that Wnt signaling also plays essential roles in tumor prevention. Elegant work by Brown and Pineda et al. showed that normal cells rely on Wnt secretion originating from β-catenin-driven neoplasms to control the physical removal of early aberrant growths . These dThe study of self-organization is inherently challenging in vivo as it requires interrogating pathways at the level of tissue patterning across time in a complex microenvironment. To test feedback models, such as a RD model, monitoring the dynamics of morphogens from specific cells and their neighbors is required. To test an RD model fully, control of the morphogens and their spatial dynamics is important in differentiating between other potential mechanisms of gradient formation. Tuning the gradients predicted by a RD model and observing patterning at the tissue level over time is a task few have accomplished. Fortunately, multiple approaches exist to tackle these challenging problems. The combination of simple animal or mammalian organoid models with advances in live imaging, optogenetics, and microfluidic are likely to bring significant progress in revealing fundamental principles of biological self-organization.Drosophila allow dynamic manipulation and monitoring of the Wnt pathway in animals by combining optogenetics and fluorescent reporter systems [Hydra and Planaria are ideal models for the study of regeneration, as continuous stem cell regeneration takes place during normal animal growth, enabling impressive regeneration capabilities. These models can also be extensively manipulated genetically and are small and simple to maintain. Zebrafish patterning models can now be manipulated by optogenetics, allowing for noninvasive testing of a pioneering RD system [Invertebrates biologists have been studying pattern formation during development for over half a century . New tec systems . Hydra aD system .In mammalian models, genetic systems have been used to study Wnt-driven follicle patterning in mice  using a Microfluidics are another powerful tool to study self-organization. These devices allow for the manipulation of morphogens with high spatial precision via laminar flow or controlled diffusion . These hBuilding mathematical models is an underappreciated yet essential part of a productive understanding of tissue self-organization. Adequate understanding of mechanisms underlying biological self-organization is not even possible in principle without mathematical modeling. Take for example the case of intestinal crypts. Understanding the mechanism of their formation would not only require establishing the natural inter-cellular interactions, but also demonstrating that the established interactions are sufficient to reproduce the spatial pattern of the crypts. Clearly, the dynamics of a system this complex cannot be tracked mentally and thus requires computational/modeling approaches.One of the earliest attempts at a computational description of Wnt pathway dynamics may be found in Reference . There, Answering many classical developmental and cell biological questions of the animal kingdom ultimately requires understanding the mechanisms that underlie the self-organizing potential of the Wnt pathway. Yet, many decades of research have failed to explain simple tissue forms such as the regular periodicity of intestinal crypts, or why damaged imaginal discs either regenerate or duplicate the organs of an adult fly depending on which part of a disc is ablated . It now