Psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder and autism spectrum disorder are common and result in significant morbidity and mortality. Although currently classified into distinct disorder categories, they show clinical overlap and familial co-aggregation, and share genetic risk factors. Recent advances in psychiatric genomics have provided insight into the potential mechanisms underlying the overlap between these disorders, implicating genes involved in neurodevelopment, synaptic plasticity, learning and memory. Furthermore, evidence from copy number variant, exome sequencing and genome-wide association studies supports a gradient of neurodevelopmental psychopathology indexed by mutational load or mutational severity, and cognitive impairment. These findings have important implications for psychiatric research, highlighting the need for new approaches to stratifying patients for research. They also point the way for work aiming to advance our understanding of the pathways from genotype to clinical phenotype, which will be required in order to inform new classification systems and to develop novel therapeutic strategies. Psychiatric disorders are common in the population  and resuHowever, it is widely acknowledged that there is substantial heterogeneity within diagnostic categories and that the boundary between disorder and ‘normality’ is not always clear. Furthermore, many symptoms and signs overlap between disorder categories and patients often present with features of more than one disorder. In some cases, this overlap has been dealt with by recognizing diagnostic ‘interforms’ such as schizoaffective disorder , or by rAdvances in genomic technology have been key to this paradigm shift in psychiatric research. These studies provide converging evidence across a number of different levels, supporting the hypothesis that genetic risk factors are shared between disorders and challenging the validity of the classification systems currently used in research and clinical practice. The evidence suggests that investigating pathways common across disorders may help us to understand the etiology of psychiatric illness. This could revolutionize our approach to the diagnosis and treatment of these complex disorders. Here, we review recent evidence from family and genomic studies, which support an overlapping and complex genetic architecture for psychiatric disorders and provide new avenues for further investigation of underlying mechanisms.Twin, family and adoption studies have provided heritability estimates for the major psychiatric disorders, highlighting an important role for genetic factors in the etiology of mental disorders ,14-18.In the late 19th century, Emil Kraepelin, a prominent German psychiatrist, distinguished between ‘dementia praecox’ (later termed schizophrenia) and manic-depressive psychosis (later termed bipolar disorder) as the two most common functional psychoses. Many family studies seemed to support this so-called ‘Kraepelinian dichotomy’, finding no familial relationship between schizophrenia and bipolar disorder, suggesting that these disorders ‘breed true’ . These sVandeleur and colleagues  recentlyIt has long been known that schizophrenia is associated with cognitive impairment and that this often predates the onset of psychotic symptoms . Family Taken together, the evidence from family studies suggests that psychiatric disorders may be co-inherited but also suggests that independent genetic and environmental risk factors are likely to be important in determining the ultimate clinical phenotype.The epidemiological studies discussed above used the genetic relationships between individuals to study the co-inheritance of psychiatric disorders. Advances in genomic technology, including array-based genome-wide association studies (GWAS), and exome-sequencing techniques, have allowed the potential genetic mechanisms underlying the overlap between psychiatric disorders to be investigated more directly. Like other complex diseases such as hypertension and diabetes, psychiatric disorders are not inherited in a Mendelian fashion but have a complex genetic architecture involving a spectrum of mutations from small DNA sequence variations to large chromosomal rearrangements. Not only do these mutations vary in their size, they also vary in their frequency and associated effect sizes. Below, we discuss recent evidence for overlap in genetic risk factors from GWAS of single nucleotide polymorphisms (SNPs), studies of copy number variants (CNVs) and exome-sequencing studies of single nucleotide variants (SNVs), insertions and deletions (indels).CACNA1C and CACNB2). CACNA1C has previously been reported as having genome-wide significant associations with schizophrenia, bipolar disorder and major depressive disorder [ANK3[ZNF804A[NCAN[The introduction of genome-wide association platforms has enabled researchers to study large samples of patients and controls to identify common variants  with cross-disorder associations. The markers used in these studies are SNPs: points in the DNA sequence where the nucleotide base varies in the population. In a recent paper published by the Cross-Disorder Group of the Psychiatric Genomics Consortium (PGC), four SNPs were identified as being significantly associated with the five psychiatric disorders studied: schizophrenia, bipolar disorder, major depressive disorder, ASD and ADHD . Two of disorder -38, and der [ANK3,37, ZNF83[ZNF804A,40 and N804A[NCAN,42, all To date, GWAS of common SNPs have shown that individual SNPs have modest effect sizes . It is therefore hypothesized that many common SNPs act together to influence risk of psychiatric disorders. Schizophrenia GWAS data support a polygenic basis for the disorder and estimate that common SNPs explain approximately one-third of the total variation in liability to schizophrenia ,44. ThesAn alternative method for investigating the SNP-based genetic overlap between disorders is to use a method known as genome complex trait analysis (GCTA)  to calcuDespite the high heritability of mental disorders reported in family studies, GWAS findings to date suggest that common variants only explain a relatively small proportion (about a third) of the genetic variation in liability to psychiatric illness . Furtherde novo to inherited CNVs correlate with the severity of developmental disability [Several studies have clearly demonstrated enrichment for rare CNVs in psychiatric and developmental disorders. For example, it has been shown that CNV burden is higher in patients with schizophrenia -59, ADHDsability .de novo CNVs have been found to occur at a higher rate in bipolar disorder cases than in controls, particularly in early onset cases [The role of CNVs in mood disorders is less clear. Several studies have shown that patients with bipolar disorder have a low burden of rare CNVs -66. Howeet cases ,68. The et cases .Microdeletions and duplications conferring risk of schizophrenia have been reported at a number of chromosomal locations Table  affectinRecent evidence suggests that CNVs may not only increase risk of psychiatric disorders, they may also exert protective effects. The 22q11.2 deletion is the strongest known genetic risk factor for schizophrenia. Recently, Rees and co-workers  found thde novo gene-disrupting SNVs and indels have been found to occur at higher rates in probands with ASD [GWAS and array-based techniques have enabled the detection of small common (>1%) and large rare (<1%) mutations. The development of exome-sequencing platforms has enabled the identification of small rare coding mutations, which could not previously be detected using GWAS or array-based techniques. Using samples of trios (both parents and one child) and quads (both parents with two children), with ASD -114 and with ASD ,116, beiwith ASD ,114 and with ASD  in the swith ASD -113 and with ASD ,112 age,with ASD -120.de novo mutations in small samples of patients [de novo or inherited mutations in schizophrenia. However, enrichment of loss of function de novo mutations did occur in schizophrenia cases likely to have the greatest intellectual impairment (lowest scholastic attainment), although these did not include cases with diagnoses of severe intellectual impairment. Moreover, genes with de novo mutations in schizophrenia overlapped with those affected by de novo mutations in ASD and ID but not in controls, with loss of function mutations enriched even in the very small subset of genes (N = 7) with recurrent loss of function de novo mutations in ASD or ID [de novo mutations and the mutation sites themselves showed the highest degree of evolutionary conservation  in ID, then in ASD, with least conservation seen in schizophrenia. These findings suggest that highly disruptive mutations play a relatively small role in schizophrenia, and also that the disorders differ by severity of functional impairment.The first exome-sequencing studies in schizophrenia found higher than expected rates of non-synonymous patients ,122. Twopatients ,124 did SD or ID . These fN-methyl-d-aspartate) signal transduction, proteins that interact with ARC (activity-regulated cytoskeleton-associated protein), referred to as the ARC complex [Recently, evidence for the convergence of genetic findings onto a coherent set of biological processes in psychiatric disorders has been accumulating. Results from GWAS ,44, CNV  complex , and bra complex ,126.These findings are notable for their consistency across several studies using different designs, and for their convergence onto a set of biological processes involved in the regulation of synaptic plasticity, particularly at glutamatergic synapses. Although there appears to be a concentration on post-synaptic mechanisms, some implicated genes, including the L-type calcium channels and neurexin 1 (an associated CNV locus ) also exConvergent support for glutamatergic synaptic processes is encouraging, but as already mentioned, it is likely that other processes are involved. There is a highly convincing body of evidence implicating dopaminergic dysfunction in the genesis of psychotic symptoms, which occur commonly in schizophrenia and bipolar disorder but that also occur in other neurodevelopmental disorders . Indeed,It seems probable that genetic disruption of the synaptic processes implicated to date will have widespread impacts on brain function and impair information processing within local, regional and even whole-brain networks - for example, by affecting excitatory-inhibitory balance and/or synaptic plasticity. Therefore, it is not surprising that mutations in genes involved in these processes affect cognitive function irrespective of the presence of comorbid psychopathology ,70.A spectrum of neurodevelopmental causality has previously been proposed to underlie the overlap between psychiatric disorders ,131. ThiAdvances in our understanding of the genetic architecture of psychiatric disorders support the long-standing clinical observation of overlap in the symptoms and signs of these disorders, as well as the non-specificity of many environmental risk factors . HoweverWhat is clear, however, is that research into etiology and pathogenesis does require a radical overhaul in how we diagnose psychiatric illness, moving from categorical, hierarchical diagnoses based on consensus opinion towards a more dimensional approach informed by advances in our understanding of brain mechanisms. Indeed, such an effort is currently underway by the Research Domain Criteria (RDoC) project ,133. ThiPediatricians and clinical geneticists are increasingly using genetic testing for patients referred with congenital malformations, facial dysmorphology, developmental delay, ID and ASD ,136. So There is now clear evidence that childhood-onset disorders often persist into adulthood ,141 and One of the major barriers to improving the outcome of patients with severe mental illness is the lack of effective pharmacological treatments that are well tolerated by patients. As a result, psychiatric disorders are associated with high rates of treatment resistance and non-compliance due to poor drug efficacy and unacceptable side effects. Despite considerable advances in neuroscience, there have been few if any notable advances in pharmacotherapy, and as a consequence of this and the perceived challenges of the field, many pharmaceutical companies are discontinuing research in neuroscience and psychiatry . Recent In this article, we have emphasized the accumulating evidence from genetic studies suggesting shared susceptibility across traditional diagnostic categories in psychiatry. This implies that at least some of the underlying biology may not be specific, or at least not at the level of current diagnoses. However, it is important to recognize that relatively non-specific risk factors that apply to a wide variety of cases are easier to identify than those associated with more specific outcomes. There is evidence from both family and genomic studies for risk alleles with differential effects on schizophrenia and bipolar disorder ,149 and Clinical and epidemiological evidence for the overlap between psychiatric disorders has been available for some time. There is now increasing biological evidence for this overlap. Recent genetic findings suggest that psychiatric disorders have a complex genetic architecture and support the existence of a neurodevelopmental gradient of psychopathology and associated cognitive impairment. These findings highlight the need to improve current diagnostic systems and to develop better treatments targeted at underlying biology. Future research studying networks rather than individual genes and proteins, and relating network abnormalities to behavioral, neuroimaging and clinical phenotypes will be key to achieving these aims. However, the complexity of psychiatric phenotypes and the relative inaccessibility of the human brain pose considerable challenges to both basic and clinical neuroscientific research. It seems likely that there will need to be a focus on large-scale experiments, requiring interdisciplinary and international collaboration, if we are to make significant progress.ADHD: Attention-deficit/hyperactivity disorder; ASD: Autism spectrum disorder; CNV: Copy number variant; DSM: Diagnostic and statistical manual of mental disorders; GWAS: Genome-wide association studies; ICD: International classification of diseases; ID: Intellectual disability; indel: insertion and deletion; kb: kilobases; PGC: Psychiatric genomics consortium; RDoC: Research domain criteria; SNP: Single nucleotide polymorphism; SNV: Single nucleotide variant.The authors declare that they have no competing interests.


Active and passive theories have been advanced to explain splenomegaly and cytopenias in liver disease. Dameshek proposed active downregulation of hematopoiesis. Doan proposed passive trapping of blood components in a spleen enlarged by portal hypertension. Recent findings do not support a passive process.Cytopenias and splenomegaly in both liver disease and systemic lupus erythematosus (SLE) poorly correlate with portal hypertension, and likely reflect an active process allocating stem cell resources in response to injury. Organ injury is repaired partly by bone-marrow-derived stem cells. Signaling would thus be needed to allocate resources between repair and routine marrow activities, hematologic and bone production. Granulocyte-colony stimulating factor (G-CSF) may play a central role: mobilizing stem cells, increasing spleen size and downregulating bone production. Serum G-CSF rises with liver injury, and is elevated in chronic liver disease and SLE. Signaling, not sequestration, likely accounts for splenomegaly and osteopenia in liver disease and SLE. The downregulation of a non-repair use of stem cells, bone production, suggests that repair efforts are prioritized. Other non-repair uses might be downregulated, namely hematologic production, as Dameshek proposed.Recognition that an active process may exist to allocate stem-cell resources would provide new approaches to diagnosis and treatment of cytopenias in liver disease, SLE and potentially other illnesses. In the 1940s and 1950s there were two competing theories to account for the coexistence of cytopenias and splenomegaly. Charles Doan proposed a passive process, splenic sequestration, whereby increased portal pressure causes an enlarged spleen that traps blood components, creating cytopenias. William Dameshek postulated an active process, in which a signal, possibly produced by the spleen, downregulated hematopoiesis . Doan’s In light of current knowledge, Dameshek may have conceded too soon. At least in liver disease and systemic lupus erythematosus (SLE), splenomegaly and cytopenias are poorly correlated with portal hypertension, and there is evidence for downregulation of hematopoiesis, as Dameshek suggested. Splenomegaly and cytopenias, at least to some degree, likely reflect an active process that mobilizes bone marrow stem cells and allocates their distribution among competing demands in response to injury.The theory of hypersplenism is based on the idea of splenic sequestration. Liver damage impedes portal venous inflow, causing elevated portal venous pressure and, in theory, an enlarged spleen. The enlarged spleen is alleged to sequester blood components, causing cytopenias. The theory thus accounts for both the splenomegaly and cytopenias found in association with liver disease .Portal hypertension leading to splenic enlargement and sequestration is not, however, a clean explanation of the cytopenias associated with liver disease. Despite the suggested causal relation, spleen size does not correlate with portal pressure . FurtherA patent surgical splenorenal shunt or a transjugular intrahepatic portosystemic shunt (TIPS) will reduce portal venous pressure, yet will neither resolve pre-existing cytopenias nor prevent the development of new cytopenias , 9. ThisOther factors that potentially contribute to cytopenias in liver disease have been proposed, including insufficient thrombopoietin (TPO) production by the liver, and marrow injury due to hepatitis viruses, alcohol abuse and poor diet . There aTPO levels in liver disease appear to be variable, and lack of TPO does not suggest a reason for splenomegaly nor for cytopenias other than thrombocytopenia –16. NutrAn alternative explanation is that splenomegaly in liver disease and SLE is part of a response to increased demand for stem cells needed for organ repair and triggered by a rise in serum G-CSF. G-CSF administration mobilizes stem cells from marrow with a side effect being enlargement of the spleen . Serum GIn addition to splenomegaly and cytopenias, liver disease and SLE are also characterized by the development of osteopenia that is not explained by hypersplenism , 30. G-CDownregulation of bone production by the G-CSF mediated process of stem cell mobilization suggests that repair efforts take precedence over the routine marrow activity of bone production. If so, then downregulating hematopoiesis along with bone production would be logical and exactly what Dameshek proposed well before the discovery that bone-marrow-derived stem cells repair damaged organs. Clinical observations and experimental work indicate that bone marrow stem cell resources are finite; thus, allocation between competing uses would be needed.In the years since Doan’s theory superseded Dameshek’s, there have been reports of inhibition of bone marrow culture by sera from cytopenic SLE patients and from cirrhotics, as Dameshek had postulated , 33. At The discovery that liver injury is repaired in part by bone-marrow-derived stem cells has shown that in liver injury there is a demand for stem cell resources . EckerslThe mobilization of stem cells from bone marrow involves cytokine signaling including G-CSF. Clinically, G-CSF is used to mobilize stem cells to allow collection, via apheresis, of sufficient numbers for bone marrow stem cell transplantation. One of the side effects of G-CSF administration is enlargement of the spleen. The G-CSF dose is limited to minimize the risk of over-enlargement of the spleen and splenic rupture, which is a reported complication .As administered G-CSF communicates demand for stem cells in bone marrow transplant donors, so may endogenous G-CSF in liver injury. Lemoli et al. noted a significant increase in serum G-CSF following liver injury , with a corresponding increase in the number of stem cells in circulation. Non-hepatic abdominal surgery did not show a similar increase in serum G-CSF .The rise in serum G-CSF does not appear to be restricted to hepatic injury in the form of surgery. Stoiser et al. found significantly increased serum G-CSF in patients with acute malaria who had evidence of concurrent liver injury with elevated serum bilirubin and alanine transaminase (ALT). The effect also does not appear to be limited to acute liver injury . Kaya etSplenomegaly is thus more consistently associated with increased serum G-CSF than with elevated portal venous pressure. G-CSF both mobilizes stem cells and downregulates bone production. Downregulation of bone production, and potentially hematopoiesis, in conjunction with stem cell mobilization would not seem logical unless bone marrow stem cell resources were insufficient to meet all demands simultaneously.Animal experiments and clinical studies have raised the possibility that bone marrow stem cell resources are finite and that insufficient stem cell resources may manifest as cytopenias. The concept of finite stem cell resources has been incorporated into clinical practice in the timing of chemotherapy and bone marrow stem cell collection for autologous stem cell transplantation. Stem cell mobilization is intended to allow collection of sufficient numbers of stem cells for successful transplantation, but this does not work in all cases. Prior chemotherapy is associated with insufficient stem cell collection, which researchers believe is due to the toxicity of chemotherapy to stem cells , 39. To In addition to prior chemotherapy, platelet count at the time of mobilization is a significant predictor of stem cell yield, with lower platelet counts associated with insufficient collection . A histoAnimal experiments are also consistent with reduced stem cell resources manifesting as cytopenias. Seed et al. studied beagles exposed to gamma radiation for 22 hours per day for life with different groups receiving different exposure rates. Platelet and leucocyte counts declined with initial irradiation, but then plateaued. The higher the daily radiation exposure, the lower the plateaus. Despite the ongoing irradiation, the plateaus were generally maintained over an initial 1,000-day observation period. Erythrocyte counts were more resistant to radiation dose and did not decline in the lower exposure groups but did at higher levels .The pattern suggests a process whereby production of erythrocytes is maintained, in preference to platelets and leucocytes, as marrow resources are diminished. The appearance of cytopenias in liver disease also appears to conserve erythrocyte production in preference to platelets and leucocytes. Qamar et al. found that during follow-up (median 54.9 months), patients with compensated cirrhosis developed thrombocytopenia at a median of 28 months, leucopenia at a median of 30 months and anemia at a median of 39.6 months . The simA similar pattern of mortality in irradiated dogs and cirrhotics is also consistent with diminished stem cell resources in liver disease. In irradiated dogs, the risk of death increased with the degree of cytopenias . In cirrIf insufficient stem cell resources result in cytopenias, then we might expect a reduced demand for stem cell resources to allow resumption of normal hematologic production and correction of cytopenias. For example, if freed from the need to support an injured liver, stem cell resources might resume hematologic production. Liver transplantation does reverse pre-transplant cytopenias in most instances, and can do so months prior to any significant decrease in spleen size , 22. Of P < .001) prior to transplant, and had received livers from older donors (P < .04). No significant differences were noted in recipient age, etiology of liver disease, bilirubin level, international normalized ratio (INR), Mayo end-stage liver disease (MELD) score, United Network for Organ Sharing (UNOS) status, or other donor variables. The lower pre-transplant platelet count suggests, as in autologous stem cell transplant patients, reduced stem cell resources. The older donor livers may require more stem cell support from recipients who are already “stem cell poor” [Stanca et al. investigated the persistence of thrombocytopenia after liver transplantation and found that patients with persistent thrombocytopenia had significantly lower platelet counts , Interleukin 17 (IL-17) and Interleukin 23 (IL-23) are critical components of stem cell mobilization, at least in mice. Mice with a genetic defect resulting in chronically elevated serum G-CSF display higher than normal numbers of circulating stem cells. Additionally, these mice have high serum levels of IL-17 and IL-23. Antibody blocking of any one of the three cytokines reduces stem cell mobilization . G-CSF, Splenic embolization has been employed to improve cytopenias in patients with liver disease , 51. TheIn mice, IL-23 is produced in part in the spleen . SplenicThe above in combination suggest not the passive process of splenic sequestration promoted by Doan, but rather, the active management of stem cell resources, employing signaling, including the downregulation of hematopoiesis suggested by Dameshek. A management process diverting bone marrow stem cell resources away from hematologic and bone production, and toward hepatic repair, could thus account for splenomegaly, cytopenias and loss of bone mass observed in patients with liver disease.If there were a mechanism that managed stem cell resources, that mechanism ought to be active not solely in liver disease, but also in other situations where there are competing demands for stem cell resources. Bone-marrow-derived cells can, in fact, incorporate into tissues other than the liver , raisingWith activation of a stem cell allocation mechanism, one might anticipate findings that are due to allocation rather than to the injury that is triggering the allocation process. If the allocation process is active in liver disease, then other disease states that activate the same allocation mechanism might share similar findings: namely, splenomegaly; progressive hematologic abnormalities with associated mortality; osteopenia; evidence of stem cell mobilization signaling, such as elevation of serum G-CSF; and possibly suppression of hematopoiesis. We looked for other disease states that have chronic injury and thus might have activation of a stem cell allocation mechanism. Patients with (SLE) suffer chronic multi-organ injury and have findings matching the above , 53–55.Hematologic abnormalities are common in patients with SLE, and include anemia, leucopenia and thrombocytopenia . Cytopenp = 0.007) [Splenomegaly does occur in SLE, and may be due to a response to demand for stem cell resources rather than portal hypertension. Hellmich et al. found that patients with SLE and neutropenia had a mean serum G-CSF level more than double that of SLE patients without neutropenia (= 0.007) . ElevatiMore extensive injury could be expected to generate greater demand for stem cell resources for repair. Splenomegaly in SLE patients does correlate with SLE disease activity, in that patients with more severe disease were found to have larger splenic volumes .Again paralleling liver disease, patients with SLE may develop osteoporosis. The elevated serum G-CSF noted by Hellmich might contribute, at least in patients with sufficient stem cell demand to have chronic elevation of serum G-CSF . In factThere may be downregulation of hematologic production in SLE as in liver disease. Pyrovolaki et al. have reported upregulation of apoptosis of hematopoietic progenitor cells in SLE patients . DainiakIrradiated dogs and patients treated with chemotherapy have cytopenias attributable to reduced bone marrow stem cell resources. We have suggested that the cytopenias in liver disease may also reflect limited stem cell resources, due not to destruction of stem cells, but rather to diversion of stem cells to repair efforts. Cytopenias in patients with SLE may also reflect reduced stem cell resources due to repair efforts. Statkute et al. reported that SLE patients had significantly lower stem cell mobilization than patients with multiple sclerosis treated with the same mobilization regimen .The contribution of bone marrow stem cells to the repair of organs was unknown at the time when Doan and Dameshek developed their theories to account for the association between liver disease, splenomegaly and cytopenias. The discovery that bone marrow contributes to organ repair has two relevant consequences. One, that there is a normal sequence of events in a response to a demand for stem cells; and two, that there may be competition for stem cell resources in the event of an injury.The normal response to stem cell demand appears to include splenic enlargement as demonstrated in bone marrow stem cell donors, where G-CSF administration both mobilizes stem cells and causes splenic enlargement. That enlargement is not accompanied by a drop in platelet count, and in fact white blood cell counts increase, suggesting that cytopenias are not due to spleen size alone nor to G-CSF directly , 7. The If spleen size is not altered by portal pressure in liver disease, then by what is it altered? The elevated serum G-CSF reported in two studies of patients with liver disease suggests an alternative, that splenic enlargement in liver disease is, as in bone marrow donors, part of the normal response to demand for stem cells , 28. ConInjury that triggers stem cell demand for organ repair will increase the total demand for bone marrow stem cells. Unless stem cell resources are infinite, this added demand might result in a need for prioritization. Experience with cancer patients and irradiated dogs indicates that stem cell resources are not infinite, and that low stem cell resources may be evidenced as cytopenias , 40. WhiIf stem cell resources are finite, then non-repair uses for stem cells might be downregulated in the event of injury, an active process such as Dameshek envisioned. G-CSF does inhibit bone production while mobilizing stem cells from bone marrow . This suThe above is neither intended to provide a comprehensive explanation of the cytopenias of liver disease and SLE, nor to try to simplify the interactions among bone marrow, spleen, and blood components. On the contrary, an active process would add complexity by suggesting that there is at least some contribution by a process not currently recognized. How much of a contribution to cytopenias an active suppression of hematopoiesis might make is unclear. Cytopenias are most likely multifactorial, and downregulation of hematopoiesis would more likely have identifiable effects in chronic rather than acute injury. Acute malaria causes liver injury with increased serum G-CSF, yet hematologic abnormalities can be present within days of onset of symptoms, sooner than would be expected due to an altered rate of production , 60.Cytopenias in SLE are likely to be particularly complex in nature. There are more than 100 autoantibodies reported in SLE, including autoantibodies to platelet glycoproteins thought to result in platelet destruction , 62. In Although Dameshek may be correct in that there is an active process suppressing hematopoiesis, this does not mean that Doan’s theory of sequestration is entirely incorrect. While evidence that portal pressure affects spleen size is lacking, blood components can be trapped in the spleen. Note that in primary immune thrombocytopenia, tagging platelets with Indium 111 often demonstrates platelet sequestration in the spleen, and that in this disease splenectomy can be effective in relieving thrombocytopenia .On the whole, the current evidence does support Dameshek’s theory that there is suppression of hematopoiesis, at least in some instances.The existence of an active signaling mechanism directing allocation of stem cell resources would raise the possibility for errors of that system. For example, over-suppression of hematologic production might account for some cases of cytopenias, notably those that occur following viral hepatitis .Knowledge that a signaling mechanism may be in action directing the flow of stem cell resources could aid in the work-up of anemias. Evaluation of anemia in patients with SLE, liver disease or other chronic illness could include evaluation of stem cell demand, such as obtaining serum levels of IL-23 and G-CSF.A signaling mechanism could also provide an opportunity for therapy. Rather than treating cytopenias in patients with liver disease by embolizing portions of the spleen, clinicians could seek agents that block the routing of stem cells to repair. This would have the disadvantage of reducing repair efforts, but would also offer the potential to lessen cytopenias without permanent damage to the spleen.


Pancreas transplantation has emerged as an effective treatment for patients with diabetes mellitus, especially those with established end-stage renal disease. Surgical and immunosuppressive advances have significantly improved allograft survival. The procedure reduces mortality compared with diabetic kidney transplant recipients and wait listed patients. Improvements in diabetic nephropathy and retinopathy have also been demonstrated. Pancreas transplantation can improve cardiovascular risk profiles, improve cardiac function and decrease cardiovascular events. Lastly, improvements in diabetic neuropathy and quality of life can result from pancreas transplantation. Pancreas transplantation remains the most effective method to establish durable euglycemia for patients with diabetes mellitus. Diabetes mellitus afflicts about 6% of the general population; it is currently the third most common disease and the fourth leading cause of death by disease in the United States. Of the estimated 21 million diabetic individuals in the United States, 1 to 2 million has insulin-dependent diabetes mellitus (IDDM). Nearly 300,000 new cases of IDDM are diagnosed each year, and the incidence is increasing [1]. Pancreas transplantation has assumed an increasingly important role in the treatment of IDDM. It is currently the only available treatment that reliably provides an insulin-independent state, resulting in euglycemia and normal glycosylated hemoglobin levels by re-establishing endogenous insulin secretion responsive to normal feedback controls  transplant), where the kidney graft is obtained from either a living or deceased donor. The usual indication for this procedure at most centers is a type 1 diabetes patient with ESRD.Simultaneous Pancreas-Kidney (SPK) Transplantation In SPK transplantation, the pancreas and kidney are usually obtained from the same deceased donor. Therefore, changes in kidney function can be used to determine whether rejection is occurring in either organ -6.Pancreas-after-Kidney (PAK) Transplantation This is the second most common pancreas transplant procedure. The indication for this procedure is a patient with type 1 diabetes who has identified a living donor for kidney transplant and wants to plan a later PAK transplant, or the type 1 diabetes patient who already has a kidney transplant that has stable graft function, desires the potential benefits of euglycemia, and has the cardiac reserve to undergo the procedure -7.Pancreas Transplant Alone (PTA) Pancreas transplant alone is the least common pancreas transplant procedure performed. Frequent, severe, hypoglycemic events are the most common indication for this procedure. The American Diabetes Association position statement suggests that indications for pancreas transplant (in the absence of kidney failure) are “frequent, acute and severe metabolic complications  requiring medical attention” as well as “clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating; and consistent failure of insulin-based management to prevent acute complications” .SURGICAL ISSUES IN PANCREAS TRANSPLANTATIONBladder vs. Enteric Duct Management With bladder drainage (BD), urine amylase can be used as a marker of graft function. Biopsies of the pancreas graft are also easily obtained across the bladder wall through cystoscopy. However, this procedure also creates potential complications. Metabolic acidosis occurs in most cases, and extracellular volume depletion is common, occasionally severe enough to require hospitalization; both complications are due to the loss of sodium bicarbonate-rich pancreatic secretions into the urine. Additional problems that can complicate BD include bladder leak, reflux pancreatitis, particularly with neurogenic bladder, chemical cystitis/urethritis, and frequent bladder infections, duodenitis in the connecting segment, bladder tumors, bladder calculi, urethral stricture, urethral erosion, epididymitis, prostatitis, and prostatic abscess. The frequency of urological complications is high (50%–77%), but they rarely result in graft or patient loss.The alternative to BD is enteric drainage (ED) of the exocrine duct. In this procedure, the pancreatic duct is inserted into the small bowel using a small “button” of duodenum or with a Roux-en-Y limb. There is less need for monitoring the pancreas graft, overall, because immunosuppression has improved and frequency of rejection episodes has decreased after pancreas transplant of all types. Indications for enteric conversion surgery (20%–25%) are frequent episodes of severe extracellular volume depletion, severe metabolic acidosis, urological complications, or problems with the duodenal segment.SPK transplants performed with either BD or ED have equal pancreas graft survival.Portal vs. Systemic Venous Drainage When placed in the systemic circulation—called systemic venous drainage (SVD)—the insulin secreted into the pancreatic venous effluent is not extracted immediately by the liver, as it would be if it emptied into the portal circulation. Systemic concentrations of insulin, both fasting and postprandial, are elevated as a result. Subsequently, a procedure was developed where the graft was placed in the portal circulation and the pancreatic duct was drained into the small intestine. This combined portal venous drainage (PVD) with ED procedure resulted in much lower peripheral insulin concentrations than pancreas transplant recipients with SVD, comparable to nondiabetic kidney transplants receiving similar immunosuppression.COMPLICATIONSThe complexity of the whole pancreas transplant procedure, along with the likelihood of pre-existing disease secondary to their diabetes, exposes the recipient to a variety of significant operative and post-operative risks. The extent of the post-operative problems likely limited the widespread acceptance of pancreas transplantation in the early era of its development. Serious surgical complications following the procedure include thrombosis of graft vessels, intra-abdominal hemorrhage, anastomotic leak (enteric or bladder), graft pancreatitis, pancreatic fistula formation and intra-abdominal sepsis, all of which may require re-laparotomy and the possibility of graft loss. In recent years, with improvements in donor and recipient selection criteria, surgical technique, immunosuppression protocols (reduced incidence of early and acute rejection), and prophylaxis regimes , there has been a significant decrease in the overall incidence of serious complications and the rate of re-laparotomy.IMMUNOSUPPRESSIONThe most common regimen in all pancreas transplant categories in 2000 was tacrolimus/mycophenolate mofetil  with cyclosporine/MMF a distant second (5%–20%) . The comMany centers still use corticosteroids in their immunosuppression protocol, which may allow a reduced dose of calcineurin inhibitor, but others have tried to move to a “steroid-free” protocol with the assumption that this will decrease risk of weight gain, glucose intolerance, dyslipidemia, and bone loss.The results of clinical pancreas transplantation continue to improve as immunosuppressive strategies become more targeted. Although corticosteroid withdrawal or avoidance is a clinical reality, particularly in SPK and PAK recipients, CNI minimization or elimination remains a work in progress. Induction immunosuppression is routinely used in whole pancreas transplantation, with >75% of recipients receiving either 1) a T-cell depleting polyclonal antibody  or monoclonal antibody ; 2) a non-depleting monoclonal anti-CD25 antibody ; or 3) both. The initial results with alemtuzumab induction appear quite promising, although it appears to be more effective when used as a conventional induction agent rather than a tolerance-inducing or maintenance immunosuppressant. In SPK recipients, both T-cell depleting and non-depleting antibody agents for induction have been used, whereas in solitary PTX, the use of T-cell depleting antibodies has been greater. Monotherapy can be achieved in a proportion of patients, but it remains unclear which regimen is most effective and safe. Future clinical studies will continue to focus on long-term outcomes, appropriate donor and recipient selection, immunologic monitoring, immunosuppressive reduction, and outcomes-based research.RESULTS AND OUTCOMEWhole-organ SPK transplant with normal graft function consistently improves 7- to 10-year patient survival compared with deceased donor kidney transplant, SPK transplant with loss of pancreas graft function, or dialysis in type 1 diabetic patients waiting for a transplant .Patient survival after SPK transplant is consistently better than that observed after cadaveric-donor kidney transplant, with the possible exception of recipients over age 50. Although this advantage may, in part, be due to improved glucose after SPK transplant compared with kidney transplant alone, differences between the recipients who undergo these procedures, and between the donor grafts used for these two procedures, would likely also contribute to the difference in survival described between these two procedures. Mortality after SPK transplant is equal to living-donor kidney transplant alone after 10 years, and both PAK and pancreas transplant alone may increase 4-year mortality compared with remaining on the waiting list for those procedures. In these cases, specific quality of life (QOL) concerns and impact of pancreas transplant on specific diabetic complications need to be weighed against potential early increase in mortality before these procedures are considered.Whole pancreas transplantation has proven to be a safe procedure with a 1- and 3-year patient survival rates for all forms of pancreas transplant  in the US since 1998 at almost 95%, and 89%, respectively  [Serum glucose level normalizes immediately after pancreas transplant, at the expense of hyperinsulinemia if SVD is used. Insulin secretion demonstrates oscillations despite denervation, as well as normal first- and second-phase secretion responses, unless there is a decrease in graft function or increased insulin resistance. C peptide concentrations are often slightly elevated, both basally and after mixed meal stimulus, but similar to those of non-diabetic kidney transplant recipients. Although fasting proinsulin is increased, it does not necessarily represent failing graft function, and glucagon response to hypoglycemia improves over time. Glucagon and symptom response to hypoglycemia return to normal or near normal over time; epinephrine and growth hormone responses though improve do not become normal after pancreas transplant. Hypoglycemic symptoms and documented events are uncommon and tend to diminish over time but may be due to a variety of factors. It should be cautioned that glucagon secretion in response to hypoglycemia does not improve with either allo- or auto-transplantation of islets into the liver, in human or animal studies, as described with pancreas transplant, and may be related to their location in the liver .Diabetic nephropathy can be prevented by a functioning pancreas graft, and pathological changes of diabetes can reverse over time after more than five years of normal pancreas function . DiabetiThe most common cause of death in diabetes and transplant patients is vascular disease. Improved glucose control, as with SPK transplant, can improve vascular reactivity and microvascular integrity and responses, but other factors after transplant may prevent or minimize these improvements in some patients . ChangesISLET CELL TRANSPLANTATIONIslet cell transplantation is an attractive alternative therapy to conventional insulin treatment or vascularized whole pancreas transplantation for type 1 diabetic patients by islet cells isolation from donor pancreata and embolization into the recipient liver via the portal vein. Compared to pancreas transplantation, islet cell transplantation is technically much simpler , has lower morbidity and offers the opportunity for storage of the islet graft in tissue culture or cryopreservation for banking -15.With recent advances in methods of islet isolation and the introduction of more potent and less diabetogenic immunosuppressive therapies, islet cell transplantation has progressed from bench to clinical reality. Presently, several international centres have demonstrated successful clinical outcomes with high rates of insulin independence after islet transplantation . OngoingOver the past few years, there has been tremendous progress in clinical islet transplantation, from refinements of the Edmonton Protocol to novel strategies for improved islet isolation, implantation and recipient immunosuppression. One of the most critical areas of research is the islet isolation procedure, which remains highly labor intensive, expensive and relatively inconsistent. Even the highest grade preparations only recover about 20%–50% of the potential islet mass. Moreover, rates for successful islet isolation at leading centers vary from 25% to 75%, depending largely on the quality of the pancreas, the amount of cold storage and the heterogeneity of collagenase preparations -15.As islet transplantation moves forward, one of the first challenges is to reliably achieve insulin independence with single-donor grafts. Based on experience with islet auto-transplantation after total pancreatectomy, a minimum of 300,000 islets are necessary to achieve insulin independence in 70% of recipients . This isDevelopment of novel immunosuppressive protocols using more specific and less toxic drugs, ultimately towards inducing tolerance, is an important step in applying islet transplantation earlier in the course of the disease, including transplantation in children. Moreover, advances in identifying other sources of islet cells, together with progress in better understanding the biology of diabetes, will help increase the limited supply of islets through gene therapy, stem-cell biology techniques or xenotransplantation. It is anticipated that continued international collaboration will further stimulate excitement in the field, as innovative solutions are created to meet the remarkable challenges that lie ahead.


Research exploring links between exercise and depression now span several decades, yet several clinically relevant research questions remain unanswered. This opinion article briefly describes the status of selected research issues from the exercise depression literature and offer insights into research areas that are currently lacking. We draw particular attention to the potential of research exploring links between sedentary behavior and depression.To date, the strongest evidence on the benefits of physical activity in depression comes from randomized controlled trials (RCTs), in which changes in depression severity have been assessed before and after a prescribed exercise intervention . Meta-anRecently, physical exercise interventions have also been compared to Internet-delivered treatments for depression. In the largest community-based effectiveness trial of exercise for depression, Hallgren et al. randomized 946 outpatients to one of the three 12-week interventions: prescribed physical exercise, Internet-based cognitive behavioral therapy (ICBT), and usual care by a physician, consisting of brief CBT-focused therapy and antidepressant treatment . Superviexercise on mental health outcomes. However, exercise is only one subtype of physical activity, involving planned, repetitive movement, purposefully engaged in to improve fitness and/or health  and depression in children and adolescents . The anaEvidence supporting an association between sedentary behavior and depression in adults is growing but currently limited by methodological weaknesses . MoreoveSuch research questions could be addressed through RCTs, with the aim of examining the effectiveness of physical activity interventions targeting sedentary behavior, and through prospective cohort studies, where the same individuals are tracked over time using objective assessments of daily activity. RCTs should be adequately powered, should involve an active control group , and should include long-term follow-up assessments to determine the maintenance of treatment response.via influences on the 5-HT system and interactions with adiposity. Cytokine activation of indoleamine-2,3-dioxygenase leads to relative depletion of tryptophan (TRP) and accumulation of kynurenine (KYN), a neurotoxic by-product shown to induce depression (The mechanisms underlying relationships of exercise, physical activity, and sedentary behavior with improved depression remain understudied. A myriad of biologically plausible factors have been implicated as putative exercise-related mechanisms, including altered 5-HT, NE, and BDNF , 27, incpression . Importapression . The autpression .Higher levels of adiposity may function as both a precursor and a consequence of depression, reflecting a bidirectional relationship that may be driven partly by inflammation . For exaFor sedentary behavior, there is evidence – albeit not specifically in the context of depression – identifying relationships with C-reactive protein and other inflammation-related markers , 39. HowIn sum, evidence-based treatment for depression continues to expand, but successful treatment and maintenance of treatment response remain limited. Thus, there is a continued need for research into factors that predict successful treatment outcomes. Further research is certainly needed into the effects of planned exercise on depression, including the optimal dose–response and underlying causal mechanisms. However, additional longitudinal studies are also necessary to better understand the complex relationship between habitual physical activity, sedentary behavior, and depression severity. Importantly, these investigations should include children and adolescents. Studies that attempt to assess how changes in levels of activity and inactivity may moderate/mediate the response to empirically supported depression treatments will be particularly relevant. From a public health perspective, it may also be relevant to determine whether those who meet the minimum physical activity levels recommended for general health  respond With the emerging evidence on the distinct impacts of health outcomes on sedentary behavior – too much sitting as distinct from too little exercise – there is an even broader focus on the overall physical activity spectrum, including the light-intensity physical activities that can displace significant amounts of sedentary time . Such brInterventions that encourage an overall lifestyle change oriented toward more activity and less sedentary behavior will likely benefit this patient group. However, further research is needed to better understand the plausibly influential roles of both activity and inactivity in this prevalent disorder.Mats Hallgren initiated the article and wrote the first draft. All coauthors provided input into subsequent revisions.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.


Intracranial tumors are the second most frequent malignancies in children and posterior fossa is a common location for these neoplasias during childhood. Recent advances in surgical techniques, radiotherapy and chemotherapy resulted in dramatic increase in the survival rates of these children, however they are still source of a significant morbidity and mortality. Endocrinological complications and late sequelae of childhood posterior fossa tumours are common among the survivors of these tumours and include growth retardation, hypothyroidism, pubertal disorders, gonadal dysfunction and osteopenia. These complications have significant impact on the quality of life of the survivors of childhood posterior fossa tumours. In this paper, the frequency, etiology, and management of these complications will be reviewed. Primary malignant central nervous system (CNS) tumors are the second most common malignancies in children and are the most common pediatric solid organ tumor . The mosIn most patients with posterior fossa tumors, a combined modality approach that includes surgery, radiation therapy and CT is used in the treatment. Long-term survival is now achieved in majority of the patients, but each component of therapy have a potential to cause late complications that have a profound effect on quality of life in survivors. Endocrine-reproductive problems are among the most common late sequelae in survivors of childhood cancers in general, and in posterior fossa tumors . These pMedulloblastomas are the most extensively studied posterior fossa tumours in regard to endocrine late consequences. Medulloblastomas are treated with external beam RT to the craniospinal axis, in addition to a boost to the tumor site, after surgical excision of the tumor . ContempNew studies focuse on investigating the use of reduced posterior fossa high dose volume boost in order to prevent normal brain tissue from excess radiation exposure. Contemporaray, techniques, such as intensity modulated RT and proton radiation therapy, are under evaluation to limit radiation exposure to normal tissues . AlthougBecause of the above mentioned risks and serious complications, the initial management of childhood medulloblastoma include adjuvant CT with decreased doses of RT in average-risk children or substituted CT for RT in the initial management of infants and young children. However, CT itself has unwanted long-term effects especially on the gonads. Depending on the cumulative doses, cyclophosphamide, Ifosfamide, meclorethamine, procarbazine, busulfan, melphalan and cisplatin are associated with gonadotoxicity in both sexes .Growth velocity and adult height of pediatric posterior fossa tumour survivors may be negatively influenced by both endocrine and non-endocrine factors. Non-endocrine factors are mainly radiation-induced direct damage to the vertebral growth plates. Spinal irradiation damages both the epiphyseal plates and the bony matrix. Children treated with spinal irradiation often have stunted spinal growth, which becomes more prominent during adolescence . BesidesGH deficiency may also contribute to suboptimal growth in some of these children. In general, GH is the most sensitive hormone to radiation-induced damage, and GH deficiency is therefore, the most common endocrinopathy seen in pediatric cancer survivors following cranial irradiation. GH deficiency develops in a dose- and time-dependent manner with the risk increasing above the doses higher than 18 Gy of radiation and the time interval increases from treatment . It has Early recognition of suboptimal growth in children with posterior fossa tumours are important and requires regular and precise monitoring of both standing height and sitting height measurements. After reviewing the child’s growth curves and treatment-related risk factors, GH provacation tests are indicated in most cases with documented suboptimal growth. Failure in two GH stimulation tests, using two different pharmacologic stimuli, is required for the diagnosis of GH deficiency. In patients who received irradiation, insulin-induced hypoglycemia may be the most sensitive and reliable pharmacologic test of GH status, however because it carries the risk of serious hypoglycemia-related events, it should be performed only in experienced clinics under close surveillance. Insulin-like growth factor-1 (IGF-1) and IGF-binding protein 3 (IGF-BP3), which are commonly used as surrogate markers of GH secretion in children assessed for short stature, are not reliable indicators of GH status following cranial irradiation or documented hypothalamic-pituitary injury due to tumoral expansion . In chilOnce the risks and benefits have been carefully discussed, GH therapy can be provided to patients with GH deficiency. Several prognostic factors in regard to adult height was identified. In a report of 183 childhood cancer survivors treated with GH, higher final height was associated with a younger bone age at the time of initiation of GH and higher doses of GH, while a higher dose of spinal irradiation was negatively associated with final height .Survivors of childhood posterior fossa tumours develop hypothyroidism in varying frequency and the etiology of hypothyroidism depends on the exposure and the dose of radiation. Since both neck and hypothalamopituitary area may have exposed to radiation, the patients can develop primary hypothyroidism, central hypothyroidism or a mixed form of hypothyroidism. The diagnosis of primary hypothyroidism is based on high serum TSH levels and low serum free thyroxine (fT4) values, whereas in central and mixed hypothyroidism low fT4 is accompanied by a normal or modestly elevated TSH. In a study investigating thyroid dysfunction in pediatric posterior fossa tumours, hypothyroidism was found in 12/23 patients in the course of treatment, in 2 patients hormone deficits diagnosed directly after irradiation, in 10 patients, hypothyroidism was observed at the completion of the whole therapy .In survivors of medulloblastoma, both primary and central hypothyroidism has been reported. Primary hypothyroidism is seen more commonly than central hypothyroidism (38% and 19% respectively) . Age is Exposure of radiation to neck during craniospinal irradiation in children with posterior fossa tumours pose a risk for both benign and malignant thyroid neoplasms . The raiHypogonadotroic hypogonadism or gonadal damage may cause delayed or arrested puberty depending on age in the survivors of childhood posterior fossa tumours. Those who have already reached sexual maturity can also develop treatment-related luteinizing hormone (LH)/follicle-stimulating hormone (FSH) deficiency. Presentation in adul females includes secondary amenorrhea, and in males, loss of libido, erectile dysfunction, and reduced energy.Delayed puberty is defined by the absence of breast development in girls by 13 years of age and testicular size less than 4 ml in boys by 14 years of age. Absence of progression or completion of puberty that had already started is called arrested puberty. The patients who are treated with radiation doses >30 to 40 Gy to the hypothalamic-pituitary axis are at risk for deficits of LH and FSH called hypogonadotropic hypogonadism (low Serum FSH and LH levels)  measuredHypogonadotropic hypogonadism in survivors of posterior fossa tumors results from radiation exposure of brain, whereas primary gonadal failure may result from both radiation exposure to gonads and/or damaging effects of CT to the gonads. Ovarian  and testThe human testis has two primary functions: sperm production and testosterone production. One or both of these functions may be damaged by cancer treatment. Germ cells and Sertoli cells form the seminiferous tubules where spermatogenesis occurs; Leydig cells are responsible for the production of testosterone.The following chemotherapeutic agents are associated with impaired spermatogenesis, which is dependent on the cumulative dose : MechlorLeydig cells are susceptible to radiation-induced damage at higher doses than those associated with germ cell dysfunction and the risk is directly related to testicular radiation dose and inversely related to age at treatment . The majOvarian dysfunction may result from treatment with gonadotoxic CT , or radiation-induced damage to the ovaries ,32,35,39In survivors of CNS malignancies, or those treated with cranial RT, puberty may progress at a rapid tempo with accelerated skeletal development resulting in short stature ,46,47,48ACTH deficiency is not a frequent endocrinopathy in posterior fossa tumour survivors and if present, it is related to high-dose irradiation >30 Gy to hypothalamo-pituitary area resulting in ACTH deficiency ,50. TranDual energy x-ray absorptiometry (DEXA) has traditionally been used to determine BMD. However it is important to emphasize that the results obtained with DEXA in children and adolescents must be interpreted according to age, height, and pubertal stage using normative Z-scores rather than T-scores. Children who have undergone irradiation for posterior fossa tumors have diminished total body and lumbar spine BMD, as compared with those of the general population ,52,53. IIn addition to radiation and gonadotropin deficiency, GH deficiency may contribute to low BMD in survivors of posterior fossa tumours. Sedentary lifestyle and suboptimal nutrition, which is often problematic in these group of children may also worsen BMD. Subjects at high risk for low BMD and those who experience fractures should undergo screening with bone density studies at entry into a long-term follow-up program. Calcium and vitamin D supplementation, and regular weight-bearing exercise should be encouraged in these children with borderline or low BMD. Sex hormone and GH replacement therapies should be implemented in those with hormone deficiencies to prevent pathological fractures, thus improving the quality of life.Peer-review: Internal peer-reviewed, Financial Disclosure: The author declared that this study has received no financial support.


It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression. Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES  Both hyin utero estrogen levels increase later breast cancer risk is that data must be available for both fetal hormonal environment and breast cancer incidence approximately 50 years later. These data can be obtained from daughters whose mothers took the synthetic estrogen diethylstilbestrol (DES) during pregnancy.The reason why high birth weight is linked to increased breast cancer risk may be due to elevated pregnancy estrogenic environment , but alsin utero for Continuation of Follow-up of DES-Exposed Cohorts trial .In the early 1940s, physicians started prescribing DES to pregnant women who exhibited signs of being in danger of having a miscarriage. The rationale for this practice was that miscarriage is preceded by a drop in estrogen levels, and providing women with estrogen might help to sustain the pregnancy. However, Herbst and colleagues  discoverin utero DES exposure and breast cancer are discussed for the purpose of weighing evidence as to whether fetal hormonal environment can impact breast cancer risk in women several decades later. Since causal studies can readily be performed using animal models, findings obtained in DES-exposed mouse and rat offspring also are discussed. Importantly, animal studies were done prior to any epidemiological studies addressing a possible link between maternal DES exposure and breast cancer risk among daughters could be performed. By the 1980s, exposed daughters in the cohorts began to be old enough to develop breast cancer and several human studies have been performed since to determine if maternal exposure to DES during pregnancy increases an offspring’s breast cancer risk.In this review, findings related to The idea that DES prevents miscarriage was tested in the 1940s by Smith and Smith ,7 in a cDES Timeline [The exact number of women who used DES is not known, but it is estimated to have been between 5 to 10 million women worldwide. These numbers may be an underestimation, as DES was marketed by several drug companies and under several different trade names and was included in some prenatal vitamin preparations. Further, in 1954 DES use was approved for livestock to promote growth, and two years later approximately two-thirds of US beef cattle were treated with DES [Timeline , DES prein utero or neonatal DES exposure on mammary gland development [Since estrogens are linked to increased breast cancer risk, and since maternal DES exposure induces cancers in the offspring’s reproductive tissues, a concern rose that daughters exposed to DES might exhibit increased risk of developing breast cancer. Animal studies were first done to investigate the effect of elopment -15 and lelopment -21; theyThe animal studies show that the doses of DES relevant to pregnant women increased later risk of developing mammary tumors. Specifically, female offspring of rat dams exposed to a total of 1.2 μg DES either on gestation week 2 or 3 , to 0.6 in utero estrogenic environment impacts the development of the mammary gland, which begins with the formation of the mammary lines on gestational day 10 in the mouse and rat [in utero exposure to DES leads to an increase in TEB numbers [In addition to an increase in mammary tumorigenesis in animal models, high  and rat . Ductal  and rat ,26. At p and rat . TEBs gi and rat , and cor and rat . Further and rat ,29. Afte and rat ,31. Impo numbers ,32. It iSeveral published studies have investigated breast cancer risk in the daughters of DES mothers, the majority of which were cohort studies done in the US. As the women in the cohorts aged, their breast cancer risk grew higher, compared with matched non-exposed controls ,33-36. Tin utero DES exposure and mammographic density. However, since a surrogate marker of having been exposed to elevated pregnancy hormonal environment - high birth weight - is associated with increased mammographic density [Density of TEBs in rodents might be modeling mammographic density in women. Mammographic density is determined as a ratio between epithelial area containing the epithelial and stromal/connective tissue cells, and the whole breast . Mammographic density thus reflects the number of epithelial cells, especially terminal ductal lobular units , and it  density , it is pin utero estrogen-exposed females is caused by a high number of mammary stem cells or an increase in their potential to generate daughter cells. Our unpublished data support this conclusion and show that in utero exposure to the synthetic estrogen ethinyl estradiol increases the stem-cell like population in the developing mammary gland.To summarize, animal and human studies have generated similar findings and indicate that there is a causal link between maternal exposure to DES during pregnancy and increased breast cancer risk among female offspring. According to animal studies, the increase in risk may reflect the presence of a higher number of TEBs in the mammary epithelium in the DES offspring. Baik and colleagues  have proin utero DES exposure would induce mutations in the mammary tissue [When determining how maternal exposure to DES during pregnancy can impact mammary gland development and breast cancer risk, several questions need to be answered. First, what are the changes in the fetal mammary gland caused by DES? Second, how are these changes maintained to adult life? The second point is especially important, since there is no evidence that y tissue , or thaty tissue ,35.in utero or neonatal exposure to estrogens, including DES, alters fetal and neonatal mammary gland development in humans [Several signaling factors, expressed in the epithelial cells and mesenchyma, have been identified that are critical for fetal mammary gland development ,26. Inten humans  and micen humans . A likeln humans -50.in utero. Umekita and colleagues [Relatively little is known about long-term changes in the transcriptome of the mammary glands in animals exposed to estrogenic compounds lleagues  investiglleagues . The moslleagues . NF-kB illeagues  and antilleagues , and amolleagues .in utero environment are likely to have been epigenetically induced. This is because the epigenetic signature in all fetal cells, including germ cells, is established during early development and the signature then interprets the information in the genetic code that is inherited from both parents by means that do not involve a change in DNA sequence [There is general agreement that the changes in the transcriptome of adult tissues found to be affected by alterations in the sequence .Gene expression can be altered as a consequence of mutations or epigenetic changes. In contrast to gene mutations within the DNA, epigenetic changes involve post-transcriptional modifications; that is, methylation of gene promoter regions, histone modifications, deposition of certain histone variants along specific gene sequences and microRNA (miRNA) expression. Although both changes are heritable, an important distinction between the two is that mutations are not reversible, but epigenetic modifications generally are.3) onto the 5-carbon of the cytosine ring within CpG dinucleotides. Histone modifications are complex, as they involve not just histone methylation but also acetylation, deacetylation and other post-translational changes. These modifications occur in the amino-terminal tails of histones and affect the 'openness' of the chromatin, which determines whether a gene is expressed or silenced  [Probably the most common mechanism of epigenetic gene silencing is methylation , and it ription) ,57. Trimription) ,59. PcG/ription) ,61, and ription) . Over 2,ription)  and theyription) -66. As dDNMTs may be key players in regulating histones and the entire epigenomic machinery, since DNA methylation events often precede histone modifications . UpregulIn utero exposure to DES is reported to increase the expression of DNMT1 in the epididymis [in utero.We and others have observed that the expression of DNMTs is persistently altered in estrogen-regulated tissues following estrogenic exposures during early life. ididymis  and uterididymis . We founididymis . These cIn utero DES exposure alters methylation patterns of several genes in estrogen’s target tissues, including Hox genes [in utero to the synthetic estrogen ethinyl estradiol using global sequencing approaches [ox genes ,73, c-foox genes , and Nsbox genes , but it proaches . Among tin utero has been reported [As an increase in EZH2 expression in the mammary glands of mice exposed to DES reported , histonereported  recentlyreported . Similarreported  and exprreported  in the uin utero exposure to ethinyl estradiol lowers the expression of many of the same miRNAs in the adult mammary gland [in utero DES-exposed offspring may be a result of epigenetic silencing of miRNAs that target them.Maternal exposures during pregnancy have been found to induce persistent changes in miRNA expression in the offspring. miRNAs are short non-coding single-stranded RNAs composed of approximately 21 to 22 nucleotides that regulate gene expression by sequence-specific base-pairing with the 3’ untranslated region of target mRNAs. miRNA binding induces post-transcriptional repression of target genes , either ry gland  as are dry gland . Since mry gland ,84 or asry gland , and thery gland ,87, the BRCA1 or BRCA2 mutations, are those encoding RARB, ER-α, INK4a/ARF, BRCA1, PRA, PRB, RASSF1A, HIN-1, and CRBP1. Many of these genes also are PcG target genes. Methylation of many other, 'non-tumor suppressor' PcG target genes also are observed in cancer [in utero exposure to synthetic estrogen causes hypermethylation of PcG target genes [Methylation of PcG target genes and tumor suppressor genes in peripheral blood cells, detected years before diagnosis, is associated with increased breast cancer risk, particularly in women with a high familial risk -90. Simin cancer ,92. It hn cancer . Since iet genes  and incret genes , in somein utero estrogenic environment.Several miRNAs are altered in breast tumors in women, compared with normal tissue . There iDeveloping germ cells undergo epigenetic erasure when they, as primordial germ cells, enter into the fetal gonads around embryonic day 10 to 11 (in mice and rats), and then undergo gender-specific reprogramming as germ cells . It is nSkinner’s group  has inveWe have investigated changes in the methylation patterns of the mammary glands in three generations of female offspring of rat dams exposed to ethinyl estradiol or vehicle during pregnancy . A totalDNMT1, DNMT3A and DNMT3B were all downregulated. Effects on female germ cells were not studied, but we and others have found increased DNMT expression in the breast and reproductive tissues in in utero ethinyl estradiol- or DES-exposed animals [in utero.In addition to changes in histones and DNA methylation, miRNA expression may be affected in germ cells by hormonal exposures during early development. Meunier and colleagues  investig animals -71. It iSome researchers have begun to investigate whether the effects of maternal DES exposure during pregnancy extend to the third generation in humans. Although there is no evidence that DES granddaughters have cervical and ovarian abnormalities similar to DES daughters, there is evidence that they may have more menstrual irregularities and a higher rate of infertility than non-exposed granddaughters . In addiMillions of women in the US, Europe and Australia have been exposed to DES in the womb, and consequently exhibit about a two times higher breast cancer risk than unexposed women. The increase in risk may not be limited to the DES-exposed daughters, but could also increase breast cancer risk in granddaughters and great granddaughters. Such outcome would be consistent with the findings we obtained in studies using a synthetic estrogen ethinyl estradiol (EE2) . If DES in utero DES exposure induces epigenetic changes in reproductive tract tissues [in utero. Second, we should investigate whether the transgenerational increase in breast cancer risk can be prevented with drugs that reverse epigenetic modifications. Our preliminary studies in mice suggest that this is achievable in daughters by using the well-tolerated and non-toxic histone deacetylase inhibitor valproic acid and DNMT inhibitor hydralazine. However, whether these compounds also prevent an increase in granddaughters and great granddaughters in experimental models remains to be investigated.To achieve this goal, we need to understand how maternal DES exposure during pregnancy increases a daughter’s breast cancer risk. A plausible model is proposed in Figure  tissues ,72-75,77 tissues . DES expin utero are destined to be at an increased risk of developing breast cancer, and this risk may extend to their daughters and granddaughters as well. It is of critical importance to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.In summary, women exposed to DES DES: Diethylstilbestrol; DNMT: DNA methyltransferase; ER: Estrogen receptor; EZH2: Protein enhancer of Zeste-2; miRNA: microRNA; NF: Nuclear factor; PcG: Polycomb group; Six1: Sine oculis homeobox 1; TEB: Terminal end bud.LH-C has served as an expert witness in a case concerning daughters of DES-exposed mothers on behalf of the plaintiffs.


Emotion dysregulation is a critical transdiagnostic mental health problem that needs to be further examined in personality disorders (PDs). The current study examined dialectical behavior therapy (DBT) skills use, emotion dysregulation, and dysfunctional coping among adults who endorsed symptoms of cluster B PDs and psychopathy. We hypothesized that skills taught in DBT and emotion dysregulation are useful for adults with PDs other than borderline personality disorder (BPD).N = 29), those who reported symptoms consistent with any other cluster B PD (N = 22), and those with no reported cluster B PD symptoms (N = 77) as measured by the Personality Diagnostic Questionnaire-4 + .Using a self-report questionnaire, we examined these constructs in three groups of community adults: those who reported symptoms consistent with borderline personality disorder (BPD; Both PD groups reported higher emotion dysregulation and dysfunctional coping when compared to the no PD group. Only the BPD group had significantly lower DBT skills use. DBT skills use was found to be a significant predictor of cluster B psychopathology but only before accounting for emotion dysregulation. When added to the regression model, emotion dysregulation was found to be a significant predictor of cluster B psychopathology but DBT skills use no longer had a significant effect. Across all groups, DBT skills use deficits and maladaptive coping, but not emotion dysregulation, predicted different facets of psychopathy.Emotion dysregulation and use of maladaptive coping are problems in cluster B PDs, outside of BPD, but not in psychopathy. Inability to use DBT skills may be unique to BPD. Because this study relied exclusively on self-report, this data is preliminary and warrants further investigation. With the advent of the National Institute of Mental Health (NIMH) Research Domain Criteria Project  in 2008Despite not being included in the RDoC framework, emotion dysregulation is one of the most widely supported transdiagnostic mechanisms of disorders. One influential contemporary model defines emotion dysregulation as a multidimensional set of difficulties with: 1) emotional awareness, 2) clarity, (3) acceptance, (4) impulsivity, (5) achieving goals, and (6) use of emotion regulation strategies when upset . Such di emotiona clarity,Diagnostic and Statistical Manual of Mental Disorders, 4thEdition Text Revision (DSM-IV-TR) criteria ) A closer examination of group differences on the different facets of emotion dysregulation highlights similarities and differences between the cluster B PDs. Except for problems with awareness, BPD participants reported significantly higher difficulties in all aspects of emotion regulation when compared to controls. In contrast, those in the NPD, ASPD, and HPD groups only showed impairments in emotional acceptance, clarity (similar to BPD), and use of emotion regulation strategies (better than BPD) when compared with controls. There was no evidence in our sample of impairments in goal directed behaviors and impulsivity when upset in NPD, HPD, and ASPD, although these difficulties were present in BPD, a finding consistent with the literature , 76. TakDimensional differences of emotion regulation between PDs are not unique in the literature. For example, participants diagnosed with BPD, with and without comorbid avoidant PD (AVPD), reported similar but increased difficulties with engaging in goal directed behavior, having emotional clarity and inhibiting impulses when distressed when compared to participants with neither BPD or AVPD . FurtherInterestingly, reported use of DBT skills was significantly lower in the BPD group when compared to the other groups, but similar between those who endorsed other cluster B PDs and those in the no PD group. Nevertheless, those in the BPD, NPD, HPD, and ASPD groups endorsed similar levels of dysfunctional coping that were significantly higher than those reported by control participants. These findings may suggest that although excess of problematic behavior is common in cluster B PDs, deficits in DBT-related skillful behavior may be unique to BPD . It is also possible that the measure for use of DBT skills may not be best fitted to capture DBT skills deficits in participants that reported symptoms consistent with other cluster B PDs and that it may be uniquely tailored for BPD. Some past evidence for NPD and ASPD suggested a different clinical mechanism in these disorders when compared to BPD , which mn = 12), NPD (n = 10), ASPD (n = 2), or HPD (n = 6) exclusively , we could not compare groups formed of specific disorders and decided to combine non-BPD cluster B PDs into a group. Nevertheless, a descriptive examination of the DBT skills use endorsed by those who reported symptoms consistent with only one of the cluster B disorders  for managing stress or solving problems in their lives. These results add to the existing body of literature highlighting the excess of maladaptive behaviors  associated with psychopathy , 53, 87.Neither facet of psychopathy was associated with problematic emotion regulation. These results add to a mixed body of literature connecting the impulsive facets of psychopathy to emotion dysregulation , 71. ForThere were several limitations in the current study. First, the analyses examining group differences were limited by a small sample size, which restricts the statistical power to detect significant differences. Our hypotheses should therefore be tested in larger samples. Second, questions can be raised concerning the personality disorders measure. In addition to the inherent issues regarding the use of self-report for diagnoses, the PDQ has suboptimal psychometric properties and therefore, the hypotheses need to be further analyzed with stricter measures where there is a lower likelihood of false positives. Also, the group names were maintained merely to denote PDs within the B cluster; the current study did not account for other non-cluster B PDs. In addition, the BPD group included comorbidity with any other cluster-B personality disorder. Therefore, it is difficult to differentiate the specific contribution of BPD on skills use (when compared to other cluster-B PDs). Follow-up studies with more rigorous methodologies need to be conducted before making too strong of inferences about these results particularly related to the diagnostic characteristics described in the current study. Third, one-third of the original sample was excluded due to responses deemed suspect on the PDQ validity scales. Considering psychopathy is associated with pathological lying, it is unclear if the suspect answers are a result of not paying attention to the questionnaire, or are an indicator of psychopathology. Fourth, the percentages of participants reporting symptoms consistent with cluster B PDs were higher than prevalence rates reported in previous epidemiological studies . While DSM-5 and our understanding of transdiagnostic mechanisms across those disorders, future research exploring DBT skills use and emotion dysregulation in cluster B PDs and in psychopathy is warranted. Emotion regulation appears to have significant transdiagnostic relevance in the context of cluster B pathologies, but may have less relevance to psychopathy. Considering our findings that DBT skills use deficits may not be as pervasive as hypothesized, one way to interpret these results more broadly is that emotion regulation and DBT skills use may be much more nuanced than they are currently being conceptualized (or utilized). Taking a more multidimensional approach to measuring differences across pathologies is needed in both research and clinical practice to better understand core problems of behavior.Given the evolution of the diagnostic conceptualizations of PDs in the th Edition (Text Revision); DSS, DBT Skills Use Subscale; ELS, Erratic Lifestyle; HPD, Histrionic Personality Disorder; IPM, Interpersonal Manipulation; NIMH, National Institute of Mental Health; NPD, Narcissistic Personality Disorder; PCL-R, Psychopathy Checklist-Revised; PD, Personality Disorder; PDQ-4+, Personality Disorder Questionnaire-4+; RDoC, Research Domain Criteria Project; SQ, Suspect Questionnaire Scale; SRP-SF, Self-Report Psychopathy Scale-Short Form; TG, Too Good ScaleAPA, American Psychological Association; ASPD, Antisocial Personality Disorder; AVPD, Avoidant Personality Disorder; BPD, Borderline Personality Disorder; CA, Callous Affect; CT, Criminal Tendencies; DBT, Dialectical Behavior Therapy; DBT-ST, Dialectical Behavior Therapy Skills Training; DBT-WCCL, Dialectical Behavior Therapy-Revised Ways of Coping Checklist; DERS, Difficulties in Emotion Regulation Scale; DSM-IV-TR, Diagnostic and Statistical Manual of Mental disorders, 4