Childhood maltreatment and adult psychopathology: pathways to hypothalamic-pituitary-adrenal axis dysfunction

OBJECTIVE: The aim of this paper was to examine the relationship between childhood maltreatment and adult psychopathology, as reflected in hypothalamic-pituitary-adrenal axis dysfunction. METHOD: A selective review of the relevant literature was undertaken in order to identify key and illustrative research findings. RESULTS: There is now a substantial body of preclinical and clinical evidence derived from a variety of experimental paradigms showing how early-life stress is related to hypothalamic-pituitary-adrenal axis function and psychological state in adulthood, and how that relationship can be modulated by other factors. DISCUSSION: The risk for adult psychopathology and hypothalamic-pituitary-adrenal axis dysfunction is related to a complex interaction among multiple experiential factors, as well as to susceptibility genes that interact with those factors. Although acute hypothalamic-pituitary-adrenal axis responses to stress are generally adaptive, excessive responses can lead to deleterious effects. Early-life stress alters hypothalamic-pituitary-adrenal axis function and behavior, but the pattern of hypothalamic-pituitary-adrenal dysfunction and psychological outcome in adulthood reflect both the characteristics of the stressor and other modifying factors. CONCLUSION: Research to date has identified multiple determinants of the hypothalamic-pituitary-adrenal axis dysfunction seen in adults with a history of childhood maltreatment or other early-life stress. Further work is needed to establish whether hypothalamic-pituitary-adrenal axis abnormalities in this context can be used to develop risk endophenotypes for psychiatric and physical illnesses.OBJETIVO: A meta deste artigo foi a de estudar as relações ente maus-tratos na infância e psicopatologia no adulto, como reflexo de uma disfunção do eixo hipotálamo-pituitária-adrenal. MÉTODO: Uma revisão seletiva da literatura relevante foi feita para identificar achados-chave e ilustrativos. RESULTADOS: Existe atualmente um volume significativo de achados científicos pré-clínicos e clínicos derivados de paradigmas experimentais, que demonstram que o estresse precoce está relacionado à função do eixo hipotálamo-pituitária-adrenal e a estados psicológicos no indivíduo adulto, e como esta relação pode ser modulada por outros fatores. DISCUSSÃO: O risco para o desenvolvimento de psicopatologia no adulto e disfunções do eixo hipotálamo-pituitária-adrenal está relacionado à complexa interação de múltiplos fatores vivenciais, assim como a genes que levam a uma susceptibilidade, que interagem com estes fatores. Embora as respostas agudas do eixo hipotálamo-pituitária-adrenal sejam geralmente adaptativas, as respostas excessivas podem levar a efeitos deletérios. O estresse precoce pode alterar a função do eixo hipotálamo-pituitária-adrenal assim como o comportamento, porém, o padrão da disfunção do eixo hipotálamo-pituitária-adrenal e a evolução psicológica na vida adulta refletem ambas as características do estressor e outros fatores modificadores. CONCLUSÃO: A pesquisa atual identificou múltiplos determinantes da disfunção do eixo hipotálamo-pituitária-adrenal encontrados em adultos com história de maus-tratos na infância ou outros estressores precoces. Trabalhos futuros são necessários para estabelecer se as anormalidades do eixo hipotálamo-pituitária-adrenal neste contexto podem ser usadas para o desenvolvimento de endofenótipos de risco para doenças físicas ou psiquiátricas.Universidade Federal de São Paulo (UNIFESP) Instituto PROVEBrown University Warren Alpert Medical School Butler HospitalUNIFESP, Instituto PROVESciEL

8-Oxo-7,8-dihydro-2'-deoxyguanosine and other lesions along the coding strand of the exon 5 of the tumour suppressor gene P53 in a breast cancer case-control study.

The next-generation sequencing studies of breast cancer have reported that the tumour suppressor P53 (TP53) gene is mutated in more than 40% of the tumours. We studied the levels of oxidative lesions, including 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), along the coding strand of the exon 5 in breast cancer patients as well as in a reactive oxygen species (ROS)-attacked breast cancer cell line using the ligation-mediated polymerase chain reaction technique. We detected a significant ‘in vitro’ generation of 8-oxodG between the codons 163 and 175, corresponding to a TP53 region with high mutation prevalence, after treatment with xanthine plus xanthine oxidase, a ROS-generating system. Then, we evaluated the occurrence of oxidative lesions in the DNA-binding domain of the TP53 in the core needle biopsies of 113 of women undergoing breast investigation for diagnostic purpose. An increment of oxidative damage at the −G− residues into the codons 163 and 175 was found in the cancer cases as compared to the controls. We found significant associations with the pathological stage and the histological grade of tumours. As the major news of this study, this largest analysis of genomic footprinting of oxidative lesions at the TP53 sequence level to date provided a first roadmap describing the signatures of oxidative lesions in human breast cancer. Our results provide evidence that the generation of oxidative lesions at single nucleotide resolution is not an event highly stochastic, but causes a characteristic pattern of DNA lesions at the site of mutations in the TP53, suggesting causal relationship between oxidative DNA adducts and breast cancer

Correlations between caregiver psychiatric symptoms and offspring psychopathology in a low-resource setting

Objective: Associations between parental/caregiver depression and adverse child outcomes are well established and have been described through one or more mechanisms: child psychopathology following exposure to a depressed caregiver, child psychopathology exacerbating a caregiver's depression, and caregiver and offspring depression sharing the same etiology. Data from low and middle-income countries is scarce. We examined correlations between common symptoms of mental disorders in caregivers and their offspring's psychopathology in a Brazilian sample. Methods: In this cross-sectional study, adult caregivers were screened for depression during routine home visits by community health workers as part of the Brazilian Family Health Strategy. Caregivers with suspected depression were assessed using the Zung Self-Rating Depression Scale and the Self-Reporting Questionnaire (SRQ-20). Children's symptoms were evaluated using the Strengths and Difficulties Questionnaire (SDQ). Results: The sample included 68 primary caregivers and 110 children aged 6 to 15 years. Higher caregiver scores on the SRQ-20 correlated significantly with psychiatric symptoms in offspring. Conclusion: These results substantiate our hypothesis that child psychopathology correlates with caregivers' psychiatric symptoms. This paper adds to the growing literature on community mental health assessment and can help guide future strategies for reducing the burden of common mental disorders in caregivers and children alike in low and middle-income countries.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/17485-4]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Instituto LemannNIMH [D43 TW009675, T32 MH096724, T32-MH19139, K01MH104514]Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Columbia University Department of Psychiatry/New York State Psychiatric Institute [T32MH096724]Univ Fed Sao Paulo UNIFESP, Dept Psiquiatria, Sao Paulo, SP, BrazilNew York State Psychiat Inst & Hosp, Div Epidemiol, New York, NY 10032 USAColumbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USANew York State Psychiat Inst & Hosp, Div Child Psychiat, New York, NY 10032 USAUniv Fed Sao Paulo UNIFESP, Dept Psiquiatria, Sao Paulo, SP, Brazil(FAPESP) [2012/17485-4]NIMH [D43 TW009675, T32 MH096724, T32-MH19139, K01MH104514]Columbia University Department of Psychiatry/New York State Psychiatric Institute [T32MH096724]Web of Scienc

A note on the universality of the Hagedorn behavior of pp-wave strings

Following on from recent studies of string theory on a one-parameter family of integrable deformations of $AdS_{5}\times S^{5}$ proposed by Lunin and Maldacena, we carry out a systematic analysis of the high temperature properties of type IIB strings on the associated pp-wave geometries. In particular, through the computation of the thermal partition function and free energy we find that not only does the theory exhibit a Hagedorn transition in both the $(J,0,0)$ and $(J,J,J)$ class of pp-waves, but that the Hagedorn temperature is insensitive to the deformation suggesting an interesting universality in the high temperature behaviour of the pp-wave string theory. We comment also on the implications of this universality on the confinement/deconfinement transition in the dual $\mathcal{N}=1$ Leigh-Strassler deformation of ${\cal N}=4$ Yang-Mills theory.Comment: 25 pages; fixed minor typo; added reference

Childhood Sexual Abuse and Indicators of Immune Activity: A Systematic Review

Background: Childhood sexual abuse (CSA) is a prevalent subtype of early life stress associated with changes in immunological and neuroendocrine systems leading to inflammatory responses of the organism and increasing several inflammatory and immune markers. We aimed to conduct a systematic review concerning the association between CSA and indicators of immune activity.Methods: We conducted a search for articles in PubMed, Scopus, PsycINFO, and Web of Science, using the key words: (“Child sexual abuse” OR “childhood maltreatment” OR “sexual violence” OR “posttraumatic stress disorder” OR “rape”) AND (“cytokines” OR “inflammatory markers” OR “interleukin” OR “tumor necrosis factor” OR “C-reactive protein”). PRISMA guidelines were used in order to improve the quality of this research, and MeSH terms were used in PubMed.Results: A total of 3,583 studies were found and, after application of the exclusion criteria, 17 studies were included in this review. Most studies reported an increase of inflammatory activity associated with the presence of early abuse. IL-6, TNF- α, and C-reactive protein were the most frequently analyzed markers and some studies showed higher levels in individuals that suffered CSA compared with controls, although the results were heterogeneous, as was the assessment of CSA, repeated trauma, and time of occurrence. It was not possible to perform a meta-analysis because the results were diversified.Conclusion: CSA is associated with changes in inflammatory markers levels. Improving the assessment of subtypes of trauma is important to further understand the complex correlations of CSA and its biological consequences such as psychiatric and physical illness in later life

On the perturbative chiral ring for marginally deformed N=4 SYM theories

For \cal{N}=1 SU(N) SYM theories obtained as marginal deformations of the \cal{N}=4 parent theory we study perturbatively some sectors of the chiral ring in the weak coupling regime and for finite N. By exploiting the relation between the definition of chiral ring and the effective superpotential we develop a procedure which allows us to easily determine protected chiral operators up to n loops once the superpotential has been computed up to (n-1) order. In particular, for the Lunin-Maldacena beta-deformed theory we determine the quantum structure of a large class of operators up to three loops. We extend our procedure to more general Leigh-Strassler deformations whose chiral ring is not fully understood yet and determine the weight-two and weight-three sectors up to two loops. We use our results to infer general properties of the chiral ring.Comment: LaTex, 40 pages, 4 figures, uses JHEP3; v2: minor correction

Homozygous Inactivating Mutation In Nanos3 In Two Sisters With Primary Ovarian Insufficiency.

Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis of NANOS3 in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lys mutation in NANOS3 was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 and in silico molecular modelling suggests destabilization of protein-RNA interaction. In vitro analyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation in NANOS3 suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology.201478746

The posttraumatic stress disorder project in Brazil: neuropsychological, structural and molecular neuroimaging studies in victims of urban violence

<p>Abstract</p> <p>Background</p> <p>Life trauma is highly prevalent in the general population and posttraumatic stress disorder is among the most prevalent psychiatric consequences of trauma exposure. Brazil has a unique environment to conduct translational research about psychological trauma and posttraumatic stress disorder, since urban violence became a Brazilian phenomenon, being particularly related to the rapid population growth of its cities. This research involves three case-control studies: a neuropsychological, a structural neuroimaging and a molecular neuroimaging study, each focusing on different objectives but providing complementary information. First, it aims to examine cognitive functioning of PTSD subjects and its relationships with symptomatology. The second objective is to evaluate neurostructural integrity of orbitofrontal cortex and hippocampus in PTSD subjects. The third aim is to evaluate if patients with PTSD have decreased dopamine transporter density in the basal ganglia as compared to resilient controls subjects. This paper shows the research rationale and design for these three case-control studies.</p> <p>Methods and design</p> <p>Cases and controls will be identified through an epidemiologic survey conducted in the city of São Paulo. Subjects exposed to traumatic life experiences resulting in posttraumatic stress disorder (cases) will be compared to resilient victims of traumatic life experiences without PTSD (controls) aiming to identify biological variables that might protect or predispose to PTSD. In the neuropsychological case-control study, 100 patients with PTSD, will be compared with 100 victims of trauma without posttraumatic stress disorder, age- and sex-matched controls. Similarly, 50 cases and 50 controls will be enrolled for the structural study and 25 cases and 25 controls in the functional neuroimaging study. All individuals from the three studies will complete psychometrics and a structured clinical interview (the Structured Clinical Interview for DSM-IV and the Clinician-Administered PTSD Scale, Beck Anxiety Inventory, Beck Depression Inventory, Global Assessment of Function, The Social Adjustment Scale, Medical Outcomes Study 36-Item Short-Form Health Survey, Early Trauma Inventory, Clinical global Impressions, and Peritraumatic Dissociative Experiences Questionnaire). A broad neuropsychological battery will be administered for all participants of the neuropsychological study. Magnetic resonance scans will be performed to acquire structural neuroimaging data. Single photon emission computerized tomography with [(99m)Tc]-TRODAT-1 brain scans will be performed to evaluate dopamine transporters.</p> <p>Discussion</p> <p>This study protocol will be informative for researchers and clinicians interested in considering, designing and/or conducting translational research in the field of trauma and posttraumatic stress disorder.</p

Quality assessment of LNP-RNA therapeutics with orthogonal analytical techniques

The availability of analytical methods for the characterization of lipid nanoparticles (LNPs) for in-vivo intracellular delivery of nucleic acids is critical for the fast development of innovative RNA therapies. In this study, analytical protocols to measure (i) chemical composition, (ii) drug loading, (iii) particle size, concentration, and stability as well as (iv) structure and morphology were evaluated and compared based on a comprehensive characterization strategy linking key physical and chemical properties to in-vitro efficacy and toxicity. Furthermore, the measurement protocols were assessed either by testing the reproducibility and robustness of the same technique in different laboratories, or by a correlative approach, comparing measurement results of the same attribute with orthogonal techniques. The characterization strategy and the analytical measurements described here will have an important role during formulation development and in determining robust quality attributes ultimately supporting the quality assessment of these innovative RNA therapeutics.publishedVersio