Health and frailty among older spousal caregivers: an observational cohort study in Belgium.

BACKGROUND: Among older couples, spouses are first in line to provide care, and they are key elements in the home support of dependent older persons. In this context, ensuring the health of these older spousal caregivers should be an important issue for all of the providers who care for older adults. The aim of this study was to longitudinally assess the health of older spousal caregivers considering frailty, nutrition, cognition, physical performance and mood disorders. METHODS: In this longitudinal, observational cohort study, participants were assessed at home in Wallonia, Belgium. At baseline, 82 community-dwelling spouses of older patients with cognitive deficits or functional impairment were assessed; 78 caregivers were assessed at follow-up (16 months). The clinical instruments used included Frailty Phenotype (Fried), the Mini Nutritional Assessment-short form (MNA-SF), Short Physical Performance Battery (SPPB), Geriatric Depression Scale (GDS-15), clock drawing test, medications, Zarit Burden Index (ZBI), and Caregiver Reaction Assessment (CRA). Biological assessments included plasma interleukin-6 (IL-6), ultrasensitive C-reactive protein (CRP), cortisol, albumin and insulin growth factor-1 (IGF-1). RESULTS: Among caregivers, 54% were women, and the mean age was 80 years. Among care-receivers, 83% had cognitive impairment. Caregivers were more likely to be in a pre-frail stage. In one-third of the caregivers, the frailty status worsened. Transitions were observed between each of the states, except from frail to robust. In contrast to frailty, items including nutrition, cognitive status, SPPB and mood assessments were stable over time, with approximately 70% of the caregivers not experiencing significant change at follow-up. Caregiver experiences assessed with the Zarit Burden Interview and CRA were relatively stable over 16 months. CONCLUSION: Many caregivers of geriatric patients are spouses who are old themselves. A failure in the health of the caregiver may anticipate an undesired care breakdown. Caregiver health and its determinants should be explored in future longitudinal studies that cover a longer time period.

Impact of high magnification sperm selection on neonatal outcomes: a retrospective study.

PURPOSE: The aim of this study was to compare the effect of the deselection of spermatozoa presenting vacuole-like structures using IMSI (intracytoplasmic morphologically selected sperm injection) with ICSI (intracytoplasmic sperm injection) by means of neonatal outcomes. METHODS: In a retrospective two-center analysis, a total of 848 successful IMSI or ICSI cycles ending with a live birth, induced abortion, or intrauterine fetal death (IUFD) were included. RESULTS: The IMSI and ICSI groups included 332 and 655 babies or fetuses, respectively. The parents were older in the IMSI group than in the ICSI group (mothers were 35.1 vs 32.9 years, and fathers were 39.1 vs 36.2 years). The multiple pregnancy rate was higher in the IMSI group. The mean pregnancy duration and mean birth weight were almost identical in both groups. There was no significant difference in major congenital malformations between the two groups. However, this rate was decreased in the IMSI group compared to that in the ICSI group (1.8 vs 3.2%), the difference being mainly found in singletons (1.4 vs 3.3%). Boys were more often affected than girls in both groups. The percentages of chromosomal abnormalities did not differ between the IMSI and ICSI groups (0.6 and 0.8%). The reported congenital malformations mainly affected the heart, urogenital, and musculoskeletal systems. CONCLUSIONS: In the present study, the malformation rates observed in the IMSI and ICSI groups were not significantly different, even if slightly lower after IMSI. However, the observed difference followed the same trends observed in previous reports, indicating the possible impact of IMSI on decreasing congenital malformation occurrences. This highlights the necessity to prospectively evaluate the impact of IMSI on neonatal outcome after IVF treatment.

Expression of the growth hormone/insulin-like growth factor axis during Balb/c thymus ontogeny and effects of growth hormone upon ex vivo T cell differentiation.

AIMS: We address the question of the expression and the role of the growth hormone/insulin-like growth factor (GH/IGF) axis in the thymus. METHODS: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. The effect of GH on T cell differentiation was explored via thymic organotypic culture. RESULTS: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1 displayed distinct expression profiles depending on the developmental stage. The protein concentrations of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and the GH receptor (GHR) antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. CONCLUSION: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T cell differentiation could implicate a different local growth factor or cytokine.

The role of the thymus in the integrated evolution of the recombinase-dependent adaptive immune response and the neuroendocrine system.

Before being able to react against infectious non-self-antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process takes place only in the thymus. The development of an autoimmune response directed to neuroendocrine glands has been shown to result from a thymus dysfunction in programming immunological self-tolerance to neuroendocrine-related antigens. This thymus dysfunction leads to a breakdown of immune homeostasis with an enrichment of 'forbidden' self-reactive T cells and a deficiency in self-antigen-specific natural regulatory T cells in the peripheral T lymphocyte repertoire. A large number of neuroendocrine self-antigens are expressed by the thymic epithelium, under the control of the autoimmune regulator (AIRE) gene/protein in the medulla. Based on the close homology and cross-tolerance between thymic type 1 diabetes-related self-antigens and peripheral antigens targeted in ß-cells by autoimmunity, a novel type of vaccination is currently developed for the prevention and cure of type 1 diabetes. If this approach were found to be effective in reprogramming immunological tolerance that is absent or broken in this disease, it could pave the way for the design of negative/tolerogenic self-vaccines against other endocrine and organ-specific autoimmune disorders.

Coxsackievirus B4 Transplacental Infection Severely Disturbs Central Tolerogenic Mechanisms in the Fetal Thymus.

Thymus plays a fundamental role in central tolerance establishment, especially during fetal life, through the generation of self-tolerant T cells. This process consists in T cells education by presenting them tissue-restricted autoantigens promiscuously expressed by thymic epithelial cells (TECs), thus preventing autoimmunity. Thymus infection by Coxsackievirus B (CV-B) during fetal life is supposed to disturb thymic functions and, hence, to be an inducing or accelerating factor in the genesis of autoimmunity. To further investigate this hypothesis, in our current study, we analyzed thymic expression of autoantigens, at the transcriptional and protein level, following in utero infection by CV-B4. mRNA expression levels of Igf2 and Myo7, major autoantigens of pancreas and heart, respectively, were analyzed in whole thymus and in enriched TECs together along with both transcription factors, Aire and Fezf2, involved in autoantigens expression in the thymus. Results show that in utero infection by CV-B4 induces a significant decrease in Igf2 and Myo7 expression at both mRNA and protein level in whole thymus and in enriched TECs as well. Moreover, a correlation between viral load and autoantigens expression can be observed in the whole thymus, indicating a direct effect of in utero infection by CV-B4 on autoantigens expression. Together, these results indicate that an in utero infection of the thymus by CV-B4 may interfere with self-tolerance establishment in TECs by decreasing autoantigen expression at both mRNA and protein level and thereby increase the risk of autoimmunity onset.

Modulation of IGF2 Expression in the Murine Thymus and Thymic Epithelial Cells Following Coxsackievirus-B4 Infection.

Coxsackievirus B4 (CV-B4) can infect human and murine thymic epithelial cells (TECs). In a murine TEC cell line, CV-B4 can downregulate the transcription of the insulin-like growth factor 2 (Igf2) gene coding for the self-peptide of the insulin family. In this study, we show that CV-B4 infections of a murine TEC cell line decreased Igf2 P3 promoter activity by targeting a region near the transcription start site; however, the stability of Igf2 transcripts remained unchanged, indicating a regulation of Igf2 transcription. Furthermore, CV-B4 infections decreased STAT3 phosphorylation in vitro. We also showed that mice infected with CV-B4 had an altered expression of Igf2 isoforms as detected in TECs, followed by a decrease in the pro-IGF2 precursor in the thymus. Our study sheds new light on the intrathymic regulation of Igf2 transcription during CV-B4 infections and supports the hypothesis that a viral infection can disrupt central self-tolerance to insulin by decreasing Igf2 transcription in the thymic epithelium.

Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes.

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet ß-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

Transcriptomic biomarkers of the response of hospitalized geriatric patients with infectious diseases.

BACKGROUND: Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response in acute phase of the infectious disease is poorly understood. RESULTS: Herein the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of 28 healthy aged probands and 39 aged patients in acute phase of infectious disease (day 2-4 after hospitalization) or in convalescence phase (day 7-10). This study provides a list of 24 differentially abundant transcript species in the acute phase versus healthy aged. For instance, transcripts associated with inflammatory and anti-inflammatory reactions (TNFRSF1A, IL1R1, IL1R2, IL10RB) and with oxidative stress (HMOX1, GPX1, SOD2, PRDX6) were more abundant while those associated with T-cell functions (CD28, CD69, LCK) were less abundant in acute phase. The abundance of seven of these transcripts (CD28, CD69, LCK, CTSD, HMOX1, TNFRSF1A and PRDX6) was already known to be altered in healthy aged probands compared to healthy young ones and was further affected in aged patients in acute phase, compromising an efficient response. CONCLUSION: This work provides insights of the state of acute phase response to infections in elderly patients and could explain further the lack of appropriate response in the elderly compared to younger persons.

Assessment of Thymic Output Dynamics After in utero Infection of Mice With Coxsackievirus B4.

The thymus is the main organ of the lymphatic system, in which T cells undergo a rigorous selection to ensure that their receptors (TCRs) will be functional and will not react against the self. Genes encoding for TCR chains are fragmented and must be rearranged by a process of somatic recombination generating TCR rearrangement excision circles (TRECs). We recently documented coxsackievirus B4 (CV-B4) infection of Swiss albino mouse thymus in the course of in utero transmission. In the current study, we intended to evaluate thymic output in this experimental model. For this purpose, pregnant Swiss albino mice were inoculated with CV-B4 at day 10 or 17 of gestation, and thymus and spleen were sampled from offspring at different time points and then subjected to quantification of TREC molecules and Ptk7 gene expression. Results showed a pronounced effect of in utero CV-B4 infection on the thymus with an increase in the cellularity and, consequently, the weight of the organ. sj and DßTREC analysis, by real-time PCR, revealed a significant decrease following CV-B4 infection compared to controls, a decrease which gets worse as time goes by, both in the thymus and in the periphery. Those observations reflect a disturbance in the export of T cells to the periphery and their accumulation within the thymus. The evaluation of Ptk7 transcripts in the thymus, for its part, showed a decrease in expression, especially following an infection at day 10 of gestation, which supports the hypothesis of T cell accumulation in a mature stage in the thymus. The various effects observed correlate either negatively or positively with the viral load in the thymus and spleen. Disruption in thymic export may indeed interfere with T cell maturation. We speculate that this may lead to a premature release of T cells and the possibility of circulating autoreactive or proliferation-impaired T cell clones.

Housekeeping Gene Expression in the Fetal and Neonatal Murine Thymus Following Coxsackievirus B4 Infection.

The thymus fulfills the role of T-cell production and differentiation. Studying transcription factors and genes involved in T-cell differentiation and maturation during the fetal and neonatal periods is very important. Nevertheless, no studies to date have been interested in evaluating the expressions of housekeeping genes as internal controls to assess the varying expressions of different genes inside this tissue during that period or in the context of viral infection. Thus, we evaluated by real-time quantitative polymerase chain reaction (qPCR) the expression of the most common internal control genes in the thymus of Swiss albino mice during the fetal and neonatal period, and following in utero infection with Coxsackievirus B4. The stability of expression of these reference genes in different samples was investigated using the geNorm application. Results demonstrated that the expression stability varied greatly between genes. Oaz1 was found to have the highest stability in different stages of development, as well as following Coxsackievirus B4 infection. The current study clearly demonstrated that Oaz1, with very stable expression levels that outperformed other tested housekeeping genes, could be used as a reference gene in the thymus and thymic epithelial cells during development and following Coxsackievirus B4 infection.

Aire and Foxp3 expression in a particular microenvironment for T cell differentiation.

OBJECTIVE: The thymus is the primary lymphoid organ responsible for T cell development and the establishment of central self-tolerance. Among thymic epithelial cells, thymic nurse cells (TNC) interact closely with immature thymocytes and constitute a special microenvironment for T cell differentiation and selection. In addition, TNC express neuroendocrine self-antigens such as oxytocin and insulin-like growth factor-2, whose intrathymic transcription is regulated by the autoimmune regulator gene/protein (Aire). Both effector and natural regulatory T cell (nTreg) lineages develop in the thymus, but the mechanisms leading to nTreg selection in the thymus are still unclear. Foxp3 is the most specific nTreg marker that is required for nTreg functional activity, but not for engagement into the Treg lineage. Aire has been suggested to be a potential factor implicated in this role. The objective of this study was to characterize Aire and Foxp3 expression in TNC/thymocyte complexes. METHODS: Aire and Foxp3 expression was investigated by RT-qPCR in TNC/thymocyte complexes isolated by enzymatic digestion and sedimentation. Aire and Foxp3 proteins were located by confocal microscopy and specific immunocytochemistry. RESULTS: Both Aire and Foxp3 transcripts were detected in TNC/thymocyte complexes. Foxp3 was detected in the nucleus of thymocytes internalized into TNC. Aire was located mainly in TNC cytoplasm and, although to a lower degree, in the nucleus of some TNC-associated thymocytes. CONCLUSIONS: Aire and Foxp3 are present in the particular TNC microenvironment which has previously been shown to support thymic selection. The differential localization of these two markers suggests a role for TNC in nTreg development.

The presentation of neuroendocrine self-peptides in the thymus: an essential event for individual life and vertebrate survival.

Confirming Burnet's early hypothesis, elimination of self-reactive T cells in the thymus was demonstrated in the late 1980s, and an important question immediately arose about the nature of the self-peptides expressed in the thymus. Many genes encoding neuroendocrine-related and tissue-restricted antigens (TRAs) are transcribed in thymic epithelial cells (TECs). They are then processed for presentation by proteins of the major histocompatibility complex (MHC) expressed by TECs and thymic dendritic cells. MHC presentation of self-peptides in the thymus programs self-tolerance by two complementary mechanisms: (1) negative selection of self-reactive "forbidden" T cell clones starting already in fetal life, and (2) generation of self-specific thymic regulatory T lymphocytes (tTreg cells), mainly after birth. Many studies, including the discovery of the transcription factors autoimmune regulator (AIRE) and fasciculation and elongation protein zeta family zinc finger (FEZF2), have shown that a defect in thymus central self-tolerance is the earliest event promoting autoimmunity. AIRE and FEZF2 control the level of transcription of many neuroendocrine self-peptides and TRAs in the thymic epithelium. Furthermore, AIRE and FEZF2 mutations are associated with the development of autoimmunity in peripheral organs. The discovery of the intrathymic presentation of self-peptides has revolutionized our knowledge of immunology and is opening novel avenues for prevention/treatment of autoimmunity.

The Severe Deficiency of the Somatotrope GH-Releasing Hormone/Growth Hormone/Insulin-Like Growth Factor 1 Axis of Ghrh-/- Mice Is Associated With an Important Splenic Atrophy and Relative B Lymphopenia.

A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this study was to directly address this question through the use of Ghrh-/- mice that exhibit a severe deficiency of their somatotrope axis. After control backcross studies and normalization for the reduced global weight of transgenic mice, no difference in weight and cellularity of the thymus was observed in Ghrh-/- mice when compared with C57BL/6 wild-type (WT) control mice. Similarly, no significant change was observed in frequency and number of thymic T cell subsets. In the periphery, Ghrh-/- mice exhibited an increase in T cell proportion associated with a higher frequency of sjTREC and naïve T cells. However, all Ghrh-/- mice displayed an absolute and relative splenic atrophy, in parallel with a decrease in B cell percentage. GH supplementation of transgenic mice for 6 weeks induced a significant increase in their global as well as absolute and relative splenic weight. Interestingly, the classical thymus involution following dexamethasone administration was shown to recover in WT mice more quickly than in mutant mice. Altogether, these data show that the severe somatotrope deficiency of Ghrh-/- mice essentially impacts the spleen and B compartment of the adaptive immune system, while it only marginally affects thymic function and T cell development.

Accumulation of IL-17+ Vγ6+ γδ T cells in pregnant mice is not associated with spontaneous abortion.

Introduction: Pregnancy is an immune paradox. While the immune system is required for embryo implantation, placental development and progression of gestation, excessive inflammation is associated with pregnancy failure. Similarly, the cytokine IL-17A plays an important role in defence against extracellular pathogens, but its dysregulation can lead to pathogenic inflammation and tissue damage. Although expression of IL-17 has been reported during pregnancy, the cellular source of this cytokine and its relevance to gestation are not clear. Objectives: Here we define the kinetics and cellular source of IL-17A in the uterus during healthy and abortion-prone murine pregnancy. Methods: The CBA/J x DBA/2J abortion-prone mating was used and compared to CBA/J x BALB/c control mating. Results: We demonstrate that, irrespective of gestational health, the number of IL-17-producing cells peaks during midterm pregnancy and is largely derived from the γδ T-cell lineage. We identify γδ T, Th17, CD8 T and NKT cells as the cellular source of IL-17A in pregnant mice. Furthermore, we positively identify the Vγ6+ subset of uterine γδ T cells as the main producer of IL-17A during both healthy pregnancy and abortive pregnancy. Conclusions: To conclude, the accumulation of uterine IL-17+ innate-like T cells appears not to adversely impact the developing foetus. Collectively, our results show that IL-17+ γδ T cells are present in the uterus throughout the course of normal gestation and therefore may play an important role in healthy pregnancy.

Growth Hormone (GH) Deficient Mice With GHRH Gene Ablation Are Severely Deficient in Vaccine and Immune Responses Against Streptococcus pneumoniae.

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh-/-) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh-/- mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh-/- mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh-/- mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh-/- mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh-/- mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh-/- mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae.

The Somatotrope Growth Hormone-Releasing Hormone/Growth Hormone/Insulin-Like Growth Factor-1 Axis in Immunoregulation and Immunosenescence.

Most scientific reports debate the thymotropic and immuno-stimulating properties of the somatotrope growth hormone-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, but there is still some disagreement about the physiological role of this axis in basal conditions. Moreover, some authors have hypothesized that the physiological role of the somatotrope axis only appears in stressful conditions (such as sepsis or infective and inflammatory diseases). This chapter will provide an extended overview of the expression of the components (signals and receptors) of the somatotrope axis and their properties on cells of the innate and adaptive immune system. It will also summarize some clinical studies suggesting a benefit for a short-term GH treatment in acute immunodeficiencies, and the importance of GH supplementation in adult GH deficiency. A new transgenic mouse model, the hypothalamic GHRH-deficient (Ghrh-/-) mouse, which exhibits a severe deficiency of the somatotrope axis, will be presented since it will be of great help in further deciphering the regulation by the GHRH/GH/IGF-1 axis on both immune development and function. Finally, we will discuss the implication of aging-related somatopause in relation to the general context of Immunosenescence.

Exploring the link between innate immune activation and thymic function by measuring sCD14 and TRECs in HIV patients living in Belgium.

Microbial translocation is now viewed as a central event in the pathogenesis of chronic inflammation during HIV infection. Thymic function failure is another crucial factor involved in HIV disease progression. The goal of this study was to explore the hypothesis of potential links between microbial translocation and thymic function in HIV-1 patients living in Belgium. The extent of microbial translocation was assessed through the measurement of soluble CD14 (sCD14). T-cell receptor excision circles (sjTRECs and dßTRECs) were used as a measure of thymic function. Data were collected from 75 HIV-infected patients. Simple and complex linear regressions were done to analyze the link between these two processes. We found a statistically relevant negative correlation between thymopoiesis (sjTREC) and sCD14 level (p = 0.004). These results suggest a link between thymic function failure, microbial translocation and innate immune activation.

The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader-Willi Syndrome.

BACKGROUND AND OBJECTIVES: Patients with Prader-Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT)-producing neurons were documented in adults. Animal data demonstrated that early treatment with OXT restores sucking after birth. Our aim is to reproduce these data in infants with PWS. METHODS: We conducted a phase 2 escalating dose study of a short course (7 days) of intranasal OXT administration. We enrolled 18 infants with PWS under 6 months old (6 infants in each step) who received 4 IU of OXT either every other day, daily, or twice daily. We investigated the tolerance and the effects on feeding and social skills and changes in circulating ghrelin and brain connectivity by functional MRI. RESULTS: No adverse events were reported. No dose effect was observed. Sucking assessed by the Neonatal Oral-Motor Scale was abnormal in all infants at baseline and normalized in 88% after treatment. The scores of Neonatal Oral-Motor Scale and videofluoroscopy of swallowing significantly decreased from 16 to 9 (P < .001) and from 18 to 12.5 (P < .001), respectively. Significant improvements in Clinical Global Impression scale scores, social withdrawal behavior, and mother-infant interactions were observed. We documented a significant increase in acylated ghrelin and connectivity of the right superior orbitofrontal network that correlated with changes in sucking and behavior. CONCLUSIONS: OXT is well tolerated in infants with PWS and improves feeding and social skills. These results open perspectives for early treatment in neurodevelopment diseases with feeding problems.

Oxytocin synthesis and oxytocin receptor expression by cell lines of human small cell carcinoma of the lung stimulate tumor growth through autocrine/paracrine signaling.

The objective of the present work was to investigate the existence of an oxytocin (OT)-mediated autocrine/paracrine signaling upon small cell carcinoma of the lung (SCCL) cell growth. In that view, OT receptor (OTR) expression, concomitant with OT synthesis and secretion, was evidenced on three different SCCL cell lines (DMS79, H146, and H345) and related to the vasopressin (VP) system. Specific OT, VP, OTR, V1a VP receptor (V1aR), and V1b/V3 VP receptor (V1bR/V3R) transcripts were identified by reverse transcription-PCR in all cell lines studied. Binding of 125I-(d(CH2)(5)(1), Tyr(Me)(2),Thr(4),Orn(8),Tyr(9)-NH2)-vasotocin (OVTA) was observed on all SCCL cell lines, with a K(d) (dissociation constant) ranging from 0.025-0.089 nM, depending on the cell line and the analytical method. Selectivity of 125I-OVTA binding was confirmed by displacement curves obtained with various OTR and VP receptor agonists and antagonists (OT, OVTA, L-371,257, VP, F180). Immunocytochemistry identified cellular OT and VP, and peptide secretion was measured in supernatants of SCCL cultures. [3H]Thymidine incorporations, applied on H345 cells, demonstrated a dose-dependent mitogenic effect of exogenous OT (1 and 100 nM) that was abolished by the OTR antagonist OVTA. A decrease of proliferation was also observed with OVTA alone, showing a functional mitogenic effect of tumor-derived OT. Taken together, these observations demonstrate the existence of a functional OT-mediated autocrine/paracrine signaling actively implicated in growth and development of SCCL tumors. Furthermore, these findings point to the potential of OT antagonists for development as therapeutic agents for the treatment of SCCL.

Oxytocin in survivors of childhood-onset craniopharyngioma.

Quality of survival of childhood-onset craniopharyngioma patients is frequently impaired by hypothalamic involvement or surgical lesions sequelae such as obesity and neuropsychological deficits. Oxytocin, a peptide hormone produced in the hypothalamus and secreted by posterior pituitary gland, plays a major role in regulation of behavior and body composition. In a cross-sectional study, oxytocin saliva concentrations were analyzed in 34 long-term craniopharyngioma survivors with and without hypothalamic involvement or treatment-related damage, recruited in the German Childhood Craniopharyngioma Registry, and in 73 healthy controls, attending the Craniopharyngioma Support Group Meeting 2014. Oxytocin was measured in saliva of craniopharyngioma patients and controls before and after standardized breakfast and associations with gender, body mass index, hypothalamic involvement, diabetes insipidus, and irradiation were analyzed. Patients with preoperative hypothalamic involvement showed similar oxytocin levels compared to patients without hypothalamic involvement and controls. However, patients with surgical hypothalamic lesions grade 1 (anterior hypothalamic area) presented with lower levels (p = 0.017) of oxytocin under fasting condition compared to patients with surgical lesion of posterior hypothalamic areas (grade 2) and patients without hypothalamic lesions (grade 0). Craniopharyngioma patients' changes in oxytocin levels before and after breakfast correlated (p = 0.02) with their body mass index. Craniopharyngioma patients continue to secrete oxytocin, especially when anterior hypothalamic areas are not involved or damaged, but oxytocin shows less variation due to nutrition. Oxytocin supplementation should be explored as a therapeutic option in craniopharyngioma patients with hypothalamic obesity and/or behavioral pathologies due to lesions of specific anterior hypothalamic areas. Clinical trial number: KRANIOPHARYNGEOM 2000/2007(NCT00258453; NCT01272622).