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Supplementary Materials and Methods; Supplementary Figure 1: Effects of AMG 900 on nuclear morphology and centrosome features are consistent with aurora-B inhibition in MDA-MB-231 cell line; Supplementary Figure 2: Elevated expression of ABC transporter gene ABCB1 and ABCB4 in MDA-MB-231 (F11) PTX-r cell line; Supplementary Figure 3: Cell-cycle profiles of TNBC cell lines treated with paclitaxel or ixabepilone.

Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule-targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser10, a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F11; parental), MDA-MB-231 (F11) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F11) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F11) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors. Mol Cancer Ther; 12(11); 2356–66. ©2013 AACR.

The Wittig reaction to synthesize olefins is a very attractive method in organic synthesis. Recently, this methodology has been achieved utilizing simple metal catalysts and diazo compounds in addition to a phosphine and an aldehyde. The following work investigates the use of a variety of metallophthalocyanines (MPc’s) to catalyze Wittig-like reactions from ethyldiazoacetate. We also examine the influence of substitution on the aromatic ring of the aldehyde as well as various phosphines, arsines and antimony complexes. We have been able to exclusively synthesize the trans-olefins in excellent yields in short periods of time (1 h).

Scholars and practitioners recognize that adaptation is necessary, and can enhance program outcomes, when scaling early interventions. This study used a framework for implementation that identified critical elements for understanding the adaptation process including: a) who made the adaptations, such as model developers and staff members, b) what elements were adapted, c) how adaptations occurred, such as adding or removing elements, d) when adaptations took place, such as at the beginning of implementation or as an on-going process, and e) why the adaptations occurred. Erikson Institute’s Fussy Baby Network ® (FBN) service program has been implemented in seven cities across the United States. Implementation of FBN in the New Orleans and Gulf Coast (NOGC) region began in 2012. Using a longitudinal phenomenological study design, FBNNOGC program and institutional staff were interviewed over three years at ten time points. This study identified five adaptations of FBN to NOGC: a) increasing length and intensity of services, b) adding a family advocate, c) integrating academic and clinical contexts, d) changing the program name, branding, and outreach materials, and e) networking with other providers. No adaptations were made to the program model or training, which ensured program fidelity.

Objectives To clarify the effectiveness of perinatal social support interventions in reducing postpartum depression among minority, low-income women. Methods The Transdisciplinary Research Consortium for Gulf Resilience on Women's Health supported a community-based participatory research project to improve perinatal health among low-income, first-time pregnant women living in a vulnerable Gulf Coast region. Community health workers (CHWs) were partnered with recruited women, and used a mix of mobile technology and home visits to develop a supportive relationship during the perinatal period. Results Women enrolled in the CHW-led intervention had lower (F: 2.38, p = 0.04) average postpartum depression scores (EPDS) 6 months postpartum than a comparison population. The difference, however, was not seen among women in the intervention group who reported relatively poor relationships with their CHWs. Conclusions for Practice Results reinforce the evidence that perinatal social support can affect postpartum depression outcomes. CHWs are increasingly utilized by public programs to reach at-risk populations. We discuss the potential efficacy of CHW programs, but also, the need to pair outreach with effective monitoring and evaluation of the relationship development between CHW and clients.

Objective Unicompartmental knee arthroplasty (UKA) is a viable option for relieving pain and improving function in patients with isolated compartment knee osteoarthritis (OA). Certain surgeons prefer total knee arthroplasty (TKA) over UKA even when patients are candidates for UKA. Therefore, the decision to perform a UKA or a TKA when both are indicated is not straightforward. The goal of this study was to compare pre-operative and post-operative patient-reported outcome (PRO) scores for patients who underwent both a UKA and a contralateral TKA. Methods In this study, 17 patients were identified who underwent UKA in one knee and TKA in the contralateral knee either simultaneously or at different time points between 2003 and 2014. All procedures were performed by one of two fellowship trained surgeons at a large academic medical center. Patients were evaluated pre-operatively and then post-operatively using the validated PRO measurements Short Form 12 (SF12), Knee Society Functional Score (KSS), and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaires. Student’s paired t-tests were conducted to compare PRO scores for UKA and TKA pre-operatively and post-operatively. Results Post-operatively, mean follow-up was 2.5 years (range, 3 months to 9 years). There was no significant difference in PRO scores between pre-operative values for UKA and TKA, and no significant difference between post-operative values for UKA and TKA (e.g. SF12 pre-operative difference between UKA and TKA mean = 1.6, p = 0.57; SF12 post-operative difference between UKA and TKA mean = 1.9, p = 0.51). Conclusion UKA and TKA are comparable in terms of PROs at mid-term follow-up. When choosing between UKA and TKA, the surgeon should expect similar PROs for each, and can therefore take into account other considerations when making a selection.

Assessment procedures for infants, toddlers, and preschoolers should include caregiver interviews, caregiver-report questionnaires, observational coding procedures, and collateral reports (i.e., medical, child care, etc.). This multimodal assessment approach provides clinicians a systematic means to incorporate the many factors that impact an infant’s clinical presentation. The prior chapter focuses on one aspect of a multimodal psychiatric evaluation, specifically observing the dyadic interaction. In this chapter, we outline key considerations regarding instrument selection, application and interpretation, and provide an in-depth list of dyadic observational measures which have been found to have useful clinical applications.

BACKGROUND: Beneficial roles for glucagon-like peptide 1 (GLP-1)/GLP-1R signaling have recently been described in diseases, where low-grade inflammation is a common phenomenon. We investigated the effects of GLP-1 in Brunner's glands and duodenum with abundant expression of GLP-1 receptors, as well as GLP-1 effect on colonic inflammation.METHODS: RNA from Brunner's glands of GLP-1R knockout and wild-type mice were subjected to full transcriptome profiling. Array results were validated by quantitative reverse transcription polymerase chain reaction in wild-type mice and compared with samples from inflammatory bowel disease (IBD) patients and controls. In addition, we performed a detailed investigation of the effects of exogenous liraglutide dosing in a T-cell driven adoptive transfer (AdTr) colitis mouse model.RESULTS: Analyses of the Brunner's gland transcriptomes of GLP-1R knockout and wild-type mice identified 722 differentially expressed genes. Upregulated transcripts after GLP-1 dosing included IL-33, chemokine ligand 20 (CCL20), and mucin 5b. Biopsies from IBD patients and controls, as well as data from the AdTr model, showed deregulated expression of GLP-1R, CCL20, and IL-33 in colon. Circulating levels of GLP-1 were found to be increased in mice with colitis. Finally, the colonic cytokine levels and disease scores of the AdTr model indicated reduced levels of colonic inflammation in liraglutide-dosed animals.CONCLUSIONS: We demonstrate that IL-33, GLP-1R, and CCL20 are deregulated in human IBD, and that prophylactic treatment with 0.6 mg/kg liraglutide improves disease in AdTr colitis. In addition, GLP-1 receptor agonists upregulate IL-33, mucin 5b, and CCL20 in murine Brunner's glands. Taken together, our data indicate that GLP-1 receptor agonists affect gut homeostasis in both proximal and distal parts of the gut.

The foundations of social-emotional development are based in the primary caregiving relationship. In the first months of life, development in this area is primarily influenced by the infant’s relationship(s) with his primary caregiver(s), and in turn these relationships are influenced by the infant’s development and behavior. This chapter briefly reviews typical infant development month by month and the bi-directional impact of the relationship and infant behavior on social-emotional development. The ways in which multiple individuals and systems can influence parenting decisions typically formulated during this age period, such as breastfeeding, sleep arrangements, and childcare placement, are highlighted. The chapter ends with a brief review of the assessment process and social-emotional assessment tools that can be used with very young infants and their caregivers.

Current literature indicates that risk for maternal depression is substantial in low-income families. A large body of research also indicates that when mothers are depressed, children are at risk for a number of developmental difficulties. While mutual influence between child and parental difficulties has been noted, few studies examine risk factors for both depression and child aggression within ecological models. The present cross-site study examined the unique and additive contributions of contextual factors, including SES and family functioning, on maternal depression and child aggression in Early Head Start families. A multiethnic sample of parents and their children, between the ages of 12 and 43 months, participated in this study. Families came from five Early Head Start programs across the United States, representing both urban and rural areas. Structural equation models (SEM) demonstrate mutual links between depression and aggression, mediated at least in part by ecological factors. SEM indicated that 36.4% of the variance in child aggression is accounted for in a model linking aggressive behavior to parent depression, stress, and couple-level functioning, as well as other family interaction variables. A second model focusing on maternal depression revealed that 44.5% of the variance in maternal depression was accounted for through family factors, including couple-related support and satisfaction and parenting stress. In this second model, child aggression was indirectly linked to maternal depression. These data have important implications for programs serving at-risk families.

Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the muscularis externa in the stomach and in myenteric plexus neurons throughout the gut. No GLP-1R was seen in primate liver and thyroid. GLP-1R expression seen with immunohistochemistry was confirmed by functional expression using in situ ligand binding with 125I-GLP-1. In conclusion, these results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLP-1R.

The very modern Kyoto International Conference Center provided the site for the 8th workshop on Beta cells on April 23-26, 2013. The preceding workshops were held in Boston, USA (1991); Kyoto, Japan (1994); Helsingør, Denmark (1997); Helsinki, Finland (2003); El Perello, Spain (2006); Peebles, Scotland (2009); and Helsingør, Denmark (2011). The Kyoto meeting drew more than 200 attendees from 18 different countries. There were 47 main oral presentations, and approximately 75 posters covered virtually all aspects of the pancreas function, development and genetics of disease. Here we will review some of the newest highlights.

Gastrostomy tube placement for malnutrition and weight loss stabilization occurs in many patients with ALS. We sought to compare the outcome and complications of gastrostomy tube placement by endoscopic (PEG) and multiple radiologic (RIG) methods in ALS patients. A retrospective analysis was conducted on all ALS patients evaluated at Northwestern University who received gastrostomy tubes between January 2009 and March 2012. One hundred and eight gastrostomy tube attempts were made on a total of 100 different patients. Failed gastrostomy tube placement occurred in 15.7% of PEGs and 1.9% of RIGs. Post-procedure aspiration was recognized after 10.5% PEG and 0 RIG attempts. Multivariate analysis revealed a linear increase in risk of post-procedure aspiration for every increase in ALSFRS swallow score. No statistically significant differences in failure or complications were observed when comparing two different methods of RIG (push-type vs. pull-type). Our findings support gastrostomy tube placement by radiographic methods in ALS patients. Gastrostomy tube placement by RIG was more often successful and less often associated with aspiration. Our findings add to the growing body of literature that argues for early gastrostomy tube placement in young patients with prominent bulbar involvement.

The purpose of this study was to compare pain frequency in early and late stages of ALS and to describe the relationship between pain intensity and functional status. Sixty-four patients in different stages of ALS were asked to complete the Neuropathic Pain Scale and to draw the localization of their pain on a body cartoon. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and Forced Vital Capacity (FVC) values were obtained from the medical record. A χ(2) correlation was used to compare the proportion of patients with pain in different stages of ALS. Correlation coefficient was used to describe the relationship between pain intensity and functional status (ALSFRS-R). Pain was reported by about half the patients. Using FVC values, patients were subdivided into early, intermediate and late stage of the disease. There was a negative correlation between pain intensity and functional status. There was no statistically significant difference in the presence of pain among patients in the different stages of ALS. In conclusion, our study showed that pain is common in ALS patients. Although pain intensity did correlate negatively with functional status, as expected, we were surprised to find that pain was also present in the early stages of the disease.

The sand ratPsammomys obesusis a gerbil native to deserts of North Africa and the Middle East1. Sand rats survive with low caloric intake and when given high carbohydrate diets can become obese and develop type II diabetes2which, in extreme cases, leads to pancreatic failure and death3,4. Previous studies have reported inability to detect thePdx1gene or protein in gerbils5–7, suggesting that absence of this key insulin-regulating homeobox gene might underlie diabetes susceptibility. Here we report sequencing of the sand rat genome and discovery of an extensive, mutationally-biased GC-rich genomic domain encompassing many essential genes, including the elusivePdx1.The sequence ofPdx1has been grossly affected by GC-biased mutation leading to the highest divergence observed in the animal kingdom. In addition to molecular insights into restricted caloric intake in a desert species, the discovery that specific chromosomal regions can be subject to elevated mutation rate has widespread significance to evolution.

This article investigates the effectiveness of a statewide 6-month early childhood mental health consultation (ECMHC) model on teachers’ emotional support of children and classroom organization. We provide a brief historical and theoretical background of the field of ECMHC, present the logic model for our ECMHC intervention, and discuss the existing research that supports this logic model. Research Findings: Participants included 445 teachers from 158 child care centers statewide. The mental health consultation improved the quality of early childhood teachers’ interactions (e.g., emotional support and classroom organization) with children in their care. Teachers with more experience and more than a high school degree tended to score higher on many of the Classroom Assessment Scoring System (R. C. Pianta, K. M. La Paro, & B. K. Hamre, 2008) dimensions. Practice or Policy: This study demonstrates that mental health consultants can partner successfully with early childhood educators and provide support that ...

Mixed results in the literature related to type of permanent placement and developmental outcomes of maltreated children suggest differences in postmaltreatment placement environments may be an important mechanism to consider. The goal of this study was to identify how home environment variables mediate risk in maltreated children in different types of placements. Participants included 71 maltreated and 70 non-maltreated (mean age = 7.14). Child outcomes were caregiver report of behavior problems (Child Behavior Checklist, CBCL) and cognitive assessment (Peabody Picture Vocabulary Test, PPVT, and Kaufman Brief Intelligence Test, KBIT). The home environment was examined using the Home Observation for Measurement of the Environment (HOME). The maltreated and non-maltreated groups differed significantly on cognitive scores, F(6, 268) = 3.05, p

Early childhood mental health (MH) consultants work closely with childcare teachers onsite to serve as a resource for childcare providers as they foster and enhance children's early development. The increase in the quality of care that can be supported through an early childhood MH consultation program makes this type of consultation an optimal tool for enhancing the childcare environment and overall child development. This article details the initial launch of the MH consultation program to childcare centers in the state of Louisiana. Analyses support the assertions that (a) a model of MH consultation can be implemented successfully at a statewide level, (b) MH consultation is associated with an increase in teacher self-efficacy, and (c) teachers' report that the MH consultation increased their competence in specific areas related to children's socioemotional development. Analyses indicate that there is a differential impact on teachers based on their age and level of experience. The clinical implications of these findings are discussed.

In order to investigate the effect and mechanism of liraglutide and vildagliptin in diabetic Psammomys obesus, we examined proliferation and apoptosis of beta-cells, beta-cell mass (BCM), and pancreatic insulin content after zero, six and fourteen days of treatment compared to control groups. One group of animals was kept on low-energy diet and seven groups were given high-energy diet (HED) that induced diabetes over a four week period. Non-fasting morning blood glucose, body weight, HbA(1C) and pancreatic insulin content were measured and beta cell mass (BCM), proliferation and apoptosis frequencies were determined using stereological point counting. Liraglutide significantly reduced blood glucose and even normalized it in all animals treated for six days and in 11 out of 17 animals treated for fourteen days. HED increased BCM and treatment with liraglutide did not change this. However, compared to the vehicle-treated animals pancreatic insulin content was normalized in animals treated for six and fourteen days with liraglutide. In contrast, vildagliptin, in doses causing full inhibition of plasma DPP-IV activity, neither reduced blood glucose nor altered HED-induced increases in BCM or pancreatic insulin content. These results suggest that liraglutide restores normoglycaemia and improves glycaemic control in P. obesus by increasing their insulin content and improving the function of the beta-cells. In contrast, vildagliptin does not improve glycaemic control in P. obesus nor affect beta-cell insulin content.

Young maltreated children, birth to three years, represent the age group with the highest rates of maltreatment in the United States (ACYF 2007). There are few studies to date that have investigated early childhood maltreatment and its effects on emotion regulatory processes and psychopathology. In response, the current investigation uses a dyadic assessment procedure to examine the relationship between parenting, emotion regulation, and symptoms of psychopathology among maltreating and non-maltreating parent–child interactions. The participants in this study were 123 children (66 maltreated and 57 nonmaltreated) from ages 1–3. Child and parent affect and child effortful control were observed during a parent–child interaction task. Symptoms of psychopathology were measured using the Child Behavior Checklist. The maltreated children exhibited more anger, more internalizing symptomatology, and less positive affect compared to non-maltreated children. Among maltreated children, emotion dysregulation was associated with internalizing symptomatology. Moreover, these data reveal parental positive affect was associated with lower child internalizing symptomatology and parental anger was associated with higher child internalizing symptomatology in the entire sample. This investigation offers evidence that emotion dysregulation subsequent to poor dyadic interactions is associated with early child maltreatment. These data suggest that maltreated children experience difficulties in emotion regulation which may be related to their higher levels of behavioral symptomatology.

Summary The African ice rat, Otomys sloggetti robertsi, is a member of the subfamily Otomyinae, in the superfamily of Muroidea, to which all rodents belong. Very little is known about this unique family of rodents. The study reported here examines the endocrine pancreas of this species using immunohistochemical techniques. The islets of Langerhans were scattered in the exocrine pancreas and tended to be quite small. Scattered single endocrine cells (mostly immunoreactive for insulin) were found in the exocrine pancreas and were not generally associated with ducts (as marked by pan-cytokeratin labeling). The normal islet architecture of insulin in the center and glucagon, somatostatin (SS) and pancreatic polypeptide (PP) in the rim was observed, but the islets tended to have 2–3 layers of glucagon immunoreactive cells. Examining for rarer endocrine cell types, we found that cocaine amphetamine regulated transcript (CART) immunoreactive cells were co-localized with SS; and peptide YY (PYY) immunoreactive cells could be found that were singly immunoreactive or co-localized with either PP or glucagon. Ghrelin cells were not found. MafA co-localized only with the insulin cells, while MafB, which localizes to the glucagon cells, also showed a low level of immunoreactivity in most insulin immunoreactive cells. The Nkx family of transcription factors (Nkx6.1 and 2.2) and PDX-1 were all detected in the pancreas in a similar manner to that seen in mouse and rat. In conclusion, the endocrine pancreas of the African ice rat is quite similar to that of other studied rodents, but these animals have more glucagon and SS cells than rat (Rattus) or mouse (Mus) species.

SUMMARY We studied the intra-islet localization of the glucagon-like peptide 1 receptor (GLP-1R) by colocalization studies of the GLP-1R mRNA and protein with islet cell hormones in mice, rats, and humans. In contrast to previous reports, we show that the GLP-1R is selectively located on the b cells. The localization of GLP-1R in islets and ducts was studied using ISH and double and triple fluorescence microscopy. In normal pancreatic tissue from mice and rats, GLP-1R mRNA was only detectable in the b cells. Double and triple immunofluorescence using two different GLP-1R antisera and combinations of insulin, glucagon, pancreatic polypeptide, and somatostatin showed that GLP-1R protein is almost exclusively colocalized with insulin. The same pattern was observed in human pancreas, but the GLP1R expression was more heterogeneous, with populations of insulin immunoreactive cells with high and low expression. This is the first time that the GLP-1R has been localized in human islets. Furthermore, GLP-1R immunoreactivity was found in the pancreatic ducts in mouse, rat, and human pancreas. As an important confirmation of the specificity of our methods, we found no signals for GLP-1R mRNA or protein in pancreatic tissue from gene-targeted GLP-1R–deficient mice. In conclusion, our data suggest that the GLP-1 receptor is restricted to the pancreatic b cells and the lack of receptor immunoreactivity on d cells cannot be explained suitably to correspond with published in vivo and in vitro data. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 56:841–851, 2008)

Summary Standardized clinical assessments from the point of view of children are rare. A standardized narrative assessment measure, developed to assess children's perceptions of their caregiving environments, the Narrative Story‐Stem Technique (NSST), was used with two fraternal twins, age 8, with histories of severe maltreatment and multiple foster placements. Their responses to the NSST indicate that they perceived their caregiving environments as unstable and unpredictable, though in noticeably different ways. Representations of certain family strengths were also evident. The NSST can provide highly detailed information of great utility for treatment planning and intervention regarding children's perceptions of, and experiences in, their caregiving environments.

The maltreating mothers of abused and neglected infants and toddlers were evaluated as part of an intensive intervention program. The purpose of this study was to examine cumulative risk versus specific risk factors that led to permanent loss of custody by mothers, predicated upon decisions by the Juvenile Court with regard to permanency planning. The following risk factors were analyzed as potential predictors of placement outcomes: maternal education, maternal history of abuse as a child, history of psychiatric difficulties, substance-abuse history, conviction history (excluding child-abuse charges), depressive symptomatology, degree of partner violence experienced, and cumulative number of risks the mother experienced. Results indicated that mothers who lost custody had significantly more risk factors than those who were reunified with their children. Cumulative risk was a stronger predictor than specific risk factors. Implications for intervention are discussed.

One planned consequence of the national Infant Mental Health Forum held in the United States in 2000 was the funding of five research projects conducted in Early Head Start (EHS) programs. Each project strengthened existing programs by integrating infant/toddler mental health approaches and testing the outcomes on infant/toddler development, behavior, and parent-child interactions. In two of the projects, the effect of offering enrichment for EHS staff was tested. The other three projects tested the effect of services offered directly to parents and children. This article describes the five projects and the theories, methods, and outcome measures used. In order to understand more fully the elevated risk factors in these families and the consequences for mental health in their infants and toddlers, a common set of measures was developed. Data have been used to explore the common threats to mental health and the factors that moderate the impact on infants and toddlers.

Background: Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family–based and case-control cohort (N = 1,891). Methods: Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using Taq Man assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS. Results: A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes. Conclusion: This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.

Several recent reports claim the generation of insulin-producing cells from embryonic stem cells via the differentiation of progenitors that express nestin. Here, we investigate further the properties of these insulin-containing cells. We find that although differentiated cells contain immunoreactive insulin, they do not contain proinsulin-derived C-peptide. Furthermore, we find variable insulin release from these cells upon glucose addition, but C-peptide release is never detected. In addition, many of the insulin-immunoreactive cells are undergoing apoptosis or necrosis. We further show that cells cultured in the presence of a phosphoinositide 3-kinase inhibitor, which previously was reported to facilitate the differentiation of insulin+ cells, are not C-peptide immunoreactive but take up fluorescein isothiocyanate–labeled insulin from the culture medium. Together, these data suggest that nestin+ progenitor cells give rise to a population of cells that contain insulin, not as a result of biosynthesis but from the uptake of exogenous insulin. We conclude that C-peptide biosynthesis and secretion should be demonstrated to claim insulin production from embryonic stem cell progeny.

To determine whether published subtypes of attachment disorder can be reliably identified by trained clinicians reviewing data from high-risk populations and to investigate the relationship between disorder classification and standardized measures of attachment behavior.Twenty or more children aged 18 to 48 months and their primary caregivers were recruited from three sites: a treatment team for maltreated young children (n = 20), a homeless shelter (n = 25), and Head Start centers (n = 24). All dyads completed a semistructured clinical assessment and laboratory and home-based attachment measures.All but one type of attachment disorder could be identified reliably by clinician raters (kappa range = 0.62-0.74, depending on subtype). Children from the maltreatment sample were significantly more likely to meet criteria for one or more attachment disorders than children from the other groups (p.001). As predicted, children without an attachment disorder were more likely to be classified as securely attached than those with an attachment disorder (p =.03); however, children classified as having disorganized attachment were not more likely to receive an attachment disorder diagnosis.Attachment disorders can be reliably diagnosed in young children, though research on refining disorder criteria should precede intervention trials.

Brain 4 (Brn4/Pou3f4) and Pax6 are POU-homeodomain and paired-homeodomain transcription factors, respectively, that are expressed in the brain and the glucagon-expressing cells in the pancreas. Brn4 expression begins at embryonic day 10 in the pancreas, just before pax6 and both appear in the glucagon immunoreactive cells. At a later time point, E19, no Brn4 co-localization is observed with insulin or somatostatin but a rare pancreatic polypeptide (PP)-producing cell can be found, while Pax6 is found in all endocrine cells. These data suggest that brn4 is the only alpha-cell specific transcription factor yet identified; therefore, we sought to analyze alpha-cell development and function in mice with a targeted disruption of the brn4 gene. In homozygous brn4(-/-) mice, pancreatic bud formation, glucagon cell numbers and physiological measurements all appear normal. Examination of other transcription factors found in the glucagon cells showed normal Pax6 and Nkx2.2 immunoreactivity, suggesting that Brn4 does not regulate these transcription factors. Pax6 mutant mice (pax6(Sey/Sey)), with a natural inactivating mutation in pax6, have few endocrine cells but normal numbers of Brn4 and Nkx2.2 cells. The pancreatic phenotype of the pax6 mutants can be rescued with a YAC clone containing the human Pax6 gene.

In this study we examined the expression of nestin in islets, the exocrine part, and the big ducts of the adult human pancreas by immunofluorescent double staining. Two different anti-nestin antisera in combination with various pancreatic and endothelial markers were employed. Nestin-immunoreactive cells were found in islets and in the exocrine portion. All nestin-positive cells co-expressed the vascular endothelial markers PE-CAM-1 (CD31), endoglin (CD105), and CD34 as well as vimentin. Endocrine, acinar, and duct cells did not stain for nestin. We also demonstrated that in the area of big pancreatic ducts, nestin-positive cells represent small capillaries scattered in the connective tissue surrounding the duct epithelium and do not reside between the duct cells. We detected nestin-expressing endothelial cells located adjacent to the duct epithelium where endocrine differentiation occurs. We have shown that nestin is expressed by vascular endothelial cells in human pancreas, and therefore it is unlikely that nestin specifically marks a subpopulation of cells representing endocrine progenitors in the adult pancreas.

We have performed a high-capacity, semiquantitative, reverse transcriptase-polymerase chain reaction screen for expression of fibroblast growth factor (FGF) and transforming growth factor beta (TGFbeta) family genes as well as their cognate receptors. By using cDNA prepared from embryonic day 12 to postnatal day 0 embryonic mouse pancreas, we have identified several factors potentially involved in the development of the endocrine pancreas. We find high-level early expression of TGFbeta-1 and -2, and constitutive expression of TGFbeta-3 and their receptors. Of the Inhibin/Activin members, we found exclusively Inhibin-alpha and Activin-betaB to be expressed, and the BMP family was represented by BMP4, BMP5, and BMP7. The predominant forms of the BMP and Activin type II receptors were ActR-IIB and BMPR-II and of the type I receptors, BMPR-1A and -1B were the highest expressed. FGF1, FGF7, FGF9, FGF10, FGF11, and FGF18 were also expressed in the pancreas at varying time points and levels, as well as FGF receptor forms FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, and FGFR4. To gain insight into the biological function, we misexpressed members of these families in the pancreas by using the early pancreas promoter Pdx1. Misexpression of FGF4 results in disruption of the pancreas morphology with epithelial structures interspersed in stroma tissue. The endocrine compartment was reduced to scattered single cells, and the exocrine consisted of unbranched ductal epithelia with acinar structures budding off. In contrast, misexpression of BMP-6 resulted in complete agenesis of the pancreas and reduced the size of the stomach and spleen dramatically and caused fusion of the liver and duodenum.

Recent federal reviews of the foster care system in the United States have concluded that the system is “in crisis.” Clinicians familiar with the foster care system are undoubtedly aware of significant stress points directly impacting foster families. In July of 1997, an innovative program was developed to assess and treat young foster children (under 48 months of age). A significant focus of this program's clinical work is supporting foster parents. This article begins with a brief review of the status of foster parenting in the United States. A description of challenges and obstacles faced by foster parents participating in this program and the service providers who work with them follows. Finally, a review of the various intervention strategies used by our program to address clinical challenges inherent in work with foster families is provided. ©2002 Michigan Association for Infant Mental Health.

The primary goal of this study was to test the reliability of the Partner Violence Interview and examine validity by measuring differential correlates of partner violence.Sixty young adults (30 males and 30 females) housed in an urban shelter participated in this study. All participants were between the ages of 18 and 21 years and the majority were African-American. The participants were administered two measures of partner violence exposure, one measure of community violence exposure and one measure of depression. A random selection of 30 of the participants was retested after 1 month.As predicted, current and past partner violence was common in this sample, with over 70% endorsing a history of physical violence. The Partner Violence Interview (PVI) had adequate retest reliability (Pearson r for two PVI scales =.7 and.85) and internal consistency (KR-20 for each scale =.78 to.93). Preliminary evidence of convergent validity was suggested by the fact that the PVI lifetime partner violence scale was significantly correlated with a physical violence scale from a second measure (the Conflict Tactics Scale; r =.596, p.001). Violence in past relationships, as opposed to current relationships, was associated with both lifetime community violence exposure and current level of depression.The Partner Violence Interview is a reliable, comprehensive instrument suited to high-risk populations. Homeless young adults commonly experience severe partner violence, and preventive intervention is clearly indicated for this group.

The transverse cervical artery is typically seen in both the superficial back and posterior cervical triangle dissections in a human cadaver gross anatomy course. The two most commonly used referen...

In the past 20 years, numerous publications on a variety of mammalian and non-mammalian species have appeared in the literature to supplement the excellent comparative work performed in the 70s and 80s by the Falkmer, Epple, and Youson groups. What emerges is that islets are much more complex than once thought and show a lot of similarities in rodents and higher primates. The diversity of lifestyles, metabolic demands, and diets has most likely influenced the great diversity in both structure and cell-type content of islets in lower vertebrate species. In this chapter, I try to provide an overview of the evolution from endocrine cell types in invertebrates to the higher mammals and focus on what has been reported in the literature and some of our own experiences and also include a description of other hormones reported to be found in islets.

Objective To determine the effectiveness of an intervention designed to improve outcomes for infants and toddlers in foster care. Method Records were reviewed for all children who were adjudicated as in need of care in a specific parish in Louisiana between 1991 and 1998. This period included 4 years before and 4 years after a comprehensive intervention was implemented. Children adjudicated between 1991 and 1994 were the comparison group, and those adjudicated between 1995 and 1998 were the intervention group. Results After the intervention, more children were freed for adoption and fewer children were returned to their birth families than before the intervention. There was no difference in length of time in care before and after the intervention. With regard to the same child returning in a subsequent incident of maltreatment, relative risk reduction for the intervention group ranged from 53% to 68%. With regard to the same mother maltreating another child subsequently, relative risk reduction for the intervention group ranged from 63% to 75%. Conclusions A comprehensive preventive intervention for maltreated infants and toddlers in foster care substantially reduced rates of recidivism but had no effect on length of time in care.

This article describes the case of an 8-year-old boy who was first brought to clinical attention at age 2 1/2. He was followed by several clinicians over a 6-year period and was assigned a wide variety of diagnoses. From the first assessment to hospitalization at age 8, a pattern of mother-child relationship disturbance is evident. The use of principles and recent research derived from attachment theory provides a useful basis for formulation in this complex case. This report focuses on the relationship between the patient's mother's internal working models of attachment and his behavior in infancy and early childhood.

Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone currently under investigation for use as a novel therapeutic agent in the treatment of type 2 diabetes mellitus. In vitro studies of pancreatic islets of Langerhans demonstrated that GLP-1 interacts with specific beta-cell G protein-coupled receptors, thereby facilitating insulin exocytosis by raising intracellular levels of cAMP and Ca2+. Here we report that the stimulatory influence of GLP-1 on Ca2+ signaling results, in part, from cAMP-dependent mobilization of ryanodine-sensitive Ca2+ stores. Studies of human, rat, and mouse beta-cells demonstrate that the binding of a fluorescent derivative of ryanodine (BODIPY FL-X ryanodine) to its receptors is specific, reversible, and of high affinity. Rat islets and BTC3 insulinoma cells are shown by reverse transcriptase polymerase chain reaction analyses to express mRNA corresponding to the type 2 isoform of ryanodine receptor-intracellular Ca2+ release channel (RYR2). Single-cell measurements of [Ca2+]i using primary cultures of rat and human beta-cells indicate that GLP-1 facilitates Ca2+-induced Ca2+ release (CICR), whereby mobilization of Ca2+ stores is triggered by influx of Ca2+ through L-type Ca2+ channels. In these cells, GLP-1 is shown to interact with metabolism of D-glucose to produce a fast transient increase of [Ca2+]i. This effect is reproduced by 8-Br-cAMP, but is blocked by a GLP-1 receptor antagonist (exendin-(9-39)), a cAMP antagonist ((Rp)-cAMPS), an L-type Ca2+ channel antagonist (nimodipine), an antagonist of the sarco(endo)plasmic reticulum Ca2+ ATPase (thapsigargin), or by ryanodine. Characterization of the CICR mechanism by voltage clamp analysis also demonstrates a stimulation of Ca2+ release by caffeine. These findings provide new support for a model of beta-cell signal transduction whereby GLP-1 promotes CICR by sensitizing intracellular Ca2+ release channels to the stimulatory influence of cytosolic Ca2+.

Objective: To review the current research literature on resilience to maltreatment in childhood and adolescence. Method: First, this paper addresses the methodological issues applicable to this area of research. Second, it reviews the empirical literature on the protective factors believed to contribute to resilience to maltreatment and offers commentary on specific issues raised in each study. Results: The current findings are summarized and an integrated descriptive picture, based on the extant literature of the processes and factors contributing to the development of resilience to childhood maltreatment is outlined. Conclusion: Based on this extensive review and critique of the current empirical literature on resilience to maltreatment, suggestions for future investigations in this area are recommended. Spanish abstract not available at time of publication.

Soixante-dix meres de milieu defavorise et leurs bebes de 15 mois ont ete evalues a domicile et en laboratoire pour examiner si les compte rendus des meres faisant etat de detresse et de violence domestique etaient associes a l'attachement enfant-mere et la motivation de developpement de l'enfant. Comme on l'avait predit, les meres faisant l'experience d'une violence domestique plus serieuse avaient plus de chances d'avoir des enfants ayant des attachements deorganises envers elles. Il n'y avait aucune association entre les experiences de violence domestique ou de detresse et la motivation de developpement de l'enfant. Les recherches a venir devraient evaluer la correlation entre la violence domestique chez les modes de soin adultes et les attachements enfant-mode de soin.

Mothers who have lost a baby in the perinatal period may experience relationship disturbances with infants born subsequently. This study involved mothers who had delivered a child within 19 months of losing a baby in the perinatal period. Mothers were assessed 2 months after the loss with a clinical interview. When the child born subsequent to the loss was 12 months old, the mother–child attachment relationship was assessed, and 45% of the infants had disorganized attachments to their mothers. This was significantly higher than the expected rate of 15% disorganized attachments in other middle-class samples. Based on narrative descriptions of the loss experience, measures of mothers' resolution of loss and experience of support were not related to infant attachment. Mothers who accepted more responsibility for their own grief were more likely to have subsequent infants with secure attachments to them.

In the genetic mutant mouse models ob/ob or db/db, leptin deficiency or resistance, respectively, results in severe obesity and the development of a syndrome resembling NIDDM. One of the earliest manifestations in these mutant mice is hyperinsulinemia, suggesting that leptin may normally directly suppress the secretion of insulin. Here, we show that pancreatic islets express a long (signal-transducing) form of leptin-receptor mRNA and that beta-cells bind a fluorescent derivative of leptin (Cy3-leptin). The expression of leptin receptors on insulin-secreting beta-cells was also visualized utilizing antisera generated against an extracellular epitope of the receptor. A functional role for the beta-cell leptin receptor is indicated by our observation that leptin (100 ng/ml) suppressed the secretion of insulin from islets isolated from ob/ob mice. Furthermore, leptin produced a marked lowering of [Ca2+]i in ob/ob beta-cells, which was accompanied by cellular hyperpolarization and increased membrane conductance. Cell-attached patch measurements of ob/ob beta-cells demonstrated that leptin activated ATP-sensitive potassium channels (K(ATP)) by increasing the open channel probability, while exerting no effect on mean open time. These effects were reversed by the sulfonylurea tolbutamide, a specific inhibitor of K(ATP). Taken together, these observations indicate an important physiological role for leptin as an inhibitor of insulin secretion and lead us to propose that the failure of leptin to inhibit insulin secretion from the beta-cells of ob/ob and db/db mice may explain, in part, the development of hyperinsulinemia, insulin resistance, and the progression to NIDDM.

Les relations bebe-mode de soin constituent le contexte crucial pour le developpement et la psychopathologie du bebe. De nombreuses preuves suggerent que les bebes pourraient construire des relations qualitativement differentes avec des modes de soin differents. Pour ces raisons, les relations bebe-mode de soin devraient etre la piece centrale dans l'evaluation en sante mentale infantile. Nous preconisons l'evaluation des relations du bebe avec tous les modes de soin importants a la fois dans des contextes naturels et cliniques. Dans cet article, nous decrivons notre approche, qui est attentive a la fois a la composante externe de la relation, a l'interaction comportementale, ainsi qu'a la composante interne de la relation, l'experience subjective. En integrant les resultats d'evaluations de ces deux composantes, nous determinons les deux niveaux d'adaptation de la relation et les domaines specifiques de forces et faiblesses.

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

International audience; Neurogenin3(+) (Ngn3(+)) progenitor cells in the developing pancreas give rise to five endocrine cell types secreting insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Gastrin is a hormone produced primarily by G-cells in the stomach, where it functions to stimulate acid secretion by gastric parietal cells. Gastrin is expressed in the embryonic pancreas and is common in islet cell tumors, but the lineage and regulators of pancreatic gastrin(+) cells are not known. We report that gastrin is abundantly expressed in the embryonic pancreas and disappears soon after birth. Some gastrin(+) cells in the developing pancreas co-express glucagon, ghrelin or pancreatic polypeptide, but many gastrin(+) cells do not express any other islet hormone. Pancreatic gastrin(+) cells express the transcription factors Nkx6.1, Nkx2.2 and low levels of Pdx1, and derive from Ngn3(+) endocrine progenitor cells as shown by genetic lineage tracing. Using mice deficient for key transcription factors we show that gastrin expression depends on Ngn3, Nkx2.2, NeuroD1 and Arx, but not Pax4 or Pax6. Finally, gastrin expression is induced upon differentiation of human embryonic stem cells to pancreatic endocrine cells expressing insulin. Thus, gastrin(+) cells are a distinct endocrine cell type in the pancreas and an alternative fate of Ngn3+ cells.

A female patient with malignant hyperthermia experiencing arrhythmias, temperature elevation, and muscle spasm is described. Diagnosis was confirmed by muscle biopsy. Complications can be prevented with early identification and treatment with dantrolene. Elective surgery can be managed safely with careful team planning. (J GYNECOL SURG 12:61, 1996)