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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)

Objective. To investigate for the presence of increased titers of circulating antibody to putative infectious agents and for detectable viral RNA or bacterial DNA in children with active recent-onset juvenile der- matomyositis (DM). Methods. Magnetic resonance imaging–directed muscle biopsies were performed in 20 children with active, untreated, recent-onset juvenile DM and in age-matched children with neurologic disease. Sera were tested for complement-fixing antibody to Coxsack-ievirus B (CVB), influenza A and B, parainfluenza 1 and 3, Mycoplasma pneumoniae, mumps, respiratory syncytial virus, and Reovirus; and by immunofluorescence for IgG antibody to Toxoplasma gondii cytomegalovirus and IgM antibody to Epstein-Barr virus. Muscle from juvenile DM patients and control children, CD-1 Swiss mice with and without CVB1 infection, and viral stock positive for CVB1–6 were tested using reverse-transcriptase polymerase chain reaction with 5 primer sets, 4 probes (1 Coxsackievirus, 3 Enterovirus), and universal primers for DNA. Results. No increased antibody, viral RNA, or bacterial DNA was present in the juvenile DM patients or the control children. Conclusion. Juvenile DM may be triggered by unidentified agent(s) in the genetically susceptible host.

The Reg3 peptides INGAP-PP and human Reg3α/β (HIP) have been hypothesized to stimulate β-cell neogenesis in the pancreas. Administration of INGAP-PP has been shown to cause an increase in β-cell mass in multiple animal models, reverse streptozotocin (STZ) induced diabetes in mice and reduces HbA1c levels in type 2 diabetic humans. In this study, we have examined the ability of the INGAP-PP and HIP peptides to induce β-cell formation in vivo in normal mice through short-term administration of the peptides. We assessed the peptides ability to induce an increase in extra-islet insulin-positive cell clusters by looking at β-cell number by point counting morphometry on pancreata that had been randomized using the smooth fractionator principle in non-diabetic NMRI mice after short-term injections of the peptides (5 d). Five day continuous BrdU labeling was used to determine if the new β-cells were derived from replicating β-cells. Real time quantitative RT-PCR and immuno-histochemistry was used to analyze changes in pancreatic transcription factor expression. A 1.5- to 2-fold increase in the volume of small extra-islet insulin-positive clusters post 5 d treatment with INGAP-PP and HIP as compared with mice treated with a non-peptide control or scrambled peptide (p

The research hypothesis was that memory strategy deficits can occur because of students' failure to understand the task and to evaluate their own performance. The effect of performance feedback on memory strategy use, performance evaluation, and recall was assessed with students with and without mild mental retardation with a mental age of approximately 8.5 years. For students with retardation, feedback resulted in more accurate performance evaluation and recall, but memory strategy use did not increase. By contrast, for students without retardation, feedback resulted in more accurate performance evaluation and greater recall accuracy and memory strategy use. We concluded that students with retardation may not have the appropriate memory strategies in their repertoire and, therefore, feedback does not result in strategy use. It seems likely that memory strategy use in this population would be increased by a training package that includes strategy instruction as well as feedback.

Mutations in optineurin have recently been linked to amyotrophic lateral sclerosis (ALS).To determine whether optineurin-positive skeinlike inclusions are a common pathologic feature in ALS, including SOD1 -linked ALS.Clinical case series.Academic referral center.We analyzed spinal cord sections from 46 clinically and pathologically diagnosed ALS cases and ALS transgenic mouse models overexpressing ALS-linked SOD1 mutations G93A or L126Z.We observed optineurin-immunoreactive skeinlike inclusions in all the sporadic ALS and familial ALS cases without SOD1 mutation, but not in cases with SOD1 mutations or in transgenic mice overexpressing the ALS-linked SOD1 mutations G93A or L126Z.The data from this study provide evidence that optineurin is involved in the pathogenesis of sporadic ALS and non- SOD1 familial ALS, thus supporting the hypothesis that these forms of ALS share a pathway that is distinct from that of SOD1-linked ALS.

Children's responses on a Narrative Story Stem Technique (NSST) were coded using scales reflecting essential attachment constructs, specifically, attachment, exploratory, sociability, and caregiving behavioral systems, as originally conceived by Bowlby ( 1973 , 1982 ) and elaborated upon by his followers (Cassidy, 2008 ). NSST responses were examined in relation to both mother- and teacher-reported psycho-social adjustment and risk using the MacArthur HealthBehavior Questionnaire (HBQ). Forty-six children participated (average age 6 years 10 months), 19 of whom had high-risk backgrounds, and the rest demographically matched. Findings indicate that NSST scales were associated with behavior on certain HBQ scales, in expected directions. NSST responses appeared to differentiate socially competent children from children with the specific psycho-social risks of externalizing behavior problems and social isolation, according to mother-reports, on the one hand, and peer vulnerability and internalizing problems, according to teacher-reports, on the other. Implications for clinical applications are discussed.

SummaryReactive oxygen species (ROS) contribute to target-cell damage in inflammatory and iron-overload diseases. Little is known about iron transport regulation during inflammatory attack. Through a combination of in vitro and in vivo studies, we show that the proinflammatory cytokine IL-1β induces divalent metal transporter 1 (DMT1) expression correlating with increased β cell iron content and ROS production. Iron chelation and siRNA and genetic knockdown of DMT1 expression reduce cytokine-induced ROS formation and cell death. Glucose-stimulated insulin secretion in the absence of cytokines in Dmt1 knockout islets is defective, highlighting a physiological role of iron and ROS in the regulation of insulin secretion. Dmt1 knockout mice are protected against multiple low-dose streptozotocin and high-fat diet-induced glucose intolerance, models of type 1 and type 2 diabetes, respectively. Thus, β cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications.

In 2007 a young Japanese female was reported to suffer from a congenital brain malformation with a non-functioning pancreatic endocrine tumor arising from intracranial ectopic pancreatic tissue. Ectopic pancreas is normally confined to other endodermally-derived organs and not previously reported to be found in the brain. Therefore, we sought to better understand the true pancreatic nature of the tissue and to further understand the mechanism by which ectopic pancreas could appear in the brain. A detailed immunohistochemical analysis for pancreatic hormones, transcription factors, ductal/exocrine markers and stem cell markers on sections from the resected tumor tissue was performed. All five endocrine cell types are observed but pancreatic polypeptide cells are quite rare and ghrelin and glucagon cells are more numerous than in normal human pancreas. Insulin immunoreactive cells stain for c-peptide. The β-cell specific transcription factor, Nkx6.1, is expressed only in the insulin immunoreactive cells while neither Ptf1a or PDX-1 immunoreactive cells can be observed. Duct-like structures stain strongly for pan-cytokeratin and E-cahderin. The exocrine like tissue stains strongly for pancreatic amylase, lipase and chymotrypsin. Ngn-3 cells were very rare and not in the pancreatic area. Examining for endodermal markers we observed Sox17 had a weak staining in some areas of the pancreatic tissue but was much less widely expressed than FoxA2. The tumor tissue did not stain for the stem cell markers, Oct-4 and Sox2. It is speculated that the ectopic pancreas domain may arise from misexpression of homeodomain transcription factors related to Pdx1 within a domain of Ptf1a expression.

Acomys, also called spiny mice, were once used as a diabetes model. We have recently demonstrated that the closest relatives to the Acomys, members of the family Gerbillinae, lack the transcription factor Pdx-1. Therefore, we sought to determine if members of this family also lack Pdx-1, and describe the pancreatic morphology in three different species of Acomys: Acomys cahirinus (Egyptian spiny mouse), Acomys cilicicus (Asia Minor spiny mouse) and Acomys dimidiatus (eastern spiny mouse). We successfully cloned the Acomys Pdx-1 gene and we demonstrate by immunocytochemistry that the Pdx-1 protein is expressed in the pancreatic insulin immunoreactive cells and in a subset of the somatostatin cells. The basic islet structure is very similar to other rodents - with the insulin cells in the center, and glucagon, somatostatin, PP and occasional PYY cells in the periphery. No ghrelin or CART cells were identified. Nkx6.1 was localized specifically to the insulin immunoreactive cells, while Nkx2.2 was found in all endocrine cells except the somatostatin immunoreactive cells. Both MafA and MafB were expressed in the islets; MafA being specific for the insulin cells, while MafB was primarily in the glucagon cells but also found in some insulin cells. Isl-1 was localized in all endocrine cell types. In conclusion, the closest relatives to the Gerbils express a Pdx-1 protein that is 90% similar to other rodents but also has a unique 3 amino acid insert compared to other species. During the evolution of the spiny mice and the gerbils, it appears that the Pdx-1 gene was lost.

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.

The pancreatic insulin-producing β-cell is a highly specialized cell that develops into the main endocrine cell types in the islets of Langerhans of the pancreas from the primitive gut endoderm. A large number of specific transcription factors have been demonstrated to be crucial to the development and function of this highly specialized cell. Recently, genome-wide association scans as well as study of maturity onset diabetes of the young genes has demonstrated that most of these genes are expressed in the pancreatic β-cell and are involved in not only transcriptional functions but also the insulin secretory apparatus. This chapter provides a short overview of these subjects.

The aim of this study was to characterize bovine and porcine pancreatic development by immunohistochemistry. In the pig, staining for both glucagon and insulin was noted at day 19. In cattle, glucagon staining was observed at day 25 and insulin staining from day 26. In both species, glucagon-stained cells were abundant initially, but later insulin-stained cells became most abundant. A few cells displayed co-localization of glucagon and insulin staining during initial development in both species. Initially, most of the cells of the pancreatic primordia and the duodenal epithelium displayed Pdx-1-staining. All insulin-stained cells displayed Pdx-1-stained nuclei, whereas no glucagon-stained cells did so. Many Pdx-1-stained cells lacked insulin staining, but with development, the relative number of these cells diminished. Nkx6.1-staining was initially seen in a pattern similar to that for Pdx-1, but was lacking duodenal staining. Subsequently, the number of Nkx6.1-stained cells diminished, but increased again to a level where practically all insulin-stained cells also presented Nkx6.1-staining. Glucagon-stained cells, on the other hand, never had Nkx6.1 staining. In conclusion, the localization of the two transcription factors, Pdx-1 and Nkx6.1, demonstrated that pancreas development appears to be controlled by mechanisms comparable with those operating in humans.

This study examines type-specific and cumulative experiences of violence among a vulnerable population of youth. Sixty high-risk, shelter-dwelling, urban youth were interviewed regarding their history of childhood maltreatment, exposure to community violence (ECV), and experience with intimate partner violence (IPV). Results show a high prevalence and high degree of overlap among multiple types of violence exposure. Childhood physical, sexual (CSA), and emotional (CEA) abuse were interrelated and were associated with ECV. Cumulative experiences of childhood abuse (CCA) had a graded association with IPV victimization. In multivariate analyses, CCA and ECV were independently associated with IPV victimization. Gender moderated the effect of one association: CEA raised the risk of IPV victimization for girls but not for boys. Only CSA predicted IPV perpetration. Findings suggest that cumulative exposures to violence create cumulative risk for experiencing more violence. Shelter-dwelling, urban youth may be particularly vulnerable to this additive effect.

The Meriones Jirds belong to the genus of Gerbillinae (Rodentia: Muridae). We and others have previously reported the lack of the pancreatic beta-cell transcription factor, Pdx-1 in the fat sand rat, Psammomys obesus. The aim of the study was to investigate the expression and localization of Pdx-1 in phylogenetically related members of the Gerbillinae subfamily. In addition, we characterized by IHC the expression pattern of islet hormones and additional important pancreatic transcription factors in order to evaluate overall endocrine pancreas appearance. PCR showed that Pdx-1 was easily amplified from a wide range of phylogenetically distant species but not from 13 different gerbilline species. Identical to P. obesus the important beta-cell transcription factor Pdx-1 was absent from all five jirds. However, expression of other critical islet transcription factors and islet hormones was generally normal. Insulin was localized in the center of the islets with glucagon, somatostatin and pancreatic polypeptide (PP) found in the islet mantle. PYY cells were also observed and colocalized with PP cells. The NKX family of transcription factors were localized to the same cell types as seen in other rodents. MafA was nuclear localized in some of the insulin immunoreactive but not in other cell types, while MafB was found not only in the glucagon cells but also in many of the insulin cells. In conclusion, Pdx-1 appears to be lacking in all gerbils and despite the lack of Pdx-1, the Meriones Jirds have islets that are morphologically similar to other rodents and express hormones and transcription factors in the expected pattern except for MafA and MafB.

Sulfidopeptide leukotrienes (LTs) include LTC4, LTD4, and LTE4. They contract airway smooth muscle and reduce heart contractility in mammals. In this study, LTC4, LTD4, and LTE4 were compared for their effects on bullfrog heart and lung contractility in vitro. LTC4, LTD4, and LTE4 all stimulated lung contraction and increased heart contractility, but LTC4 was more potent than the other two leukotrienes. LY 171883, a mammalian LTD4 receptor antagonist, failed to block the heart and lung responses to LTC4 but did blunt the responses to LTD4 and LTE4. Metabolism studies carried out with 3H-LTC4 demonstrated conversion to LTD4 and small amounts of LTE4 by heart, but not by lung. Thus, bullfrogs respond to leukotrienes in ways which may be similar to (increase in lung contractility) or different from (increase in heart contractility) mammals. Leukotriene receptors appear to be highly conserved, despite the fact that tissue responsiveness to leukotrienes has changed over evolutionary time.

Riluzole is the only FDA approved drug for the treatment of amyotrophic lateral sclerosis. Riluzole is assumed to be mainly metabolized by the liver cytochrome CYP1A2 and by the extra-hepatic cytochrome CYP1A1. CYP1A2 and CYP1A1 genetic polymorphisms are known, but their relationship to riluzole metabolism in ALS patients has not been investigated. The aim of this study was to determine whether the polymorphisms of the CYP1A2 and the CYP1A1 genes in ALS patients are associated with riluzole metabolic profiles. Thirty-two patients with a diagnosis of probable or definite ALS and who were on riluzole, participated in the study. Trough and peak plasma riluzole levels were measured using analytical chromatography-mass spectrometry methods. Association of the genotypes of the SNPs spanning the CYP1A1 and CYP1A2 genes (including one SNP in the intergenic region) with mean riluzole peak and trough levels was studied using ANOVA and Tukey's HSD. The mean peak riluzole level was 202+/-111 ng/ml and mean trough level 54.3+/-37.5 ng/ml. Our data do not support any association of the four CYP1A1 and CYP1A2 polymorphisms with the riluzole metabolic profile. In conclusion, genetic variations in CYP1A1 and CYP1A2 genes do not seem to influence riluzole levels. Further work is needed to better understand the genetic regulation of CYP1A enzymes and their role in riluzole metabolism.

To understand the molecular mechanisms regulating pancreatic endocrine development and function, pancreatic gene expression was compared between Ngn3-deficient mice and littermate controls on embryonic days 13 and 15. Microarray analysis identified 504 genes with significant differences in expression. Fifty-two of these showed at least twofold reduction in Ngn3 knockouts compared to controls. Many of them were previously described to be involved in endocrine development and function. Among the genes not previously characterized were Rhomboid veinlet-like 4, genes involved in tetrahydrobiopterin biosynthesis and the Iroquois-type homeobox gene Irx1, the latter was selected for further investigation. In situ hybridisation demonstrated that two Iroquois genes, Irx1 and Irx2, were expressed in pancreatic endoderm of wild-type, but not Ngn3 mutant embryos. Furthermore, ectopic Ngn3 induced prominent Irx2 expression in chicken endoderm. Co-labelling established that Irx1 and Irx2 mRNA is located to glucagon-, but not insulin- or somatostatin-producing cells in mice and chicken. These data suggest that Irx1 and Irx2 serve an evolutionary conserved role in the regulation of α-cell-specific gene expression.

The desert gerbil Psammomys obesus, an established model of type 2 diabetes (T2D), has previously been shown to lack pancreatic and duodenal homeobox gene 1 (Pdx-1) expression. Pdx-1 deficiency leads to pancreas agenesis in both mice and humans. We have therefore further examined the pancreas of P. obesus during embryonic development. Using Pdx-1 antisera raised against evolutionary conserved epitopes, we failed to detect Pdx-1 immunoreactivity at any time points. However, at E14.5, Nkx6.1 immunoreactivity marks the nuclei of all epithelial cells of the ventral and dorsal pancreatic buds and the only endocrine cell types found at this time point are glucagon and PYY. At E18.5 the pancreas is well branched and both glucagon- and ghrelin-positive cells are scattered or found in clusters, whereas insulin-positive cells are not found. At E22.5, the acini of the exocrine pancreas are starting to mature, and amylase and carboxypeptidase A immunoreactivity is found scattered and not in all acini. Ghrelin-, glucagon-, PYY-, gastrin-, somatostatin (SS)-, pancreatic polypeptide (PP)-, and insulin-immunoreactive cells are found scattered or in small groups within or lining the developing ductal epithelium as marked by cytokeratin 19. Using degenerate PCR, the P. obesus Neurogenin-3 (Ngn-3) gene was cloned. Nucleotide and amino acid sequences show high homology with known Ngn-3 sequences. Using specific antiserum, we can observe that Ngn-3-immunoreactive cells are rare at E14.5 but readily detectable at E18.5 and E22.5. In conclusion, despite the lack of detection of Pdx-1, the P. obesus pancreas develops similarly to Muridae species, and the Ngn-3 sequence and expression pattern is highly conserved in P. obesus.

The best means for the diagnosis and treatment of reactive attachment disorder of infancy and early childhood have not been established. Though some longitudinal data on institutionalized children is available, reports of maltreated young children who are followed over time and assessed with measures of attachment are lacking. This paper presents the clinical course of a set of maltreated fraternal twins who were assessed and treated from 19 months to 30 months of age and then seen in follow-up at 3 and 8 years of age. A summary of the early assessment and course is provided and findings from follow-up assessments of the cognitive, behavioral, and interpersonal functioning of each child is analysed. Follow-up measures, chosen to capture social-cognitive processing of these children from an attachment perspective, are highlighted. Finally, findings from the case are discussed from nosological and theoretical perspectives.

Wnt signalling is involved in many developmental processes such as proliferation, differentiation, cell fate decisions, and morphogenesis. However, little is known about Wnt signalling during pancreas development. Multiple Wnt ligands and Frizzled receptors are expressed in the embryonic mouse pancreas, the surrounding mesenchyme, and have also been detected in the chicken endoderm during development. The aim of this study was to investigate the role of canonical Wnt signalling on endocrine cell development by use of the in ovo electroporation of the chicken endoderm. Overexpression with a constitutive active form of beta-catenin in combination with Ngn3 resulted in reduced numbers of glucagon cells. dnLEF-1 or naked-1 did not alter endocrine cell differentiation when co-expressed with Ngn3, but dnLEF-1 appeared to have some potential for inhibiting delamination of Ngn3 cells. In addition, neuronal beta-III-tubulin, which had previously been considered a specific marker for neuronal cells, was observed in the pancreas and was upregulated in the electroporated Ngn3 cells and thus may be a new endocrine marker in the chicken.

A total of 42 freshman medical students were evaluated before a major exam, after the exam and before grades were announced and after grades were announced. They completed measures relating to mood, emotions, coping, social support and stakes. Significant time and academic performance differences were found in many domains.

Objective: To determine if Reactive Attachment Disorder (RAD) can be reliably identified in maltreated toddlers in foster care, if the two types of RAD are independent, and to estimate the prevalence of RAD in these maltreated toddlers. Methods: Clinicians treating 94 maltreated toddlers in foster care were interviewed regarding signs of attachment disorder at intake in an intervention program. Results: Using categorical and continuous measures, both types of RAD can be reliably identified in maltreated toddlers. Both continuous scores and categorical diagnoses indicated that a substantial minority of maltreated young children do exhibit signs of attachment disorders sufficient to meet criteria in DSM-IV and ICD-10. The two types were moderately convergent and at times co-occurred in the same child. Prevalence of RAD in this high-risk sample was 38–40%. Indiscriminate/disinhibited RAD was identified in children with and without an attachment figure. Within this maltreated group, toddlers whose mothers had a history of psychiatric disturbance were more likely to be diagnosed with attachment disorders. Conclusions: RAD may be reliably identified in maltreated toddlers. Emotionally withdrawn/inhibited and indiscriminate/disinhibited types of RAD are not entirely independent.

It is well established that gut and pancreas development depend on epithelial-mesenchymal interactions. We show here that several Wnt, Frizzled, and secreted frizzled-related protein (sFRP) encoding mRNAs are present during mouse pancreatic morphogenesis. Wnt5a and 7b mRNA is broadly expressed in foregut mesenchyme starting around embryonic day 10 in mice. Other members expressed are Wnt2b, Wnt5b, and Wnt11. In addition, genes for the Wnt receptors, Frizzled2, 3, 4, 5, 6, 7, 8, and 9 are expressed. To understand potential Wnt functions in pancreas and foregut development in vivo, we analyzed transgenic F0 mouse fetuses expressing Wnt1 and 5a cDNAs under control of the PDX-1 gene promoter. In PDX-Wnt1 fetuses, the foregut region normally comprising the proximal duodenum instead resembles a posterior extension of the stomach, often associated with complete pancreatic and splenic agenesis. Furthermore, the boundary between expression domains of gastric and duodenal markers is shifted in a posterior direction. In PDX-Wnt5a fetuses, several structures derived from the proximal foregut are reduced in size, including the pancreas, spleen, and stomach, without any apparent shift in the stomach to duodenum transition. In these fetuses, overall pancreatic morphology is changed and the pancreatic epithelium is dense and compact, consistent with Wnt5A effects on cell movements and/or attachment. Taken together, these results suggest that Wnt genes participate in epithelial-mesenchymal signaling and may specify region identity in the anterior foregut. © 2002 Wiley-Liss, Inc.

The Parent-Infant Relationship Global Assessment Scale (PIRGAS; Zero to Three, 1994) provides a continuously distributed scale of infant-parent relationship adaptation, raging from 'well-adapted' to 'dangerously impaired'. The present study examines the predictive validity of the PIRGAS in a high-risk sample by coding relationship adaptation level from a single sample of 10 min of unstructured free play between mothers and their 20-month-old infants and examining its relationship to subsequent interaction with mothers and behavior problems at 24 months. Relationship adaptation assessed reliably from observations of only 10 min of free play between mothers and their infants at 20 months of age using PIRGAS predicted subsequent mother- infant interaction in a laboratory based problem-solving paradigm (Crowell procedure) at 24 months and internalizing symptomatology of Child Behavior Checklist at age 24 months. These results contribute to the predictive validity of the PIRGAS as a measure of mother-infant relationship adaptation.

Myotonic dystrophy type 1 (DM1) is the most common inherited muscle disorder and may present in numerous ways due to characteristic multisystem involvement. We report a 47-year-old man who presented with an 8-year history of slowly progressive dyspnea and episodic stridor. The laryngeal paresis was documented with videostroboscopy and laryngeal electromyography, and treated with tracheostomy and antimyotonia agents.

Background Understanding the evolution of the vertebrate pancreas is key to understanding its functions. The chondrichthyes (cartilaginous fish such as sharks and rays) have often been suggested to possess the most ancient example of a distinct pancreas with both hormonal (endocrine) and digestive (exocrine) roles. The lack of genetic, genomic and transcriptomic data for cartilaginous fish has hindered a more thorough understanding of the molecular-level functions of the chondrichthyan pancreas, particularly with respect to their “unusual” energy metabolism (where ketone bodies and amino acids are the main oxidative fuel source) and their paradoxical ability to both maintain stable blood glucose levels and tolerate extensive periods of hypoglycemia. In order to shed light on some of these processes, we carried out the first large-scale comparative transcriptomic survey of multiple cartilaginous fish tissues: the pancreas, brain and liver of the lesser spotted catshark, Scyliorhinus canicula. Results We generated a mutli-tissue assembly comprising 86,006 contigs, of which 44,794 were assigned to a particular tissue or combination of tissues based on mapping of sequencing reads. We have characterised transcripts encoding genes involved in insulin regulation, glucose sensing, transcriptional regulation, signaling and digestion, as well as many peptide hormone precursors and their receptors for the first time. Comparisons to mammalian pancreas transcriptomes reveals that mechanisms of glucose sensing and insulin regulation used to establish and maintain a stable internal environment are conserved across jawed vertebrates and likely pre-date the vertebrate radiation. Conservation of pancreatic hormones and genes encoding digestive proteins support the single, early evolution of a distinct pancreatic gland with endocrine and exocrine functions in jawed vertebrates. In addition, we demonstrate that chondrichthyes lack pancreatic polypeptide (PP) and that reports of PP in the literature are likely due cross-reaction with PYY and/or NPY in the pancreas. A three hormone islet organ is therefore the ancestral jawed vertebrate condition, later elaborated upon only in the tetrapod lineage. Conclusions The cartilaginous fish are a great untapped resource for the reconstruction of patterns and processes of vertebrate evolution and new approaches such as those described in this paper will greatly facilitate their incorporation into the rank of “model organism”. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1074) contains supplementary material, which is available to authorized users.

The homeodomain protein PDX-1 is critical for pancreas development and is a key regulator of insulin gene expression. PDX-1 nullizygosity and haploinsufficiency in mice and humans results in pancreatic agenesis and diabetes, respectively. At embryonic day (e) 10.5, PDX-1 is expressed in all pluripotential gut-derived epithelial cells destined to differentiate into the exocrine and endocrine pancreas. At e15, PDX-1 expression is downregulated in exocrine cells, but remains high in endocrine cells. The aim of this study was to determine whether targeted overexpression of PDX-1 to the exocrine compartment of the developing pancreas at e15 would allow for respecification of the exocrine cells. Transgenic (TG) mice were generated in which PDX-1 was expressed in the exocrine pancreas using the exocrine-specific elastase-1 promoter. These mice exhibited a marked dysmorphogenesis of the exocrine pancreas, manifested by increased rates of replication and apoptosis in acinar cells and a progressive fatty infiltration of the exocrine pancreas with age. Interestingly, the TG mice exhibited improved glucose tolerance, but absolute β-cell mass was not increased. These findings indicate that downregulation of PDX-1 is required for the proper maintenance of the exocrine cell phenotype and that upregulation of PDX-1 in acinar cells affects β-cell function. The mechanisms underlying these observations remain to be elucidated.

Before the discovery of insulin the diagnosis of diabetes mellitus was equivalent to being sentenced to death. It was thus a miracle that insulin treatment would rescue the lives of diabetics, and Banting and MacLeod were awarded the Nobel Prize in 1923 for their pioneering work in Toronto (1). As time went by, it became apparent that diabetic patients suffer from late complications such as neuropathy, retinopathy, vascular diseases and kidney failure. Such complications are now ascribed to inappropriate fluctuations in blood glucose levels as revealed in recent clinical trials (DCCT &UKPDS) (2-4). Insulin thus provides a treatment of diabetes - not a cure.

bHLH (basic-Helix-Loop-Helix) transcription factors are essential during the commitment of a multitude of cell fate decisions throughout vertebrate development, most extensively characterized within cells of ectodermal or mesodermal origin. Not surprisingly, members of this protein class are also instrumental in regulating cellular differentiation in the developing endoderm, including the endocrine cells of the lung, pancreas, stomach, and gut (1-4). These observations have begun to unravel an extensive similarity between the developing ectoderm and endoderm - involving not merely the sharing of molecular mechanisms, but include sharing of identical gene networks. These data provide a beginning of understanding the pancreatic precursor cell state and how individual endocrine cells may escape to complete differentiation. This leaves us in possession with an excellent platform from which further insight into endodermal endocrine differentiation may be obtained.

α-cell specific transcription of the glucagon gene is mainly conferred by the glucagon promoter G1-element, while additional elements G2, G3, and G4 have broad islet cell specificity. Transcription of the glucagon gene has been shown to be stimulated by Pax6 through binding to the glucagon gene promoter G3-element. In this report, we show that Pax6 additionally binds the glucagon gene promoter G1-element and forms a transcriptionally active complex with another homeodomain protein, Cdx2/3. Two distinct mutations in the G1-element, that both reduce promoter activity by 85–90%, is shown to eliminate binding of either Pax6 or Cdx2/3. Additionally, Pax6 enhanced Cdx2/3 mediated activation of a glucagon reporter in heterologous cells. We discuss how Pax6 may contribute to cell-type specific transcription in the pancreatic islets by complex formation with different transcription factors.

Background & Aims: The endoderm-specific homeodomain transcription factor IDX-1 is critical for pancreas development and for the regulation of islet cell–specific genes. During development, IDX-1 is expressed in the epithelial cells of the endoderm in the pancreatic anlage of the foregut. The aim of this study was to determine whether IDX-1 may have potential properties of a master homeotic determinant of pancreas and/or gut development. Methods: Transgenic mice were generated in which the expression of IDX-1 was misdirected by a promoter of the mesoderm-specific homeodomain protein Hoxa-4 known to express in the stomach and hindgut during development. The expectation was the formation of ectopic pancreatic tissue or alterations of gut patterning or morphology. Results: Although no ectopic induction of pancreatic markers was found in these transgenic mice, they manifested an altered midgut-hindgut union and agenesis of the cecum. Further, IDX-1 binds to the gut-specific homeodomain protein Cdx-2 and inhibits transactivation of the sucrase-isomaltase promoter by Cdx-2. Conclusions: These findings further support the emerging understanding that interactions among different classes of homeodomain proteins, expressed in a spatially and temporally restricted manner during development, determine the pattern of organogenesis. A possible mechanism for the dysmorphogenesis of the proximal colon may be an inhibition of Cdx-2 actions by IDX-1. GASTROENTEROLOGY 1998;115:381-387

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10(-7)), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10(-7)), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10(-7)). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R(2)(partial) = 0.0061; p = 6.59 × 10(-8)) and rs803675 (R(2)(partial) = 0.0060; p = 6.96 × 10(-8)). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease.

The authors report an unusual case of venous infarction of the spinal cord associated with endoscopic sclerotherapy for esophageal varices. MR imaging findings included signal abnormalities and abnormal enhancement of the affected spinal cord and T-8 vertebral body. A review of the hemodynamic changes associated with portal hypertension and the normal venous drainage of the spinal cord is presented.

Background The SQSTM1 gene encodes p62, a major pathologic protein involved in neurodegeneration. Objective To examine whether SQSTM1 mutations contribute to familial and sporadic amyotrophic lateral sclerosis (ALS). Design Case-control study. Setting Academic research. Patients A cohort of 546 patients with familial (n = 340) or sporadic (n = 206) ALS seen at a major academic referral center were screened for SQSTM1 mutations. Main Outcome Measures We evaluated the distribution of missense, deletion, silent, and intronic variants in SQSTM1 among our cohort of patients with ALS. In silico analysis of variants was performed to predict alterations in p62 structure and function. Results We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS). Predictive in silico analysis classified 8 of 9 missense variants as pathogenic. Conclusions Using candidate gene identification based on prior biological knowledge and the functional prediction of rare variants, we identified several novel SQSTM1 mutations in patients with ALS. Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.

Background Mutations in optineurin have recently been linked to amyotrophic lateral sclerosis (ALS). Objective To determine whether optineurin-positive skeinlike inclusions are a common pathologic feature in ALS, including SOD1 -linked ALS. Design Clinical case series. Setting Academic referral center. Subjects We analyzed spinal cord sections from 46 clinically and pathologically diagnosed ALS cases and ALS transgenic mouse models overexpressing ALS-linked SOD1 mutations G93A or L126Z. Results We observed optineurin-immunoreactive skeinlike inclusions in all the sporadic ALS and familial ALS cases without SOD1 mutation, but not in cases with SOD1 mutations or in transgenic mice overexpressing the ALS-linked SOD1 mutations G93A or L126Z. Conclusion The data from this study provide evidence that optineurin is involved in the pathogenesis of sporadic ALS and non- SOD1 familial ALS, thus supporting the hypothesis that these forms of ALS share a pathway that is distinct from that of SOD1 -linked ALS.