Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development

Establishment of the left-right axis is a fundamental process of vertebrate embryogenesis. Failure to develop left-right asymmetry leads to incorrect positioning and morphogenesis of numerous internal organs, and is proposed to underlie the etiology of several common cardiac malformations. The transcriptional modulator Cited2 is essential for embryonic development: Cited2-null embryos die during gestation with profound developmental abnormalities, including cardiac malformations, exencephaly and adrenal agenesis. Cited2 is also required for normal establishment of the left-right axis; we demonstrate that abnormal heart looping and right atrial and pulmonary isomerism are consistent features of the left-right-patterning defect. We show by gene expression analysis that Cited2 acts upstream of Nodal, Lefty2 and Pitx2 in the lateral mesoderm, and of Lefty1 in the presumptive floor plate. Although abnormal left-right patterning has a major impact on the cardiac phenotype in Cited2-null embryos, laterality defects are only observed in a proportion of these embryos. We have therefore used a combination of high-resolution imaging and three-dimensional (3D) modeling to systematically document the full spectrum of Cited2-associated cardiac defects. Previous studies have focused on the role of Cited2 in cardiac neural crest cell development, as Cited2 can bind the transcription factor Tfap2, and thus affect the expression of Erbb3 in neural crest cells. However, we have identified Cited2-associated cardiac defects that cannot be explained by laterality or neural crest abnormalities. In particular, muscular ventricular septal defects and reduced cell density in the atrioventricular (AV) endocardial cushions are evident in Cited2-null embryos. As we found that Cited2 expression tightly correlated with these sites, we believe that Cited2 plays a direct role in development of the AV canal and cardiac septa. We therefore propose that, in addition to the previously described reduction of cardiac neural crest cells, two other distinct mechanisms contribute to the spectrum of complex cardiac defects in Cited2-null mice; disruption of normal left-right patterning and direct loss of Cited2 expression in cardiac tissues.

5-HT1A receptors of the lateral septum regulate inhibitory avoidance but not escape behavior in rats

Serotonin in the lateral septum (LS) has been implicated in the modulation of defensive behaviors and in anxiety. However, it is currently unknown whether changes in 5-HT mechanisms in this brain area may selectively affect defensive responses associated with specific subtypes of anxiety disorders recognized in clinical settings. To address this question, we evaluated the effect of the intra-LS injection of the 5-HT1A/7 receptor agonist 8-CH-DPAT (0.6, 3.0, 15.0 nmol) in male Wistar rats exposed to the elevated T-maze animal model of anxiety. This test allows the measurement of two behavioral defensive responses in the same rat: inhibitory avoidance and escape behavior. In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. The effects of 8-OH-DPAT were compared to those caused by a standard anxiolytic compound, the benzodiazepine receptor agonist midazolam (MDZ, 20 nmol). We also investigated whether the intra-LS injection of the 5-HT1A receptor antagonist WAY-100635 (0.37 nmol) was able to block the effects of 8-OH-DPAT. All animals were also tested in an open field for locomotor activity assessments. Results showed that whereas intra-LS administration of MDZ decreased avoidance latencies, suggesting an anxiolytic action, 8-OH-DPAT caused the opposite effect. Neither drug affected the escape performance. Intra-LS administration of WAY-100635 blocked the anxiogenic effect caused by 8-OH-DPAT. No changes to locomotion were detected in the open field. The data suggests that LS 5-HT1A receptors are involved in the control of inhibitory avoidance behavior and that a failure in this regulatory mechanism may be of importance to the physiopathology of generalized anxiety disorder. (c) 2008 Elsevier Inc. All rights reserved.

Functional MR Imaging of visuo-spatial network in Autism Spectrum Disorder

Individuals with Autism Spectrum Disorder (ASD) are generally thought to have impaired attentional and executive function upon which all their cognitive and behaviour functions are based. Mental Rotation is a recognized visuo-spatial task, involving spatial working memory, known to involve activation in the fronto-parietal networks. To elucidate the functioning of fronto-parietal networks in ASD, the aim of this study was to use fMRI techniques with a mental rotation task, to characterize the underlying functional neural system. Sixteen male participants (seven highfunctioning autism or Asperger's syndrome; nine ageand performance IQ-matched controls) underwent fMRI. Participants were presented with 18 baseline and 18 rotation trials, with stimuli rotated 3- dimensionaUy (45°-180°). Data were acquired on a 3- Tesla scanner. The most widely accepted area reported to be involved in processing of visuo-spatial information. Posterior Parietal Cortex, was found to be activated in both groups, however, the ASD group showed decreased activation in cortical and subcortical frontal structures that are highly interconnected, including lateral and medial Brodmann area 6, frontal eye fields, caudate, dorsolateral prefrontal cortex and anterior cingulate. The suggested connectivity between these regions indicates that one or more circuits are impaired as a result of the disorder. In future it is hoped that we are able to identify the possible point of origin of this dysfunction, or indeed if the entire network is dysfunctional.

Developmental vitamin D deficiency alters adult behaviour: An informative animal model of schizophrenia

Background: There is growing evidence that vitamin D is active in the brain but until recently there was a lack of evidence about its role during brain development. Guided by certain features of the epidemiology of schizophrenia, we have explored the role of vitamin D in the developing brain and behaviour using whole animal models. Methods: Sprague-Dawley rats were fed a vitamin D deficient diet (DVD) or control diet 6 weeks prior to mating and housed under UVB-free lighting conditions. On the day of birth all rats were fed a control diet for the remainder of the study. We observed behaviour at two timepoints; on the day of birth to study maternal behaviour, and at 10 weeks of age to study offspring behaviour in adulthood, under baseline and drug induced conditions (MK-801, haloperidol, amphetamine). Results: Prenatal vitamin D deficiency results in subtle alterations in maternal behaviour as well as long lasting effects on the adult offspring, despite a return to normal vitamin D levels during postnatal life. These affects were specific to transient prenatal vitamin D depletion as adult vitamin D depletion, combined prenatal and chronic postnatal vitamin D depletion, or ablation of the vitamin D receptor in mice led to markedly different outcomes. Conclusions: The developmental vitamin D (DVD) model now draws strength from epidemiological evidence of schizophrenia and animal experiments. Although the DVD model does not replicate every aspect of schizophrenia, it has several attractive features: (1) the exposure is based on clues from epidemiology; (2) it reproduces the increase in lateral ventricles; (3) it reproduces well-regarded behavioural phenotypes associated with schizophrenia (e.g. MK- 801 induced hyperlocomotion); and (4) it implicates a disturbance in dopamine signaling. In summary, low prenatal levels of vitamin D can influence critical components of orderly brain development and that this has a long lasting effect on behaviour.

The selection of intended actions and the observation of others' actions: A time-resolved fMRI study

Whenever we plan, imagine, or observe an action, the motor systems that would be involved in preparing and executing that action are similarly engaged. The way in which such common motor activation is formed, however, is likely to differ depending on whether it arises from our own intentional selection of action or from the observation of another's action. In this study, we use time-resolved event-related functional MRI to tease apart neural processes specifically related to the processing of observed actions, the selection of our own intended actions, the preparation for movement, and motor response execution. Participants observed a finger gesture movement or a cue indicating they should select their own finger gesture to perform, followed by a 5-s delay period; participants then performed the observed or self-selected action. During the preparation and readiness for action, prior to initiation, we found activation in a common network of higher motor areas, including dorsal and ventral premotor areas and the pre-supplementary motor area (pre-SMA); the more caudal SMA showed greater activation during movement execution. Importantly, the route to this common motor activation differed depending on whether participants freely selected the actions to perform or whether they observed the actions performed by another person. Observation of action specifically involved activation of inferior and superior parietal regions, reflecting involvement of the dorsal visual pathway in visuomotor processing required for planning the action. In contrast, the selection of action specifically involved the dorsal lateral prefrontal and anterior cingulate cortex, reflecting the role of these prefrontal areas in attentional selection and guiding the selection of responses. (c) 2005 Elsevier Inc. All rights reserved.

Tricho-rhino-phalangeal syndrome: first brazilian case

Thrico-rhino-falangeal syndrome is a rare genetic disease characterized by the presence of typical alterations with a long, bulbous nose, hair alterations, a long flat philtrum, and one-shaped epiphyses of the phalanges. We describe herein the first Brazilian case of a 24-year-old woman with thrico-rhino-falangeal syndrome type I. Physical examination demonstrated typical nose and hair abnormalities, and one-shaped epiphyses of the phalanges, and the genetic study confirmed the diagnosis. Thrico-rhino-falangeal syndrome is characterized by musculoskeletal alterations that at the first view may simulate juvenile idiopathic arthritis. These musculoskeletal deformities could imply the differential diagnosis with rheumatic diseases.

The usefulness of acetic acid wash and chemiluminescent illumination (Vizilite) in the visualization of oral mucosal white lesions

A diligent and careful examination of the mouth and oral structures has been historically deficient in revealing premalignant and malignant oral lesions. Conventional screening practice for oral neoplastic lesions involves visual scrutiny of the oral tissues with the naked eye under projected incandescent or halogen illumination. Visualization is the principal strategy used to find patients with lesions at risk for malignant transformation; hence, any procedure which highlights neoplastic lesions should aid the clinician. This pilot study examined the usefulness of acetic acid wash and chemiluminescent light (Vizilite) in enhancing visualization of oral mucosal white lesions, and its ability to highlight malignant and potentially malignant lesions. Fifty five patients referred for assessment of a white lesion, were prospectively screened with Vizilite, and an incisional biopsy performed for a definitive diagnosis. The age, sex, and smoking status of all patients were recorded, and all lesions were photographed. The visibility, location, size, border, and presence of satellite lesions, were also recorded. The Vizilite tool enhanced intraoral visualization of 26 white lesions, but it could not distinguish between epithelial hyperplasia, dysplasia, or carcinoma. Indeed, all lesions appeared ‘‘aceto-white’’, regardless of the definitive diagnosis. On one occasion, Vizilite aided in the identification of a satellite lesion that was not observed by routine visual inspection. Vizilite appears to be a useful visualization tool, but it does not aid in the identification of malignant and potentially malignant lesions of the oral mucosa.

Visuospatial processing and the function of prefrontal-parietal networks in autism spectrum disorders: a functional MRI study

Objective: Individuals with autism spectrum disorders typically have normal visuospatial abilities but impaired executive functioning, particularly in abilities related to working memory and attention. The aim of this study was to elucidate the functioning of frontoparietal networks underlying spatial working memory processes during mental rotation in persons with autism spectrum disorders. Method: Seven adolescent males with normal IQ with an autism spectrum disorder and nine age- and IQ-matched male comparison subjects underwent functional magnetic resonance imaging scans while performing a mental rotation task. Results: The autism spectrum disorders group showed less activation in lateral and medial premotor cortex, dorsolateral prefrontal cortex, anterior cingulate gyrus, and caudate nucleus. Conclusions: The finding of less activation in prefrontal regions but not in parietal regions supports a model of dysfunction of frontostriatal networks in autism spectrum disorders.

Multifidus muscle recovery is not automatic after resolution of acute, first-episode low back pain

Study Design. A clinical study was conducted on 39 patients with acute, first-episode, unilateral low back pain and unilateral, segmental inhibition of the multifidus muscle. Patients were allocated randomly to a control or treatment group. Objectives. To document the natural course of lumbar multifidus recovery and to evaluate the effectiveness of specific, localized, exercise therapy on muscle recovery. Summary of Background Data. Acute low back pain usually resolves spontaneously, but the recurrence rate is high. Inhibition of multifidus occurs with acute, first-episode, low back pain, and pathologic changes in this muscle have been linked with poor outcome and recurrence of symptoms. Methods. Patients in group 1 received medical treatment only. Patients in group 2 received medical treatment and specific, localized, exercise therapy. Outcome measures for both groups included 4 weekly assessments of pain, disability, range of motion, and size of the multifidus cross-sectional area. Independent examiners were blinded to group allocation. Patients were reassessed at a 10-week follow-up examination. Results. Multifidus muscle recovery was not spontaneous on remission of painful symptoms in patients in group 1. Muscle recovery was more rapid and more complete in patients in group 2 who received exercise therapy (P = 0.0001). Other outcome measurements were similar for the two groups at the 4-week examination. Although they resumed normal levels of activity, patients in group 1 still had decreased multifidus muscle size at the 10-week follow-up examination. Conclusions. Multifidus muscle recovery is not spontaneous on remission of painful symptoms. Lack of localized, muscle support may be one reason for the high recurrence rate of low back pain following the initial episode.

Variation of Patterns of Malocclusion by Site of Pharyngeal Obstruction in Children

Objective: To correlate the type of dental occlusion and the type of pharyngeal lymphoid tissue obstruction in children. Design: Cross-sectional study. Setting: Ambulatory ear, nose, and throat clinic of Faculdade de Medicina da Universidade de Sao Paulo. Patients: One hundred fourteen children aged 3 to 12 years presenting with mouth breathing and snoring due to tonsil and/or adenoid enlargement. Interventions: Oroscopy and nasal fiber pharyngoscopy complemented by lateral head radiography to diagnose the type of obstruction, and clinical examination to evaluate the dental occlusion. Main Outcome Measures: Tonsil and adenoid obstruction (classified from grades 1-4) and sagittal, transverse, and vertical evaluation of dental occlusion. Results: Obstructive enlargement of both tonsils and adenoids was detected in 64.9% of the sample; isolated enlargement of the adenoids, in 21.9%; isolated enlargement of the palatine tonsils, in 7.0%; and nonobstructive tonsils and adenoids, in 6.1%. All types of pharyngeal obstruction were related to a high prevalence of posterior crossbite (36.8%). Statistically significant association was found between sagittal dental occlusion and the site of lymphoid tissue obstruction (P = .02). A higher rate of class II relationship (43.2%) was detected in the group with combined adenoid and tonsil obstructive enlargement. Isolated tonsil obstruction showed a higher rate of class III relationship (37.5%). Conclusions: Different sites of obstruction of the upper airway due to enlarged lymphoid tissue are associated with different types of dental malocclusion. Findings are relevant to orthodontic and surgical decision making in these mouth-breathing patients.

Insertion/deletion polymorphism of the angiotensin converting enzyme gene and loss of the insertion allele in aldosterone-producing adenoma

The genetic mechanisms responsible for the formation of adrenocortical adenomas which autonomously produce aldosterone are largely unknown, The adrenal renin-angiotensin system has been implicated in the pathophysiology of these tumours, Angiotensin-converting enzyme (ACE) catalyses the generation of angiotensin II, and the insertion/deletion (I/D) polymorphism of the ACE gene regulates up to 50% of plasma and cellular ACE variability in humans. We therefore examined the genotypic and allelic frequency distributions of the ACE gene I/D polymorphism in 55 patients with aldosterone-producing adenoma, APA, (angiotensin-unresponsive APA n = 28, angiotensin-responsive APA n = 27), and 80 control subjects with no family history of hypertension, We also compared the ACE gene I/D polymorphism allelic pattern in matched tumour and peripheral blood DNA in the 55 patients with APA, The frequency of the D allele was 0.518 and 0.512 and the I allele was 0.482 and 0.488 in the APA and control subjects respectively, Genotypic and allelic frequency analysis found no significant differences between the groups, Examination of the matched tumour and peripheral blood DNA samples revealed the loss of the insertion allele in four of the 25 patients who were heterozygous for the ACE I/D genotype. The I/D polymorphism of the ACE gene does not appear to contribute to the biochemical and phenotypic characteristics of APA, however, the deletion of the insertion allele of the ACE gene I/D polymorphism in 16% of aldosterone-producing adenomas may represent the loss of a tumour suppressor gene/s or other genes on chromosome 17q which may contribute to tumorigenesis in APA.

Standard Examination System for Laparoscopy in Penetrating Abdominal Trauma

Background: The high missed occult small bowel injuries (SBI) associated with laparoscopy in trauma (LIT) is a major reason why some surgeons still preclude LIT today. No standardized laparoscopic examination for evaluation of the peritoneal cavity is described for trauma. The objective of this article is to verify if a systematic standardized laparoscopic approach could correctly identify SBI in the peritoneal cavity for penetrating abdominal trauma (PAT). Methods: Victims with PAT were evaluated in a prospective, nonrandomized study. A total of 75 hemodynamically stable patients with suspected abdominal injuries were operated by LIT and converted to laparotomy if criteria were met: SBI and lesions to blind spot zones-retroperitoneal hematoma, injuries to segments VI or VII of the liver, or injuries to the posterior area of the spleen. Inclusion criteria were equivocal evidence of abdominal injuries or peritonea] penetration; systolic blood pressure >90 mm Hg and <3 L of IV fluids in the first hour of admission; Glasgow Coma Scale score >12; and age >12 years. Exclusion criteria were back injuries; pregnancy; previous laparotomy; and chronic cardiorespiratory disease. Results: Sixty patients were males and there were 38 stab wounds and 37 gunshot wounds. No SBI was missed, but a pancreatic lesion was undiagnosed due to a retroperitoneal hematoma. Twenty patients (26.6%) were converted. Unnecessary laparotomies were avoided in 73.33%. Therapeutic LIT was possible in 22.7%. Accuracy was 98.66% with 97.61% sensitivity and 100% specificity. Conclusions: Standard systematic laparoscopic exploration was 100% effective to detect SBI in the peritoneal cavity. Conversion from LIT to laparotomy should be done if injuries to blind spot zones are found which are poorly evaluated by LIT. Therapeutic LIT is feasible in PAT.

Risk factors for post-stroke depression

Objective. To examine possible risk factors in post-stroke depression (PSD) other than site of lesion in the brain Data sources. 191 first-ever stroke patients were examined physically shortly after their stroke and examined psychiatrically and physically 4 months post-stroke. Setting. A geographically defined segment of the metropolitan area of Perth, Western Australia, from which all strokes over a course of 18 months were examined (the Perth Community Stroke Study). Measures. Psychiatric Assessment Schedule, Mini Mental State Examination, Barthel Index, Frenchay Activities Index, physical illness and sociodemographic data were collected. Post-stroke depression (PSD) included both major depression and minor depression (dysthymia without the 2-year time stipulation) according to DSM-III (American Psychiatric Association) criteria. Patients depressed at the time of the stroke were excluded. Patients. 191 first-ever stroke patients, 111M, 80F, 28% had PSD, 17% major and 11% minor depression. Results. Significant associations with PSD at 4 months were major functional impairment, living in a nursing home, being divorced and having a high pre-stroke alcohol intake (M only). There was no significant association with age, sex, social class, cognitive impairment or pre-stroke physical illness. Conclusion. Results favoured the hypothesis that depression in an unselected group of stroke patients is no more common, and of no more specific aetiology, than it is among elderly patients with other physical illness.

Role of galectin-1 in the olfactory nervous system

The olfactory nervous system is responsible for the detection of odors. Primary sensory olfactory neurons are located in a neuroepithelial sheet lining the nasal cavity. The axons from these neurons converge on to discrete loci or glomeruli in the olfactory bulb. Each glomerulus consists of the termination of thousands of primary axons on the dendrites of second-order olfactory neurons. What are the molecular mechanisms which guide growing olfactory axons to select sites in the olfactory bulb? We have shown that subpopulations of these axons differentially express cell surface carbohydrates and that these different subpopulations target and terminate in particular regions of the olfactory bulb. Interestingly, the olfactory neurons and glial components in the olfactory pathway between the nose and brain express galectin-1. By using in vitro assays of neurite outgrowth we found that both galectin-1 and it's ligands were capable of specifically stimulating neurite elongation. Examination of the olfactory system in galectin-1 null mutants revealed that a subpopulation of axons failed to navigate to their target site in the olfactory bulb. This is the first phenotypic effect observed in galectin-1 null mutants and indicates that galectin-1 has a role in the growth and/or guidance of a subpopulation of axons in the olfactory system during development.

Postlepidapedon Zdzitowiecki, 1993 and Gibsonivermis n g (Digenea: Lepocreadiidae) from fishes of the southern Great Barrier Reef, Australia, and their relationship to Intusatrium Durio & Manter, 1968

The genus Intusatrium Durio & Manter, 1968 is redefined based on a re-examination of paratypes of the type-species, I. robustum Durio & Manter, 1968, and is considered monotypic with characteristic terminal genitalia: internal seminal vesicle elongate tubular, with rather thick wall, divided by slight change in wall thickness into longer proximal and shorter distal region; pars prostatica subcylindrical; ejaculatory duct relatively short, with wrinkled/wall. The genus Postlepidapedon Zdzitowiecki, 1993 is redefined and Intusatrium secundum Durio & Manter, 1968 is attributed to it as a new combination. Postlepidapedon secundum n. comb. is redescribed from a paratype and new material from Choerodon graphicus. P. spissum n. sp. from Choerodon venustus, C. cyanodus, C. fasciatus and C. schoenleinii is recognised on the basis of its thick-walled internal seminal vesicle. I! uberis n. sp. from Choerodon schoenleinii and C. venustus is distinguished by the shape and contents of the cirrus-sac with narrow, convoluted internal seminal vesicle, large vesicular pars prostatica and short, muscular ejaculatory duct. A new genus, Gibsonivermis, erected for Intusatrium berryi Gibson, 1987, is characterised by the elongate narrow cirrus-sac and a uroproct. G. berryi n. comb. is redescribed from Sillago ciliata, S. maculata and Sillago sp.