High-frequency developmental abnormalities in p53-deficient mice

BACKGROUND: Several strains of mice carrying null mutations of the tumour suppressor gene p53 have been developed. It has been reported that homozygous mice from all of these strains develop normally to birth, but then succumb rapidly to neoplasia. RESULTS: Here, we report that a significant proportion of female p53-/- mice die during embryogenesis or in the period between birth and weaning, being subject to a spectrum of abnormalities. In a significant proportion (23%) of p53-/- female embryos, the normal process of neural tube closure failed, leading to exencephaly and subsequent anencephaly. Although this phenomenon was predominantly associated with females, we observed one affected male embryo. In addition to a spectrum of neural tube defects, many of these embryos exhibited a range of craniofacial malformations, including ocular abnormalities and defects in upper incisor tooth formation. We observed a significant reduction in the number of p53-/- female progeny of p53+/- x p53+/- matings, and also in an in utero analysis of the p53+/- female progeny of p53-/- x p53+/+ matings. When male mice were exposed to irradiation prior to mating, a significant increase in the rate of abnormality was seen in the progeny, which was specifically associated with p53 deficiency. CONCLUSIONS: We have identified a high rate of developmental abnormalities associated with p53 deficiency. This manifests itself as a spectrum of lesions, predominantly female-associated defects in neural tube closure. These defects may arise either because p53 plays a physiological role at the time of neural tube closure, or because of an abnormally high frequency of mutation within the haploid gametes of p53-null parents.     

Expression and localization in the fish retina of a homologue of the Alzheimer's related PS1 gene

Early-onset familial Alzheimer's disease (early-onset FAD) has been linked with mutations in the presenilin gene, PS1. Mutations in PS1 may affect the processing/trafficking of b-amyloid precursor-protein (bAPP) and favour the production of toxic amyloid-b fragments that are associated with neural degeneration. This study reports the expression of a PS1-like cDNA in the carp (Cyprinus carpio) retina (the encoded protein shows 76% identity to the human PS1 protein). Carp PS1 mRNA was localized by in situ hybridization to the photoreceptor cell, inner nuclear and ganglion cell layers. Expression of the PS1 gene in the rat retina was also confirmed. The retinal expression of PS1 raises the possibility that PS1 mutations also lead to neural degeneration in the retina.     

Neurophysiological abnormalities in the Westphal variant of Huntington''s disease

Infants with cystic fibrosis (CF) often are infected with Staphylococcus aureus (S. aur.), which is followed by colonization with Pseudomonas aeruginosa (P. aerug.). In spite of an excessive, neutrophil-dominated inflammatory response in the respiratory tract, patients with CF often succumb to pulmonary infections with P. aerug. Because peripheral blood neutrophils of these patients have normal functions, we examined whether hypothesized alterations of the airway surface liquids (ASL) in these patients significantly impair neutrophil bactericidal activity in the microenvironment of the CF lung. The ionic composition of CF ASL is still not entirely defined and has been speculated to be abnormally high or abnormally low in Na+ and Cl- concentrations; estimates of osmolarities have ranged from 200 (hypo-osmolar) to 285 (iso-osmolar) to > 300 meq/L (hyper-osmolar). Our data indicate that bacterial killing activity of human peripheral blood neutrophils against P. aerug. or S. aur. is not decreased in buffers in which NaCl was replaced with equimolar concentrations of choline Cl, KCl, or N-methyl-D-glucamine chloride to maintain isotonicity. Amiloride or benzamil, known modulators of Na+ transport in neutrophils, did not interfere with this neutrophil function. Deviations from isotonicity of +/- 50% also failed to diminish bactericidal activity of neutrophils significantly. In contrast, superoxide production and enzyme secretion in response to the chemotactic peptide N-formylmethionylleucylphenylalanine appeared to be sensitive to the ionic milieu of the assay buffers. Our results suggest that the postulated alterations in the ionic composition of ASL in CF lungs are insufficient to explain why neutrophils fail to clear infections with P. aerug. in these patients.     

Metabolic abnormalities in developmental dyslexia detected by 1H magnetic resonance spectroscopy

BACKGROUND: Neurological and physiological deficits have been reported in the brain in developmental dyslexia. The temporoparietal cortex has been directly implicated in dyslexic dysfunction, and substantial indirect evidence suggests that the cerebellum is also implicated. We wanted to find out whether the neurological and physiological deficits manifested as biochemical changes in the brain. METHODS: We obtained localised proton magnetic resonance spectra bilaterally from the temporo-parietal cortex and cerebellum of 14 well-defined dyslexic men and 15 control men of similar age. FINDINGS: We found biochemical differences between dyslexic men and controls in the left temporo-parietal lobe (ratio of choline-containing compounds [Cho] to N-acetylaspartate [NA] p< or =0.01) and right cerebellum (Cho/NA, p< or = 0.01; creatine [Cre] to NA p< or =0.05; (not significant). We found lateral biochemical differences in dyslexic men in both these brain regions (Cho/NA in temporo-parietal lobe, left vs right, p< or =0.01; Cre/NA in cerebellum, left vs right, p< or =0.001). We found no such lateral differences in controls. There was no significant relation between the degree of contralateral chemical difference and handedness in dyslexic or control men. INTERPRETATION: We suggest that the observed differences reflect changes in cell density in the temporo-parietal lobe in developmental dyslexia and that the altered cerebral structural symmetry in dyslexia is associated with abnormal development of cells or intracellular connections or both. The cerebellum is biochemically asymmetric in dyslexic men, indicating altered development of this organ. These differences provide direct evidence of the involvement of the cerebellum in dyslexic dysfunction.     

Parental recognition of developmental abnormalities in autism

Administration of carrageenan (CA; 0.5 mg) to the plantar tissue of rats resulted in reversible inflammatory injury. The edema was monitored by changes in paw volume using a plethysmometer. Simultaneous administration of CA and nifedipine, intraperitoneally, at different doses (10, 20 and 50 mg/kg) prevented the inflammatory action, and the effect was dose- and time-dependent. In order to improve the nifedipine effects, we prepared liposomed nifedipine which, administered intraperitoneally, showed a greater anti-inflammatory action. In the presence of the L-type channel agonist Bay K 8644, the inflammation produced by CA increased and it was counteracted by free or liposomed nifedipine. The significance of these findings with respect to the mechanism of the anti-inflammatory action of nifedipine is discussed.     

Visual variant of Alzheimer's disease: Distinctive neuropsychological features.

A subgroup of patients with probable Alzheimer disease (AD) reported a history of isolated visual disturbances (VS) early in the course of disease, without the characteristic memory complaints. Brain imaging and neuropathologic studies indicated that this subgroup had larger involvement of visual cortical areas and relative sparing of temporal. frontal, and limbic structures compared with classic AD. Consistent with these findings, the authors hypothesized that the cognitive deficits in this subgroup would be distinctly different from those seen in more typical AD patients. The authors studied 10 probable AD patients with VS (AD&±&|S), 22 patients without VS (AD–), and 25 healthy controls with a neuropsychological test battery. Compared with AD–, AD&±&|S patients performed significantly better on tests of verbal memory and had greater impairment on tests of visuospatial skills, suggesting a distinct pattern of cognitive dysfunction consistent with metabolic and neuropathologic reports. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Biochemical screening of congenital developmental abnormalities using determination of fetoplacental antigens

In a prospective study of screening of maternal serum levels of alpha-1-fetoprotein (MS AFP) and trofoblast-specific beta-1-glycoprotein (MS SP1) were examined in samples from pregnant women between the 16th and 18th week of pregnancy. We detected 8 fetuses with chromosomal aberation, 8 fetuses with neural tube defects and 10 fetuses with inborn cardial defects. Our study confirms higher MS SP1 levels in women with fetuses with chromosomal aberation, while MS AFP's tendency is to decrease. When combining MS SP1 + MS AFP + age of mother (over 35), 75% of fetuses with chromosomal aberation were detected. In women with neural tube defect 75% fetuses were detected by MS AFP + MS SP1 combination.     

No association between the K variant of the butyrylcholinesterase gene and pathologically confirmed Alzheimer's disease

The polymorphic K variant of the butyrylcholinesterase ( BCHE-K ) gene recently has been demonstrated to have an elevated frequency in Alzheimer's disease (AD) patients carrying the epsilon4 allele of the apolipoprotein (APO E) gene when compared with a control population. We therefore genotyped a large series of pathologically confirmed AD patients and controls to confirm this association. We found no change in the frequency of this genetic variant, either in the AD group as a whole or in early- or late-onset patients when compared with age-matched controls. Stratification of these groups with reference to the APO E epsilon4 allele also showed no difference between AD and control groups. To determine if a biological effect were present, we also looked at senile plaque and neurofibrillary tangle densities in the frontal, temporal, parietal and occipital cortices in AD patients either carrying or not carrying a copy of the K variant. We found no difference in plaque or tangle load between these two groups in either the total, late-onset or early-onset AD subjects. Stratification of the total AD group in terms of APO E epsilon4 allele possession, and further comparison of plaque and tangle load between carriers and non-carriers of BCHE-K still failed to disclose a relationship between BCHE-K and AD. We conclude that in the population studied here there is no association between BCHE-K and AD, or that if such a relationship exists it is precluded by another, as yet unknown factor.     

Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli

Hippocampal and select cortical neuronal populations in Alzheimer's disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. Therefore, in this study, we investigated whether components, known to trigger cellular proliferation and differentiation, upstream of the ras/mitogen-activated kinase pathway, could contribute to the activation of a signal transduction cascade in Alzheimer's disease. We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls. SOS is increased in susceptible pyramidal neurons, while Grb2 shows more subtle alterations in subcellular distribution. Importantly, both SOS-1 and Grb2 show considerable overlap with early cytoskeletal abnormalities suggesting that the alteration in signal transduction molecules is a concurrent, if not preceding, event in the pathogenesis of Alzheimer's disease. Taken together with the cell cycle abnormalities previously reported, these findings suggest that a signal derived from the cell surface contributes to a stimulus for neurons in Alzheimer's disease to re-enter the cell cycle.     

Chlorpyrifos elicits mitotic abnormalities and apoptosis in neuroepithelium of cultured rat embryos

Case records of 27 dogs with medically managed congenital portosystemic shunts were reviewed. Fourteen were followed up by telephone questionnaires to the owners. Age, breed, sex, clinical signs and blood results were similar to previous studies. Weight and quality of life were stable or improved on treatment in all cases. Total serum protein concentration and alanine aminotransferase and alkaline phosphatase activities fell significantly during treatment. Fourteen dogs were euthanased, four were lost to follow-up and nine remained alive. Mean survival time for the dogs euthanased was 9.9 months. Mean follow-up period for the dogs still alive was 56.9 months and all had survived more than 36 months from diagnosis. Surviving dogs with intrahepatic shunts had a significantly shorter follow-up period than dogs with extrahepatic shunts. Two prognostic indicators were identified, age at initial signs and blood urea concentration on presentation, both correlating with survival time. It was demonstrated that a significant proportion of dogs with portosystemic shunts managed medically have a good prognosis.     

Differential developmental fates of the two calcium currents in early embryos of the ascidian Ciona intestinalis

Two voltage-dependent calcium currents have been described in unfertilized eggs of the ascidian Ciona intestinalis: a low threshold, slowly activating current, and a high threshold fast one. According to the classical criteria for classification of calcium currents, they both share some of the features of L-like and T-like currents. We have studied these two calcium currents further by measuring their sensitivity to permeant ions, temperature and inhibitors. Both currents were sensitive to relatively high concentrations of nitrendipine, which was a selective blocker of the low threshold channel. The lanthanide ion gadolinium was a potent blocker of the low threshold current, and cadmium preferentially inhibited the high threshold current. The two calcium currents were regulated in a different manner after fertilization. The density of the high threshold current remained relatively constant, while the low threshold current was lost by the time of first cleavage. This loss following fertilization is similar to the loss of a low threshold sodium current in fertilized eggs of the ascidian Boltenia villosa. Block of the cell cycle with various compounds did not prevent loss of the low threshold calcium current. This observation adds weight to the hypothesis that a loss of excitability is a general property of early development. We conclude that fertilization can differentially modulate channel populations before first cleavage. The mechanism by which this occurs in the ascidian embryo has yet to be discovered.     

Adenovirus E1A expression controlled by the red pigment promoter in transgenic mice: a model for developmental abnormalities of the eye

Four transgenic founder mice were produced that carry the adenovirus E1A gene under control of the human red pigment promoter. Two of the founder animals passed the transgene to progeny, and one line was bred to homozygosity. The line of mice homozygous for the transgene expressed E1A-specific RNA at a low level in their eyes; no expression could be detected in other tissues that were tested. Either the founder animals or their progeny exhibited developmental abnormalities of their eyes, including a small eye phenotype, retinal dysplasia, anterior cleavage syndrome, and retinal pigment epithelium dysplasia. Individuals from the same line of mice exhibited subsets of the abnormalities, e.g., many animals had one normal size eye and one small eye, even though both eyes contained E1A-specific RNA. No tumors resulted from E1A expression in animals monitored for 22 months.     

An assessment of the developmental toxicity of inorganic arsenic

A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.     

An integrated model of developmental coaching.

This article outlines a coaching paradigm derived from constructive-developmental psychology, family therapy supervision, and theories of organizational cognition. The paradigm is one of transformative, developmental coaching, and thus it differs from both cognitive-behavioral and psychodynamic approaches. The paradigm is exemplified by a model of the mental space (topology) in which executive coaching is thought to take place. The paradigm and the model are developmental in a twofold sense, that of ontic development occurring in cognitive organisms maturing over their lifetime (nature) and of agentic development brought about by humans (nurture). An introduction to the model is presented, followed by the topology of the mental space of coaching, a summary, and suggested topics for future research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alzheimer's disease and its Lewy body variant: a clinical analysis of postmortem verified cases

OBJECTIVE: The authors compared clinical findings of Alzheimer's disease and the so-called Lewy body variant of Alzheimer's disease. METHOD: Available data were analyzed on the clinical features of 58 patients with Alzheimer's disease and 24 patients with the Lewy body variant of Alzheimer's disease who underwent postmortem examination. RESULTS: The proportion of men was significantly larger in the Lewy body variant group than in the Alzheimer's disease group (66.7% versus 34.5%), and, concordantly, the Lewy body variant group was slightly taller. The prevalence of hallucinations and delusions was significantly higher in Lewy body variant subjects than the Alzheimer's disease subjects, but there were no significant differences between the two groups in educational attainment, family history of dementia, age at onset, duration of illness, cognitive impairment, overall severity of illness, or neuropsychological findings. Patients with the Lewy body variant of Alzheimer's disease tended to experience more frequent extrapyramidal side effects of neuroleptics than did the patients with Alzheimer's disease, but for patients in the two groups who were not exposed to neuroleptics, there was little difference in frequency of extrapyramidal side effects. CSF concentration of homovanillic acid (HVA) was significantly lower in the Lewy body variant patients, even when correction was made for height. CONCLUSIONS: The Lewy body variant of Alzheimer's disease may be suspected in elderly male dementia patients who otherwise meet criteria for Alzheimer's disease but who manifest significant psychiatric symptoms and neuroleptic-induced extrapy-ramidal side effects and have low levels of CSF HVA.     

Transendothelial migration and trafficking of leukocytes in LFA-1-deficient mice

The leukocyte integrin LFA-1 plays an important role in leukocyte trafficking and the immune response. Using LFA-1-deficient mice, we demonstrate that LFA-1 regulates the trafficking of lymphocytes to peripheral lymph nodes, and, to a lesser degree, to mesenteric lymph nodes and acute inflammatory sites. LFA-1, either because of its role in initial adhesion and/ or the passage of leukocytes across endothelial cells, plays a vital role in T lymphocyte and neutrophil transendothelial migration. Neutrophils and activated T lymphocytes from LFA-1-deficient mice were unable to cross endothelial cell monolayers in response to a chemokine gradient, whereas wild-type (WT) T lymphocytes and neutrophils were capable of migration. By contrast, LFA-1-deficient T lymphocytes displayed normal chemotaxis to the same chemokine. Our studies with LFA-1-deficient monocytes indicate that LFA-1 acts in concert with complement receptor 3 to mediate transendothelial migration of these cells, as anti-CD18 monoclonal antibodies (mAb) blocked both WT and LFA-1-deficient monocyte transendothelial migration, whereas anti-CD11 b mAb preferentially blocked transendothelial migration of LFA-1-deficient monocytes. Finally, whereas anti-CD31 mAb blocked WT monocyte and neutrophil transendothelial cell migration they did not block LFA-1-deficient monocyte and neutrophil transendothelial migration.