Growth and development in rats and deficiency of magnesium and pyridoxine

Eight-eight female weanling Sprague-Dawley rats were fed diets containing either 650 or 150 mg magnesium/kg diet and 7.0 or 3.5 mg pyridoxine-HCl/kg diet, in a 2 x 2 factorial arrangement, during growth, gestation, and lactation. The objective of the study was to determine whether concurrent dietary deficiencies of magnesium and pyridoxine were synergistic, additive, or antagonistic with regards to effects on reproductive performance, growth, and development of offspring, and tissue content of magnesium and calcium. Body weight of dams and pups was not different between groups until day 9 of lactation, at which point those animals in either low magnesium group weighed less than the other. Litter size and birth weight were not different. Development, as measured by timing of unfolding of the external ear, opening of both eyes, and clinical emergence of incisors, was delayed in pups from litters in the low magnesium groups. A synergistic effect on delay of onset of ear unfolding by deficiency of both magnesium and pyridoxine was observed. Calcium content of heart and kidney from dams was increased in the low magnesium groups. Renal calcium was not further increased by the level of pyridoxine deficiency in this study. The calcium to magnesium ratio in heart from pups was higher in those from litters in the low magnesium and pyridoxine group than in the others. Results indicate that simultaneous deficiencies of magnesium and pyridoxine may impair function synergistically. Because these two nutrients are often reported to be presented in inadequate amounts in diets of women in their reproductive years, the potential exists for impaired reproductive success.     

Atypical onset of symptoms in Huntington disease: severe cognitive decline preceding chorea or other motor manifestations.

OBJECTIVE: To describe the onset of Huntington disease (HD) in a patient with atypical progression of symptoms. BACKGROUND: The authors report the case of a 39-year-old man with severe cognitive impairment and diffuse cortical atrophy before the onset of motor manifestations or symptoms of an extrapyramidal movement disorder. METHOD: Clinical examinations, neuropsychologic assessments, magnetic resonance imaging, electroencephalogram, and genetic testing were conducted. RESULTS AND CONCLUSIONS: Although HD was eventually confirmed through genetic testing, chorea was not part of the clinical picture until well after the patient had developed a frank dementia, with a decline in global intellectual functioning, memory deficits, slowed information processing speed, and executive dysfunction. This case indicates HD may present with atypical clinical features in the early course of the disease, and warrants diagnostic consideration in patients with early dementia of unknown etiology.     

Pharmacokinetic and pharmacodynamic effects of the novel benzodiazepine antagonist 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one in humans

2-Phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) is pharmacologically characterized as benzodiazepine antagonist with low inverse agonistic effects. Single oral doses up to 650 mg and subchronic doses up to 100 mg daily for seven days are well tolerated by young healthy volunteers. Plasma concentrations of CGS 8216 are variable, not dose-related and relatively low considering the doses administered. A high plasma concentration ratio of metabolite vs. parent compound (3:1) points to an extensive gastrointestinal first-pass metabolism. CGS 8216 influences the human electroencephalogram similar to anxiolytic and vigilance enhancing drugs in doses which do not change performance of psychometric tests. CGS 8216 antagonizes the diazepam-induced impairment of alertness.     

Development and validation of a multivariate predictor of mortality in very low birth weight

Accurate prognosis is critical to the design of all prospective research aimed at improving survival. Predictions based on birth weight, gestational age, or any other single variable, fail to take into account the potentially important contribution of other factors. In order to develop a practical and accurate multivariate model, we studied all singleton pregnancies resulting in viable liveborn infants who weighed less than or equal to 1500 g at birth during 1984 and 1985 at the New York Hospital-Cornell Medical Center. When gestational age, birth weight, and/or crown-heel length were considered, no maternal characteristics were significant predictors of mortality. The model with the maximal predictive accuracy (84.5%) used birth weight and 5-minute Apgar score to calculate a probability of mortality. This prognostic model was then validated in a separate cohort of singletons born in 1986. We conclude that clinical trials should require stratification before randomization, using the calculated probability of mortality, rather than birth weight or gestational age alone. Given the ability of models, such as the one presented here, to generate reasonable estimates of mortality, this information might also be used in the clinical setting to assist parents and physicians in individualized decision-making processes for a given infant.     

The relation between conduction velocity and axonal length

Motor evoked potentials (MEPs) obtained by electrical root stimulation and F waves were used to examine the proximal nerve conduction velocity (CV) to tibialis anterior (TA), extensor digitorum brevis (EDB), flexor carpi radialis (FCR), and abductor pollicis brevis (APB) muscles in 40 humans. By subtracting motor latencies obtained by stimulating the peripheral nerve at the same point from the F-wave and MEP latencies, we could measure the CV over identical proximal segments. It was found that proximal CV to TA and FCR was significantly higher than to EDB and APB, respectively. Combining the data of the proximal CV to all four muscles in relation with axonal length resulted in a highly significant inverse relationship (r² = 0.77). Thus the axonal length explained to a large extent the higher CV of the arm nerves and also the inverse relation between body height and CV. The distal CV was always lower than proximal CV; however, there was no support for an additional effect of this gradient in explaining the relationship between CV and height since it was constant for all body heights. © John Wiley & Sons, Inc.     

The α1β1 and α2β1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis

Angiogenesis is a complex process, involving functional cooperativity between cytokines and endothelial cell (EC) surface integrins. In this study, we investigated the mechanisms through which the alpha(1)beta(1) and alpha(2)beta(1) integrins support angiogenesis driven by vascular endothelial growth factor (VEGF). Dermal microvascular EC attachment through either alpha(1)beta(1) or alpha(2)beta(1) supported robust VEGF activation of the Erk1/Erk2 (p44/42) mitogen-activated protein kinase signal transduction pathway that drives EC proliferation. Haptotactic EC migration toward collagen I was dependent on alpha(1)beta(1) and alpha(2)beta(1) as was VEGF-stimulated chemotaxis of ECs in a uniform collagen matrix. Consistent with the functions of alpha(1)beta(1) and alpha(2)beta(1) in supporting signal transduction and EC migration, antibody antagonism of either integrin resulted in potent inhibition of VEGF-driven angiogenesis in mouse skin. Moreover, combined antagonism of alpha(1)beta(1) and alpha(2)beta(1) substantially reduced tumor growth and angiogenesis of human squamous cell carcinoma xenografts. Collectively, these studies identify critical collaborative functions for the alpha(1)beta(1) and alpha(2)beta(1) integrins in supporting VEGF signal transduction, EC migration, and tumor angiogenesis.     

Chromosome triplication found across the tribe Brassiceae

We have used an approximately 8.7-Mb BAC contig of Arabidopsis thaliana Chromosome 4 to trace homeologous chromosome regions in 21 species of the family Brassicaceae. Homeologs of this segment could be identified in all tested species. Painting of pachytene chromosomes of Calepina, Conringia, and Sisymbrium species (2n = 14, 16), traditionally placed in tribe Brassiceae, showed one homeologous copy of the Arabidopsis contig, while the remaining taxa of the tribe (2n = 14-30) revealed three, and three Brassica species (2n = 34, 36, and 38) and Erucastrum gallicum (2n = 30) had six copies corresponding to the 8.7-Mb segment. The multiple homeologous copies corresponded structurally to the Arabidopsis segment or were rearranged by inversions and translocations within the diploidized genomes. These chromosome rearrangements accompanied by chromosome fusions/fissions led to the present-day chromosome number variation within the Brassiceae. Phylogenetic relationships based on the chloroplast 5'-trnL (UAA)-trnF(GAA) region and estimated divergence times based on sequence data of the chalcone synthase gene are congruent with comparative painting data and place Calepina, Conringia, and Sisymbrium outside the clade of Brassiceae species with triplicated genomes. Most likely, species containing three or six copy pairs descended from a common hexaploid ancestor with basic genomes similar to that of Arabidopsis. The presumed hexaploidization event occurred after the Arabidopsis-Brassiceae split, between 7.9 and 14.6 Mya.     

Susceptibility of corneal allografts and xenografts to antibody-mediated rejection

The effects of passive transfer of antisera containing cytotoxic antibodies to allo- and xenoantigens on survival of corneal allografts and xenografts were evaluated in experimental models. Corneas from allogeneic B10 or xenogeneic rat Lewis donors were grafted orthotopically into BALB/c mice. Recipient mice were treated with donor-specific antisera administered at the period of grafting or at 2 weeks after transplantation. Rejection was determined by the severity of corneal opacity using a standard scoring system. Treatment of graft recipients with donor-specific antisera accelerated the onset of graft rejection and significantly shortened survival times of both corneal allografts and xenografts. Corneal xenografts, which had been accepted after treatment with anti-CD4 monoclonal antibody, were acutely rejected by the passive transfer of antiserum against xenoantigens. The results suggest that corneal grafts are vulnerable to antibody-dependent immunity and that cytotoxic antibodies against graft donor antigens can mediate rejection of both corneal allografts and xenografts.     

Seven novel and four recurrent point mutations in the factor VIII (F8C) gene

Haemophilia A is a X‐linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are “private”, because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype‐phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated. © 2001 Wiley‐Liss, Inc.     

Lesion of posterior parietal cortex in rats does not disrupt place avoidance based on either distal or proximal orienting cues

A current topic in neurobiology is the study of the role of various brain structures in processing of spatial information. The present study was aimed at elucidating the role of the rat posterior parietal cortex in performing a place avoidance task. Two variants of the task were used: an arena frame task, in which animals were trained to avoid a sector defined by local cues bound to the surface of a rotating arena, and the room frame task, in which the shock sector was defined with respect to distal room landmarks. The results showed that both control and lesioned rats were able to efficiently solve both tasks, while locomotion was not altered. These results suggest that the posterior parietal cortex is not crucial for the processing of either proximal or distal cues in place avoidance.