Transgenic rescue of GATA-1-deficient mice with GATA-1 lacking a FOG-1 association site phenocopies patients with X-linked thrombocytopenia

Association of GATA-1 and its cofactor Friend of GATA-1 (FOG-1) is essential for erythroid and megakaryocyte development. To assess functions of GATA-1-FOG-1 association during mouse development, we used the GATA-1 hematopoietic regulatory domain to generate transgenic mouse lines expressing a mutant GATA-1, which contains a substitution of glycine 205 for valine (V205G) that abrogates its association with FOG-1. We examined whether the transgenic expression of mutant GATA-1 rescues GATA-1 germ line mutants from embryonic lethality. In high-expressor lines we observed that the GATA-1(V205G) rescues GATA-1-deficient mice from embryonic lethality at the expected frequency, revealing that excess GATA-1(V205G) can eliminate the lethal anemia that is due to GATA-1 deficiency. In contrast, transgene expression comparable to the endogenous GATA-1 level resulted in much lower frequency of rescue, indicating that the GATA-1-FOG-1 association is critical for normal embryonic hematopoiesis. Rescued mice in these analyses exhibit thrombocytopenia and display dysregulated proliferation and impaired cytoplasmic maturation of megakaryocytes. Although anemia is not observed under steady-state conditions, stress erythropoiesis is attenuated in the rescued mice. Our findings reveal an indispensable role for the association of GATA-1 and FOG-1 during late-stage megakaryopoiesis and provide a unique model for X-linked thrombocytopenia with inherited GATA-1 mutation.     

Focal Lesion in Upper Part of Brachial Plexus can be Detected by Magnetic Cervical Motor Root Stimulation

BackgroundThe utilities of magnetic cervical motor root stimulation are well known for lesions in the lower part of the brachial plexus, but not for lesions in the other parts.ObjectiveThe aim of paper is to show the utilities of magnetic cervical motor root stimulation for lesions in the upper part of the brachial plexus.MethodsWe analyzed the brachial plexus using both electrical stimulation at Erb's point and magnetic cervical motor root stimulation in a patient with brachial plexopathy caused by tumor invasion.ResultsOn the fourth day after onset, magnetic cervical motor root stimulation revealed abnormal findings in the upper part of the brachial plexus. Two weeks after onset, needle electromyography supported the existence of the focal lesion.ConclusionMagnetic cervical motor root stimulation is useful in detecting abnormal findings in the upper part of the brachial plexus, even at the acute phase.     

Factors affecting independence in eating among elderly with Alzheimer's disease

Aim: In elderly patients with dementia, disturbed eating behavior is understood to be a core symptom or a behavioral and psychological symptom of dementia (BPSD). The purpose of the present study was to investigate the factors affecting self‐feeding in elderly patients with Alzheimer's disease (AD). Methods: A total of 150 AD patients who were hospitalized in dementia wards, or were residents of institutions or group homes were enrolled. The patients underwent an eating behavior examination, cognitive assessment, neurological examination and vital function tests. The eating behavior examination consisted of observation of the patients at mealtime. Items assessing eating behavior included the number of feeding cycles, stopping of eating or agitation and dysfunction. Results: Logistic regression analysis carried out to identify factors with a significant effect on decreased independence in eating were difficulty in beginning a meal (OR = 14.498, CI = 2.067–101.690), presence of dysphagia signs (OR = 5.214, CI = 1.031–26.377) and the severity of dementia (OR = 4.538, CI = 1.154–17.843). Conclusion: The present study is the first to generate objective data showing that difficulty in beginning a meal is a factor that hinders independence in eating in AD, in addition to the presence of dysphagia signs and the severity of dementia. Assisting AD patients in maintaining eating independence might be effectively achieved by eliminating environmental factors that interfere with beginning a meal, and by providing assistance that will promote beginning a meal. The present results show the necessity of developing effective methods for assisting elderly patients with AD. Geriatr Gerontol Int 2012; 12: 481–490.     

Isolated pyramidal tract impairment in the central nervous system of adult-onset Krabbe disease with novel mutations in the GALC gene

This report describes a 60-year-old female patient with Krabbe disease who presented with slowly progressive gait disturbance due to mild spastic paraplegia. Brain magnetic resonance imaging showed high-intensity lesions along the upper parts of the bilateral pyramidal tracts in fluid-attenuated inversion recovery images. Central motor conduction time was prolonged both in the upper and the lower extremities, while central sensory conduction time was normal. The reduced lymphocyte galactocerebrosidase (GALC) activity and two novel mutations in the GALC gene, p.G496S and p.G569S, proved the diagnosis of Krabbe disease. Our findings show that adult-onset Krabbe disease is characterized by isolated pyramidal tract impairment in the central nervous system, both neurophysiologically and radiologically.     

Homogeneously enhancing breast lesions on contrast enhanced US: differential diagnosis by conventional and contrast enhanced US findings

Objective

To clarify the details of homogeneously enhancing lesions on contrast-enhanced ultrasonography (CEUS) and also to elucidate whether their differential diagnosis is possible.

Methods

Seventy-three homogeneously enhancing lesions on CEUS were retrospectively selected. Two radiologists first assessed conventional US findings alone in consensus to differentiate malignant vs. benign lesions. Then, qualitative and quantitative CEUS findings were analyzed to determine the useful findings for the differential diagnosis. Determined CEUS findings were applied to the indeterminate lesions based on conventional US findings to see whether CEUS can improve the diagnostic performance.

Results

There were 42 cancers (58 %) out of 73. Sensitivity and specificity using conventional US findings alone were 91 and 55 %, respectively. Among the CEUS findings tested, multivariate analysis revealed only the type 3 enhancement pattern, which indicates a larger enhancing area than the precontrast hypoechoic lesion, was related to malignancy (p < 0.05). By adding this information, however, no improvement was achieved in the diagnostic performance as determined by conventional US findings.

Conclusions

Approximately half of the homogeneously enhancing lesions on CEUS are malignant, and differentiation of malignant from benign lesions may be possible, at least to some extent, by meticulous assessment of the conventional US rather than CEUS findings.

     

Human monoclonal antibody AVP-21D9 to protective antigen reduces dissemination of the Bacillus anthracis Ames strain from the lungs in a rabbit model

Dutch-belted and New Zealand White rabbits were passively immunized with AVP-21D9, a human monoclonal antibody to protective antigen (PA), at the time of Bacillus anthracis spore challenge using either nasal instillation or aerosol challenge techniques. AVP-21D9 (10 mg/kg) completely protected both rabbit strains against lethal infection with Bacillus anthracis Ames spores, regardless of the inoculation method. Further, all but one of the passively immunized animals (23/24) were completely resistant to rechallenge with spores by either respiratory challenge method at 5 weeks after primary challenge. Analysis of the sera at 5 weeks after primary challenge showed that residual human anti-PA levels decreased by 85 to 95%, but low titers of rabbit-specific anti-PA titers were also measured. Both sources of anti-PA could have contributed to protection from rechallenge. In a subsequent study, bacteriological and histopathology analyses revealed that B. anthracis disseminated to the bloodstream in some na?ve animals as early as 24 h postchallenge and increased in frequency with time. AVP-21D9 significantly reduced the dissemination of the bacteria to the bloodstream and to various organs following infection. Examination of tissue sections from infected control animals, stained with hematoxylin-eosin and the Gram stain, showed edema and/or hemorrhage in the lungs and the presence of bacteria in mediastinal lymph nodes, with necrosis and inflammation. Tissue sections from infected rabbits dosed with AVP-21D9 appeared comparable to corresponding tissues from uninfected animals despite lethal challenge with B. anthracis Ames spores. Concomitant treatment with AVP-21D9 at the time of challenge conferred complete protection in the rabbit inhalation anthrax model. Early treatment increased the efficacy progressively and in a dose-dependent manner. Thus, AVP-21D9 could offer an adjunct or alternative clinical treatment regimen against inhalation anthrax.     

Distribution and immunohistochemical localization of GDNF protein in selected neural and non-neural tissues of rats during development and changes in unilateral 6-hydroxydopamine lesions

The tissue distribution of glial cell line-derived neurotrophic factor (GDNF) during development and changes in GDNF levels by unilateral 6-hydroxydopamine lesions were investigated in rats using a newly established enzyme immunoassay system and by immunohistochemistry. The detection limit of the assay was 0.3 pg/0.2 ml and the system recognized glycosylated mature GDNF. Concentrations of GDNF were relatively high in the kidney and testis during the embryonic and neonatal periods, respectively, and decreased with age. In the striatum, hippocampus and brain stem, GDNF reached a maximal level at around postnatal day 14. However, brain levels were generally lower than those in non-neural tissues. In the CNS, GDNF immunoreactivity was observed in striatal neurons, pyramidal neurons in the hippocampus and the Vth layer of the cortex, large neurons in the diagonal band and brain stem, and spinal motor neurons. It was also evident in several non-neural, tissue-specific cells, such as cells in the renal collecting ducts and distal tubules, and testicular Sertoli cells. Destruction of nigral dopaminergic neurons by 6-hydroxydopamine enhanced the levels of striatal GDNF protein, with apparent involvement of astrocytes. These results suggest that GDNF is normally synthesized in neurons, but may also be produced by astroglial cells in damaged brains.