Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment

Cellular mechanisms conferring neuroprotection in the brains of patients with Alzheimer disease (AD) remain incompletely understood. Erythropoietin (Epo) and the erythropoietin receptor (EpoR) are expressed in neural tissues and protect against oxidative and other stressors in various models of brain injury and disease. Our objective in this study was to determine whether EpoR is upregulated in the brains of persons with sporadic AD and mild cognitive impairment (MCI). Postmortem hippocampus and temporal cortex from subjects with AD, MCI, and no cognitive impairment (NCI) were procured from the Religious Orders Study. Total immunoreactive EpoR protein was determined by Western blotting. Astrocytes expressing immunoreactive EpoR were quantified in 4 temporal and 6 hippocampal regions, and correlated with clinical, neuropsychologic, and neuropathologic indices. Total immunoreactive EpoR protein was markedly increased in AD and MCI temporal cortex versus NCI tissues. Composite measures of glial EpoR expression in temporal cortex layers I to IV were significantly greater in the MCI group compared with the NCI and AD groups. Hippocampal EpoR scores were increased in persons with MCI and AD relative to those with NCI. There was substantial subregional heterogeneity in disease-related EpoR expression patterns in AD and MCI temporal cortex and hippocampus. There was no association of EpoR-positive astrocytes with summary measures of global cognition or AD pathology. We conclude that upregulation of EpoR in temporal cortical and hippocampal astrocytes is an early, potentially neuroprotective, event in the pathogenesis of sporadic AD.     

Dynamic patterns of neurotrophin 3 expression in the postnatal mouse inner ear

Recent studies indicate that neurotrophin 3 (NT3) may be important for the maintenance and function of the adult inner ear, but the pattern of postnatal NT3 expression in this organ has not been characterized. We used a reporter mouse in which cells expressing NT3 also express beta-galactosidase, allowing for their histochemical visualization, to determine the pattern of NT3 expression in cochlear and vestibular organs. We analyzed animals from birth (P0) to adult (P135). At P0, NT3 was strongly expressed in supporting cells and hair cells of all vestibular and cochlear sense organs, Reissner's membrane, saccular membrane, and the dark cells adjacent to canal organs. With increasing age, staining disappeared in most cell types but remained relatively high in inner hair cells (IHCs) and to a lesser extent in IHC supporting cells. In the cochlea, by P0 there is a longitudinal gradient (apex > base) that persists into adulthood. In vestibular maculae, staining gradients are: striolar > extrastriolar regions and supporting cells > hair cells. By P135, cochlear staining is restricted to IHCs and their supporting cells, with stronger expression in the apex than the base. By the same age, in the vestibular organs, NT3 expression is weak and restricted to saccular and utricular supporting cells. These results suggest that NT3 might play a long-term role in the maintenance and functioning of the adult auditory and vestibular systems and that supporting cells are the main source of this factor in the adult.     

Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features

OBJECTIVE: Constipation is a common heterogeneous condition, possibly encompassing different clinical subtypes. Little is known about the comparative epidemiology of constipation subtypes. This study was conducted to estimate the prevalence of constipation subtypes and determine whether subtypes differ by sociodemographic factors. METHODS: Between June and September 1997, a telephone interview was conducted with individuals about their bowel habits in the preceding 3 months. Survey data on 15 constipation-related symptoms were used to identify individuals who met prespecified symptom criteria for the following mutually exclusive subgroups: functional constipation, irritable bowel syndrome (IBS), outlet obstruction or delay (outlet), both IBS and outlet (IBS-outlet), and frequent laxative users (i.e., at least every other day). A total of 10,018 eligible individuals in the United States 18 yr of age or older completed the interview. Test-retest reliability of reporting symptoms was assessed in a separate national survey. The Spearman's correlation coefficient for reporting symptoms ranged from 0.54 to 0.83; all but three symptoms had correlations above 0.68. RESULTS: The overall prevalence of constipation was 14.7%. By subtype, prevalence was 4.6% for functional, 2.1% for IBS, 4.6% for outlet, and 3.4% for IBS-outlet. An additional 1.8% of respondents reported laxative use at least every other day. Outlet was the most common subtype among women, whereas functional constipation was the most common subtype among men. The gender ratio varied by subtype, with elevated ratios for outlet (F/M = 1.65) and IBS-outlet (F/M = 2.27) subtypes. The age pattern differed among each of the four subtypes. Prevalence of functional subtype decreased with increasing age. In contrast, outlet subtype did not seem to vary by age, and IBS (both men and women) and IBS-outlet (women only) subtypes increased to age 35 yr and declined thereafter. Prevalence of functional constipation increased with increasing education. Outlet type was more common in nonwhites compared to whites. Finally, 45% of individuals with constipation reported having the condition for 5 yr or more. CONCLUSIONS: Constipation is a heterogeneous condition. Differences in epidemiological profile by age, sex ratio, and relation to other sociodemographical factors support the distinction of two and possibly more symptom-based subtypes.     

Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells

Usher syndrome type IIA (USH2A), characterized by progressive photoreceptor degeneration and congenital moderate hearing loss, is the most common subtype of Usher syndrome. In this article, we show that the USH2A protein, also known as usherin, is an exceptionally large ( approximately 600-kDa) matrix protein expressed specifically in retinal photoreceptors and developing cochlear hair cells. In mammalian photoreceptors, usherin is localized to a spatially restricted membrane microdomain at the apical inner segment recess that wraps around the connecting cilia, corresponding to the periciliary ridge complex described for amphibian photoreceptors. In sensory hair cells of the cochlea, it is associated transiently with the hair bundles during postnatal development. Targeted disruption of the Ush2a gene in mice leads to progressive photoreceptor degeneration and a moderate but nonprogressive hearing impairment, mimicking the visual and hearing deficits in USH2A patients. These data suggest that usherin is required for the long-term maintenance of retinal photoreceptors and for the development of cochlear hair cells. We propose a model in which usherin in photoreceptors is tethered via its C terminus to the plasma membrane and its large extracellular domain projecting into the periciliary matrix, where they may interact with the connecting cilium to fulfill important structural or signaling roles.     

Emergency Medical Service (EMS) systems in developed and developing countries

OBJECTIVES: To compare patient- and injury-related characteristics of trauma victims and pre-hospital trauma care systems among different developed and developing countries. METHOD: We collated de-identified patient-level data from national or local trauma registries in Australia, Austria, Canada, Greece, Germany, Iran, Mexico, New Zealand, the Netherlands, the United Kingdom and the United States. Patient and injury-related characteristics of trauma victims with injury severity score (ISS) >15 and the pre-hospital trauma care provided to these patients were compared among different countries. RESULTS: A total of 30,339 subjects from one or several regions in 11 countries were included in this analysis. Austria (51%), Germany (41%) and Australia (30%) reported the highest proportion of air ambulance use. Monterrey, Mexico (median 10.1min) and Montreal, Canada (median 16.1min) reported the shortest and Germany (median: 30min) and Austria (median: 26min) reported the longest scene time. Use of intravenous fluid therapy among advanced EMS systems without physicians as pre-hospital care providers, varied from 30% (in the Netherlands) to 55% (in the US). The corresponding percentages in advanced EMS systems with physicians actively involved in pre-hospital trauma care, excluding Montreal in Canada, ranged from 63% (in London, in the UK) to 75% in Germany and Austria. Austria and Germany also reported the highest percentage of pre-hospital intubation (61% and 56%, respectively). CONCLUSION: This study provides an early look at international variability in patient mix, process of care, and performance of different pre-hospital trauma care systems worldwide. International efforts should be devoted to developing a minimum standard data set for trauma patients.     

Natural course and pathogenesis of transient focal neurologic symptoms during pregnancy

OBJECTIVES: To determine the pathogenesis and course of transient focal neurologic symptoms in pregnant women and to identify prognostic variables that will enable targeted workup. DESIGN: Case-control series. SETTING: Tertiary care university hospital. PATIENTS: Pregnant patients with acute transient focal neurologic symptoms. Women with histories of migraine, recurrent thromboembolism, or cerebrovascular disease were excluded. INTERVENTIONS: Diffusion-weighted imaging (DWI), perfusion-weighted imaging, fluid-attenuated inversion recovery (FLAIR) imaging, gradient-recalled echo imaging, and magnetic resonance venography (MRV) and angiography to determine the presence of brain ischemia and venous thrombosis. Patients underwent echocardiography, duplex ultrasonography, and a battery of hypercoagulability tests and were followed up a mean of 12 months after the event. RESULTS: Twenty-eight controls and 14 patients were enrolled from 23 773 pregnancies. Mean age was 31.2 (range, 24-41) years and mean gestational age at symptom onset was 28 (range, 17-44) weeks. No controls reported transient focal neurologic symptoms, migraine aura, or headache. Presenting symptoms included dysphasia (6 patients) and hemisensory (5) and hemimotor (7) syndrome. In 4 patients, these symptoms were preceded by scintillating scotoma; in 9 patients, focal symptoms were followed by a first-ever, throbbing, migraine-like headache. Only 1 patient had evidence of frank infarction on magnetic resonance imaging (MRI); 2 patients had single, small, hyperintense bright foci on FLAIR imaging without accompanying lesions on DWI, and 11 patients had normal MRI and MRV results. Echocardiography, carotid duplex ultrasonography, and hypercoagulability results were negative in all patients. None of the patients had ischemic events and 4 (29%) developed migraines with aura headaches during follow-up. CONCLUSIONS: Focal neurologic symptoms in healthy pregnant women are frequently preceded by aural visual phenomena and can usually be attributed to a first-ever migraine attack. Cerebral ischemia is less common than migraine and can be reliably diagnosed with MRI. Extensive evaluations to assess a putative hypercoagulable state and cardiocerebrovascular pathology may not be warranted in all such patients.     

Suppression of gastric cancer cell growth by targeting the beta-catenin/T-cell factor pathway

BACKGROUND: Functional activation of beta-catenin/T-cell factor (Tcf) signaling plays an important role in the early events of carcinogenesis. Recently, it was demonstrated that adenomatous polyposis coli or beta-catenin genes are mutated frequently in gastric cancer cells. The objective of the current study was to use a gene-targeting approach to kill human gastric cancer cells selectively with activated beta-catenin/Tcf signaling. METHODS: A recombinant adenovirus that carries a lethal gene (p53 up-regulated modulator of apoptosis [PUMA]) under the control of a beta-catenin/Tcf-responsive promoter (AdTOP-PUMA) was used selectively to target gastric cancer cells (AGS) that posses an active beta-catenin/Tcf pathway. The combined effect of AdTOP-PUMA and several chemotherapeutic agents (5-florouracil, doxorubicin, paclitaxel) also was evaluated. Cell viability was measured by methylene blue assay, protein expression was measured by Western blot analysis, and cell cycle and apoptosis were evaluated by fluorescent-activated cell sorter analysis. RESULTS.: The TOP-PUMA adenovirus inhibited AGS cell growth in a dose- and time-dependent fashion. Growth inhibition was associated with the up-regulation of PUMA expression and the induction of apoptosis. Chemotherapy synergistically enhanced the killing effect of AdTOP-PUMA. CONCLUSIONS: Selective targeting of gastric cancer cells with the activated beta-catenin pathway may be a novel and effective therapy in gastric cancer. Combination of this gene-therapy approach with standard therapy may improve efficacy and reduce toxicity.