Alterations in pyramidal neurons from the sensorimotor cortex may be responsible for some of the cognitive and motor symptoms of Huntington's disease (HD). The present experiments used R6/2 transgenic mice that express exon 1 of the human HD gene with an expanded number of CAG repeats. We characterized alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents and their modulation by cyclothiazide (CTZ) as well as N-methyl-D-aspartate (NMDA) currents and their Mg2+ sensitivity in acutely dissociated cortical pyramidal neurons in R6/2 transgenic and wild-type (WT) mice at 21 days (before overt symptoms), 40 days (when symptoms begin), and 80 days (fully symptomatic). AMPA currents, alone or in the presence of CTZ, were smaller in 21- and 40-day-old R6/2 groups compared with WT mice. In R6/2 mice, more neurons displayed desensitizing AMPA currents in the presence of CTZ, indicating increased expression of "flop" splice variants, whereas the majority of WT cells expressed the "flip" variants of AMPA receptor subunits. NMDA peak currents also were smaller in R6/2 pyramidal neurons at 21 days. At 40 days, NMDA currents were similar in WT and R6/2 mice but Mg2+ sensitivity was greater in R6/2 mice, resulting in smaller NMDA currents in the presence of Mg2+. Differences in AMPA and NMDA currents between WT and R6/2 cells were no longer detected at 80 days. Our findings indicate that currents induced by glutamate receptor agonists are decreased in isolated cortical pyramidal neurons from R6/2 mice and that this decrease occurs early. Altered glutamate receptor function could contribute to changes in cortical output and may underlie some of the cognitive and motor impairments in this animal model of HD.

Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In addition to acting on AMPA receptors, kainate and domoate also activate high-affinity kainate-type glutamate receptors. The receptor type that mediates their neurotoxicity remains uncertain. Here, we show that the transmembrane AMPA receptor-associated protein (TARP) ␥-2 (or stargazin) and the related TARP ␥-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocampal enriched ␥-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. ␥-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking ␥-8. This work decisively demonstrates that TARP-associated AMPA receptors mediate kainate neurotoxicity and identifies TARPs as targets for modulating neurotoxic properties of AMPA receptors.excitotoxicity ͉ epilepsy ͉ PSD-95 ͉ synapse T he ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptors are selective cation channels and mediate most of the postsynaptic depolarization that induces neuronal firing. Dynamic trafficking of neuronal AMPA receptor proteins participates in the plasticity of synaptic transmission that underlies aspects of learning and memory. AMPA receptor channels comprise heterotetramers of subunits GluR1-4, and each subunit can be alternatively spliced as either a flip or flop form (1, 2). The distinct expression of these AMPA receptor subunits and alternatively spliced isoforms in discrete neuronal populations helps determine differential AMPA receptor function and synaptic plasticity throughout the brain (3-7).Neuronal AMPA receptors also contain transmembrane AMPA receptor-regulatory protein (TARP) auxiliary subunits (8). The TARP family comprises five isoforms: ␥-2 (or stargazin), ␥-3, ␥-4, ␥-7, and ␥-8, which are predominantly expressed in adult cerebellum, adult cerebral cortex, early developmental brain, cerebellar Purkinje cells, and adult hippocampus, respectively (9, 10). Stargazer mice, which show absence epilepsy and cerebellar ataxia, have a genetic mutation in stargazin, the prototypical TARP (11). Physiological studies have shown that cerebellar granule cells from stargazer mice selectively lack functional AMPA receptors (12). Biochemical and cell biological studies have shown that stargazin binds to AMPA receptors and traffics the receptors to the neuronal cell surface (13,14). Interaction of stargazin with the postsynaptic density-95 and related proteins (15) mediates synaptic clustering of AMPA receptors (16,17). Stargazin also cooperates with postsynaptic density-95 to control synaptic plasticity (18)(19)(20). In addition to trafficking AMPA receptors, stargazin modulates th...

Objective: Our aim was to examine underserved women’s perceptions on mobile versus fixed mammography in Santa Clara, California through a focus group study.Background: Research has shown that medically underserved women have higher breast cancer mortality rates correlated with under-screening and a disproportional rate of late-stage diagnosis. The Community Health Partnership in Santa Clara County, California runs the Community Mammography Access Project (CMAP) that targets nearly 20,000 medically underserved women over the age of 40 in the county through the collaborative effort of an existing safety net of healthcare providers. However, little data exists on the advantages or disadvantages of mobile mammography units from the patient perspective. Methods: We assessed underserved women’s perspectives on mammography services in Santa Clara County through two focus groups from women screened at mobile or fixed site programs. Patients were recruited from both CMAP clinics and a county hospital, and focus group data were analyzed using content analysis.Results: We found that women from both the mobile and fixed sites shared similar motivating factors for getting a mammogram. Both groups recognized that screening was uncomfortable but necessary for good health and had positive feedback about their personal physicians. However, mobile participants, in particular, appreciated the atmosphere of mobile screening, reported shorter wait times, and remarked on the good communication from the clinic staff and empathetic treatment they received. However, mobile participants also expressed concern about the quality of films at mobile sites due to delayed initial reading of the films. Conclusions: Mobile mammography offers a unique opportunity for women of underserved populations to access high satisfaction screenings, and it encourages a model similar to CMAP in other underserved areas. However, emphasis should be placed on providing a warm and welcoming environment for patients and ensuring the quality of mammography images.

Antisense digoxigenin‐labeled deoxyoligonucleotides probes and non‐isotopic in situ hybridization (HIS) techniques have been used to explore the NMDA‐NR1 receptor subunit mRNA distribution in different brain areas of rats which had their dopaminergic nigrostriatal pathway previously lesioned with intracerebral administration of 6‐OH‐dopamine (6‐OH‐DA). Intense and significant hybridization signals for NR1 mRNA were found in dentate gyrus and regions CA1‐CA2‐CA3 of the hippocampus, in layers II‐III and V‐VI of the cerebral cortex, and in the cerebellum of sham‐treated rats. Basal ganglia structures such as the striatum exhibited few NR1 mRNA hybridization signals as compared to the hippocampus and cerebral cortex. In contrast, both zona compacta and reticulata of substantia nigra (SN) showed a reduced number of cells with nevertheless intense NR1 mRNA HIS signals. The NR1 mRNA distribution in the brain was affected in a brain regional selective manner by 6‐OH‐DA induced lesions of DA neuronal systems. A striking increase in NR1 mRNA HIS signals was observed in both striata after unilateral lesioning with 6‐OH‐DA. Instead, in SN compacta but not in reticulata, a moderate but significant bilateral reduction of NR1 mRNA was observed after unilateral 6‐OH‐DA injection. No significant changes in NR1 mRNA were detected in cerebral cortex and other brain regions after 6‐OH‐DA treatment. These studies, and others reported in the literature, support the view that extensive lesions of nigrostriatal DA‐containing neurons in the brain may trigger compensatory or adaptative responses in basal ganglia structures such as striatum and substantia nigra which involve glutamatergic neurons and the genic expression of NMDA receptors. © 1996 Wiley‐Liss, Inc.

Background Home mechanical ventilation (HMV) is a viable and effective strategy for patients with chronic respiratory failure (CRF). The Chilean Ministry of Health started a program for adults in 2008. Methods This study examined the following data from a prospective cohort of patients with CRF admitted to the national HMV program: characteristics, mode of admission, quality of life, time in the program and survival. Results A total of 1105 patients were included. The median age was 59 years (44–58). Women accounted for 58.1% of the sample. The average body mass index (BMI) was 34.9 (26–46) kg/m2. A total of 76.2% of patients started HMV in the stable chronic mode, while 23.8% initiated HMV in the acute mode. A total of 99 patients were transferred from the children's program. There were 1047 patients on non-invasive ventilation and 58 patients on invasive ventilation. The median baseline PaCO2 level was 58.2 (52–65) mmHg. The device usage time was 7.3 h/d (5.8–8.8), and the time in HMV was 21.6 (12.2–49.5) months. The diagnoses were COPD (35%), obesity hypoventilation syndrome (OHS; 23.9%), neuromuscular disease (NMD; 16.3%), non-cystic fibrosis bronchiectasis or tuberculosis (non-CF BC or TBC; 8.3%), scoliosis (5.9%) and amyotrophic lateral sclerosis (ALS; 5.24%). The baseline score on the Severe Respiratory Insufficiency questionnaire (SRI) was 47 (± 17.9) points and significantly improved over time. The lowest 1- and 3-year survival rates were observed in the ALS group, and the lowest 9-year survival rate was observed in the non-CF BC or TB and COPD groups. The best survival rates at 9 years were OHS, scoliosis and NMD. In 2017, there were 701 patients in the children's program and 722 in the adult´s program, with a prevalence of 10.4 per 100,000 inhabitants. Conclusion The most common diagnoses were COPD and OHS. The best survival was observed in patients with OHS, scoliosis and NMD. The SRI score improved significantly in the follow-up of patients with HMV. The prevalence of HMV was 10.4 per 100,000 inhabitants. Trial registration This study was approved by and registered at the ethics committee of North Metropolitan Health Service of Santiago, Chile (N° 018/2021).