Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in Huntington's disease (HD) patients. Here we examined spontaneous EPSCs in striatal medium-sized spiny neurons in slices from a mouse model of HD (R6/2). Spontaneous EPSC frequency was similar in young (3-4 weeks) transgenics and controls but decreased significantly in transgenics when overt behavioral symptoms began (5-7 weeks) and was most pronounced in severely impaired transgenics (11-15 weeks). These differences were maintained after bicuculline or tetrodotoxin, indicating they were specific to glutamatergic input and likely presynaptic in origin. Decreases in presynaptic and postsynaptic protein markers, synaptophysin and postsynaptic density-95, occurred in 11-15 week R6/2 mice, supporting the electrophysiological results. Furthermore, isolated, large-amplitude synaptic events (>100 pA) occurred more frequently in transgenic animals, particularly at 5-7 weeks, suggesting additional dysregulation of cortical inputs. Large events were blocked by tetrodotoxin, indicating a possible cortical origin. Addition of bicuculline and 4-aminopyridine facilitated the occurrence of large events. Riluzole, a compound that decreases glutamate release, reduced these events. Together, these observations indicate that both progressive and transient alterations occur along the corticostriatal pathway in experimental HD. These alterations are likely to contribute to the selective vulnerability of striatal medium-sized spiny neurons.
Hospitals now have the responsibility to implement strategies to prevent adverse outcomes after discharge. This systematic review addressed the effectiveness of hospital-initiated care transition strategies aimed at preventing clinical adverse events (AEs), emergency department (ED) visits, and readmissions after discharge in general medical patients. MEDLINE, CINAHL, EMBASE, and Cochrane Database of Clinical Trials (January 1990 to September 2012) were searched, and 47 controlled studies of fair methodological quality were identified. Forty-six studies reported readmission rates, 26 reported ED visit rates, and 9 reported AE rates. A "bridging" strategy (incorporating both predischarge and postdischarge interventions) with a dedicated transition provider reduced readmission or ED visit rates in 10 studies, but the overall strength of evidence for this strategy was low. Because of scant evidence, no conclusions could be reached on methods to prevent postdischarge AEs. Most studies did not report intervention context, implementation, or cost. The strategies hospitals should implement to improve patient safety at hospital discharge remain unclear.
The mechanisms responsible for seizure generation in cortical dysplasia (CD) are unknown, but morphologically abnormal cells could contribute. We examined the passive and active membrane properties of cells from pediatric CD in vitro. Normal- and abnormal-appearing cells were identified morphologically by using infrared videomicroscopy and biocytin in slices from children with mild to severe CD. Electrophysiological properties were assessed with patch clamp recordings. Four groups of abnormal-appearing cells were observed. The first consisted of large, pyramidal cells probably corresponding to cytomegalic neurons. Under conditions that reduced the contribution of K(+) conductances, these cells generated large Ca(2+) currents and influx when depolarized. When these cells were acutely dissociated, peak Ca(2+) currents and densities were greater in cytomegalic compared with normal-appearing pyramidal neurons. The second group included large, nonpyramidal cells with atypical somatodendritic morphology that could correspond to "balloon" cells. These cells did not display active voltage- or ligand-gated currents and did not appear to receive synaptic inputs. The third group included misoriented and dysmorphic pyramidal neurons, and the fourth group consisted of immature-looking pyramidal neurons. Electrophysiologically, neurons in these latter two groups did not display significant abnormalities when compared with normal-appearing pyramidal neurons. We conclude that there are cells with abnormal intrinsic membrane properties in pediatric CD. Among the four groups of cells, the most abnormal electrophysiological properties were displayed by cytomegalic neurons and large cells with atypical morphology. Cytomegalic neurons could play an important role in the generation of epileptic activity.
There is considerable concern that bovine prions from cattle with bovine spongiform encephalopathy (BSE) may have been passed to humans (Hu), resulting in a new form of Creutzfeldt-Jakob disease (CJD). We report here the transmission of bovine (Bo) prions to transgenic (Tg) mice expressing BoPrP; one Tg line exhibited incubation times of Ϸ200 days. Like most cattle with BSE, vacuolation and astrocytic gliosis were confined in the brainstems of these Tg mice. Unexpectedly, mice expressing a chimeric Bo͞Mo PrP transgene were resistant to BSE prions whereas mice expressing Hu or Hu͞Mo PrP transgenes were susceptible to Hu prions. A comparison of differences in Mo, Bo, and Hu residues within the C terminus of PrP defines an epitope that modulates conversion of PrP C into PrP Sc and, as such, controls prion transmission across species. Development of susceptible Tg(BoPrP) mice provides a means of measuring bovine prions that may prove critical in minimizing future human exposure.
Huntington's disease (HD) is characterized by loss of striatal gamma-aminobutyric acid (GABA)ergic medium-sized spiny projection neurons (MSSNs), whereas some classes of striatal interneurons are relatively spared. Striatal interneurons provide most of the inhibitory synaptic input to MSSNs and use GABA as their neurotransmitter. We reported previously alterations in glutamatergic synaptic activity in the R6/2 and R6/1 mouse models of HD. In the present study, we used whole-cell voltage clamp recordings to examine GABAergic synaptic currents in MSSNs from striatal slices in these two mouse models compared to those in age-matched control littermates. The frequency of spontaneous GABAergic synaptic currents was increased significantly in MSSNs from R6/2 transgenics starting around 5-7 weeks (when the overt behavioral phenotype begins) and continuing in 9-14-week-old mice. A similar increase was observed in 12-15-month-old R6/1 transgenics. Bath application of brain-derived neurotrophic factor, which is downregulated in HD, significantly reduced the frequency of spontaneous GABAergic synaptic currents in MSSNs from R6/2 but not control mice at 9-14 weeks. Increased GABA current densities also occurred in acutely isolated MSSNs from R6/2 animals. Immunofluorescence demonstrated increased expression of the ubiquitous alpha1 subunit of GABA(A) receptors in MSSNs from R6/2 animals. These results indicate that increases in spontaneous GABAergic synaptic currents and postsynaptic receptor function occur in parallel to progressive decreases in glutamatergic inputs to MSSNs. In conjunction, both changes will severely alter striatal outputs to target areas involved in the control of movement.
In 40 of 50 US states, scheduled dialysis is withheld from undocumented immigrants with end-stage renal disease (ESRD); instead, they receive intermittent emergency-only dialysis to treat life-threatening manifestations of ESRD. However, the comparative effectiveness of scheduled dialysis vs emergency-only dialysis and the influence of treatment on health outcomes, utilization, and costs is uncertain. OBJECTIVE To compare the effectiveness of scheduled vs emergency-only dialysis with regard to health outcomes, utilization, and costs in undocumented immigrants with ESRD. DESIGN, SETTING, AND PARTICIPANTS Observational cohort study of 181 eligible adults with ESRD receiving emergency-only dialysis in Dallas, Texas, who became newly eligible and applied for private commercial health insurance in February 2015; 105 received coverage and were enrolled in scheduled dialysis; 76 were not enrolled in insurance for nonclinical reasons (eg, lack of capacity at a participating outpatient dialysis center) and remained uninsured, receiving emergency-only dialysis. We examined data on eligible persons during a 6-month period prior to enrollment (baseline period,
Background Incorporating clinical information from the full hospital course may improve prediction of 30-day readmissions. Objective To develop an all-cause readmissions risk-prediction model incorporating electronic health record (EHR) data from the full hospital stay, and to compare “full-stay” model performance to a “first day” and 2 other validated models, LACE (includes Length of stay, Acute [non-elective] admission status, Charlson Comorbidity Index, and Emergency department visits in the past year), and HOSPITAL (includes Hemoglobin at discharge, discharge from Oncology service, Sodium level at discharge, Procedure during index hospitalization, Index hospitalization Type [nonelective], number of Admissions in the past year, and Length of stay). Design Observational cohort study. Subjects All medicine discharges between November 2009 and October 2010 from 6 hospitals in North Texas, including safety net, teaching, and nonteaching sites. Measures Thirty-day nonelective readmissions were ascertained from 75 regional hospitals. Results Among 32,922 admissions (validation = 16,430), 12.7% were readmitted. In addition to many first-day factors, we identified hospital-acquired Clostridium difficile infection (adjusted odds ratio [AOR]: 2.03, 95% confidence interval [CI]: 1.18-3.48), vital sign instability on discharge (AOR: 1.25, 95% CI: 1.15-1.36), hyponatremia on discharge (AOR: 1.34, 95% CI: 1.18-1.51), and length of stay (AOR: 1.06, 95% CI: 1.04-1.07) as significant predictors. The full-stay model had better discrimination than other models though the improvement was modest (C statistic 0.69 vs 0.64-0.67). It was also modestly better in identifying patients at highest risk for readmission (likelihood ratio +2.4 vs. 1.8–2.1) and in reclassifying individuals (net reclassification index 0.02–0.06). Conclusions Incorporating clinically granular EHR data from the full hospital stay modestly improves prediction of 30-day readmissions. Given limited improvement in prediction despite incorporation of data on hospital complications, clinical instabilities, and trajectory, our findings suggest that many factors influencing readmissions remain unaccounted for. Further improvements in readmission models will likely require accounting for psychosocial and behavioral factors not currently captured by EHRs.
Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic ‘pacemakers’, or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2–14 years). Magnetic resonance imaging (MRI), 18fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normal-pyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be ‘pacemaker’ cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.
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