Potassium channel dysfunction in human neuronal models of Angelman syndrome

Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases

Long-term medical utilization following ventilator-associated pneumonia in acute stroke and traumatic brain injury patients: a case-control study

<p>Abstract</p> <p>Background</p> <p>The economic burden of ventilator-associated pneumonia (VAP) during the index hospitalization has been confirmed in previous studies. However, the long-term economic impact is still unclear. The aim of this study is to examine the effect of VAP on medical utilization in the long term.</p> <p>Methods</p> <p>This is a retrospective case-control study. Study subjects were patients experiencing their first traumatic brain injury, acute hemorrhagic stroke, or acute ischemic stroke during 2004. All subjects underwent endotracheal intubation in the emergency room (ER) on the day of admission or the day before admission, were transferred to the intensive care unit (ICU) and were mechanically ventilated for 48 hours or more. A total of 943 patients who developed VAP were included as the case group, and each was matched with two control patients without VAP by age ( ± 2 years), gender, diagnosis, date of admission ( ± 1 month) and hospital size, resulting in a total of 2,802 patients in the study. Using robust regression and Poisson regression models we examined the effect of VAP on medical utilization including hospitalization expenses, outpatient expenses, total medical expenses, number of ER visits, number of readmissions, number of hospitalization days and number of ICU days, during the index hospitalization and during the following 2-year period.</p> <p>Results</p> <p>Patients in the VAP group had higher hospitalization expenses, longer length of stay in hospital and in ICU, and a greater number of readmissions than the control group patients.</p> <p>Conclusions</p> <p>VAP has a significant impact on medical expenses and utilization, both during the index hospitalization during which VAP developed and in the longer term.</p

Clinical characteristics and therapeutic outcomes of nosocomial super-infection in adult bacterial meningitis

<p>Abstract</p> <p>Background</p> <p>Super-infection in adult bacterial meningitis (ABM) is a condition wherein the cerebrospinal fluid (CSF) grows new pathogen(s) during the therapeutic course of meningitis. It is an uncommon but clinically important condition rarely examined in literature.</p> <p>Methods</p> <p>Twenty-seven episodes of super-infection states in 21 ABM patients collected in a 9.5-year study period (January 2001 to June 2010) were evaluated. The clinical characteristics, implicated pathogens, results of antimicrobial susceptibility tests, and therapeutic outcomes were analyzed.</p> <p>Results</p> <p>Twenty-one patients (13 men, 8 women) aged 25-73 years (median, 45 years) had post-neurosurgical state as the preceding event and nosocomial infection. The post-neurosurgical states included spontaneous intracranial hemorrhage (ICH) with craniectomy or craniotomy with extra-ventricular drainage (EVD) or ventriculo-peritoneal shunt (VPS) in 10 patients, traumatic ICH with craniectomy or craniotomy with EVD or VPS in 6 patients, hydrocephalus s/p VPS in 2 patients, and one patient each with cerebral infarct s/p craniectomy with EVD, meningeal metastasis s/p Omaya implant, and head injury. All 21 patients had EVD and/or VP shunt and/or Omaya implant during the whole course of ABM. Recurrent fever was the most common presentation and the implicated bacterial pathogens were protean, many of which were antibiotic resistant. Most patients required adjustment of antibiotics after the pathogens were identified but even with antimicrobial therapy, 33.3% (7/21) died. Morbidity was also high among survivors.</p> <p>Conclusions</p> <p>Super-infection in ABM is usually seen in patients with preceding neurosurgical event, especially insertion of an external drainage device. Repeat CSF culture is mandatory for diagnostic confirmation because most of the implicated bacterial strains are non-susceptible to common antibiotics used. Unusual pathogens like anaerobic bacteria and fungi may also appear. Despite antimicrobial therapy, prognosis remains poor.</p

Ultrasonographic median nerve cross-section areas measured by 8-point "inching test" for idiopathic carpal tunnel syndrome: a correlation of nerve conduction study severity and duration of clinical symptoms

<p>Abstract</p> <p>Background</p> <p>Incremental palmar stimulation of the median nerve sensory conduction at the wrist, the "inching test", provides an assessment with reference to segments proximal and distal to the entrapment. This study used high-resolution ultrasonography (US) to measure the median nerve's cross-section areas (CSAs) like the "inching test" and to correlate with the nerve conduction study (NCS) severity and duration of carpal tunnel syndrome (CTS).</p> <p>Methods</p> <p>Two hundred and twelve (212) "CTS-hands" from 135 CTS patients and 50 asymptomatic hands ("A-hands") from 25 control individuals were enrolled. The median nerve CSAs were measured at the 8-point marked as <it>i</it>4, <it>i</it>3, <it>i</it>2, <it>i</it>1, <it>w</it>, <it>o</it>1, <it>o</it>2, and <it>0</it>3 in inching test. The NCS severities were classified into six groups based on motor and sensory responses (i.e., negative, minimal, mild, moderate, severe, and extreme). Results of US studies were compared in terms of NCS severity and duration of clinical CTS symptoms.</p> <p>Results</p> <p>There was significantly larger CSA of the NCS negative group of "CTS-hands" than of "A-hands". The cut-off values of the CSAs of the NCS negative CTS group were 12.5 mm², 11.5 mm²and 10.1 mm²at the inlet, wrist crease, and outlet, respectively. Of the 212 "CTS-hands", 32 were NCS negative while 40 had minimal, 43 mild, 85 moderate, 10 severe, and two extreme NCS severities. The CSAs of "CTS-hands" positively correlated with different NCS severities and with the duration of CTS symptoms. By duration of clinical symptoms, 12 of the 212 "CTS-hands" were in the 1 month group; 82 in >1 month and ≤12 months group, and 118 in >12 months group. In "inching test", segments <it>i</it>4-<it>i</it>3 and <it>i</it>3-<it>i</it>2 were the most common "positive-site". The corresponding CSAs measured at <it>i</it>4 and <it>i</it>3, but not at <it>i</it>2, were significantly larger than those measured at points that were not "positive-site".</p> <p>Conclusions</p> <p>Using the 8-point measurement of the median nerve CSA from inlet to outlet similar to the "inching test" has positive correlations with NCS severity and duration of CTS clinical symptoms, and can provide more information on anatomic changes. Combined NCS and US studies using the 8-point measurement may have a higher positive rate than NCS alone for diagnosing CTS.</p

Neuromuscular abnormality and autonomic dysfunction in patients with cerebrotendinous xanthomatosis

<p>Abstract</p> <p>Background</p> <p>Cerebrotendinous xanthomatosis (CTX) is a rare lipid-storage disease. Neuromuscular abnormality and autonomic system (ANS) dysfuction in CTX are rarely examined in large-scale studies in the literature. We studied the peripheral nervous system, myopathology, and autonomic system of four CTX patients and performed a literature review of the reported CTX patients with peripheral neuropathy.</p> <p>Methods</p> <p>Four biochemically and genetically confirmed CTX patients, belonging to two families, were included for study and all received nerve conduction study (NCS), muscle biopsy for histopathologic and ultrastructural study, skin biopsy for intraepidermal nerve fiber (INEF) density measurement, autonomic testings including sympathetic skin response, R-R interval variation and head-up tilt test using an automated tilt table to record the changes of blood pressure and heart rate in different postures. The Q-Sweat test was also applied for the detection of sweat amount and onset time of response. The clinical characteristics, study methods and results of 13 studies of peripheral neuropathy in CTX patients in the literature were also recorded for analysis.</p> <p>Results</p> <p>The results of NCS study showed axonal sensory-motor polyneuropathy in three CTX cases and mixed axonal and demyelinating sensor-motor polyneuropathy in one. The myopathological and histopathologic studies revealed mild denervation characteristics, but the ultrastructural study revealed changes of mitochondria and the membranous system, and increased amounts of glycogen, lipofuscin and lipid deposition. The ANS study revealed different degrees of abnormalities in the applied tests and the INEF density measurement showed small fiber neuropathy in three of the four CTX patients. The literature review of peripheral neuropathy in CTX revealed different types of peripheral neuropathy, of which axonal peripheral neuropathy was the most common.</p> <p>Conclusions</p> <p>Peripheral neuropathy, especially the subtype of axonal sensori-motor neuropathy, is common in patients with CTX. Evidence of lipid metabolic derangement in CTX can be reflected in ultrastructural studies of muscles. With an adequate multi-parametric evaluation, a high incidence of ANS abnormalities can be seen in this rare lipid-storage disease, and a high incidence of small fiber involvement is also reflected in the IENF density measurement of skin biopsies.</p

Arousal increases neural gain via the locus coeruleus-norepinephrine system in younger adults but not in older adults

In younger adults, arousal amplifies attentional focus to the most salient or goal-relevant information while suppressing other information. A computational model of how the locus coeruleus-norepinephrine (LC-NE) system can implement this increased selectivity under arousal and an fMRI study comparing how arousal affects younger and older adults’ processing indicate that the amplification of salient stimuli and the suppression of non-salient stimuli are separate processes, with aging affecting suppression without impacting amplification under arousal. In the fMRI study, arousal increased processing of salient stimuli and decreased processing of non-salient stimuli for younger adults. In contrast, for older adults, arousal increased processing of both low and high salience stimuli, generally increasing excitatory responses to visual stimuli. Older adults also showed decline in LC functional connectivity with frontoparietal networks that coordinate attentional selectivity. Thus, among older adults, arousal increases the potential for distraction from non-salient stimuli

Differential Collective Cell Migratory Behaviors Modulated by Phospholipid Nanocarriers

10.1021/acsnano.1c03060ACS Nano151117412-1742