Propranolol Modulates Cerebellar Circuit Activity and Reduces Tremor.

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a ß-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through ß1 and ß2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in ß1 and ß2 null mice or Car8wdl/wdl mice lacking ß1 and ß2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through ß-adrenergic receptors and may contribute to tremor therapeutics.

Kctd7 deficiency induces myoclonic seizures associated with Purkinje cell death and microvascular defects.

Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. KCTD7-driven disease is part of a large family of progressive myoclonic epilepsy syndromes displaying a broad spectrum of clinical severity. Animal models of KCTD7-related disease are lacking, and little is known regarding how KCTD7 protein defects lead to epilepsy and cognitive dysfunction. We characterized Kctd7 expression patterns in the mouse brain during development and show that it is selectively enriched in specific regions as the brain matures. We further demonstrate that Kctd7-deficient mice develop seizures and locomotor defects with features similar to those observed in human KCTD7-associated diseases. We also show that Kctd7 is required for Purkinje cell survival in the cerebellum and that selective degeneration of these neurons is accompanied by defects in cerebellar microvascular organization and patterning. Taken together, these results define a new model for KCTD7-associated epilepsy and identify Kctd7 as a modulator of neuron survival and excitability linked to microvascular alterations in vulnerable regions.

Neuromodulation of the cerebellum rescues movement in a mouse model of ataxia.

Deep brain stimulation (DBS) relieves motor dysfunction in Parkinson's disease, and other movement disorders. Here, we demonstrate the potential benefits of DBS in a model of ataxia by targeting the cerebellum, a major motor center in the brain. We use the Car8 mouse model of hereditary ataxia to test the potential of using cerebellar nuclei DBS plus physical activity to restore movement. While low-frequency cerebellar DBS alone improves Car8 mobility and muscle function, adding skilled exercise to the treatment regimen additionally rescues limb coordination and stepping. Importantly, the gains persist in the absence of further stimulation. Because DBS promotes the most dramatic improvements in mice with early-stage ataxia, we postulated that cerebellar circuit function affects stimulation efficacy. Indeed, genetically eliminating Purkinje cell neurotransmission blocked the ability of DBS to reduce ataxia. These findings may be valuable in devising future DBS strategies.

Risk factors for 30-day readmission and indication for ERCP following laparoscopic cholecystectomy: a retrospective NSQIP cohort study.

BACKGROUND: Laparoscopic cholecystectomy (LC) is one of the safest, most commonly performed surgical procedures, but postoperative complications including bile leak, retained stone, cholangitis, and gallstone pancreatitis following LC occur in up to 2.6% of cases and may require readmission with possible endoscopic retrograde cholangiopancreatography (ERCP) intervention. There is a paucity of literature on factors predictive of need for ERCP following LC. The goal of this study is to describe the prevalence and risk factors for readmission with indication for ERCP. METHODS: We queried the ACS/NSQIP 2012-2017 Participant User Files for patients who underwent LC. Patient demographics, comorbidities, operative characteristics, and postoperative outcomes were evaluated. Multivariate logistic regression was used to identify risk factors for readmission with indication for ERCP intervention. RESULTS: Of 275,570 patients, 11,010 (4.00%) were readmitted within the 30-day postoperative period. Among these, 930 (8.44%) were admitted with indication for ERCP intervention. On multivariate regression, readmissions were more likely in older patients, inpatients, and patients with baseline comorbidities, acute preoperative morbidity, and those discharged to care facilities. The use of intraoperative cholangiogram was associated with lower odds of readmission. Less than 10% of readmitted patients had an indication for ERCP. Those who were readmitted with an indication for ERCP were more likely to have undergone emergency surgery, experienced longer operative times, and had elevated preoperative LFTs or gallstone pancreatitis prior to surgery. The risk of 30-day mortality was significantly higher among patients who experienced any complications after their surgery (OR 13.03, 95% CI 10.57-16.07, p < 0.001). CONCLUSIONS: Older patients, patients with greater preoperative morbidity, and those discharged to care facilities were more likely to be readmitted for any reason following laparoscopic cholecystectomy, whereas patients with evidence of complicated gallstone disease were more likely to be readmitted with an indication for ERCP, even when controlling for the use of intraoperative cholangiogram. Initiatives aimed at reducing readmission with indication for ERCP should focus on these patient subgroups.

Purkinje cell neurotransmission patterns cerebellar basket cells into zonal modules defined by distinct pinceau sizes.

Ramón y Cajal proclaimed the neuron doctrine based on circuit features he exemplified using cerebellar basket cell projections. Basket cells form dense inhibitory plexuses that wrap Purkinje cell somata and terminate as pinceaux at the initial segment of axons. Here, we demonstrate that HCN1, Kv1.1, PSD95 and GAD67 unexpectedly mark patterns of basket cell pinceaux that map onto Purkinje cell functional zones. Using cell-specific genetic tracing with an Ascl1CreERT2 mouse conditional allele, we reveal that basket cell zones comprise different sizes of pinceaux. We tested whether Purkinje cells instruct the assembly of inhibitory projections into zones, as they do for excitatory afferents. Genetically silencing Purkinje cell neurotransmission blocks the formation of sharp Purkinje cell zones and disrupts excitatory axon patterning. The distribution of pinceaux into size-specific zones is eliminated without Purkinje cell GABAergic output. Our data uncover the cellular and molecular diversity of a foundational synapse that revolutionized neuroscience.

Purkinje cell misfiring generates high-amplitude action tremors that are corrected by cerebellar deep brain stimulation.

Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. Here, we found that genetically silencing cerebellar Purkinje cell output blocked tremor in mice that were given the tremorgenic drug harmaline. We show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the activity of their target cerebellar nuclei cells. We mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease.

Emerging connections between cerebellar development, behaviour and complex brain disorders.

The human cerebellum has a protracted developmental timeline compared with the neocortex, expanding the window of vulnerability to neurological disorders. As the cerebellum is critical for motor behaviour, it is not surprising that most neurodevelopmental disorders share motor deficits as a common sequela. However, evidence gathered since the late 1980s suggests that the cerebellum is involved in motor and non-motor function, including cognition and emotion. More recently, evidence indicates that major neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, attention-deficit hyperactivity disorder and Down syndrome have potential links to abnormal cerebellar development. Out of recent findings from clinical and preclinical studies, the concept of the 'cerebellar connectome' has emerged that can be used as a framework to link the role of cerebellar development to human behaviour, disease states and the design of better therapeutic strategies.

Molecular layer interneurons shape the spike activity of cerebellar Purkinje cells.

Purkinje cells receive synaptic input from several classes of interneurons. Here, we address the roles of inhibitory molecular layer interneurons in establishing Purkinje cell function in vivo. Using conditional genetics approaches in mice, we compare how the lack of stellate cell versus basket cell GABAergic neurotransmission sculpts the firing properties of Purkinje cells. We take advantage of an inducible Ascl1CreER allele to spatially and temporally target the deletion of the vesicular GABA transporter, Vgat, in developing neurons. Selective depletion of basket cell GABAergic neurotransmission increases the frequency of Purkinje cell simple spike firing and decreases the frequency of complex spike firing in adult behaving mice. In contrast, lack of stellate cell communication increases the regularity of Purkinje cell simple spike firing while increasing the frequency of complex spike firing. Our data uncover complementary roles for molecular layer interneurons in shaping the rate and pattern of Purkinje cell activity in vivo.

Social Media and the Dissemination of Research: Insights from the Most Widely Circulated Articles in Plastic Surgery.

BACKGROUND: The purpose of this study is to quantify the relationship between social media use and the dissemination of research across nontraditional channels. METHODS: Between June and August of 2016, the authors identified 10 plastic surgery journals with the highest impact factor and their 10 most widely circulated articles. Article age; journal impact factor; "distinguished" article designation; and social media metadata of the first authors, last authors, and journals were incorporated into a multivariate regression model to predict the Altmetric Attention Score, a quantitative measure of popularity across Web-based media platforms. RESULTS: A total of 100 articles, 181 authors, and 10 journals were identified. Older articles tended to be less popular. The article's popularity was associated with the journal's audience size, but not with the author's social media activity. For each 1000 additional Twitter followers of the journal of publication, the Altmetric score is greater by a factor of 1.72 (95 percent CI, 1.076 to 2.749), which is the equivalent of 72 percent more Tweets. There is also a small but statistically significant negative association between the author's social media audience size and the popularity of his or her articles: for every 1000 additional followers, the Altmetric score is lower by a factor of 0.822 (95 percent CI, 0.725 to 0.932), which is the equivalent of 17.8 percent fewer Tweets. CONCLUSION: The popularity of an article across social media platforms is associated with the journal's audience on social media, not with the magnitude of the author's social media activity.

Distraction Osteogenesis for Surgical Treatment of Craniosynostosis: A Systematic Review.

BACKGROUND: Distraction osteogenesis has been proposed as an alternative to cranial remodeling surgery for craniosynostosis, but technique descriptions and outcome analyses are limited to small case series. This review summarizes operative characteristics and outcomes of distraction osteogenesis and presents data comparing distraction osteogenesis to cranial remodeling surgery. METHODS: A systematic review of the literature was undertaken. Descriptive analysis, operative technical data, outcomes, or postoperative complications of distraction osteogenesis for craniosynostosis were included. RESULTS: A total of 1325 citations were reviewed, yielding 53 articles and 880 children who underwent distraction osteogenesis for craniosynostosis. Distraction plates were used in 754 patients (86 percent), whereas springs were used for the remaining 126 patients (14 percent). Standard and spring distraction osteogenesis was reported to successfully treat the primary condition 98 percent of the time. Suboptimal results were reported in 11 patients (1.3 percent), and minor complications were reported in 19.5 percent of cases (n = 172).Major complications were rare, occurring in 3.5 percent of cases (n = 31), and included two reported deaths. Absolute operative times and blood loss were marginally greater for cranial remodeling surgery cases, but the differences were not statistically significant. CONCLUSIONS: Distraction osteogenesis is an effective cranial vault remodeling technique for treating craniosynostosis. No statistical differences were found with respect to operative time, blood loss, need for transfusion, or intensive care unit resources compared with cranial remodeling surgery. Outcome studies with longer follow-up periods specifically investigating cost, relapse, and reoperation rates are necessary to effectively compare this treatment modality as an alternative to cranial remodeling surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates.

The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.

The importance of timing in optimizing cranial vault remodeling in syndromic craniosynostosis.

BACKGROUND: The purpose of this study was to gain insight into the impact of age at repair on relapse rates in syndromic patients undergoing cranial vault remodeling. METHODS: Retrospective chart review was performed for patients surgically treated for syndromic craniosynostosis from 1990 to 2013. Surgical procedures were assigned a Whitaker category based on need for reoperation as follows: no additional surgery required (category I); minor contouring revisions required (II); major revisions required (III); or failure of original surgery (IV). Age at surgery was grouped as follows: younger than 6 months; aged 6 to 9 months; and older than 9 months. Multivariable logistic regression analysis was performed to determine the relationship between age at surgery and need for reoperation by Whitaker category. RESULTS: Fifty-two patients undergoing a total of 65 planned cranial vault remodeling procedures were included. Multivariate logistic regression analysis revealed that patients younger than 6 months at the time of primary surgery carried a 4.10 greater odds (95 percent CI, 1.31 to 12.87; p = 0.016) of requiring a subsequent major reoperation, and being older than 9 months of age carried a 13.2 greater odds (95 percent CI, 1.39 to 124.30; p = 0.024) of requiring a subsequent minor revision. CONCLUSIONS: Timing of surgery is an important factor to consider when planning vault remodeling in syndromic craniosynostosis. Based on our institution's experience, when there is no concern for elevated intracranial pressure the ideal operative window for these procedures in the syndromic population appears to be 6 to 9 months of age.

Electron transport in acceptor-sensitized polymer-oxide solar cells: the importance of surface dipoles and electron cascade effects.

Fullerene and acenequinone compounds have been examined as electron mediators between a p-type semiconductive polymer and two n-type oxide semiconductors. Composite interlayer materials and photovoltaic test cells were assembled and studied for their fluorescence quenching, current-voltage, and quantum efficiency behavior to characterize the efficacy of the acceptor-sensitizers as electron-selective interlayers. The sensitizers are generally more effective with titanium dioxide than with zinc oxide, due to the difference in magnitude of dipole-induced vacuum level shifts at the respective oxide interfaces. In titanium dioxide-based solar cells, where dipole effects are weak, photovoltage and fill factor increase in a trend that matches the increase in the first reduction potential of the acceptor-sensitizers. Photosensitization of the oxide semiconductor by the acceptor-sensitizers is observed to operate either in parallel with the polymer as an alternate photosensitizer or in series with the polymer in a two-photon process, according to an acceptor-sensitizer's first reduction potential. In zinc oxide-based solar cells, where dipole effects are stronger, the acceptor-sensitizers impaired most devices, which is attributed to an upward shift of the oxide's conduction band edge caused by dipole-induced vacuum level shifts. These results have broad implications for designing electron-selective interlayers and solid-state photocells using sensitized oxide semiconductors.