Search

• A classification and genetic basis for hypolipidemia disorders is provided. • We suggest guidance for the diagnosis and treatment of these disorders. • We discuss challenges encountered by patients with hypolipidemia disorders. • Topics for future research are highlighted. The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals. [ABSTRACT FROM AUTHOR]

Background: Post-operative AF (POAF) is the most common complication following cardiac surgery, occurring in 30% to 60% of patients undergoing bypass and/or valve surgery. POAF is associated with longer intensive care unit/hospital stays, increased healthcare utilization, and increased morbidity and mortality. Injection of botulinum toxin type A into the epicardial fat pads resulted in reduction of AF in animal models, and in two clinical studies of cardiac surgery patients, without new safety observations.Methods: The objective of NOVA is to assess the use of AGN-151607 (botulinum toxin type A) for prevention of POAF in cardiac surgery patients. This randomized, multi-site, placebo-controlled trial will study one-time injections of AGN-151607 125 U (25 U / fat pad) and 250 U (50 U / fat pad) or placebo during cardiac surgery in ∼330 participants. Primary endpoint: % of patients with continuous AF ≥ 30 s. Secondary endpoints include several measures of AF frequency, duration, and burden. Additional endpoints include clinically important tachycardia during AF, time to AF termination, and healthcare utilization. Primary and secondary efficacy endpoints will be assessed using continuous ECG monitoring for 30 days following surgery. All patients will be followed for up to 1 year for safety.Conclusions: The NOVA Study will test the hypothesis that injections of AGN-151607 will reduce the incidence of POAF and associated resource utilization. If demonstrated to be safe and effective, the availability of a one-time therapy for the prevention of POAF would represent an important treatment option for patients undergoing cardiac surgery. [ABSTRACT FROM AUTHOR]

Objectives: Understanding the successful characteristics of team formation during different scenarios in Australian Football matches can assist coaches in making important tactical match-day and training decisions. The aims of this study were to explore the outcomes of entries inside 50 m of the goal, in Australian Football and to determine whether there was an association between team formation and team defensive performance after a turnover.Design: Observational.Methods: Global Positioning System (GPS) data, technical event data and video files from 22 matches in one season were obtained from an elite Australian Football club. Of 1092 forward 50 entries, 392 possession chains that resulted in a turnover were analysed. Variables representing team formation of players at the occurrence of turnover were compared between positive and negative outcomes of the subsequent possession chain. Logistic regression and decision tree modelling were also used to explore associations and variable importance.Results: None of 18 team formation characteristics differed between positive and negative outcomes of turnovers. Multivariate modelling identified that having a team formation with greater width than length made it more likely to result in a positive outcome (Decision tree classification accuracy = 69.5%, AUROC = 0.72).Conclusions: No single characteristic of team formation affects the outcome of a turnover possession chain, however team formation that was wider than it was long may be associated with a more desirable outcome. The lack of association between most team formation characteristics and defensive outcomes, highlight the risk of over emphasising team formation in tactical planning for some phases of play. [ABSTRACT FROM AUTHOR]

The craniocervical junction (CCJ) protects critical neurovascular structures while allowing for a significant amount of head and neck motion. 1,2 Traumatic injuries at the CCJ are not uncommon, mainly occurring secondary to high-energy mechanisms in the young or low-energy mechanisms in the elderly. 3 Unlike the subaxial spine, neurological deficits are less common with CCJ trauma, however neurological injuries in this area can be devastating. 4 Given the complex bony, neurologic, and vascular anatomy at the CCJ, it is imperative that spine surgeons understand the diagnosis and management of C1 and C2 fractures. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the gross, histologic, and systemic changes caused by implantation of metal fragments commonly used in commercial bullets into the intervertebral disc.Background Context: Long-term complications of retained bullet fragments in the spine have been documented in the literature; however, the impact of different metal projectiles on the intervertebral disc has not been described. This study was performed to assess the local effects of the metallic bullet fragments on the intervertebral disc and their systemic effects regarding metal ion concentrations in serum and solid organs.Study Design: Animal Model Study.Methods: Funding for this project was provided by the Cervical Spine Research Society in the amount of $10,000. Copper, lead, and aluminum alloys from commercially available bullets were surgically implanted into sequential intervertebral discs in the lumbar spine of six canines. Kirschner wire implantation and a sham operation were performed as controls. Radiographs were performed to confirm the location of the bullets. Animals were sacrificed at 4, 6, and 9 months postimplantation. Whole blood, plasma, cerebrospinal fluid, kidney tissue, and liver tissue samples were analyzed for copper and lead concentrations. Histologic and gross samples were examined at the time of sacrifice.Results: Significant tissue reactions were noted in the discs exposed to copper and lead. Copper resulted in significantly more severe disc degeneration than either the lead or aluminum alloy. In the short interval follow-up of this study, no statistically significant trend was observed in whole blood, plasma, cerebrospinal fluid, and tissue levels.Conclusion: This study demonstrates that the canine intervertebral disc is differentially susceptible to metallic fragments depending on the composition. Trends were noted for increasing levels of lead and copper in liver tissue samples although statistical significance could not be reached due to short time interval and small sample size. The metallic composition of retained fragments can be a determining factor in deciding on surgical intervention. [ABSTRACT FROM AUTHOR]

Mycoplasma pneumoniae is a bacterial pathogen of humans that is a major causative agent of chronic respiratory disease. M. pneumoniae infections often recur even after successful treatment of symptoms with antibiotics, and resistance to antibiotics is increasing worldwide, with nearly complete resistance in some places. Although biofilms often contribute to chronicity and resistance, M. pneumoniae biofilms remain poorly characterized. Scanning electron microscopy revealed that cells of wild-type (WT) M. pneumoniae strain M129 biofilms, as well as mutants II-3 and II-3R, in vitro became increasingly rounded as the biofilm towers matured over 5 days. The role of gliding motility in biofilm formation was addressed by analyzing differences in biofilm architecture in non-motile mutant II-3R and hypermotile mutant prpC- and by using time-lapse microcinematography to measure flux of cells around biofilm towers. There were no major differences in biofilm architecture between WT and motility mutants, with perhaps a slight tendency for the prpC- cells to spread outside towers during early stages of biofilm formation. Consistent with an insignificant role of motility in biofilm development, flux of cells near towers, which was low, was dominated by exit of cells. Immunofluorescence microscopy revealed that motility-associated attachment organelle (AO) proteins exhibited no discernable changes in localization to foci over time, but immunoblotting identified a decrease in steady-state levels of protein P200, which is required for normal gliding speed, as the WT culture aged. Non-adherent strain II-3 and non-motile strain II-3R also exhibited a steady decrease in P200 steady-state levels, suggesting that the decrease in P200 levels was not a response to changes in gliding behavior during maturation. We conclude that M. pneumoniae cells undergo morphological changes as biofilms mature, motility plays no major role in biofilm development, and P200 loss might be related to maturation of cells. This study helps to characterize potential therapeutic targets for M. pneumoniae infections. [ABSTRACT FROM AUTHOR]

The ability to make effective decisions is an important function of any football coach, whether during training, team selection, match-day performance or post-match player evaluation. It is not yet known how elite Australian football coaches make decisions during matches, in time-constrained but well-resourced environments. This study is the first to explore the decision-making of elite Australian football coaches during matches, in pursuit of identifying opportunities to improve the translation and implementation of research findings into the competitive match environment. Using semi-structured interviews and thematic analysis, a six-stage framework of the decision-making of elite Australian football coaches during matches was developed. The stages include (1) Opportunity trigger, (2) Understand the opportunity, (3) Determine the need for action, (4) Explore options, (5) Take action and (6) Evaluate the decision. Coaches relied on subjective and objective sources of information and consulted with assistant coaches, performance analysts, and sport scientists. The findings enable researchers to ensure future interventions to improve decision-making during matches are well integrated. They also provide an opportunity for coaches to reflect on their own decision-making process, identifying targeted areas for improvement in their own practice. • Insights into how elite football coaches make decisions during matches are explored in the context of Australian football. • A framework is proposed to explain and understand the coach's in-match decision-making, guided by bounded rationality. • Opportunities for targeted reflection on coaching practice and research intervention are presented. [ABSTRACT FROM AUTHOR]

Sodium deficit poses a life-threatening challenge to body fluid homeostasis and generates a sodium appetite - the behavioral drive to ingest sodium. Dr. Randall R. Sakai greatly contributed to our understanding of the hormonal responses to negative sodium balance and to the central processing of these signals. Reactivity to the taste of sodium solutions and the motivation to seek and consume sodium changes dramatically with body fluid balance. Here, we review studies that collectively suggest that sodium deficit recruits the mesolimbic system to play a role in the behavioral expression of sodium appetite. The recruitment of the mesolimbic system likely contributes to intense sodium seeking and reinforces sodium consumption observed in deficient animals. Some of the hormones that are released in response to sodium deficit act directly on both dopamine and nucleus accumbens elements. Moreover, the taste of sodium in sodium deficient rats evokes a pattern of dopamine and nucleus accumbens activity that is similar to responses to rewarding stimuli. A very different pattern of activity is observed in non-deficient rats. Given the well-characterized endocrine response to sodium deficit and its central action, sodium appetite becomes an ideal model for understanding the role of mesolimbic signaling in reward, reinforcement and the generation of motivated behavior. [ABSTRACT FROM AUTHOR]

Drugs of abuse increase the frequency and magnitude of brief (1–3 s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release – possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. [ABSTRACT FROM AUTHOR]

• Food-deprivation potentiated locomotor activity after acute amphetamine exposure. • Food-deprivation affected moving velocity after acute amphetamine exposure. • Food-deprivation increased heart rate in response to acute amphetamine exposure. • Motor neuron spike count increased in food-deprived larvae post-amphetamine. • Neuron activity duration increased in food-deprived larvae post-amphetamine. Psychostimulant drugs increase behavioral, cardiac and brain responses in humans and other animals. Acute food deprivation or chronic food restriction potentiates the stimulatory effects of abused drugs and increases the propensity for relapse to drug seeking in drug-experienced animals. The mechanisms by which hunger affects cardiac and behavioral activities are only beginning to be elucidated. Moreover, changes in motor neuron activities at the single neuron level induced by psychostimulants, and their modulation by food restriction, remain unknown. Here we investigated how food deprivation affects responses to d-amphetamine by measuring locomotor activity, cardiac output, and individual motor neuron activity in zebrafish larvae. We used wild-type larval zebrafish to record behavioral and cardiac responses and the larvae of Tg(mnx1:GCaMP5) transgenic zebrafish to record motor neuron responses. Physiological state gated responses to d-amphetamine. That is, d-amphetamine evoked significant increases in motor behavior (swimming distances), heart rate and motor neuron firing frequency in food-deprived but not fed zebrafish larvae. The results extend the finding that signals arising from food deprivation are a key potentiator of the drug responses induced by d-amphetamine to the zebrafish model. The larval zebrafish is an ideal model to further elucidate this interaction and identify key neuronal substrates that may increase vulnerability to drug reinforcement, drug-seeking and relapse. [ABSTRACT FROM AUTHOR]

Many watershed studies rely on pressure transducers to measure and report stream and groundwater levels in order to characterize the hydrology of the region. The accuracy of pressure transducers in some applications have recently been questioned in studies reporting artificially exaggerated high or low pressure readings that cannot be explained by daily hydrological fluctuations. In a watershed field investigation, data analyses have revealed, for some sensors, patterns of artificial changes in stream and groundwater levels as a function of water and atmospheric temperature. These patterns do not follow the expected variation that could be caused by natural phenomena (i.e. changes in head caused by evapotranspiration). Laboratory analyses of temperature-induced artificial pressure changes reproduces this error and yielded functional relationships for thermal artifact corrections. Using these relationships, stream and groundwater levels can be back-calculated yielding a more accurate watershed hydrologic characterization. By removing the thermal artifacts from laboratory and field data, errors are reduced by up to 65% (laboratory) and 81% (field data). The developed procedure can be used in other settings where pressure transducers are used, such as studies in rainfall/runoff variations, runoff measurements in urban settings, and the impacts of new development in rural watersheds. [ABSTRACT FROM AUTHOR]

Highlights: [•] Natural rewards reinforce behavior by eliciting phasic increases in dopamine (DA transients). [•] Abused drugs pharmacologically evoke DA transients and thus mimic natural rewards. [•] We propose a reclassification of addictive DA transporter inhibitors (DAT-Is). [•] Reclassification based on their ability to elicit DA transients via DA cell bursting. [•] This bursting could be basis for initial reinforcement of drug-seeking/-taking. [ABSTRACT FROM AUTHOR]

Abstract: Many therapies designed to reduce food intake and body weight act, in part, by blocking the dopamine transporter (DAT) — a protein responsible for clearing extracellular dopamine (DA) after release thereby terminating its action. Here, we found that a single injection of the drug trodusquemine (MSI-1436) decreased food intake in rats. To assess the effects of MSI-1436 on DAT function, fast-scan cyclic voltammetry was used to measure DA concentration changes in the ventral striatum. DA release was evoked by electrical stimulation of the ventral tegmental area every 5min. After 3 baseline measurements, rats were injected with MSI-1436 (10mg/kg), the known DAT blocker bupropion (80mg/kg) or saline and evoked DA release and reuptake were monitored for an additional hour. Neither saline nor MSI-1436 caused a significant change in the magnitude of evoked release from baseline values whereas bupropion caused a significant increase. In addition, neither saline nor MSI-1436 significantly increased DA decay rates while such an increase was observed with bupropion. Thus, over a time course when MSI-1436 suppresses food intake it does not affect DAT function. The results support MSI-1436 as an anti-obesity treatment which spares DAT. [ABSTRACT FROM AUTHOR]

Abstract: BOTOX® is a botulinum toxin type A product from Allergan that is approved in more than 70 countries, where it addresses unmet patient needs across a variety of indications. BOTOX® is a well-characterized and highly purified biological product that is not interchangeable with any other botulinum neurotoxin. The pharmacology, efficacy and safety profile of BOTOX® has been established in numerous preclinical and clinical studies in addition to meta-analyses. BOTOX® exhibits a predictable response, with a concomitant low rate of neutralizing antibody formation. Allergan is committed to the development of new indications and novel biologics that are designed to benefit individuals with unmet medical needs. [Copyright &y& Elsevier]

Abstract: Since the late 1970s, local injections of BoNT have provided clinical benefit for patients with inappropriately contracting muscles with or without pain or sensory disturbance. Marketing authorization for some BoNTs, depending on country, include core indications of dystonia (blepharospasm and cervical dystonia), large muscle spastic disorders (not yet approved in the United States, e.g., adult post-stroke spasticity and equinus foot deformity), hyperhidrosis and aesthetic. Subsequent development has extended to selected conditions characterized by recurrent or chronic pain (migraine headache), and urologic indications (neurogenic/idiopathic overactive bladder; prostate hyperplasia), with multiple additional opportunities available. Portfolio management requires a careful individual opportunity assessment of scientific and technical aspects (basic science foundation, potential to treat unmet medical need, product-specific risk in specific populations, therapeutic margin/safety profile, and probability of successful registration pathway). This article describes ongoing development targets for BOTOX®. [Copyright &y& Elsevier]

Study objective: The aim of this study is to characterize hospital and patient characteristics associated with administration of thrombolysis in acute ischemic stroke patients in the United States. Methods: This retrospective, observational, cohort study used data from the Nationwide Inpatient Sample, an administrative discharge database. A total of 366,194 hospitalizations admitted through the emergency department with a primary diagnosis of acute ischemic stroke were selected for analysis. The primary outcome considered in this study is whether the patient received thrombolytic therapy on hospital day 0 or 1. Results: Thrombolysis was used in 1.12% (95% confidence interval [CI] 0.95% to 1.32%) of ischemic stroke hospitalizations. Most hospitals (69.5%; 95% CI 68.4% to 70.6%) treating ischemic stroke patients did not use thrombolysis during the study period. For the hospitals that used thrombolysis, the mean annual number of patients treated with thrombolysis per hospital was 3.06 (95% CI 2.68 to 3.44). In the binary logistic regression analysis, hospital characteristics associated with high use of thrombolysis were teaching hospital status and increasing number of stroke patients treated annually. Patient characteristics associated with higher use of thrombolysis were age younger than 55 years, male sex, and low comorbidity as measured by the modified Charlson Index; white race; and private self-pay health insurance. Conclusion: Use of thrombolysis for ischemic stroke in the United States from 1999 to 2004 was infrequent and showed significant differences, depending on hospital and patient demographic characteristics. [Copyright &y& Elsevier]

Abstract: Turkel CC, Bowen B, Liu J, Brin MF. Pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity. Objective: To examine the safety of botulinum toxin type A (BTX-A). Design: Analysis of pooled data of 9 double-blind, placebo-controlled studies of patients with spasticity after stroke. Setting: University hospitals and specialty rehabilitation centers in the United States. Participants: A total of 482 patients with upper-limb spasticity and 310 with lower-limb spasticity (overall mean age, 58y; 60% men). Intervention: Treatment with BTX-A (n=534; 1–3 treatments; mean dose, 231U) or placebo (n=258). Main Outcome Measure: Adverse events. Results: Most patients (69%) received only 1 treatment with BTX-A. Patients were followed for a mean of 17.8 weeks (range, 0.1–44.7wk) after each treatment. A total of 352 (65.9%) patients in the BTX-A group and 163 (63.2%) in the placebo group reported at least 1 adverse event (P=.475). The most frequent adverse events reported by patients (>5% but <10% in either group) were respiratory infection, seizures, incoordination, and injection site pain, none of which occurred at a significantly higher rate in the BTX-A group (all P>.05). The majority of adverse events were rated as mild or moderate in severity. Only nausea was reported at a significantly higher rate in the BTX-A group (12/534 [2.2%]) than the placebo group (0/258) (P=.011); in contrast, injection site pain, chest pain, and allergic reaction were reported significantly more frequently in the placebo group. Conclusions: BTX-A has an acceptable safety profile for treatment of patients with focal spasticity following stroke, a population in which adverse events and comorbidities are common. [Copyright &y& Elsevier]

Squamous cells form the outermost layers of the epidermis, and though they are readily discarded from the tissue, they serve a vital water barrier function while in the stratum corneum. The generation of cornified or squamous keratinocytes involves a complex, multi-step differentiation process that insures the proper physical and immunological barrier functions of the epidermis are maintained. The regulation of keratinocyte terminal differentiation is influenced by a large number of signaling pathways. This article will review some recent findings regarding the roles of the protein kinase C (PKC) family in normal keratinocyte differentiation, as well as their involvement in skin diseases, especially skin cancer.Cell facts

Staurosporine (stsp) induces assembly of cornified envelopes in mouse keratinocyte cultures. To clarify whether this effect is the consequence of a coordinated differentiation program similar to that observed in epidermis, we assessed the expression of multiple differentiation-specific markers in stsp-treated keratinocytes. In medium containing 0.05 mM Ca&sup2+; in which the basal cell phenotype is normally maintained, stsp induced dose-dependent increases in keratin 1, epidermal and keratinocyte transglutaminases, SPR-1, loricrin, and profilaggrin mRNA. Based on nuclear run-on analysis, stsp-mediated marker expression was found to be due at least in part to increased transcription. Since protein kinase C (PKC) activation is required for keratinocyte differentiation, we tested whether stsp influenced this signaling pathway. Stsp induced the translocation of multiple PKC isoforms from the cytosol to membrane and/or cytoskeletal fractions, inducing isozyme downregulation within 24 h. Moreover, AP-1 DNA binding activity was elevated in stsp-treated keratinocytes, consistent with the notion that this agent influences keratinocyte-specific gene expression via the PKC pathway. Stsp-mediated marker expression was inhibited by the PKC inhibitor GF 109203X. In cells pre-treated with bryostatin 1 to selectively down-modulate specific PKC isoforms, stsp-induced loricrin, filaggrin, and SPR-1 expression was suppressed when PKC α, &epsiv;, and/or δ were downregulated, suggesting that these isozymes may be necessary for marker expression in response to this agent. Thus, in addition to its effects on cornified envelope assembly, stsp induces a coordinate program of differentiation-specific keratinocyte gene expression that is mediated at least in part by the PKC signaling pathway. [ABSTRACT FROM AUTHOR]

Mycoplasma mobile carries out gliding motility using a novel motor whose proposed mechanism more closely resembles eukaryotic cytoskeletal motors than other bacterial ones. High-resolution microscopy and techniques that take advantage of the special properties of the mycoplasma cell reveal that this motor propels cells in steps of discrete size. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide. One major obstacle to treatment is a lack of effective molecular-targeted therapies. In this study, we find that EphA2 expression and signaling are enriched in human HCC and associated with poor prognosis. Loss of EphA2 suppresses the initiation and growth of HCC both in vitro and in vivo. Furthermore, CRISPR/CAS9-mediated EphA2 inhibition significantly delays tumor development in a genetically engineered murine model of HCC. Mechanistically, we discover that targeting EphA2 suppresses both AKT and JAK1/STAT3 signaling, two separate oncogenic pathways in HCC. We also identify a small molecule kinase inhibitor of EphA2 that suppresses tumor progression in a murine HCC model. Together, our results suggest EphA2 as a promising therapeutic target for HCC. • High EphA2 signaling is associated with worse clinical outcomes in HCC patients • Inhibition of EphA2 suppresses HCC growth both in vitro and in vivo • EphA2 promotes hepatocarcinogenesis by dual activation of AKT and JAK1/STAT3 signaling • EphA2 inhibitor ALW-II-41-27 suppresses HCC growth Wang et al. define the role of receptor tyrosine kinase EphA2 in the development of hepatocellular carcinoma and elucidate its mechanisms of action. Inhibition of EphA2 is a promising strategy for the treatment of advanced hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Proper epidermal keratinocyte differentiation, which is necessary for cutaneous barrier function, is altered in many common skin diseases. Keratinocyte differentiation is controlled by a complex signaling network involving multiple members of the protein kinase C and mitogen-activated protein kinase signaling kinases. Using an RNA interference knockdown approach, Adhikary et al. identified essential nodes in this signaling network, revealing remarkable kinase specificity. [ABSTRACT FROM AUTHOR]

Like many skin phenotypes, susceptibility to carcinogenesis is profoundly influenced by genetic background. Sand et al. (this issue) explored the sensitizing effects of epidermal protein kinase C ɛ (PKCɛ)expression in the hairless SKH-1 mouse strain commonly used in UV carcinogenesis studies. They reported that PKCɛ overexpression profoundly sensitized these mice to UV skin carcinogenesis and activated oncogenic pathways similar to those reported in FVB/N mice. [ABSTRACT FROM AUTHOR]

The permeability barrier function of the epidermis is one of the most vital jobs performed by the skin; however, our understanding of the function and regulation of tight junctions in the epidermis remains limited. Helfrich et al. identify a key role for atypical protein kinase C (aPKC) activity, as a component of the Par3–Par6 polarity complex, in epidermal barrier function.Journal of Investigative Dermatology (2007) 127, 742–744. doi:10.1038/sj.jid.5700694 [ABSTRACT FROM AUTHOR]

This paper presents a computational model in describing the spatial and temporal changes in the chemical and physical characteristics of biodegradable polymer solids during hydrolytic degradation and erosion processes. A set of coupled governing differential equations are formulated to account for the diffusion of water molecules into the polymers, scission kinetics from a hydrolytic process, formation of monomers, and diffusion of the soluble monomers out of the polymer body. A multi-network model is adopted for capturing the hydrolytic scission, in which a long polymeric chain is being converted to monomers and byproducts. As the monomers leave the polymer body, surface and bulk erosion mechanisms are described and changes in the shape and size of the polymer body also take place. The governing differential equations are solved using a finite difference approach. It is noted that hydrolytic degradation induces temporal and spatial changes in the chemical and physical properties of polymers; and thus, the polymers that are initially homogeneous with regards to the above properties become heterogeneous due to the spatial changes in their macromolecular networks during biodegradation. The responses obtained from the model are compared with available experimental data of PLGA biodegradable polymer. • A multi-network model to describe hydrolytic scission. • Tracking changes in geometry and sizes of degrading polymers. • A coupled model for diffusion of fluid, hydrolysis and erosion processes. [ABSTRACT FROM AUTHOR]

We investigated whether ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) is involved in development of hepatocellular carcinoma (HCC). We analyzed clinical and gene expression data from The Cancer Genome Atlas. Albumin -Cre (HepWT) mice and mice with hepatocyte-specific disruption of Abl1 (Hep Abl –/– mice) were given hydrodynamic injections of plasmids encoding the Sleeping Beauty transposase and transposons with the MET gene and a catenin β1 gene with an N-terminal truncation, which induces development of liver tumors. Some mice were then gavaged with the ABL1 inhibitor nilotinib or vehicle (control) daily for 4 weeks. We knocked down ABL1 with short hairpin RNAs in Hep3B and Huh7 HCC cells and analyzed their proliferation and growth as xenograft tumors in mice. We performed RNA sequencing and gene set enrichment analysis of tumors. We knocked down or overexpressed NOTCH1 and MYC in HCC cells and analyzed proliferation. We measured levels of phosphorylated ABL1, MYC, and NOTCH1 by immunohistochemical analysis of an HCC tissue microarray. HCC tissues had higher levels of ABL1 than non-tumor liver tissues, which correlated with shorter survival times of patients. HepWT mice with the MET and catenin β1 transposons developed liver tumors and survived a median 64 days; Hep Abl –/– mice with these transposons developed tumors that were 50% smaller and survived a median 81 days. Knockdown of ABL1 in human HCC cells reduced proliferation, growth as xenograft tumors in mice, and expression of MYC, which reduced expression of NOTCH1. Knockdown of NOTCH1 or MYC in HCC cells significantly reduced cell growth. NOTCH1 or MYC overexpression in human HCC cells promoted proliferation and rescued the phenotype caused by ABL1 knockdown. The level of phosphorylated (activated) ABL1 correlated with levels of MYC and NOTCH1 in human HCC specimens. Nilotinib decreased expression of MYC and NOTCH1 in HCC cell lines, reduced the growth of xenograft tumors in mice, and slowed growth of liver tumors in mice with MET and catenin β1 transposons, reducing tumor levels of MYC and NOTCH1. HCC samples have increased levels of ABL1 compared with nontumor liver tissues, and increased levels of ABL1 correlate with shorter survival times of patients. Loss or inhibition of ABL1 reduces proliferation of HCC cells and slows growth of liver tumors in mice. Inhibitors of ABL1 might be used for treatment of HCC. [ABSTRACT FROM AUTHOR]

Lists topics included in the July 1999 issue of the 'Journal of Investigative Dermatology.' Prevention of alopecia areata; Involvement of proteases in pemphigus blistering; Factors responsible for phenotypic conversion of intraepidermal melanocyte.

A better understanding of the neural mechanisms regulating impaired satiety to palatable foods is essential to treat hyperphagia linked with obesity. The satiation hormone amylin signals centrally at multiple nuclei including the ventral tegmental area (VTA). VTA–to–medial prefrontal cortex (mPFC) projections encode food reward information to influence behaviors including impulsivity. We hypothesized that modulation of VTA-to-mPFC neurons underlies amylin-mediated decreases in palatable food-motivated behaviors. We used a variety of pharmacological, behavioral, genetic, and viral approaches (n = 4–16/experiment) to investigate the anatomical and functional circuitry of amylin-controlled VTA-to-mPFC signaling in rats. To first establish that VTA amylin receptor (calcitonin receptor) activation can modulate mPFC activity, we showed that intra-VTA amylin decreased food-evoked mPFC cFos. VTA amylin delivery also attenuated food-directed impulsive behavior, implicating VTA amylin signaling as a regulator of mPFC functions. Palatable food activates VTA dopamine and mPFC neurons. Accordingly, dopamine receptor agonism in the mPFC blocked the hypophagic effect of intra-VTA amylin, and VTA amylin injection reduced food-evoked phasic dopamine levels in the mPFC, supporting the idea that VTA calcitonin receptor activation decreases dopamine release in the mPFC. Surprisingly, calcitonin receptor expression was not found on VTA-to-mPFC projecting neurons but was instead found on GABAergic (gamma-aminobutyric acidergic) interneurons in the VTA that provide monosynaptic inputs to this pathway. Blocking intra-VTA GABA signaling, through GABA receptor antagonists and DREADD (designer receptor exclusively activated by designer drugs)–mediated GABAergic neuronal silencing, attenuated intra-VTA amylin-induced hypophagia. These results indicate that VTA amylin signaling stimulates GABA-mediated inhibition of dopaminergic projections to the mPFC to mitigate impulsive consumption of palatable foods. [ABSTRACT FROM AUTHOR]

The mechanism of action of botulinum neurotoxin type A (BoNT/A) is well characterized, but some published evidence suggests the potential for neuronal retrograde transport and cell-to-cell transfer (transcytosis) under certain experimental conditions. The present study evaluated the potential for these processes using a highly selective antibody for the BoNT/A-cleaved substrate (SNAP25 197 ) combined with 3-dimensional imaging. SNAP25 197 was characterized in a rat motor neuron (MN) pathway following toxin intramuscular injections at various doses to determine whether SNAP25 197 is confined to MNs or also found in neighboring cells or nerve fibers within spinal cord (SC). Results demonstrated that SNAP25 197 immuno-reactive staining was colocalized with biomarkers for MNs, but not with markers for neighboring neurons, nerve fibers or glial cells. Additionally, a high dose of BoNT/A, but not a lower dose, resulted in sporadic SNAP25 197 signal in distal muscles and associated SC regions without evidence for transcytosis, suggesting that the staining was due to systemic spread of the toxin. Despite this spread, functional effects were not detected in the distal muscles. Therefore, under the present experimental conditions, our results suggest that BoNT/A is confined to MNs and any evidence of distal activity is due to limited systemic spread of the toxin at higher doses and not through transcytosis within SC. Lastly, at higher doses of BoNT/A, SNAP25 197 was expressed throughout MNs and colocalized with synaptic markers on the plasma membrane at 6 days post-treatment. These data support previous studies suggesting that SNAP25 197 may be incorporated into SNARE-protein complexes within the affected MNs. [ABSTRACT FROM AUTHOR]

• Acute water deprivation did not alter sensitivity to brain stimulation reward (BSR). • Chemogenetic activation of glutamatergic neurons in SFO also did not alter BSR sensitivity. • In contrast, chronic 5-day water restriction reduced sensitivity to BSR. • Prolonged water restriction may alter sensitivity to other reward-seeking behaviors. States of physiological need motivate individuals to seek and consume stimuli that restore homeostatic balance. This goal-directed behavior is driven, in part, by pathways that process reward and are sensitive to changes in physiological state, including the mesolimbic dopamine system. The effects of hunger and its physiological markers have been more widely studied for their role in modulating reward signaling pathways. However, fluid need produces robust goal-directed behavior and has also been shown to affect neural substrates of reward processing. To test how acute and chronic states of thirst might alter reward sensitivity, we used the intracranial self-stimulation (ICSS) rate-frequency paradigm (Carlezon & Chartoff, 2007) with male and female Long Evans rats. We hypothesized that sensitivity to ICSS would increase under an acute need state for water and would decrease under chronic deprivation. We found that acute water deprivation for 22-hours prior to the ICSS session did not alter any parameters of reward sensitivity. To elicit motivated behavior toward water in the absence of physiological need, we chemogenetically activated glutamatergic neurons of the subfornical organ (SFO). Despite eliciting more water consumption than acute deprivation, acute chemogenetic activation of SFO neurons also did not alter reward sensitivity. Finally, subjects underwent a five-day chronic water restriction protocol with daily ICSS sessions to determine the effects of sustained physiological need. Chronic water restriction resulted in reduced sensitivity to ICSS. Together, these results indicate that persistent changes in physiological state alter the responsiveness of reward circuitry that could potentially exacerbate maladaptive reward-seeking behaviors. [ABSTRACT FROM AUTHOR]

Background: OnabotulinumtoxinA for the treatment of facial lines is a widely used cosmetic medical procedure and, as such, the safety and tolerability profile is of interest to health care providers and patients. Based on data from individual studies that were conducted according to regulatory guidelines to provide adequate safety and efficacy data to support product licensure (registration studies), the overall benefit:risk profile of onabotulinumtoxinA for facial lines has been favorable. Objective: Our objective was to increase statistical power through meta-analysis to detect treatment group differences in adverse event (AE) incidence that may not have been evident in individual registration studies. Methods: Individual participant data (n = 1678) were from 6 randomized, double-blind, placebo-controlled and 3 open-label studies. Two double-blind, placebo-controlled studies were for lateral canthal lines (3-18 U/side) and all others were for glabellar lines (10 or 20 U). Doses used reflect global product labeling in countries where licensed. Results: Participant population was non-Hispanic white (43%) or Asian (52%) and predominantly female (88%). In double-blind, placebo-controlled studies, overall AE incidence did not significantly differ by treatment group (onabotulinumtoxinA vs placebo). The only individual AEs with significantly greater incidence in the onabotulinumtoxinA group were eyelid sensory disorder (2.5% vs 0.3%, P = .004; verbatim phrases “tight,” “pressured,” “heavy,” “drooping feeling,” “feeling of droopiness”) and eyelid ptosis (1.8% vs 0%, P = .02), both present only in glabellar studies. Overall treatment-related (per investigator) AE incidence was greater in the onabotulinumtoxinA group versus placebo (24% vs 16%, P = .005), and treatment-related eyelid edema was an additional AE with significantly higher incidence in the onabotulinumtoxinA group versus placebo (P = .04). Incidence of all 3 of these AEs significantly decreased as number of treatment cycles increased. Eyelid sensory disorder and eyelid edema were more common in Asian participants. Acne, injection site pruritus, oral herpes, rash, lower respiratory tract infection, dental caries, and eye pain were significantly more common in placebo-treated compared with onabotulinumtoxinA-treated participants. Serious AE incidence did not significantly differ by treatment (onabotulinumtoxinA vs placebo) and no serious AEs were treatment related. There were no symptoms of weakness remote to the injection site or related to the central nervous system. Limitations: Limitations included: (1) highly visible efficacy of onabotulinumtoxinA may have resulted in reporting bias; (2) reliance on participant intervisit recall; (3) a relatively short follow-up period (1 year); (4) conclusions are based solely on the doses analyzed (ie, those used in the respective trials); and (5) exclusion of patients with severe medical disease in registration studies. Conclusion: This meta-analysis confirms the safety and tolerability of onabotulinumtoxinA for glabellar and lateral canthal lines, at the doses studied, based on the most comprehensive controlled safety analysis of onabotulinumtoxinA performed to date. The AEs observed were generally mild to moderate; most treatment-related AEs were related either to physical injection of product or local pharmacologic effects. Even with the increased statistical power of a large sample size, no new onabotulinumtoxinA-associated AEs emerged. [Copyright &y& Elsevier]

For over a quarter century, local injections of BoNT have provided clinical benefit for conditions with unmet need, characterized by inappropriately contracting muscles with or without pain or sensory disturbance. Marketing authorization for some BoNT''s, depending on country, include core indications dystonia (blepharospasm and cervical dystonia), large muscle spastic disorders (adult post-stroke spasticity and equinus foot deformity), hyperhidrosis and aesthetics. Subsequent development has extended to primary pain (migraine headache), and neuro-urologic (neurogenic/idiopathic overactive bladder; prostate hypertrophy) with multiple additional opportunities available. Portfolio management requires a careful individual opportunity assessment of scientific and technical aspects (basic science foundation, potential to treat unmet medical need, product-specific risk in specific populations, therapeutic margin/safety profile, probability of successful registration pathway), and potential return on investment (successful subsequent commercialization, competitive environment, synergy with corporate product offerings). A development decision process with specific examples from currently approved and ongoing development targets for BoNT will be discussed. [Copyright &y& Elsevier]

Interactions between grazing animals and vegetation are assessed from three temporal perspectives: millions, thousands and hundreds of years. Data abundance and quality are highest for recent time periods, but geological data provide a background to the understanding of present-day grazing-vegetation interactions. The Quaternary glaciations and recent anthropogenic influences have contributed to the loss of European mega-herbivores. The geological record from the Eemian interglacial in Denmark suggests that presence of elephant and rhinoceros did not create widespread openings in forest cover. Large populations of giant deer in Ireland became extinct 11000 years ago. We propose a theory that the giant deer were sufficiently abundant to convert juniper scrub communities into open grassland at a regional scale. The balance between grazers and browsers has undergone continuous change during the last 10000 years with significant consequences for forest composition and structure. Hunting statistics and archival records permit crude reconstructions of population dynamics for certain ungulate species. High resolution pollen analysis and long-term monitoring generate reconstructions of vegetation that can be compared with fluctuating grazing pressure during the last few hundred years. Such data can be used to validate simulation models of grazing-vegetation interactions. [ABSTRACT FROM AUTHOR]