Now showing items 1-20 of 2022

    • Associations of autozygosity with a broad range of human phenotypes

      Montasser, M.E.; Shuldiner, A.R.; O'connell, J.R (Nature Publishing Group, 2019)
      In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding. Copyright 2019, The Author(s).
    • Individual differences in pain sensitivity are associated with cognitive network functional connectivity following one night of experimental sleep disruption

      Letzen, J.E.; Remeniuk, B.; Smith, M.T.; Finan, P.H.; Seminowicz, D.A. (John Wiley and Sons Inc., 2019)
      Previous work suggests that sleep disruption can contribute to poor pain modulation. Here, we used experimental sleep disruption to examine the relationship between sleep disruption-induced pain sensitivity and functional connectivity (FC) of cognitive networks contributing to pain modulation. Nineteen healthy individuals underwent two counterbalanced experimental sleep conditions for one night each: uninterrupted sleep versus sleep disruption. Following each condition, participants completed functional MRI including a simple motor task and a noxious thermal stimulation task. Pain ratings and stimulus temperatures from the latter task were combined to calculate a pain sensitivity change score following sleep disruption. This change score was used as a predictor of simple motor task FC changes using bilateral executive control networks (RECN, LECN) and the default mode network (DMN) masks as seed regions of interest (ROIs). Increased pain sensitivity after sleep disruption was positively associated with increased RECN FC to ROIs within the DMN and LECN (F(4,14) = 25.28, pFDR = 0.05). However, this pain sensitivity change score did not predict FC changes using LECN and DMN masks as seeds (pFDR > 0.05). Given that only RECN FC was associated with sleep loss-induced hyperalgesia, findings suggest that cognitive networks only partially contribute to the sleep-pain dyad. Copyright 2019 The Authors.
    • CCR5 receptor antagonism inhibits hepatitis C virus (HCV) replication in vitro

      Blackard, J.T.; Kong, L.; Kottilil, S. (Public Library of Science, 2019)
      Background and aim The hepatitis C virus (HCV) is a single-strand RNA virus that infects millions of people worldwide. Recent advances in therapy have led to viral cure using two- and three- drug combinations of direct acting inhibitors of viral replication. CCR5 is a chemokine receptor that is expressed on hepatocytes and represents a key co-receptor for HIV. We evaluated the effect of CCR5 blockade or knockdown on HCV replication in Huh7.5JFH1 cells. Methods Cells were exposed to varying concentrations of maraviroc (CCR5 inhibitor), cenicriviroc (CCR2/CCR5 inhibitor), sofosbuvir (nucleotide polymerase inhibitor), or raltegravir (HIV integrase inhibitor). Results HCV RNA was detected utilizing two qualitative strand-specific RT-PCR assays. HCV core antigen and NS3 protein was quantified in the supernatant and cell lysate, respectively. siRNA was utilized to knockdown CCR5 gene expression in hepatocytes. Alternatively, anti-CCR5 antibodies were employed to block the receptor. Supernatant levels of HCV RNA (expressed as fold change) were not reduced in the presence of raltegravir but were reduced 8.55-fold and 12.42-fold with cenicriviroc and maraviroc, respectively. Sofosbuvir resulted in a 16.20- fold change in HCV RNA levels. HCV core and NS3 protein production was also reduced in a dose-dependent manner. Two distinct anti-CCR5 antibodies also resulted in a significant reduction in HCV protein expression, as did siRNA knockdown of CCR5 gene expression. Conclusions These data provide evidence that CCR5 modulation could have a significant effect on HCV replication in an in vitro system. Further evaluation of the role of CCR5 inhibition in clinical settings may be warranted. Copyright 2019 Blackard et al.
    • Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

      Adhikari, B.M.; Ryan, M.C.; Hong, L.E. (John Wiley and Sons Inc., 2019)
      Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10−3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = −.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug. Copyright 2019 The Authors.
    • Pancreatic ductal adenocarcinoma: Machine learning-based quantitative computed tomography texture analysis for prediction of histopathological grade

      Qiu, W.; Wang, Z.; Chen, R. (Dove Medical Press Ltd, 2019)
      Purpose: To assess the performance of combining computed tomography (CT) texture analysis with machine learning for discriminating different histopathological grades of pancreatic ductal adenocarcinoma (PDAC). Methods: From July 2012 to August 2017, this retrospective study comprised 56 patients with confirmed histopathological PDAC (32 men, 24 women, mean age 64.04±7.82 years) who had undergone preoperative contrast-enhanced CT imaging within 1 month before surgery. Two radiologists blinded to the histopathological outcome independently segmented lesions for quantitative texture analysis. Histogram features, co-occurrence, and run-length texture were calculated. A support-vector machine was constructed to predict the pathological grade of PDAC based on preoperative texture features. Results: Pathological analysis confirmed 37 low-grade PDAC (five well-differentiated/grade I and 32 moderately differentiated/grade II) and 19 high-grade PDAC (19 poorly differentiated/grade III) tumors. There were no significant differences in clinical or biological characteristics between patients with high-grade and low-grade tumors (P>0.05). There were significant differences between low-grade PDAC and high-grade PDAC on nine histogram features, seven run-length features, and two co-occurrence features. Cluster shade was the most important predictor (sensitivity 0.315). Using these texture features, the support-vector machine achieved 86% accuracy, 78% sensitivity, 95% and specificity. Conclusion: Machine learning-based CT texture analysis accurately predicted histopathological differentiation grade of PDAC based on preoperative texture features, leading to maximization patient survival and achievement of personalized precision treatment. Copyright 2019 Qiu et al.
    • Clinical predictors of delayed engraftment in autologous hematopoietic cell transplant recipients

      Lutfi, F.; Skelton IV, W.P.; Wang, Y. (King Faisal Specialist Hospital and Research Centre, 2019)
      Objective/background: Clinical predictors of delayed engraftment following autologous hematopoietic cell transplantation (AHCT) are poorly described in the literature. The purpose of this study was to identify pretransplant characteristics contributing to delayed engraftment (DE) following AHCT. Methods: A retrospective, single institution study of 1162 consecutive patients undergoing AHCT from January 1996 to August 2016 was studied for DE. DE was defined as platelet count ≤ 50,000/µl, hemoglobin ≤ 8 g/dL, or absolute neutrophil count ≤ 1000/mm3. Results: Of the 1162 AHCT recipients, 263 (22.6%) were identified as having DE at 30-days post-AHCT with 80.0% being solely due to delayed platelet engraftment. Patients with Non-Hodgkin lymphoma (NHL) represented 18% of the original cohort, but accounted for 45% of those with DE, whereas multiple myeloma patients represented 59% of the initial cohort, but only 29% of those that had DE. At 3 months post-AHCT, transfusion dependence (p = .0083) prior to AHCT, low-infused CD34+ cell dose < 3 × 106/kg (p = .0012), and low preAHCT platelet count < 150 × 103/µL (p = .0027) were significantly associated with delayed engraftment. Conclusion: Transfusion dependence prior to AHCT, pre-AHCT platelet count, and CD34+ cell dose were the strongest predictors of delayed engraftment in patients undergoing AHCT.
    • T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

      Paluskievicz, C.M.; Cao, X.; Zheng, P.; Liu, Y.; Bromberg, J.S. (Frontiers, 2019)
      Treg play a central role in maintenance of self tolerance and homeostasis through suppression of self-reactive T cell populations. In addition to that role, Treg also survey cancers and suppress anti-tumor immune responses. Thus, understanding the unique attributes of Treg-tumor interactions may permit control of this pathologic suppression without interfering with homeostatic self-tolerance. This review will define the unique role of Treg in cancer growth, and the ways by which Treg inhibit a robust anti-tumor immune response. There will be specific focus placed on Treg homing to the tumor microenvironment (TME), TME formation of induced Treg (iTreg), mechanisms of suppression that underpin cancer immune escape, and trophic nonimmunologic effects of Treg on tumor cells. Copyright Copyright 2019 Paluskievicz, Cao, Abdi, Zheng, Liu and Bromberg.
    • Novel activators and small-molecule inhibitors of STAT3 in cancer

      Yang, L.; Lin, S.; Xu, L. (Elsevier Ltd, 2019)
      Excessive activation of signal transducer and activator of transcription 3 (STAT3) signaling is observed in a subset of many cancers, making activated STAT3 a highly promising potential therapeutic target supported by multiple preclinical and clinical studies. However, early-phase clinical trials have produced mixed results with STAT3-targeted cancer therapies, revealing substantial complexity to targeting aberrant STAT3 signaling. This review discusses the diverse mechanisms of oncogenic activation of STAT3, and the small molecule inhibitors of STAT3 in cancer treatment. Copyright 2019 The Authors
    • Galeterone and the next generation galeterone analogs, VNPP414 and VNPP433-3β exert potent therapeutic effects in castration-/drug-resistant prostate cancer preclinical models in vitro and in vivo

      Kwegyir-Afful, A.K.; Ramalingam, S.; Ramamurthy, V.P.; Purushottamachar, P.; Murigi, F.N.; Huang, W.; Kane, M.A.; Zhang, Y.; Ambulos, N.; Hussain, A.; et al. (MDPI AG, 2019)
      These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT). In addition, Gal/NGGAs (alone or in combination) also inhibited the growth of ENZ-, docetaxel-, and mitoxantrone-resistant human PC cell lines. The NGGAs exhibited improved pharmacokinetic profiles over Gal in mice. Importantly, in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than Gal) markedly suppressed (84% vs. Gal, 47%; p < 0.01) the growth of castration-resistant PC (CRPC) CWR22Rv1 xenograft tumors, with no apparent host toxicity. ENZ was ineffective in this CRPC xenograft model. In summary, our findings show that targeting AR/AR-V7 and Mnk1/2 for degradation represents an effective therapeutic strategy for PC/CRPC treatment and supports further development of VNPP433-3β towards clinical investigation. Copyright 2019 by the authors.
    • Thyroid Storm with Multiorgan Failure Treated with Plasmapheresis

      Miller, A.; Silver, K.D. (Hindawi Limited, 2019)
      Background. Thyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. First line treatment of thyroid storm is directed towards decreasing thyroid hormone production and peripheral conversion of T4 to T3, and treating adrenergic symptoms. When medical therapy fails, plasmapheresis is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis. Case. A 50-year-old male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to another hospital with fever and altered mentation. He was found to have pneumonia on imaging and was started on antibiotics. He developed shock complicated by atrial fibrillation with rapid ventricular rate which was treated with amiodarone. He was transferred to our hospital for further management. On arrival, TSH was <0.01 mIU/L, free T4 was >7 ng/dL and total T3 was 358 ng/dL. The endocrinology team determined he was in thyroid storm. His medical treatment of thyroid storm was aggressively titrated to maximal therapy. His hospital course was complicated by transaminitis, respiratory failure requiring intubation, shock requiring vasopressor support, kidney failure requiring continuous renal replacement therapy, and heart failure. Despite maximal anti-thyroid therapy, he had not improved clinically and T4 and T3 remained markedly elevated. A 4-day course of plasmapheresis was initiated resulting in marked lowering of T4 and T3 and clinical stability. Conclusion. While current guidelines for plasmapheresis for thyroid storm recommend individualized decision making, no further clarification is provided on who would be a good candidate for the procedure. We present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis after failing maximal medical therapy. Given the significant improvement seen with plasmapheresis, endocrinologists should consider this mode of treatment earlier in the course of thyroid storm when patients are not improving with medical therapy alone. Copyright 2019 Ann Miller and Kristi D. Silver.
    • Myelin pathology: Involvement of molecular chaperones and the promise of chaperonotherapy

      Scalia, F.; De, Macario, E.C.; Macario, A.J.L. (MDPI AG, 2019)
      The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment. Copyright 2019 by the authors.
    • Prevalence and factors associated with hypertension among adults in rural Sylhet district of Bangladesh: a cross-sectional study

      Khanam, R.; Ahmed, S.; Kibria, G.M.A. (BMJ Publishing Group, 2019)
      Objectives Low-income and middle-income countries are undergoing epidemiological transition, however, progression is varied. Bangladesh is simultaneously experiencing continuing burden of communicable diseases and emerging burden of non-communicable diseases (NCDs). For effective use of limited resources, an increased understanding of the shifting burden and better characterisation of risk factors of NCDs, including hypertension is needed. This study provides data on prevalence and factors associated with hypertension among males and females 35 years and older in rural Bangladesh. Methods This is a population-based cross-sectional study conducted in Zakiganj and Kanaighat subdistricts of Sylhet district of Bangladesh. Blood pressure was measured and data on risk factors were collected using STEPS instrument from 864 males and 946 females aged 35 years and older between August 2017 and January 2018. Individuals with systolic blood pressure of ?140 mm Hg or diastolic blood pressure of ?90 mm Hg or taking antihypertensive drugs were considered hypertensive. Bivariate and multivariate analyses were performed to identify factors associated with hypertension. Results The prevalence of hypertension was 18.8% (95% CI 16.3 to 21.5) and 18.7% (95% CI 16.3 to 21.3) in adult males and females, respectively. Among those who were hypertensive, the prevalence of controlled, uncontrolled and unaware/newly identified hypertension was 23.5%, 25.9% and 50.6%, respectively among males and 38.4%, 22.6% and 39.0%, respectively among females. Another 22.7% males and 17.8% females had prehypertension. Increasing age and higher waist circumference (?90 cm for males and ?80 cm for females) were positively associated with hypertension both in males (OR 4.0, 95% CI 2.5 to 6.4) and females (OR 2.8, 95% CI 2.0 to 4.1). Conclusions In view of the high burden of hypertension and prehypertension, a context-specific scalable public health programme including behaviour change communications, particularly to increase physical activity and consumption of healthy diet, as well as identification and management of hypertension needs to be developed and implemented. Copyright Author(s) (or their employer(s)) 2019.
    • Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion

      Nakamura, Y.; Dryanovski, D.I.; Covey, D.P. (eLife Sciences Publications Ltd, 2019)
      Cocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine causes dissociation of the Sig-1R from ADP-ribosylation factor (ARF6), a G-protein regulating EV trafficking, leading to activation of myosin light chain kinase (MLCK). Blockade of Sig-1R function, or inhibition of ARF6 or MLCK also prevented cocaine-induced EV release and cocaine-stimulated 2-AG-modulation of inhibitory synapses in DA neurons. Our results implicate the Sig-1R-ARF6 complex in control of EV release and demonstrate that cocaine-mediated 2-AG release can occur via EVs.
    • The Dissociative Subtype of PTSD Interview (DSP-I): Development and Psychometric Properties

      Eidhof, M.B.; ter Heide, F.J.J.; Loewenstein, R.J. (Routledge, 2019)
      The inclusion of the dissociative subtype of post-traumatic stress disorder (PTSD-DS) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) reflects the importance of assessing PTSD-DS. We developed the Dissociative Subtype of PTSD Interview (DSP-I). This clinician-administered instrument assesses the presence and severity of PTSD-DS (i.e., symptoms of depersonalization or derealization) and contains a supplementary checklist that enables assessment and differentiation of other trauma-related dissociative symptoms (i.e., blanking out, emotional numbing, alterations in sensory perception, amnesia, and identity confusion). The psychometric properties were tested in 131 treatment-seeking individuals with PTSD and histories of multiple trauma, 17.6 % of whom met criteria for PTSD-DS in accordance with the DSP-I. The checklist was tested in 275 treatment-seeking individuals. Results showed the DSP-I to have high internal consistency, good convergent validity with PTSD-DS items of the CAPS-5, and good divergent validity with scales of somatization, anxiety and depression. The depersonalization and derealization scales were highly associated. Moreover, the DSP-I accounted for an additional variance in PTSD severity scores of 8% over and above the CAPS-5 and number of traumatic experiences. The dissociative experiences of the checklist were more strongly associated with scales of overall distress, somatization, depression, and anxiety than scales of depersonalization and derealization. In conclusion, the DSP-I appears to be a clinically relevant and psychometrically sound instrument that is valuable for use in clinical and research settings. Copyright 2019 The Author(s).
    • Complete Genome Sequence of wAna, the Wolbachia Endosymbiont of Drosophila ananassae

      Gasser, M.T.; Chung, M.; Bromley, R.E.; Nadendla, S.; Dunning Hotopp, J.C. (American Society for Microbiology, 2019)
      Here, we present the complete genome sequence of the Wolbachia endosymbiont wAna, isolated from Drosophila ananassae and derived from Oxford Nanopore and Illumina sequencing. We anticipate that this will aid in Wolbachia comparative genomics and the assembly of D. ananassae specifically in regions containing extensive lateral gene transfer events. Copyright 2019 Gasser et al.
    • Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

      Halperin, Kuhns, V.L.; Lewis, R.M.; Ryan, K.A.; O'Connell, J.R.; Woodward, O.M. (Nature Publishing Group, 2019)
      Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits. Copyright 2019, The Author(s).
    • Toward the elimination of bias in Pediatric Research

      Bearer, C.; Agostoni, C.; Czinn, S.J.; EL-Khuffash, A. (Nature Publishing Group, 2019)
    • Short- and Long-Term Antidepressant Clinical Trials for Major Depressive Disorder in Youth: Findings and Concerns

      Safer, D.J.; Zito, J.M. (Frontiers Media S.A., 2019)
      The diagnosis of major depressive disorder (MDD) in U.S. youth is increasing as is the rate of antidepressant medication (ADM) treatment for the disorder. Fluoxetine and escitalopram are FDA approved for the short term and maintenance treatment of MDD in youth. Placebo-controlled short-term ADM trials represent the basis for Food and Drug Administration (FDA) approval. Meta-analyses in 2007 and 2016 revealed that short-term ADM treatment of youth diagnosed with MDD resulted in no meaningful benefit for children and only marginal benefit for adolescents. Placebo substitution trials of ADM short-term responders represent the basis for FDA approval of ADM maintenance treatment. These ADM placebo substitution maintenance trials for youth with MDD are characterized by high dropout rates, a rapid withdrawal that often can follow the switch to placebo, and relapse rates that are not dissimilar from those in the natural course of the disorder. Without the evidence from problematic ADM placebo substitution trials, there is no acceptable support for the inclusion of ADM in maintenance treatment for MDD in youth. Copyright 2019 Safer and Zito.
    • Differential mitochondrial morphology in ventral striatal projection neuron subtypes

      Chandra, R.; Calarco, C.A.; Lobo, M.K. (John Wiley and Sons Inc., 2019)
      The two striatal projection neuron subtypes (medium spiny neurons- MSNs), those enriched in dopamine receptor 1 versus 2 (D1-MSNs and D2-MSNs), display dichotomous properties at the level of the transcriptome, projections, morphology, and electrophysiology. Recent work illustrates dichotomous mitochondrial length in NAc MSN subtype dendrites after cocaine self-administration, with a shift toward smaller mitochondria, due to enhanced fission, occurring in D1-MSN dendrites and a shift toward larger mitochondria in D2-MSN dendrites. However, to date there has been no comparison of mitochondrial morphological properties between MSN subtypes. In this study, we examine mitochondrial morphology in NAc D1-MSNs versus D2-MSNs. We observe an increase in the frequency of smaller length mitochondria in D2-MSN dendrites relative to D1-MSN dendrites, while D1-MSN dendrites display an increase in larger length mitochondria. The differences in mitochondrial length occur in both NAc core and shell, although to a greater extent in NAc core. Finally, we demonstrate that the mitochondrial fusion molecule, Opa1, is differentially expressed in NAc MSN subtypes, with D1-MSNs displaying higher expression of Opa1 ribosome-associated mRNA. The difference in Opa1 levels may account for the bias toward enhanced smaller mitochondria in D2-MSNs and enhanced larger mitochondria in D1-MSNs. Collectively, our study demonstrates differential mitochondrial size and a potential molecular mediator of these mitochondrial differences in NAc MSN subtypes.
    • High-efficiency, high-flux in-line hemofiltration using a high blood flow extracorporeal circuit

      Grazioli, A.; Rabin, J.; Madathil, R.J.; King, J.D.; DiChiacchio, L.; Rector, R.P.; Deatrick, K.B.; Wu, Z.J.; Herr, D.L. (SAGE Publications Ltd, 2019)
      The ability of current renal replacement therapy modalities to achieve rapid solute removal is limited by membrane surface area and blood flow rate. Extracorporeal membrane oxygenation offers high blood flow and hemodynamic support that may be harnessed to overcome limitations in traditional renal replacement therapy. Using an extracorporeal membrane oxygenation circuit, we describe a high blood flow, high-efficiency hemofiltration technique using in-line hemofilters (hemoconcentrators) and standard replacement fluid to enhance solute clearance. Using this approach and a total of 5 L of replacement volume per treatment, creatinine (Cr) clearances of 8.3 L/hour and 11.2 L/hour using one and two hemoconcentrators, respectively, were achieved. With use of a high blood flow rate of up to 5 L/min, this hemofiltration technique can potentially offer clearance of 30 times that of continuous renal replacement therapy and of 6 times that of hemodialysis which may expand the ability to remove substances traditionally not considered removable via existing extracorporeal therapies. Copyright The Author(s) 2019.