UW Neurological Surgery Recent PubMed Publications

Chlamydia muridarum Genital and Gastrointestinal Infection Tropism Is Mediated by Distinct Chromosomal Factors.

Infect Immun. 2018 07;86(7):

Authors: Morrison SG, Giebel AM, Toh EC, Spencer HJ, Nelson DE, Morrison RP

Abstract
Some members of the genus Chlamydia, including the human pathogen Chlamydia trachomatis, infect multiple tissues, including the genital and gastrointestinal (GI) tracts. However, it is unknown if bacterial targeting to these sites is mediated by multifunctional or distinct chlamydial factors. We previously showed that disruption of individual large clostridial toxin homologs encoded within the Chlamydia muridarum plasticity zone were not critical for murine genital tract infection. Here, we assessed whether cytotoxin genes contribute to C. muridarum GI tropism. Infectivity and shedding of wild-type (WT) C. muridarum and three mutants containing nonsense mutations in different cytotoxin genes, tc0437, tc0438, and tc0439, were compared in mouse genital and GI infection models. One mutant, which had a nonsense mutation in tc0439, was highly attenuated for GI infection and had a GI 50% infectious dose (ID50) that was 1,000 times greater than that of the WT. GI inoculation with this mutant failed to elicit anti-chlamydial antibodies or to protect against subsequent genital tract infection. Genome sequencing of the tc0439 mutant revealed additional chromosomal mutations, and phenotyping of additional mutants suggested that the GI attenuation might be linked to a nonsense mutation in tc0600 The molecular mechanism underlying this dramatic difference in tissue-tropic virulence is not fully understood. However, isolation of these mutants demonstrates that distinct chlamydial chromosomal factors mediate chlamydial tissue tropism and provides a basis for vaccine initiatives to isolate chlamydia strains that are attenuated for genital infection but retain the ability to colonize the GI tract and elicit protective immune responses.

PMID: 29661932 [PubMed - indexed for MEDLINE]

Functions of CaBP1 and CaBP2 in the peripheral auditory system.

Hear Res. 2018 07;364:48-58

Authors: Yang T, Hu N, Pangršič T, Green S, Hansen M, Lee A

Abstract
CaBPs are a family of Ca2+ binding proteins related to calmodulin. Two CaBP family members, CaBP1 and CaBP2, are highly expressed in the cochlea. Here, we investigated the significance of CaBP1 and CaBP2 for hearing in mice lacking expression of these proteins (CaBP1 KO and CaBP2 KO) using auditory brain responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). In CaBP1 KO mice, ABR wave I was larger in amplitude, and shorter in latency and faster in decay, suggestive of enhanced synchrony of auditory nerve fibers. This interpretation was supported by the greater excitability of CaBP1 KO than WT neurons in whole-cell patch clamp recordings of spiral ganglion neurons in culture, and normal presynaptic function of CaBP1 KO IHCs. DPOAEs and ABR thresholds were normal in 4-week old CaBP1 KO mice, but elevated ABR thresholds became evident at 32 kHz at 9 weeks, and at 8 and 16 kHz by 6 months of age. In contrast, CaBP2 KO mice exhibited significant ABR threshold elevations at 4 weeks of age that became more severe in the mid-frequency range by 9 weeks. Though normal at 4 weeks, DPOAEs in CaBP2 KO mice were significantly reduced in the mid-frequency range by 9 weeks. Our results reveal requirements for CaBP1 and CaBP2 in the peripheral auditory system and highlight the diverse modes by which CaBPs influence sensory processing.

PMID: 29661613 [PubMed - indexed for MEDLINE]

Ca2+-Binding Protein 1 Regulates Hippocampal-dependent Memory and Synaptic Plasticity.

Neuroscience. 2018 06 01;380:90-102

Authors: Yang T, Britt JK, Cintrón-Pérez CJ, Vázquez-Rosa E, Tobin KV, Stalker G, Hardie J, Taugher RJ, Wemmie J, Pieper AA, Lee A

Abstract
Ca2+-binding protein 1 (CaBP1) is a Ca2+-sensing protein similar to calmodulin that potently regulates voltage-gated Ca2+ channels. Unlike calmodulin, however, CaBP1 is mainly expressed in neuronal cell-types and enriched in the hippocampus, where its function is unknown. Here, we investigated the role of CaBP1 in hippocampal-dependent behaviors using mice lacking expression of CaBP1 (C-KO). By western blot, the largest CaBP1 splice variant, caldendrin, was detected in hippocampal lysates from wild-type (WT) but not C-KO mice. Compared to WT mice, C-KO mice exhibited mild deficits in spatial learning and memory in both the Barnes maze and in Morris water maze reversal learning. In contextual but not cued fear-conditioning assays, C-KO mice showed greater freezing responses than WT mice. In addition, the number of adult-born neurons in the hippocampus of C-KO mice was ∼40% of that in WT mice, as measured by bromodeoxyuridine labeling. Moreover, hippocampal long-term potentiation was significantly reduced in C-KO mice. We conclude that CaBP1 is required for cellular mechanisms underlying optimal encoding of hippocampal-dependent spatial and fear-related memories.

PMID: 29660444 [PubMed - indexed for MEDLINE]

Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels.

J Neurosci. 2018 05 02;38(18):4430-4440

Authors: Nanou E, Lee A, Catterall WA

Abstract
Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca2+) channel type 2.1 (CaV2.1) by neuronal Ca2+ sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in CaV2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of CaV2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of CaV2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice.SIGNIFICANCE STATEMENT Many forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca2+ (CaV) channels. Regulation of CaV2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of CaV2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with CaV2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits.

PMID: 29654190 [PubMed - indexed for MEDLINE]

Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-β signaling.

Proc Natl Acad Sci U S A. 2018 05 01;115(18):E4245-E4254

Authors: Tsai YL, Ha DP, Zhao H, Carlos AJ, Wei S, Pun TK, Wu K, Zandi E, Kelly K, Lee AS

Abstract
The discovery that endoplasmic reticulum (ER) luminal chaperones such as GRP78/BiP can escape to the cell surface upon ER stress where they regulate cell signaling, proliferation, apoptosis, and immunity represents a paradigm shift. Toward deciphering the mechanisms, we report here that, upon ER stress, IRE1α binds to and triggers tyrosine kinase SRC activation, leading to ASAP1 phosphorylation and Golgi accumulation of ASAP1 and Arf1-GTP, resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. At the cell surface, GRP78 binds to and acts in concert with a glycosylphosphatidylinositol-anchored protein, CD109, in blocking TGF-β signaling by promoting the routing of the TGF-β receptor to the caveolae, thereby disrupting its binding to and activation of Smad2. Collectively, we uncover a SRC-mediated signaling cascade that leads to the relocalization of ER chaperones to the cell surface and a mechanism whereby GRP78 counteracts the tumor-suppressor effect of TGF-β.

PMID: 29654145 [PubMed - indexed for MEDLINE]

Intra-session and Inter-day Reliability of the Myon 320 Electromyography System During Sub-maximal Contractions.

Front Physiol. 2018;9:309

Authors: Sorbie GG, Williams MJ, Boyle DW, Gray A, Brouner J, Gibson N, Baker JS, Easton C, Ugbolue UC

Abstract
Electromyography systems are widely used within the field of scientific and clinical practices. The reliability of these systems are paramount when conducting research. The reliability of Myon 320 Surface Electromyography System is yet to be determined. This study aims to determine the intra-session and inter-day reliability of the Myon 320 Surface Electromyography System. Muscle activity from fifteen participants was measured at the anterior deltoid muscle during a bilateral front raise exercise, the vastus lateralis muscle during a squat exercise and the extensor carpi radialis brevis (ECRB) muscle during an isometric handgrip task. Intra-session and inter-day reliability was calculated by intraclass correlation coefficient, standard error of measurement and coefficient of variation (CV). The normalized root mean squared (RMS) surface electromyographic signals produced good intra-session and inter-day testing intraclass correlation coefficient values (range: 0.63-0.97) together with low standard error of measurement (range: 1.49-2.32) and CV (range: 95% Confidence Interval = 0.36-12.71) measures for the dynamic-and-isometric contractions. The findings indicate that the Myon 320 Surface Electromyography System produces good to fair reliability when examining intra-session and inter-day reliability. Findings of the study provide evidence of the reliability of electromyography between trials which is essential during clinical testing.

PMID: 29651252 [PubMed]

Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma.

Genes Dev. 2018 04 01;32(7-8):512-523

Authors: Cimino PJ, Kim Y, Wu HJ, Alexander J, Wirsching HG, Szulzewsky F, Pitter K, Ozawa T, Wang J, Vazquez J, Arora S, Rabadan R, Levine R, Michor F, Holland EC

Abstract
Glioblastoma is the most frequently occurring and invariably fatal primary brain tumor in adults. The vast majority of glioblastomas is characterized by chromosomal copy number alterations, including gain of whole chromosome 7 and loss of whole chromosome 10. Gain of whole chromosome 7 is an early event in gliomagenesis that occurs in proneural-like precursor cells, which give rise to all isocitrate dehydrogenase (IDH) wild-type glioblastoma transcriptional subtypes. Platelet-derived growth factor A (PDGFA) is one gene on chromosome 7 known to drive gliomagenesis, but, given its location near the end of 7p, there are likely several other genes located along chromosome 7 that select for its increased whole-chromosome copy number within glioblastoma cells. To identify other potential genes that could select for gain of whole chromosome 7, we developed an unbiased bioinformatics approach that identified homeobox A5 (HOXA5) as a gene whose expression correlated with gain of chromosome 7 and a more aggressive phenotype of the resulting glioma. High expression of HOXA5 in glioblastoma was associated with a proneural gene expression pattern and decreased overall survival in both human proneural and PDGF-driven mouse glioblastoma. Furthermore, HOXA5 overexpression promoted cellular proliferation and potentiated radioresistance. We also found enrichment of HOXA5 expression in recurrent human and mouse glioblastoma at first recurrence after radiotherapy. Overall, this study implicates HOXA5 as a chromosome 7-associated gene-level locus that promotes selection for gain of whole chromosome 7 and an aggressive phenotype in glioblastoma.

PMID: 29632085 [PubMed - indexed for MEDLINE]

Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats.

Neurotoxicol Teratol. 2018 May - Jun;67:50-64

Authors: Sprowles JLN, Amos-Kroohs RM, Braun AA, Sugimoto C, Vorhees CV, Williams MT

Abstract
Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES households experience more stress and are more likely to be exposed to environmental neurotoxins such as lead (Pb) and manganese (Mn) than children in higher SES households. Co-exposure to stress, Pb, and Mn during early development may increase the risk of central nervous system dysfunction compared with unexposed children. To investigate the potential interaction of these factors, Sprague-Dawley rats were bred, and litters born in-house were culled on postnatal day (P)1 to 6 males and 6 females. One male and female within each litter were assigned to one of the following groups: 0 (vehicle), 10 mg/kg Pb, 100 mg/kg Mn, or 10 mg/kg Pb + 100 mg/kg Mn (PbMn), water gavage, and handled only from P4-28 with half the litters reared in cages with standard bedding (29 litters) and half with no bedding (Barren; 27 litters). Mn and PbMn groups had decreased anxiety, reduced acoustic startle, initial open-field hypoactivity, increased activity following (+)-methamphetamine, deficits in egocentric learning in the Cincinnati water maze (CWM), and deficits in latent inhibition conditioning. Pb increased anxiety and reduced open-field activity. Barren-reared rats had decreased anxiety, CWM deficits, increased startle, and initial open-field hyperactivity. Mn, PbMn, Pb Barren-reared groups had impaired Morris water maze performance. Pb altered neostriatal serotonin and norepinephrine, Mn increased hippocampal serotonin in males, Mn + Barren-rearing increased neostriatal serotonin, and Barren-rearing decreased neostriatal dopamine in males. At the doses used here, most effects were in the Mn and PbMn groups. Few interactions between Mn, Pb, and rearing stress were found, indicating that the interaction of these three variables is not as impactful as hypothesized.

PMID: 29631003 [PubMed - indexed for MEDLINE]

Shifting the treatment model for resectable pancreatic cancer.

Lancet Gastroenterol Hepatol. 2018 06;3(6):375-376

Authors: Ko AH

PMID: 29625842 [PubMed - indexed for MEDLINE]

The solution structure of monomeric CCL5 in complex with a doubly sulfated N-terminal segment of CCR5.

FEBS J. 2018 06;285(11):1988-2003

Authors: Abayev M, Rodrigues JPGLM, Srivastava G, Arshava B, Jaremko Ł, Jaremko M, Naider F, Levitt M, Anglister J

Abstract
The inflammatory chemokine CCL5, which binds the chemokine receptor CCR5 in a two-step mechanism so as to activate signaling pathways in hematopoetic cells, plays an important role in immune surveillance, inflammation, and development as well as in several immune system pathologies. The recently published crystal structure of CCR5 bound to a high-affinity variant of CCL5 lacks the N-terminal segment of the receptor that is post-translationally sulfated and is known to be important for high-affinity binding. Here, we report the NMR solution structure of monomeric CCL5 bound to a synthetic doubly sulfated peptide corresponding to the missing first 27 residues of CCR5. Our structures show that two sulfated tyrosine residues, sY10 and sY14, as well as the unsulfated Y15 form a network of strong interactions with a groove on a surface of CCL5 that is formed from evolutionarily conserved basic and hydrophobic amino acids. We then use our NMR structures, in combination with available crystal data, to create an atomic model of full-length wild-type CCR5:CCL5. Our findings reveal the structural determinants involved in the recognition of CCL5 by the CCR5 N terminus. These findings, together with existing structural data, provide a complete structural framework with which to understand the specificity of receptor:chemokine interactions.
DATABASE: Structural data are available in the PDB under the accession number 6FGP.

PMID: 29619777 [PubMed - indexed for MEDLINE]

Microsurgical Resection of a Large Intraventricular Trigonal Tumor: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2018 Mar 30;:

Authors: Cheng CY, Shetty R, Sekhar LN

Abstract
A 62-yr-old woman presented with incidentally detected left trigonal mass by magnetic resonance imaging (MRI) performed during workup for left-sided hearing loss and vertigo of 5-yr duration. Due to persistent dizziness, headache, and progressive enlargement of the tumor in follow-up scans, operation was planned. Because the tumor extended superiorly, a superior parietal lobule approach was selected.She underwent a left parietal craniotomy. A strip electrode was used to localize the motor and sensory regions, and neuronavigation was used to confirm the entry site. A small transsulcal corticotomy was performed posterior to a large cortical vein. The tumor was pinkish in color with a well-defined capsule. It was centrally debulked by using curettes, pituitary forceps, and the ultrasonic aspirator. Tumoral blood supply from the choroid plexus and the posterior choroidal vessels were cauterized and divided. Additional blood supply coming from the anterior choroidal vessels was also found and cauterized. After circumferential dissection of the tumor capsule, the tumor was removed completely. The pathology indicated WHO Grade I meningioma. The patient had mild expressive and receptive aphasia postoperatively, but improved progressively. The postoperative MRI showed total resection with no evidence of brain injury. At 3-mo follow-up, the speech was normal; she was independent for all daily activities, but had not yet returned to work (Karnofsky score 80).This 3-D video shows the technical nuances of microsurgical resection of an intraventricular tumor through a narrow brain corridor.Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 29618124 [PubMed - as supplied by publisher]

Physician Time Burden Associated with Querying Prescription Drug Monitoring Programs.

Pain Med. 2018 10 01;19(10):1952-1960

Authors: Bachhuber MA, Saloner B, LaRochelle M, Merlin JS, Maughan BC, Polsky D, Shaparin N, Murphy SM

Abstract
Objective: Prescription drug monitoring programs (PDMPs) enable prescribers to review patient prescription histories, and their use is mandatory in many states. We estimated the cost of physicians retrieving PDMP patient reports compared with a model where a delegate (i.e., administrative staff) retrieves reports.
Methods: We performed a cost analysis with a one-year time horizon, from the perspective of physicians' employers. We obtained specialty-specific estimates of controlled substance prescribing frequency from the National Ambulatory Medical Care Survey, 2012-2014. We defined three PDMP usage cases based on the frequency of queries: comprehensive (before every Schedule II-IV controlled substance prescription), selective (before new Schedule II-IV prescriptions and every six months for continuing medications), and minimal (before new Schedule II or III prescriptions and annually for continuing medications).
Results: The delegate model was less costly for all specialties in the comprehensive usage case and most specialties in the selective usage case, and it was similar to physician model costs in the minimal usage case. Estimated annual costs of the physician model to a large health care system (1,000 full-time equivalent physicians) were $1.6 million for comprehensive usage, $1.1 million for selective usage, and $645,313 for minimal usage. The delegate model was less costly in the comprehensive (savings of $907,283) and selective usage cases (savings of $156,216).
Conclusions: Relying on delegates vs physicians to retrieve reports is less costly in most cases. Automation and integration of PDMP data into electronic health records may reduce costs further. Physicians, health care systems, and states should collaborate to streamline access to PDMPs.

PMID: 29618105 [PubMed - indexed for MEDLINE]

Microvascular Decompression of Facial Nerve and Pexy of the Left Vertebral Artery for Left Hemifacial Spasm: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2018 Mar 29;:

Authors: Cheng CY, Shetty R, Martinez V, Sekhar LN

Abstract
A 73-yr-old man presented with intractable left hemifacial spasm of 4 yr duration. Brain magnetic resonance imaging showed significant compression of left facial nerve by the left vertebral artery (VA) and anterior inferior cerebellar artery (AICA).The patient underwent a left retrosigmoid craniotomy and a microvascular decompression of the cranial nerve (CN) VII. Intraoperatively, we found that the distal AICA had a protracted subarcuate extradural course.1 This was relieved by intra/extradural dissection. The left VA and the AICA loop were compressing the root exit zone of CN VII. The VA was mobilized, and pexy into the petrosal dura was done with 8-0 nylon sutures (Ethilon Nylon Suture, Ethicon Inc, a subsidiary of Johnson & Johnson, Somerville, New Jersey). Once this was done, the lateral spread disappeared.2 The AICA loop was decompressed with 2 pieces of Teflon felt (Bard PTFE felt, Bard peripheral Vascular Inc, a subsidiary of CR Bard Inc, Temp, Arizona). After this, wave V of the brainstem auditory evoked potential (BAEP) disappeared completely, with no recovery despite the application of the nicardipine on the internal auditory artery (IAA). The IAA appeared to be stretched by the microvascular decompression. Arachnoidal dissection was done to release the CN VIII and an additional felt piece was placed to elevate the AICA loop; the BAEP recovered completely. The patient had a complete disappearance of the hemifacial spasm postoperatively, and hearing was unchanged.This 3-D video shows the technical nuances of performing a vertebropexy, release of the AICA from its extradural subarcuate course, and the surgical maneuvers in the event of an unexpected change in neuromonitoring response. The suture technique of vertebropexy is preferred to a loop technique, to avoid kinking of the VA.3Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 29617905 [PubMed - as supplied by publisher]

Fewer thromboembolic events after implementation of a venous thromboembolism risk stratification tool.

J Surg Res. 2018 05;225:148-156

Authors: Turrentine FE, Sohn MW, Wilson SL, Stanley C, Novicoff W, Sawyer RG, Williams MD

Abstract
BACKGROUND: Deep venous thrombosis and pulmonary embolus are leading preventable causes of death after surgery. Venous thromboembolism (VTE) prophylaxis management guidelines, with evidenced-based recommendations, are available in the literature. However, over 40% of "at-risk" surgical patients fail to receive appropriate VTE prophylaxis. Decision support-based interventions to reduce venous thromboembolic events were explored.
METHODS: A venous thromboembolic risk stratification tool embedded in the electronic medical record, Epic, linking risk category to venous thromboembolic prophylaxis order sets was created, implemented, and analyzed for general surgery patients. Logistic regression analysis was used to compare rates of venous thromboembolic events before and after the intervention, controlling for age, gender, race, body mass index, inpatient status, transfer status, elective/emergent case status, American Society of Anesthesiologists classification, and wound classification.
RESULTS: Venous thromboembolic events in the preintervention and postintervention periods were 55 (1.25%) and 12 (0.64%), respectively (P = 0.033). All-cause mortality events decreased after intervention from 49 (1.12%) to 14 (0.75%; P = 0.187). Multivariable analyses show that the risk of a venous thromboembolic event after intervention was half (odds ratio = 0.532; 95% confidence interval, 0.284-0.997; P = 0.049) as likely compared to that in the preintervention period. From 2012 to 2015, our institution moved from the ninth decile (poor) to the first decile (best) for the incidence of venous thromboembolic events among 760 National Surgical Quality Improvement Program hospitals across the nation.
CONCLUSIONS: Postoperative thromboembolic events decreased after implementation of a VTE risk stratification tool, linking risk category to venous thromboembolic prophylaxis order sets, embedded in the electronic medical record, Epic.

PMID: 29605025 [PubMed - indexed for MEDLINE]

Plasmodium falciparum Liver Stage Infection and Transition to Stable Blood Stage Infection in Liver-Humanized and Blood-Humanized FRGN KO Mice Enables Testing of Blood Stage Inhibitory Antibodies (Reticulocyte-Binding Protein Homolog 5) In Vivo.

Front Immunol. 2018;9:524

Authors: Foquet L, Schafer C, Minkah NK, Alanine DGW, Flannery EL, Steel RWJ, Sack BK, Camargo N, Fishbaugher M, Betz W, Nguyen T, Billman ZP, Wilson EM, Bial J, Murphy SC, Draper SJ, Mikolajczak SA, Kappe SHI

Abstract
The invention of liver-humanized mouse models has made it possible to directly study the preerythrocytic stages of Plasmodium falciparum. In contrast, the current models to directly study blood stage infection in vivo are extremely limited. Humanization of the mouse blood stream is achievable by frequent injections of human red blood cells (hRBCs) and is currently the only system with which to study human malaria blood stage infections in a small animal model. Infections have been primarily achieved by direct injection of P. falciparum-infected RBCs but as such, this modality of infection does not model the natural route of infection by mosquito bite and lacks the transition of parasites from liver stage infection to blood stage infection. Including these life cycle transition points in a small animal model is of relevance for testing therapeutic interventions. To this end, we used FRGN KO mice that were engrafted with human hepatocytes and performed a blood exchange under immune modulation to engraft the animals with more than 50% hRBCs. These mice were infected by mosquito bite with sporozoite stages of a luciferase-expressing P. falciparum parasite, resulting in noninvasively measurable liver stage burden by in vivo bioluminescent imaging (IVIS) at days 5-7 postinfection. Transition to blood stage infection was observed by IVIS from day 8 onward and then blood stage parasitemia increased with a kinetic similar to that observed in controlled human malaria infection. To assess the utility of this model, we tested whether a monoclonal antibody targeting the erythrocyte invasion ligand reticulocyte-binding protein homolog 5 (with known growth inhibitory activity in vitro) was capable of blocking blood stage infection in vivo when parasites emerge from the liver and found it highly effective. Together, these results show that a combined liver-humanized and blood-humanized FRGN mouse model infected with luciferase-expressing P. falciparum will be a useful tool to study P. falciparum preerythrocytic and erythrocytic stages and enables the testing of interventions that target either one or both stages of parasite infection.

PMID: 29593746 [PubMed]

Alcohol-Related Nurse Care Management in Primary Care: A Randomized Clinical Trial.

JAMA Intern Med. 2018 05 01;178(5):613-621

Authors: Bradley KA, Bobb JF, Ludman EJ, Chavez LJ, Saxon AJ, Merrill JO, Williams EC, Hawkins EJ, Caldeiro RM, Achtmeyer CE, Greenberg DM, Lapham GT, Richards JE, Lee AK, Kivlahan DR

Abstract
Importance: Experts recommend that alcohol use disorders (AUDs) be managed in primary care, but effective approaches are unclear.
Objective: To test whether 12 months of alcohol care management, compared with usual care, improved drinking outcomes among patients with or at high risk for AUDs.
Design, Setting, and Participants: This randomized clinical trial was conducted at 3 Veterans Affairs (VA) primary care clinics. Between October 11, 2011, and September 30, 2014, the study enrolled 304 outpatients who reported heavy drinking (≥4 drinks per day for women and ≥5 drinks per day for men).
Interventions: Nurse care managers offered outreach and engagement, repeated brief counseling using motivational interviewing and shared decision making about treatment options, and nurse practitioner-prescribed AUD medications (if desired), supported by an interdisciplinary team (CHOICE intervention). The comparison was usual primary care.
Main Outcomes and Measures: Primary outcomes, assessed by blinded telephone interviewers at 12 months, were percentage of heavy drinking days in the prior 28 days measured by timeline follow-back interviews and a binary good drinking outcome, defined as abstinence or drinking below recommended limits in the prior 28 days (according to timeline follow-back interviews) and no alcohol-related symptoms in the past 3 months as measured by the Short Inventory of Problems.
Results: Of 304 participants, 275 (90%) were male, 206 (68%) were white, and the mean (SD) age was 51.4 (13.8) years. At baseline, both the CHOICE intervention (n = 150) and usual care (n = 154) groups reported heavy drinking on 61% of days (95% CI, 56%-66%). During the 12-month intervention, 137 of 150 patients in the intervention group (91%) had at least 1 nurse visit, and 77 of 150 (51%) had at least 6 nurse visits. A greater proportion of patients in the intervention group than in the usual care group received alcohol-related care: 42% (95% CI, 35%-49%; 63 of 150 patients) vs 26% (95% CI, 19%-35%; 40 of 154 patients). Alcohol-related care included more AUD medication use: 32% (95% CI, 26%-39%; 48 of 150 patients in the intervention group) vs 8% (95% CI, 5%-13%; 13 of 154 patients in the usual care group). No significant differences in primary outcomes were observed at 12 months between patients in both groups. The percentages of heavy drinking days were 39% (95% CI, 32%-47%) and 35% (95% CI, 28%-42%), and the percentages of patients with a good drinking outcome were 15% (95% CI, 9%-22%; 18 of 124 patients) and 20% (95 % CI, 14%-28%; 27 of 134 patients), in the intervention and usual care groups, respectively (P = .32-.44). Findings at 3 months were similar.
Conclusions and Relevance: The CHOICE intervention did not decrease heavy drinking or related problems despite increased engagement in alcohol-related care.
Trial Registration: clinicaltrials.gov Identifier: NCT01400581.

PMID: 29582088 [PubMed - indexed for MEDLINE]

In Reply: Cranial Chordoma: A New Preoperative Grading System.

Neurosurgery. 2018 06 01;82(6):E180

Authors: Brito da Silva H, Sekhar L

PMID: 29566169 [PubMed - indexed for MEDLINE]

Implementation of a nationwide health economic consultation service to assist substance use researchers: Lessons learned.

Subst Abus. 2018;39(2):185-189

Authors: Murphy SM, Leff JA, Linas BP, Morgan JR, McCollister K, Schackman BR

Abstract
BACKGROUND: Health economic evaluation findings assist stakeholders in improving the quality, availability, scalability, and sustainability of evidence-based services, and in maximizing the efficiency of service delivery. The Center for Health Economics of Treatment Interventions for Substance Use Disorders, HCV, and HIV (CHERISH) is a NIDA-funded multi-institutional center of excellence whose mission is to develop and disseminate health-economic research on healthcare utilization, health outcomes, and health-related behaviors that informs substance use disorder treatment policy, and HCV and HIV care of people who use substances.
METHODS: We designed a consultation service that is free to researchers whose work aligns with CHERISH's mission. The service includes up to six hours of consulting time. After prospective consultees submit their request online, they receive a screening call from the consultation service director, who connects them with a consultant with relevant expertise. Consultees and consultants complete web-based evaluations following the consultation; consultees also complete a six-month follow-up. We report on the status of the service from its inception in July 2015 through June 2017.
RESULTS: We have received 28 consultation requests (54% Early Stage Investigators, 57% MD or equivalent, 28% PhD, 61% women) on projects typically related to planning a study or grant application (93%); 71% were HIV/AIDS-related. Leading topics included cost-effectiveness (43%), statistical-analysis/econometrics (36%), cost (32%), cost-benefit (21%), and quality-of-life (18%). All consultees were satisfied with their overall experience, and felt that consultation expectations and objectives were clearly defined and the consultant's expertise was matched appropriately with their needs. Results were similar for consultants, who spent a median of 3 hours on consultations.
CONCLUSIONS: There is a need for health-economic methodological guidance among substance use, HCV, and HIV researchers. Lessons learned pertain to the feasibility of service provision, the need to implement systems to measure and improve service value, and strategies for service promotion.

PMID: 29558284 [PubMed - indexed for MEDLINE]

Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation.

Antimicrob Agents Chemother. 2018 06;62(6):

Authors: Mani N, Cole AG, Phelps JR, Ardzinski A, Cobarrubias KD, Cuconati A, Dorsey BD, Evangelista E, Fan K, Guo F, Guo H, Guo JT, Harasym TO, Kadhim S, Kultgen SG, Lee ACH, Li AHL, Long Q, Majeski SA, Mao R, McClintock KD, Reid SP, Rijnbrand R, Snead NM, Micolochick Steuer HM, Stever K, Tang S, Wang X, Zhao Q, Sofia MJ

Abstract
AB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC50] = 0.08 to 0.27 μM; EC90 = 0.33 to 1.32 μM) with no significant cytotoxicity (50% cytotoxic concentration > 10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC50s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a de novo infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467 resulted in a trend toward antiviral activity greater than that of either agent alone, consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports its further evaluation for safety, pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.

PMID: 29555628 [PubMed - indexed for MEDLINE]

A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.

Nat Med. 2018 05;24(4):408-416

Authors: Kisalu NK, Idris AH, Weidle C, Flores-Garcia Y, Flynn BJ, Sack BK, Murphy S, Schön A, Freire E, Francica JR, Miller AB, Gregory J, March S, Liao HX, Haynes BF, Wiehe K, Trama AM, Saunders KO, Gladden MA, Monroe A, Bonsignori M, Kanekiyo M, Wheatley AK, McDermott AB, Farney SK, Chuang GY, Zhang B, Kc N, Chakravarty S, Kwong PD, Sinnis P, Bhatia SN, Kappe SHI, Sim BKL, Hoffman SL, Zavala F, Pancera M, Seder RA

Abstract
Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.

PMID: 29554083 [PubMed - indexed for MEDLINE]