Inhibitory control of sharp-wave ripple duration during learning in hippocampal recurrent networks.

Recurrent excitatory connections in hippocampal regions CA3 and CA2 are thought to play a key role in the generation of sharp-wave ripples (SWRs), electrophysiological oscillations tightly linked with learning and memory consolidation. However, it remains unknown how defined populations of inhibitory interneurons regulate these events during behavior. Here, we use large-scale, three-dimensional calcium imaging and retrospective molecular identification in the mouse hippocampus to characterize molecularly identified CA3 and CA2 interneuron activity during SWR-associated memory consolidation and spatial navigation. We describe subtype- and region-specific responses during behaviorally distinct brain states and find that SWRs are preceded by decreased cholecystokinin-expressing interneuron activity and followed by increased parvalbumin-expressing basket cell activity. The magnitude of these dynamics correlates with both SWR duration and behavior during hippocampal-dependent learning. Together these results assign subtype- and region-specific roles for inhibitory circuits in coordinating operations and learning-related plasticity in hippocampal recurrent circuits.

Epitope and Fc-Mediated Cross-linking, but Not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity.

CD137 (TNFRSF9, 4-1BB) agonist antibodies (mAb) have demonstrated potent antitumor activity with memory response while causing hepatotoxicity in mouse models. In clinical trials, the degrees of liver toxicity of anti-CD137 vary from grade 4 transaminitis (urelumab) to nonexistent (utomilumab). To exploit the antitumor potential of CD137 signaling, we identified a new class of CD137 agonist mAbs with strong antitumor potency without significant transaminitis in vivo compared with CD137 agonists previously reported. These mAbs are cross-reactive to mouse and cynomolgus monkey and showed cross-linking-dependent T-cell costimulation activity in vitro Antitumor efficacy was maintained in Fc gamma receptor (FcγR) III-deficient mice but diminished in FcγRIIB-deficient mice, suggesting the critical role for FcγRIIB to provide cross-linking in vivo Interestingly, a single dose of an affinity-reduced variant was sufficient to control tumor growth, but a higher affinity variant did not improve efficacy. These observations suggest that binding epitope and FcγR interaction, but not necessarily high affinity, are important for antitumor efficacy and reduced liver toxicity of CD137 mAb. Our study suggests the possibility of CD137 agonist therapy with improved safety profile in humans.

Ethanol Lock Therapy Markedly Reduces Catheter-Related Blood Stream Infections in Adults Requiring Home Parenteral Nutrition: A Retrospective Study From a Tertiary Medical Center.

BACKGROUND: The use of central venous catheter (CVC) access for home parenteral nutrition (HPN) is associated with catheter-related bloodstream infections (CRBSIs). There are limited data on the use of ethanol lock therapy (ELT) to prevent CRBSI in adult HPN patients. Our aim was to determine whether the routine institution of ELT decreased the incidence of CRBSI compared with historic controls at Emory University Hospital (EUH) in Atlanta, Georgia, USA. METHODS: EUH medical records of adult HPN patients discharged with a tunneled, silicone CVC on ELT were retrospectively studied during a pre-hoc determined 14-month observation period (n = 87; 13,386 catheter days) and compared with clinically similar HPN patients from the same institution before institution of the ELT protocol for all appropriate patients. The ELT protocol involved instilling 2 mL of 70% ethanol into each catheter lumen daily after the HPN cycle, following initial flushing with normal saline. RESULTS: Only 5 of 87 patients (5.7%) who received ELT were diagnosed with a CRBSI (0.45/1000 catheter days) during observation. We compared these data with our previously published clinically matched patient population from EUH (n = 22) receiving HPN via a silicone CVC without ELT. Of these historical controls, 45.5% were diagnosed with 1 or more CRBSIs (8.7/1000 catheter days) during observation (P < .001 vs the current ELT cohort). CONCLUSIONS: In this retrospective study with historical controls from the same academic center, institution of ELT in adults requiring HPN via a silicone CVC was associated with a marked (19-fold) reduction in CRBSI.

Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors.

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215-21. ©2017 AACR.

Micronutrient Alterations During Continuous Renal Replacement Therapy in Critically Ill Adults: A Retrospective Study.

BACKGROUND: Continuous renal replacement therapy (CRRT) is commonly used to provide renal replacement therapy in the intensive care unit. Limited published data suggest that CRRT may lead to depletion of water-soluble vitamins and trace elements. The goal of this study was to identify the incidence of trace element and vitamin deficiencies in critically ill patients during CRRT. MATERIALS AND METHODS: This study is based on a retrospective chart review of patients who were referred to Emory University Hospital's nutrition support services and had at least 1 serum micronutrient level measured during CRRT (thiamin, pyridoxine, ascorbic acid, folate, zinc, and copper) between April 1, 2009, and June 1, 2012. RESULTS: Seventy-five patients were included in the study. Nine of 56 patients (16%) had below-normal whole blood thiamin concentrations, and 38 of 57 patients (67%) had below-normal serum pyridoxine levels. Serum ascorbic acid and folate deficiencies were identified among 87% (13 of 15) and 33% (3 of 9) of the study patients, respectively. Nine of 24 patients had zinc deficiency (38%), and 41 of 68 patients had copper deficiency (60%). Of the 75 total subjects, 60 patients (80%) had below-normal levels of at least 1 of the micronutrients measured. CONCLUSIONS: The incidence of various micronutrient deficiencies in critically ill patients who required CRRT was higher than previously reported. Prospective studies are needed to determine the impact of CRRT on micronutrient status and the potential clinical and metabolic efficacy of supplementation in the intensive care unit setting.

Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells.

Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.

Pharmacodynamic effects of daclizumab in the intrathecal compartment.

OBJECTIVE: It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug. METHODS: Forty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open-label clinical trials. MRI contrast-enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease. RESULTS: Rapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant (P < 0.0001) decreases in CSF levels of T-cell activation marker CD27 and IgG index. Interleukin 2 (IL-2) CSF levels increased from baseline levels during treatment, consistent with reduced IL-2 consumption by T cells, as a consequence of daclizumab's saturation of high-affinity IL-2 receptors. CSF levels of IL-12p40, chitinase-3-like protein-1 (CHI3L1), chemokine C-X-C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression. INTERPRETATION: These observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.

Optic neuropathy, myelopathy, anemia, and neutropenia caused by acquired copper deficiency after gastric bypass surgery.

Malabsorptive bariatric surgery is rapidly becoming a major cause of copper deficiency given the increasing prevalence of these procedures for morbid obesity. Acquired copper deficiency can present with clinically significant hematologic and neurological manifestations. Although hematologic manifestations of copper deficiency are rapidly reversible, significant neurological improvement after copper supplementation therapy is unusual and many patients remain debilitated and may only experience, at best, stabilization of the neurological manifestations. Here we present a case of an undiagnosed copper deficiency several years after bariatric gastric bypass surgery, in a patient who concomitantly used zinc-containing denture cream for several years, associated with anemia, neutropenia, myelopathy, respiratory failure, and bilateral optic neuropathy, which caused major vision loss. This patient was also a heterozygote carrier of the 5,10-methylenetetrahydrofolate reductase A1298C gene polymorphism, which may affect copper metabolism. Intravenous copper repletion resulted in rapid correction of hematologic indices. However, neurological manifestations, including vision loss responded only modestly to copper supplementation, despite achieving normal blood copper concentrations. Clinicians should consider copper deficiency in patients at risk, as in this case, as a delayed diagnosis can lead to irreversible disability due to neurological manifestations.

Characterization of post-hospital infections in adults requiring home parenteral nutrition.

OBJECTIVE: Limited data are available on the incidence and risk factors for infection in patients requiring home parenteral nutrition (HPN). METHODS: A retrospective study was conducted in 101 consecutive adults (63 female, 38 male) discharged on HPN from the Emory University Hospital, Atlanta, GA. New bloodstream infections (BSIs) requiring rehospitalization and other infections were evaluated. RESULTS: Most infections (75%) developed during the initial 6 mo after hospital discharge; rates of BSI were particularly high during the first 4 mo. Fifty-six patients (55.4%) developed 102 BSIs (11.5 BSIs/1000 catheter-days). Most BSIs were attributed to gram-positive organisms (46%), including coagulase-negative Staphylococcus, Staphylococcus aureus, Enterococcus species, and others, followed by Candida species (20%) and gram-negative organisms (13%). Twenty-one percent of BSIs were polymicrobial. The BSI incidence rate ratio was significantly increased for patients with mean prehospital discharge blood glucose concentrations in the highest quartile versus the lowest quartile (incidence rate ratio 2.4, P = 0.017). Patients with a peripherally inserted central catheter versus non-peripherally inserted central catheter central venous catheters had significantly higher rates of BSI (P = 0.018). Thirty-nine patients (38.6%) developed 81 non-BSIs, including pneumonia, urinary tract infections, and surgical site infections. Postdischarge PN dextrose, lipid, and total calorie doses were unrelated to BSI but were variably related to the rate of non-BSIs. CONCLUSIONS: Adult patients on HPN exhibit a very high incidence of post-hospital infections. Higher mean blood glucose levels during predischarge hospitalization and the use of peripherally inserted central catheters at discharge are associated with an increased risk of BSI in the postdischarge home setting.

A double-blind, randomized clinical trial comparing soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit patients requiring parenteral nutrition.

OBJECTIVE: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. PATIENTS: Adult medical-surgical intensive care unit patients. INTERVENTION: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions. MEASUREMENTS: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. RESULTS: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. CONCLUSION: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults.

Characterization of posthospital bloodstream infections in children requiring home parenteral nutrition.

BACKGROUND: Home parenteral nutrition (HPN) is lifesaving for children with intestinal failure. Catheter-associated bloodstream infections (CA-BSI) are common in hospitalized patients receiving parenteral nutrition (PN), but data evaluating CA-BSI in children receiving HPN are limited. OBJECTIVE: To determine the incidence and characteristics of CA-BSI in children receiving HPN. METHODS: Medical records of 44 children receiving HPN during a 3-year period were reviewed. End points were CA-BSI during the initial 6 months after discharge. CA-BSI was defined as isolation of pathogens from blood requiring antimicrobial therapy. RESULTS: The primary indication for HPN was short bowel syndrome (46%), and 59 BSI were documented during the initial 6 months of HPN in 29 (66%) children. Of CA-BSI, polymicrobial infections accounted for 52%; gram-positive, 29%; gram-negative, 17%; and fungal, 2%. CA-BSI incidence per 1000 catheter-days was highest during the first month posthospital discharge (72 episodes; 95% confidence interval [CI], 45.4-109.6). CA-BSI incidence density ratio for children receiving HPN for >90 days compared with those receiving HPN for <30 days was 2.2 (P < .05). Logistic regression revealed that Medicaid insurance and age <1 year were associated with increased risk for CA-BSI (odds ratio [OR], 4.4 [95% CI, 1.13-16.99] and 6.6 [1.50-28.49], respectively; P < .05). CONCLUSIONS: The incidence of CA-BSI in children receiving HPN is highest during the first month posthospital discharge. Strategies to address care in the immediate posthospital discharge period may reduce the burden of infectious complications of HPN.

Amino acid composition in parenteral nutrition: what is the evidence?

PURPOSE OF REVIEW: Complete parenteral nutrition solutions contain mixed amino acid products providing all nine essential amino acids and a varying composition of nonessential amino acids. Relatively little rigorous comparative efficacy research on altered parenteral nutrition amino acid composition has been published in recent years. RECENT FINDINGS: Limited data from randomized, double-blind, adequately powered clinical trials to define optimal doses of total or individual amino acids in parenteral nutrition are available. An exception is the growing number of studies on the efficacy of glutamine supplementation of parenteral nutrition or given as a single parenteral agent. Parenteral glutamine appears to confer benefit in selected patients; however, additional data to define optimal glutamine dosing and the patient subgroups who may most benefit from this amino acid are needed. Although some promising studies have been published, little data are available in the current era of nutrition support on the clinical efficacy of altered doses of arginine, branched chain amino acids, cysteine, or taurine supplementation of parenteral nutrition. SUMMARY: Despite routine use of parenteral nutrition, surprisingly little clinical efficacy data are available to guide total or specific amino acid dosing in adult and pediatric patients requiring this therapy. This warrants increased attention by the research community and funding agencies to better define optimal amino acid administration strategies in patient subgroups requiring parenteral nutrition.

Nutrition support in end-stage liver disease.

Protein-calorie malnutrition is common in end-stage liver disease, irrespective of cause, and adversely affects clinical outcomes. Early diagnosis is important to allow appropriate intervention to prevent malnutrition-associated complications. Correction of nutrient deficiencies through oral supplementation, enteral tube feeding, or parenteral feeding can improve clinical outcomes in this patient population. This article addresses the causes of malnutrition, methods used to assess nutritional status, and treatment strategies in end-stage liver disease.