Faculty Bibliography
Searched for:
person:schwag04
in-biosketch:true
Total Results:
19
Encoding the glucose identity by discrete hypothalamic neurons via the gut-brain axis
Animals need daily intakes of three macronutrients: sugar, protein, and fat. Under fasted conditions, however, animals prioritize sugar as a primary source of energy. They must detect ingested sugar-specifically D-glucose-and quickly report its presence to the brain. Hypothalamic neurons that can respond to the caloric content in the gut regardless of the identity of macronutrient have been identified, but until now, the existence of neurons that can encode the specific macronutrients remained unknown. We found that a subset of corticotropin-releasing factor (CRF)-expressing neurons in the hypothalamic paraventricular nucleus (CRFPVN) respond specifically to D-glucose in the gut, separately from other macronutrients or sugars. CRFPVN neuronal activity is essential for fasted mice to develop a preference for D-glucose. These responses of CRFPVN neurons to intestinal D-glucose require a specific spinal gut-brain pathway including the dorsal lateral parabrachial nuclei. These findings reveal the neural circuit that encodes the identity of D-glucose.
PMID: 40543511
ISSN: 1097-4199
CID: 5871472
Comprehensive Evidence-Based Guidelines for Implantable Peripheral Nerve Stimulation (PNS) in the Management of Chronic Pain: From the American Society Of Interventional Pain Physicians (ASIPP)
BACKGROUND:Peripheral nerve stimulation (PNS) has been used for over 50 years to treat chronic pain by delivering electrical pulses through small electrodes placed near targeted peripheral nerves those outside the brain and spinal cord. Early PNS systems often required invasive neurosurgical procedures. However, since 2015, the Food and Drug Administration (FDA) approved percutaneously implanted PNS leads and neurostimulators offering a much less invasive, non-opioid option for managing recalcitrant chronic pain. The following FDA-cleared PNS systems are commercially available in the United States for the management of chronic, intractable pain:• Freedom® Peripheral Nerve Stimulator (PNS) System (Curonix LLC, 2017) • StimRouter® Neuromodulation System (Bioness, now Bioventus, 2015)• SPRINT® PNS System (SPR® Therapeutics, Inc., 2016) • Nalu™ Neurostimulation System (Nalu Medical Inc., 2019)• ReActiv8® Implantable Neurostimulation System (Mainstay Medical Limited, 2020) The American Society of Interventional Pain Physicians (ASIPP) has published evidence-based consensus guidelines for the application of PNS systems in managing chronic pain. OBJECTIVE:The guidelines aim to provide evidence-based recommendations for the utilization of peripheral nerve stimulation (PNS) in the management of moderate to severe chronic pain. These guidelines exclude field stimulation, or sacral nerve stimulation. METHODS:A multidisciplinary panel of experts in various medical and pharmaceutical fields, convened by ASIPP, reviewed the evidence, considered patient perspectives, and formulated recommendations for implantable peripheral nerve stimulation in chronic pain management. The methodology included developing key questions with evidence-based statements and recommendations. The grading of evidence and recommendations followed a modified approach described by ASIPP, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method, and the Agency for Healthcare Research and Quality (AHRQ) strength of recommendations methods. The evidence review includes existing guidelines, systematic reviews, comprehensive reviews, randomized controlled trials (RCTs), and observational studies on the effectiveness and safety of implantable peripheral nerve stimulation in managing chronic pain. The quality of published studies was assessed using appropriate instruments for systematic reviews, RCTs, and observational studies.In the development of consensus statements and guidelines, we used a modified Delphi technique, which has been described to minimize bias related to group interactions. Panelists without a primary conflict of interest voted to approve specific guideline statements. Each panelist could suggest edits to the guideline statement wording and could suggest additional qualifying remarks or comments as to the implementation of the guideline in clinical practice to achieve consensus and for inclusion in the final guidelines, each guideline statement required at least 80% agreement among eligible panel members without primary conflict of interest. RESULTS:A total of 31 authors participated in the development of these guidelines. Of these, 23 participated in the voting process. A total of 8 recommendations were developed. Overall, 100% acceptance was obtained for 8 of 8 items. Thus, with appropriate literature review, consensus-based statements were developed for implantable peripheral nerve stimulation in chronic pain management. In preparation of these guidelines, evidence synthesis included 7 systematic reviews, 8 RCTs, and 9 observational studies covering all PNS treatments. The evidence was developed using GRADE criteria or certainty of evidence, and qualitative synthesis based on the best available evidence. The evidence level and recommendations are as follows: For implantable peripheral nerve stimulation systems following a trial or selective lumbar medial branch stimulation without a trial, the evidence is Level III or fair with moderate certainty. Evidence Level: Fair; Strength of Recommendation: ModerateFor temporary peripheral nerve stimulation for 60 days, the evidence is Level III or fair, with moderate certainty. EVIDENCE LEVEL/METHODS:Fair; Strength of Recommendation: ModerateBased on the available evidence, it is our recommendation to expand the existing PNS related local coverage determination (LCD) to include craniofacial pain, phantom limb pain, and nociceptive pain in the lower back as present evidence shows Level III or fair with moderate certainty. LIMITATIONS/CONCLUSIONS:The primary limitation of these guidelines is the paucity of the available literature. CONCLUSION/CONCLUSIONS:These evidence-based guidelines support the use of implantable peripheral nerve stimulation leads and neurostimulators in patients with moderate to severe chronic pain refractory to two or more conservative treatments. These guidelines aim to optimize patient outcomes and promote health equity through the integration of PNS technology in clinical practice.
PMID: 39565237
ISSN: 2150-1149
CID: 5758552
Multiorganizational consensus to define guiding principles for perioperative pain management in patients with chronic pain, preoperative opioid tolerance, or substance use disorder
Significant knowledge gaps exist in the perioperative pain management of patients with a history of chronic pain, substance use disorder, and/or opioid tolerance as highlighted in the US Health and Human Services Pain Management Best Practices Inter-Agency Task Force 2019 report. The report emphasized the challenges of caring for these populations and the need for multidisciplinary care and a comprehensive approach. Such care requires stakeholder alignment across multiple specialties and care settings. With the intention of codifying this alignment into a reliable and efficient processes, a consortium of 15 professional healthcare societies was convened in a year-long modified Delphi consensus process and summit. This process produced seven guiding principles for the perioperative care of patients with chronic pain, substance use disorder, and/or preoperative opioid tolerance. These principles provide a framework and direction for future improvement in the optimization and care of 'complex' patients as they undergo surgical procedures.
PMID: 37185214
ISSN: 1532-8651
CID: 5544112
Microsomal triglyceride transfer protein regulates intracellular lipolysis in adipocytes independent of its lipid transfer activity
BACKGROUND:The triglyceride (TG) transfer activity of microsomal triglyceride transfer protein (MTP) is essential for lipoprotein assembly in the liver and intestine; however, its function in adipose tissue, which does not assemble lipoproteins, is unknown. Here we have elucidated the function of MTP in adipocytes. APPROACH AND RESULTS/RESULTS:mice maintained higher body temperature by mobilizing more fatty acids. Biochemical studies indicated that MTP deficiency de-repressed adipose triglyceride lipase (ATGL) activity and increased TG lipolysis. Both wild type MTP and mutant MTP deficient in TG transfer activity interacted with and inhibited ATGL activity. Thus, the TG transfer activity of MTP is not required for ATGL inhibition. C-terminally truncated ATGL that retains its lipase activity interacted less efficiently than full-length ATGL. CONCLUSION/CONCLUSIONS:Our findings demonstrate that adipose-specific MTP deficiency increases ATGL-mediated TG lipolysis and enhances energy expenditure, thereby resisting diet-induced obesity. We speculate that the regulatory function of MTP involving protein-protein interactions might have evolved before the acquisition of TG transfer activity in vertebrates. Adipose-specific inhibition of MTP-ATGL interactions may ameliorate obesity while avoiding the adverse effects associated with inhibition of the lipid transfer activity of MTP.
PMID: 36228741
ISSN: 1532-8600
CID: 5352142
Pain, Analgesic Use, and Patient Satisfaction With Spinal Versus General Anesthesia for Hip Fracture Surgery : A Randomized Clinical Trial
BACKGROUND:The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported. OBJECTIVE:To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia. DESIGN:Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505). SETTING:46 U.S. and Canadian hospitals. PARTICIPANTS:Patients aged 50 years or older undergoing hip fracture surgery. INTERVENTION:Spinal or general anesthesia. MEASUREMENTS:Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care. RESULTS:A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups. LIMITATION:Missing outcome data and multiple outcomes assessed. CONCLUSION:Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia. PRIMARY FUNDING SOURCE:
PMID: 35696684
ISSN: 1539-3704
CID: 5277802
Ex Vivo Resection and Autotransplantation for Conventionally Unresectable Tumors - An 11-year Single Center Experience
BACKGROUND AND AIMS:Ex vivo surgery may provide a chance at R0 resection for conventionally unresectable tumors. However, long-term outcomes have not been well documented. In this study, we analyze our 11-year outcomes to define its role. STUDY DESIGN:We retrospectively analyzed 46 consecutive patients who underwent ex vivo surgery at our institution 2008-2019. RESULTS:The types of tumors were: carcinoma (n = 20), sarcoma (n = 20) and benign to low grade tumor (n = 6). The type of ex vivo surgery was chosen based on tumor location and vascular involvement. The most commonly performed procedure was ex vivo hepatectomy (n = 18), followed by ex vivo resection and intestinal autotransplantation (n = 12), ex vivo Whipple procedure and liver autotransplantation (n = 8) and multivisceral ex vivo procedure (n = 7). Twenty-three patients (50%) are currently alive with median follow-up of 4.0-years (11 months-11.8 years). The overall survival was 70%/59%/52%, at 1-/3-/5-years, respectively. Patient survival for benign to low grade tumors, sarcoma, and carcinoma was 100%/100%/100%, 65%/60%/50%, and 65%/45%/40%, at 1-/3-/5-years, respectively. Ninety-one percent patients had R0 resection, and 57% had no recurrence to date with median follow-up of 3.1-years. Two patients (4.3%) died within 30 days due to sepsis and gastroduodenal artety (GDA) stump blowout. Two additional patients died between 30 and 90 days due to sepsis. Perioperative mortality in the last 23 consecutive cases was limited to 1 patient who died of sepsis between 30 and 90 days. CONCLUSIONS:For a selected group of patients with conventionally unresectable tumors, ex vivo surgery can offer effective surgical removal with a reasonably low perioperative mortality at experienced centers.
PMID: 32833756
ISSN: 1528-1140
CID: 5143512
Bile acid composition regulates GPR119-dependent intestinal lipid sensing and food intake regulation in mice
OBJECTIVES:mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation. DESIGN:mice. RESULTS:mice. CONCLUSION:BAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.
PMID: 32111630
ISSN: 1468-3288
CID: 5048102
Oleoylethanolamide differentially regulates glycerolipid synthesis and lipoprotein secretion in intestine and liver
Dietary fat absorption takes place in the intestine, and the liver mobilizes endogenous fat to other tissues by synthesizing lipoproteins that require apoB and microsomal triglyceride transfer protein (MTP). Dietary fat triggers the synthesis of oleoylethanolamide (OEA), a regulatory fatty acid that signals satiety to reduce food intake mainly by enhancing neural PPARα activity, in enterocytes. We explored OEA's roles in the assembly of lipoproteins in WT and Ppara -/- mouse enterocytes and hepatocytes, Caco-2 cells, and human liver-derived cells. In differentiated Caco-2 cells, OEA increased synthesis and secretion of triacylglycerols, apoB secretion in chylomicrons, and MTP expression in a dose-dependent manner. OEA also increased MTP activity and triacylglycerol secretion in WT and knockout primary enterocytes. In contrast to its intestinal cell effects, OEA reduced synthesis and secretion of triacylglycerols, apoB secretion, and MTP expression and activity in human hepatoma Huh-7 and HepG2 cells. Also, OEA reduced MTP expression and triacylglycerol secretion in WT, but not knockout, primary hepatocytes. These studies indicate differential effects of OEA on lipid synthesis and lipoprotein assembly: in enterocytes, OEA augments glycerolipid synthesis and lipoprotein assembly independent of PPARα. Conversely, in hepatocytes, OEA reduces MTP expression, glycerolipid synthesis, and lipoprotein secretion through PPARα-dependent mechanisms.
PMCID:6277166
PMID: 30369486
ISSN: 1539-7262
CID: 5035202
A direct tissue-grafting approach to increasing endogenous brown fat
There is widespread evidence that increasing functional mass of brown adipose tissue (BAT) via browning of white adipose tissue (WAT) could potentially counter obesity and diabetes. However, most current approaches focus on administration of pharmacological compounds which expose patients to highly undesirable side effects. Here, we describe a simple and direct tissue-grafting approach to increase BAT mass through ex vivo browning of subcutaneous WAT, followed by re-implantation into the host; this cell-therapy approach could potentially act synergistically with existing pharmacological approaches. With this process, entitled "exBAT", we identified conditions, in both mouse and human tissue, that convert whole fragments of WAT to BAT via a single step and without unwanted off-target pharmacological effects. We show that ex vivo, exBAT exhibited UCP1 immunostaining, lipid droplet formation, and mitochondrial metabolic activity consistent with native BAT. In mice, exBAT exhibited a highly durable phenotype for at least 8 weeks. Overall, these results enable a simple and scalable tissue-grafting strategy, rather than pharmacological approaches, for increasing endogenous BAT and studying its effect on host weight and metabolism.
PMCID:5962549
PMID: 29785004
ISSN: 2045-2322
CID: 3147942
Central Regulation of Endogenous Glucose Production Is Impaired in Type 2 Diabetes Mellitus [Meeting Abstract]
ISI:000359482700046
ISSN: 1939-327x
CID: 2677332
