A protease and a lipoprotein jointly modulate the conserved ExoR-ExoS-ChvI signaling pathway critical in Sinorhizobium meliloti for symbiosis with legume hosts.

Sinorhizobium meliloti is a model alpha-proteobacterium for investigating microbe-host interactions, in particular nitrogen-fixing rhizobium-legume symbioses. Successful infection requires complex coordination between compatible host and endosymbiont, including bacterial production of succinoglycan, also known as exopolysaccharide-I (EPS-I). In S. meliloti EPS-I production is controlled by the conserved ExoS-ChvI two-component system. Periplasmic ExoR associates with the ExoS histidine kinase and negatively regulates ChvI-dependent expression of exo genes, necessary for EPS-I synthesis. We show that two extracytoplasmic proteins, LppA (a lipoprotein) and JspA (a lipoprotein and a metalloprotease), jointly influence EPS-I synthesis by modulating the ExoR-ExoS-ChvI pathway and expression of genes in the ChvI regulon. Deletions of jspA and lppA led to lower EPS-I production and competitive disadvantage during host colonization, for both S. meliloti with Medicago sativa and S. medicae with M. truncatula. Overexpression of jspA reduced steady-state levels of ExoR, suggesting that the JspA protease participates in ExoR degradation. This reduction in ExoR levels is dependent on LppA and can be replicated with ExoR, JspA, and LppA expressed exogenously in Caulobacter crescentus and Escherichia coli. Akin to signaling pathways that sense extracytoplasmic stress in other bacteria, JspA and LppA may monitor periplasmic conditions during interaction with the plant host to adjust accordingly expression of genes that contribute to efficient symbiosis. The molecular mechanisms underlying host colonization in our model system may have parallels in related alpha-proteobacteria.

The critical care literature 2022.

The number of critically ill patients that present to emergency departments across the world has risen steadily for nearly two decades. Despite a decrease in initial emergency department (ED) volumes early in the COVID-19 pandemic, the proportion of critically ill patients is now higher than pre-pandemic levels [1]. The emergency physician (EP) is often the first physician to evaluate and resuscitate a critically ill patient. In addition, EPs are frequently tasked with providing critical care long beyond the initial resuscitation. Prolonged boarding of critically ill patients in the ED is associated with increased duration of mechanical ventilation, increased intensive care unit (ICU) length of stay, increased hospital length of stay, increased medication-related adverse events, and increased in-hospital, 30-day, and 90-day mortality [2-4]. Given the continued increase in critically ill patients along with the increases in boarding critically ill patients in the ED, it is imperative for the EP to be knowledgeable about recent literature in resuscitation and critical care medicine, so that critically ill patients continue to receive evidence-based care. This review summarizes important articles published in 2022 that pertain to the resuscitation and management of select critically ill ED patients. These articles have been selected based on the authors review of key critical care, resuscitation, emergency medicine, and medicine journals and their opinion of the importance of study findings as it pertains to the care of the critically ill ED patient. Topics covered in this article include cardiac arrest, post-cardiac arrest care, rapid sequence intubation, mechanical ventilation, fluid resuscitation, and sepsis.

Implementation and perception of outpatient pharmacists prescribing hormonal contraceptives in North Carolina.

BACKGROUND: North Carolina (NC) House Bill 96, effective February 2022, enabled trained immunizing pharmacists across the state to prescribe hormonal contraceptives (HCs). However, the extent and barriers to deployment are unknown. The purpose of this study was to describe the uptake and challenges from outpatient pharmacists who trained to provide HCs in an outpatient practice to assist others in the implementation of this service. OBJECTIVES: The primary objective was to estimate the proportion of trained NC pharmacists who provided HCs in an outpatient setting. The secondary objective was to identify barriers during the implementation of this service. METHODS: This cross-sectional, anonymous, web-based survey was emailed on December 13, 2022, to NC-licensed pharmacists enrolled in the required training. A reminder email was sent on January 10, 2023, with all responses considered up to January 31, 2023. Pharmacists licensed in NC who performed at least 50% of their clinical practice in an outpatient setting were included. The primary endpoint was having prescribed HC (Y/N). All endpoints were analyzed using descriptive statistics. RESULTS: Of 1633 pharmacists eligible, 96 completed responses were included in the analysis (5.9%). Training was incomplete in 11 of 96 (11.5%), and 66 of 96 (68.8%) completed the training without implementing the service. Of the remaining 19 of 96 (19.8%) that developed a HC service, 15 of 96 (15.6%) had prescribed HCs. Among the 15 prescribing pharmacists, all reported positive patient feedback, while 7 reported improved job satisfaction. Among all 96 respondents, barriers reported included time constraints (49%) and a lack of appropriate reimbursement (43.8%). CONCLUSION: Few HC-trained NC outpatient pharmacists are prescribing HCs. Addressing prescribing barriers would potentially expand the scope of this service and further innovate the outpatient pharmacy setting.

The critical care literature 2021.

An emergency physician (EP) is often the first provider to evaluate, resuscitate, and manage a critically ill patient. Over the past two decades, the annual hours of critical care delivered in emergency departments across the United States has dramatically increased. During the period from 2006 to 2014, the extent of critical care provided in the emergency department (ED) to critically ill patients increased approximately 80%. During the same time period, the number of intubated patients cared for in the ED increased by approximately 16%. In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. Prolonged ED boarding times for critically ill patients is associated with increased duration of mechanical ventilation, increased intensive care unit (ICU) length of stay, increased hospital length of stay, increased medication-related adverse events, and increased in-hospital, 30-day, and 90-day mortality. As a result, it is imperative for the EP to be knowledgeable about recent developments in resuscitation and critical care medicine, so that the critically ill ED patient care receive current evidence-based care. These articles have been selected based on the authors review of key critical care, resuscitation, emergency medicine, and medicine journals and their opinion of the importance of study findings as it pertains to the care of the critically ill ED patient. Topics covered in this article include cardiac arrest, post-cardiac arrest care, rapid sequence intubation, mechanical ventilation, fluid resuscitation, cardiogenic shock, transfusions, and sepsis.

Greater Social Isolation and Social Constraints Prior to Hematopoietic Stem Cell Transplant Are Associated with Greater Anxiety and Depressive Symptoms.

BACKGROUND: Hematopoietic stem cell transplantation (hereafter "HCT") is a physically and psychologically difficult treatment for patients with hematological cancers. This study examined relationships among patients' reports of pre-transplant social isolation, social constraints, and psychological distress. METHOD: We used baseline data from a multisite randomized controlled trial evaluating the effects of expressive helping writing to reduce physical and emotional symptoms in HCT patients. We collected data prior to randomization and before either allogenic or autologous HCT using validated scales to assess social constraints, social isolation, anxiety, and depressive symptoms. We analyzed data using bivariate analysis and multivariate linear regression. We also explored whether social isolation mediated the effect of social constraints on both of our outcomes: anxiety and depressive symptoms. RESULTS: Among 259 adults recruited prior to transplant, 43.6% were women (mean age = 57.42 years, SD = 12.34 years). In multivariate analysis controlling for relevant covariates, both social isolation (ß = 0.24, p < 0.001) and social constraints (ß = 0.28, p < 0.001) were associated with anxiety. When both social constraints and social isolation were in the model, only greater social isolation (ß = 0.79, p < 0.001) was associated with depressive symptoms. Social isolation fully mediated the association between social constraints and anxiety and depressive symptoms. CONCLUSION: For patients awaiting either allogenic or autologous HCT, the negative association between social constraints and anxiety and depressive symptoms may be related, in part, to the mechanism of perceived social isolation. Interventions prior to and during HCT are needed to support patients' psychological health and sense of social connectedness.

Single-Stage Surgical Management of Atrioventricular Septal Defects with Coarctation of the Aorta.

Surgical options for coarctation of aorta (CoA) with atrioventricular septal defect (AVSD) include single-stage repair vs. staged approach with neonatal CoA repair and delayed AVSD repair. The durability of left atrioventricular valve (LAVV) function after neonatal repair is questioned, and the optimal approach remains controversial. Eighteen CoA-AVSD patients who underwent single-stage repair 2005-2015 by a single surgeon were retrospectively analyzed. Fifteen patients had complete and three had partial AVSD. Birth weight was 3.19 kg (2.17-4.08). Age at surgery was 16 days (6-127). One- and ten-year survival were 80% and 69%. Freedom from reintervention was 60% and 40% at one and ten-year respectively. Reinterventions included relief of left ventricular outflow tract obstruction (LVOTO) (n = 4), repair of cleft LAVV (n = 3), and LAVV and aortic valve replacement (n = 1). Freedom from LAVV reintervention was 85.6% and 66% at 1 and 10 years respectively. There were four deaths: two post-operative and two following hospital discharge. Mortality was due to sepsis in three patients, and heart failure related to LVOTO and LAVV insufficiency in one. At 68-month (0.6-144) follow-up the majority had mild or less LAVV regurgitation, and all had normal LV dimension and systolic function. There was no recurrent arch obstruction. Single-stage surgical repair of CoA-AVSD is feasible and reasonable. Survival and freedom from reintervention in our cohort approximate those outcomes of two-stage repair with durable left AV valve function and no recurrent arch obstruction. These patients are frequently syndromic and demonstrate mortality risk from non-cardiac causes. Consideration of a single-staged approach is warranted for appropriate patients with CoA-AVSD.

Cost-Effectiveness Analysis of Branded Drugs With Market Demand and Insurance.

OBJECTIVES: Cost-effectiveness analysis of branded pharmaceuticals presumes that both cost (or price) and marginal effectiveness levels are exogenous. This assumption underlies most judgments of the cost-effectiveness of specific drugs. In this study, we show the theoretical implications of letting both factors be endogenous by modeling pharmaceutical price setting with and without health insurance, along with patient response to the prices that depend on marginal effectiveness. We then explore the implications of these models for cost-effectiveness ratios. METHODS: We used simple textbook models of patient demand and pricing behavior of drug firms to predict market equilibria in the drug and insurance markets and to generate calculations of the cost-effectiveness ratios in those settings. RESULTS: We found that ratios in market settings can be much different from those calculated in cost-effectiveness studies based on exogenous prices and treatment of all patients at risk rather than those who would demand treatment in a market setting. We also found that there may be considerable similarity in these market cost-effectiveness ratios across different products because drug firms with market power set profit-maximizing prices. CONCLUSIONS: We found that market cost-effectiveness ratios will always indicate an excess of benefits over cost. Insurance will lead to less favorable ratios than without insurance, but when insurers bargain with drug firms, rather than taking their prices as given, cost-effectiveness ratios will be more favorable.

The critical care literature 2020.

Given the dramatic increase in critically ill patients who present to the emergency department for care, along with the persistence of boarding of critically ill patients, it is imperative for the emergency physician to be knowledgeable about recent developments in resuscitation and critical care medicine. This review summarizes important articles published in 2020 that pertain to the resuscitation and care of select critically ill patients. These articles have been selected based on the authors annual review of key critical care, emergency medicine and medicine journals and their opinion of the importance of study findings as it pertains to the care of critically ill ED patients. Several key findings from the studies discussed in this paper include the administration of dexamethasone to patients with COVID-19 infection who require mechanical ventilation or supplemental oxygen, the use of lower levels of positive end-expiratory pressure for patients without acute respiratory distress syndrome, and early initiation of extracorporeal membrane oxygenation for out-of-hospital cardiac arrest patients with refractory ventricular fibrillation if resources are available. Furthermore, the emergency physician should not administer tranexamic acid to patients with acute gastrointestinal bleeding or administer the combination of vitamin C, thiamine, and hydrocortisone for patients with septic shock. Finally, the emergency physician should titrate vasopressor medications to more closely match a patient's chronic perfusion pressure rather than target a mean arterial blood pressure of 65 mmHg for all critically ill patients.

The critical care literature 2019.

An emergency physician (EP) is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. In recent years, the annual hours of critical care delivered in emergency departments across the United States has steadily increased. From 2006 to 2014, emergency department (ED) visits for critically ill patients increased approximately 80%. In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, more than 50% of ED patients that require admission to the ICU remain in the ED for more than 6 h. Prolonged ED wait times for critically ill patients to be transferred to the ICU is associated with increased hospital, 30-day, and 90-day mortality. It is during these early hours of critical illness, while the patient is in the ED, where lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in resuscitation and critical care medicine. This review summarizes important articles published in 2019 pertaining to the resuscitation and care of select critically ill patients. We chose these articles based on our opinion of the importance of the study findings and their application to emergency medicine. The following topics are covered: sepsis, rapid sequence intubation, mechanical ventilation, neurocritical care, post-cardiac arrest care, and ED-based ICUs.

Provider Perceptions of Telemedicine Video Visits to Home in a Veteran Population.

Background: Clinical Video Telemedicine to Home (CVTH) allows primary care clinicians to conduct clinical encounters with patients in remote locations through a secure synchronous video connection, offering improved access to care and increased patient satisfaction. Introduction: Although implementation of CVTH continues to grow, little is known about clinician perceptions of clinical applicability or utilization barriers. We assessed provider attitudes and perceived barriers toward implementation of CVTH visits at the Seattle Veterans Affairs Primary Care Clinic. Materials and Methods: Data are presented from a cross-sectional survey. A total of 49 clinicians, including faculty, MD residents, nurse practitioner residents, and pharmacists, were surveyed with 13 questions gauging opinions of CVTH and prior experience with video telemedicine. Results: Forty-seven providers (96%) were interested in incorporating CVTH into their practice. Forty-one clinicians (83.7%) were concerned about patient technological competency, and 39 (79.6%) were worried about insufficient internet connectivity. A large majority of providers saw opportunities to provide medication reconciliation and improve access to care for geographically distant or homebound patients. Discussion: Although limited by its descriptive data and analysis, this study provides evidence that primary care providers are most likely to offer CVTH visits to patients who find it physically challenging to attend a clinic appointment or have chief complaints perceived as not requiring a physical examination. Conclusions: Although most providers are interested in using video visits to care for patients who live remotely, they are concerned about using CVTH visits for patients who might require a physical examination or technological assistance.

The critical care literature 2018.

An emergency physician (EP) is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. In recent years, the annual hours of critical care delivered in emergency departments (EDs) across the United States increased more than 200% (Herring et al., 2013). In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, more than 50% of ED patients that require admission to the intensive care unit (ICU) remain in the ED for more than 6 h (Rose et al., 2016). Longer ED boarding times for critically ill patients is associated with a negative impact on inpatient morbidity and mortality (Mathews et al., 2018). It is during these early hours of critical illness, while the patient is in the ED, where lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in critical care medicine. This review summarizes important articles published in 2018 pertaining to the resuscitation and care of select critically ill patients. We chose these articles based on our opinion of the importance of the study findings and their application to clinical care in the ED. The following topics are covered: cardiac arrest, post-arrest care, septic shock, rapid sequence intubation, mechanical ventilation, fluid resuscitation, and metabolic acidosis.

The critical care literature 2017.

An emergency physician (EP) is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. Between 2001 and 2009, the annual hours of critical care delivered in emergency departments (EDs) across the United States increased >200% [1]! This trend has persisted since then. In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, >33% of critically ill patients who are brought to an ED remain there for >6 h [1]. Longer ED boarding times for critically ill patients have been associated with a negative impact on inpatient morbidity and mortality [2]. During these crucial early hours of illness, detrimental pathophysiologic processes begin to take hold. It is during these early hours of illness where lives can be saved, or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in critical care medicine. This review summarizes important articles published in 2017 pertaining to the resuscitation and care of select critically ill patients in the ED. We chose these articles based on our opinion of the importance of the study findings and their application to clinical care. The following topics are covered: sepsis, vasolidatory shock, cardiac arrest, post-cardiac arrest care, post-intubation sedation, and pulmonary embolism.

Combined Residency Programs in Emergency Medicine.

There are currently 5 combined residencies in emergency medicine (EM), namely EM/pediatrics, EM/internal medicine, EM/internal medicine/critical care, EM/family medicine and EM/anesthesiology. These combined programs vary from 5-6 years in length. Like categorical programs, the decision to enter a 5- or 6-year program should be an informed and comprehensive decision. We describe the history and current status of the combined EM programs, discuss the process of applying to a combined EM program, describe the life of combined EM residents, and explore common career opportunities available to combined EM program graduates.

Probing ion current in solid-electrolytes at the meso- and nanoscale.

We present experimental approaches to probe the ionic conductivity of solid electrolytes at the meso- and nanoscales. Silica ionogel based electrolytes have emerged as an important class of solid electrolytes because they maintain both fluidic and high-conductivity states at the nanoscale, but at the macroscale they are basically solid. Single mesopores in polymer films are shown to serve as templates for cast ionogels. The ionic conductivity of the ionogels was probed by two experimental approaches. In the first approach, the single-pore/ionogel membranes were placed between two chambers of a conductivity cell, in a set-up similar to that used for investigating liquid electrolytes. The second approach involved depositing contacts directly onto the membrane and measuring conductivity without the bulk solution present. Ionic conductivity determined by the two methods was in excellent agreement with macroscopic measurements, which suggested that the electrochemical properties of ionogel based electrolytes are preserved at the mesoscale, and ionogels can be useful in designing meso-scaled energy-storage devices.

Association of Hospital Participation in a Medicare Bundled Payment Program With Volume and Case Mix of Lower Extremity Joint Replacement Episodes.

Importance: Medicare's Bundled Payments for Care Improvement (BPCI) initiative for lower extremity joint replacement (LEJR) surgery has been associated with a reduction in episode spending and stable-to-improved quality. However, BPCI may create unintended effects by prompting participating hospitals to increase the overall volume of episodes paid for by Medicare, which could potentially eliminate program-related savings or prompt them to shift case mix to lower-risk patients. Objective: To evaluate whether hospital BPCI participation for LEJR was associated with changes in overall volume and case mix. Design, Setting, and Participants: Observational study using Medicare claims data and a difference-in-differences method to compare 131 markets (hospital referral regions) with at least 1 BPCI participant hospital (n = 322) and 175 markets with no participating hospitals (n = 1340), accounting for 580 043 Medicare beneficiaries treated before (January 2011-September 2013) and 462 161 after (October 2013-December 2015) establishing the BPCI initiative. Hospital-level case-mix changes were assessed by comparing 265 participating hospitals with a 1:1 propensity-matched set of nonparticipating hospitals from non-BPCI markets. Exposures: Hospital BPCI participation. Main Outcomes and Measures: Changes in market-level LEJR volume in the before vs after BPCI periods and changes in hospital-level case mix based on demographic, socioeconomic, clinical, and utilization factors. Results: Among the 1 717 243 Medicare beneficiaries who underwent LEJR (mean age, 75 years; 64% women; and 95% nonblack race/ethnicity), BPCI participation was not significantly associated with a change in overall market-level volume. The mean quarterly market volume in non-BPCI markets increased 3.8% from 3.8 episodes per 1000 beneficiaries before BPCI to 3.9 episodes per 1000 beneficiaries after BPCI was launched. For BPCI markets, the mean quarterly market volume increased 4.4% from 3.6 episodes per 1000 beneficiaries before BPCI to 3.8 episodes per 1000 beneficiaries after BPCI was launched. The adjusted difference-in-differences estimate between the market types was 0.32% (95% CI, -0.06% to 0.69%; P = .10). Among 20 demographic, socioeconomic, clinical, and utilization factors, BPCI participation was associated with differential changes in hospital-level case mix for only 1 factor, prior skilled nursing facility use (adjusted difference-in-differences estimate, -0.53%; 95% CI, -0.96% to -0.10%; P = .01) in BPCI vs non-BPCI markets. Conclusions and Relevance: In this observational study of Medicare beneficiaries who underwent LEJR, hospital participation in Bundled Payments for Care Improvement was not associated with changes in market-level lower extremity joint replacement volume and largely was not associated with changes in hospital case mix. These findings may provide reassurance regarding 2 potential unintended effects associated with bundled payments for LEJR.

The critical care literature 2016.

An emergency physician (EP) is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. Between 2001 and 2009, the annual hours of critical care delivered in emergency departments (EDs) across the United States increased >200%! (Herring et al., 2013). This trend has persisted since then. In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, >33% of critically ill patients who are brought to an ED remain there for >6h (Herring et al., 2013). During these crucial early hours of illness, detrimental pathophysiologic processes begin to take hold. During this time, lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in critical care medicine. This review summarizes important articles published in 2016 pertaining to the care of select critically ill patients in the ED. The following topics are covered: intracerebral hemorrhage, traumatic brain injury, anti-arrhythmic therapy in cardiac arrest, therapeutic hypothermia, mechanical ventilation, sepsis, and septic shock.

Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice.

BACKGROUND: Alcohol use disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (New Engl J Med, 2003, 348, 1786). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol (EtOH) consumption in both the 2-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of EtOH withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of EtOH in seizure sensitive DBA/2J (DBA) mice. METHODS: Naïve adult female and male DBA mice were given separate injections of 4 g/kg i.p. EtOH with vehicle or tigecycline (0, 20, 40, or 80 mg/kg i.p.). The 80 mg/kg dose was tested at 3 time points (0, 4, and 7 hours) post EtOH treatment. Handling-induced convulsions (HICs) were measured before and then over 12 hours following EtOH injection. HIC scores and areas under the curve were tabulated. In separate mice, blood EtOH concentrations (BECs) were measured at 2, 4, and 7 hours postinjection of 4 g/kg i.p. EtOH in mice treated with 0 and 80 mg/kg i.p. tigecycline. RESULTS: AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose-responsive reduction in acute AWD convulsions, with no sex differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination. CONCLUSIONS: Tigecycline effectively reduced AWD symptoms in DBA mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action.

Binge Ethanol Consumption Increases Inflammatory Pain Responses and Mechanical and Cold Sensitivity: Tigecycline Treatment Efficacy Shows Sex Differences.

BACKGROUND: Physicians have long reported that patients with chronic pain show higher tendencies for alcohol use disorder (AUD), and AUD patients appear to have higher pain sensitivities. The goal of this study was to test 2 hypotheses: (i) binge alcohol consumption increases inflammatory pain and mechanical and cold sensitivities; and (ii) tigecycline is an effective treatment for alcohol-mediated-increased pain behaviors and sensitivities. Both female and male mice were used to test the additional hypothesis that important sex differences in the ethanol (EtOH)-related traits would be seen. METHODS: "Drinking in the Dark" (DID) alcohol consuming and nondrinking control, female and male, adult C57BL/6J mice were evaluated for inflammatory pain behaviors and for the presence of mechanical and cold sensitivities. Inflammatory pain was produced by intraplantar injection of formalin (10 µl, 2.5% in saline). For cold sensation, a 20 µl acetone drop was used. Mechanical withdrawal threshold was measured by an electronic von Frey anesthesiometer. Efficacy of tigecycline (80 mg/kg i.p.) to reduce DID-related pain responses and sensitivity was tested. RESULTS: DID EtOH consumption increased inflammatory pain behavior, while it also produced sustained mechanical and cold sensitivities in both females and males. Tigecycline produced antinociceptive effects in males; a pro-nociceptive effect was seen in females in the formalin test. Likewise, the drug reduced both mechanical and cold sensitivities in males, but females showed an increase in sensitivity in both tests. CONCLUSIONS: Our results demonstrated that binge drinking increases pain, touch, and thermal sensations in both sexes. In addition, we have identified sex-specific effects of tigecycline on inflammatory pain, as well as mechanical and cold sensitivities. The development of tigecycline as an AUD pharmacotherapy may need consideration of its pro-nociceptive action in females. Further studies are needed to investigate the mechanism underlying the sex-specific differences in nociception.

Effective Reduction in High Ethanol Drinking by Semisynthetic Tetracycline Derivatives.

BACKGROUND: New pharmacotherapies to treat alcohol use disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol (EtOH) drinking in mice. To test the hypothesis that suppression of high EtOH consumption is a general property of tetracyclines, we screened several derivatives for antidrinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose-response relationship. METHODS: Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% EtOH over a 4-day period. Mice were administered a tetracycline or its vehicle 20 hours prior to drinking. Water and EtOH consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for EtOH content measurement immediately following the final bout of drinking. RESULTS: Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced EtOH drinking, and doxycycline showed a strong effect size trend toward reduced drinking. Subsequent studies with these 3 drugs revealed a dose-dependent decrease in EtOH consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on EtOH drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in EtOH consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition coefficients or distribution constants. CONCLUSIONS: Due to its effectiveness in reducing high EtOH consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.