Morphine and its pharmacological derivatives are the most prescribed analgesics for moderate to severe pain management. However, chronic use of morphine reduces pathogen clearance and induces ...bacterial translocation across the gut barrier. The enteric microbiome has been shown to have a critical role in the preservation of the mucosal barrier function and metabolic homeostasis. Here, we show for the first time, using bacterial 16s rDNA sequencing, that chronic morphine treatment significantly alters the gut microbial composition and induces preferential expansion of Gram-positive pathogenic and reduction in bile-deconjugating bacterial strains. A significant reduction in both primary and secondary bile acid levels was seen in the gut, but not in the liver with morphine treatment. Morphine-induced microbial dysbiosis and gut barrier disruption was rescued by transplanting placebo-treated microbiota into morphine-treated animals, indicating that microbiome modulation could be exploited as a therapeutic strategy for patients using morphine for pain management.
Leptin and the sympathetic nervous system have a unique role in linking nutritional status to skeletal metabolism in mammals. Such a regulatory mechanism has not been identified in birds but would be ...beneficial to signal information about energy reserves to an organ system essential for locomotion, reproduction, and survival. To explore this potential role of leptin and the sympathetic nervous system in birds, an ex vivo chick tibiotarsal model was used to test the effects of leptin and sympathetic activity on longitudinal bone growth and the expression of chondrocyte markers. Reverse transcription-PCR analysis revealed the expression of chicken leptin receptor mRNA as well as both α-adrenergic (α1A, α2A, α2B, α2C) and β adrenergic (β1, β2) receptor subtype mRNA in the whole bone. Incubation with norepinephrine (NE; 0, 10, or 100 μM for 4 d) caused a significant increase in distal condyle length as compared with vehicle-treated, contralateral tibiotarsi. In contrast, no change in condyle length was detected after leptin treatment (0 or 10 nM or 1 μM for 4 d). Analysis of cell proliferation by bromodeoxyuridine incorporation revealed no increase in bromodeoxyuridine-positive cells in the condyles in response to leptin or NE treatments. Real-time PCR analysis showed that NE enhanced type X collagen mRNA expression, a marker of mature hypertrophic chondrocytes, with no effect on type II collagen mRNA, the matrix protein secreted by proliferating chondrocytes. Leptin treatment had no effect on the expression of either matrix protein. Treatment with agonists specific for α- or β-adrenergic receptors indicates that the activation of α-adrenergic receptors is most likely responsible for the sympathetic effect on type X collagen gene expression. These results suggest that NE and other sympathetic agonists have positive effects on bone elongation and the changes in critical genes associated with this process. These neurotransmitters may facilitate this by promoting chondrocyte maturation. These studies represent novel evidence suggesting a role of sympathetic tone in the regulation of skeletal growth in avian species.
Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV) infection. Further studies also demonstrate that opioid ...addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population.
Human Immunodeficiency Virus (HIV) pathogenesis has been closely linked with microbial translocation, which is believed to drive inflammation and HIV replication. Opioid drugs have been shown to ...worsen this symptom, leading to a faster progression of HIV infection to Acquired Immunodeficiency Syndrome (AIDS). The interaction of HIV and opioid drugs has not been studied at early stages of HIV, particularly in the gut microbiome where changes may precede translocation events. This study modeled early HIV infection by examining Simian Immunodeficiency Virus (SIV)-infected primates at 21 days or less both independently and in the context of opioid use. Fecal samples were analyzed both for 16S analysis of microbial populations as well as metabolite profiles via mass spectrometry. Our results indicate that changes are minor in SIV treated animals in the time points examined, however animals treated with morphine and SIV had significant changes in their microbial communities and metabolic profiles. This occurred in a time-independent fashion with morphine regardless of how long the animal had morphine in its system. Globally, the observed changes support that microbial dysbiosis is occurring in these animals at an early time, which likely contributes to the translocation events observed later in SIV/HIV pathogenesis. Additionally, metabolic changes were predictive of specific treatment groups, which could be further developed as a diagnostic tool or future intervention target to overcome and slow the progression of HIV infection to AIDS.
Abstract
Clinical observations show a strong correlation between microbial translocation and HIV disease progression. Chronic morphine, on its own, is known to induce bacterial translocation, impair ...immune activation and pathogenic clearance during infection and results in long-term persistent inflammation in the affected organs. Lack of response to therapy, and non-AIDS related comorbidities have been linked to immune activation as a consequence of microbial translocation. The gut microbiota plays a significant role in maintaining gut homeostasis and barrier integrity. Loss of microbes, which are part of the normal flora in healthy hosts, increase the susceptibility to a more virulent composition, that can contribute to barrier disruption and microbial translocation. In this study, we show that morphine induces bacterial translocation across gut mucosa, which is exacerbated with HIV infection. We also show HIV and morphine mediated gut microbiome changes and its influence on the immune system leading to persistent inflammation. Finally, we show that these co-morbidities preferentially favor class firmicutes over others and also increase adherence and alter virulence factors to tweak the host immune system to bring about the said effects.
Opioids are known to exacerbate HIV pathogenesis, however current studies have been limited by models of HIV infection. Given that HIV causes many systemic effects via direct infection of host cells ...as well as indirect bystander effects, it is important to establish a systemic infection model in a small animal so that genetic tools can be utilized to elucidate the mechanisms of action. In this study, the systemic effects of EcoHIV infection, a modified HIV which can infect mouse cells, are examined in conjunction with morphine. EcoHIV infection with opioid treatment induced bacterial translocation from the lumen of the gut into systemic compartments such as liver, which is similar to observations in human patients with LPS. Bacterial translocation corresponds with alterations in gut morphology, disorganization of the tight junction protein occludin, and a concurrent increase in systemic inflammation in both IL-6 and TNFα. Long term infection also had increased expression of inflammatory cytokines in the CNS when co-treated with morphine. Overall, this study shows that EcoHIV is an appropriate model to study the effects of opioids on HIV pathogenesis, including the HIV-induced pathology at early stages of pathogenesis in the gut.
Wound healing is a goal for advanced technology in the surgical space to benefit clinical outcomes. Surgical staplers are commonly used in a variety of open and minimally invasive abdominal and ...thoracic procedures. Assessment of wound healing traits, such as perfusion, has been challenging due to technical limitations. A novel technique that utilizes micro-computed tomography methodology to measure perfusion was designed to compare the micro-perfusion of staple lines between commercial stapler reloads that employ different staple height strategies.
Following an Institutional Animal Care and Use Committee-approved protocol, rats were euthanized and immediately heparinized prior to a subtotal gastrectomy with either graduated-height or single-height staples. Rats were then perfused with barium, following which stomachs were removed and immediately fixed in formalin to prevent degradation. Stomachs were then imaged using micro-computed tomography and subsequent analysis was utilized to quantify fluid volume and patent vasculature proximity to staples within the staple line region for each group.
Average perfusion volume was significantly higher with graduated-height staples (0.33% ± 0.18%) compared to single-height staples (0.16% ± 0.09%,
=0.011). Average vessel-to-staple line distance was not significant but trended lower with graduated-height staples (0.35±0.02 mm) compared to single-height staples (0.36±0.03 mm,
=0.18).
Graduated-height staples had significantly higher perfusion volume than single-height staples, which likely has a downstream benefit on wound healing and clinical outcomes.
This study shows a higher perfusion volume around the staple lines using graduated-height staples as compared to single-height staples and this may contribute to better wound healing in patients.
The authors evaluated the roles of auditory-verbal short-term memory, visual short-term memory, and group membership in predicting language comprehension, as measured by an experimental sentence ...comprehension task (SCT) and the Test for Auditory Comprehension of Language--Third Edition (TACL-3; E. Carrow-Woolfolk, 1999) in 38 participants: 19 with Down syndrome (DS), age 12 to 21 years, and 19 typically developing (TD) children, age 3 to 5 years, matched on syntax comprehension, as measured by TACL-3 Subtests II and III. Of the 5 dependent measures of comprehension, auditory-verbal short-term memory accounted for significant amounts of variance in 4; group membership, 1 (semantic role assignment); and visual short-term memory, 0. In the group with DS, hearing status predicted variation in Grammatical Morphemes (TACL-3 Subtest II). Using the SCT, the authors also investigated the effects of varying sentence voice and supporting visual context on sentence comprehension. SCT performance was significantly poorer in terms of (a) referent selection and semantic role assignment, for passive (vs. active) sentences in both groups, and (b) semantic role assignment in all sentences for the group with DS (vs. the TD group). Vocabulary strengths in the group with DS were found with the Peabody Picture Vocabulary Test--Third Edition (L. M. Dunn & L. M. Dunn, 1997) but not the TACL-3 Vocabulary subtest.KEY WORDS: language comprehension, Down syndrome, memory, preschool children, language functions and disorders
The primary results from the Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) trial have previously been reported. The objective of the current manuscript is to report ...long-term outcomes.
The VAM-IHCA trial was a multicenter, randomized, double-blind, placebo-controlled trial conducted at ten hospitals in Denmark. Adult patients (age ≥ 18 years) were eligible for the trial if they had an in-hospital cardiac arrest and received at least one dose of epinephrine during resuscitation. The trial drugs consisted of 40 mg methylprednisolone (Solu-Medrol®, Pfizer) and 20 IU of vasopressin (Empressin®, Amomed Pharma GmbH) given as soon as possible after the first dose of epinephrine. This manuscript report outcomes at 6 months and 1 year including survival, survival with favorable neurological outcome, and health-related quality of life.
501 patients were included in the analysis. At 1 year, 15 patients (6.3%) in the intervention group and 22 patients (8.3%) in the placebo group were alive corresponding to a risk ratio of 0.76 (95% CI, 0.41–1.41). A favorable neurologic outcome at 1 year, based on the Cerebral Performance Category score, was observed in 14 patients (5.9%) in the intervention group and 20 patients (7.6%) in the placebo group (risk ratio, 0.78 95% CI, 0.41–1.49. No differences existed between groups for favorable neurological outcome and health-related quality of life at either 6 months or 1 year.
Administration of vasopressin and methylprednisolone, compared with placebo, in patients with in-hospital cardiac arrest did not improve long-term outcomes in this trial.
To describe the clinical trial “Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest” (VAM-IHCA).
The VAM-IHCA trial is an investigator-initiated, multicenter, randomized, ...placebo-controlled, parallel group, double-blind, superiority trial of vasopressin and methylprednisolone during adult in-hospital cardiac arrest. The study drugs consist of 40 mg methylprednisolone and 20 IU of vasopressin given as soon as possible after the first dose of adrenaline. Additional doses of vasopressin (20 IU) will be administered after each adrenaline dose for a maximum of four doses (80 IU).
The primary outcome is return of spontaneous circulation and key secondary outcomes include survival and survival with a favorable neurological outcome at 30 days. 492 patients will be enrolled. The trial was registered at the EU Clinical Trials Register (EudraCT Number: 2017-004773-13) on Jan. 25, 2018 and ClinicalTrials.gov (Identifier: NCT03640949) on Aug. 21, 2018.
The trial started in October 2018 and the last patient is anticipated to be included in January 2021. The primary results will be reported after 3-months follow-up and are, therefore, anticipated in mid-2021.
The current article describes the design of the VAM-IHCA trial. The results from this trial will help clarify whether the combination of vasopressin and methylprednisolone when administered during in-hospital cardiac arrest improves outcomes.
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