Evidence that opioids may have toll-like receptor 4 and MD-2 effects

Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically-employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.     

New therapies, new concerns: rituximab-associated lung injury

The indications for use of B-cell depleting therapy with the monoclonal antibody rituximab are progressively increasing in patients with renal disease. This includes patients with nephrotic syndrome and renal graft rejection. Late-onset pulmonary injury associated with rituximab therapy has been increasingly recognized. While frequently reversible, it can be fatal. The spectrum of pulmonary disease associated with rituximab therapy, its investigation, and treatment are briefly reviewed.     

Composition and morphology of epidermal cyst lipids

The contents of epidermal cysts were used as a source of desquamated human keratinocytes uncontaminated by sebaceous, subcutaneous, or bacterial lipids. Lipids extracted with chloroform:methanol mixtures included six series of ceramides (41% of the total extractable lipid), cholesterol (27%), cholesteryl esters (10%), fatty acids (9%), cholesteryl sulfate (1.9%), a novel class of ceramide esters (3.8%), and a sterol diester (0.9%). Electron microscopy revealed that the lipids in the cyst contents existed as multiple intercellular lamellae, as in stratum corneum. One lamella, adjacent to the horny cell protein envelope, was resistant to lipid extraction and is thought to represent covalently bound lipid on the outer surface of the keratinocyte. The results indicate that the degradation of intercellular lipid lamellae is not required for desquamation.     

Assessment of biocompatibility and initial evaluation of genipin cross-linked elastin-like polypeptides in the treatment of an osteochondral knee defect in rabbits

Polypeptides based on the alternating hydrophobic and cross-linking domain structure of human elastin are capable of undergoing self-assembly to produce polymeric matrices with unique biological and mechanical properties. Here, we test the initial feasibility of using a genipin cross-linked elastin-based material as an acellular plug in the treatment of an osteochondral defect in the rabbit knee. Full-thickness defects in the weight-bearing surface of the medial femoral condyle in 18 New Zealand White rabbits were surgically produced and press fitted with cylindrical pads composed of genipin cross-linked elastin-like polypeptides, with identical wounds in the opposite knee left untreated as controls. The biocompatibility of the material, overall wound healing and regeneration of subchondral tissue was assessed at 2, 4 and 6 weeks by histological evaluation, synovial fluid analysis and microcomputerized tomography scanning. Histological analysis revealed the regeneration of subchondral bone at the periphery of the material, with evidence of hyaline-like overgrowth across the apical surface in 11/16 cases. Pads developed tight contacts with host tissue and appeared completely biocompatible, with no evidence of localized immune response or increased inflammation compared to controls. The material was stable to 6 weeks, with an aggregate elastic modulus calculated at ～470 kPa when tested under confined compression. Further studies are required to assess material degradation over time and long-term replacement with repair tissue.     

The effect of premorbid attention-deficit/hyperactivity disorder on neuropsychological functioning in individuals with acute mild traumatic brain injuries

Introduction. Mild traumatic brain injury (mTBI) is a frequent, yet undertreated condition that typically manifests with transient neurological and cognitive symptoms that resolve over the course of several weeks. In contrast, attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that presents initially in childhood but often persists into adulthood. mTBI and ADHD include overlapping symptomatology, making it difficult for clinicians to disentangle the sequelae of each condition when they co-occur in the same individual. We hypothesized that neuropsychological tests would be sensitive to preexisting ADHD in inpatients with acute mTBIs. Method. We retrospectively examined the medical charts of 100 inpatients, aged 18–40 years (96% Caucasian; 77% male) with mTBIs in an acute care setting, half of whom had self-reported the presence of premorbid ADHD, and half of whom were matched controls. We analyzed group differences across neuropsychological tests of attention, processing speed, and executive functions, examined the profile ratings of independent, blinded, board-certified neuropsychologists, and correlated cognitive performance with time from traumatic injury to testing. Results. Individuals with premorbid ADHD (a) performed significantly worse than their matched counterparts on several tests of attention, processing speed, and working memory, and (b) were significantly more likely to produce profiles later rated as impaired by independent, board-certified clinical neuropsychologists. In addition, time from traumatic injury to testing was found to be negatively correlated with neurocognitive performance. Conclusions. These findings (a) argue for the utility of a brief assessment of premorbid ADHD in the acute care of individuals with mTBIs and (b) provide clinicians with a barometer for gauging the relative contributions of premorbid ADHD to neuropsychological impairments in the neurocognitive profiles of individuals with mTBIs. Reported effect sizes will assist clinicians in accurately weighing the impact of premorbid ADHD when interpreting such profiles.     

Hepatobiliary cystadenoma: a rare hepatic tumor in a child

This report describes a 3-year-old child with a hepatobiliary cystadenoma. Cystadenomas are benign, multilocular, cystic neoplasms that usually occur in middle-aged women. The patients may be asymptomatic, but often there are vague abdominal complaints related to extrinsic compression of the stomach, duodenum, or biliary tree. Recurrence following incomplete excision and the presence of carcinoma within otherwise benign cysts has been documented. Complete resection is the therapy of choice, and thorough histopathologic evaluation is imperative.