Accelerating the Washout of Inhalational Anesthetics from the Dräger Primus Anesthetic Workstation: Effect of Exchangeable Internal Components

Background: To establish guidelines for the preparation of the Primus anesthetic workstation (Drager, Lubeck, Germany) for malignant hyperthermia-susceptible patients, the authors evaluated the effect of replacing the workstation's exchangeable internal components on the washout of isoflurane.

Methods: Primus workstations were exposed to isoflurane, and contaminated internal components were replaced as follows: group 1, no replacement; group 2, new ventilator diaphragm; group 3, autoclaved ventilator diaphragm; group 4, autoclaved integrated breathing system; group 5, flushed integrated breathing system; group 6, autoclaved ventilator diaphragm and integrated breathing system. The fresh gas flow was set at 10 l/min, and subsequently reduced to 3 l/min when a concentration of 5 ppm was achieved. Isoflurane concentration was measured in the inspiratory limb of the circle circuit every minute.

Results: Washout times for isoflurane decreased in the following order: group 1 (67 +/- 6.5 min) > groups 2 and 3 (50 +/- 4.1 and 50 +/- 5.7 min, respectively) > group 5 (43 +/- 9.5 min) > group 4 (12 +/- 1.5 min) > group 6 (3.2 +/- 0.4 min). Isoflurane concentration increased approximately threefold when the fresh gas flow was reduced to 3 l/min.     

Burst Activation of the Cerebral Cortex by Flash Stimuli during Isoflurane Anesthesia in Rats

Background: The degree of suppression of sensory functions during general anesthesia is controversial. Here, the authors investigated whether discrete flash stimuli induced cortical field potential responses at an isoflurane concentration producing burst suppression and compared the spatiotemporal properties and frequency spectra of flash-induced burst responses with those occurring spontaneously.

Methods: Rats were equipped with multiple epidural and intracortical electrodes to record cortical field potentials in the right hemisphere at several locations along the anterior-posterior axis. At isoflurane concentrations of 1.1, 1.4, and 1.8%, discrete light flashes were delivered to the left eye while cortical field potentials were continuously recorded.

Results: Isoflurane at 1.4-1.8% produced burst suppression. Each flash produced a visual evoked potential in the primary visual cortex followed by secondary bursting activity in more anterior regions. The average latency and duration of these bursts were 220 and 810 ms, respectively. The spontaneous and flash-induced bursts were similar in frequency, duration, and spatial distribution. They had maximum power in the frontal (primary motor) cortex with a dominant frequency of 10 Hz.     

Hyperlocomotion during Recovery from Isoflurane Anesthesia Is Associated with Increased Dopamine Turnover in the Nucleus Accumbens and Striatum in Mice

Background: It was recently reported that isoflurane increases dopamine release in the striatum in rats both in vivo and in vitro, and that isoflurane inhibits uptake of dopamine in the rat brain synaptosomes. However, the functional role of these effects of isoflurane on dopamine neurons is uncertain. Dopaminergic mechanisms within the nucleus accumbens and striatum play an important role in the control of locomotor activity, and a change in dopamine turnover depends essentially on a change in impulse flow in the dopamine neurons. In this study, the effects of isoflurane on locomotor activity and on dopamine turnover were investigated in discrete brain regions in mice.

Methods: Mice were placed in individual airtight clear plastic chambers and spontaneously breathed isoflurane in 25% oxygen and 75% nitrogen (fresh gas flow, 4 l/min). Locomotor activity was measured with an Animex activity meter. Animals were decapitated after treatments with or without isoflurane, and the concentrations of monoamines and their metabolites in different brain areas were measured by high-performance liquid chromatography.

Results: During the 10 min after the cessation of the 20-min exposure to isoflurane, there was a significant increase in locomotor activity in animals breathing 1.5% isoflurane but not 0.7% isoflurane. This increase in locomotor activity produced by 1.5% isoflurane was abolished by a low dose of haloperidol (0.1 mg/kg), a dopamine receptor antagonist. Regional brain monoamine assays revealed that 1.5% isoflurane significantly increased the 3,4-dihydroxyphenylacetic acid:dopamine ratio (one indicator of transmitter turnover) in the nucleus accumbens and striatum, but a concentration of 0.7% did not. This significant increase in dopamine turnover in these regions continued during 20 min after the cessation of the administration of 1.5% isoflurane.     

Targeted Disruption of the CXCL12/CXCR4 Axis Inhibits Osteolysis in a Murine Model of Myeloma‐Associated Bone Loss

The plasma cell (PC) malignancy, multiple myeloma (MM), is unique among hematological malignancies in its capacity to cause osteoclast (OC)‐mediated skeletal destruction. We have previously shown that elevated plasma levels of PC‐derived CXCL12 are associated with presence of X‐ray detectable osteolytic lesions in MM patients. To further investigate this relationship, plasma levels of CXCL12 and βCrossLaps, a marker of bone loss, were measured. A strong correlation between levels of CXCL12 and OC‐mediated bone resorption was identified. To confirm the OC‐activating potential of MM PC‐derived CXCL12 in vivo, we established a model of MM‐mediated focal osteolysis, wherein MM PC lines, such as RPMI‐8226, were injected into the tibias of nude mice. Implanting RPMI‐8226 gave rise to osteolytic lesions proximal to the tumor, resulting in a 5% decrease in bone volume (BV) compared with vehicle control. Importantly, bone loss was significantly inhibited with systemic administration of the CXCL12/CXCR4 antagonist T140. Furthermore, implanting CXCL12‐overexpressing RPMI‐8226 cells resulted in a 13% decrease in BV and was associated with increased OC recruitment proximal to the tumor, increased serum matrix metalloproteinase activity, and increased levels of collagen I degradation products. These findings confirm our hypothesis that MM PC‐derived CXCL12 stimulates the recruitment and activity of OC, thereby contributing to the formation of MM osteolytic lesions.     

Disruption of the dynein‐dynactin complex unveils motor‐specific functions in osteoclast formation and bone resorption

Osteoclastic bone resorption requires strict interplay between acidified carrier vesicles, motor proteins, and the underlying cytoskeleton in order to sustain the specialized structural and functional polarization of the ruffled border. Cytoplasmic dynein, a large processive mechanochemical motor comprising heavy, intermediate, and light chains coupled to the dynactin cofactor complex, powers unilateral motility of diverse cargos to microtubule minus‐ends. We have recently shown that regulators of the dynein motor complex constitute critical components of the osteoclastic bone resorptive machinery. Here, by selectively modulating endogenous dynein activity, we show that the integrity of the dynein‐dynactin motor complex is an essential requirement for both osteoclast formation and function. Systematic dissection of the osteoclast dynein‐dynactin complex revealed that it is differentially localized throughout RANKL‐induced osteoclast formation and activation, undergoing microtubule‐coupled reorganization upon the establishment of cellular polarization. In osteoclasts actively resorbing bone, dynein‐dynactin intimately co‐localizes with the CAP‐Gly domain‐containing microtubule plus‐end protein CLIP‐170 at the resorptive front, thus orientating the ruffled border as a microtubule plus‐end domain. Unexpectedly, disruption of the dynein‐dynactin complex by exogenous p50/dynamitin expression retards osteoclast formation in vitro, owing largely to prolonged mitotic stasis of osteoclast progenitor cells. More importantly, loss of osteoclastic dynein activity results in a drastic redistribution of key intracellular organelles, including the Golgi and lysosomes, an effect that coincides with impaired cathepsin K secretion and diminished bone resorptive function. Collectively, these data unveil a previously unrecognized role for the dynein‐dynactin motor complex in osteoclast formation and function, serving not only to regulate their timely maturation but also the delivery of osteolytic cargo that is essential to the bone resorptive process. © 2013 American Society for Bone and Mineral Research     

Role of EP4 prostaglandin E2 receptor in the ischemic liver

Prostaglandin E(2) (PGE(2)) mediates a variety of both innate and adaptive immunity responses through 4 distinct receptors, EP1-4. Recent studies have suggested the physiological and pathological role of EP4 in various inflammatory diseases. In this study, we investigated the importance of the EP4 receptor, and the efficacy of a selective EP4 agonist to alter hepatic ischemia/reperfusion (I/R) injury, an important cause of damage in liver resection and transplantation. We used an established murine I/R injury model, 70% partial hepatic ischemia for 90 minutes in male C57BL/6 mice. The local expression of EP4 messenger RNA (mRNA) in the naive and the ischemic liver at 2 hours after reperfusion was examined using RT-PCR analysis. Some mice received the EP4 selective agonist during I/R. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured as markers of hepatic injury. EP4 expression in the liver was significantly up-regulated at 2 hours after reperfusion. Furthermore, treatment with EP4 agonist significantly inhibited hepatic injury at 6 hours after reperfusion. Our data suggest an inhibitory role of EP4 PGE(2) receptor in hepatic I/R injury and the therapeutic efficacy of a selective EP4 agonist for liver protection.     

Expression of the proto-oncogene eIF4E in inflammation of the oral cavity.

OBJECTIVE: eIF4E (4E) is elevated in 100% of head and neck squamous cell carcinoma (HNSCC) and in premalignant lesions of the larynx. However, it is not elevated in normal mucosa. In this study, we hypothesize that 4E is not significantly elevated in inflammation unlike its expression in premalignant lesions of the oral cavity. STUDY DESIGN: Biopsies from the oral cavity were divided into 5 groups: (1) normal mucosa, (2) chronic inflammation, (3) mild dysplasia from leukoplakic lesions, (4) mild dysplasia in surgical margins of patients with HNSCC, and (5) HNSCC. Immunohistochemical qualitative analysis was then performed. RESULTS: None of the 15 specimens in group 1 and 100% of the 15 specimens in group 5 expressed 4E. Of the 29 specimens in group 2 only 4/29 (13%) overexpressed 4E compared with 10/31 (32%) in group 3 and 9/21 (42%) in group 4. There was a significant difference between groups 2 and 3 and groups 2 and 4 (P < 0.0001 and P < 0.003 respectively) but no significant difference between groups 1 and 2 (P = 0.13) and between groups 3 and 4 (P = 0.30). CONCLUSION: 4E is not significantly elevated in inflammation of the oral cavity thus fulfilling one of the criteria that biomarkers require to be useful in a clinical setting.     

Renal transplantation during the SARS‐CoV‐2 pandemic in the UK: Experience from a large‐volume center

There is uncertainty about the safety of kidney transplantation during the SARS‐CoV‐2 pandemic due to the risk of donor transmission, nosocomial infection and immunosuppression use. We describe organ donation and transplant practice in the UK and assess whether kidney transplantation conferred a substantial risk of harm. Data from the UK transplant registry were used to describe kidney donation and transplant activity in the UK, and a detailed analysis of short‐term, single‐center, patient results in two periods: during the pre‐pandemic era from 30th December 2019 to 8th March 2020 (“Pre‐COVID era”) and the 9th March 2020 to 19th May 2020 (“COVID era”). Donor and recipient numbers fell by more than half in the COVID compared to the pre‐COVID era in the UK, but there were more kidney transplants performed in our center (42 vs. 29 COVID vs. pre‐COVID respectively). Overall outcomes, including re‐operation, delayed graft function, primary non‐function, acute rejection, length of stay and graft survival were similar between COVID and pre‐COVID era. 6/71 patients became infected with SARS‐CoV‐2 but all were discharged without critical care requirement. Transplant outcomes have remained similar within the COVID period and no serious sequelae of SARS‐CoV‐2 infection were observed in the peri‐transplant period.