Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans.

AIMS: Changes in serotonergic sensory modulation associated with overexpression of 5-HT3 receptors in the central nervous system (CNS) have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration. METHODS: Fifteen patients were given a single 16 mg intravenous 15 minute infusion of ondansetron, followed by serial blood and a single CSF sampling. Population pharmacokinetic (PK) modelling was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two-compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS. RESULTS: The individual model-estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26. CONCLUSIONS: After intravenous administration, CSF concentrations of ondansetron were approximately 7-fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration-time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain.

Decadal Bering Sea seascape change: consequences for Pacific walruses and indigenous hunters.

The most significant factors currently affecting the Pacific walrus (Odobenus rosmarus divergens) population are climate change and consequent changes in sea-ice morphology and dynamics. This paper integrates recent physical sea-ice change in the Bering Sea with biological and ecological conditions of walruses in their winter-spring reproductive habitat. Historically, walrus in winter-spring depended on a critical mass of sea-ice habitat to optimize social networking, reproductive fitness, feeding behavior, migration, and energetic efficiency. During 2003-2013, our cross-disciplinary, multiscale analysis from shipboard observations, satellite imagery, and ice-floe tracking, reinforced by information from indigenous subsistence hunters, documented change of sea-ice structure from a plastic continuum to a "mixing bowl" of ice floes moving more independently. This fragmentation of winter habitat preconditions the walrus population toward dispersal mortality and will also negatively affect the availability of resources for indigenous communities. We urge an expanded research and management agenda that integrates walrus natural history and habitat more completely with changing sea-ice morphology and dynamics at multiple scales, while also meeting the needs of local communities.

An LC-ESI-MS/MS method for determination of ondansetron in low-volume plasma and cerebrospinal fluid: Method development, validation, and clinical application.

Ondansetron is used in clinical settings as an antiemetic drug. Although the animal studies showed its potential effectiveness also in treating neuropathic pain, the results from humans are inconclusive. The lack of efficacy of ondansetron in a subset of patients might be due to the overexpression of P-glycoprotein, which could result in low concentrations of ondansetron in the central nervous system (CNS). A surrogate of the CNS exposure might be drug concentration in the cerebrospinal fluid (CSF), especially in humans, as assessing the drug disposition directly in the patient's brain would be challenging. The study aimed to develop a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine concentrations of ondansetron in human K3EDTA plasma and CSF. Ondansetron was extracted from biological matrices by liquid-liquid extraction. The quantification was performed on a Sciex QTRAP 6500+ mass spectrometer with labeled ondansetron as an internal standard. The calibration range was 0.25-350 ng/mL in plasma and 0.025-100 ng/mL in CSF; for both matrices, 25 µL of samples was required for the assays. The method was validated according to the FDA and EMA guidelines and showed acceptable results. A pilot study confirmed its suitability for clinical samples: after 4-16 mg of intravenous ondansetron, the determined concentrations in plasma were 1.22-235.90 ng/mL, while in CSF - 0.018-11.93 ng/mL. In conclusion, the developed method fulfilled all validation requirements and can be applied to pharmacokinetic studies assessing the CNS ondansetron exposure in humans. The method's advantages, such as a low volume of matrix and a wide calibration range, support its use in a study in which rich sampling and various drug doses are expected.

A comprehensive satellite-based assessment across the Pacific Arctic Distributed Biological Observatory shows widespread late-season sea surface warming and sea ice declines with significant influences on primary productivity.

Massive declines in sea ice cover and widespread warming seawaters across the Pacific Arctic region over the past several decades have resulted in profound shifts in marine ecosystems that have cascaded throughout all trophic levels. The Distributed Biological Observatory (DBO) provides sampling infrastructure for a latitudinal gradient of biological "hotspot" regions across the Pacific Arctic region, with eight sites spanning the northern Bering, Chukchi, and Beaufort Seas. The purpose of this study is two-fold: (a) to provide an assessment of satellite-based environmental variables for the eight DBO sites (including sea surface temperature (SST), sea ice concentration, annual sea ice persistence and the timing of sea ice breakup/formation, chlorophyll-a concentrations, primary productivity, and photosynthetically available radiation (PAR)) as well as their trends across the 2003-2020 time period; and (b) to assess the importance of sea ice presence/open water for influencing primary productivity across the region and for the eight DBO sites in particular. While we observe significant trends in SST, sea ice, and chlorophyll-a/primary productivity throughout the year, the most significant and synoptic trends for the DBO sites have been those during late summer and autumn (warming SST during October/November, later shifts in the timing of sea ice formation, and increases in chlorophyll-a/primary productivity during August/September). Those DBO sites where significant increases in annual primary productivity over the 2003-2020 time period have been observed include DBO1 in the Bering Sea (37.7 g C/m2/year/decade), DBO3 in the Chukchi Sea (48.0 g C/m2/year/decade), and DBO8 in the Beaufort Sea (38.8 g C/m2/year/decade). The length of the open water season explains the variance of annual primary productivity most strongly for sites DBO3 (74%), DBO4 in the Chukchi Sea (79%), and DBO6 in the Beaufort Sea (78%), with DBO3 influenced most strongly with each day of additional increased open water (3.8 g C/m2/year per day). These synoptic satellite-based observations across the suite of DBO sites will provide the legacy groundwork necessary to track additional and inevitable future physical and biological change across the region in response to ongoing climate warming.

On the variability of the Bering Sea Cold Pool and implications for the biophysical environment.

The Bering Sea experiences a seasonal sea ice cover, which is important to the biophysical environment found there. A pool of cold bottom water (<2°C) is formed on the shelf each winter as a result of cooling and vertical mixing due to brine rejection during the predominately local sea ice growth. The extent and distribution of this Cold Pool (CP) is largely controlled by the winter extent of sea ice in the Bering Sea, which can vary considerably and recently has been much lower than average. The cold bottom water of the CP is important for food security because it delineates the boundary between arctic and subarctic demersal fish species. A northward retreat of the CP will likely be associated with migration of subarctic species toward the Chukchi Sea. We use the fully-coupled Regional Arctic System Model (RASM) to examine variability of the extent and distribution of the CP and its relation to change in the sea ice cover in the Bering Sea during the period 1980-2018. RASM results confirm the direct correlation between the extent of sea ice and the CP and show a smaller CP as a consequence of realistically simulated recent declines of the sea ice cover in the Bering Sea. In fact, the area of the CP was found to be only 31% of the long-term mean in July of 2018. In addition, we also find that a low ice year is followed by a later diatom bloom, while a heavy ice year is followed by an early diatom bloom. Finally, the RASM probabilistic intra-annual forecast capability is reviewed, based on 31-member ensembles for 2019-2021, for its potential use for prediction of the winter sea ice cover and the subsequent summer CP area in the Bering Sea.

Phytoplankton bloom stages estimated from chlorophyll pigment proportions suggest delayed summer production in low sea ice years in the northern Bering Sea.

Decreased sea ice cover in the northern Bering Sea has altered annual phytoplankton phenology owing to an expansion of open water duration and its impact on ocean stratification. Limitations of satellite remote sensing such as the inability to detect bloom activity throughout the water column, under ice, and in cloudy conditions dictate the need for shipboard based measurements to provide more information on bloom dynamics. In this study, we adapted remote sensing land cover classification techniques to provide a new means to determine bloom stage from shipboard samples. Specifically, we used multiyear satellite time series of chlorophyll a to determine whether in-situ blooms were actively growing or mature (i.e., past-peak) at the time of field sampling. Field observations of chlorophyll a and pheophytin (degraded and oxidized chlorophyll products) were used to calculate pheophytin proportions, i.e., (Pheophytin/(Chlorophyll a + Pheophytin)) and empirically determine whether the bloom was growing or mature based on remotely sensed bloom stages. Data collected at 13 north Bering Sea stations each July from 2013-2019 supported a pheophytin proportion of 28% as the best empirical threshold to distinguish a growing vs. mature bloom stage. One outcome was that low vs. high sea ice years resulted in significantly different pheophytin proportions in July; in years with low winter-to-spring ice, more blooms with growing status were observed, compared to later stage, more mature blooms following springs with abundant seasonal sea ice. The detection of growing blooms in July following low ice years suggests that changes in the timing of the spring bloom triggers cascading effects on mid-summer production.

Characterization of Patients With and Without Painful Peripheral Neuropathy After Receiving Neurotoxic Chemotherapy: Traditional Quantitative Sensory Testing vs C-Fiber and Aδ-Fiber Selective Diode Laser Stimulation.

Painful chemotherapy induced peripheral neuropathy (CIPN) is a common complication of chemotherapy with drugs such as taxanes and platinum compounds. Currently, no methods are available for early detection of sensory changes that are associated with painful CIPN, nor are there biomarkers that are specific to painful CIPN. This study aimed to compare Diode Laser fiber type-selective stimulator (DLss), a method to selectively stimulate cutaneous C and Aδ fibers, to traditional quantitative sensory testing (QST) in determining psychophysical differences between patients with painful CIPN and a control group. Sensory testing was performed on the dorsal mid-foot of 20 patients with painful neuropathy after taxane- or platinum-based chemotherapy, and 20 patients who received similar neurotoxic chemotherapy, without painful CIPN. In a multivariable analysis, C-fiber to Aδ fiber detection threshold ratio, measured by DLss, was significantly different between the groups (P <.05). While QST parameters such as warmth detection threshold were different between the groups in univariate analyses, these findings were likely attributable to group differences in patient age and cumulative chemotherapy dose. PERSPECTIVE: In this study, fiber-specific DLss test showed potential in identifying sensory changes that are specific for painful neuropathy, encouraging future testing of this approach as a biomarker for early detection of painful CIPN. TRIAL REGISTRATION: The study was approved by the Washington University Institutional Review Board (#201807162) and registered at ClinicalTrials.gov (NCT03687970).

Headache outcomes following treatment of unruptured intracranial aneurysms: a prospective analysis.

OBJECTIVE: To analyze headache patterns prior to and following treatment of unruptured intracranial aneurysms and identify factors associated with different headache outcomes. METHODS: A prospective observational study of patients being treated for unruptured intracranial aneurysms. Headache patterns were established prior to aneurysm treatment and for 6 months following treatment. Factors associated with different headache outcomes were investigated. RESULTS: In all patients (n = 44), 90-day headache frequency decreased from an average of 31 days prior to aneurysm treatment to 17 days following treatment (p < 0.001). In patients with active pretreatment headaches (n = 28), 90-day headache frequency decreased from 49 days to 26 days (p = 0.002). Headache frequency was reduced in 68% of patients, while 9% of patients had new or worsened headaches following aneurysm treatment. Pretreatment migraine, more severe pretreatment headaches, higher pretreatment trait anxiety, and stent-assisted aneurysm coiling were associated with a lack of headache improvement. CONCLUSIONS: The majority of patients with headaches at the time of aneurysm treatment had reductions in headache frequency during the 6 months following treatment. Potential risk factors for poor headache outcomes were identified but need to be studied further.

Episodic and chronic migraineurs are hypersensitive to thermal stimuli between migraine attacks.

OBJECTIVE: To determine if migraineurs have evidence of interictal cutaneous sensitisation. SUBJECTS AND METHODS: Thermal and mechanical pain thresholds in 20 episodic migraineurs, 20 chronic migraineurs, and 20 non-migraine control subjects were compared. Quantitative sensory testing was conducted when subjects had been migraine-free for at least 48 h. Heat, cold and mechanical pain thresholds, and heat and cold pain tolerance thresholds were measured. RESULTS: Thermal pain thresholds and thermal pain tolerance thresholds differed significantly by headache group (P = 0.001). During the interictal period, episodic and chronic migraineurs were more sensitive to thermal stimulation than non-migraine controls. CONCLUSIONS: Interictal sensitisation may predispose the migraineur to development of headaches, may be a marker of migraine activity, and a target for treatment.

Female Pacific walruses (Odobenus rosmarus divergens) show greater partitioning of sea ice organic carbon than males: Evidence from ice algae trophic markers.

The expected reduction of ice algae with declining sea ice may prove to be detrimental to the Pacific Arctic ecosystem. Benthic organisms that rely on sea ice organic carbon (iPOC) sustain benthic predators such as the Pacific walrus (Odobenus rosmarus divergens). The ability to track the trophic transfer of iPOC is critical to understanding its value in the food web, but prior methods have lacked the required source specificity. We analyzed the H-Print index, based on biomarkers of ice algae versus phytoplankton contributions to organic carbon in marine predators, in Pacific walrus livers collected in 2012, 2014 and 2016 from the Northern Bering Sea (NBS) and Chukchi Sea. We paired these measurements with stable nitrogen isotopes (δ15N) to estimate trophic position. We observed differences in the contribution of iPOC in Pacific walrus diet between regions, sexes, and age classes. Specifically, the contribution of iPOC to the diet of Pacific walruses was higher in the Chukchi Sea (52%) compared to the NBS (30%). This regional difference is consistent with longer annual sea ice persistence in the Chukchi Sea. Within the NBS, the contribution of iPOC to walrus spring diet was higher in females (~45%) compared to males (~30%) for each year (p < 0.001), likely due to specific foraging behavior of females to support energetic demands associated with pregnancy and lactation. Within the Chukchi Sea, the iPOC contribution was similar between males and females, yet higher in juveniles than in adults. Despite differences in the origin of organic carbon fueling the system (sea ice versus pelagic derived carbon), the trophic position of adult female Pacific walruses was similar between the NBS and Chukchi Sea (3.2 and 3.5, respectively), supporting similar diets (i.e. clams). Given the higher quality of organic carbon from ice algae, the retreat of seasonal sea ice in recent decades may create an additional vulnerability for female and juvenile Pacific walruses and should be considered in management of the species.

Prediction of Individual Analgesic Response to Intravenous Lidocaine in Painful Diabetic Peripheral Neuropathy: A Randomized, Placebo-controlled, Crossover Trial.

OBJECTIVES: Intravenous lidocaine can alleviate painful diabetic peripheral neuropathy (DPN) in some patients. Whether quantitative sensory testing (QST) can identify treatment responders has not been prospectively tested. MATERIALS AND METHODS: This was a prospective, randomized, double-blind, crossover, placebo-controlled trial comparing intravenous lidocaine to normal saline (placebo) for painful DPN. Thirty-four participants with painful DPN were enrolled and administered intravenous lidocaine (5 mg/kg ideal body weight) or placebo as a 40-minute infusion, after a battery of QST parameters were tested on the dorsal foot, with a 3-week washout period between infusions. RESULTS: Thirty-one participants completed both study sessions and were included in the final analysis. Lidocaine resulted in a 51% pain reduction 60 to 120 minutes after infusion initiation, as assessed on a 0 to 10 numerical rating scale, while placebo resulted in a 33.5% pain reduction (difference=17.6%, 95% confidence interval [CI], 1.9%-33.3%, P=0.03). Neither mechanical pain threshold, heat pain threshold, or any of the other measured QST parameters predicted the response to treatment. Lidocaine administration reduced mean Neuropathic Pain Symptom Inventory paresthesia/dysesthesia scores when compared with placebo by 1.29 points (95% CI, -2.03 to -0.55, P=0.001), and paroxysmal pain scores by 0.84 points (95% CI, -1.62 to -0.56, P=0.04), without significant changes in burning, pressing or evoked pain subscores. DISCUSSION: While some participants reported therapeutic benefit from lidocaine administration, QST measures alone were not predictive of response to treatment. Further studies, powered to test more complex phenotypic interactions, are required to identify reliable predictors of response to pharmacotherapy in patients with DPN.

Seasonal and latitudinal variations in sea ice algae deposition in the Northern Bering and Chukchi Seas determined by algal biomarkers.

An assessment of the production, distribution and fate of highly branched isoprenoid (HBI) biomarkers produced by sea ice and pelagic diatoms is necessary to interpret their detection and proportions in the northern Bering and Chukchi Seas. HBIs measured in surface sediments collected from 2012 to 2017 were used to determine the distribution and seasonality of the biomarkers relative to sea ice patterns. A northward gradient of increasing ice algae deposition was observed with localized occurrences of elevated IP25 (sympagic HBI) concentrations from 68-70°N and consistently strong sympagic signatures from 71-72.5°N. A declining sympagic signature was observed from 2012 to 2017 in the northeast Chukchi Sea, coincident with declining sea ice concentrations. HBI fluxes were investigated on the northeast Chukchi shelf with a moored sediment trap deployed from August 2015 to July 2016. Fluxes of sea ice exclusive diatoms (Nitzschia frigida and Melosira arctica) and HBI-producing taxa (Pleurosigma, Haslea and Rhizosolenia spp.) were measured to confirm HBI sources and ice associations. IP25 was detected year-round, increasing in March 2016 (10 ng m-2 d-1) and reaching a maximum in July 2016 (1331 ng m-2 d-1). Snowmelt triggered the release of sea ice algae into the water column in May 2016, while under-ice pelagic production contributed to the diatom export in June and July 2016. Sea ice diatom fluxes were strongly correlated with the IP25 flux, however associations between pelagic diatoms and HBI fluxes were inconclusive. Bioturbation likely facilitates sustained burial of sympagic organic matter on the shelf despite the occurrence of pelagic diatom blooms. These results suggest that sympagic diatoms may sustain the food web through winter on the northeast Chukchi shelf. The reduced relative proportions of sympagic HBIs in the northern Bering Sea are likely driven by sea ice persistence in the region.

The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects.

Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade. Furthermore, fenobam showed no signs of analgesic tolerance with up to 2 weeks of daily dosing in mice. Analgesic effects of fenobam in humans have not been reported. The purpose of this investigation was to evaluate fenobam pharmacokinetics and analgesic effects in humans. We first evaluated single-dose oral fenobam disposition in a parallel-group dose-escalation study in healthy volunteers. A second investigation tested the analgesic effects of fenobam in an established experimental human pain model of cutaneous sensitization using capsaicin cream and heat, in a double-blind placebo-controlled study. The primary outcome measure was the area of hyperalgesia and allodynia around the area applied with heat/capsaicin. Secondary outcome measures included nociception, measured as pain rating on a visual analog scale, heat pain detection threshold, and effects on cognition and mood. Fenobam plasma exposures showed considerable interindividual variability and were not linear with dose. Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between fenobam and placebo. Our results suggest highly variable fenobam disposition and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.

Somatosensory predictors of response to pregabalin in painful chemotherapy-induced peripheral neuropathy: a randomized, placebo-controlled, crossover study.

Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and treatment-resistant sequela of many chemotherapeutic medications. Ligands of α2δ subunits of voltage-gated Ca channels, such as pregabalin, have shown efficacy in reducing mechanical sensitivity in animal models of neuropathic pain. In addition, some data suggest that pregabalin may be more efficacious in relieving neuropathic pain in subjects with increased sensitivity to pinprick. We hypothesized that greater mechanical sensitivity, as quantified by decreased mechanical pain threshold at the feet, would be predictive of a greater reduction in average daily pain in response to pregabalin vs placebo. In a prospective, randomized, double-blinded study, 26 patients with painful CIPN from oxaliplatin, docetaxel, or paclitaxel received 28-day treatment with pregabalin (titrated to maximum dose 600 mg per day) and placebo in crossover design. Twenty-three participants were eligible for efficacy analysis. Mechanical pain threshold was not significantly correlated with reduction in average pain (P = 0.97) or worst pain (P = 0.60) in response to pregabalin. There was no significant difference between pregabalin and placebo in reducing average daily pain (22.5% vs 10.7%, P = 0.23) or worst pain (29.2% vs 16.0%, P = 0.13) from baseline. Post hoc analysis of patients with CIPN caused by oxaliplatin (n = 18) demonstrated a larger reduction in worst pain with pregabalin than with placebo (35.4% vs 14.6%, P = 0.04). In summary, baseline mechanical pain threshold tested on dorsal feet did not meaningfully predict the analgesic response to pregabalin in painful CIPN.

Epidurals in Pancreatic Resection Outcomes (E-PRO) study: protocol for a randomised controlled trial.

INTRODUCTION: Epidural analgesia provides an important synergistic method of pain control. In addition to reducing perioperative opioid consumption, the deliverance of analgesia into the epidural space, effectively creating a sympathetic blockade, has a multitude of additional potential benefits, from decreasing the incidence of postoperative delirium to reducing the development of persistent postsurgical pain (PPSP). Prior studies have also identified a correlation between the use of epidural analgesia and improved oncological outcomes and survival. The aim of this study is to evaluate the effect of epidural analgesia in pancreatic operations on immediate postoperative outcomes, the development of PPSP and oncological outcomes in a prospective, single-blind, randomised controlled trial. METHODS: The Epidurals in Pancreatic Resection Outcomes (E-PRO) study is a prospective, single-centre, randomised controlled trial. 150 patients undergoing either pancreaticoduodenectomy or distal pancreatectomy will be randomised to receive an epidural bupivacaine infusion following anaesthetic induction followed by continued epidural bupivacaine infusion postoperatively in addition to the institutional standardised pain regimen of hydromorphone patient-controlled analgesia (PCA), acetaminophen and ketorolac (intervention group) or no epidural infusion and only the standardised postoperative pain regimen (control group). The primary outcome was the postoperative opioid consumption, measured in morphine or morphine-equivalents. Secondary outcomes include patient-reported postoperative pain numerical rating scores, trend and relative ratios of serum inflammatory markers (interleukin (IL)-1ß, IL-6, tumour necrosis factor-α, IL-10), occurrence of postoperative delirium, development of PPSP as determined by quantitative sensory testing, and disease-free and overall survival. ETHICS AND DISSEMINATION: The E-PRO trial has been approved by the institutional review board. Recruitment began in May 2016 and will continue until the end of May 2018. Dissemination plans include presentations at scientific conferences and scientific publications. TRIAL REGISTRATION NUMBER: NCT02681796.

How central is central poststroke pain? The role of afferent input in poststroke neuropathic pain: a prospective, open-label pilot study.

Central poststroke pain (CPSP) is a neuropathic pain disorder, the underlying mechanisms of which are not well understood. It has been suggested that stroke-associated loss of inhibitory neurons in the spinothalamic tract causes disinhibition of thalamic neurons, which autonomously generate ectopic nociceptive action potentials responsible for the pain experience. We hypothesized that CPSP is a result of misinterpretation of afferent sensory input by the sensitized neurons within the brain, rather than generated spontaneously by the damaged central nervous system (CNS) neurons. To test this hypothesis, we prospectively recruited 8 patients with definite CPSP affecting at least 1 extremity. In an open-label intervention, an ultrasound-guided peripheral nerve block with lidocaine was performed to block afferent sensory input from a painful extremity. Spontaneous and evoked pain, neuropathic pain descriptors, and lidocaine plasma concentrations were measured. The blockade of peripheral sensory input resulted in complete abolition of pain in 7 of the 8 subjects within 30 minutes (the primary outcome measure of the study), and >50% pain relief in the remaining participant. Median (interquartile range) spontaneous pain intensity changed from 6.5 (4.3-7.0) at baseline to 0 (0-0) after the block (P = 0.008). All mechanical/thermal hypersensitivity was abolished by the nerve block. The results suggest that it is unlikely that CPSP is autonomously generated within the CNS. Rather, this pain is dependent on afferent input from the painful region in the periphery, and may be mediated by misinterpretation of peripheral sensory input by sensitized neurons in the CNS.

Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers.

INTRODUCTION: Heat/capsaicin skin sensitization is a well-characterized human experimental model to induce hyperalgesia and allodynia. Using this model, gabapentin, among other drugs, was shown to significantly reduce cutaneous hyperalgesia compared to placebo. Since the larger thermal probes used in the original studies to produce heat sensitization are now commercially unavailable, we decided to assess whether previous findings could be replicated with a currently available smaller probe (heated area 9 cm(2) versus 12.5-15.7 cm(2)). STUDY DESIGN AND METHODS: After Institutional Review Board approval, 15 adult healthy volunteers participated in two study sessions, scheduled 1 week apart (Part A). In both sessions, subjects were exposed to the heat/capsaicin cutaneous sensitization model. Areas of hypersensitivity to brush stroke and von Frey (VF) filament stimulation were measured at baseline and after rekindling of skin sensitization. Another group of 15 volunteers was exposed to an identical schedule and set of sensitization procedures, but, in each session, received either gabapentin or placebo (Part B). RESULTS: Unlike previous reports, a similar reduction of areas of hyperalgesia was observed in all groups/sessions. Fading of areas of hyperalgesia over time was observed in Part A. In Part B, there was no difference in area reduction after gabapentin compared to placebo. CONCLUSION: When using smaller thermal probes than originally proposed, modifications of other parameters of sensitization and/or rekindling process may be needed to allow the heat/capsaicin sensitization protocol to be used as initially intended. Standardization and validation of experimental pain models is critical to the advancement of translational pain research.

Massive phytoplankton blooms under Arctic sea ice.

Phytoplankton blooms over Arctic Ocean continental shelves are thought to be restricted to waters free of sea ice. Here, we document a massive phytoplankton bloom beneath fully consolidated pack ice far from the ice edge in the Chukchi Sea, where light transmission has increased in recent decades because of thinning ice cover and proliferation of melt ponds. The bloom was characterized by high diatom biomass and rates of growth and primary production. Evidence suggests that under-ice phytoplankton blooms may be more widespread over nutrient-rich Arctic continental shelves and that satellite-based estimates of annual primary production in these waters may be underestimated by up to 10-fold.

A major ecosystem shift in the northern Bering Sea.

Until recently, northern Bering Sea ecosystems were characterized by extensive seasonal sea ice cover, high water column and sediment carbon production, and tight pelagic-benthic coupling of organic production. Here, we show that these ecosystems are shifting away from these characteristics. Changes in biological communities are contemporaneous with shifts in regional atmospheric and hydrographic forcing. In the past decade, geographic displacement of marine mammal population distributions has coincided with a reduction of benthic prey populations, an increase in pelagic fish, a reduction in sea ice, and an increase in air and ocean temperatures. These changes now observed on the shallow shelf of the northern Bering Sea should be expected to affect a much broader portion of the Pacific-influenced sector of the Arctic Ocean.