Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry.

Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.

PCR-based prevalence of a fatal reovirus of the blue crab, Callinectes sapidus (Rathbun) along the northern Atlantic coast of the USA.

There is a need for more information on the relationship between diseases and fluctuations of wild populations of marine animals. In the case of Callinectes sapidus reovirus 1 (CsRV1, also known as RLV), there is a lack of baseline information on range, prevalence and outbreaks, from which to develop an understanding of population-level impacts. An RT-qPCR assay was developed that is capable of detecting 10 copies of the CsRV1 genome. In collaboration with state, federal and academic partners, blue crabs were collected from sites throughout the north-eastern United States to assess the northern range of this pathogen. In addition, archived crab samples from the Chesapeake Bay were assessed for CsRV1 by RT-qPCR and histology. PCR-based assessments indicate that CsRV1 was present at all but one site. Prevalence of CsRV1 as assessed by RT-qPCR was highly variable between locations, and CsRV1 prevalence varied between years at a given location. Mean CsRV1 prevalence as assessed by RT-qPCR was >15% each year, and peak prevalence was 79%. The wide geographic range and highly variable prevalence of CsRV1 indicate that more study is needed to understand CsRV1 dynamics and the role the virus plays in blue crab natural mortality.

Elevated water temperature increases the levels of reo-like virus and selected innate immunity genes in hemocytes and hepatopancreas of adult female blue crab, Callinectes sapidus.

Seasonal changes in water temperature directly affect the aquatic ecosystem. The blue crab, Callinectes sapidus, inhabiting the Chesapeake Bay has been adapted to seasonal changes of the environmental conditions. In this, the animals halt their physiological process of the growth and reproduction during colder months while they resume these processes as water temperatures increase. We aimed to understand the effect of the elevated temperatures on a disease progression of reo-like virus (CsRLV) and innate immunity of adult female C. sapidus. Following a rise in water temperature from 10 to 23 °C, CsRLV levels in infected crabs rose significantly in hemocytes and multiple organs. However, in hemocytes, the elevated temperature had no effect on the levels of three innate immune genes: Cas-ecCuZnSOD-2, CasPPO and CasLpR three carbohydrate metabolic genes: CasTPS, CasGlyP; and CasTreh and the total hemocyte counts (THC). Interestingly, the hemocytes of CsRLV infected animals exposed to 23 °C for 10 days had significantly elevated levels of Cas-ecCuZnSOD-2 and CasTPS, compared to those of the uninfected ones also exposed to the same condition and compared to hatchery-raised females kept at 23 °C. Despite the lack of changes in THC, the types of hemocytes from the animals with high CsRLV levels differed from those of uninfected ones and from hatchery animals kept at 23 °C: CsRLV-infected crabs had hemocytes of smaller size with less cytosolic complexity than uninfected crabs. It therefore appears that the change in temperature influences rapid replication of CsRLV in all internal tissues examined. This implies that CsRLV may have broad tissue tropism. Interestingly, the digestive tract (mid- and hindgut) contains significantly higher levels of CsRLV than hemocytes while hepatopancreas and ovary have lower levels than hemocytes. Innate immune responses differ by tissue: midgut and hepatopancreas with upregulated Cas-ecCuZnSOD-2 similar to that found in hemocytes. By contrast, hepatopancreas showed a down-regulated CasTPS, suggesting carbohydrate stress during infection.

Real-life experience with first generation HCV protease inhibitor therapy in Germany: The prospective, non-interventional PAN cohort.

BACKGROUND AND AIMS: The efficacy and safety of peginterferon alfa-2a (PEG-IFN) plus ribavirin (RBV) and either boceprevir (BOC) or telaprevir (TVR), and physician adherence to treatment algorithms were evaluated in patients included in an ongoing non-interventional study (PAN) enrolling adults with chronic hepatitis C virus (HCV) infection managed in German office-based practices. METHODS: The analysis included HCV genotype 1-infected, treatment-naïve and treatment-experienced patients treated with BOC or TVR. Demographic, treatment history, virological response, safety, and patient management data were collected. RESULTS: Of a total 1087 patients, 58.1 % achieved sustained virological responses (SVR). Response rates were higher in treatment-naïve (BOC 55 %; TVR 63.4 %) and prior relapse patients (BOC 63.2 %; TVR 74.5 %) versus previous null-responders (BOC 14.3 %; TVR 25 %). The most commonly reported adverse event overall was fatigue (60.6 %); 45.8 % patients experienced hemoglobin < 10 g/dL. Patients with cirrhosis had lower rates of SVR versus those without (42.9 % vs. 60.7 %, respectively), and had a higher incidence of serious adverse events (SAEs) (16.7 % vs. 8.6 %, respectively) and treatment discontinuation (44.6 % vs. 25.2 %, respectively). According to recommended response-guided treatment algorithms, about 70 % of patients were managed appropriately, 11/10 % (BOC/TVR) received unnecessarily extended therapy, and 19/7 % (BOC/TVR) received inappropriately shortened therapy. CONCLUSIONS: The efficacy and safety of BOC- and TVR-based triple therapy in this large, "real-world" cohort were largely comparable to that reported in pivotal clinical trials, although SVR rates were lower overall. Recommended futility or treatment extension rules were violated in a substantial proportion of patients with potential implications for response, adverse events and costs.

Significant impact of patient age on outcome after liver resection for HCC in cirrhosis.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The majority of patients with HCC have cirrhosis. Beside liver transplantation the resection is an established curative treatment option for patients with HCC in cirrhosis. However, the long term success is limited by a high tumor recurrence rate. Furthermore, by many patients surgical resection is restricted by poor liver function. The purpose of this study was to investigate the influence of patient age on long term outcome after liver resection in patients with HCC in cirrhotic liver. Further purpose was to define the potential prognostic factors. PATIENTS AND METHODS: The outcome of 141 patients with liver cirrhosis after curative resection was analyzed using a prospective database. Only patients with postoperative histological assurance of HCC were included in the database. Patients with fibrolamellar HCC were excluded. RESULTS: By patients below 70 years of age the 1-, 3- and 5-year survival rates were 78.5%, 56.5% and 47.1%. By patients over 70 years the 1-, 3- and 5-year survival rates were 59.9%, 40.3% and 6.7%. Cumulative survival of the total collective was significant influenced by patient age, Clavien grade, positive lymph vessels, mechanical ventilation and BMI. The overall postoperative morbidity was 44.7%. No intraoperative deaths were observed, but 11 patients (8 older than 70 and 3 younger than 70 years) died during the hospital stay. Clavien grade correlated with preoperative increased GGT, need for intraoperative blood and fresh frozen plasma transfusion. CONCLUSIONS: Patient age and postoperative complications are more relevant for the outcome than many tumor factors, especially by patients over 70 years of age. In contrast, the prognosis of patients below 70 years of age is significantly better and a 5 year survival rate above 50% could be shown in our patients. However, by carefully selected elderly patients with HCC in cirrhosis an acceptable long term survival is reachable.

Discovery of an opportunistic starfish pathogen, Orchitophrya stellarum, in captive blue crabs, Callinectes sapidus.

Histophagous scuticociliate infections were discovered in blue crabs, Callinectes sapidus, held in research facilities at the Virginia Institute of Marine Science. Ciliates were observed infecting every tissue examined including the gills, heart, muscle, hepatopancreas, and epidermis. Hemolymph smears and histological tissue sections indicated a morphological similarity to Mesanophrys chesapeakensis, the only recorded histophagous ciliate infecting blue crabs. However, subsequent analysis of the ribosomal ITS region (ITS1-5.8S-ITS2) of the ciliate indicated the parasite was Orchitophrya stellarum, a parasitic ciliate previously reported infecting sea stars from Europe, Australia, and North America. A simple Polymerase Chain Reaction (PCR-RFLP) assay was developed to detect and differentiate between O. stellarum and M. chesapeakensis. Its application confirmed the presence of O. stellarum infecting blue crabs held in an additional research facility in Maryland. For growth studies, cultures of O. stellarum grew optimally on 10% blue crab serum in crustacean saline held at 10-20°C. A field survey of blue crabs collected during the winters of 2011-2012 and sea stars (Asterias forbesi) during the winter of 2010 from the Chesapeake Bay and eastern shore of Virginia did not identify additional infected individuals.

Treatment of hepatocellular carcinoma with sorafenib - focus on special populations and adverse event management.

Sorafenib, a receptor tyrosine kinase-inhibitor with anti-proliferative and anti-angiogenic activity, is currently the only approved systemic treatment for patients with hepatocellular carcinoma. It inhibits downstream signaling of VEGFR-2, PDGFR, c-Kit receptors and BRAF. Over the last four years comprehensive experience with sorafenib in this indication has been accumulated. In this review we discuss the current data on the use of sorafenib in patients with advanced HCC including special patient populations such as patients with impaired liver function, patients after transplantation, and others. The most frequent side-effects and practical tips on how to manage them are discussed in detail. In addition, we summarize the current experimental data on the use of sorafenib in combination treatment, e. g., together with transarterial chemoembolisation or other targeted agents.

Ischemic-type biliary lesions after ortothopic liver transplantation: diagnosis with magnetic resonance cholangiography.

PURPOSE: To determine the accuracy of magnetic resonance (MR) cholangiography for detection of ischemic-type biliary lesions (ITBL) following orthotropic liver transplantation (OLT). MATERIALS AND METHODS: MR cholangiography was performed in 16 patients with established diagnosis of ITBL following OLT. Two blinded observers reviewed all images in consensus and recorded diagnostic features including presence of intrahepatic and extrahepatic biliary strictures, dilatations, beading, pruning, and filling defects. Sensitivity, specificity, positive predictive value, and accuracy of MR cholangiography were calculated. Final diagnosis was established at endoscopic retrograde cholangiography. RESULTS: MR cholangiography proved to be a valuable tool for the detection of stenoses and dilatations in patients with ITBL following OLT. Sensitivity of the different diagnostic features ranged between 71% and 100%, specificity between 50% and 100%, accuracy between 81% and 100%, and positive predictive value between 87% and 100%. CONCLUSION: MR cholangiography proved to be an accurate imaging technique to noninvasively detect biliary complications in patients with ITBL after OLT.

CD154, a marker of antigen-specific stimulation of CD4 T cells, is associated with response to treatment in patients with chronic HCV infection.

CD4 T-cell function is crucial for the eradication of HCV, and insufficient function is observed in chronic carriers. The monitoring of T-cell responses is complicated by the scarcity of antigen-specific T cells and the relative inefficiency of virus-specific T cells to produce effector cytokines. CD154 is a marker of activation expressed on T cells induced through their T-cell receptor. We analysed CD4 T-cell responses in 72 patients with chronic or resolved HCV infection (23 treatment naïve, 49 treatment experienced, including 16 who had achieved a sustained response). In an additional prospective protocol, 20 of the chronically infected patients were analysed before and after 8-12 weeks of combination therapy with peg-interferon-α and ribavirin. T-cell responses were measured by detecting the expression of CD154 and Th1 cytokines after stimulation with recombinant HCV proteins and were correlated with pretreatment status and outcome of therapy. Broader T-cell responses were observed in treatment naïve than in experienced patients, while the outcome of a preceding therapy regimen did not influence T-cell responses. In the prospective cohort, an on-treatment increase in CD154+ cytokine- T-cell activity was associated with response to treatment, while a decrease was observed in nonresponders. Stronger antigen-independent activity of CD154+ cytokine+ T cells was observed in responders than in nonresponders. Our data indicate that CD154 as a marker of activation of CD4 T cells is a suitable tool for the analysis of T-cell responses in patients with HCV infection.

Real-time PCR-based assay for quantitative detection of Hematodinium sp. in the blue crab Callinectes sapidus.

Hematodinium sp. is a parasitic dinoflagellate infecting the blue crab Callinectes sapidus and other crustaceans. PCR-based assays are currently being used to identify infections in crabs that would have been undetectable by traditional microscopic examination. We therefore sought to define the limits of quantitative PCR (qPCR) detection within the context of field collection protocols. We present a qPCR assay based on the Hematodinium sp. 18S rRNA gene that can detect 10 copies of the gene per reaction. Analysis of a cell dilution series vs. defined numbers of a cloned Hematodinium sp. 18S rRNA gene suggests a copy number of 10,000 per parasite and predicts a sensitivity of 0.001 cell equivalents. In practice, the assays are based on analysis of 1% of the DNA extracted from 200 microl of serum, yielding a theoretical detection limit of 5 cells ml(-1) hemolymph, assuming that 1 cell is present per sample. When applied to a limited field survey of blue crabs collected in Maryland coastal bays from May to August 2005, 24 of 128 crabs (18.8%) were identified as positive for Hematodinium sp. infection using qPCR. In comparison, only 6 of 128 crabs (4.7%) were identified as positive using traditional hemolymph microscopic examination. The qPCR method also detected the parasite in gill, muscle, heart and hepatopancreas tissues, with 17.2% of the crabs showing infection in at least one of these tissues. Importantly, it is now possible to enumerate parasites within defined quantities of crab tissue, which permits collection of more detailed information on the epizootiology of the pathogen.

[Strategies for the prevention of hepatocellular carcinoma in the context of chronic viral hepatitis]. / Strategien zur Prävention des hepatozellulären Karzinoms bei der Hepatitis-Virus-Infektion.

Liver cirrhosis induced by HBV and HCV infections is the main risk factor for the development of hepatocellular carcinoma (HCC). Therefore, prevention of chronic infection with hepatitis viruses and prevention of the development of cirrhosis are essential for the primary prevention of HCC. A consequent vaccination program for HBV is suitable to reduce the rate of infections and the HCC-associated mortality. Since no vaccine is available for HCV, the reduction of risky behaviour and the improvement of hygiene standards are the mainstays for prevention of HCV. An efficient antiviral therapy aimed at the durable suppression of the viral load reduces the risk of progression to cirrhosis and development of HCC in precirrhotic stages of chronic HBV or HCV infections. In cirrhotic patients, the risk of developing HCC remains elevated even if a sustained virological response is achieved, thus requiring further screening with the intention of the early detection of HCC. It is too early to judge whether virological nonresponders profit from continued antiviral therapy. Therefore, the early diagnosis of chronic HBV or HCV infection is the single most important factor for the prevention of HCC. Secondary prevention after surgical resection or local ablative therapy may reduce the frequency of late recurrence. Liver transplantation is today the most effective measure of secondary prevention for selected patients with HCC. Due to its antiproliferative effects, the immunosuppressive drug sirolimus may play a role for secondary prevention of HCC following transplantation.

Association of TLR7 single nucleotide polymorphisms with chronic HCV-infection and response to interferon-a-based therapy.

An efficient immune response against hepatitis C virus (HCV) is necessary to clear infection. As HCV is a single-stranded RNA virus, a role for TLR7 in the immune response against HCV is possible, and early clinical studies have demonstrated an antiviral effect of TLR7 stimulation. We tested the hypothesis that genetic variations of TLR7 are associated with chronic HCV-infection and outcome of therapy. The prevalence of three TLR7 variations was analysed in 978 patients with chronic HCV-infection, 898 patients with chronic liver disease of other aetiologies, and in 203 healthy controls. The prevalence of TLR7 variations was correlated with the response to interferon-alpha-based treatment in 544 patients with chronic HCV-infection. We analysed TLR7 polymorphisms by melting curve analysis and reconstructed haplotypes. The c.32A>T variation was over-represented in female patients with chronic HCV-infection compared to patients with other chronic liver diseases and to healthy controls (P < 0.05). In contrast, c.2403 G>A was less prevalent in male patients with chronic HCV-infection (P < 0.05). No association was observed for the third variant, c.1-120T>G. Haplotype analysis confirmed the differential distribution of TLR7 variants between the groups. Within the group of female patients with chronic HCV-infection, c.32T was predictive of an unfavourable outcome of interferon-alpha therapy (P < 0.05). This study reports the association of TLR7 variants with chronic HCV-infection and with the response to interferon-alpha therapy in patients with chronic HCV-infection. Our results suggest that variations of TLR7 impair the immune response to HCV and imply a gender-specific effect of this X-chromosomal variation.

Substance P release in the spinal dorsal horn following peripheral nerve injury.

Spinal microdialysis was used to study the potassium induced in vivo release of substance P (SP) in the rat dorsal horn at different time points (3, 14, and 60 days) following partial sciatic nerve ligation (PNL) or sciatic nerve axotomy. The withdrawal threshold to innocuous mechanical stimuli was investigated with von Frey filaments in the PNL rats prior to microdialysis. The release of SP was significantly elevated at 60 days following PNL but not following complete nerve injury. However, the PNL rats in all time groups displayed mechanical hypersensitivity, which implies that this late change in SP release seems to be unrelated to the development of neuropathy. The present results indicate that there is an increase of the releasable pool of SP in the dorsal horn at late post-operative times after PNL. This change in SP release may reflect an altered sensory processing or may instead relate to adaptive responses to promote recovery.

Effects of fluvoxamine and paroxetine on sleep structure in normal subjects: a home-based Nightcap evaluation during drug administration and withdrawal.

BACKGROUND: Acute and chronic administration of the selective serotonin reuptake inhibitors (SSRIs) have been widely reported to disrupt sleep in laboratory studies. This study examines the naturalistic, longitudinal effects of paroxetine and fluvoxamine on sleep quality in the home setting. METHOD: Fourteen healthy volunteers free of medical and neuropsychiatric symptoms entered a 31-day protocol: 7 days of drug-free baseline (days 1-7), 19 days of drug treatment (steady state during days 18-26), and 5 days of acute withdrawal (days 27-31). On day 8, the subjects were randomly assigned to receive either 100 mg/day of fluvoxamine or 20 mg/day of paroxetine (half receiving each drug) in divided morning and evening oral doses. Investigators remained blinded to drug assignment until all sleep data had been analyzed. Sleep was monitored using the Nightcap ambulatory sleep monitor. Four standard and 3 novel measures were computed and compared using multivariate analysis of variance, analysis of variance, and Bonferroni-corrected comparison of means. RESULTS: Sleep disruption was most clearly demonstrated using the novel measures eyelid quiescence index, rhythmicity, and eyelid movements per minute in non-rapid eye movement sleep, but was also apparent as determined by standard measures of sleep efficiency, number of awakenings, and sleep onset latency. Paroxetine disrupted sleep more than fluvoxamine, and paroxetine-induced sleep disruption persisted into the withdrawal phase. Rapid eye movement sleep was suppressed during treatment (especially for fluvoxamine) and rebounded during withdrawal (especially for paroxetine). CONCLUSION: We confirm laboratory polysomnographic findings of SSRI-induced sleep quality changes and demonstrate the Nightcap's efficacy as an inexpensive longitudinal monitor for objective sleep changes induced by psychotropic medication.

SSRI treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects.

Clinical lore and a small number of published studies report that the selective serotonin reuptake inhibitors (SSRIs) intensify dreaming. This study examines the dream effects of paroxetine and fluvoxamine in order to both increase clinical knowledge of these agents and to test an important potential method for probing the relationship between REM sleep neurobiology and dreaming in humans. Fourteen normal, paid volunteers (4 males, 10 females; mean age 27.4 year, range 22--39) free of medical or neuropsychiatric symptoms as well as of psychotropic or sleep affecting drugs completed a 31-day home-based study consisting of: 7 days drug-free baseline; 19 days on either 100 mg fluvoxamine (7 Ss) or 20 mg paroxetine (7 Ss) in divided morning and evening doses; and 5 days acute discontinuation. Upon awakening, subjects wrote dream reports, self-scored specific emotions in their reports and rated seven general dream characteristics using 5-point Likert scales. Dream reports were independently scored for bizarreness, movement and number of visual nouns by three judges. REM sleep-related measures were obtained using the Nightcap ambulatory sleep monitor. Mean dream recall frequency decreased during treatment compared with baseline. Dream report length and judge-rated bizarreness were greater during acute discontinuation compared with both baseline and treatment and this effect was a result of the fluvoxamine-treated subjects. The subjective intensity of dreaming increased during both treatment and acute discontinuation compared with baseline. Propensity to enter REM sleep was decreased during treatment compared with baseline and acute discontinuation and the intensity of REM sleep increased during acute discontinuation compared with baseline and treatment. The decrease in dream frequency during SSRI treatment may reflect serotonergic REM suppression while the augmented report length and bizarreness during acute SSRI discontinuation may reflect cholinergic rebound from serotonergic suppression.

Dreaming and the brain: toward a cognitive neuroscience of conscious states.

Sleep researchers in different disciplines disagree about how fully dreaming can be explained in terms of brain physiology. Debate has focused on whether REM sleep dreaming is qualitatively different from nonREM (NREM) sleep and waking. A review of psychophysiological studies shows clear quantitative differences between REM and NREM mentation and between REM and waking mentation. Recent neuroimaging and neurophysiological studies also differentiate REM, NREM, and waking in features with phenomenological implications. Both evidence and theory suggest that there are isomorphisms between the phenomenology and the physiology of dreams. We present a three-dimensional model with specific examples from normally and abnormally changing conscious states.

Dreaming and waking consciousness: a character recognition study.

The formal features of dream characters were studied in a sample of 320 dream reports submitted by 33 adult subjects (13 male, 20 female) of varying ages in a university extension course. Subjects were queried by questionnaire about dream characters immediately after recording their dreams upon awakening in their normal home setting. It was found that 48% of characters represented a named personage known to the dreamer, 35% were generically identified by their social role (e.g., policeman) or abstract relation to the dreamer (e.g., a friend) while only 16% were wholly novel. Seventy-seven percent of characters were pseudosensorily present in the dream whereas 23% were present only by mention or thought. Subjects were allowed to endorse one or more of four bases of recognition and, among named characters, 32% were identified by 'appearance', 21% by 'behavior', 45% by 'face', and 44% by 'just knowing' (with the respective percentages for generic characters being 39%, 38%, 9% and 40%). Fourteen percent of named and generic characters had associated some element of bizarreness most frequently consisting of an incongruous feature. Comparing the 25 longest and 25 shortest reports, named subjects were significantly more common in the shortest reports whereas generic and unknown characters were more common in the longest reports. Results are interpreted in neurocognitive terms as possibly reflecting a decrease during dreaming relative to waking in the exchange of information between inferotemporal face identification areas and prefrontal areas subserving logic and working memory.

Measurement of cholecystokinin release in vivo in the rat spinal dorsal horn.

The microdialysis technique, used to monitor extracellular levels of transmitter substances in the central nervous system of laboratory animals as a reflection of transmitter release, is based on the ability of neurotransmitters to diffuse in the extracellular fluid from the site of release and to cross a semipermeable dialysis membrane. Even though the surgical procedure is not very complicated, the detection of released substances in the recovered dialysate may be difficult. Especially, the measurement of neuropeptide release is limited by the low extracellular concentration and of low recovery as compared to, for example, monoamines. Thus, for example, cholecystokinin (CCK), which is the most abundant neuropeptide in the central nervous system, is found at concentrations that are several orders of magnitude lower than those of classical transmitters. Therefore a highly sensitive detection method is of utmost importance. In the dorsal horn of the spinal cord CCK is found mainly in interneurons and in terminals of descending fibers. CCK seems to be involved in nociceptive transmission and CCK attenuates morphine-induced antinociception. We here describe in vivo microdialysis in the lumbar dorsal horn of the rat with subsequent quantification of the level of CCK-like immunoreactivity (-LI) by a highly sensitive radioimmunoassay.

Peripheral axotomy influences the in vivo release of cholecystokinin in the spinal cord dorsal horn-possible involvement of cholecystokinin-B receptors.

An increased expression of cholecystokinin (CCK) messenger RNA (mRNA) as well as CCK-B receptor mRNA in dorsal root ganglion (DRG) cells following peripheral axotomy has previously been demonstrated. In the present in vivo microdialysis study, the effect of unilateral sciatic nerve section on basal and potassium-induced release of CCK-like (CCK-LI) immunoreactivity in the rat dorsal horn was investigated. We also compared the effects of the CCK-B receptor antagonist CI988 on basal and potassium-stimulated CCK-LI release in intact animals and in chronically axotomized rats. Perfusion of the microdialysis probe with KCl (100 mM) induced a more than 6-fold increase of the extracellular level of CCK-LI in control animals. In contrast, following unilateral sciatic nerve section the same KCl stimulation failed to evoke a release of CCK-LI ipsilaterally. However, after systemic administration of CI988 (1 mg kg-1, i.v.), 100 mM KCl induced a significant increase of the extracellular CCK-LI level in axotomized rats, similar to that observed in control animals. In control animals no effect of CI988 on KCl-stimulated CCK-LI release could be detected. CI988 by itself had no influence on the extracellular CCK-LI level in either nerve injured or control animals. The present data suggest that axotomy reduces the release of CCK-like immunoreactivity in the spinal cord by a mechanism involving the CCK-B receptor binding site.

To dream or not to dream? Relevant data from new neuroimaging and electrophysiological studies.

The study of sleep and dreams has enjoyed a major breakthrough with recent findings from brain imaging studies in humans. Several independent groups have shown global deactivation of the brain during non rapid eye movement sleep and a regionally selective reactivation during rapid eye movement sleep. These results are complemented by new brain lesion and electrophysiological recording data to give a detailed picture of the brain dynamics of changes in conscious state.