Pain- and morphine-associated transcriptional regulation of neuropeptide FF and the G-protein-coupled NPFF2 receptor gene

Neuropeptide FF (NPFF) is involved in pain modulation, especially plasticity during inflammatory and neuropathic pain, and opiate interactions. Its nociceptive functions may be mediated by the NPFF2 receptor. To elucidate the role of the NPFF system in plasticity associated with pathologic pain, we studied the changes of NPFF mRNA and NPFF2 receptor mRNA in rat models of acute colonic inflammation, inflammatory pain, and neuropathic pain. Furthermore, we studied the mRNA levels of both NPFF and NPFF2 receptor in morphine-tolerant rats and after acute morphine injections. We found an activation of spinal NPFF and NPFF2 receptor during early inflammatory pain. Supraspinally, we found an up-regulation of NPFF2 receptor mRNA during acute colonic inflammation and neuropathic pain. Acute, but not chronic, morphine activated the genes supraspinally. The results give further evidence for the involvement of the NPFF system in pain modulation and may provide new therapeutic opportunities for pathologic pain.     

Developmental changes in cellular and extracellular structural macromolecules in the secondary palate and in the nasal cavity of the mouse

Vaziri Sani F, Kaartinen V, El Shahawy M, Linde A, Gritli‐Linde A. Developmental changes in cellular and extracellular structural macromolecules in the secondary palate and nasal cavity of the mouse. Eur J Oral Sci 2010; 118: 221–236. © 2010 The Authors. Journal compilation© 2010 Eur J Oral Sci The aim of this study was to analyse the hitherto largely unknown expression patterns of some specific cellular and extracellular molecules during palate and nasal cavity development. We showed that epithelia of the developing palate and the vomerine epithelium express similar sets of structural proteins. With the exception of keratin 15, which becomes barely detectable in the elevated palatal shelves, nearly all of these proteins become upregulated at the presumptive areas of fusion and in the adhering epithelia of the palate and nasal septum. In vivo and in vitro analyses indicated that reduction in the amount of keratin 15 protein is independent of Tgfβ–Alk5 signalling. Foxa1 expression also highlighted the regionalization of the palatal and nasal epithelia. Owing to the lack of reliable markers of the palatal periderm, the fate of peridermal cells has been controversial. We identified LewisX/stage‐specific embryonic antigen‐1 as a specific peridermal marker, and showed that numerous peridermal cells remain trapped in the medial epithelial seam (MES). The fate of these cells is probably apoptosis together with the rest of the MES cells, as we provided strong evidence for this event. Heparan sulphate, chondroitin‐6‐sulphate, and versican displayed dynamically changing distribution patterns. The hitherto‐unknown innervation pattern of the developing palate was revealed. These findings may be of value for unravelling the pathogenesis of palatal clefting.     

Cold retrograde cerebral perfusion improves cerebral protection during moderate hypothermic circulatory arrest: A long-term study in a porcine model.

BACKGROUND: Deep hypothermic circulatory arrest is an effective method of cerebral protection, but it is associated with long cardiopulmonary bypass times and coagulation disturbances. Previous studies have shown that retrograde cerebral perfusion can improve neurologic outcomes after prolonged hypothermic circulatory arrest. We tested the hypothesis that deep hypothermic retrograde cerebral perfusion could improve cerebral outcome during moderate hypothermic circulatory arrest. METHODS: Twelve pigs (23-29 kg) were randomly assigned to undergo either retrograde cerebral perfusion (15 degrees C) at 25 degrees C or hypothermic circulatory arrest with the head packed in ice at 25 degrees C for 45 minutes. Flow was adjusted to maintain superior vena cava pressure at 20 mm Hg throughout retrograde cerebral perfusion. Hemodynamic, electrophysiologic, metabolic, and temperature monitoring were carried out until 4 hours after the start of rewarming. Daily behavioral assessment was performed until elective death on day 7. A postmortem histologic analysis of the brain was carried out on all animals. RESULTS: In the retrograde cerebral perfusion group, 5 (83%) of 6 animals survived 7 days compared with 2 (33%) of 6 in the hypothermic circulatory arrest group. Complete behavioral recovery was seen in 4 (67%) animals after retrograde cerebral perfusion but only in 1 (17%) animal after hypothermic circulatory arrest. Postoperative levels of serum lactate were higher, and blood pH was lower in the hypothermic circulatory arrest group. There were no significant hemodynamic differences between the study groups. CONCLUSIONS: Cold hypothermic retrograde cerebral perfusion during moderate hypothermic circulatory arrest seems to improve neurologic outcome compared with moderate hypothermic circulatory arrest with the head packed in ice.     

Analyzing Citizens’ and Health Care Professionals’ Searches for Smell/Taste Disorders and Coronavirus in Finland During the COVID-19 Pandemic: Infodemiological Approach Using Database Logs

BackgroundThe COVID-19 pandemic has prevailed over a year, and log and register data on coronavirus have been utilized to establish models for detecting the pandemic. However, many sources contain unreliable health information on COVID-19 and its symptoms, and platforms cannot characterize the users performing searches. Prior studies have assessed symptom searches from general search engines (Google/Google Trends). Little is known about how modeling log data on smell/taste disorders and coronavirus from the dedicated internet databases used by citizens and health care professionals (HCPs) could enhance disease surveillance. Our material and method provide a novel approach to analyze web-based information seeking to detect infectious disease outbreaks.ObjectiveThe aim of this study was (1) to assess whether citizens’ and professionals’ searches for smell/taste disorders and coronavirus relate to epidemiological data on COVID-19 cases, and (2) to test our negative binomial regression modeling (ie, whether the inclusion of the case count could improve the model).MethodsWe collected weekly log data on searches related to COVID-19 (smell/taste disorders, coronavirus) between December 30, 2019, and November 30, 2020 (49 weeks). Two major medical internet databases in Finland were used: Health Library (HL), a free portal aimed at citizens, and Physician’s Database (PD), a database widely used among HCPs. Log data from databases were combined with register data on the numbers of COVID-19 cases reported in the Finnish National Infectious Diseases Register. We used negative binomial regression modeling to assess whether the case numbers could explain some of the dynamics of searches when plotting database logs.ResultsWe found that coronavirus searches drastically increased in HL (0 to 744,113) and PD (4 to 5375) prior to the first wave of COVID-19 cases between December 2019 and March 2020. Searches for smell disorders in HL doubled from the end of December 2019 to the end of March 2020 (2148 to 4195), and searches for taste disorders in HL increased from mid-May to the end of November (0 to 1980). Case numbers were significantly associated with smell disorders (P<.001) and taste disorders (P<.001) in HL, and with coronavirus searches (P<.001) in PD. We could not identify any other associations between case numbers and searches in either database.ConclusionsNovel infodemiological approaches could be used in analyzing database logs. Modeling log data from web-based sources was seen to improve the model only occasionally. However, search behaviors among citizens and professionals could be used as a supplementary source of information for infectious disease surveillance. Further research is needed to apply statistical models to log data of the dedicated medical databases.     

Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: results from a Nordic multicentre study

OBJECTIVES: This prospective multicentre study was conducted to assess the efficacy of the monoclonal anti-CD20 antibody rituximab in patients with chronic lymphocytic leukaemia (CLL). Secondary objectives were defined as the tolerability and feasibility of rituximab in patients with CLL. METHODS: Twenty-four heavily pretreated patients with CLL were treated with a standard dose of 375 mg m-2 of rituximab given once weekly for four doses. RESULTS: The overall response rate was 35% and all the responses were partial as defined by the revised NCI criteria. In 17 (85%) of 20 patients with initially measurable peripheral lymph nodes the size of lymph nodes decreased by at least 50%, while an improvement of the bone marrow infiltration was observed only in two (11%) of 18 evaluable patients. The median duration of the overall response was 12.5 wk. Rituximab was relatively well tolerated. Although side-effects were common (75%) they were usually mild or moderate. There was only one grade 3 adverse event and no grade 4 events. CONCLUSIONS: Standard-dose rituximab has activity in heavily pretreated patients with CLL, although the response is mainly limited to the lymph nodes and of short duration. Since rituximab has in vitro synergism with chemotherapeutic agents and is well tolerated by CLL patients, it is reasonable to investigate rituximab in combination with other treatments.     

Quality of life after mitral valve repair

BACKGROUND AND AIM OF THE STUDY: Mitral valve repair for degenerative and ischemic mitral valve regurgitation has been shown to be a durable procedure. The study aim was to evaluate the quality of life of patients who had undergone mitral valve repair, and to compare it to that of an age- and gender-adjusted Finnish general population. METHODS: Among 130 late survivors after mitral valve repair, 109 (83.8%) answered the RAND-36 Health Survey questionnaire; these patients form the basis of the present study. RESULTS: The Wilcoxon test showed significantly higher mental health (p = 0.04) and pain scores (p = 0.015) and a lower role functioning/physical score (p = 0.008) in the study group. The scores of the other RAND-36 Health Survey variables of the study group were similar to those of the age- and gender-adjusted general population. The mean total score for the study group was 512 (median 532, IQR 360-678), compared to 522 (median 538, IQR 468-549) in the general population (p = 0.72) (only 95 patients were included in the analysis due to isolated missing scores). CONCLUSION: The quality of life of long-term survivors after mitral valve repair, as assessed by the RAND-36 Health Survey, is similar to that of an age- and gender-adjusted general Finnish population.     

Measurement of GABAA receptor binding in vivo with [11C]flumazenil: a test-retest study in healthy subjects

[(11)C]Flumazenil is widely used in positron emission tomography (PET) studies to measure GABA(A) receptors in vivo in humans. Although several different methods have been applied for the quantification of [(11)C]flumazenil binding, the reproducibility of these methods has not been previously examined. The reproducibility of a single bolus [(11)C]flumazenil measurements was studied by scanning eight healthy volunteers twice during the same day. Grey matter regions were analyzed using both regions-of-interest (ROI) and voxel-based analysis methods. Compartmental kinetic modelling using both arterial and reference region input function were applied to derive the total tissue distribution volume (V(T)) and the binding potential (BP) (BP(P) and BP(ND)) of [(11)C]flumazenil. To measure the reproducibility and reliability of each [(11)C]flumazenil binding parameter, absolute variability values (VAR) and intraclass correlation coefficients (ICC) were calculated. Tissue radioactivity concentration over time was best modelled with a 2-tissue compartmental model. V(T) showed with all methods good to excellent reproducibility and reliability with low VARs (mean of all brain regions) (5.57%-6.26%) and high ICCs (mean of all brain regions) (0.83-0.88) when using conventional ROI analysis. Also voxel-based analysis methods yielded excellent reproducibility (VAR 5.75% and ICC 0.81). In contrast, the BP estimates using pons as the reference tissue yielded higher VARs (8.08%-9.08%) and lower ICCs (0.35-0.80). In conclusion, the reproducibility of [(11)C]flumazenil measurements is considerably better with outcome measures based on arterial input function than those using pons as the reference tissue. The voxel-based analysis methods are proper alternative as the reliability is preserved and analysis automated.