Oral aphthous-like ulceration due to tiotropium bromide

Unwanted side-effects of a drug therapy are well known to oral medicine specialists and other colleagues. Usually they manifest itself as dry mouth, taste disturbances, various allergic or toxic reactions on the lips and/or in the oral cavity. However, the list of the drugs which might induce unwanted reactions is everyday becoming longer as more and more drugs are introduced on the market. Certain problems when diagnosing and reporting unwanted side effects of the drugs exist as only accurate method of diagnosis is repeated drug use in controlled clinical setting where fatal consequences due to the anaphilactic shock could be avoided. We report a side effect reaction to tiotropium bromide (Spiriva) cap used with HandiHaler manifesting itself as an oral ulceration in a 65 yrs old male. On the third day of drug intake the patient developed oral ulceration two times in a period of few months. Other medications he has been using for several years. To our knowledge this is a first report as an oral side-effect of this drug used for treatment of chronic obstructive pulmonary disease (COPD).     

Microscopic Visualization of Metabotropic Glutamate Receptors on the Surface of Living Cells Using Bifunctional Magnetic Resonance Imaging Probes

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Medial prefrontal theta phase coupling during spatial memory retrieval

Memory retrieval is believed to involve a disparate network of areas, including medial prefrontal and medial temporal cortices, but the mechanisms underlying their coordination remain elusive. One suggestion is that oscillatory coherence mediates inter‐regional communication, implicating theta phase and theta‐gamma phase‐amplitude coupling in mnemonic function across species. To examine this hypothesis, we used non‐invasive whole‐head magnetoencephalography (MEG) as participants retrieved the location of objects encountered within a virtual environment. We demonstrate that, when participants are cued with the image of an object whose location they must subsequently navigate to, there is a significant increase in 4–8 Hz theta power in medial prefrontal cortex (mPFC), and the phase of this oscillation is coupled both with ongoing theta phase in the medial temporal lobe (MTL) and perceptually induced 65–85 Hz gamma amplitude in medial parietal cortex. These results suggest that theta phase coupling between mPFC and MTL and theta‐gamma phase‐amplitude coupling between mPFC and neocortical regions may play a role in human spatial memory retrieval. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Post-Event Processing in Social Anxiety Disorder: Idiosyncratic Priming in the Course of CBT

Post-event processing (PEP) is the cognitive rumination that follows social events for patients with social anxiety. The PEP period was examined in relation to two anxiety provoking tasks in cognitive behavioural group therapy for social anxiety disorder: (1) Attending the first group therapy session (n = 75), and (2) An individually tailored in-session exposure task (n = 50). An assessment of PEP was conducted the week following each task as an indication of the extent of rumination over that event during the subsequent week. Significant PEP occurred after both events, and greater baseline social anxiety predicted greater levels of PEP related to both tasks. Anxiety ratings, as conceptualized by SUDS, were positively correlated with the severity of subsequent PEP related to the exposure task. There was also support for the stability of PEP across the two tasks and for the specificity of the content of PEP as rumination related to social failure, rather than rumination related to depressive symptoms. This study provides additional empirical support for the role of PEP in the cognitive model of social anxiety disorder.     

Progress in prion vaccines and immunotherapies

The transmissible spongiform encephalopathies have presented a challenge to physicians and scientists attempting to develop immunologically-based treatments. Self-tolerance has been one of the major obstacles to successfully raising antibodies against the prion protein (PrP), the host-encoded protein whose misfolded form (PrPSc) is linked to the protein-only infectious agent responsible for these disorders. Recently, it has been shown that antibodies directed against the normal cellular isoform of PrP (PrPC) can reduce or eliminate PrP isoform conversion in both in vitro and in vivo model systems. Similar studies with a PrPSc-specific epitope target are in progress. There is now rational hope that this devastating group of diseases may soon be amenable to immunotherapy and immunoprophylaxis.     

Glucuronidation of monohydroxylated warfarin metabolites by human liver microsomes and human recombinant UDP-glucuronosyltransferases

Our understanding of human phase II metabolic pathways which facilitate detoxification and excretion of warfarin (Coumadin) is limited. The goal of this study was to test the hypothesis that there are specific human hepatic and extrahepatic UDP-glucuronosyltransferase (UGT) isozymes, which are responsible for conjugating warfarin and hydroxylated metabolites of warfarin. Glucuronidation activity of human liver microsomes (HLMs) and eight human recombinant UGTs toward (R)- and (S)-warfarin, racemic warfarin, and major cytochrome P450 metabolites of warfarin (4'-, 6-, 7-, 8-, and 10-hydroxywarfarin) has been assessed. HLMs, UGT1A1, 1A8, 1A9, and 1A10 showed glucuronidation activity toward 4'-, 6-, 7-, and/or 8-hydroxywarfarin with K(m) values ranging from 59 to 480 microM and V(max) values ranging from 0.03 to 0.78 microM/min/mg protein. Tandem mass spectrometry studies and structure comparisons suggested glucuronidation was occurring at the C4'-, C6-, C7-, and C8-positions. Of the hepatic UGT isozymes tested, UGT1A9 exclusively metabolized 8-hydroxywarfarin, whereas UGT1A1 metabolized 6-, 7-, and 8-hydroxywarfarin. Studies with extrahepatic UGT isoforms showed that UGT1A8 metabolized 7- and 8-hydroxywarfarin and that UGT1A10 glucuronidated 4'-, 6-, 7-, and 8-hydroxywarfarin. UGT1A4, 1A6, 1A7, and 2B7 did not have activity with any substrate, and none of the UGT isozymes evaluated catalyzed reactions with (R)- and (S)-warfarin, racemic warfarin, or 10-hydroxywarfarin. This is the first study identifying and characterizing specific human UGT isozymes, which glucuronidate major cytochrome P450 metabolites of warfarin with similar metabolic rates known to be associated with warfarin metabolism. Continued characterization of these pathways may enhance our ability to reduce life-threatening and costly complications associated with warfarin therapy.     

The practical management of artifact in computerised physiological data

Computerised physiological data contains artifact that needs to be identified and possibly removed. Whilst computers may eventually satisfactorily perform this function, at present only manual removal is possible for the majority of intensive care computer groups. We assessed the effects of artifact and its removal on the physiological data of 3 patients. Artifact was manually removed from 7 days of data in 4 parameters (heart rate, respiratory rate, systolic blood pressure [sbp] and transcutaneous oxygen [tcpO2]) by 3 independent observers. Six hour time periods were analysed. Median and mean values before and after the manual removal of artifact were compared. Overall. 6.5% of data was removed as artifact. This was greatest for tcp02 (9.9%) and sbp (10.6%), with smaller amounts for respiratory rate (2.8%) and heart rate (2.4%). Sbp showed a marked difference in the amount of data removed between patients, whereas tcp02 data contained quite large volumes of artifact, but this was fairly consistent between patients, Removal of artifact affected mean values more than median values. One observer considered that both physiological and non-physiological artifact should be removed, whereas the other two observers removed only non-physiological artifact. Agreement in results between the latter was good. Our results suggest that interobserver variability should have a minimal effect on values, once rules identifying the type of artifact to be removed are agreed. Removal of artifact did not have a clinically significant effect on results, but may be an important consideration in the statistical analysis of computerised physiological data.Abbreviations CPTM computerised physiological trend monitoring - tcp02 transcutaneous pressure of oxygen - sbp systolic blood pressure