Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: structure-activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.     

1-Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: synthesis and evaluation of biological activities

A series of 1-acyl-1H-[1,2,4]triazole-3,5-diamine analogues were synthesized as cyclin-dependent kinase (CDK) inhibitors. These compounds showed potent and selective CDK1 and CDK2 inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. Representative compound 3b demonstrated in vivo efficacy in a human melanoma A375 xenograft model in nude mice.     

Smoking cessation 1: pharmacological treatments

In part 1 of this 3-part review of interventions for tobacco dependence, the authors present evidence regarding the efficacy of pharmacological treatments for smoking cessation. They also present evidence and recommendations included in the U.S. Department of Health and Human Services Treating Tobacco Use and Dependence: Clinical Practice Guideline (the Guideline), evidence from studies published after the Guideline, and recommendations of their own. The authors review nicotine replacement therapies, antidepressants, and other pharmacotherapies, followed by pharmacological treatments for special populations. The evidence indicates that a variety of effective smoking cessation medications are available. First-line medications include nicotine replacement therapies and bupropion. Pharmacotherapy is a vital component of smoking cessation interventions and should be offered to all smokers who want to quit unless contraindicated. There is a need for further research on pharmacotherapies for smoking cessation, and the authors discuss key areas for future research.     

Perisaccadic mislocalization of visual targets by head-free gaze shifts: visual or motor?

Such perisaccadic mislocalization is maximal in the direction of the saccade and varies systematically with the target-saccade onset delay. We have recently shown that under head-fixed conditions perisaccadic errors do not follow the quantitative predictions of current visuomotor models that explain these mislocalizations in terms of spatial updating. These models all assume sluggish eye-movement feedback and therefore predict that errors should vary systematically with the amplitude and kinematics of the intervening saccade. Instead, we reported that errors depend only weakly on the saccade amplitude. An alternative explanation for the data is that around the saccade the perceived target location undergoes a uniform transient shift in the saccade direction, but that the oculomotor feedback is, on average, accurate. This "visual shift" hypothesis predicts that errors will also remain insensitive to kinematic variability within much larger head-free gaze shifts. Here we test this prediction by presenting a brief visual probe near the onset of gaze saccades between 40 and 70° amplitude. According to models with inaccurate gaze-motor feedback, the expected perisaccadic errors for such gaze shifts should be as large as 30° and depend heavily on the kinematics of the gaze shift. In contrast, we found that the actual peak errors were similar to those reported for much smaller saccadic eye movements, i.e., on average about 10°, and that neither gaze-shift amplitude nor kinematics plays a systematic role. Our data further corroborate the visual origin of perisaccadic mislocalization under open-loop conditions and strengthen the idea that efferent feedback signals in the gaze-control system are fast and accurate.     

IgG rheumatoid factors against the four human Fc-gamma subclasses in early rheumatoid arthritis (the Swedish TIRA project)

Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analysed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG1-4) as sources of antigen. Sera from 40 patients with recent onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype-specific ELISA) were analysed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF-positive RA-sera, IgG-RF was found directed against hIgG1 and hIgG2, but not against hIgG3 or hIgG4. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgM-RF (r = 0.666) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.     

Literature‐based immunization recommendations for patients requiring immunosuppressive medications for autoimmune bullous dermatoses

Autoimmune bullous diseases, such as pemphigus, pemphigoid, and dermatitis herpetiformis, are uniquely associated with vulnerability in the mucocutaneous barrier against infection. The management of immunobullous diseases is complex and may at times require immunosuppressive medications. Iatrogenic immunosuppression may increase susceptibility to vaccine‐preventable illnesses. Currently, there are no guidelines to assist the clinician treating patients with immunobullous disease regarding the delivery of various vaccinations. The aim of this review is to provide recommendations for immunization in the unique setting of immunobullous disease. Recommendations are based on careful review of the literature in other conditions requiring iatrogenic immunosuppression, as well as the most recent Centers for Disease Control and Prevention guidelines. Immunization with nonlive vaccines appears to be a safe and effective strategy for preventing infection in the particularly susceptible patient with immunobullous disease. Opportunities for live vaccine administration may become available at lower levels of immune suppression or during clinical remission when immunosuppressive regimens can be reduced. Anticipatory vaccination before the initiation of iatrogenic immunosuppression is ideal. Although immunologic response to vaccination may be suboptimal during immunosuppression, nonlive vaccination is strongly recommended for this patient population.     

Whole-body ultra-low dose CT using spectral shaping for detection of osteolytic lesion in multiple myeloma

Objectives

The aim of this study was to investigate the radiation dose and image quality of a whole-body low-dose CT (WBLDCT) using spectral shaping at 100 kV (Sn 100 kV) for the assessment of osteolytic lesions in patients with multiple myeloma.

Methods

Thirty consecutive patients were retrospectively selected, who underwent a WBLDCT on a third-generation dual-source CT (DSCT) (Sn 100 kV, ref. mAs: 130). They were matched with patients, who were examined on a second-generation DSCT with a standard low-dose protocol (100 kV, ref. mAs: 111). Objective and subjective image quality, radiation exposure as well as the frequency of osteolytic lesions were evaluated.

Results

All scans were of diagnostic image quality. Subjective overall image quality was significantly higher in the study group (p = 0.0003). Objective image analysis revealed that signal intensities, signal-to-noise ratio and contrast-to-noise ratio of the bony structures were equal or significantly higher in the control group. There was no significant difference in the frequency of osteolytic lesions (p = 0.259). The median effective dose of the study protocol was significantly lower (1.45 mSv vs. 5.65 mSv; p < 0.0001).

Conclusion

WBLDCT with Sn 100 kV can obtain sufficient image quality for the depiction of osteolytic lesions while reducing the radiation dose by approximately 74%.

Key points

? Spectral shaping using tin filtration is beneficial for whole-body low-dose CT? Sn 100 kV yields sufficient image quality for depiction of osteolytic lesions? Whole-body low-dose CT can be performed with a median dose of 1.5 mSv

     

Cogniform Disorder and Cogniform Condition: proposed diagnoses for excessive cognitive symptoms.

In neuropsychological practice, individuals often present with evidence of excessive cognitive complaints or invalid test performances indicative of symptom exaggeration; however, clinicians often struggle with how to diagnose these cases once they have been identified. Difficulties in subsuming these individuals within existing DSM-IV diagnoses such as Malingering, Factitious Disorder, and Conversion Disorder are discussed, including: (a) lack of a diagnostic category that adequately targets the specific features of this relatively common condition and (b) the use of criteria that require the clinician to make judgments about internal states that are difficult to evaluate in an objective manner (e.g., intentional versus unintentional production of exaggerated symptoms). Two diagnostic categories--Cogniform Disorder and Cogniform Condition--are proposed as new subtypes of the Somatoform Disorders to encompass cases of excessive cognitive complaints and inadequate test-taking effort in the absence of sufficient evidence to diagnose Malingering. Of the two new categories, Cogniform Disorder is defined as a more pervasive form in which the individual tends to exhibit the excessive cognitive symptoms in widespread areas of his or her life, thereby suggesting a conversion-like adoption of the sick role manifested primarily as cognitive dysfunction. Guidelines for improving the evidence-based diagnosis of these cases, particularly with regards to criteria related to intentionality, secondary gain, and sick role factors, are also discussed.