Inhibition of interferon γ induced interleukin 12 production: A potential mechanism for the anti-inflammatory activities of tumor necrosis factor

Inflammation is associated with production of cytokines and chemokines that recruit and activate inflammatory cells. Interleukin (IL) 12 produced by macrophages in response to various stimuli is a potent inducer of interferon (IFN) γ production. IFN-γ, in turn, markedly enhances IL-12 production. Although the immune response is typically self-limiting, the mechanisms involved are unclear. We demonstrate that IFN-γ inhibits production of chemokines (macrophage inflammatory proteins MIP-1α and MIP-1β). Furthermore, pre-exposure to tumor necrosis factor (TNF) inhibited IFN-γ priming for production of high levels of IL-12 by macrophages in vitro. Inhibition of IL-12 by TNF can be mediated by both IL-10-dependent and IL-10-independent mechanisms. To determine whether TNF inhibition of IFN-γ-induced IL-12 production contributed to the resolution of an inflammatory response in vivo, the response of TNF^+/+ and TNF^−/− mice injected with Corynebacterium parvum were compared. TNF^−/− mice developed a delayed, but vigorous, inflammatory response leading to death, whereas TNF^+/+ mice exhibited a prompt response that resolved. Serum IL-12 levels were elevated 3-fold in C. parvum-treated TNF^−/− mice compared with TNF^+/+ mice. Treatment with a neutralizing anti-IL-12 antibody led to resolution of the response to C. parvum in TNF^−/− mice. We conclude that the role of TNF in limiting the extent and duration of inflammatory responses in vivo involves its capacity to regulate macrophage IL-12 production. IFN-γ inhibition of chemokine production and inhibition of IFN-γ-induced IL-12 production by TNF provide potential mechanisms by which these cytokines can exert anti-inflammatory/repair function(s).     

Normalization of abnormal T waves in ischemia.

Inverted T waves due to coronary artery disease and previous myocardial infarction were observed to revert ot normal, upright position during ischemia in 38 patients. The normalization of inverted T waves was seen on the electroencephalograms of 19 patients during spontaneously occurring angina pectoris and of 11 patients when ischemia was provoked by treadmill exercise; for 8 patients, normalization occurred during the administration of isoproterenol hydrochloride and during the consequent episode of angina pectoris. The mechanism for normalization may be the algebraic sum of the extent of ST segment elevation and the amplitude of the T waves of acute ischemia plus the extent of preexisting ST segment depression and the degree of T wave inversion, to result in isoelectric ST segment and upright T wave. As with myocardial infarction, reciprocal changes may also be recorded. However, the reciprocal nature may be masked since either acute ST segment elevation of T wave inversion, or both, may not be recorded in the leads reflecting the ischemic area because of normalization.     

Retrograde aortic valve crossing of the corevalve prosthesis using the buddy balloon technique

In rare cases, retrograde aortic valve crossing during transcatheter aortic valve implantation may be challenging despite improvements in delivery catheter profile, size, and steerability compared with the first generation devices. Herein, we report a case of challenging transfemoral Medtronic CoreValve placement that was possible, thanks to the buddy balloon technique, using a peripheral 6‐F compatible balloon. © 2013 Wiley Periodicals, Inc.     

Bilateral motor tasks involve more brain regions and higher neural activation than unilateral tasks: an fMRI study

Movements that involve simultaneous coordination of muscles of the right and left lower limbs form a large part of our daily activities (e.g., standing, rising from a chair). This study used functional magnetic resonance imaging to determine which brain areas are used to control coordinated lower-limb movements, specifically comparing regions that are activated during bilateral exertions to those performed unilaterally. Plantarflexor exertions were produced at a target force level of 15 % of the participants’ maximum voluntary contraction, in three conditions, with their right (dominant) foot, with their left foot, and with both feet simultaneously. A voxel-wise analysis determined which regions were active in the bilateral, but not in the unilateral conditions. In addition, a region of interest (ROI) approach was used to determine differences in the percent signal change (PSC) between the conditions within motor areas. The voxel-wise analysis showed a large number of regions (cortical, subcortical, and cerebellar) that were active during the bilateral condition, but not during either unilateral condition. The ROI analysis showed several motor regions with higher activation in the bilateral condition than unilateral conditions; further, the magnitude of bilateral PSC was more than the sum of the two unilateral conditions in several of these regions. We postulate that the greater levels of activation during bilateral exertions may arise from interhemispheric inhibition, as well as from the greater need for motor coordination (e.g., synchronizing the two limbs to activate together) and visual processing (e.g., monitoring of two visual stimuli).     

Application of an activity‐based receptor bioassay to investigate the in vitro activity of selected indole‐ and indazole‐3‐carboxamide‐based synthetic cannabinoids at CB1 and CB2 receptors

Synthetic cannabinoids (SCs) are the most chemically diverse group of new psychoactive substances. This group has been associated with several intoxications, many with fatal outcomes. Although advancements have been achieved in pharmacology, metabolism, and detection of these compounds in recent years, these aspects are still unresolved for many SCs. The aim of this study was to investigate the in vitro potency of 14 indole‐ and indazole‐based SCs by applying a stable CB1 or CB2 receptor activation assay and correlating the activity with their structure. The half‐maximal effective concentration (EC₅₀) of 5‐chloropentyl, 5‐bromopentyl, and 5‐iodopentyl JWH‐122 analogs varied from 74.1 to 283.7 nM for CB1 and 7.05 to 23.4 nM for CB2, where the addition of a chlorine atom enhanced the potency at CB1 compared with the bromo and iodo analogs. AM‐2201 was the most active at CB1 within this naphthoylindole family, with an EC₅₀ of 23.5 nM but with the lowest efficacy (E_max 98.8%). Within the indole‐3‐carboxamide derivatives, 5F‐MDMB‐PICA was the most active compound, with a CB1/CB2 EC₅₀ of 3.26/0.87 nM and an E_max around three times higher than JWH‐018. ADB‐FUBINACA was the most potent tested SC overall, with a CB1/CB2 EC₅₀ of 0.69/0.59 nM, and an E_max around 3‐fold higher than that for JWH‐018 at CB1. The data obtained in this study confirm how small differences in the structure of SCs might lead to large differences in their activity, especially at CB1, which may be correlated with differences in their toxic effects in humans.     

Graduate orthodontic education in Turkey: the residents' perspective

The aim of the present study was to explore residents' perceptions of their educational and clinical treatment experiences including the number of clinical cases undertaken, patient completion rates, techniques utilised and the scientific component of Turkish graduate orthodontic programmes. Residents recorded in the list of Turkish Orthodontic Society were sent an e‐mail to participate in a survey containing 46 multiple‐choice questions and ten one‐line answers. An e‐mail with a personalised online link was sent to a total of 227 residents throughout the Turkey. Data were categorised, and basic statistics including chi‐square comparative analyses were performed. A total of 136 (response rate of 59.91%) residents completed the survey. The majority of residents (58.08%) were either ‘very satisfied’ or ‘satisfied’ with their programme. Respondents said they have just the right amount of formal didactic teaching sessions or dedicated and protected academic time. Most residents (69.11%) indicated their programme offers training in numerous philosophies; whilst 97.79% said they have sufficient clinically based training and 42.64% said they have sufficient research‐based training. Overall, residents in the Turkey are satisfied with their orthodontic programme. They receive comprehensive training with the opportunity to start and complete a significant number of their patients. The survey findings suggest that orthodontic programmes in Turkey are deficient in providing care to underserviced populations and disabled patients. Programmes could improve the opportunity for residents to treat patients requiring interdisciplinary treatment.