Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents

We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase. Oral administration of Imidazole 24b blocked CP-55940-induced hypothermia, demonstrating cannabinoid CB(1) receptor antagonist efficacy in vivo. Using ex vivo autoradiography, Imidazole 24b resulted in dose-dependent increases in brain cannabinoid CB(1) receptor occupancy (RO) at 2h post-dosing in rats, indicating that approximately 50% receptor occupancy is sufficient for attenuation of receptor agonist-induced hypothermia. Imidazole 24b administered to C57Bl/6 mice and to dietary-induced obese (DIO) Sprague-Dawley rats attenuated overnight food intake with a minimal effective dose of 10 mg/kg, p.o. Administration had no effect in cannabinoid CB(1) receptor-deficient mice. DIO rats were dosed orally with vehicle, Imidazole 24b (1, 3 or 10 mg/kg), or dexfenfluramine (3 mg/kg) for 2 weeks. At 3 mg/kg, Imidazole 24b reduced cumulative food intake, leading to a non-significant decrease in weight gain. Imidazole 24b at 10 mg/kg and dexfenfluramine treatment inhibited food intake and attenuated weight gain. These findings suggest that selective cannabinoid CB(1) receptor inverse agonists such as Imidazole 24b have potential for the treatment of obesity.     

A possible influence of gingival dimensions on attachment loss and gingival recession following placement of artificial crowns

The aim of the present study was to determine the influence of gingival dimensions on the development of gingival recession following placement of artificial crowns. The study population consisted of 11 periodontally healthy patients in whom 44 maxillary anterior teeth and/or premolars had to be crowned. A total of 36 teeth (82%) had, after crown placement, a mean intracrevicular crown margin of 0.57 +/- 0.47 mm. Thirty-nine teeth without restorations served as controls. Immediately after incorporation, as well as after 3, 6, 9, and 12 months, periodontal examinations were carried out. Gingival thickness was determined sonometrically and averaged 1.25 +/- 0.40 mm. Mean periodontal probing depth was 1.80 +/- 0.54 mm. Twelve months later, crowned teeth had experienced a mean attachment loss of 0.17 +/- 0.99 mm as compared to an attachment gain of 0.18 +/- 0.46 mm at control teeth. At test teeth, the gingival margin had receded a mean of 0.43 +/- 0.74 mm. In multivariate analyses considering the correlated structure of the data employing generalized estimating equation methods, crown placement was identified as a major factor for attachment loss and development of gingival recession. In addition, a shallow probing depth and narrow band of gingiva negatively influenced the level of periodontal attachment. The present results point to the importance of a more detailed periodontal diagnosis of the dentogingival region before placement of artificial crowns.     

13-loci STR multiplex system for Brazilian seized samples of marijuana: individualization and origin differentiation

International Journal of Legal Medicine - It is known that Cannabis in Brazil could either originate from Paraguay or be cultivated in Brazil. While consumer markets in the North and Northeast...     

Performance of a capnodynamic method estimating effective pulmonary blood flow during transient and sustained hypercapnia

The capnodynamic method is a minimally invasive method continuously calculating effective pulmonary blood flow (CO_EPBF), equivalent to cardiac output when intra pulmonary shunt flow is low. The capnodynamic equation joined with a ventilator pattern containing cyclic reoccurring expiratory holds, provides breath to breath hemodynamic monitoring in the anesthetized patient. Its performance however, might be affected by changes in the mixed venous content of carbon dioxide (C_vCO₂). The aim of the current study was to evaluate CO_EPBF during rapid measurable changes in mixed venous carbon dioxide partial pressure (P_vCO₂) following ischemia–reperfusion and during sustained hypercapnia in a porcine model. Sixteen pigs were submitted to either ischemia–reperfusion (n?=?8) after the release of an aortic balloon inflated during 30 min or to prolonged hypercapnia (n?=?8) induced by adding an instrumental dead space. Reference cardiac output (CO) was measured by an ultrasonic flow probe placed around the pulmonary artery trunk (CO_TS). Hemodynamic measurements were obtained at baseline, end of ischemia and during the first 5 min of reperfusion as well as during prolonged hypercapnia at high and low CO states. Ischemia–reperfusion resulted in large changes in P_vCO₂, hemodynamics and lactate. Bias (limits of agreement) was 0.7 (?0.4 to 1.8) L/min with a mean error of 28% at baseline. CO_EPBF was impaired during reperfusion but agreement was restored within 5 min. During prolonged hypercapnia, agreement remained good during changes in CO. The mean polar angle was ?4.19° (?8.8° to 0.42°). Capnodynamic CO_EPBF is affected but recovers rapidly after transient large changes in P_vCO₂ and preserves good agreement and trending ability during states of prolonged hypercapnia at different levels of CO.     

Effect of left ventricular remodeling after cardiac resynchronization therapy on frequency of ventricular arrhythmias

We evaluated whether cardiac resynchronization therapy affects the prevalence of ventricular tachycardia in relation to reverse remodeling in patients with end-stage heart failure. Clinical, echocardiographic, and implantable cardioverter-defibrillator (ICD) data of 17 patients with ICDs were obtained before and after they had received an upgrade to an ICD-cardiac resynchronization therapy device.     

Treatment of Generalized Lichen Nitidus with PUVA

Generalized lichen nitidus refractory to topical and systemic corticosteroids completely responded to PUVA. The similarity of lichen nitidus to lichen planus and the presumed lymphocytotoxic effect of PUVA were the bases for our use of oral photochemotherapy.     

Prognostic tools for hypertrophic scar formation based on fundamental differences in systemic immunity

Unpredictable hypertrophic scarring (HS) occurs after approximately 35% of all surgical procedures and causes significant physical and psychological complaints. Parallel to the need to understanding the mechanisms underlying HS formation, a prognostic tool is needed. The objective was to determine whether (systemic) immunological differences exist between patients who develop HS and those who develop normotrophic scars (NS) and to assess whether those differences can be used to identify patients prone to developing HS. A prospective cohort study with NS and HS groups in which (a) cytokine release by peripheral blood mononuclear cells (PBMC) and (b) the irritation threshold (IT) after an irritant (sodium lauryl sulphate) patch test was evaluated. Univariate regression analysis of PBMC cytokine secretion showed that low MCP‐1, IL‐8, IL‐18 and IL‐23 levels have a strong correlation with HS (P < .010‐0.004; AUC = 0.790‐0.883). Notably, combinations of two or three cytokines (TNF‐a, MCP‐1 and IL‐23; AUC: 0.942, Nagelkerke R²: 0.727) showed an improved AUC indicating a better correlation with HS than single cytokine analysis. These combination models produce good prognostic results over a broad probability range (sensitivity: 93.8%, specificity 86.7%, accuracy 90,25% between probability 0.3 and 0.7). Furthermore, the HS group had a lower IT than the NS group and an accuracy of 68%. In conclusion, very fundamental immunological differences exist between individuals who develop HS and those who do not, whereas the cytokine assay forms the basis of a predictive prognostic test for HS formation, the less invasive, easily performed irritant skin patch test is more accessible for daily practice.     

Postictal generalized EEG suppression is not associated with periictal cardiac autonomic instability in people with convulsive seizures

Purpose: Postictal generalized EEG suppression (PGES) seems to be a pathophysiologic hallmark in ictal recordings of sudden unexpected death in epilepsy (SUDEP). It has recently been suggested that presence and duration of PGES might be a predictor of SUDEP risk. Little is known about the etiology of PGES. Methods: We conducted a retrospective case–control study in 50 people with convulsive seizures (CS) recorded on digital video–electroencephalography (EEG). One CS per individual was reviewed for presence and duration of PGES by two independent observers: Preictal and postictal heart rate (HR) (1 min before seizure onset and 1, 3, 5, 15, and 30 min after seizure end) and frequency domain measures of heart rate variability (HRV), including the ratio of low frequency (LF) versus high frequency (HF) power, were analyzed. The relationship between PGES and periictal autonomic changes was evaluated, as well as its association with several clinical variables. Key Findings: Thirty‐seven individuals (74%) exhibited PGES and 13 (26%) did not. CS resulted in a significant increase of periictal HR and the LF/HF ratio. PGES was associated with neither periictal HR (mean HR difference between PGES+ and PGES? seizures: ?2 beats per minute [bpm], 95% confidence interval [CI] ?10 to +6 bpm) nor HRV change. There was no association between the duration of PGES and periictal HR change. People with PGES were more likely to be asleep before seizure onset (odds ratio [OR] 4.7, 95% CI 1.2–18.3) and had a higher age of onset of epilepsy (median age 15 vs. 4 years). Significance: PGES was not associated with substantial changes in measures of cardiac autonomic instability but was more prevalent in CS arising from sleep.