Neuropeptide Y (NPY)-like immunoreactivity in rat sympathetic neurons and small granule-containing cells

The distribution of neuropeptide Y-like immunoreactivity (NPY-LI) was examined in the rat superior cervical and hypogastric ganglia. NPY-LI was localized in the majority of the sympathetic neurons, a few small granule-containing (SGC) cells and nerve terminals. Most of the NPY-immunoreactive sympathetic neurons were also tyrosine hydroxylase (TH)-immunoreactive but in hypogastric ganglia few neurons with NPY-LI were devoid of TH-immunoreactivity. Electron microscopically NPY-LI was found in the Golgi complexes of sympathetic neurons, in large cytoplasmic granules (100-150 nm in diameter) of the SGC cells and in large dense-cored vesicles (80-100 nm in diameter) of the nerve terminals. NPY-LI coexists mainly with noradrenaline in sympathetic neurons, and may have regulatory functions in sympathetic ganglia and in target organs.     

Localization of [Met5]- and [Leu5]-enkephalin-like immunoreactivity in nerve terminals in human paravertebral sympathetic ganglia

Both [Leu⁵]- and [Met⁵]-enkephalin have been localized immunohistochemically in nerve fibres and in small, intensely fluorescent cells of adult human sympathetic ganglia. The nerve fibres showing enkephalin-like immunoreactivity formed a network varying in density around the sympathetic neurons, some being closely related to the perikarya. No labelled neuronal cell bodies were found. No structures within the ganglion were labelled after reaction with antibodies to vasoactive intestinal polypeptide, adrenocorticotrophin or substance P. No differences between the distributions of [Leu⁵]-and [Met⁵]-enkephalin-like immunoreactivities were found.The physiological roles of enkephalins are still unknown, but it is possible that they might act as neurotransmitters or neuromodulators in the human sympathetic nervous system.     

Reduced brain serotonergic activity after repeated treatment with β-adrenoceptor antagonists

Rats were treated subchronically (14 days) or acutely (single dose) with the ₁-selective adrenoceptor antagonist metoprolol or the ₂-selective adrenoceptor antagonist ICI 118,551. Metoprolol (350 mg/kg/day for 14 days, orally) significantly reduced the 5-hydroxytryptophan (5-HTP) accumulation when measured 30 min after inhibition of L-amino acid decarboxylase by NSD 1015 (100 mg/kg IP) in the limbic forebrain, the corpus striatum, the cerebral cortex, the brain stem, and in the cerebellum. ICI 118,551 (0.5 mg/kg, twice daily for 14 days, SC) also significantly reduced the 5-HTP accumulation in the same brain regions except in the corpus striatum and the brain stem. Simultaneously assayed tryptophan levels were largely unaffected. Thus sustained -adrenoceptor blockade causes a decrease in the in vivo rate of tryptophan hydroxylation in various rat brain regions. The subchronic treatments with metoprolol or ICI 118,551 also significantly reduced the endogenous levels of 5-hydroxytryptamine (5-HT) in the various rat brain regions studied. Acute treatment with either metoprolol (2 mg/kg SC) or ICI 118,551 (0.5 mg/kg SC) did not affect the 5-HTP accumulation or the endogenous 5-HT levels in the brain regions studied. This inhibitory effect on brain 5-HT systems produced by sustained -adrenoceptor blockade may be of significance both for the long-term cardiovascular action and for occasional neuropsychiatric side effects during -blocking therapy.     

Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator.

In the present study, the involvement of cytochrome P450 enzyme(s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent KM in the range of 0.09 to 1.9 mM and Vmax from 22 to 120 pmol/mg/min. A strong correlation between the formation rate of metabolites and 6beta-hydroxylation of testosterone was obtained within a panel of liver microsomes from 15 individuals (r2 = 0.6 to 0.94). Moreover, ketoconazole and troleandomycin, specific inhibitors of CYP3A4 metabolism, demonstrated a significant inhibition of laquinimod metabolism. Furthermore, in incubations with recombinant CYP3A4, all the primary metabolites were formed. In vitro interaction studies with CYP3A4 substrates and possible concomitant medication demonstrated that laquinimod inhibits the metabolism of ethinyl estradiol with an IC50 value of about 150 microM, which is high above the plasma level of laquinimod after clinically relevant doses. Ketoconazole, troleandomycin, erythromycin, prednisolone, and ethinyl estradiol inhibited the metabolism of laquinimod, and IC50 values of 0.2, 11, 24, 87, and 235 microM, respectively, were calculated. In conclusion, the present study demonstrates that laquinimod is a low affinity substrate for CYP3A4 in human liver microsomes. The likelihood for in vivo effects of laquinimod on the metabolism of other CYP3A4 substrates is minor. However, inhibitory effects on the metabolism of laquinimod by potent and specific inhibitors of CYP3A4, such as ketoconazole, are anticipated and should be considered in the continued clinical program for laquinimod.     

Predictors of death during 10 years after coronary artery bypass grafting with particular emphasis on age

OBJECTIVES: To describe predictors of death during 10 years of follow-up after coronary artery bypass grafting (CABG); to evaluate whether age interacts with the influence of various predictors on outcome; and to compare the mortality during 10 years after CABG with the mortality in an age- and sex-matched control population. DESIGN: Prospective, observational study. SETTING: Department of Thoracic and Cardiovascular Surgery at Sahlgrenska University Hospital and Scandinavian Heart Centre in G?teborg, Sweden. PARTICIPANTS: All patients from western Sweden who underwent CABG between 1 June 1988 and 1 June 1991 without simultaneous valve surgery and with no previous CABG. MAIN OUTCOME MEASUREMENTS: All-cause mortality during 10 years but more than 30 days after CABG. RESULTS: In all, 2000 patients participated in the survey. The following factors appeared as independent predictors of death: preoperative factors-age, history of congestive heart failure, cerebrovascular disease, history of intermittent claudication, current smoking, degree of left ventricular impairment, valvular disease and duration of angina pectoris; peroperative factors-ventilator time and neurological complications; postoperative factors-arrhythmia, requirement of digitalis and requirement of antidiabetics. There was an interaction between age and history of cerebrovascular disease with a stronger impact on outcome in younger patients. The late (>30 days after CABG) 10-year mortality in the study cohort was 29.6% compared with 25.9% in the control population (P=0.02). CONCLUSION: Among patients who underwent CABG, 13 independent predictors for mortality were found, mainly among preoperative factors but also among peroperative factors, postoperative complications and medication requirement after CABG.     

Methylparaben concentration in commercial Brazilian local anesthetics solutions

Objective

To detect the presence and concentration of methylparaben in cartridges of commercial Brazilian local anesthetics.

Material and methods

Twelve commercial brands (4 in glass and 8 in plastic cartridges) of local anesthetic solutions for use in dentistry were purchased from the Brazilian market and analyzed. Different lots of the commercial brands were obtained in different Brazilian cities (Piracicaba, Campinas and São Paulo). Separation was performed using high performance liquid chromatography (HPLC) with UV-Vis detector. The mobile phase used was acetonitrile:water (75:25 - v/v), pH 4.5, adjusted with acetic acid at a flow rate of 1.0 ml.min^-1.

Results

When detected in the solutions, the methylparaben concentration ranged from 0.01% (m/v) to 0.16% (m/v). One glass and all plastic cartridges presented methylparaben.

Conclusion

1. Methylparaben concentration varied among solutions from different manufacturers, and it was not indicated in the drug package inserts; 2. Since the presence of methylparaben in dental anesthetics is not regulated by the Brazilian National Health Surveillance Agency (ANVISA) and this substance could cause allergic reactions, it is important to alert dentists about its possible presence.     

CBCT结合显微超声技术处理根管内折断器械的临床研究

目的：评价锥体束CT（CBCT）结合显微超声技术处理根管内折断器械的临床疗效。方法：选取济宁医学院附属医院口腔科2012年9月～2013年6月初次根管治疗中出现的器械折断病例24例,对患牙CBCT扫描,进行三维重建,对折断器械的根管进行三维定位及评估,制定临床决策,实施断械取出,计算取出率。结果：CBCT能准确定位断械所在根管,清晰显示根管形态、弯曲度、折断器械位置及周围牙本质厚度。24例断械病例中,20例选择取出治疗,其中16例成功取出,4例未能取出,成功率为80％。4例因折断器械均位于根尖部,弯曲根管下段,且周围牙本质薄弱不选择取出治疗。结论：CBCT结合显微超声技术为临床上评估及取出根管内器械折断病例提供了有效方法。     

Bone cement with reduced proportion of monomer in total hip arthroplasty: Preclinical evaluation and randomized study of 47 cases with 5 years' follow-up

Bone cement with reduced amount of monomer and low curing temperature may improve implant fixation due to reduced toxicity. We analyzed the mechanical, chemical and thermal properties of such a cement (Cemex Rx) using Palacos R as control. The in vivo performance of the 2 cements was also evaluated in a prospective randomized study of 47 hips, where either of the cement types was used to fixate Lubinus SP2 prostheses with the stem made of titanium alloy. Cemex Rx had a reduced tensile strength, probably because this cement was manually mixed, as recommended by the manufacturer. A standardized laboratory test showed lower curing temperature for Cemex, but measurements at 37° and with prechilled Palacos R and Cemex Rx, as in clinical work, showed no difference. In the clinical study radiostereometric measurements of cup and stem migration showed similar values in the 2 groups up to 5 years after the operation. The cement mantle was stable in both groups, but the stems migrated similarly inside the cement mantle regardless of the type of cement used. Proximal wear was low (0.04-0.05 mm/year) and tended to be lower in the Cemex group (p = 0.02). Aluminum and vanadium levels in serum increased 5 years after the operation, but no difference was noted between the 2 groups. Collagen markers (PICP, ICTP) showed similar increases in bone turnover 6 weeks and 6 months after operation in both groups.