Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta?=??0.0264, p value?=?3.5?×?10^–8) in the discovery panel and was replicated in replication panel (beta?=??0.07, p value?=?0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value?=?1.4?×?10^–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

     

Intrahepatic absorbable fine mesh packing of hepatic injuries: Preliminary clinical report

A previous report from the authors' institution reported the effectiveness of hepatic packing with absorbable fine mesh (AFMP) for the control of hemorrhage in an animal model with an otherwise lethal hepatic injury. The technique has subsequently been applied to 12 abdominal trauma patients with hemodynamic instability and actively hemorrhaging hepatic injuries. Two patients expired in the operating room owing to uncontrolled hemorrhage from hepatic and associated injuries for a mortality of 16.7%. AFMP was successful in controlling hemorrhage in the remaining 10 patients. Hepatic injuries ranged from grade II to grade V, and all were actively hemorrhaging at the time of exploration. None of the surviving 10 patients experienced early or late recurrent bleeding attributable to the hepatic injuries, and there were no intraabdominal abscesses or late deaths. Liver function studies returned to normal prior to discharge in all surviving patients. Follow-up included serial computed tomographic scans, which demonstrated fibrosis incorporating the mesh packing. Complete resolution of injury and mesh appears to proceed over approximately a 6-month period. AFMP is a safe, effective method for controlling hepatic hemorrhage. It is easy to perform in the operating room, offers an excellent matrix for hemostasis, provides tamponade of bleeding sites, and does not require reoperation for removal of packing material, as is necessary with conventional, nonabsorbable packing techniques.

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Resumen En una publicación previa se informó la eficacia del empaquetamiento hepático con una fina malla absorbible en el control de la hemorragia en un modelo animal experimental sometido a lesión hepática letal. Desde entonces la técnica ha sido aplicada en 12 pacientes con trauma abdominal e inestabilidad hemodinámica y lesiones hepáticas sangrantes. Dos pacientes expiraron en la mesa de operaciones por hemorragia no controlada proveniente de la arteria hepática y de otras lesiones asociadas, con una tasa de mortalidad de 16.7%. La malla fue eficaz en cuanto a controlar la hemorragia en el resto de los pacientes. Las lesiones hepáticas variaron en cuanto a severidad entre los Grados II a V y todas exhibían hemorragia activa en el momento de la exploración. Ninguno de los 10 sobrevivientes desarrolló sangrado recurrente temprano o tardío que pudiera ser atribuible a las lesiones hepáticas y no se observaron abscesos intraabdominales o muertes tardías. Las pruebas de función hepática retornaron a valores normales con anterioridad al egreso, en la totalidad de los sobrevivientes. El seguimiento incluyó tomografías computadorizadas seriadas, que demostraron fibrosis del área de empaquetamiento con la malla; la resolución completa de la lesión y de la malla parece tener lugar en el curso de seis meses, aproximadamente. La malla representa un método seguro y eficaz de control de la hemorragia hepática, es fácil de aplicar en el quirófano, ofrece una excelente matriz para la hemostasia, produce taponamiento de los sitos sangrantes y no requiere reoperación para remover el material de empaquetamiento, como sí lo requieren las técnicas convencionales de empaquetamiento con materiales no absorbibles.

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Résumé Nous avons déjà rapporté l'efficacité du packing périhépatique par un filet fin résorbable (FFA) pour contrôler l'hémorragic autrement mortelle provenant d'une lésion hépatique chez l'animal. Cette même technique a été utilisée utilisée chez 12 patients ayant un traumatisme sévère du foie avec une hémodynamique instable. Deux patients sont décédés en salle d'opération des lésions hépatiques et des structures avoisinantes soit une mortalité de 16.7%. La technique de FFA a été couronnée de succès chez les 10 autres patients. Les lésions ont été classées selon leur sévérité du grade II au grade V et toutes saignaient activement au moment de l'opération. Aueun des patients survivants n'a eu de récidive hémorragique attribuable à la lésion hépatique et il n'y a eu aucun abcès intra-abdominal ni de mortalité tardive. La fonction hépatique est redevenue normale avant la sortie chez tous les autres patients. La surveillance du suivi a comporté une tomodensitométrie montrant une fibrose autour du filet. La résolution complète de la lésion et la résorption du filet évoluent en général sur six mois. La technique de FFA est sûre et efficace dans le contrôle de l'hémoragie provenant des traumatismes du foie. La méthode est facile à appliquer en salle d'opération, procure une hémostase excellent par tamponnade et ne nécessite pas de réintervention pour enlever le packing comme quand on utilise le matériel traditionnel non résorbable.

     

Hypertension two years after renal transplantation: causes and consequences

The incidence of hypertension 2 years after renal transplantation and the possible causes of hypertension were studied retrospectively. A group of 93 patients treated with cyclosporin (CyA), azathioprine (Aza), and/or prednisolone (Pred) were compared to a group of 31 patients treated with Aza and Pred. There were more patients with hypertension in the CyA group (73%) than in the Aza group (58%). Hypertension before transplantation predisposed to hypertension after transplantation. After transplantation, hypertension was most common among patients with polycystic kidney disease (46%), chronic glomerulonephritis (67%), and diabetes (71%). The accumulated immunosuppressive medication (CyA/Pred) did not affect the occurrence of hypertension. Hypertensive patients had significantly poorer graft function than did normotensive patients (serum creatinine level 229 mol/l vs 162 mol/l, P<0.01). The 10-year graft survival was markedly impaired in the group with hypertension (42% vs 65% for normotensives, P<0.05). The 10-year patient survival was 59% vs 79% (P=NS). The study further confirms the frequent finding that hypertension has a negative effect on graft and patient survival rates.     

Cadmium in kidneys in Swedes measured in vivo using X-ray fluorescence analysis

An X-ray fluorescence (XRF) technique using plane polarized X-rays for excitation was used for in vivo measurements of cadmium in the kidney cortex among non-occupationally exposed members of the general population in southern Sweden. The measured concentrations of cadmium in the kidney cortex of smokers (median 28 g/g, n = 10) were significantly higher (P = 0.0036) as compared to those in non-smokers (median 8 g/g, n = 10), and so were the cadmium concentrations in blood and urine. The results show that smoking considerably increases the cadmium concentration in the kidney cortex and that smoking is a major source of cadmium exposure in the general population of Sweden. Except in the presence of very deeply situated kidneys, where the minimum detectable concentration is high, non-invasive in vivo XRF analysis of kidney cadmium should be a useful tool for evaluating the effects of long-term low-level exposure to cadmium and the risk of kidney damage.     

Improving the nicotinic pharmacophore with a series of (Isoxazole)methylene-1-azacyclic compounds: synthesis, structure-activity relationship, and molecular modeling

A series of (isoxazole)methylene-1-azacyclic compounds was prepared. The compounds were tested for affinity to central nicotinic acetylcholine receptors (nAChRs) and central muscarinic receptors. The compounds covered a broad range of affinities for the nAChRs (IC(50) = 0.32 to >1000 nM), with selectivities for the nAChRs over the muscarinic receptors in the range of 3-183. The high-affinity compound (Z)-26 (3-(4-methyl-5-isoxazolyl)methylene-1-azabicyclo[2.2. 2]octane, IC(50) = 3.2 nM) having only one energy minimum was used as the reference structure in a computational study. This ligand has enabled definition of an important distance parameter, and the existence of this parameter was supported by showing that other potent nicotinic ligands (for example, nicotine and epibatidine) fit the model.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the in vivo and in vitro dechlorination of pentachlorophenol

The metabolism of pentachlorophenol has been studied in the rat after pretreatments with phenobarbital, 3-methyl-cholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition to the previously identified metabolite, tetrachloro-p-hydroquinone, trichloro-p-hydroquinone has been identified in urine as a metabolite. The formation of the latter represents a type of dechlorination different from that of the formation of tetrachlorohydroquinone. The inducing agents, 3-methylcholanthrene and TCDD have similar effects on the dechlorination and increase the formation of tetrachloro-p-hydroquinone more pronounced than does phenobarbital. In contrast to phenobarbital they also increase the formation of trichloro-p-hydroquinone and the total elimination of pentachlorophenol and its metabolites. The in vivo findings are supported by in vitro studies with microsomes from rats pretreated with phenobarbital or TCDD. Use of the inhibitor -diethylaminoethyl-diphenyl propylacetate (SKF 525-A) in vitro showed a more pronounced inhibition on microsomes from phenobarbital-treated rats than on microsomes from untreated or TCDD-treated rats.Gas chromatography-mass spectrometry have been used for the identification and quantification of pentachlorophenol and its metabolites.

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Zusammenfassung Der Metabolismus von Pentachlorphenol nach Vorbehandlung der Versuchstiere (Ratten) mit phenobarbital, 3-Methylcholantren oder 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) ist untersucht worden. Zu dem schon früher nachgewiesenen Metaboliten Tetrachlor-p-Hydrochinon wurde nun auch Trichlor-p-Hydrochinon als Harnmetabolit festgestellt. Die Bildung des letzteren stellt eine andere Art von Dechlorierung dar als diejenige die bei der Entstehung von Tetrachlor-p-Hydrochinon vorliegt. 3-Methylcholantren und TCDD haben ähnlichen Einfluß auf die Dechlorierung und steigern die Bildung von Tetrachlor-p-Hydrochinon mehr ausgeprägt als es bei phenobarbital der Fall ist. Im Gegensatz zu phenobarbital steigern sie auch die Bildung von Tri-chlor-p-Hydrochinon sowie die totale Eliminierung von Pentachlorphenol und von Metaboliten. Die in vivo-Befunde werden von in vitro-Studien mit Mikrosomen von mit phenobarbital oder TCDD vorbehandelten Ratten gestützt. Anwendung des Inhibitors -Diethylaminoethyl-Diphenyl-Propylacetat (SKF 525-A) zeigte in vitro eine ausgeprägtere Inhibition der Mikrosomen von mit phenobarbital behandelten Ratten als der Mikrosomen von unbehandelten oder TCDD-behandelten Ratten. Nachweis und Bestimmung von Pentachlorphenol und seinen Metaboliten wurden gaschromatographisch-massenspektrometrisch durchgeführt.

     

The effect of lithium on amphetamine-induced locomotor stimulation

Rats were treated chronically with -methyl-p-tyrosine methyl-ester HCl (-MT) twice daily for 0–14 days. At 1 h after the (last) -MT injection, d-amphetamine sulphate was given and motor activity was measured in an ANIMEX activity meter for 4 h. Amphetamine-induced excitatory and stereotyped behaviour was scored according to a rating scale in a separate experiment. A single dose of -MT markedly reduced the activity response after amphetamine. After 1–3 days of -MT treatment, tolerance to its amphetamine-antagonistic affect started to develop, reaching a maximal degree after 7–14 days. The pattern of the amphetamine response, monophasic in control rats, became biphasic in the -MT tolerant rats with an early (at 0–1 h) and a late (2–4 h) peak of motor activity. The late peak appeared within 3 days, while the early peak appeared after 7 days of -MT treatment. The results on amphetamine-induced excitatory and stereotyped behaviour in essence agreed with the motor-activity data. It is concluded that tolerance to the amphetamine-antagonistic action of -MT is not complete. Its rate of development varies in a complex pattern, indicating the presence of more than one mechanism of tolerance.     

T-maze learning, spontaneous activity and food intake recovery following systemic administration of the noradrenaline neurotoxin, DSP4

Following systemic administration of the noradrenaline (NA) neurotoxin, DSP4 (50 mg/kg), rats were found to be retarded in the rate at which they acquired the "right-turn" running response in a modified T-maze choice situation, as measured by the total number of errors per session and median latency to reach the goal box. Desipramine (DMI, 20 mg/kg), injected 30 min before DSP4 blocked the acquisition retardation. DSP4 was found to have a short-lasting effect upon spontaneous motor activity, while food and water intake recovery was complete within 7 days of the injection. Both the NA-accumulation data and endogenous NA concentrations indicated profound NA, but not 5-hydroxytryptamine (5-HT) and dopamine (DA), depletions in the cortex, hippocampus and cerebellum. These data seem to confirm the role of the locus coeruleus-noradrenaline (LC-NA) system in an instrumental learning situation.     

Effects of air pollutants on the oxidative metabolism and phagocytic capacity of pulmonary alveolar macrophages

Isolated rabbit pulmonary alveolar macrophages were found to be a convenient biological model system, relevant for studies of the toxicity of air pollutants. The phagocytic capacity and the oxygen consumption were used as test parameters and studied simultaneously on the same cells. The toxicity of extracts of airborne particles (phi less than 15 microns) collected in urban and rural areas was investigated and compared to a cigarette-smoke condensate. An extract of particles from a car tunnel was found to be the most toxic air sample, inhibiting phagocytosis as well as respiration of the macrophages at a concentration representing 5 m3 air/ml cell suspension. A corresponding sample collected on a roof of a five-storied building in the central area of a city (population 600,000) was found to inhibit phagocytosis but did not affect respiration. Further investigations revealed that one effect of the "tunnel" extract could be explained as an uncoupling of the mitochondrial respiratory control. Compared to the cigarette-smoke condensate, the toxicity of the air samples was infinitesimal.