A new class of selective myocardial calcium channel modulators. 2. Role of the acetal chain in oxadiazol-3-one derivatives

In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC(50) = 0.04 microM), which is 20 times more active than diltiazem (EC(50) = 0.79 microM), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.     

The effect of age and diet on the ultrastructure of hymenopteran flight muscle

The changes in the ultrastructure of the flight muscles, with age and diet in Nasonia vitripeniss are described.

On the normal diet of dipteran puparia the principal age change is a loss of glycogen particles from around the mitochondria and myofibrils. The mitochondria are less tightly packed and there is some enlargement of the vesicles of the sarcoplasmic reticulum.

On a diet of 10 per cent sterile sucrose a 47 per cent increase in life-span occurs as compared with the puparia fed animals. In the aged sucrose fed animals there is a displacement of the mitochondria, and they contain inclusions with occasional myelin figures. There is a tendency for the cristae to be orientated to lie in the longitudinal plane. Glycogen deposits disappear from the myofibrils. In some cases there is a disorganisation of the myofilament structure of the muscle.

The age changes recorded are compared with work on flight muscle of other insect species. The significance of the changes with age and diet are discussed.     

Fibrin formation during asanguinous normothermic perfusion of the isolated rat liver

A progressive accumulation of fibrin in the small vessels of the isolated perfused rat liver was documented by both histological and autohistoradiographic techniques. These changes occurred initially in the sinusoids and later extended to the interlobular branches of the portal vein. Fibrin deposition was accompanied by a reduction of perfusion flow, an increase of the lactate-pyruvate ratio in the perfusion medium, and a depletion of liver tissue glycogen. All of these changes were prevented by adding streptokinase to the perfusing solution. Mechanisms leading to intravascular accumulation of fibrin and the possible involvement of this process in failure of prolonged liver preservation, hemorrhagic accidents following liver transplantation, and liver allograft rejection are discussed. The use of fibrinolytic agents for perfusion preservation of the isolated liver appears promising.

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Résumé L'accumulation progressive de la fibrine dans les petits vaisseaux du foie isolé de rat, perfusé à l'aide d'un système modifié après Scholz, a été démontrée à l'aide des techniques histologiques et autohistoradiographiques. Dans un état initial on constate que les sinusoïdes sont afféctés, puis les modifications s'étendent vers les branches interlobulaires. La déposition de la fibrine a été accompagnée par la réduction du débit de perfusion, par l'accroissement du rapport lactate-pyruvate dans le milieu de perfusion et la diminution du glycogène tissulaire. Toutes ces modifications ont été prévenues par l'adjonction de la streptokinase dans le milieu de perfusion. Les mécanismes qui déterminent l'accumulation intravasculaire de la fibrine et leurs possibles implications dans l'échec de la conservation prolongée du foie, dans l'apparition des accidents hémorragiques du transplant hépatique aussi que dans la réaction de rejet des greffes sont mis en discussion. De même on fait des appréciations sur les perspectives offertes par l'utilisation des agents fibrinolytiques dans la conservation du foie.

     

Factors influencing reliability of liver stiffness measurements using transient elastography (M-probe)—Monocentric experience

Aim

To retrospectively assess the feasibility of transient elastography (TE) and the factors associated with failed and unreliable liver stiffness measurements (LSMs), in patients with chronic liver diseases.

Material and methods

Our retrospective study included 8218 consecutive adult patients with suspected chronic liver diseases. In each patient, LSMs were performed with a FibroScan^® device (Echosens, France), with the M probe. Failure of TE measurements was defined if no valid measurement was obtained after at least 10 shots and unreliable if fewer than 10 valid shots were obtained, success rate (SR) <60% and/or interquartile range interval/median value (IQR/Med) ≥30%.

Results

From the 8218 patients, failed and unreliable LSMs were observed in 29.2% of cases. In univariant analysis, the following risk factors were associated with failed and unreliable measurements: age over 50 years (OR 2.04; 95%CI 1.84–2.26), female gender (OR 1.32; 95%CI 1.20–1.45), BMI > 27.7 kg/m² (OR 2.89, 95%CI 2.62–3.19), weight > 77 kg (OR 2.17; 95%CI 1.97–2.40) and height < 162 cm (OR 1.26; 95%CI 1.14–1.40). In multivariate analysis all the factors mentioned above were independently associated with the risk of failed and unreliable measurements.If all the negative predictive factors were present (woman, older than 50 years, with BMI > 27.7 kg/m², heavier than 77 kg and shorter than 162 cm), the rate of failed and unreliable measurements was 58.5%.In obese patients (BMI ≥ 30 kg/m²), the rate of failed and unreliable measurements was 49.5%.

Conclusion

Failed and unreliable LSMs were observed in 29.1% of patients. Female gender, older age, higher BMI, higher weight and smaller height were significantly associated with failed and unreliable LSMs.     

Is ARFI elastography reliable for predicting fibrosis severity in chronic HCV hepatitis?

AIM:To determine whether acoustic radiation force impulse(ARFI) elastography is a reliable method for predicting fibrosis severity in patients with chronic hepatitis C virus(HCV) hepatitis.METHODS:We performed a multicenter study including 274 subjects with HCV chronic hepatitis in which we compared ARFI with liver biopsy(LB).In each patient we performed LB(evaluated according to the Metavir score) and ARFI measurements(using a Siemens Acuson S2000TM ultrasound system:10 valid measurements were performed and median values were calculated and expressed in meters/second(m/s).RESULTS:A direct,strong,correlation(Spearman r = 0.707) was found between ARFI measurements and fibrosis(P < 0.0001).For predicting the presence of fibrosis(F ≥ 1 Metavir),significant fibrosis(F ≥ 2),severe fibrosis(F ≥ 3) and cirrhosis(F = 4),the cutoff values of 1.19,1.21,1.58 and 1.82 m/s were determined,respectively,liver stiffness measurements had 73%,84%,84% and 91% Se respectively;93%,91%,94%,90% Sp,respectively;with AUROCs of 0.880,0.893,0.908 and 0.937,respectively.CONCLUSION:ARFI measurement is a reliable method for predicting the severity of fibrosis in HCV patients     

Epidemiology and history of human parasitic diseases in Romania

Intestinal parasitic diseases such as enterobiasis, giardiasis, and ascariasis are detected most frequently in Romania, but their importance is definitely surpassed by trichinellosis, cystic echinococcosis, and toxoplasmosis. Malaria was common until its eradication in 1963, and only imported cases are reported nowadays. The aim of this review was to bring together essential data on the epidemiology and history of human parasitoses in Romania. Information on 43 parasitic diseases was collected from numerous sources, most of them unavailable abroad or inaccessible to the international scientific community. Over time, Romanian people of all ages have paid a significant tribute to the pathogenic influences exerted by the parasites. Sanitary and socio-economical consequences of the parasites diseases have great negative impact on the quality of life of affected individuals and the overall well-being of the population. Implementation of efficient public health measures and informative campaigns for the masses as well as changing the inadequate habits that are deeply rooted in the population are mandatory for cutting successfully this Gordian knot.     

Repositioning metformin in cancer: genetics,drug targets,and new ways of delivery

After sitting many years on the shelves of drug stores as a harmless antidiabetic drug, metformin comes back in the spotlight of the scientific community as a surprisingly effective antineoplastic drug. Metformin targets multiple pathways that play pivotal roles in cancer progression, impacting various cellular processes, such as proliferation, cell death, metabolism, and even the cancer stemness features. The biomolecular characteristics of tumors, such as appropriate expression of organic cation transporters or genetic alterations including p53, K-ras, LKB1, and PI3K may impact metformin’s anticancer efficiency. This could indicate a need for tumor genetic profiling in order to identify patients most likely to benefit from metformin treatment. Considering that the majority of experimental models suggest that higher, supra-clinical doses of metformin should be used in order to obtain an antineoplastic effect, new ways of drug delivery could be developed, such as metformin-loaded nanoparticles or incorporation of metformin into microparticles used in transarterial chemoembolization, with the aim of obtaining higher intratumoral drug concentrations and a targeted therapy which will ultimately maximize metformin’s efficacy.     

A novel tetrode microdrive for simultaneous multi-neuron recording from different regions of primate brain

A unique custom-made tetrode microdrive for recording from large numbers of neurons in several areas of primate brain is described as a means for assessing simultaneous neural activity in cortical and subcortical structures in nonhuman primates (NHPs) performing behavioral tasks. The microdrive device utilizes tetrode technology with up to six ultra-thin microprobe guide tubes (0.1mm) that can be independently positioned, each containing reduced diameter tetrode and/or hexatrode microwires (0.02 mm) for recording and isolating single neuron activity. The microdrive device is mounted within the standard NHP cranial well and allows traversal of brain depths up to 40.0 mm. The advantages of this technology are demonstrated via simultaneously recorded large populations of neurons with tetrode type probes during task performance from a) primary motor cortex and deep brain structures (caudate-putamen and hippocampus) and b) multiple layers within the prefrontal cortex. The means to characterize interactions of well-isolated ensembles of neurons recorded simultaneously from different regions, as shown with this device, has not been previously available for application in primate brain. The device has extensive application to primate models for the detection and study of inoperative or maladaptive neural circuits related to human neurological disorders.