Inhibition of uropathogenic biofilm growth on silicone rubber in human urine by lactobacilli – a teleologic approach

The ability of three Lactobacillus strains to inhibit the adhesion and growth of naturally occurring uropathogens on silicone rubber was investigated in human urine. The importance of biosurfactant production by Lactobacillus in discouraging uropathogen growth was determined in relation to the binding affinities of the lactobacilli for silicone rubber. L. fermentum B54 markedly inhibited uropathogen growth on the silicone rubber disks after 8 days for all five men included in the study, albeit to various extents ranging from 77% to 100%. In urine from women, however, this inhibition was less clear, as it was absent for two of the four women participating in this study. L. casei rhamnosus 36 completely discouraged uropathogen growth on the disks after 8 days for three of the four women, whereas its effect in urine from men was less pronounced (inhibition ranged from 48% to 100% and was absent for one man). L. casei rhamnosus ATCC 7469^T was the least inhibitory Lactobacillus strain tested and inhibition was absent for a number of both male and female participants, possibly as a result of the low binding affinity of this strain for silicone rubber and of its inability to release biosurfactants. We conclude that the inhibition of uropathogen growth is dependent on the Lactobacillus strain involved, and for L. fermentum B54 it was demonstrated to be sex-related. Hence, inhibition must be considered a multifactorial process.     

Metastatic Soft Tissue Sarcoma in Adults

In the present paper the treatment of advanced and metastatic soft tissue sarcoma is reviewed with the primary emphasis on chemotherapy. One of the major advances in the treatment of soft tissue sarcomas is their treatment by multidisciplinary teams in specialized centers. Despite optimal local treatment of the primary tumor, disseminated disease will develop in many patients. Consequently, chemotherapy has been extensively studied but, unfortunately, the responsiveness of these tumors to chemotherapy has been disappointingly low. Doxorubicin and ifosfamide appear to be the most effective drugs — the latter with a somewhat higher toxicity at effective dosages. Other drugs with some first line activity are dacarbazine, liposomal doxorubicin and possibly trabectedin (ET-743). Imatinib is very effective in gastrointestinal stromal tumors (GIST) where it is now the treatment of choice. The combination of doxorubicin and ifosfamide increases the response rate without affecting overall survival. For these reasons, single agent doxorubicin is, in many centers, considered the standard treatment for advanced soft tissue sarcoma, and combination chemotherapy should be reserved for special subgroups of patients such as young patients with chemosensitive tumors. Chemotherapy for patients with advanced and metastatic soft tissue sarcoma is inadequate at present and new drugs are desperately needed. Fortunately, exciting new drugs are under development and hopefully they will improve the treatment of patients with this disease.     

Foramen Thyroideum: A Comparative Study in Embryos,Fetuses, and Adults

The incidence and characteristics of foramen thyroideum (FT) in embryonic and/or fetal larynges have not been established. In the present study, 90 adult larynges and 53 embryonic-fetal larynges were studied. The incidence of FT during the embryonic-fetal period (57%) was statistically different from the adult period (31%) (P = 0.005). All the FT found in the adult period contained vessels and/or nerves, while in the embryonic and fetal period only 63% presented neurovascular elements (P < 0.001). The origin of FT in the embryonic period and its persistence during adult life is discussed.     

Hippocampal dopamine receptors modulate the motor activation and the increase in dopamine levels in the rat nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

A number of studies have shown that chemical stimulation (using N-methyl-D-aspartate (NMDA) infusions) or electrical stimulation of the ventral hippocampus (VH) elicits locomotor activation and sustained increases in nucleus accumbens (NAc) dopamine (DA) levels in rodents. How DA neurotransmission in NAc is involved in these effects has also been well established. However, the modulatory role of the DA receptors located in VH is not yet fully understood. The purpose of this study was to characterize the role played by VH D1 and D2 subtype receptors in both the locomotor activation and NAc DA increases induced by NMDA stimulation of the VH. This was assessed by studying how retrodialysis application of NMDA (50 mM, 10 min) affects motor activity and NAc DA levels during simultaneous retrodialysis administration of the D1/D5 receptor antagonist SCH 23390 (100 and 250 microM, 60 min) or the D2 receptor antagonist raclopride (100 and 250 microM, 60 min). SCH 23390 attenuated or completely abolished NMDA-evoked locomotor activation and the concurrent increase in NAc DA levels. On the other hand, raclopride was initially able to attenuate the effects of VH NMDA stimulation. However, in the last phase of the experiments, animals showed an important increase in clonic seizure activity with a simultaneous and dramatic increase in NAc DA levels. Our results show that the NMDA receptor-mediated effects in the VH require both D1 and, probably, D2 receptors and suggest that DA in VH strongly modulates the excitatory outputs from this brain area.     

Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats.

Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 microg/kg, s.c.) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF1) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.     

Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies

Risperidone is a potent antagonist of both dopamine and serotonin receptors. However, little is known about the underlying molecular mechanism by which risperidone acts. Although a number of genetic variants have been observed to correlate with treatment response there are no definitive predictors of response. We performed a genome-wide gene expression analysis (Human Genome U219 Array Plate) of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. Our results revealed that cellular risperidone treatment is associated with a range of gene expression changes, which are time (6–48 h) and dose related (0.1–10 μM). We found that functional clusters of these changes correspond to Gene Ontology categories related to neural cell development functions, and synaptic structure and functions. We also identified Canonical Pathways related to these functional categories: neurogenesis and axon guidance; synaptic vesicle; and neurotransmitter signaling (dopamine, serotonin and glutamate). Finally, we identified candidate genes for pharmacogenetic studies related to the main risperidone secondary effects: motor disorders, cardiovascular disorders and metabolic disorders. Our results suggest that risperidone treatment affects the neurogenesis and neurotransmission of neuroblastoma cells, which is in agreement with the “initiation and adaptation” model to explain the mechanism of action of psychotropic drugs.     

Diary

Autoimmunity encompasses a wide spectrum of diseases from organ-specific diseases like Hashimoto thyroiditis, to systemic diseases such as systemic lupus erythematosus. These diseases are characterized by inflammation and the production of a wide range of autoantibodies directed against multiple autoantigens. Although their etiology is still poorly understood, genetic, immunological, hormonal, and environmental factors are major predisposing and triggering factors. These multiple factors, like pieces in a mosaic, may interplay in different forms, leading to the expression of various autoimmune manifestations and diseases. This phenomenon, which has been referred by us as the “mosaic of autoimmunity”, illuminates the diversity of autoimmune manifestations among susceptible individuals. From this theoretical framework we conducted a wide search of the literature, on the prevalence of thyroid autoimmunity, the commonest of the autoimmune conditions, among other autoimmune diseases, and discuss the possible clinical significance of this association.     

Starch digestibility modulation significantly improves glycemic variability in type 2 diabetic subjects: A pilot study

Background and aimsIn type 2 diabetes (T2D) patients, the reduction of glycemic variability and postprandial glucose excursions is essential to limit diabetes complications, beyond HbA1c level. This study aimed at determining whether increasing the content of Slowly Digestible Starch (SDS) in T2D patients’ diet could reduce postprandial hyperglycemia and glycemic variability compared with a conventional low-SDS diet.Methods and resultsFor this randomized cross-over pilot study, 8 subjects with T2D consumed a controlled diet for one week, containing starchy products high or low in SDS. Glycemic variability parameters were evaluated using a Continuous Glucose Monitoring System.Glycemic variability was significantly lower during High-SDS diet compared to Low-SDS diet for MAGE (Mean Amplitude of Glycemic Excursions, p < 0.01), SD (Standard Deviation, p < 0.05), and CV (Coefficient of Variation, p < 0.01). The TIR (Time In Range) [140–180 mg/dL[ was significantly higher during High-SDS diet (p < 0.0001) whereas TIRs ≥180 mg/dL were significantly lower during High-SDS diet. Post-meals tAUC (total Area Under the Curve) were significantly lower during High-SDS diet.ConclusionOne week of High-SDS Diet in T2D patients significantly improves glycemic variability and reduces postprandial glycemic excursions. Modulation of starch digestibility in the diet could be used as a simple nutritional tool in T2D patients to improve daily glycemic control.Registration numberin clinicaltrials.gov: NCT 03289494.