Intoxication caused by new psychostimulants: analytical methods to disclose acute and chronic use of benzofurans and ethylphenidate

International Journal of Legal Medicine - The acute and chronic toxicity of several new psychoactive substances (NPS) is unknown, and only little information is available on the pharmacology and...     

Imprinting of maternal thyroid hormones in the offspring

Thyroid hormones (THs) during pregnancy contribute significantly to cellular differentiation and development in several tissues of the offspring, principally the central nervous system (CNS). TH deficiencies, such as hypothyroidism or hypothyroxinemia, are highly frequent during pregnancy worldwide and known to be detrimental for the development of the fetus. The function of CNS in the offspring gestated under TH deficiency will be irreversible impaired, causing low intellectual quotient, attention deficit, and mental retardation. On the other hand, little is known about the effects of TH deficiency in the offspring immune system, being the prevalent notion that the effects are reversible and only for a while will affect the number of B and T cells. Recent studies have shown that maternal hypothyroidism can altered the function of immune system in the offspring, rendering the female offspring more susceptible to suffer autoimmune-inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and to be more resistant to a bacterial infection. In this article we discuss these recent findings, as well as the possible mechanisms underlying these effects and the potential implications for human health.     

Colorectal cancer prognosis twenty years later

AIM:To evaluate changes in colorectal cancer(CRC) survival over the last 20 years.METHODS:We compared two groups of consecutive CRC patients that were prospectively recruited:Group Ⅰincluded 1990 patients diagnosed between 1980 and 1994.GroupⅡincluded 871 patients diagnosed in 2001.RESULTS:The average follow up time was 21 mo(1-229)for GroupⅠand 50 mo(1-73.4)for GroupⅡ.Overall median survival was significantly longer in Group Ⅱthan in GroupⅠ(73 mo vs 25 mo,P<0.001)and the difference was significant for all ...     

Nontuberculous Mycobacterial Pulmonary Infection in Patients with Cystic Fibrosis

The prevalence of nontuberculous mycobacteria (NTM) recovered from patients with cystic fibrosis (CF) appears to be increasing, probably related to improved surveillance and microbiological procedures and an increase in the life expectancy of patients with CF. The distinction between active lung infection and colonization is often difficult to assess in patients with CF because of the marked overlap in the clinical and radiological presentation of CF lung disease and lung disease caused by NTM infection. The possibility of active NTM lung infection should be considered in those patients with compatible radiographic changes and/or progressive deterioration in lung function who do not improve with specific antibiotic therapy and who have repeatedly positive sputum cultures and smears for NTM. Patients with repeatedly positive results of acid-fast smears are more likely to be infected than colonized. Pseudomonas overgrowth may confuse the results of sputum and bronchoalveolar lavage fluid cultures. Decontamination of respiratory samples from patients with CF with 5% oxalic acid results in improved bacteriological recovery of NTM. Skin tests are of limited value as a screening tool for NTM. Since the course of NTM lung infection is often slow, careful follow-up with repeated sputum cultures, chest radiographs and computed tomography (CT) scans may be needed.Treatment of NTM lung disease in patients with CF presents great difficulties because of abnormal gastrointestinal drug absorption and pharmacokinetics in this patient population. Treatment varies according to the mycobacterial species isolated. Long-term multidrug regimens including rifampin (rifampicin) and ethambutol are usually required. Monitoring serum drug levels is a useful indicator of correct dosage in order to prevent adverse effects due to potential drug interactions and altered pharmacokinetics in patients with CF.     

Preclinical discovery of duloxetine for the treatment of depression

INTRODUCTION: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD. AREAS COVERED: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine. EXPERT OPINION: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD.     

Mitochondrial Networking Protects ��-Cells From Nutrient-Induced Apoptosis

OBJECTIVE

Previous studies have reported that β-cell mitochondria exist as discrete organelles that exhibit heterogeneous bioenergetic capacity. To date, networking activity, and its role in mediating β-cell mitochondrial morphology and function, remains unclear. In this article, we investigate β-cell mitochondrial fusion and fission in detail and report alterations in response to various combinations of nutrients.

RESEARCH DESIGN AND METHODS

Using matrix-targeted photoactivatable green fluorescent protein, mitochondria were tagged and tracked in β-cells within intact islets, as isolated cells and as cell lines, revealing frequent fusion and fission events. Manipulations of key mitochondrial dynamics proteins OPA1, DRP1, and Fis1 were tested for their role in β-cell mitochondrial morphology. The combined effects of free fatty acid and glucose on β-cell survival, function, and mitochondrial morphology were explored with relation to alterations in fusion and fission capacity.

RESULTS

β-Cell mitochondria are constantly involved in fusion and fission activity that underlies the overall morphology of the organelle. We find that networking activity among mitochondria is capable of distributing a localized green fluorescent protein signal throughout an isolated β-cell, a β-cell within an islet, and an INS1 cell. Under noxious conditions, we find that β-cell mitochondria become fragmented and lose their ability to undergo fusion. Interestingly, manipulations that shift the dynamic balance to favor fusion are able to prevent mitochondrial fragmentation, maintain mitochondrial dynamics, and prevent apoptosis.

CONCLUSIONS

These data suggest that alterations in mitochondrial fusion and fission play a critical role in nutrient-induced β-cell apoptosis and may be involved in the pathophysiology of type 2 diabetes.Mitochondria mediate β-cell responses to extracellular glucose by generating ATP and initiating a cascade of events culminating in the release of insulin. It is not surprising that β-cell mitochondria have become an important target for investigations into the etiology of type 2 diabetes. Mitochondria are highly dynamic organelles whose morphology is regulated by cycles of fusion and fission, collectively termed mitochondrial dynamics (1,2). Networks are formed when mitochondria undergo fusion events that cause the compartments of participating mitochondria to become continuous. As a result, the constituents of each network share solutes, metabolites, and proteins (3–5) as well as a transmembrane electrochemical gradient (1,6). The disruption of such networks has been shown to have a profound effect on the progression of cells to apoptosis, particularly in cases where reactive oxygen species (ROS) are involved (7). As such, mitochondrial networking is thought to be a potential defense mechanism allowing for the buffering of mitochondrial ROS and calcium overload (8,9).Chronically elevated levels of glucose and fatty acid are thought to contribute to the progression of type 2 diabetes by adversely affecting β-cells and thereby causing a deterioration in insulin secretion (10). In vivo, a reduction in insulin gene expression due to reduced Pdx-1 binding has been observed in rats perifused with glucose and intralipids (11,12). In addition, exposure to high levels of glucose and/or free fatty acid has been shown to affect β-cell viability by inducing mitochondrial apoptosis and has been linked to ROS-induced mitochondrial calcium overload and damage (13). Recent studies indicate that nutrient-induced ROS increases subcellular mitochondrial membrane potential (ΔΨmt) heterogeneity and fragmentation of the mitochondrial architecture (14,15). These findings suggest that mitochondrial fragmentation-defragmentation might play a role in the effects of noxious stimuli. Although the functional significance of these changes has not been studied in β-cells, studies of mitochondrial morphology in other cells have demonstrated that the ability of mitochondria to form networks influences both ROS and calcium handling (7–9).Previous studies have reported that β-cell mitochondria form less elaborate network structures, compared with COS cells for example, and raise doubts on the existence of mitochondrial networking in these cells. Until now, technologies for examining and quantifying the ability of mitochondria to undergo fusion and fission were unavailable.In this work, we show that the densely packed appearance of mitochondria in the β-cell represents the existence of multiple juxtaposed units that do not share continuous matrix lumen but do go through frequent fusion and fission events. We further demonstrate that mitochondrial dynamics are disrupted by exposure to the combination of high fat and glucose, gradually leading to the arrest of fusion activity and complete fragmentation of the mitochondrial architecture. Inhibiting mitochondrial fission preserved mitochondrial morphology and dynamics and prevented β-cell apoptosis.     

Littoral-cell angioma of the spleen： A case report

Littoral-cell angioma (LCA) is a primary splenic vascular tumor that arises from the normal littoral cells lining the sinus channels of the splenic red pulp. We report a case of LCA of the spleen, which has been infrequently communicated in the literature. A 76-year-old man with a 2-wk history of weight loss, abdominal pain and changes in bowel habits was admitted to our hospital. Imaging studies (CT and MRI) showed multiple lesions in the spleen. Splenectomy was performed. Lining cells were positive for CD31/CD68 markers. Our case was associated with a serrated colonic adenoma. LCA is a benign vascular tumor of the spleen that needs to be included in the differential diagnosis of multiple splenic nodules.     

Validation protocol of an automated in-line flow-through diffusion equipment for in vitro permeation studies.

Transdermal drug delivery experiments are often tedious and time consuming in terms of sampling, labor, etc. In this way, the automation of such experiments has increased in the last few years. A protocol suitable to validate an automated diffusion equipment with seven in-line flow-through cells is described. The proposed protocol was divided into two parts. First, validation of each component which makes up the whole equipment, including the study of the statistical variability of the internal volumes between the cells, the temperature into the different chambers, the time and sample volumes, etc. In the second part, a series of permeation studies were carried out comparing the performance of the system against a classical Franz-type diffusion cell. Ketoprofen was used as a model drug. It was proved the low variability of the replicates obtained with the automated flow-through diffusion cells. The best work conditions as flow rate into the receptor chamber, temperature, etc., as well as the best mathematical approach for the diffusion data, were determined. The advantages in terms of time saved and easiness of validation of the flow-through cell design in comparison to the Franz-type cell were evidenced.