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Cadmium is a widespread carcinogen. We previously showed that the administration of low CdCl 2 doses for 24 h to healthy C3H10T1/2Cl8 mouse embryonic fibroblast cell line at the beginning of Cell Transformation Assay (CTA), up regulates genes involved in metal scavenging and antioxidant defense, like metallothioneines, glutathione S-transferases and heat shock proteins. Still, although most cells thrive normally in the following weeks, malignancy is triggered by CdCl 2 and leads to the appearance of foci of transformed cells at the end of the CTA. In this work we aim at elucidating the early metabolic deregulation induced by cadmium, underlying healthy cell transformation into malignant cells. Respiratory metabolism was investigated through Seahorse Agilent assays, while oxidative stress level was assessed through fluorescent probes; DNA damage was evaluated by Comet assay, and mitochondrial morphology was analyzed in confocal microscopy. Results show that the initial response to CdCl 2 involves mitochondria rearrangement into a perinuclear network. However, SOD1 and SOD2 activities are inhibited, leading to increased superoxide anion level, which in turn causes DNA strand breaks. From the metabolic point of view, cells increase their glycolytic flux, while all extra NADH produced is still efficiently reoxidized by mitochondria. Our results confirm previously shown response against cadmium toxicity; new data about glycolytic increase and mitochondrial rearrangements suggest pathways leading to cell transformation. In this work we exploit the widely used, well known CTA, which allows following healthy cells transformation into a malignant phenotype, to understand early events in cadmium-induced carcinogenesis. Unlabelled Image • Mitochondria are key targets in cadmium-induced carcinogenicity. • Cellular response to cadmium toxicity involves up-regulation of glycolysis. • Cadmium inhibits SOD1 activity, raising superoxide anion (O 2 −) intracellular concentration. [ABSTRACT FROM AUTHOR]

Cadmium is a toxic metal able to enter the cells through channels and transport pathways dedicated to essential ions, leading, among others, to the dysregulation of divalent ions homeostasis. Despite its recognized human carcinogenicity, the mechanisms are still under investigation. A powerful tool for mechanistic studies of carcinogenesis is the Cell Transformation Assay (CTA). We have isolated and characterized by whole genome microarray and bioinformatics analysis of differentially expressed genes (DEGs) cadmium-transformed cells from different foci (F1, F2, and F3) at the end of CTA (6 weeks). The systematic analysis of up- and down-regulated transcripts and the comparison of DEGs in transformed cells evidence different functional targets and the complex picture of cadmium-induced transformation. Only 34 in common DEGs are found in cells from all foci , and among these, only 4 genes are jointly up-regulated (Ccl2 , Ccl5 , IL6 and Spp1), all responsible for cytokines/chemokines coding. Most in common DEGs are down-regulated, suggesting that the switching-off of specific functions plays a major role in this process. In addition, the comparison of dysregulated pathways immediately after cadmium treatment with those in transformed cells provides a valuable means to the comprehension of the overall process. • Cell transformation Assay and toxicogenomics are integrated to study cadmium carcinogenesis mechanisms • Inflammatory response is the only common feature in Cd-transformed cells from all different foci • Switching-off of specific functions plays a major role in Cd-induced carcinogenesis • Comparison of triggering signals and deregulated pathways in transformed cells provides hints on cadmium mechanisms [ABSTRACT FROM AUTHOR]

Background and Objectives: Many acute treatment options exist for migraine. However, large-scale, head-to-head comparisons of treatment effectiveness from real-world patient experience reports are lacking., Methods: This is a retrospective analysis of 10,842,795 migraine attack records extracted from an e-diary smartphone application between June 30, 2014, and July 2, 2020. We analyzed 25 acute medications among 7 classes-acetaminophen, nonsteroid anti-inflammatory drugs (NSAIDs), triptans, combination analgesics, ergots, antiemetics, and opioids. Gepants and ditan were not included in this analysis. Different doses and formulations of each medication, according to the generic names, were combined in this analysis. We used a 2-level nested logistic regression model to analyze the odds ratio (OR) of treatment effectiveness of each medication by adjusting concurrent medications and the covariance within the same user. Subgroup analyses were conducted for users in the United States, the United Kingdom, and Canada., Results: Our final analysis included 4,777,524 medication-outcome pairs from 3,119,517 migraine attacks among 278,006 users. Triptans (mean OR 4.8), ergots (mean OR 3.02), and antiemetics (mean OR 2.67) were the top 3 classes of medications with the highest effectiveness, followed by opioids (mean OR 2.49), NSAIDs (other than ibuprofen, mean OR 1.94), combination analgesics (acetaminophen/acetylsalicylic acid/caffeine) (OR 1.69, 95% CI 1.67-1.71), others (OR 1.49, 95% CI 1.47-1.50), and acetaminophen (OR 0.83, 95% CI 0.83-0.84), using ibuprofen as the reference. Individual medications with the highest ORs were eletriptan (OR 6.1, 95% CI 6.0-6.3), zolmitriptan (OR 5.7, 95% CI 5.6-5.8), and sumatriptan (OR 5.2, 95% CI 5.2-5.3). The ORs of acetaminophen, NSAIDS, combination analgesics, and opioids were mostly around or less than 1, suggesting similar or lower reported effectiveness compared with ibuprofen. The ORs for 24 medications, except that of acetylsalicylic acid, achieved statistical significance with p < 0.0001, and our nested logistic regression model achieved an area under the curve (AUC) of 0.849. Country-specific subgroup analyses revealed similar ORs of each medication and AUC (United States 0.849, United Kingdom 0.864, and Canada 0.842), demonstrating the robustness of our analysis., Discussion: Using a big data approach, we analyzed patient-generated real-time records of 10 million migraine attacks and conducted simultaneous head-to-head comparisons of 25 acute migraine medications. Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice., Classification of Evidence: This study provides Class IV evidence that for patients with migraine, selected acute medications (e.g., triptans, ergots, antiemetics) are associated with higher odds of user-rated positive response than ibuprofen.

The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animals. In the present study, their effects on stress-induced deficit in cognitive performances as assessed in a modified object recognition test were investigated in mice. The object recognition task measures the ability of a mouse to remember an object it has previously explored in a learning trial. During this acquisition session, the mouse was stressed by the presence of a pair of rats under the grid floor of the apparatus. One hour later, it was placed again in the environment with the known and a novel object, but in the absence of the rats. While non-exposed mice spent more time exploring the new object, mice that had been exposed to the rats during acquisition failed to discriminate between the known and the new object during retrieval. This cognitive impairment in stressed mice was prevented by the administration of SSR149415 (10 mg/kg, ip), SSR125543 (10 mg/kg, ip) and the selective serotonin reuptake inhibitor, fluoxetine (10 mg/kg, ip). Under similar conditions, the cognitive enhancer donepezil (1 mg/kg, ip) failed to reverse object recognition deficit. These results indicate that the effects of SSR149415 and SSR125543 in the modified object recognition test, in stressed mice, involve the ability of mice to cope with stress rather than an effect on cognition per se. Together, these data suggest that SSR149415 and SSR125543 may be of interest to reduce the cognitive deficits following exposure to stress-related events, such as acute stress disorder., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Learning and memory, like most physiological processes, seem to be under the control of circadian rhythm. The recently cloned mPer1 and mPer2 genes play an important role in the regulation of the circadian rhythm. In this study, we tested mPer1 and mPer2 mutant mice in two different learning and memory paradigms, a water-maze place navigation task and contextual fear conditioning. In both learning tests, the hippocampus is critically involved. None of these learning types were affected by the mutations, suggesting that mPer1 and mPer2 do not play a major role in the regulation of hippocampus-dependent learning and memory.

The sigma(1) (sigma(1)) receptor exerts a potent neuromodulatory role in the brain with relevant consequences in memory processes, response to stress, depression and pharmacodependence. Its precise endogenous ligand is not yet identified but the sigma(1) receptor appears to be one target for the nongenomic rapid effects of neuroactive steroids in the brain. The aim of the present study was to establish whether differences in sigma(1) receptor-mediated behaviours could be observed among mouse strains, in relation with differences in either sigma(1) receptor expression or steroid levels. The sigma(1)-receptor immunohistochemical distribution appeared similar between Swiss and C57BL/6 strains in all the brain structures examined. The levels of in vivo [(3)H](+)-SKF-10 047 binding to sigma(1) receptors were lower in Swiss than in C57BL/6. Adrenalectomy/castration significantly increased [(3)H](+)-SKF-10 047 binding only in Swiss. The behavioural efficacy of the selective sigma( 1) agonists igmesine and PRE-084 -- reversion of the scopolamine-induced amnesia in the passive avoidance test; diminution of the immobility duration in the forced swimming test -- were significantly higher in C57BL/6 than in Swiss. Steroid levels were measured in the brain in basal conditions and after stress. C57BL/6 mice presented in both conditions, the lowest progesterone levels, this steroid acting as an endogenous sigma(1) antagonist. Collectively, the results suggested that strain differences in neuroactive steroid and particularly, progesterone, biosynthesis and sensitivity may contribute to the differential behavioural efficacy of sigma(1)-receptor ligands. Noteworthy, these observations are coherent with strain differences observed in the intensity of cocaine-induced reward properties, known to critically involve the sigma(1) receptor.

1. The sigma(1) (sigma(1)) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the sigma(1) receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia. 2. In order to establish the involvement of sigma(1) receptors in memory, a 16-mer oligodeoxynucleotide antisense to the sigma(1) receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti-amnesic effects induced by the selective sigma(1) agonist PRE-084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN-treated animals. 3. The aODN treatment failed to affect the dissociation constant (K(d)) but significantly decreased the number of sigma(1) sites (B(max)) labelled with [(3)H]-(+)-SKF-10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN. 4. Cannulation and injections failed to affect the open-field behaviour of the animals. However, the anti-amnesic effects of PRE-084 and DHEA sulphate against the dizocilpine-induced impairments were blocked after aODN treatment in the short- and long-term memory tests. The anti-amnesic effects of pregnenolone sulphate remained unchanged. 5. These observations bring a molecular basis to the modulatory role of sigma(1) receptors in memory, and reveal that the anti-amnesic action of neuroactive steroids may not similarly involve an interaction with sigma(1) receptors.

Steroids, synthesized in peripheral glands or centrally in the brain--the latter being named neurosteroids--exert an important role as modulators of the neuronal activity by interacting with different receptors or ion channels. In addition to the modulation of GABA(A), NMDA or cholinergic receptors, neuroactive steroids interact with an atypical intracellular receptor, the sigma(1) protein. This receptor has been cloned in several species, and highly selective synthetic ligands are available. At the cellular level, sigma1 agonists modulate intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergic systems. At the behavioral level, the sigma1 receptor is involved in learning and memory processes, the response to stress, depression, neuroprotection and pharmacodependence. Pregnenolone, dehydroepiandrosterone, and their sulfate esters behave as sigma1 agonists, while progesterone is a potent antagonist. This review will detail the physiopathological consequences of these interactions, focusing on recent results on memory and depression. The therapeutical interest of selective sigma1 receptor agonists in alleviating aging-related cognitive deficits will be discussed.

The interaction of neuroactive steroids with the sigma(1)-receptor was investigated in Swiss mice submitted to the forced swimming test. The sigma(1)-agonists igmesine and (+)-SKF-10,047 and the steroid dehydroepiandrosterone sulfate (DHEAS) showed some antidepressant-like activity by shortening the immobility time, these effects being blocked by the sigma(1)-antagonist BD1047 or progesterone. The sigma(1)-agonist PRE-084 or pregnenolone sulfate failed to affect the immobility time. In adrenalectomized/castrated (AdX/CX) mice, the effects of igmesine and DHEAS were significantly potentiated, and PRE-084 or pregnenolone sulfate induced significant decreases of immobility time. The augmented effects in AdX/CX were fully blocked by BD1047. The effects of the classical antidepressants, desipramine or fluoxetine, were unchanged in AdX/CX mice. The effect of stress on the sigma(1)-receptor binding and neurosteroid levels was then examined in different brain structures, in terms of in vivo (+)-[(3)H]SKF-10,047 binding to sigma(1)-sites and neurosteroids levels. In the hippocampus, but not in the cortex or cerebellum, inhibition of in vivo (+)-[(3)H]SKF-10,047 binding was measured in parallel to the extent of progesterone levels according to the endocrine conditions. These data confirmed the antidepressant ability of sigma(1)-receptor agonists and revealed that the endogenous steroidal levels tonically interfere with the efficacy of the sigma(1)-system. It was observed that local modifications in progesterone levels are directly related to the changes of in vivo sigma(1)-binding. Such observations may be of major importance in view of the therapeutic use of selective sigma(1)-agonists in depression.

Aim of this work is to present and discuss the radiologic protocol we have developed for the preoperative assessment of patients with severe pulmonary emphysema candidate to lung volume reduction surgery (LVRS). The operation aims at improving respiratory mechanics and reducing small airway obstruction by removing variable amounts of emphysematous parenchyma. January to September, 1996, twelve patients were submitted to LVRS. Before surgery all patients were examined with standard chest radiographs during maximal inspiration and expiration, chest Computed Tomography (CT), High Resolution Computed Tomography (HRCT) and air trapping quantitation on HRCT scans. Diaphragm and chest wall excursions, patterns, site and distribution of emphysema, as well as heterogeneity (i.e., the uneven distribution of emphysematous and normal parenchyma) were investigated. Air trapping was quantitated with a dedicated software. Postoperative studies were carried out 2 months later in six patients and included: maximal inspiratory and expiratory chest radiographs and air trapping assessment on 3 standardized HRCT scans. All parameters considered improved in every patient. Radiologic studies proved to be of crucial importance for patient selection and LVRS planning. Despite our limited number of patients, the diagnostic protocol adopted in our Hospital appears a valuable tool for both pre- and post-operative assessment of the patients candidate to LVRS.

Video-assisted thoracic surgery (VATS) is used in a growing range of pulmonary and mediastinal conditions. By avoiding thoracotomy, VATS is minimally invasive and allows shorter postoperative hospitalization. The advantages of video-assisted thoracoscopic techniques are obvious in the patients with severe cardiorespiratory failure. We investigated the role of CT before VATS. From September, 1991, to January, 1994, two hundred and eight patients were submitted to VATS: 80 pleurectomies, 63 lobectomies, 42 wedge resections, 11 bullectomies, 8 biopsies and 4 pneumonectomies were performed in patients with diffuse lung disease. All patients underwent conventional CT and an additional HRCT was performed in 164 patients. Bullae site, number, characteristics and size must be assessed. The possible relationship of bullae to impaired respiratory function must be studied. When nodules are present, their site, depth and relationship to fissures must be defined. With small and deep-seated nodules a thin snap-open mandrel device should be used for intraoperative detection. When lobectomies are contemplated, fissures must be accurately studied to assess their integrity and whether they completely separate the lobes. Fibrous adhesions can prevent pulmonary collapse; unfortunately, some of them cannot be detected by CT. Another limitation is the difficulty in assessing whether fissures are incomplete. To conclude, CT integrated with HRCT provides useful information for correct video-assisted thoracic surgical management.

The role of color-Doppler US was investigated in the diagnosis of solid focal breast lesions. The results obtained with this method over the last two years were reviewed. Seventy-two patients with solid breast lesions were considered: conventional US scans of the nodules were performed first and color-Doppler scans followed, to depict vascularization. In benign focal lesions color-Doppler US never demonstrated more than a single vascular pole afferent to the lesion. In 92.5% of histologically malignant lesions, color-Doppler US easily demonstrated two or more feeding vessels. The analysis of our series confirmed the presence of a typical vascular pattern related to breast carcinoma which is easy to depict by means of color-Doppler US: this new technique is therefore of great value in the differentiation of benign from malignant breast masses, especially in the cases where conventional US and mammography alone failed to yield unquestionable and final results.

The authors report their experience with the color Doppler study of the prostate in a series of 1,075 transrectal US exams performed September 1991 to June 1992. US-guided biopsy was performed in 82 patients; histopathology confirmed the diagnosis in 32 cases. Color-Doppler US provided accurate blood vessel mapping in the normal gland. As for benign prostate conditions, color-Doppler features definitely helped a diagnosis to be made, especially in nodular hyperplasia. Carcinomas usually exhibited marked and inhomogeneous increase in the vascularization of peri- and intralesional areas. This feature was especially valuable in isoechoic carcinomas where US is known to exhibit limitations. The authors suggest that the integration of clinical, laboratory and US with color-Doppler findings allows higher diagnostic accuracy.

Videoendoscopic thoracic surgery is often employed to remove peripheral lung nodules. Since manual palpation is excluded, the authors obviate the difficulty of intraoperative nodule localization by employing a thin snap open mandrel under CT to guidance localize, fix and anchor the nodule. Traction can be exerted on the device allowing for rapid nodule identification and facilitating wedge resection removal. This technical innovation, as yet applied only to a limited number of cases, widens the indications of videothoracoscopic surgery and appears complication-free.