Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND: In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. PATIENTS AND METHODS: HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. RESULTS: Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

Drought sensitivity of Amazonian carbon balance revealed by atmospheric measurements.

Feedbacks between land carbon pools and climate provide one of the largest sources of uncertainty in our predictions of global climate. Estimates of the sensitivity of the terrestrial carbon budget to climate anomalies in the tropics and the identification of the mechanisms responsible for feedback effects remain uncertain. The Amazon basin stores a vast amount of carbon, and has experienced increasingly higher temperatures and more frequent floods and droughts over the past two decades. Here we report seasonal and annual carbon balances across the Amazon basin, based on carbon dioxide and carbon monoxide measurements for the anomalously dry and wet years 2010 and 2011, respectively. We find that the Amazon basin lost 0.48 ± 0.18 petagrams of carbon per year (Pg C yr(-1)) during the dry year but was carbon neutral (0.06 ± 0.1 Pg C yr(-1)) during the wet year. Taking into account carbon losses from fire by using carbon monoxide measurements, we derived the basin net biome exchange (that is, the carbon flux between the non-burned forest and the atmosphere) revealing that during the dry year, vegetation was carbon neutral. During the wet year, vegetation was a net carbon sink of 0.25 ± 0.14 Pg C yr(-1), which is roughly consistent with the mean long-term intact-forest biomass sink of 0.39 ± 0.10 Pg C yr(-1) previously estimated from forest censuses. Observations from Amazonian forest plots suggest the suppression of photosynthesis during drought as the primary cause for the 2010 sink neutralization. Overall, our results suggest that moisture has an important role in determining the Amazonian carbon balance. If the recent trend of increasing precipitation extremes persists, the Amazon may become an increasing carbon source as a result of both emissions from fires and the suppression of net biome exchange by drought.

Maternal left ventricular hypertrophy and diastolic dysfunction and brain natriuretic peptide concentration in early- and late-onset pre-eclampsia.

OBJECTIVE: Pre-eclampsia (PE) is associated with maternal cardiac remodeling and diastolic dysfunction. The aim of this study was to assess and compare maternal left ventricular structure and diastolic function and levels of brain natriuretic peptide (BNP) in women with early-onset (< 34 weeks' gestation) vs those with late-onset (≥ 34 weeks' gestation) PE. METHODS: This was a prospective, cross-sectional, observational study of 30 women with early-onset PE, 32 with late-onset PE and 23 normotensive controls. Maternal cardiac structure and diastolic function were assessed by echocardiography and plasma levels of BNP were measured by enzyme immunoassay. RESULTS: Early- and late-onset PE were associated with increased left ventricular mass index and relative wall thickness compared with normotensive controls. In women with early-onset PE, the prevalence of concentric hypertrophy (40%) and diastolic dysfunction (23%) was also significantly higher (both P < 0.05) compared with women with late-onset PE (16% for both). Maternal serum BNP levels were significantly higher (P < 0.05) in women with early-onset PE and correlated with relative wall thickness and left ventricular mass index. CONCLUSIONS: Early-onset PE is associated with more severe cardiac impairment than is late-onset PE, as evidenced by an increased prevalence of concentric hypertrophy, diastolic dysfunction and higher levels of BNP. These findings suggest that early-onset PE causes greater myocardial damage, increasing the risk of both peripartum and postpartum cardiovascular morbidity. Although these cardiovascular effects are easily identified by echocardiographic parameters and measuring BNP, further studies are needed to assess their clinical utility. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Lipid bodies accumulation in Leishmania infantum-infected C57BL/6 macrophages.

Lipid bodies (LBs) are intracellular accumulations of neutral lipids surrounded by a single membrane. These organelles are involved in the production of eicosanoids, which modulate immunity by either promoting or dampening inflammatory responses. Leishmania infantum, the etiological agent of visceral leishmaniasis in Brazil, is an intracellular parasite that causes disease by suppressing macrophage microbicidal responses. C57BL/6 mouse bone marrow-derived macrophages infected with L. infantum strain LcJ had higher numbers of LB+ cells (P<.0001) and total LBs than noninfected cultures. Large (>3 µm) LBs were present inside parasitophorous vacuoles (PVs). These results contrast with those of L. infantum-infected BALB/c macrophages, in which the only LBs are derived from parasite, not macrophage origin. Increased LBs in C57BL/6 macrophages in close association with parasites would position host LBs where they could modulate L. infantum infection. These results imply a potential influence of the host genetics on the role of LBs in host-pathogen interactions. Overall, our data support a model in which the expression, and the role of LBs upon infection, ultimately depends on the specific combination of host-pathogen interactions.

Dermoscopic patterns of melanoma metastases: interobserver consistency and accuracy for metastasis recognition.

BACKGROUND: Cutaneous metastases of malignant melanoma (CMMM) can be confused with other skin lesions. Dermoscopy could be helpful in the differential diagnosis. OBJECTIVES: To describe distinctive dermoscopic patterns that are reproducible and accurate in the identification of CMMM. METHODS: A retrospective study of 146 dermoscopic images of CMMM from 42 patients attending a melanoma unit between 2002 and 2009 was performed. Firstly, two investigators established six dermoscopic patterns for CMMM. The correlation of 73 dermoscopic images with their distinctive patterns was assessed by four independent dermatologists to evaluate the reproducibility in the identification of the patterns. Finally, 163 dermoscopic images, including CMMM and nonmetastatic lesions, were evaluated by the same four dermatologists to calculate the accuracy of the patterns in the recognition of CMMM. RESULTS: Five CMMM dermoscopic patterns had a good interobserver agreement (blue naevus-like, naevus-like, angioma-like, vascular and unspecific). When CMMM were classified according to these patterns, correlation between the investigators and the four dermatologists ranged from κ = 0.56 to κ = 0.7. In total, 71 CMMM, 16 angiomas, 22 blue naevi, 15 malignant melanomas, 11 seborrhoeic keratoses, 15 melanocytic naevi with a globular pattern and 13 pink lesions with a vascular pattern were evaluated according to the previously described CMMM dermoscopy patterns, showing an overall sensitivity of 67.9% (range 54.9-76%) and a specificity of 79.9% (range 68.5-93.5%) for the diagnosis of CMMM. CONCLUSIONS: Five dermoscopic patterns of CMMM with good interobserver agreement obtained a high sensitivity and specificity in the diagnosis of metastasis, with the accuracy varying according to the experience of the observer.

Assessment of melatonin-alpha adrenergic receptor complexes by molecular docking analysis.

The pineal melatonin (N-acetyl-5-methoxytryptamine) is a molecule associated in a way or another with probably all physiological systems, aiming to fulfil its functional integrative roles in central nervous system activity, sleep and wakefulness cycles, energy metabolism and thermoregulation, immune, reproductive, endocrine, cardiovascular, respiratory and excretory systems. Within this context, the present study aimed to assess in silico the formation of complexes between ligand melatonin and other potential receptor proteins by molecular docking analyses. The main steps established in this experimental procedure were: a) search and selection of the 3D structure of the melatonin from DrugBank; b) search and selection of 3D structures of other target receptor proteins using STRING, protein BLAST and database PDB; and c) formation of the complexes between melatonin and receptors selected using AutoDock4.0 server by molecular docking analyses. High reliability score and significant similarity were only identified between type 1B melatonin and alpha-2A adrenergic receptor. Thus, molecular docking assays were carried out using ligand melatonin and crystallographic structures of the alpha-2A adrenergic receptor coupled to an antagonist (ID PDB 6kux) and a partial agonist (ID PDB 6kuy) available in the database PDB. Binding energy values of -6.79 and -6.98 kcal/mol and structural stability by non-covalent intermolecular interactions were predicted during the formation of complexes between melatonin and alpha-2A adrenergic receptor 6kux and 6kuy, respectively. In this way, the findings described in current study may indicate strong interactions between melatonin and adrenoceptors, suggesting its possible partial agonist effect on the activation of the alfa-2A adrenergic receptor.

Insights on catheter-related bloodstream infections: a prospective observational study on the catheter colonization and multidrug resistance.

BACKGROUND: Central venous catheter-related bloodstream infection (CRBSI) is a huge public health concern with considerable impact on mortality and health costs. AIM: A three-year observational study enrolling three tertiary hospitals located in Lisbon, Portugal, was designed to identify the major aetiological agents of CRBSI, their ability to colonize central venous catheters and their antimicrobial resistance profiles. METHODS: Aetiological agents of CRBSI were identified by Vitek 2. Whole-genome sequencing was used to confirm CRBSI by the most prevalent aetiological agents and characterize their resistome. Central venous catheter colonization (namely by biofilm assembly) was monitored by scanning electron microscopy. FINDINGS: Staphylococci were the most prevalent causative agent (36/58, 62.0%), with S. aureus and coagulase-negative S. epidermidis accounting for 24.1% and 36.2% of CRBSIs, respectively. Fifty-nine of 72 staphylococci isolates were meticillin resistant. Comparative genomic analysis of central venous catheters/haemoculture pairs of isolates revealed genomic matches for 35 of 36 pairs and a good correlation between antibiotic susceptibility phenotype and the presence of antimicrobial resistance genetic determinants. Biofilms were present on 48.6% of the central venous catheters; nevertheless, no statistically significant association was established between biofilm assembly and CRBSI, and the presence/absence of ica operon and agr groups did not correlate with biofilm phenotypes, highlighting the need for further studies to elucidate biofilms' role on this healthcare-associated infection. CONCLUSION: Whole-genome sequencing was shown to be a valuable tool to confirm CRBSI. Although more than 42.3% of the central venous catheters were colonized by staphylococci, no statistically significant association was found between CRBSI and biofilms.

Non-invasive management of non-melanoma skin cancer in patients with cancer predisposition genodermatosis: a role for confocal microscopy and photodynamic therapy.

BACKGROUND: Patients with genodermatosis such as Gorlin syndrome (GS) and Xeroderma pigmentosum (XP) require a close follow-up for early diagnosis and treatment of skin cancer. We aimed to evaluate the efficacy of methyl-aminolevulinate (MAL) photodynamic therapy (PDT) in basal cell carcinomas (BCCs) from patients with GS and XP, and to determine the utility of reflectance confocal microscopy (RCM) in the diagnosis and the evaluation of therapeutic response. PATIENTS AND METHODS: We included four patients with GS and two siblings with XP. Single or multiple lesions in localized areas were treated with 1-3 cycles of MAL PDT. RCM was performed before and 3 months after the treatment in target lesions in all the patients. Patients were followed up for 3 years. RESULTS: In XP patients, we treated 13 pigmented BCCs on the face. All the lesions responded to the treatment and six lesions showed a complete clinical clearing. In GS patients, facial or trunk areas with multiple BCCs were treated (up to 200). Complete clinical remission was obtained in 25-67% of the lesions. Some nodular and pigmented lesions failed to achieve a complete remission. RCM could identify already described confocal features for BCC. Tumour remissions could be assessed by this technique. CONCLUSIONS: Methyl-aminolevulinate PDT may be useful for the treatment of superficial BCC in GS and XP. In some nodular lesions, PDT may complement surgery reducing tumour size. RCM may be regarded in the future as a complementary technique in BCC for the diagnosis and post-treatment assessment to non-invasive therapeutic modalities.

[Melanocytic nevi, melanoma, and pregnancy]. / Nevus, melanoma y embarazo.

Malignant melanoma is among the malignant tumors whose incidence has risen markedly in recent decades. For many years the medical community debated the potential adverse effects of female hormones (whether of exogenous or pregnancy-related endogenous origin), on melanocytic nevi and malignant melanoma. Given that women have been delaying pregnancy until their thirties or forties and that the incidence of malignant melanoma increases in those decades, the likelihood of this tumor developing during pregnancy has increased. Recent clinical and experimental evidence has suggested that pregnancy does not affect prognosis in malignant melanoma and that it does not seem to lead to significant changes in nevi. This review examines the relationship between malignant melanoma and hormonal and reproductive factors. Evidence was located by MEDLINE search (in PubMed and Ovid) for articles in English and Spanish for the period from 1966 to March 2010; additional sources were found through the reference lists of the identified articles.

Fas ligand triggers pulmonary silicosis.

We investigated the role of Fas ligand in murine silicosis. Wild-type mice instilled with silica developed severe pulmonary inflammation, with local production of tumor necrosis factor (TNF)-alpha, and interstitial neutrophil and macrophage infiltration in the lungs. Strikingly, Fas ligand-deficient generalized lymphoproliferative disease mutant (gld) mice did not develop silicosis. The gld mice had markedly reduced neutrophil extravasation into bronchoalveolar space, and did not show increased TNF-alpha production, nor pulmonary inflammation. Bone marrow chimeras and local adoptive transfer demonstrated that wild-type, but not Fas ligand-deficient lung macrophages recruit neutrophils and initiate silicosis. Silica induced Fas ligand expression in lung macrophages in vitro and in vivo, and promoted Fas ligand-dependent macrophage apoptosis. Administration of neutralizing anti-Fas ligand antibody in vivo blocked induction of silicosis. Thus, Fas ligand plays a central role in induction of pulmonary silicosis.

Effect of oral administration of diphenyl diselenide on antioxidant status, and activity of delta aminolevulinic acid dehydratase and isoforms of lactate dehydrogenase, in streptozotocin-induced diabetic rats.

Male albino rats with diabetes induced by the administration of streptozotocin (STZ) (45 mg/kg, i.v.) were treated with oral administration of diphenyl diselenide (DPDS) pre-dissolved in soya bean oil. A significant reduction in blood glucose levels was observed in STZ-induced diabetic rats treated with DPDS compared with an untreated STZ diabetic group. The pharmacological effect of DPDS was accompanied by a marked reduction in the level of glycated proteins, and restoration of the observed decreased levels of vitamin C and reduced glutathione (GSH; in liver and kidney tissues) of STZ-treated rats. DPDS also caused a marked reduction in the high levels of thiobarbituric acid reactive substances (TBARS) observed in STZ-induced diabetic group. Finally, the inhibition of catalase, delta aminolevulinic acid dehydratase (eth-ALA-D) and isoforms of lactate dehydrogenase (LDH) accompanied by hyperglycemia were prevented by DPDS in all tissues examined. Hence, in comparison with our earlier report, the present findings suggests that, irrespective of the route of administration and the delivery vehicle, DPDS can be considered as an anti-diabetic agent due to its anti-hyperglycemic and antioxidant properties.

The role of thiol-reducing agents on modulation of glutamate binding induced by heavy metals in platelets.

In the present study, we investigated if thiol-reducing agents are capable of altering mercury (Hg2+), lead (Pb2+) and cadmium (Cd2+) effects on platelet glutamatergic system. Dimercaprol (BAL), a dithiol chelating agent therapeutically used for the treatment of heavy metals poisoning, was capable of protecting the [3H]-glutamate binding against the effects caused by Pb2+ and Hg2+. 2,3-Dimercaptopropane-1-sulfonic acid (DMPS), another dithiol-reducing chelating agent, was capable of protecting the effect caused by Cd2+, Pb2+ and Hg2+. The similar effect was observed with addition of dithiothreitol (DTT) on [3H]-glutamate binding in human platelets. Dithiol-reducing agents (BAL, DMPS and DTT) alone did not alter [3H]-glutamate binding. In contrast, reduced glutathione (GSH), a monothiol-reducing agent, caused a significant inhibition on [3H]-glutamate binding at all concentrations tested. GSH did not modify heavy metal effects on [3H]-glutamate binding in platelets. The findings of the present investigation indicate that dithiol-reducing agents are capable of altering Hg2+, Pb2+ and Cd2+ effects on platelet glutamatergic system. In vitro data on chelating-metal interactions provide only an estimated guide to the treatment of heavy metal poisoning. Consequently, more studies in intoxicated patients are necessary to determine the precise use of the peripheral models and chelating agents.

Repeated administration of diphenyl ditelluride induces hematological disorders in rats.

In the present study, we investigated potential toxic effects of diphenyl ditelluride, as measured by biochemical and hematological parameters. Rats were given a daily dose of 0.3 micromol/kg diphenyl ditelluride by subcutaneous route and sacrificed at different times (24 and 48 h). Hepatic and renal TBARS levels were changed by diphenyl ditelluride exposure at the dose 0.9 micromol/Kg in rats. Diphenyl ditelluride exposure demonstrated an increase in AST (aspartate aminotransferase), ALT (alanine aminotransferase) and LDH (lactate dehydrogenase) activities. Plasma creatinine and urea levels increase after diphenyl ditelluride exposure. Diphenyl ditelluride also produced a significant decrease in plasma triglyceride and cholesterol levels. In contrast, this compound, at all doses tested, induced a marked increase in total leukocyte counts. The present study suggests that diphenyl ditelluride induces hematological disorders and provides evidence for renal and hepatic toxicity in rats.

Mammary epithelial cell phagocytosis downstream of TGF-ß3 is characterized by adherens junction reorganization.

After weaning, during mammary gland involution, milk-producing mammary epithelial cells undergo apoptosis. Effective clearance of these dying cells is essential, as persistent apoptotic cells have a negative impact on gland homeostasis, future lactation and cancer susceptibility. In mice, apoptotic cells are cleared by the neighboring epithelium, yet little is known about how mammary epithelial cells become phagocytic or whether this function is conserved between species. Here we use a rat model of weaning-induced involution and involuting breast tissue from women, to demonstrate apoptotic cells within luminal epithelial cells and epithelial expression of the scavenger mannose receptor, suggesting conservation of phagocytosis by epithelial cells. In the rat, epithelial transforming growth factor-ß (TGF-ß) signaling is increased during involution, a pathway known to promote phagocytic capability. To test whether TGF-ß enhances the phagocytic ability of mammary epithelial cells, non-transformed murine mammary epithelial EpH4 cells were cultured to achieve tight junction impermeability, such as occurs during lactation. TGF-ß3 treatment promoted loss of tight junction impermeability, reorganization and cleavage of the adherens junction protein E-cadherin (E-cad), and phagocytosis. Phagocytosis correlated with junction disruption, suggesting junction reorganization is necessary for phagocytosis by epithelial cells. Supporting this hypothesis, epithelial cell E-cad reorganization and cleavage were observed in rat and human involuting mammary glands. Further, in the rat, E-cad cleavage correlated with increased γ-secretase activity and ß-catenin nuclear localization. In vitro, pharmacologic inhibitors of γ-secretase or ß-catenin reduced the effect of TGF-ß3 on phagocytosis to near baseline levels. However, ß-catenin signaling through LiCl treatment did not enhance phagocytic capacity, suggesting a model in which both reorganization of cell junctions and ß-catenin signaling contribute to phagocytosis downstream of TGF-ß3. Our data provide insight into how mammary epithelial cells contribute to apoptotic cell clearance, and in light of the negative consequences of impaired apoptotic cell clearance during involution, may shed light on involution-associated breast pathologies.

Changes in postural control in patients with Parkinson's disease: a posturographic study.

OBJECTIVES: Postural instability is one of the most disabling features in Parkinson's disease (PD), and often leads to falls that reduce mobility and functional capacity. The objectives of this study were to analyse the limit of stability (LOS) and influence of the manipulation of visual, somatosensorial and visual-vestibular information on postural control in patients with PD and healthy subjects. DESIGN: Cross-sectional. SETTING: Movement Disorders Unit, university setting. PARTICIPANTS: Eighty-two subjects aged between 37 and 83 years: 41 with Parkinson's disease in the 'on' state and 41 healthy subjects with no neurological disorders. Both groups were matched in terms of sex and age. MAIN OUTCOME MEASURES: Unified Parkinson's Disease Rating Scale (UPDRS)-motor score, modified Hoehn and Yahr staging, Dynamic Gait Index (DGI) and posturography with integrated virtual reality. The parameters analysed by posturography were LOS area, area of body centre of pressure excursion and balance functional reserve in the standing position in 10 conditions (open and closed eyes, unstable surface with eyes closed, saccadic and optokinetic stimuli, and visual-vestibular interaction). RESULTS: The mean UPDRS motor score and DGI score were 27 [standard deviation (SD) 14] and 21 (SD 3), respectively. Thirteen participants scored between 0 and 19 points, indicating major risk of falls. Posturographic assessment showed that patients with PD had significantly lower LOS area and balance functional reserve values, and greater body sway area in all posturographic conditions compared with healthy subjects. CONCLUSIONS: Patients with PD have reduced LOS area and greater postural sway compared with healthy subjects. The deterioration in postural control was significantly associated with major risk of falls.

Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism.

Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER+ astrocytes in the brain microenvironment, can promote BM of TN breast cancers, and suggests existing endocrine agents may provide some clinical benefit towards reducing and managing BM.

Effect of diphenyl diselenide, diphenyl ditelluride and ebselen on cerebral Na(+), K(+)-ATPase activity in rats.

In the present study, we investigated the in vitro effect of diphenyl ditelluride, diphenyl diselenide and ebselen on Na(+), K(+)-ATPase activity of rat brain. The results demonstrated that all compounds significantly inhibited (in the muM range) Na(+), K(+)-ATPase activity. Diphenyl ditelluride, at low concentrations, provoked an increase in Na(+), K(+)-ATPase activity. Dithiothreitol (DTT), at 3mM, protected the inhibition caused by diphenyl ditelluride, diphenyl diselenide and ebselen in Na(+), K(+)-ATPase activity. Post-incubation of diphenyl diselenide-treated homogenate with DTT completely recovered enzyme activity. DTT was able to recover the enzyme inhibition induced by 20muM of diphenyl ditelluride, but was partially able to recover inhibition induced by high concentrations of organotellurium compound. Conversely, DTT did not recover ebselen-induced Na(+), K(+)-ATPase inhibition. The mechanism of inhibition by diphenyl diselenide, diphenyl ditelluride and ebselen in Na(+), K(+)-ATPase activity revealed: decreased maximal velocity and K(m). Cerebral Na(+), K(+)-ATPase is a potential molecular target for the toxic effect of organochalcogens and the inhibition may occur through a change in the crucial thiol groups of this enzyme.