Reversibility of alexithymia with effective treatment of moderate-to-severe psoriasis: longitudinal data from EPIDEPSO.

BACKGROUND: Alexithymia refers to difficulty in identifying and expressing emotions. Alexithymia is associated with high burden of disease in patients with psoriasis. OBJECTIVES: To investigate whether alexithymia was reversible in patients with psoriasis following real-life therapeutic intervention. METHODS: The Epidemiological Study in Patients with Recently Diagnosed Psoriasis (EPIDEPSO; NCT01964443) was a 1-year multicentre observational study investigating the prevalence of alexithymia and other psychosocial comorbidities in patients with psoriasis with ≤ 10 years' disease duration and eligible for systemic treatment. Alexithymia was assessed using the Toronto Alexithymia Scale (TAS-20) at baseline, 6 months and 1 year. RESULTS: There was a statistically significant decrease in the prevalence of alexithymia in the follow-up cohort, from 26·7% at baseline to 21·2% at 6 months and 18·8% at 1 year. More than half of the patients (n = 77, 53·8%) who were alexithymic at baseline experienced reversion of their alexithymia. Reversion of alexithymia was higher in patients who reached a high level of disease control, defined as ≥ 75% or ≥ 90% improvement in Psoriasis Area and Severity Index. Reversion of alexithymia was associated with dramatic improvement in quality of life, anxiety and depression. Moreover, hazardous alcohol use, highly prevalent in patients with alexithymia, was reduced almost threefold at 1 year. CONCLUSIONS: Alexithymia and associated high disease burden may be reversible in patients with effective treatment of psoriasis. Proactive recognition of patients who are unable to identify and express their feelings is important.

Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer.

TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.

[Mineralogical composition of urinary stones, risk factors and metabolic disturbances in patients with calcium-oxalate urolithiasis].

AIM: To identify the most likely metabolic disturbances and risk factors for stone formation in a group of patients with calcium oxalate urolithiasis, and to establish the relationship between the mineralogical composition of calculi and impaired excretion of inhibitors and promoters of stone formation. MATERIALS AND METHODS: Fifty patients with calcium oxalate urolithiasis were tested using a complex of physicochemical methods. Patients assessment included evaluation of quantitative mineralogical composition of calculi, daily urine pH profile and daily urinary excretion of urates, calcium, magnesium, oxalate, phosphate and citrate ions. RESULTS: The main mineralogical phase of the stones in over 80% of patients was calcium oxalate monohydrate; none of the patients had pure dihydrate stones. The most frequent metabolic disorders were hypocitraturia, hypercalciuria and hyperuricosuria. Predominant risk factors were excessive body weight and insufficient fluid intake. Only one patient had an idiopathic stone formation. It was established for the first time that patients with calcium oxalate stones, containing 10 or more mass percent of apatites had statistically significantly lower daily urinary calcium and oxalate excretion and simultaneously increased phosphate excretion. CONCLUSIONS: The study findings showed that patients with calculi based on calcium oxalate dihydrate should undergo testing for daily urinary excretion of calcium and citrate while pa-tients with calcium oxalate stones containing 10 or more mass percent of apatites should also be tested for daily phosphate excretion and urine pH-profile. Daily urinary citrate excretion was reduced in all study patients, and urate excretion was significantly increased, apparently due to an imbalanced diet and excessive intake of animal protein. Menopausal and postmenopausal women are at a particular risk due to low urinary citrate excretion and high urinary calcium excretion regardless of stone composition.

Prevalence of alexithymia in patients with psoriasis and its association with disease burden: a multicentre observational study.

BACKGROUND: Single-centre studies show that alexithymia, defined as difficulty in recognizing and describing emotions, is more prevalent among patients with psoriasis than in the general population. However, its prevalence and the consequences of the association between alexithymia and psoriasis are unclear. OBJECTIVES: The primary objective of this study was to determine the prevalence of alexithymia, as defined by a score ≥ 61 in the 20-item Toronto Alexithymia Scale, in a large sample of patients who had plaque psoriasis for ≤ 10 years and were eligible for phototherapy or systemic treatment. The secondary objectives were to investigate the relationship between alexithymia and the clinical and psychological aspects of psoriasis. METHODS: Data were collected in the framework of an observational, multicentre, international study, the EPidemiological Study In Patients With Recently DiagnosEd PSOriasis (EPIDEPSO), aiming at investigating the prevalence of alexithymia and other psychosocial comorbidities in patients with psoriasis of ≤ 10 years' disease duration. RESULTS: The prevalence of alexithymia within a cohort of 670 patients was 24·8% (95% confidence interval 21·7-28·2). Patients with alexithymia had a higher burden of psoriasis, including significant impairment of quality of life, higher levels of anxiety and depression, a higher risk of alcohol dependency and impairment of work productivity, compared with patients without alexithymia. CONCLUSIONS: It is important to identify alexithymic patients with psoriasis in clinical practice as they experience a higher disease burden and have a lower ability to express their feelings.

Quality of life and patient benefit following transition from methotrexate to ustekinumab in psoriasis.

BACKGROUND: TRANSIT (NCT01059773) compared immediate and gradual transition from methotrexate to ustekinumab in psoriasis patients via multiple measures, including patient-reported outcomes. OBJECTIVE: To evaluate patient perception of treatment benefits in TRANSIT. METHODS: A total of 489 psoriasis patients received ustekinumab, with immediate cessation of methotrexate (Arm 1) or 4 weeks' overlap with decreasing methotrexate dose (Arm 2). Ustekinumab was administered at weeks 0, 4, 16, 28 and 40. Dermatology Life Quality Index (DLQI), EuroQol 5-item (EQ-5D), visual analogue scale (VAS) valuation technique and patient benefit index (PBI) were employed. Mean global PBI and sub-scores were calculated from the sum of the benefit items weighted by their respective relevance at baseline. Patient-relevant benefit was defined as PBI ≥1 (scale: 0 [no benefit] to 4 [maximum benefit]). Correlations of global PBI with Psoriasis Area and Severity Index (PASI) and DLQI were examined. RESULTS: Relationships between PBI and clinical data were evaluable in 340 patients. The most important treatment goals at baseline included: 'be healed of all skin defects', 'have confidence in therapy', 'get better skin quickly' and 'regain control of the disease'. Benefit in PBI global score was achieved at week 4 by 93% of patients in Arm 1 and 91% in Arm 2. Global PBI scores increased in both Arms between weeks 4 and 52. Global PBI correlated weakly with PASI change from baseline (correlation coefficient range: -0.22 to -0.40), and moderately with DLQI (-0.29 to -0.54). Overall DLQI score was lower than baseline at all times; and the percentage of patients with an overall score of 0 or 1 increased with time. Correspondingly, EQ VAS scores increased with time. DLQI and EQ VAS results were similar between arms. CONCLUSIONS: Regardless of the strategy for transitioning from methotrexate, ustekinumab was associated with rapid and sustained improvement in patient-reported outcomes. PBI appears a suitable tool for assessing patient-relevant treatment benefits in psoriasis patients.

[Quantitative mineralogical analysis and structure of urinary stones in patients living in Ivanovo region].

This paper focuses on developing and implementing a method of quantitative mineralogical analysis of urinary stones based on powder diffraction data analysis using 4 Topas (Bruker) software. Mineralogical composition of 100 urinary stones from urolithiasis patients living in Ivanovo region was examined. More than 70% of stones consisted of calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD), and their mixtures with hydroxylapatite. Forty four percent of urinary stones consisted of one component (COM, uric acid (UA) or, less frequently, hydroxyapatite (HA); 56% of urinary stones comprised two, three or four components. The most common mineral was COM (more than 70% of cases), the rarest were calcium oxalate trihydrate (CT), brushite and newberrite. The most common combinations of minerals in mixed stones were COM+HA, COM+COD and COM+COD+HA. The texture, the surface composition and its changes in the course of chemolysis in different types of stones were examined using scanning electron microscopy (SEM) and X-ray microanalysis (XRM). Implications for using analytical chemical and physical techniques for the diagnosis and treatment of urolithiasis were discussed.

Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes.

A novel two-step protocol for intracellular drug delivery has been evaluated in vitro. As a first step TO-PRO-3 (a cell-impermeable dye that displays a strong fluorescence enhancement upon binding to nucleic acids) encapsulated in thermosensitive liposomes was released after heating to 42°C. A second step consisted of ultrasound-mediated local permeabilization of cell membrane allowing TO-PRO-3 internalization observable as nuclear staining. Only the combination of two consecutive steps - heating and sonication in the presence of SonoVue microbubbles led to the model drug TO-PRO-3 release from the thermosensitive liposomes and its intracellular uptake. This protocol is potentially beneficial for the intracellular delivery of cell impermeable drugs that suffer from rapid clearance and/or degradation in blood and are not intrinsically taken up by cells.

Magnetic control of vascular network formation with magnetically labeled endothelial progenitor cells.

We describe the applications of new cellular magnetic labeling method to endothelial progenitor cells (EPC), which have therapeutic potential for revascularization. Via their negative surface charges, anionic magnetic nanoparticles adsorb non-specifically to the EPC plasma membrane, thereby triggering efficient spontaneous endocytosis. The label is non-toxic and does not affect the cells' proliferative capacity. The expression of major membrane proteins involved in neovascularisation is preserved. Labeled cells continue to differentiate in vitro and to form tubular structures in Matrigel (an in vitro model of neovascularization). This process was followed in situ by using high-resolution MRI. Finally, we show that magnetic forces can be used to move magnetically labeled EPC in vitro and to modify their organization in Matrigel both in vitro an in vivo. Magnetic cell targeting opens up new possibilities for vascular tissue engineering and for delivering localized cell-based therapies.

Single-cell detection by gradient echo 9.4 T MRI: a parametric study.

Recent studies have shown that cell migration can be monitored in vivo by magnetic resonance imaging after intracellular contrast agent incorporation. This is due to the dephasing effect on proton magnetization of the local magnetic field created by a labelled cell. Anionic iron oxide nanoparticles (AMNP) are among the most efficient and non-toxic contrast agents to be spontaneously taken up by a wide variety of cells. Here we measured the iron load and magnetization of HeLa tumour cells labelled with AMNP, as a function of the external magnetic field. High-resolution gradient echo 9.4 T MRI detected individual labelled cells, whereas spin echo sequences were poorly sensitive. We then conducted a systematic study in order to determine the gradient echo sequence parameters (echo time, cell magnetization and resolution) most suitable for in vivo identification of single cells.

Spatial and temporal control of transgene expression in vivo using a heat-sensitive promoter and MRI-guided focused ultrasound.

BACKGROUND: Among the techniques used to induce and control gene expression, a non-invasive, physical approach based on local heat in combination with a heat-sensitive promoter represents a promising alternative but requires accurate temperature control in vivo. MRI-guided focused ultrasound (MRI-FUS) with real-time feedback control allows automatic execution of a predefined temperature-time trajectory. The purpose of this study was to demonstrate temporal and spatial control of transgene expression based on a well-defined local hyperthermia generated by MRI-FUS. METHODS: Expression of the green fluorescent protein (GFP) marker gene was used. Two cell lines were derived from C6 glioma cells. The GFP expression of the first one is under the control of the CMV promoter, whereas it is under the control of the HSP70 promoter in the second one and thus inducible by heat. Subcutaneous tumours were generated by injection in immuno-deficient mice and rats. Tumours were subjected to temperatures varying from 42 to 50 degrees C for 3 to 25 min controlled by MRI-FUS and analyzed 24 h after the heat-shock. Endogenous HSP70 expression and C6 cell distribution were also analyzed. RESULTS: The results demonstrate strong expression at 50 degrees C applied during a short time period (3 min) without affecting cell viability. Induced expression was also clearly shown for temperature in the range 44-48 degrees C but not at 42 degrees C. CONCLUSIONS: Heating with MRI-FUS allows a tight and non-invasive control of transgene expression in a tumour.

[The metabolism and biological activity of glucuronidation substrates in experimental diabetes mellitus]. / Metabolizm i biologicheskaia aktivnost' substratov gliukuronidirovaniia pri éksperimental'nom sakharnom diabete.

The study was undertaken to examine the impact of experimental diabetes mellitus on the biotransformation of some drugs, their toxicity and hypoglycemic action, as well as on the biotransformation of endogenous testosterone and the androgenic status. The accelerated metabolism of both exogenous and endogenous substrates which occurred in diabetes mellitus caused a decrease in their biological activity.

[The biological activity of chalone-like proteoglycans isolated from the spleen and thymus at various periods of ontogeny]. / Biologicheskaia aktivnost' keilonopodobnykh proteoglikanov, vydelennykh iz selezenki i timusa v raznye periody ontogeneza.

Chalone-like proteoglycans from sheep and bovine thymus and spleen were shown to suppress cell proliferation in murine thymus or spleen. Their effect appeared to be organ-specific but not species-specific. Administration of the proteoglycans resulted in a decrease in the mitotic activity of thymus and spleen cells 24h (strain C57BL), three days (hybrids), four days (nude mice) or five days (highly cancerous strain C3H/He and white mongrel mice) after birth. These changes are probably due to genetic peculiarities of immune system formation in different mouse strains. The activity of chalone-like proteoglycans from spleen and thymus of 1-, 3- and 6-months old sheep was lower than that of adult sheep (two and five years old) indicating that the proteoglycan activity increases during ontogenesis.

[Change in carbohydrate metabolism, secretion of insulin and glucagon in normoglycemic rats during administration of various doses of nicotinamide]. / Izmenenie uglevodnogo obmena, sekretsii insulina i gliukagona u normoglikemicheskikh krys pri vvedenii razlichnykh doz nikotinamide.

Development of hypoglycemia, a slight decrease in concentration of glucagon in blood as well as increase in activity of malate-and glucose-6-phosphate dehydrogenases in liver cytosol were detected in rats injected subcutaneously with nicotinamide at a dose of 31.25 mg/kg 6 hrs before decapitation. Increase of the single dose up to 125 mg/kg caused hypoglycemia, distinct increase in concentration of insulin and glucagon in blood plasma simultaneously with a pronounced inhibition of the enzymatic activity in liver tissue. Effect of nicotinamide on carbohydrate metabolism appears to have a dissimilar character depending on the drug dose: its small doses accelerated utilization and oxidation of glucose but did not affect the secretion of insulin and glucagon.

[The activity of growth-regulating substances isolated from the spleen and thymus of healthy cows and of those with hemoblastoses]. / Issledovanie aktivnosti rostreguliruiushchikh veshchestv, vydelennykh iz selezenki i timusa zdorovykh i bol'nykh gemoblastozami korov.

Certain agents of the proteoglycan nature possessing organ-specific rather than the species-specific antimitotic chalone activity have been obtained from the normal bovine spleen and thymus. The preparations obtained by the same method from the spleen and the thymus of animals affected by lympholeukemia and lymphosarcoma did not reveal the antimitotic activity; moreover, they were of high mitogenic organ-specific character. A connection between the mitogenic factor produced by lymphocytic cells and the bovine leukemia virus is possible.

[Effect of nicotinamide on body glucose utilization in animals]. / Vliianie nikotinamida na utilizatsiiu gliukozy organizmom zhivotnykh.

A single administration of nicotinamide (62.5 mg/kg) was found to enhance the relative activity of exogenous insulin, to decrease glucose level in the peripheral blood, to increase the activity of malate dehydrogenase and glucose-6-phosphate dehydrogenase in the liver cytosol in intact mice and to increase the rate of exogenous glucose utilization in rabbits. The character of nicotinamide effect on carbohydrate metabolism in intact animals is suggested to be dose-dependent. When administered in low doses, the drug increases tissue sensitivity to endo- and exogenous insulin.

[Metabolic products of methandrostenolone in the body of white rats studied by high-performance liquid chromatography]. / Izuchenie produktov metabolizma metandrostenolona v organizme belykh krys metodom vysokoéffektivnoi zhidkostnoi khromatografii.

Metabolism of the anabolic steroidal hormone methandrostenolone in Wistar rats was studied by high performance liquid chromatography (HPLC) and redioisotope techniques. The conditions for isolation of methandrostenolone metabolites by HPLC were developed. Reduction of the double bonds was shown to be an early stage in methandrostenolone biotransformation. The main portion of the metabolites was excreted with urine as glucuronide conjugates. No sulfoesters were found.

[Dynamic distribution of methandrostenolone in the body of white rats]. / Dinamika raspredeleniia metandrostenolona v organizma belykh krys.

Dynamics of distribution of anabolic steroidal hormone methandrostenolone and routes of its elimination from the organism of Wistar rats were studied by using methods of radioisotopes and high-performance liquid chromatography. Methandrostenolone metabolites were shown to be excreted mainly in the urine. Methandrostenolone metabolism is a complicated process in the course of which redistribution of metabolites among various organs occurs. The anabolic effect of methandrostenolone is supposed to be due to the formation of its metabolites.