Sanguinarine overcomes P-glycoprotein-mediated multidrug-resistance via induction of apoptosis and oncosis in CEM-VLB 1000 cells.

Permeability-glycoprotein (Pgp) positive cells are known to be encoded by the multidrug-resistance gene (MDR1), and characterized by a reduced ability to accumulate drugs. The vinblastin-resistant, Pgp positive CEM-VLB 1000 and its wild type (Pgp-negative and vinblastin-sensitive) counterpart CEM-T4 human leukemia cells, when treated with the alkaloid sanguinarine, were both found to undergo apoptosis at concentrations of 1.5 microg/ml and oncosis/blister cell death (BCD) at concentrations of 12.5 microg/ml. The aim of this study was to assess the ability of sanguinarine to overcome Pgp-mediated multidrug-resistance (MDR), and also to characterize the cell death processes of apoptosis and oncosis (or bimodal cell death) induced by sanguinarine in MDR cells. The cell death processes of apoptosis and oncosis in CEM-VLB 1000 and CEM-T4 cell lines were found to be qualitatively similar when assessed by light microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling, annexin-V-binding, trypan blue exclusion and western blot analysis. Western blotting revealed an increase in the Bax/Bcl-2 ratio and activation of caspase-3 in apoptosis but not oncosis in both cell lines. The Pgp-positive CEM-VLB 1000 cells and their wild type CEM-T4 cells were both equally sensitive to sanguinarine. Thus, sanguinarine may overcome the phenomenon of Pgp-mediated MDR by inducing apoptosis through increasing the Bax/Bcl-2 ratio and activating caspase-3, and oncosis, which involved neither.     

Cadmium in kidneys in Swedes measured in vivo using X-ray fluorescence analysis

An X-ray fluorescence (XRF) technique using plane polarized X-rays for excitation was used for in vivo measurements of cadmium in the kidney cortex among non-occupationally exposed members of the general population in southern Sweden. The measured concentrations of cadmium in the kidney cortex of smokers (median 28 g/g, n = 10) were significantly higher (P = 0.0036) as compared to those in non-smokers (median 8 g/g, n = 10), and so were the cadmium concentrations in blood and urine. The results show that smoking considerably increases the cadmium concentration in the kidney cortex and that smoking is a major source of cadmium exposure in the general population of Sweden. Except in the presence of very deeply situated kidneys, where the minimum detectable concentration is high, non-invasive in vivo XRF analysis of kidney cadmium should be a useful tool for evaluating the effects of long-term low-level exposure to cadmium and the risk of kidney damage.     

Gastritis staging: interobserver agreement by applying OLGA and OLGIM systems

Atrophic gastritis remains a difficult histopathological diagnosis with low interobserver agreement. The aim of our study was to compare gastritis staging and interobserver agreement between general and expert gastrointestinal (GI) pathologists using Operative Link for Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM). We enrolled 835 patients undergoing upper endoscopy in the study. Two general and two expert gastrointestinal pathologists graded biopsy specimens according to the Sydney classification, and the stage of gastritis was assessed by OLGA and OLGIM system. Using OLGA, 280 (33.4 %) patients had gastritis (stage I–IV), whereas with OLGIM this was 167 (19.9 %). OLGA stage III– IV gastritis was observed in 25 patients, whereas by OLGIM stage III–IV was found in 23 patients. Interobserver agreement between expert GI pathologists for atrophy in the antrum, incisura angularis, and corpus was moderate (kappa?=?0.53, 0.57 and 0.41, respectively, p?<?0.0001), but almost perfect for intestinal metaplasia (kappa?=?0.82, 0.80 and 0.81, respectively, p?<?0.0001). However, interobserver agreement between general pathologists was poor for atrophy, but moderate for intestinal metaplasia. OLGIM staging provided the highest interobserver agreement, but a substantial proportion of potentially high-risk individuals would be missed if only OLGIM staging is applied. Therefore, we recommend to use a combination of OLGA and OLGIM for staging of chronic gastritis.     

Exploring young people's expectations of a youth mental health care service

Client expectations about mental health services relate to the client's and the therapist's role, the therapeutic process and therapeutic outcomes. Research with adults shows that such expectations affect service engagement and clinical outcomes. Aim: The present study investigated expectations for adolescents and young adults, which have not been adequately investigated and may partly explain the reluctance of young people to seek professional help. Methods: Participants included 20 young people aged 12–24 attending their initial session at a youth mental health service, who were interviewed immediately prior to their initial session. Data were analysed using qualitative methods to draw main themes around each of the four expectancy types. Results: Overall, the strongest theme was that young people were unsure of what to expect from attending a mental health service. The key theme for expectations of their role as a client was readiness for therapy, and for the therapist's role the key themes were who they expected to see, the directiveness and likeability of the therapist, and the type of help they expected they would receive. The young people expected that the therapy process would involve simply talking and expected their engagement to be dependent on how much they liked their first few sessions. Outcome expectations were non‐specific and the theme of hopefulness was most evident. Conclusion: As unrealistic and unmet expectations can lead to poorer engagement and outcomes in therapy, the study highlights a need for young people to be better informed about what to expect when coming to mental health services.     

A Critical Role for Thioredoxin-Interacting Protein in Diabetes-Related Impairment of Angiogenesis

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose–mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.     

Percutaneous absorption of gold sodium thiosulfate used for patch testing

Contact allergy to gold has been shown to be correlated to wearing of golden jewellery as well as to the presence of dental gold. The prerequisite for sensitization and elicitation of an allergic contact dermatitis to gold is ionization and percutaneous absorption of the allergen. The present study was undertaken with the aim to demonstrate gold in blood after an occlusive patch testing with gold sodium thiosulfate (GSTS). Patients were patch tested with GSTS 0.5, 2.0 and 5.0% in petrolatum. Venous blood was sampled before testing as well as on day 3 (D3) or day 7 (D7). Blood gold levels were analysed by inductively coupled plasma mass spectrometry. In all 66 patients, the blood level of gold was significantly higher in the 2nd blood sample than in the 1st (median 0.34 versus 0.03 micro g/l). The increase was similar in patients allergic and not allergic to gold. There was no difference between gold levels on D3 and on D7 after epicutaneous application. Presumably, other allergens may also be taken up in blood during patch testing.     

An activated charcoal-based, liquid scintillation-analyzed airborne Rn detector

An inexpensive, easy-to-use detector for measuring airborne 222Rn based on 222Rn diffusion and absorption in activated charcoal is presented. The detector uses chemical extraction and liquid scintillation for measurement of the 222Rn concentration, is designed to be insensitive to temperature and humidity effects, and obtains sensitivity levels of 675 CPM (Bq L-1)-1 [25 CPM (pCi L-1)-1] at room temperature.     

Interventions in the therapy of electromechanical dissociation

Electromechanical dissociation (EMD) is a major arrest rhythm for which there is often inadequate treatment. The purpose of this study was to evaluate the different pharmacological and non-pharmacological interventions considered in the treatment of EMD. During the 6-year period, January 1st, 1980 to December 31st, 1985, 503 evaluable adult patients presented in a non-traumatic, non-poisoning cardiopulmonary arrest with the initial rhythm of EMD. One hundred nineteen patients obtained a pulse during resuscitation efforts following drug administration. The average time to obtaining pulses after the last drug administration was 1.97 +/- 2.21 min. The following drugs were last administered prior to transient pulses: bicarbonate, 31/119 (26%); epinephrine, 26/119 (22%); atropine, 26/119 (22%); dopamine, 13/119 (11%); calcium, 11/119 (9%); isoproterenol, 7/119 (6%); other drugs, 5/119 (4%). Ninety-five percent of the successful resuscitations received eight or less drug interventions and all saves received three or less drug interventions. Two hundred twenty-four patients (44.5%) had 288 non-pharmacological interventions. Twenty-three patients developed a pulse after intervention in the following distribution: MAST suit (N = 9), pericardiocentesis (N = 6), fluid challenge (N = 5), needle thoracostomy (N = 1), and intervention combinations (N = 2). The time interval between intervention and the onset of pulse was as follows: MAST suit, 4 +/- 2.8 min; pericardiocentesis, 3.7 +/- 3.6 min; fluid challenge, 4.8 +/- 4.1 min; needle thoracostomy, 6 min. The overall save rate for intervention patients was 0.9% whereas for those not having intervention it was 7.2% (P less than or equal to 0.0003).(ABSTRACT TRUNCATED AT 250 WORDS)