Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug’s antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.     

Increased oestradiol level in seminal plasma in infertile men

Seminal hormonal patterns in fertile and infertile men wereinvestigated. Follicle-stimulating hormone (FSH), luteinizinghormone (LH), prolactin, testosterone and oestradiol were assessedby radioimmunoassay, and dehydroepiandrosterone sulphate (DHAS)by bioluminescence assay, on blood and seminal plasma of 23fertile men and 83 infertile men. For fertile men, mean FSH,LH, testosterone and DHAS concentrations were lower and meanoestradiol was higher in seminal than in blood plasma; prolactindid not differ. For infertile men, mean seminal FSH and LH showeda moderate but significant increase compared with fertile men;testosterone, DHAS and prolactin did not differ but mean seminaloestradiol was significantly increased. Of the infertile men,53% had seminal oestradiol concentration above the 90^th percentilevalue for fertile men. The meaning of this seminal oestradiolincrease is unclear since it is not known whether it is thecause or the consequence of the alteration of spermatogenesisin infertile men. Further studies are required to explore thepossible therapeutic implications.     

Slime production of Staphylococcus epidermidis: Increased bacterial adherence and accumulation onto pure titanium

In an in vitro study using Staphylococcus epidermidis RP 62 A, a slime-producing strain and its isogenic slime-negative mutant M7, we demonstrated that both strains adhere to pure titanium discs with significantly higher colony counts for the slime-producing strain. The colony count was dependent on temperature, time and strain. Prolonged incubation time (24 h) under growth conditions leads to higher colony counts for the slime-producing strain RP 62 A. As the slime-negative mutant M 7 can adhere to, but not form multiple layers on metallic surfaces, increase of incubation time does not produce higher colony counts on the metallic surface. We conclude that slime production is important for adherence and subsequent accumulation of S. epidermidis onto pure titanium discs in vitro.     

The cognitive efficiency profile: Description and validation in patients with Alzheimer's disease

The rigorous diagnosis of dementia, especially in the early stages, requires clinical observation and neuropsychological tests. This article shows how a short strategy-oriented neuropsychological battery, the Cognitive Efficiency Profile (CEP), can contribute to the early diagnosis of Alheimer's disease. The CEP was given to 56 subjects who had been independently diagnosed as being cognitively unimpaired (N = 16), as having probable AD with mild dementia (N = 32) or as having “borderline” deterioration (N = 8). One-year follow-up showed that all the latter patients developed unequivocal dementia. There was a clear-cut separation in the test results between the controls and the probable AD cases when the scores were corrected for age and education. There was some overlap between the borderline cases and the probable AD patients but, in all cases, the corrected scores fell below those of normal controls. The usefulness of the CEP rests on the fact that it assesses the efficiency or the failure of strategies applied to a number of abilities related to cognitive efficiency. Coupled with clinical data, a good or a poor performance on the CEP strongly corroborates the diagnosis of normal cognitive functioning or of dementia in the elderly.     

Ceftriaxone pharmacokinetics in elderly subjects and penetration into epididymis

In a prospective study, the epididymal penetration of ceftriaxone was evaluated in order to use it in the treatment of orchi-epididymitis in men. A bolus intravenous dose of 1 g of ceftriaxone was administered to 15 patients hospitalized for surgery as part of treatment for prostatic adenoma or prostatic cancer. Nine successive blood samples were collected in the interval from 0 to 24 h after administration, and epididymis samples were taken 0.75 h after administration. Concentrations of drug in all samples were assayed by a reverse-phase-ion pairing high-performance liquid chromatography method with UV detection. The results showed that the pharmacokinetics of ceftriaxone in serum did not differ from those determined previously in healthy volunteers. The terminal half-life was 6.9 ± 1.7 h, and the mean residence time 9.5 ±2.3 h. The volume of distribution was 0.144 ± 0.018 1 kg^?1 and the total body clearance 1.17 ± 0.29 1 h^?1. The concentrations in tissue reached 27.2 ± 6μg g^?1 in right epididymis, and 25.4 ± 6.2 μg g^?1 in left epididymis. The tissue-versus-serum concentration ratios ranged from 0.175 to 0.545 (mean value, 0.295 ± 0.099). The concentrations in serum and tissue observed in this study were in excess of the MICs for bacteria considered to be susceptible to ceftriaxone, particularly Neisseria gonorrhea and coliform bacteria.     

Prevalence of raynaud phenomenon in the adult population of South Carolina

A prevalence estimate for Raynaud phenomenon among adult residents of South Carolina was based on data obtained from respondents in a statewide health survey, followed by face-to-face interviews and clinical screening for Raynaud phenomenon, using a screening procedure developed by the authors. The survey obtained 5246 personal interviews from a probability sample of over 3000 households, and 494 survey subjects participated in the clinical screening. The prevalence estimates and their standard errors were computed using survey case weights, design-based estimation, and logistic modelling techniques.

The prevalence of Raynaud phenomenon among adult residents of South Carolina was determined to be 3.5%, with a standard error of 0.6%. Prevalence was higher for females (4.3%, SE = 0.7%) than for males (2.7%, SE = 0.6%), These figures are much lower than most estimates in the existing literature on Raynaud phenomenon.     

Quality of Life Assessment in Psychiatry: The Subjective Quality of Life Profile (SQLP) -- First Results of a New Instrument

This article describes early results of a newinstrument for measuring quality of life -- the FrenchSubjective Quality of Life Profile (SQLP) questionnaire.This 36-item, self-administered questionnaire has been previously validated in a large samplepopulation with somatic disorders. It is characterizedby its multidimensional pattern and subjective approach(i.e., the degree of satisfaction with various domains of life, the degree of changeanticipated and the importance attributed to thesedomains). The SQLP was tested with three psychiatricpatient samples: people with depression, psychosis orsubstance abuse. Preliminary findings indicate that thequestionnaire is useful in describing psychiatricpatients, their characteristics, and explaining some oftheir changes.     

Aprotinin Decreases Blood Loss and Homologous Transfusions in Patients Undergoing Major Orthopedic Surgery

Background: Major orthopedic surgery can be associated with dramatic blood loss, thereby requiring high-volume homologous transfusions in patients unable to benefit from blood salvage techniques. The effect of aprotinin on blood loss and transfusion requirements during orthopedic surgery for either the resection of malignancies of the removal of infected hardware was prospectively studied.

Methods: Twenty-three patients scheduled for orthopedic surgery of the hip, femur, or pelvis for sepsis or malignant tumors, all under general anesthesia, were randomly allocated to receive during operation, in a blinded manner, either aprotinin administered as a bolus of 1.10 sup 6 kallikrein inactivation units (KIU) followed by an infusion of 5 x 105 KIU/h, or the equivalent volume of saline. The anesthesia and perioperative management, as well as the designated transfusion criteria, were standardized. The total blood loss of each patient was evaluated using intraoperative suction losses, sponge weights, and postoperative volumetric drainage. Homologous transfusion requirements were noted. Hemoglobin and hematocrit measures, as well as coagulation and fibrinolytic pathway explorations, were performed before and after surgery. Deep venous thrombosis prophylaxis was applied, and the incidence of this complication was assessed.

Results: Twelve patients received aprotinin. Aprotinin reduced the total blood loss from a median of 5,305 ml (range, 3,000-9,770 ml) to a median of 1,783 ml (range, 1,140-4,955 ml; P < 0.05). A blood loss reduction of 56% during surgery and 68% on discharge from the postanesthesia care unit was observed. Seven units (range, 4-16) of packed erythrocytes were transfused per patient in the placebo group, and 3 (range, 2-5) were transfused in the aprotinin group (P < 0.05). In the aprotinin group, platelet counts were higher, and postoperative prothrombin times and D. Dimer values were lower. The activated partial thromboplastin time values showed no significant difference between the two groups. No side effects were observed in the aprotinin group. A deep venous thrombosis developed in one patient in the placebo group.