Vesicular uptake of eosinophil peroxidase by guinea pig basophils and by cloned mouse mast cells and granule-containing lymphoid cells.

Guinea pig basophils, cloned mouse mast cells, and cloned mouse granule-containing lymphoid cells were found to utilize a vesicular transport system to internalize eosinophil peroxidase (EPO) added in vitro. Kinetic analysis indicated that EPO internalization involved the binding of EPO to the plasma membrane, the formation of complex surface invaginations, and the movement of EPO-laden vesicles, tubules, and vacuoles toward the center of the cells. EPO became associated with multivesicular bodies in granule-containing lymphoid cells and mast cells, with immature granules in mast cells, and with mature granules in basophils. In other cells, the endogenous production of granule peroxidases (neutrophils and eosinophils) or the prior uptake of exogenous peroxidatic substances (some basophils) precluded cytochemical analysis of granules for EPO. Vesicular transport of EPO provides a possible explanation for the variable detection of peroxidase activity in mast cells or basophils. It also provides a mechanism for sequestration of this potentially toxic material or for its storage for possible future use.     

Junior doctors and management: myth and reality

Uses an empirical investigation based on a survey of junior doctors in five NHS trust hospitals, to examine their attitudes towards both the general principle of clinical involvement in hospital management and the particular prospect of exercising such a role themselves. Finds that junior doctors, with few exceptions and irrespective of grade, were very positive towards clinical management roles in NHS trusts and were almost universally keen to assume management responsibilities when they were more senior. At the same time, finds junior doctors to have little concept of the doctor manager role or the recognized and demanded specific preparation for assuming management responsibilities.     

Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles

Small-molecule antimicrobial peptidomimetic amphiphiles represent a promising class of novel antimicrobials with the potential for widespread therapeutic application. To investigate the role of spatial positioning for key hydrophobic and hydrophilic groups on the antimicrobial efficacy and selectivity, positional isomers of the lead biphenyl antimicrobial peptidomimetic compound 1 were synthesized and subjected to microbial growth inhibition and mammalian toxicity assays. Positional isomer 4 exhibited 4–8× increased efficacy against the pathogenic Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli (MIC = 2 μg/mL), while isomers 2, 3, and 7 exhibited a 4× increase in activity against Acinetobacter baumannii (MIC = 4 μg/mL). Changes in molecular shape had a significant impact on Gram-negative antibacterial efficacy and the resultant spectrum of activity, whereas all structural isomers exhibited significant efficacy (MIC = 0.25–8 μg/mL) against Gram-positive bacterial pathogens (e.g., methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis).     

Myocardial infarction as a presentation of clinical in-stent restenosis.

BACKGROUND: In-stent restenosis is considered to be a gradual and progressive condition and there is scant data on myocardial infarction (MI) as a clinical presentation. METHODS AND RESULTS: Of 2,462 consecutive patients who underwent percutaneous coronary intervention between June 2001 and December 2002, clinical in-stent restenosis occurred in 212 (8.6%), who were classified into 3 groups: ST elevation MI (STEMI), non-ST elevation MI (NSTEMI) and non-MI. Of the 212 patients presenting with clinical in-stent restenosis, 22 (10.4%) had MI (creatine kinase (CK)>or=2xbaseline with elevated CKMB). The remaining 190 (89.6%) patients had stable angina or evidence of ischemia by stress test without elevation of cardiac enzymes. Median interval between previous intervention and presentation for clinical in-stent restenosis was shorter for patients with MI than for non-MI patients (STEMI, 90 days; NSTEMI, 79 days; non-MI, 125 days; p=0.07). Diffuse in-stent restenosis was more frequent in MI patients than in non-MI patients (72.7% vs 56.3%; p<0.005). Renal failure was more prevalent in patients with MI than in those without MI (31.8% vs 6.3%, p=0.001). Compared with the non-MI group, patients with MI were more likely to have acute coronary syndromes at the time of index procedure (81.8% vs 56.8%, p=0.02). CONCLUSION: Clinical in-stent restenosis can frequently present as MI and such patients are more likely to have an aggressive angiographic pattern of restenosis. Renal failure and acute coronary syndromes at the initial procedure are associated with MI.     

Predictors of Initiation and Engagement of Cognitive Processing Therapy Among Veterans With PTSD Enrolled in Collaborative Care

Collaborative care (CC) increases access to evidence‐based pharmacotherapy and psychotherapy. The study aim was to identify the characteristics of rural veterans receiving a telemedicine‐based CC intervention for posttraumatic stress disorder (PTSD) who initiated and engaged in cognitive processing therapy (CPT) delivered via interactive video. Veterans diagnosed with PTSD were recruited from 11 community‐based outpatient clinics (N = 133). Chart abstraction identified all mental health encounters received during the 12‐month study. General linear mixed models were used to identify characteristics that predicted CPT initiation and engagement (attendance at 8 or more sessions). For initiation, higher PTSD severity according to the Clinician Administered PTSD Scale (d = ?0.39, p = .038) and opt‐out recruitment (vs. self‐referral; d = ?0.49, p = .010) were negative predictors. For engagement, major depression (d = ?1.32, p = .006) was a negative predictor whereas a pending claim for military service connected disability (d = 2.02, p = .008) was a positive predictor. In general, veterans enrolled in CC initiated and engaged in CPT at higher rates than usual care. Those with more severe symptoms and comorbidity, however, were at risk of not starting or completing CPT.     

Assessing the risk of epidemic dropsy from black salve use

Epidemic dropsy is a potentially life‐threatening condition resulting from the ingestion of argemone oil derived from the seeds of Argemone mexicana Linn. Exposure to argemone oil is usually inadvertent, arising from mustard cooking oil adulteration. Sanguinarine, an alkaloid present in argemone oil, has been postulated as a causative agent with the severity of epidemic dropsy correlating with plasma sanguinarine levels. Cases of epidemic dropsy have also been reported following the topical application of argemone containing massage oil. Black salve, a topical skin cancer therapy also contains sanguinarine, but at significantly higher concentrations than that reported for contaminated massage oil. Although not reported to date, a theoretical risk therefore exists of black salve inducing epidemic dropsy. This literature review explores the presentation and pathophysiology of epidemic dropsy and assesses the risk of it being induced by black salve.     

Depression-free day to utility-weighted score: is it valid?

BACKGROUND: Cost-utility analyses using formulas to convert depression-free days (DFDs) to utility-weighted scores are increasingly common. These formulas are based on linear extrapolation of data documenting the correlation between depression symptom severity and generic health-related quality of life. OBJECTIVE: We sought to examine the validity of formulas converting DFDs to utility weights. METHODS: We undertook an observational study with data collection at baseline, 1 week and 1, 3, 6, 9, and 12 months on 77 subjects (42 inpatient, 35 outpatient) diagnosed with current major depression. Subjects were divided into treatment response categories based on changes in depression severity. Depression severity measures used were the Hamilton Rating Scale for Depression (HAM-17) and Beck Depression Inventory (BDI) and the health-related quality of life measure was the self-administered Quality of Well-Being scale (QWB-SA). DFD calculations were based on depression severity scores and converted to utility weights using available formulas. Utility-weighted data collected over the course of 1 year were used to estimate quality-adjusted life years (QALYs). RESULTS: QALYs estimated from the QWB-SA were significantly lower than those based on utility-weighted DFD calculations but the incremental QALYs were not significantly different. Using a slightly lower utility-weighted conversion factor for the BDI or a larger BDI severity range to calculate DFDs resulted in a better fit compared with the QWB-SA. CONCLUSIONS: Our results support the validity of the existing HAM-17 utility-weighted formula and suggest modifications for the BDI formula. If generic health-related quality of life measures are not available for conducting cost-utility analyses of depression interventions then the existing HAM-17 and modified BDI formulas appear to be reasonable alternatives.     

Reversal of Human Multi‐Drug Resistance Leukaemic Cells by Stemofoline Derivatives via Inhibition of P‐Glycoprotein Function

Our previous study reported multi‐drug resistance (MDR) reversing properties of synthetic stemofoline derivatives (STFD), OH‐A1, NH‐B6 and NH‐D6 on P‐glycoprotein (P‐gp) overexpressing leukaemic cells (K562/Adr); however, the mechanism was unclear. In this study, we further investigated whether the STFD reverse MDR through either the inhibition of P‐gp function or expression in K562/Adr cells, or both. The P‐gp functional studies showed that the STFD increased the accumulation of calcein‐AM, rhodamine 123 and [¹⁴C]‐doxorubicin in K562/Adr cells, while the effects have not been seen in their parental sensitive cancer cell line (K562). Further, the STFD did not alter the P‐gp expression as determined by Western blotting. This study concludes that the STFD reverse MDR via the inhibition of P‐gp function. The efficacy of the STFD to inhibit P‐gp function followed the order: NH‐B6 >  OH‐A1 >  NH‐D6. These compounds could be introduced as candidate molecules for treating cancers exhibiting P‐gp‐mediated MDR.