Quantitative determination of methylnaltrexone in human serum using liquid chromatography-tandem mass spectrometry

Methylnaltrexone (MNTX) is a novel peripherally acting μ-opioid antagonist that prevents peripheral side effects of opioid drugs such as constipation without affecting the analgesia. We developed a selective and sensitive assay to measure MTNX concentrations in human serum.The drug was measured after protein precipitation with perchloric acid using naltrexone as internal standard and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for detection. The chromatography was performed isocratically on a RP18 column using 25 mM ammonium acetate buffer (pH 4)/acetonitrile (90%/10%; flow rate 200 μl/min) as mobile phase. The MS/MS analysis was performed in positive ionization mode monitoring the m/z transitions 356.4/284.2 for MNTX and 342.4/324.2 for naltrexone.The method was validated according to selectivity, linearity, accuracy, precision, recovery, matrix effects and stability. The validation range for MNTX in serum was 0.5-250 ng/ml. The developed LC-MS/MS was shown to be valid and successfully applied to measure serum-concentration-time curves of MNTX in a pilot study in healthy volunteers.     

Smoking risk and the likelihood of quitting among African-American female light and heavy smokers

While African-American females are more likely to be light smokers compared to their counterparts of other racially classified social groups (RCSGs), they are more likely to carry a heavier burden of smoking-related morbidity and mortality. Thus, it is critical that African-American female light smokers are targeted to engage in smoking cessation. Research has revealed that African-American women are less likely to have a successful quit attempt following a cessation intervention than females from other RCSGs. It has been postulated that the low smoking cessation rates among African-American female light smokers may be due to the lack of appropriate psychosocioculturally tailored cessation interventions that address issues of stress and coping that explain why they smoke and continue to smoke that may differ from their heavy smoker counterparts. The purpose of this study was to ascertain whether African-American female light smokers differed from their heavy smoker counterparts on psychosociocultural stress and coping factors. Findings revealed no differences in the sociodemographic variables of age, income, education and BMI; in the psychosociocultural measures of acculturative stress, race-related stress and coping; or in the smoking characteristics of menthol smoking status, cotinine level and CYP2A6 metabolic functioning between light and heavy smokers. However, the study found that African-American female light smokers take longer to smoke their first cigarette of the day, have a lower smoking risk, are more likely to quit, and exhibit lower carbon monoxide levels than African-American female heavy smokers. The current study suggests that other than the obvious factors of greater likelihood of quitting, lower smoking risk, longer latency to smoke and lower carbon monoxide levels, specific smoking cessation programs may not need to be differentially psychosocio-culturally tailored for African-American female light smokers compared to their heavy-smoking counterparts.     

Recurrence of paroxysmal atrial fibrillation after cryoisolation of the pulmonary veins. Is a “redo” procedure using the cryoballoon useful?

Background

Pulmonary vein (PV) isolation with the cryoballoon technique is an effective and safe method to treat patients with paroxysmal atrial fibrillation (AF). However, the optimal treatment strategy for patients with recurrences after this ablation is unclear.

Aims

The aim of this single centre study was to evaluate the efficacy and safety of a “redo” procedure using the cryoballoon in this patient cohort. The secondary study objectives were to determine the rate of reconduction for individual PVs of the patients undergoing “redo” ablation and potential predictors of persistent PV isolation (PVI).

Methods

Between April 2006 and September 2009, all patients with paroxysmal AF recurrences after cryoballoon ablation a “redo” ablation with the cryoballoon was offered. PV conduction was determined and cryoapplications were performed in all reconnected PVs. Every 3 months, 7-day Holter ECG, symptom-driven transtelephonic ECG recordings, and questionnaires were collected for 12 months.

Results

Forty-seven patients underwent “redo” cryoballoon ablation. In all these patients, at least one PV with reconduction was found. Recurrent conduction was documented in 63 % of the left superior PV, 56 % of the left inferior PV, 43 % of the right superior PV, and 56 % of the right inferior PV. In 28 of the 47 patients (60 %), no AF recurrence was detectable during the 12-month follow-up (after 3 months blanking period). Rate of severe complications was low and not significantly different from that of the initial ablations.

Conclusion

“Redo” ablation using cryoballoon technology may be an effective and safe method to treat patients with recurrence of paroxysmal AF after cryoballoon PVI.     

A prospective, randomized multicenter trial comparing DoubleLayer and polyethylene stents for malignant distal common bile duct strictures

BACKGROUND AND STUDY AIMS: Endoscopic biliary stenting is an established treatment for malignant obstructive jaundice. Stent clogging continues to be a major problem with plastic stents. The aim of this study was to carry out a prospective comparison of two stents with different materials and shapes: the Olympus DoubleLayer stent (DLS; perfluoro alkoxy, without sideholes) and the standard polyethylene (PE) stent (with sideholes). PATIENTS AND METHODS: A total of 120 patients (70 women; mean age 71, range 36 - 91) with jaundice due to malignant strictures of the middle to distal third of the common bile duct were randomly assigned to receive either DLS (n = 60) or PE (n = 60) biliary stents. Patients with cholangitis, hemobilia, previous biliary drainage, hilar stricture, or ampullary cancer were excluded. RESULTS: In all, 28 DLS patients (47 %) and 17 PE stent patients (29 %) died without clinical evidence of stent occlusion after a mean of 114 and 105 days, respectively ( P < 0.05). Twenty-six DLS patients (43 %) and 38 PE stent patients (63 %) had symptoms of stent clogging after a mean of 144 and 99 days, respectively ( P < 0.05). Stent dysfunction (stent orifice impacted on the bile duct or duodenal wall, stent migration) was recorded in six DLS patients (10 %) and five PE patients (8 %) (n. s.). Kaplan-Meier analysis of DLS and PE stent clogging-free survival showed a significantly longer patency period with the DLS stents (P = 0.0005). CONCLUSIONS: These results show that DoubleLayer stents have a longer patency period than PE stents. Patients who received PE stents had a higher risk of stent occlusion (relative risk 3.05; 95 % CI, 1.57 - 5.89) before death than DLS patients.     

Epidemiology and etiology of urinary incontinence in the elderly

Urinary incontinence is an important and common health problem, whose prevalence increases with age. Often quality of life is clearly affected for persons concerned. In the group of elderly individuals (> or =60 years of age) 19.3% of women and 10.4% of men report urinary incontinence. Women most frequently describe urinary stress incontinence followed by incontinence with urge symptoms (urge incontinence, mixed incontinence). In men urinary incontinence without any symptoms of stress or urge incontinence is most common followed by incontinence with urge symptoms and stress incontinence. Urinary incontinence in the elderly is rarely due to a single reason but rather due to multiple factors. In urinary stress incontinence, a differentiation can be made between mechanical and functional problems of the sphincter mechanism caused by myogenic, neurogenic, hormonal, or iatrogenic factors as well as changes in connective tissue. In urinary incontinence with urge symptoms, geriatric detrusor function is mostly affected by neurogenic, myogenic, or urothelial factors whereas the detrusor muscle shows characteristic ultrastructural changes. In chronic urinary retention with consecutive urinary incontinence, especially in men infravesical obstruction is more often the reason than a geriatric bladder dysfunction.     

Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen

Recent work has demonstrated that following the clearance of infection a stable population of memory T cells remains present in peripheral organs and contributes to the control of secondary infections. However, little is known about how tissue-resident memory T cells behave in situ and how they encounter newly infected target cells. Here we demonstrate that antigen-specific CD8⁺ T cells that remain in skin following herpes simplex virus infection show a steady-state crawling behavior in between keratinocytes. Spatially explicit simulations of the migration of these tissue-resident memory T cells indicate that the migratory dendritic behavior of these cells allows the detection of antigen-expressing target cells in physiologically relevant time frames of minutes to hours. Furthermore, we provide direct evidence for the identification of rare antigen-expressing epithelial cells by skin-patrolling memory T cells in vivo. These data demonstrate the existence of skin patrol by memory T cells and reveal the value of this patrol in the rapid detection of renewed infections at a previously infected site.