Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease

BACKGROUND: 6-Thioguanine-nucleotides seem to be the active metabolites of thiopurine therapy, and their monitoring has been considered a useful tool for optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine) therapy results in much higher levels of 6-thioguanine-nucleotide levels when compared with azathioprine or mercaptopurine. AIM: To elucidate the influence of 6-thioguanine-nucleotide and methylated 6-thioguanine-nucleotide levels under tioguanine on efficacy and toxicity in Crohn's disease. METHODS: 6-Thioguanine-nucleotide and methylated 6-tioguanine-nucleotide levels were measured regularly in 26 Crohn's disease patients treated with tioguanine. Nucleotide levels were related to efficacy and toxicity. RESULTS: 6-Thioguanine-nucleotide levels rose very high [median 1241 pmol/8 x 10(8) red blood cells (range 313-1853)]. Methylated 6-thioguanine-nucleotide levels were detected in all patients [491 pmol/8 x 10(8) red blood cells (154-1775)]. 6-Thioguanine-nucleotide and methylated 6-thioguanine-nucleotide concentrations correlated significantly (r = 0.7, P < 0.0001). Nucleotide levels from patients achieving remission (n = 14) did not differ significantly from non-remitters (n = 12) [6-thioguanine-nucleotide: 1077 (599-2160) vs. 1210 (534-4665); methylated 6-thioguanine-nucleotide: 510 (214-1222) vs. 421 (145-1284)]. One patient with intermediate thiopurine S-methyltransferase activity experienced bone marrow toxicity upon dose escalation parallel with excessively high thioguanine-nucleotide levels. CONCLUSIONS: 6-Thioguanine-nucleotide as well as methylated 6-thioguanine-nucleotide levels under tioguanine therapy were not related to efficacy. This suggests that monitoring of 6-thioguanine-nucleotide levels is not a useful tool to predict response to thiopurines.     

6-thioguanine--efficacy and safety in chronic active Crohn's disease

BACKGROUND: : Azathioprine and mercaptopurine are commonly used in chronic active Crohn's disease. They share the disadvantage of a delayed onset of action and potentially serious side-effects, and are metabolized to thioguanine nucleotides which are thought to be the active metabolites. The direct use of 6-thioguanine may offer a more rapid and safer alternative. We conducted an open prospective study to investigate the efficacy and safety of 6-thioguanine in chronic active Crohn's disease. METHODS: : Thirty-seven patients with chronic active Crohn's disease and a Crohn's disease activity index of > 150 were enrolled in this study. Inclusion criteria were steroid dependence (n = 19), steroid refractoriness (n = 9) and/or intolerance (n = 16) or refractoriness (n = 6) to azathioprine. Patients were treated with 40 mg/day of 6-thioguanine for 24 weeks; a dose escalation to 80 mg was allowed at week 12. Remission was defined as a Crohn's disease activity index of < 150 associated with a decrease of > 70 points; response was defined as a decrease of > 70 points in the Crohn's disease activity index. RESULTS: : In the intention-to-treat analysis, 13 of 37 patients achieved remission (35%). Twelve of these 13 patients achieved remission after 4 weeks. Fifty-seven per cent of patients (21/37) achieved a response. The mean Crohn's disease activity index decreased from 284 +/- 74 to 153 +/- 101. 6-Thioguanine was more effective in azathioprine-intolerant than in azathioprine-refractory patients. Twelve of 16 patients intolerant to azathioprine tolerated 6-thioguanine. Adverse events included phototoxicity, pancreatitis, headache, nausea, alopecia, arthralgia, minor infections and reversible elevation of transaminases. Six patients required discontinuation of medication, two because of leucopenia. CONCLUSIONS: : In this patient group with chronic active Crohn's disease, 6-thioguanine appeared to be effective with acceptable short-term toxicity, but long-term controlled trials are clearly needed to further define its role.     

Leptin concentrations in the United States: relations with demographic and anthropometric measures

BACKGROUND: Leptin is a peptide that is strongly correlated with adiposity and is a potential determinant of obesity and its complications. OBJECTIVE: Leptin concentrations from a representative sample of the US population were examined in relation to demographic and anthropometric measures. DESIGN: Fasting serum leptin concentrations were measured in 6303 women and men aged > or =20 y in the third National Health and Nutrition Examination Survey. Anthropometric measures included body mass index, 4 skinfold thicknesses, and 4 body circumferences. Ethnic groups included non-Hispanic whites and blacks and Mexican Americans. RESULTS: The mean serum leptin concentration was much higher in women (12.7 microg/L) than in men (4.6 microg/L). In a multivariate analysis, leptin concentrations were associated with the sum of 4 skinfold thicknesses, waist and hip circumferences, ethnicity, and age. These measures explained most of the variance in leptin concentrations in women (R2 = 0.69) and in men (R2 = 0.67). Triceps skinfold thickness, when substituted for the sum of skinfold thicknesses, performed nearly as well in women (R2 = 0.68) and men (R2 = 0.67). Leptin concentrations were slightly but significantly higher in non-Hispanic blacks than in non-Hispanic whites of both sexes when these anthropometric measures and age were controlled for; Mexican Americans had concentrations that were intermediate compared with the concentrations of non-Hispanic whites and blacks. CONCLUSIONS: In this large, representative sample of the US population, demographic and anthropometric measures predicted serum leptin concentrations in women and men.     

Veiled accessory cells deduced from monocytes

Human peripheral blood monocytes were cultured under conditions which prevent macrophage development. Media containing selected charges of fetal calf serum as well as a number of serum-free and protein-free media were found to convert monocytes into homogenous populations of loosely adherent veiled cells. After one week of culture, these cells developed dendritiform elongations. Functionally, these cells acquired an increased capability of serving as accessory cells in T lymphocyte mitogenic stimulation. Phenotypically, they were strongly reduced in macrophage markers such as nonspecific esterase, phagocytosis and Fc-receptors. The majority of the population was even negative for these markers. It thus appears that highly active accessory cells, which closely approach the phenotype of lymphoid dendritic cells, could be deduced from monocytes. These accessory cells could be maintained in culture for several weeks without proliferation and without converting to macrophages. They could further be induced to differentiate to macrophages by an activity present in human serum. Ontogenetically, the accessory state as described here is a differentiation stage preceding macrophage differentiation. When macrophages differentiate from monocytes, they have to pass the transient stage of increased accessory activity.     

Unipedal stance testing as an indicator of fall risk among older outpatients

OBJECTIVE: To test the hypothesis that a decreased unipedal stance time (UST) is associated with a history of falling among older persons. DESIGN: Fifty-three subjects underwent a standardized history and physical examination and three trials of timed unipedal stance. SETTING: The electroneuromyography laboratories of tertiary care Veterans Administration and university hospitals. SUBJECTS: Ambulatory outpatients 50 years and older referred for electrodiagnostic studies. OUTCOME MEASURES: UST and fall histories during the previous year. RESULTS: Twenty subjects (38%) reported falling. Compared with the subjects who had not fallen, those who fell had a significantly shorter UST (9.6 [SD 11.6] vs 31.3 [SD 16.3] seconds, using the longest of the three trials, p < .00001). An abnormal UST (<30sec) was associated with an increased risk of having fallen on univariate analysis and in a regression model (odds ratio 108; 95% confidence interval 3.8, >100; p < .007). The sensitivity of an abnormal UST in the regression model was 91% and the specificity 75%. When UST was considered age was not a predictor of a history of falls. CONCLUSIONS: UST of <30sec in an older ambulatory outpatient population is associated with a history of falling, while a UST of > or = 30sec is associated with a low risk of falling.     

Healthcare utilization and costs in ARDS survivors: a 1-year longitudinal national US multicenter study

Purpose

To evaluate (1) post-discharge healthcare utilization and estimated costs in ARDS survivors, and (2) the association between patient and intensive care-related variables, and 6-month patient status, with subsequent hospitalization and costs.

Methods

Longitudinal cohort study enrolling from four ARDSNet trials in 44 US hospitals. Healthcare utilization was collected via structured interviews at 6 and 12 months post-ARDS, and hospital costs estimated via the Medical Expenditure Panel Survey. Adjusted odds ratios for hospitalization and adjusted relative medians for hospital costs were calculated using marginal two-part regression models.

Results

Of 859 consenting survivors, 839 (98%) reported healthcare utilization, with 52% female and a mean age of 49 years old. Over 12 months, 339 (40%) patients reported at least one post-discharge hospitalization, with median estimated hospital costs of US$18,756 (interquartile range $7852–46,174; 90th percentile $101,500). Of 16 patient baseline and ICU variables evaluated, only cardiovascular comorbidity and length of stay were associated with hospitalization, and sepsis was associated with hospital costs. At 6-month assessment, better patient-reported physical activity and quality of life status were associated with fewer hospitalizations and lower hospital costs during subsequent follow-up, and worse psychiatric symptoms were associated with increased hospitalizations.

Conclusions

This multicenter longitudinal study found that 40% of ARDS survivors reported at least one post-discharge hospitalization during 12-month follow-up. Few patient- or ICU-related variables were associated with hospitalization; however, physical, psychiatric, and quality of life measures at 6-month follow-up were associated with subsequent hospitalization. Interventions to reduce post-ARDS morbidity may be important to improve patient outcomes and reduce healthcare utilization.

     

Empathische Führung

Only leaders who succeed in creating a management culture that motivates and attracts employees will have good chances of succeeding in the increasing difficult battle for employees. This article discusses the idea of empathetic leadership and outlines several management styles which may have a positive effect on working atmosphere and performance. Furthermore, it explains how handling of emotions and attitude may influence leadership. In order to evoke a positive feedback for the manager himself, he needs to face his employees in an open-minded, appreciative way with great empathy for the employees?? situation. The model of motivational worlds supports the theses in this article. Furthermore, the manager can evoke a positive response by being a role model.     

Implications of salivary protein binding to commensal and pathogenic bacteria

An important function of salivary proteins is to interact with microorganisms that enter the oral cavity. For some microbes, these interactions promote microbial colonization. For others, these interactions are deleterious and result in the elimination of the microbe from the mouth, This paper reviews recent studies of the interaction of salivary proteins with two model bacteria; the commensal species Streptococcus gordonii, and the facultative pathogen Staphylococcus aureus. These organisms selectively interact with a variety of salivary proteins to influence important functions such as bacterial adhesion to surfaces, evasion of host defense, bacterial nutrition and metabolism and gene expression.