Increased cortisol metabolites and reduced activity of 11β-hydroxysteroid dehydrogenase in patients on hemodialysis.
Patients with renal failure have symptoms assumed to be attributable to the ...accumulation of toxic endo- or xenobiotics. Most of these molecules, especially those with a molecular weight>300 D, have not been identified. In addition to excretion, the kidney is involved in some defined metabolic processes. In the cortical collecting duct, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) interconverts cortisol (F) and cortisone (E), and the metabolites of these glucocorticoids, tetrahydrocortisol (THF), 5α-tetrahydrocortisol (5α-THF) and tetrahydrocortisone (THE), are excreted in urine. We hypothesized that first, these metabolites accumulate and second, their concentration pattern changes in patients on hemodialysis.
THF, 5α-THF, THE, F and E were measured in plasma of 63 patients on dialysis and in 34 healthy controls by gas-chromatography-mass spectrometry (GC/MS). In 11 patients, the metabolite clearance was determined during high flux hemodialysis by using a population pharmacokinetic approach.
Mean plasma concentrations of THF, 5α-THF and THE were more than five times higher and those of E lower in patients than in controls. The ratios of (THF + 5α-THF)/THE and F/E were increased in patients, indicating a reduced activity of 11β-HSD2. Intradialytic clearances were between 120 and 300mL/min and not sufficient to normalize the steroid concentrations.
Patients on hemodialysis exhibit pronounced increases in THF, 5α-THF and THE concentrations in plasma with insufficient removal during dialysis. Due to a reduced 11β-HSD2 activity, an abnormal pattern of the concentrations of these cortisol and cortisone metabolites is observed. Since many signs and symptoms in uremic patients resemble those observed in subjects with glucocorticoid excess, the clinical relevance of the high concentrations of these glucocorticoid metabolites deserves further investigation.
MRI can demonstrate subtle morphological changes of the right ventricle in patients with idiopathic right ventricular outflow tract tachycardia (RVOT). The present study examines the incidence and ...significance of right ventricular (RV) abnormalities detected by MRI with respect to the site of successful radiofrequency catheter ablation of the clinical tachycardia.
The study population comprised 20 patients (mean age, 40+/-12 years) undergoing elimination of recurrent RVOT by radiofrequency catheter ablation. MRI studies were performed before ablation to assess RV volumes and function, as well as structural abnormalities of the RV myocardium. Ten healthy age- and sex-matched subjects served as control subjects. The successful ablation sites, as documented by radiographs of the catheter position, were compared with MRI findings. Patients with RVOT showed no difference in respect to RV volumes and ejection fractions compared with control subjects. Whereas RV abnormalities were limited to prominent fatty deposits of the right atrioventricular groove extending into the inlet portion of the RV wall in 2 of 10 control subjects, MRI studies demonstrated morphological changes of the RV free wall in 13 (65%) of 20 patients with RVOT, including presence of fatty tissue (n=5), wall thinning (n=9), and dyskinetic wall segments (n=4). Eight of these patients had additional fat deposits, thinning, or a saccular aneurysm in the RV outflow tract, corresponding with the ablation site in 6 patients.
In RVOT, structural abnormalities of the right ventricle can be detected in a substantial number of patients despite normal RV volumes and global function. MRI abnormalities within the RV outflow tract are significantly associated with the origin of tachycardia.
Ausgangslage und Fragestellung:
Die neue Finanzierung der stationären Behandlungen mittels DRG in Schweizer Spitälern führt tendenziell zu kürzeren Aufenthalten. Ernährungsprobleme von schwerkranken ...Patienten müssen deshalb in der ambulanten Primär- oder Grundversorgung professionell (weiter-)behandelt werden. Es wird erhoben, ob dort Ernährungsprobleme bei Tumorpatienten wahrgenommen und wie diese behandelt werden. Weiter wird erfragt, ob aus Sicht von Gesundheitsfachpersonen ein Bedarf für eine wohnortnahe Ernährungsberatung vorliegt.
Methode:
Mittels Umfrage und selektiven Interviews wird die Art und Weise sowie der Bedarf der Ernährungsunterstützung durch spitalexterne Pflegefachpersonen und niedergelassene Ärzten/Ärztinnen in der ambulanten Grundversorgung bei Patienten mit einer Tumorerkrankung im Schweizer Kanton Bern erfragt.
Ergebnisse:
Die Analyse zeigt, dass die ernährungstherapeutischen Probleme mit der Mangelernährung erkannt, aber nicht systematisch mittels Screening erfasst werden. Die Befragten betreuen vor allem Tumorpatienten mit einer moderaten Mangelernährung. Ungefähr ein Viertel dieser Patienten weisen größere chronische Wunden auf. Die Ernährungstherapie beschränkt sich tendenziell auf wenige Strategien wie Ernährungstipps, Einsatz von Trinknahrung oder Organisation von Mahlzeitendienst. Bei komplexen Ernährungssituationen besteht eine Tendenz zur Einweisung ins Spital. Bezüglich Unterstützung bei enteraler Ernährung zu Hause wird das zuständige Spital oder eine Homecare-Organisation beigezogen. In gewissen Regionen gibt es die Möglichkeit der Zuweisung zur Ernährungsberatung. Die Befragten geben i.d.R. einer wohnortnahen Ernährungsunterstützung durch eine dipl. Ernährungsberater/in HF/FH den Vorzug.
Schlussfolgerungen:
Die Entwicklungen im Gesundheitswesen unterstützen eine zeitnahe und qualitativ hochstehende Behandlung. Die Gesundheitsfachpersonen sind interessiert, sich für Tumorpatienten mit einer moderaten und schweren Mangelernährung Wissen anzueignen bzw. auch eine professionelle Ernährungsberatung vor Ort zu involvieren. Es wird ein interdisziplinäres ambulantes Ernährungsteam am Spitex-Stützpunkt (spitalextere Pflegeinstitution) vor Ort sowie ein gezieltes Schulungsprogramm zur Früherkennung der Mangelernährung in der Grundversorgung vorgeschlagen.
CD8 super(+) tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity ...upon contact with cognate tumor cells. Although CD3 zeta is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLC gamma -1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56 super(lck) is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting "switch". Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56 super(lck) ( similar to 10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56 super(lck) in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56 super(lck) in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56 super(lck) activation motif (Y394), thus inhibiting effector phase functions. Cancer Res 2007; 67(23):11447-54
A rapid screening assay for chemicals inhibiting 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 or type 2 using lysates from stably transfected cells was developed. Here, we tested a series of ...environmental chemicals for anti-11β-HSD activities. Inhibition of 11β-HSD2, which may cause cortisol-dependent activation of the mineralocorticoid receptor with sodium retention and hypertension, was observed for several compounds, with diethylcarbamate being the most potent inhibitor (IC
50 6.3
μM). Abietic acid inhibited both 11β-HSD1 (IC
50 27
μM for reduction and 2.8
μM for oxidation) and 11β-HSD2 (IC
50 12
μM). Our results demonstrate for the first time that flavanone selectively inhibits 11β-HSD1 reductase activity: this enzyme being considered as essential for the local activation of glucocorticoids and representing a potential target for the therapeutic treatment of diabetes type 2. Flavanone and 2′-hydroxyflavanone efficiently inhibited reductive (IC
50 18 and 10
μM) but not oxidative activity. We observed a reduced inhibitory effect of hydroxylated flavanone derivatives and of flavones containing a double-bond between atom C2 and C3. Flavanone was specific for 11β-HSD1 and did not inhibit 11β-HSD2. Our results reveal that a variety of environmental compounds exert distinct inhibitory effects on 11β-HSD1 and 11β-HSD2, opening the possibility for selectively modulating local cortisone/cortisol availability in vivo.
The concentration‐time curves of prednisolone in cerebrospinal fluid (CSF) and plasma were measured following an equimolar i.v. bolus dose of prednisolone phosphate (five patients) and prednisolone ...phthalate (four patients). Independent of the prodrug administered, the value of the AUC (0.360 min) in CSF was more than three times lower than the corresponding value in plasma. The AUCs of unbound prednisolone in plasma were higher after prednisolone phosphate, than after prednisolone phthalate (68.1 +/− 15.7 vs 19.0 +/− 5.2 micrograms ml‐1 min, P less than 0.001). Similarly, the AUCs of prednisolone were higher in the CSF after prednisolone phosphate, than after prednisolone phthalate (17.6 +/− 2.8 vs 3.3 +/− 1.0 micrograms ml‐1 min, P less than 0.0001). The results indicate that the concentrations of prednisolone in CSF are much lower than the unbound concentrations in plasma and that therapeutic inequivalence should be expected when the two prodrugs are given in equimolar doses.
The anti-spirochete T cell immune response to immunization with
Borrelia burgdorferi was investigated. The cellular immune response to vaccination of immunocompetent BALB/c mice was characterized ...initially
in vitro by assay of the proliferative response of primary lymph node cells to
B. burgdorferi sonicate. Subsequently, an anti-spirochete T cell line (RBN2.1) and clone (97.1) were derived from lymph node cells of BALB/c mice primed with
B. burgdorferi antigen. Both the line and clone were CD4
+ by flow cytometric analysis. Significantly, RBN2.1 and clone 97.1 were able to transfer resistance to infection to syngeneic naive recipients. Assay of antigen-specific interleukin-2, interleukin-4, tumor necrosis factor-α, and interferon-γ production demonstrated that clone 97.1 was of the Th2 subclass. When
B. burgdorferi sonicate was fractionated on SDS--PAGE and then electroeluted, clone 97.1 was reactive exclusively to a spirochete protein of approximately 21 kDa. These data suggest that T-cell-mediated protective immunity to infection by
B. burgdorferi can be elicited by active immunization.
The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was ...designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n = 10) had higher mean (+/- SD) area under the plasma concentration versus time curves of total (428 +/- 67 micrograms/ml/min vs 188 +/- 28 micrograms/ml/min, p less than 0.001) and unbound prednisolone (64 +/- 10 micrograms/ml/min vs 41 +/- 10 micrograms/ml/min, p less than 0.001) than women not taking oral contraceptive steroids (n = 10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p less than 0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.
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