Calcineurin activity in tacrolimus-treated renal transplant patients early after and 5 years after transplantation

The pharmacodynamic (PD) action of tacrolimus (FK) within the T-cell is inhibition of calcineurin phosphatase (CaN). Determination of CaN activity provides us with an important PD marker. Eleven renal transplant patients treated with FK were investigated on day 14 following transplantation and 5 years later. Blood samples drawn before as well as 1, 2, 3, and 4 hours after oral intake of FK were analyzed for CaN activity and blood FK concentrations. Twenty healthy subjects had one blood sample drawn for CaN activity, which was measured as the release of (32)P from a phosphorylated peptide. Radioactivity of (32)P was quantitated by liquid scintillation counting with the results converted to units of CaN utilizing a calibration curve. On day 14, we observed significant inhibition of CaN activity at T:1, 2, and 3 compared with the predose level (P = .002; P = .015; P = .015). Furthermore, all measured CaN activities were significantly different from those observed in healthy nonmedicated subjects. In contrast, at 5 years posttransplant only the CaN activity at T:2 was significantly inhibited compared with the predose level (P = .02). Additionally, all CaN activities at this time were not significantly different from CaN activities in the healthy subjects. We were not able to demonstrate individual CaN activity profiles in the patients. The lack of CaN inhibition at 5 years after transplantation despite relevant drug concentrations, probably reflected the lower drug dose used long after transplantation. This result raises the question of whether CaN inhibition is necessary to hold graft function and whether FK possess CaN-independent mechanisms of action.     

Selective recruitment maneuvers for lobar atelectasis: effects on lung function and central hemodynamics: an experimental study in pigs

We investigated whether selective lung recruitment of a lobar collapse would improve oxygenation and lung volume as well as a general (global) lung recruitment maneuver, with fewer circulatory side effects. In 10 ventilated, anesthetized pigs, a bronchial blocker was inserted in the right lower lobe, which was selectively lavaged to create a dense lobar collapse. The pigs were randomized into two orders of lung recruitment maneuvers (40 cm H2O airway pressure for 30 s): either a selective lung recruitment maneuver (using the inner lumen of the bronchial blocker) followed by a general lung recruitment maneuver, or vice versa. Median end-expiratory lung volume and median Pao2 increased significantly by approximately 100 mL and 16 kPa, respectively, with no significant differences between the two recruitment methods. There were no circulatory changes during the selective lung recruitment maneuver, but during the general lung recruitment maneuver, mean arterial blood pressure decreased significantly by 36 (21, 41) mm Hg (median, 25th and 75th percentiles), cardiac output by 2.1 (1.6, 2.5) L/min and left ventricular end-diastolic area by 4.4 (3.5, 4.5) cm2. In conclusion, a selective recruitment maneuver improved lung function similar to a general lung recruitment maneuver but without any circulatory side effects.     

Radioimmunoassay of factor V in human plasma and platelets

Homogeneous, single-chain human factor V was used to develop a double antibody competition radioimmunoassay to measure factor V concentrations in plasma and platelets. Standard curves were constructed that allow for the detection of as little as 20 ng factor V/ml of plasma. Normal factor V concentrations range from 4 to 14 micrograms/ml of plasma with an average value of 7.0 +/- 2.0 micrograms/ml (n = 64). No correlation was observed between antigen levels and age or sex. The radioimmunoassay data are consistent with factor V clotting assays, providing freshly drawn plasma is used in the bioassay. Radioimmunoassay of washed platelets indicate that 0.63-1.93 microgram of factor V is present per 2.5 X 10(8) platelets (4612-14128 molecules of the factor V platelet). When normalized to individual hematocrits and platelet count, the data indicated that platelets contribute approximately 18%-25% of the factor V found in whole blood. In addition, two individuals with functionally deficient factor V were examined and found to be deficient in both antigen and activity.     

The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta‐analysis

Background Psoriasis vulgaris could be associated with the filaggrin null genotype since certain known susceptibility loci for psoriasis are shared with susceptibility loci for atopic dermatitis. Furthermore, filaggrin expression is lowered in psoriatic skin lesions but normally expressed in uninvolved skin. So far five relatively small patient‐based case‐control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X. Objectives To reinvestigate a possible association between psoriasis and filaggrin null mutation status by using cross‐sectional general population questionnaire data. Also, to perform a meta‐analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris. Methods Between June 2006 and May 2008, a cross‐sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18–69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4 and R501X mutations. A meta‐analysis was undertaken to investigate the relation between filaggrin gene mutations and psoriasis vulgaris. Results The prevalence of self‐reported psoriasis was 6.7% among the 3240 respondents. The prevalence of the R501X and 2282del4 filaggrin null genotypes was 9.3% in subjects who reported psoriasis and 8.0% in subjects who did not report psoriasis (OR = 1.28; 95% CI = 0.74–1.89; P = 0.78). The meta‐analysis found no association between the filaggrin null genotypes R501X and 2282del4 and psoriasis (OR = 1.04; 95% CI = 0.81–1.35). Conclusions Psoriasis was not associated with the R501X and 2282del4 filaggrin null genotypes in a general population study and in a meta‐analysis on published studies.     

Clinical and radiological outcome of medial patellofemoral ligament reconstruction with a semitendinosus autograft for patella instability

Background: Recurrent patellar instability is a common problem after dislocation. The medial patellofemoral ligament (MPFL) contributes 40–80% of the total medial restraining forces. This study assessed the clinical and radiological outcome after a follow-up of 4 years after linear MPFL reconstruction using an ipsilateral Semitendinosus tendon autograft. Study design and methods: 15 knees in 12 patients were examined with a mean of 47 months after linear reconstruction of the MPFL at a mean age of 30 years. 3 knees underwent previous surgery. 3 patients had mild trochlear dysplasia grade I or II, according to the classification of Dejour. If preoperative tibial tuberosity-trochlear groove distance (TTTG) was more than 15 mm, patients underwent additional medialisation of the tibial tuberosity (n=8) creating a similar postoperative situation for all patients. All patients were available for a postoperative evaluation, which consisted of a subjective questionnaire, the Kujala score, and the recording of potential patellar redislocation and apprehension. Patellar height and tilt was measured on plain radiographs. Postoperative CT scans were performed in patients with an additional tibial tuberosity-transfer. Results: Postoperatively, one patient reported on recurrent bilateral redislocation. Physical examination however revealed no findings. Three knees presented with persistent patellar apprehension. Thirteen knees had improved subjectively after surgery. The mean Kujala score improved significantly from 55.0 to 85.7 points. The patellar tilt decreased significantly from 11.3° to 9.2°. Four knees had patella alta preoperatively, but only two at the latest follow-up visit. Previous surgery or additional trochlear dysplasia had no influence on the clinical outcome. Conclusion: MPFL reconstruction improves clinical symptoms, reduces the patellar tilt substantially, and may correct patella alta. Additional mild trochlear dysplasia did not compromise the outcome; however, this fact needs further attention in a larger study group.