Modulation of osteopontin in proteinuria-induced renal interstitial fibrosis

Proteinuria is associated with macrophage-dependent interstitial fibrosis (IF). Osteopontin (OPN), a macrophage chemoattractant, may be involved in the transition of proteinuria to IF but protective properties have also been reported. To elucidate whether OPN may be involved in the proteinuria-induced cascade of tubulointerstitial damage, renal expression of OPN was studied during the development of proteinuria-induced renal damage and during anti-proteinuric intervention with ACE inhibition (ACEi). First, the temporal relationships between proteinuria, interstitial OPN induction, and IF in adriamycin nephrosis (AN), a model of chronic proteinuria-induced renal damage, were studied. Second, the effect of anti-proteinuric treatment on OPN expression was investigated. The time course of OPN induction and markers of renal damage was studied in rats with unilateral AN at 6-week intervals until week 30. In a second study, a renal biopsy was taken 6 weeks after induction of bilateral AN; subsequently, rats were treated with ACEi until termination (week 12). In unilateral AN, proteinuria developed gradually and stabilized at week 10. In proteinuric kidneys, OPN expression was induced from week 12 onwards. Simultaneously, a progressive increase in interstitial macrophages, alpha-smooth muscle actin (alpha-SMA), collagen type III, and focal glomerulosclerosis (FGS) was observed. In bilateral AN, ACEi reduced proteinuria and OPN protein and stabilized fibrosis. In untreated animals, OPN mRNA increased, with stable OPN protein and fibrosis and increased FGS. Thus, in AN, development of proteinuria is followed by up-regulation of OPN along with markers of renal damage. The up-regulation of OPN is reversible by anti-proteinuric treatment without a corresponding reduction in fibrosis. Whereas these data are consistent with a role for OPN in the cascade of transition from proteinuria to fibrosis, intervention with ACEi showed that reduction of OPN does not attenuate established fibrosis.     

Timing of deletion of autoreactive V{beta}6+ cells and down-modulation of either CD4 or CD8 on phenotypically distinct CD4+8+ subsets of thymocytes expressing intermediate or high levels of T cell receptor

In this paper we describe a differentiation sequence amongst adult murine thymocytes which goes from CD4+8+3lo(low) to CD4+8+3int(intermediate) to CD4+8+3hi(high) and then to mature single positive CD3hi thymocytes. Phenotypic characterization of CD4+8+3int/hi cells for a number of other surface markers is consistent with them being in transition from CD4+8+3lo phenotype to mature phenotype. The same observation was made for sensitivity towards ionomycin-mediated apoptosis. In the thymus of Mls-1a mice, where autoreactive TCR-V beta 6+ cells are negatively selected, deletion of TCR-V beta 6+ cells was first detected in the CD4+8+3int subset, and was complete by the CD4+8+3hi stage, suggesting that up-regulation of the TCR/CD3 complex is required for deletion of Mls-1a autoreactive thymocytes. No sign of apoptosis was detected among any fresh thymocyte subsets suggesting that apoptotic cells are rapidly cleared from the thymus. The CD4+8+3int/CD4+8+3hi cells are therefore populations in transit from the typical cortical thymocytes to the mature T-cells.     

Skewed T cell receptor V{alpha} repertoire among superantigen reactive murine T cells

Reactivity of murine T cells with viral or bacterial superantigensis clearly correlated with the expression of TCR V_ßdomains. Thus, T cells responding to the minor lymphocyte stimulatorylocus (Mls-1^a) or staphylococcal enterotoxin B (SEB) expresspredominantly TCR V_ß6 or V_ß8.2 respectively.We have investigated the involvement of the other major variableelement of the TCR, the V domain, in these superantigen responses.Using a panel of anti-TCR V mAbs, It is demonstrated that theTCR V repertoire among superantigen stimulated V_ß6⁺or V_ß8.2⁺ blasts (responding to Mls-1^a or SEB respectivelyin vitro) is altered in comparison with anti-CD3 stimulatedcells expressing the same V domains. Furthermore, the TCR Vrepertoire is strongly skewed in TCR V_ß8.2 transgenicmice that have undergone extensive peripheral clonal deletionafter SEB injection. These data imply that the V domain influencessuperantigen recognition by sthe TCR.     

Bilateral antegrade selective cerebral perfusion during surgery on the proximal thoracic aorta.

OBJECTIVE: To assess risk factors for hospital death and neurologic outcome after surgery on the proximal thoracic aorta using moderate hypothermic circulatory arrest and bilateral antegrade selective cerebral perfusion. METHODS: From October 1995 through June 1999, 163 patients with a mean age of 63+/-11 years underwent surgery using bilateral antegrade selective cerebral perfusion. Degenerative aneurysms (55%) and acute type A dissection (28%) were the predominant indications for operation. Forty-six (28%) operations were considered as emergency procedure. Twenty-four (15%) procedures were reoperations. RESULTS: Mean ASCP time was 48+/-20 min. Hospital mortality was 8.6% (n=14; 70% confidence limit (CL): 6.4-10.8%). Univariate risk factors for hospital mortality were acute type A dissection (P=0.003), central neurologic damage <24 h before the operation (P=0.000), preoperative hemodynamic instability (P=0.034), and rethoracotomy for any cause (P=0.036). Logistic regression analysis identified central neurologic damage <24 h (P=0.006, odds ratio 14) as an independent risk factor. Temporary neurologic damage occurred in 3.8% (n=6; 70% CL: 2.3-5.3%) of patients. Logistic regression analysis indicated preoperative hemodynamic instability (P=0.003, odds ratio 13) as an independent risk factor. Perioperative permanent central neurologic damage was reported in another 3.8% (n=6; 70% CL: 2.3-5.3%) patients. Acute type A dissection (P=0.018, odds ratio 8) and the non-use of a midline sternotomy (P=0.049, odds ratio 8) were retained as independent risk factors. CONCLUSION: Hospital mortality and perioperative neurologic complications are not significantly influenced by the duration of antegrade selective cerebral perfusion. Overall complication rate is low.     

Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial

BACKGROUND: Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels. STUDY DESIGN: Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial. SETTING & PARTICIPANTS: 34 proteinuric patients without diabetes from our outpatient renal clinic. INTERVENTION: Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet. OUTCOMES & MEASUREMENTS: Urinary excretion of KIM-1, total protein, and N-acetyl-beta-d-glucosaminidase (NAG) as a positive control for tubular injury. RESULTS: Mean baseline urine protein level was 3.8 +/- 0.4 (SE) g/d, and KIM-1 level was 1,706 +/- 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 +/- 388 ng/d; P = 0.04), losartan/high sodium (1,184 +/- 296 ng/d; P = 0.09), losartan/LS (921 +/- 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 +/- 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 +/- 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria. LIMITATIONS: Post hoc analysis. CONCLUSIONS: Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria.     

Right temporal cerebral dysfunction heralds symptoms of acute mountain sickness

Acute mountain sickness (AMS) can occur during climbs to high altitudes and may seriously disturb the behavioral and intellectual capacities of susceptible subjects. During a Himalayan expedition 32 mountaineers were examined with electroencephalography (EEG) and transcranial doppler sonography (TCD) to assess relative changes of middle cerebral artery velocity in relation to end-expiratory CO2 (EtCO2), peripheral saturation (SaO2), and symptoms of AMS. We tested the hypothesis that O2 desaturation and EtCO2 changes precede the development of AMS and result in brain dysfunction and compensatory mechanisms which can be measured by EEG and TCD, respectively. Contrary to our hypothesis, we found that subjects who later developed symptoms of AMS between 3,440 m and 5,050 m altitude exhibited an increase of slow cerebral activity in the right temporal region already at 3,440 m. Cerebral blood flow increased in these mountaineers in the right middle cerebral artery at 5,050 m. These findings indicate that regional brain dysfunction, which can be documented by EEG, heralds the appearance of clinical symptoms of AMS. Each author will disclose any financial involvement or otherwise support that may potentially bias his/her work. Received in revised form: 5 April 2006     

Preparation of advanced glycation end products in vitro.

Sir, With great interest we read the article by Chang et al. [1]on the enhancement of epithelial sodium channel mRNA expressionand protein level in renal cortical collecting duct (CCD) cellsby advanced glycation end products (AGEs). The authors showthat AGEs can increase sodium uptake in CCD cells in a     

Calculating rate and duration of distraction for deformity correction with the Ilizarov technique

Longitudinal bone lengthening with distraction histogenesis is typically carried out at a rate of 1 mm per day. Angular corrections require an adjustment of the rate of distraction according to the geometry of the external fixator relative to the bone or soft tissue being lengthened. Modeling the deformity correction construct using simple geometric principles allows calculation of both the rate of correction and the expected duration of distraction.