Combining blockers of the renin-angiotensin system or increasing the dose of an angiotensin II receptor antagonist in proteinuric patients: a randomized triple-crossover study.

Objective The goal of this study was to investigate whether increasing the dose of an angiotensin II receptor blocker (ARB) provides as much benefits as combining the ARB with an angiotensin-converting enzyme inhibitor (ACEI) in terms of blood pressure (BP) control and urinary albumin excretion (UAE) in hypertensive patients with a proteinuria.Methods We enrolled 20 hypertensive patients with proteinuric nephropathies and a reduced renal function in a randomized, 12-month, triple-crossover, prospective, open-label study to compare the effects of a regular dose of losartan (Los 100mg q.d., LOS100) vs. a high dose of losartan (Los 100mg b.i.d., LOS200) vs. losartan 100mg q.d. associated with lisinopril 20 mg q.d. (LOS100 + LIS20). Each treatment was given for 8 weeks with a 4-week initial run-in period and 2 weeks of washout between each treatment phases. 24 h UAE and ambulatory BP were measured during the running phase and at the end of each treatment period.Results Compared to pretreatment, 24 h SBP and DBP were reduced by 10/5 +/- 7/4 mmHg with LOS100 (P=0.023 vs. baseline) and, respectively, 13/6 +/- 12/5 mmHg with LOS200 (P=0.011) and 19/9 +/- 15/8 mmHg with LOS100+LIS20 (P < 0.01). UAE decreased significantly with LOS100 and to an even greater degree with LOS200 and LOS100+LIS20 (P < 0.01 vs. baseline for both and P=0.032, LOS100+LIS20 vs. LOS200). The combination had a greater impact in patients with a high baseline proteinuria as suggested by a nonparallel leftward shift of the relationship between the changes in UAE induced by the combination and those induced by LOS200. The high dose of losartan was better tolerated than the combination.Conclusion Increasing the dose of losartan from 100mg once daily to 100mg twice a day enables to obtain a greater decrease in BP and proteinuria and is better tolerated than combining the ARB with lisinopril, though the high dose appears to be slightly less effective than the combination in patients with a marked proteinuria. J Hypertens 29: 1228-1235 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Deleterious Actions Of Vegf On The Blood Retinal Barrier And Photoreceptor Survival In The Light-damage Model

Purpose: The retinal balance between pro- and anti-angiogenic factors is critical for angiogenesis control, but is also involved in cell survival. We previously reported upregulation of VEGF and photoreceptor (PR) cell death in the Light-damage (LD) model. Preliminary results showed that anti-VEGF can rescue PR from cell death. Thus, we investigated the role of VEGF on the retina and we herein described the effect of anti-VEGF antibody delivered by lentiviral gene transfer in this model.Methods: To characterize the action of VEGF during the LD, we exposed Balb/c mice subretinally injected with LV-anti-VEGF, or not, to 5'000 lux for 1h. We next evaluated the retinal function, PR survival and protein expression (VEGF, VEGFR1/2, Src, PEDF, p38MAPK, Akt, Peripherin, SWL-opsin) after LD. We analyzed Blood retinal barrier (BRB) integrity on flat-mounted RPE and cryosections stained with β-catenin, ZO-1, N-cadherin and albumin.Results: Results indicate that the VEGF pathway is modulated after LD. LD leads to extravascular albumin leakage and BRB breakdown: β-catenin, ZO-1 and N-cadherin translocate to the cytoplasm of RPE cells showing loss of cell cohesion. This phenomenon is in adequacy with the VEGF time-course expression. Assessment of the retinal function reveals that PR rescue correlates with the level of LV-anti-VEGF expression. Rhodopsin content was higher in the LV-anti-VEGF group than in controls and measures of the ONL thickness indicate that LV-anti-VEGF preserves by 82% the outer nuclear layer from degeneration. Outer segments (OS) appeared well organized with an appropriate length in the LV-anti-VEGF group compared to controls, and the expression of SWL-opsin is maintained in the OS without being mislocalized as in the LV-GFP group. Finally, LV-anti-VEGF treatment prevents BRB breakdown and maintained RPE cell integrity.Conclusions: This study involves VEGF in LD and highlights the prime importance of the BRB integrity for PR survival. Taken together, these results show that anti-VEGF is neuroprotective in this model and maintains functional PR layer in LD-treated mice.

Neurodevelopment outcome of newborns with cerebral subependymal pseudocysts at 18 and 46 months: a prospective study.

OBJECTIVES: Subependymal pseudocysts (SEPC) are cerebral periventricular cysts located on the floor of the lateral ventricle and result from regression of the germinal matrix. They are increasingly diagnosed on neonatal cranial ultrasound. While associated pathologies are reported, information about long-term prognosis is missing, and we aimed to investigate long-term follow-up of these patients. STUDY DESIGN: Newborns diagnosed with SEPC were enrolled for follow-up. Neurodevelopment outcome was assessed at 6, 18 and 46 months of age. RESULTS: 74 newborns were recruited: we found a high rate of antenatal events (63%), premature infants (66% <37 weeks, 31% <32 weeks) and twins (30%). MRI was performed in 31 patients, and cystic periventricular leukomalacia (c-PVL) was primarily falsely diagnosed in 9 of them. Underlying disease was diagnosed in 17 patients, 8 with congenital cytomegalovirus (CMV) infection, 5 with genetic and 4 with metabolic disease. Neurological examination (NE) at birth was normal for patients with SEPCs and no underlying disease, except one. Mean Developmental Quotient and IQ of these patients was 98.2 (±9.6SD; range 77-121), 94.6 (±14.2SD; 71-120) and 99.6 (±12.3SD; 76-120) at 6, 18 and 46 months of age, respectively, with no differences between the subtypes of SEPC. A subset analysis showed no outcome differences between preterm infants with or without SEPC, or between preterm of <32 GA and ≥32 GA. CONCLUSIONS: Neurodevelopment of newborns with SEPC was normal when no underlying disease was present. This study suggests that if NE is normal at birth and congenital CMV infection can be excluded, then no further investigations are needed. Moreover, it is crucial to differentiate SEPC from c-PVL which carries a poor prognosis.

Failure to thrive in a girl born into a family affected by familial dysalbuminemic hyperthyroxinemia

Autosomal dominant familial dysalbuminemic hyperthyroxinemia (FDH)is characterized by modified human serum albumin (HSA) inducing asubstantially higher affinity for thyroxine (T4). Histidin or prolinsubstitution on residue R218 produces localized conformationalchanges of HSA creating additional room for T4 binding, leadingto 14-20 fold normal total T4 (TT4) levels. Affected individuals areconsidered euthyroid. Our patient is an 18 months-old swiss girl bornto a mother known for the rare R218P mutation in the HSA gene.She presented with severe failure to thrive (height -2.92 SD, weight-3.6 SD), habitual hip dislocation without anatomical anomaly, latefontanelle closing and protruding ears. Psychomotor development isslightly retarded. Thyroid function testing confirmed extremely high TT4(1446.0 nmol/l) levels, which are similar to her brother's values (1534.4nmol/l and 1757.6 nmol/l respectively). Free T4 seems slightly elevated(26 pmol/l), probably due to methodological reasons. TSH (0.92 mU/l),free T3 (4.4 pmol/l) and thyroxin binding globulin (32 mg/l) are withinthe normal range. Her two half-brothers, affected by the samemutation, are now 18.7 (P1) and 16.6 (P2) years old and wereoriginally described by S. Pannain et al. in 2000. Both werecharacterized by growth retardation (-2.1 and -2.2 SD) before the ageof 4 years. P1 has reached a normal adult height (-0.4 SD) and P2has caught up to normal growth (-0.68 SD) with moderate bonematuration delay. Pubertal development and anterior pituitary functionare adequate. Primary growth and developmental retardation in thefirst years of life with adequate catch-up seem to be a distinctcharacteristic in FDH with R218P mutation. Hip dislocation is typicallyseen in other situations associated to thyroid disorders, like Downsyndrome. These findings might be explained by altered early thyroidhormone utilization in children with FDH.

Biochemical traits useful for the determination of genetic variation in a natural population of Myracrodruon urundeuva

The objectives of this work were to analyze seeds from 20 trees of aroeira (Myracrodruon urundeuva Fr. All.) of a natural population located in the region of Selvíria, State of Mato Grosso do Sul, Brazil, in order to evaluate their protein, lipid and carbohydrate contents, and to estimate their genetic variation. A completely randomized experimental design consisting of 20 treatments (families) was set up, with two replications. Four types of proteins were detected: albumin (35.0 to 107.3 mg/g seed), globulin (3.4 to 9.3 mg/g), prolamin (60.0 to 135.2 mg/g) and glutelin (118.0 to 286.0 mg/g). The lipid content varied between 200 and 334 mg/g seed. The total sugars also varied (26.5 to 46.3 mg/g seed), with a predominance of polyols (arabinitol, mannitol, glucitol and xylitol). The main monosaccharides detected were glucose and arabinose. Total hydrolysis of the sugars indicated the presence of neutral arabinan and xylan oligosaccharides. The starch content varied from 0.35 to 1.58 mg/g seed. These biochemical traits showed considerable genetic variability, indicating that only the collection of seeds from many different trees can provide a representative sample of the population for conservation and genetic improvement.

Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours.

AIM: Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements. METHODS: One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates. RESULTS: A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations. CONCLUSION: Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

Increased plasma levels of N-terminal brain natriuretic peptide (NT-proBNP) in type 2 diabetic patients with vascular complications.

AIMS: The plasma levels of either brain natriuretic peptide (BNP) or the N-terminal fragment of the prohormone (NT-proBNP) have recently gained extreme importance as markers of myocardial dysfunction. Patients with type 2 diabetes are at high risk of developing cardiovascular complications. This study was aimed to assess whether plasma NT-proBNP levels are at similar levels in type 2 diabetics with or without overt cardiovascular diseases. METHODS: We assayed plasma NT-proBNP in 54 type 2 diabetics, 27 of whom had no overt macro- and/or microvascular complications, while the remaining ones had either or both. The same assay was carried out in 38 healthy control subjects age and sex matched as a group with the diabetics. RESULTS: Plasma NT-proBNP was higher in diabetics (median 121 pg/ml, interquartile range 50-240 pg/ml, ) than in those without complications (37 pg/ml, 21-54 pg/ml, P<0.01). Compared with the controls (55 pg/ml, 40-79 pg/ml), only diabetics with vascular complications had significantly increased plasma NT-proBNP levels (P<0.001). In the diabetics, coronary heart disease and nephropathy (defined according to urinary excretion of albumin) were each independently associated with elevated values of plasma NT-proBNP. CONCLUSIONS: In type 2 diabetes mellitus, patients with macro- and/or micro-vascular complications exhibit an elevation of plasma NT-proBNP levels compared to corresponding patients with no evidence of vascular disease. The excessive secretion of this peptide is independently associated with coronary artery disease and overt nephropathy. The measurement of circulating NT-proBNP concentration may therefore be useful to screen for the presence of macro- and/or microvascular disease.

Free and total plasma levels of lopinavir during pregnancy, at delivery and postpartum: implications for dosage adjustments in pregnant women.

BACKGROUND: Physiological changes associated with pregnancy may alter antiretroviral plasma concentrations and might jeopardize prevention of mother-to-child HIV transmission. Lopinavir is one of the protease inhibitors more frequently prescribed during pregnancy in Europe. We described the free and total pharmacokinetics of lopinavir in HIV-infected pregnant and non-pregnant women, and evaluated whether significant alterations in its disposition and protein binding warrant systematic dosage adjustment. METHODS: Plasma samples were collected at first, second and third trimester of pregnancy, at delivery, in umbilical cord and postpartum. Lopinavir free and total plasma concentrations were measured by HPLC-MS/MS. Bayesian calculations were used to extrapolate total concentrations to trough (Cmin). RESULTS: A total of 42 HIV-positive pregnant women and 37 non-pregnant women on lopinavir/ritonavir were included in the study. Compared to postpartum and control values, total lopinavir Cmin was decreased moderately (31-39%) during pregnancy, and free Cmin minimally, showing significant alteration only at delivery (-35%). However, total and free Cmin remained in all patients above the target concentrations for wild-type virus of 1,000 ng/ml, and above the unbound IC50(WT) of 0.64-0.77 ng/ml of lopinavir, respectively. Lopinavir free fractions remained higher during pregnancy compared to postpartum and controls, and were influenced by α-1-acid-glycoprotein and albumin decrease. Free cord-to-mother ratio (0.43) was 2.7-fold higher than total cord-to-mother ratio (0.16), suggesting higher fetal exposure. CONCLUSIONS: The moderate decrease of total lopinavir concentrations during pregnancy is not associated with proportional decrease in free concentrations. Both reach a nadir at delivery, albeit not to an extent that would put treatment-naive women at risk of insufficient exposure to the free, pharmacologically active concentrations of lopinavir. No dosage adjustment is therefore needed during pregnancy as it is unlikely to further enhance treatment efficacy but could potentially increase the risk of maternal and fetal toxicity. Nonetheless, in case of viral resistance in treatment-experienced pregnant women, loss of virological control or questionable adherence, it is justified to consider lopinavir dosage adjustment based on total plasma concentration measurement.

Correlations between negative-induced cerebral dynamics and idiopathic intellectual disability: an EEG study

Intellectual disability has long been associated with deficits in socio-emotional processing. However, studies investigating brain dynamics of maladaptive socio-emotional skills associated with intellectual disability are scarce. Here, we compared differences in brain activity between low intelligence quotient (I.Q.<75, N=13) and normal controls (N=15) while evaluating their subjective emotions. Positive (P) and negative (N) valenced pictures were presented one at a time to participants of both groups, at a rate of ¾. The task required that each participant evaluate their subjective emotion and press a predefined push-button when done, alternatively P and N. Electroencephalographic (EEG) signals were continuously recorded, and the 1000ms time window following each picture was analyzed offline for power in frequency domain. Alpha low (8-10Hz) and upper (10-13Hz) frequency bands were then compared for both groups and for both P and N emotions in 12 distributed scalp electrodes. The qualitative evaluation of emotions was similar between both groups, with constant longer reaction times for the low IQ participants. The EEG signal comparison shows marked power decrease in upper alpha frequency range for N emotions in low intelligence group. Otherwise no significant difference was noticed between low and normal IQ. Main findings of the present study are (1) results do not support the hypothesis that impairment in developmental intelligence roots in maladaptive emotional processing; (2) the strong alpha power suppression during negative-induced emotions suggests the involvement of an extended neural network and more effortful inhibition processes than positive ones. We call for further studies with a larger sample.

Chemotherapy in patients with advanced pancreatic cancer: too close to death?

PURPOSE: We evaluated the attitude in using chemotherapy near the end of life in advanced pancreatic adenocarcinoma (PAC). Clinical and laboratory parameters recorded at last chemotherapy administration were analyzed, in order to identify risk factors for imminent death. METHODS: Retrospective analysis of patients who underwent at least one line of palliative chemotherapy was made. Data concerning chemotherapy (regimens, lines, and date of last administration) were collected. Clinical and laboratory factors recorded at last chemotherapy administration were: performance status, presence of ascites, hemoglobin, white blood cell (WBC), platelets, total bilirubin, albumin, LDH, C-reactive protein (C-rp), and Ca 19.9. RESULTS: We analyzed 231 patients: males/females, 53/47 %; metastatic/locally advanced disease, 80/20 %; and median age, 66 years (range 32-85). All patients died due to disease progression. Median overall survival was 6.1 months (95 % CI 5.1-7.2). At the last chemotherapy delivery, performance status was 0-1 in 37 % and 2 in 63 %. Fifty-nine percent of patients received one chemotherapy line, while 32, 8, and 1 % had second-, third-, and fourth line, respectively. The interval between last chemotherapy administration and death was <4 weeks in 24 %, ≥4-12 in 47 %, and >12 in 29 %. Median survival from last chemotherapy to death was 7.5 weeks (95 % CI 6.7-8.4). In a univariate analysis, ascites, elevated WBC, bilirubin, LDH, C-rp and Ca 19.9, and reduced albumin were found to predict shorter survival; however, none of them remained significant in a multivariate analysis. CONCLUSIONS: A significant proportion of patients with advanced PAC received chemotherapy within the last month of life. The clinical and laboratory parameters recorded at last chemotherapy delivery did not predict shorter survival.

Plasmaferese : veilig bij een goede indicatiestelling en kennis van de complicaties [Plasmapheresis, a safe treatment when applied to the correct indication and with awareness of the complications]

Plasmapheresis is an extracorporeal technique used to remove pathogenic macromolecules from the circulation, particularly autoantibodies. This is illustrated in 2 female patients. The first patient, aged 61 years, was treated successfully with non-selective plasmapheresis for acute humoral rejection shortly after receiving a renal allograft. In the second patient, aged 82 years, plasmapheresis for refractory myasthenia gravis had to be stopped because of bradycardia and hypotension during the procedure. She was treated successfully with immunoglobulins. Plasmapheresis is used to treat neurological, renal, haematological and systemic disorders. In nonselective plasmapheresis, the plasma is replaced with saline and albumin or donor plasma. In selective plasmapheresis a highly selective filter is used to remove a specific, pathogenic macromolecule. Adverse effects of the treatment include disturbances of the acid-base equilibrium or the coagulation, and allergic reactions. Most of these complications, however, can nowadays be avoided.

Recuerdos de Buenos-Ayres

Collectionneur : Sirot, Georges (1898-1977)

A propos des "small area variations": opérations pour fracture de hanche dans le canton de Vaud. [Small area variations: surgery for hip fractures in the canton of Vaud].

OBJECTIVES: Studies of small area variations of health care utilization are more and more frequent. Such variations are often considered to be an indication of variations in the quality of medical care. The variations in the rate of operations for hip fractures are among the lowest studied to date, due to the fact that a consensus exists concerning this surgery. Our objective is to examine these variations within the context of relatively small and heterogeneous districts. METHOD: Based on anonymous computerized data on public hospital stays, this study describes the variations in population rates (crude and standardized) of operations for hip fracture among the health districts of the Canton of Vaud for the period from 1986 to 1991. District populations vary from 22,000 to 164,000. Using the extremal quotient (EQ), the importance of these variations was determined. RESULTS: The study population consists of 2363 cases, of which 78% are women. Mean age is 80.4 for women and 70.6 for men. Standardized rates of operation for hip fracture per 100,000 in the Canton Vaud for the years 1986 to 1991 are, respectively: 56; 67; 86; 91; 89 and 94. The EQ for the years 1986 to 1991 are respectively: 8.2; 4.0; 3.5; 2.7; 1.9 and 1.9. The high EQ, especially for the earlier years, are contrary to the initial premise of absence of variation. The progressive implementation in the Canton Vaud of VESKA medical statistics could play a role, as could the small size of many of the districts, with resultant instability of rates. CONCLUSIONS: Considering the wide variations shown here for an operation hardly regarded as subject to variations, it is important to exercise caution in interpreting published data of small area variations.

Cerebrospinal fluid soluble amyloid-β protein precursor as a potential novel biomarkers of Alzheimer's disease.

In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± 34.3, p < 0.05) group. There was no difference between the control and the MCI-O groups (p = 0.94). Similarly, sAβPPβ concentrations in the AD group (160.2 ± 54.3) were significantly higher than in the control group (129.9 ± 44.6, p < 0.005) but did not differ from the MCI-AD group (184.0 ± 56.4, p = 0.20). The MCI-AD group differed significantly from the MCI-O (127.8 ± 46.2, p < 0.05) group. There was no difference between the control and the MCI-O groups (p > 0.99). We observed highly significant correlation of the two sAβPP forms. Age and the CSF-serum albumin ratio were significant albeit weak predictors of the sAβPPα and sAβPPβ concentrations, while carrying the APOEε4 allele did not influenced the levels of the sAβPP forms. Taken together, the results strongly suggest that CSF sAβPP concentrations may be considered as an extension of already available NDD tools.

Hematological, biochemical and ruminant parameters for diagnosis of left displacement of the abomasum in dairy cows from Southern Brazil

The objective of this work was to evaluate hematological, biochemical and ruminant parameters for diagnosis and treatment of the left displaced abomasum (LDA) in dairy cows, in the Plateau Region of Rio Grande do Sul, Brazil. Ruminant fluid, blood and urine samples were collected from 20 cows suffering LDA and from 20 healthy cows (control). The cows with LDA showed lower values of daily milk production, body weight and corporal condition score. The use of pH reagent strips showed to be functional in the field, when compared to a digital pH meter. Ruminant dynamics was damaged in cows affected by LDA, as it was evidenced by the higher reduction time of methylene blue. Serum values of lactate, beta-hydroxybutyrate, urea, albumin, free fatty acids and cholesterol shows to be auxiliary tools in the LDA characterization.