Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Haemodynamic consequences of changing bicarbonate and calcium concentrations in haemodialysis fluids.

BACKGROUND: In a previous study we demonstrated that mild metabolic alkalosis resulting from standard bicarbonate haemodialysis induces hypotension. In this study, we have further investigated the changes in systemic haemodynamics induced by bicarbonate and calcium, using non-invasive procedures. METHODS: In a randomized controlled trial with a single-blind, crossover design, we sequentially changed the dialysate bicarbonate and calcium concentrations (between 26 and 35 mmol/l for bicarbonate and either 1.25 or 1.50 mmol/l for calcium). Twenty-one patients were enrolled for a total of 756 dialysis sessions. Systemic haemodynamics was evaluated using pulse wave analysers. Bioimpedance and BNP were used to compare the fluid status pattern. RESULTS: The haemodynamic parameters and the pre-dialysis BNP using either a high calcium or bicarbonate concentration were as follows: systolic blood pressure (+5.6 and -4.7 mmHg; P < 0.05 for both), stroke volume (+12.3 and +5.2 ml; P < 0.05 and ns), peripheral resistances (-190 and -171 dyne s cm(-5); P < 0.05 for both), central augmentation index (+1.1% and -2.9%; ns and P < 0.05) and BNP (-5 and -170 ng/l; ns and P < 0.05). The need of staff intervention was similar in all modalities. CONCLUSIONS: Both high bicarbonate and calcium concentrations in the dialysate improve the haemodynamic pattern during dialysis. Bicarbonate reduces arterial stiffness and ameliorates the heart tolerance for volume overload in the interdialytic phase, whereas calcium directly increases stroke volume. The slight hypotensive effect of alkalaemia should motivate a probative reduction of bicarbonate concentration in dialysis fluid for haemodynamic reasons, only in the event of failure of classical tools to prevent intradialytic hypotension.

Anemia and chronic kidney disease are associated with poor outcomes in heart failure patients.

BACKGROUND: Chronic kidney disease (CKD) has been linked to higher heart failure (HF) risk. Anemia is a common consequence of CKD, and recent evidence suggests that anemia is a risk factor for HF. The purpose of this study was to examine among patients with HF, the association between CKD, anemia and inhospital mortality and early readmission. METHODS: We performed a retrospective cohort study in two Swiss university hospitals. Subjects were selected based the presence of ICD-10 HF codes in 1999. We recorded demographic characteristics and risk factors for HF. CKD was defined as a serum creatinine > or = 124 956;mol/L for women and > or = 133 micromol/L for men. The main outcome measures were inhospital mortality and thirty-day readmissions. RESULTS: Among 955 eligible patients hospitalized with heart failure, 23.0% had CKD. Twenty percent and 6.1% of individuals with and without CKD, respectively, died at the hospital (p < 0.0001). Overall, after adjustment for other patient factors, creatinine and hemoglobin were associated with an increased risk of death at the hospital, and hemoglobin was related to early readmission. CONCLUSION: Both CKD and anemia are frequent among older patients with heart failure and are predictors of adverse outcomes, independent of other known risk factors for heart failure.

Balanço de água no volume de solo explorado pelo sistema radicular de uma planta de citros

A produtividade das culturas agrícolas, associada às condições climáticas e edáficas, depende da disponibilidade de água e nutrientes no solo em época e quantidades apropriadas. A falta ou excesso de água no solo são fatores limitantes ao crescimento vegetal e podem diminuir a produtividade. Portanto, estudos que levem a um melhor entendimento de como a água se comporta na zona radicular de uma cultura agrícola no campo são de importância indiscutível ao adequado manejo agrícola. O objetivo do presente trabalho foi avaliar o método do balanço de água no solo aplicado ao volume de solo explorado pelo sistema radicular de uma planta de citros, considerando cinco profundidades de solo e cinco distâncias horizontais do tronco em duas direções a partir do tronco (uma ao longo e outra perpendicular à linha de plantas) e, então, verificar a contribuição de cada uma das camadas de solo avaliadas à evapotranspiração real da planta. O experimento foi realizado num Latossolo Vermelho-Amarelo distrófico argissólico em um pomar de citros, no município de Piracicaba (SP), durante dois períodos, um seco (40 dias) e um chuvoso (37 dias). Para atender ao objetivo proposto, um conjunto de 25 tensiômetros (cinco profundidades x cinco distâncias do tronco) foi instalado ao longo da linha e um outro, idêntico, perpendicular à linha, em direção à entrelinha. A armazenagem foi calculada a partir das leituras dos dois conjuntos de 25 tensiômetros cujos potenciais mátricos determinados foram convertidos em umidades volumétricas pelas curvas de retenção da água no solo. A drenagem interna e a ascensão capilar foram estimadas a partir das leituras diárias dos tensiômetros e da função K(fim) (condutividade hidráulica em função do potencial mátrico), por meio da equação de Darcy-Buckingham. Esta função K(fim) para cada profundidade foi determinada pelo método do perfil instantâneo realizado em área adjacente. A precipitação pluvial foi medida por pluviômetro com aquisição automática de dados instalado na área. Os resultados obtidos mostraram que o método do balanço de água proposto foi adequado para avaliar quanto cada camada de solo da zona radicular da planta contribuiu para o consumo total de água (evapotranspiração real) da planta, nos dois períodos estudados. Nesse sentido, a camada de 0,00 a 0,60 m de profundidade mostrou ser a que a planta deva apresentar maior volume de raízes ativas, de acordo com sua maior contribuição ao consumo de água pela planta.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

Robust volume-targeted balanced steady-state free-precession coronary magnetic resonance angiography in a breathhold at 3.0 Tesla: a reproducibility study.

BACKGROUND: Transient balanced steady-state free-precession (bSSFP) has shown substantial promise for noninvasive assessment of coronary arteries but its utilization at 3.0 T and above has been hampered by susceptibility to field inhomogeneities that degrade image quality. The purpose of this work was to refine, implement, and test a robust, practical single-breathhold bSSFP coronary MRA sequence at 3.0 T and to test the reproducibility of the technique. METHODS: A 3D, volume-targeted, high-resolution bSSFP sequence was implemented. Localized image-based shimming was performed to minimize inhomogeneities of both the static magnetic field and the radio frequency excitation field. Fifteen healthy volunteers and three patients with coronary artery disease underwent examination with the bSSFP sequence (scan time = 20.5 ± 2.0 seconds), and acquisitions were repeated in nine subjects. The images were quantitatively analyzed using a semi-automated software tool, and the repeatability and reproducibility of measurements were determined using regression analysis and intra-class correlation coefficient (ICC), in a blinded manner. RESULTS: The 3D bSSFP sequence provided uniform, high-quality depiction of coronary arteries (n = 20). The average visible vessel length of 100.5 ± 6.3 mm and sharpness of 55 ± 2% compared favorably with earlier reported navigator-gated bSSFP and gradient echo sequences at 3.0 T. Length measurements demonstrated a highly statistically significant degree of inter-observer (r = 0.994, ICC = 0.993), intra-observer (r = 0.894, ICC = 0.896), and inter-scan concordance (r = 0.980, ICC = 0.974). Furthermore, ICC values demonstrated excellent intra-observer, inter-observer, and inter-scan agreement for vessel diameter measurements (ICC = 0.987, 0.976, and 0.961, respectively), and vessel sharpness values (ICC = 0.989, 0.938, and 0.904, respectively). CONCLUSIONS: The 3D bSSFP acquisition, using a state-of-the-art MR scanner equipped with recently available technologies such as multi-transmit, 32-channel cardiac coil, and localized B0 and B1+ shimming, allows accelerated and reproducible multi-segment assessment of the major coronary arteries at 3.0 T in a single breathhold. This rapid sequence may be especially useful for functional imaging of the coronaries where the acquisition time is limited by the stress duration and in cases where low navigator-gating efficiency prohibits acquisition of a free breathing scan in a reasonable time period.

Relações da rugosidade superficial do solo com o volume de chuva e com a estabilidade de agregados em água

A rugosidade superficial do solo é afetada, dentre outros fatores, pelo tipo de preparo, volume de chuva e estabilidade dos agregados estruturais diante da ação destrutiva da água. Em um Inceptisol, num experimento de erosão sob chuva natural realizado há 15 anos, no Sul da região do Planalto Catarinense, Brasil, avaliou-se a rugosidade superficial, a qual foi expressa por meio dos índices: rugosidade (RR), tortuosidade (T) e diferença de elevação limite (LD), no cultivo do milho, em 2003, e no cultivo da aveia, em 2004, em cujos períodos experimentais precipitaram 229 e 350 mm de chuva, respectivamente. Além disso, em 2004, entre os dois cultivos, avaliou-se a estabilidade dos agregados em água, expressa pelo diâmetro médio ponderado (DMP) e diâmetro médio geométrico (DMG) dos agregados. Os tratamentos de sistemas de manejo do solo foram: preparo convencional (PC) com uma aração + duas gradagens; cultivo mínimo (CM) com uma escarificação + uma gradagem, e semeadura direta (SD), ambos cultivados com milho e aveia, além de um tratamento adicional sem cultivo do solo (SC) em preparo convencional com uma aração + duas gradagens. A rugosidade foi avaliada em cinco oportunidades no cultivo do milho e em quatro da aveia, sendo a primeira avaliação imediatamente após o preparo do solo, e as demais, em intervalos sucessivos de 15 dias. A rugosidade inicial do solo foi alta e diminuiu com o aumento do volume das chuvas nos tratamentos SC, PC e CM, enquanto, na SD, a rugosidade foi alta apenas no cultivo da aveia e apresentou variação muito pequena com o aumento da chuva. O SC apresentou a maior redução da rugosidade ao acaso, enquanto a menor redução ocorreu na SD. A rugosidade superficial foi reduzida da condição original, na qual não se retiraram os efeitos da pendente e das marcas do preparo do solo, para a condição ao acaso, na qual esses efeitos foram retirados. A rugosidade superficial ao acaso relacionou-se inversamente com o volume das chuvas naturais. O decaimento máximo da rugosidade ao acaso relacionou-se inversamente com o DMP e com o DMG dos agregados estruturais.

Hypertension is an independent predictor of mean platelet volume in patients with acute ischaemic stroke.

Introduction: Mean platelet volume (MPV) was shown to be significantly increased in patients with acute ischaemic stroke, especially in non-lacunar strokes. Moreover, some studies concluded that increased MPV is related to poor functional outcome after ischaemic stroke, although this association is still controversial. However, the determinants of MPV in patients with acute ischaemic stroke have never been investigated. Subjects and methods: We recorded the main demographic, clinical and laboratory data of consecutive patients with acute (admitted within 24 h after stroke onset) ischaemic stroke admitted in our Neurology Service between January 2003 and December 2008. MPV was generated at admission by the Sysmex XE-2100 automated cell counter (Sysmex Corporation, Kobe, Japan) from ethylenediaminetetraacetic acid blood samples stored at room temperature until measurement. The association of these parameters with MPV was investigated in univariate and multivariate analysis. Results: A total of 636 patients was included in our study. The median MPV was 10.4 ± 0.82 fL. In univariate analysis, glucose (β= 0.03, P= 0.05), serum creatinine (β= 0.002, P= 0.02), haemoglobin (β= 0.009, P < 0.001), platelet count (β=-0.002, P < 0.001) and history of arterial hypertension (β= 0.21, P= 0.005) were found to be significantly associated with MPV. In multivariate robust regression analysis, only hypertension and platelet count remained as independent determinants of MPV. Conclusions: In patients with acute ischaemic stroke, platelet count and history of hypertension are the only determinants of MPV.