Effects of bicarbonate- and lactate-buffered replacement fluids on cardiovascular outcome in CVVH patients

BACKGROUND: Bicarbonate-buffered replacement fluid (RF-bic) in continuous venovenous hemofiltration (CVVH) may be superior to lactate-buffered replacement fluid (RF-lac) in acute renal failure. In an open, randomized, multicenter study, we investigated the effects of RF-bic and RF-lac on cardiovascular outcome in patients requiring CVVH following acute renal failure. METHODS: One hundred seventeen patients between the age of 18 and 80 years were randomized to CVVH either with RF-bic (N = 61) or RF-lac (N = 56). Patients were treated with CVVH for five days or until either renal function was restored or the patient was removed from the study. Data were analyzed on day 5 or according to the "last observation carried forward" (LOCF) option. Adverse events were classified according to the WHO-Adverse Reaction Terminology system. RESULTS: Blood lactate levels were significantly lower and blood bicarbonate levels were significantly higher in patients treated with RF-bic than in those treated with RF-lac (lactate, 17.4 +/- 8.5 vs. 28.7 +/- 10.4 mg/dL, P < 0.05; bicarbonate, 23.7 +/- 0.4 vs. 21.8 +/- 0.5 mmol/L, P < 0. 01). The number of hypotensive crises was lower in RF-bic-treated patients than in RF-lac-treated patients (RF-bic 14 out of 61 patients, RF-lac in 29 out of 56 patients; 0.26 +/- 0.09 vs. 0.60 +/- 0.31 episodes per 24 h, P < 0.05). Nine out of 61 patients (15%) treated with RF-bic and 21 out of 56 patients (38%) treated with RF-lac developed cardiovascular events during CVVH therapy (P < 0. 01). A multiple regression analysis showed that the occurrence of cardiovascular events was dependent on replacement fluid and previous cardiovascular disease and not on age or blood pressure. Patients with cardiac failure died less frequently in the group treated with RF-bic (7 out of 24, 29%) than in the group treated with RF-lac (12 out of 21, 57%, P = 0.058). In patients with septic shock, lethality was comparable in both groups (RF-bic, 10 out of 27, 37%; RF-lac, 7 out of 20, 35%, P = NS). CONCLUSIONS: The results show that the administration of RF-bic solution was superior in normalizing acidosis of patients without the risk of alkalosis. The data also suggest that the use of RF-bic during CVVH reduces cardiovascular events in critically ill patients with acute renal failure, particularly those with previous cardiovascular disease or heart failure.     

Genetic determinants of plasma lipid response to dietary intervention: the role of the APOA1/C3/A4 gene cluster and the APOE gene

Polymorphisms at the APOA1/C3/A4 gene cluster and the APOE gene have been extensively studied in order to examine their potential association with plasma lipid levels, coronary heart disease risk and more recently with inter-individual variability in response to dietary therapies. Although the results have not been uniform across studies, the current research supports the concept that variation at these genes explains a significant, but still rather small, proportion of the variability in fasting and postprandial plasma lipid responses to dietary interventions. This information constitutes the initial frame to develop panels of genetic markers that could be used to predict individual responsiveness to dietary therapy for the prevention of coronary heart disease. Future progress in this complex area will come from experiments carried out using animal models, and from carefully controlled dietary protocols in humans that should include the assessment of several other candidate gene loci coding for products that play a relevant role in lipoprotein metabolism (i.e. APOB, CETP, LPL, FABP2, SRBI, ABC1 and CYP7).     

Non-invasive detection of fecal protein kinase C betaII and zeta messenger RNA: putative biomarkers for colon cancer

We have developed a non-invasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers. In this study, we used the rat colon carcinogenesis model to determine if changes in fecal protein kinase C (PKC) expression have predictive value in monitoring the neoplastic process. Weanling rats were injected with saline or azoxymethane (AOM) and 36 weeks later fecal samples and mucosa were collected, poly A+ RNA isolated, and quantitative RT-PCR performed using primers to PKC betaII and zeta. Fecal PKC betaII and zeta mRNA levels were altered by the presence of a tumor, with tumor-bearing animals having a 3-fold higher (P < 0.05) PKC betaII expression as compared with animals without tumors. In addition, AOM-injection increased mucosal PKC betaII mRNA expression compared with saline controls. No effect of tumor incidence on mucosal PKC betaII expression was observed. In contrast, fecal PKC zeta expression was 2.5-fold lower (P < 0.05) in animals injected with azoxymethane versus saline. Since tumor incidence exerts a reciprocal effect on fecal PKC betaII and zeta mRNA expression, data were also expressed as the ratio between PKC betaII and zeta. The isozyme ratio was strongly related to tumor incidence, i.e. ratio for animals with tumors was 2.18 +/- 1.25, animals without tumors was 0.50 +/- 0.16, P = 0.025. We demonstrate that the expression of fecal PKC betaII and zeta may serve as a noninvasive marker for development of colon tumors. A sensitive technique for the detection of colon cancer is of importance since early diagnosis can substantially reduce mortality.      

Targeted disruption of GAP-43 in P19 embryonal carcinoma cells inhibits neuronal differentiation. As well as acquisition of the morphological phenotype

GAP-43 is expressed in proliferating neuroblasts in vivo and in vitro, but its role during early neurogenesis has not been investigated. Here we show that neuroectodermal differentiation stimulated by retinoic acid (RA) in the embryonal carcinoma (EC) line P19 is accompanied by upregulation of GAP-43 expression in neuroepithelial precursor cells. In contrast, when upregulation of GAP-43 expression was prevented in 3 independent P19 lines because of a targeted insertion into the gene, generation of neuroepithelial precursors was inhibited. Consequently, neuronal number was significantly decreased, neuronal morphology was abnormal and fewer than 20% of all neurons were able to initiate neuritogenesis. Extracellular matrix (ECM) was unable to rescue initiation of neuritogenesis in the mutant cells, however those neurites that were extended responded normally to ECM-stimulated neurite outgrowth-promoting signals. These data suggest that GAP-43 function is required for commitment to a neuronal phenotype as well as initiation of neurite extension. However, stimulation of neurite outgrowth by ECM in P19s occurs independently of GAP-43.     

Advances in computer-assisted single-photon emission computed tomography (SPECT) for epilepsy surgery in children

Epilepsy surgery has emerged as an important option in the treatment of children with epilepsy that is refractory to antiepileptic drug management. The cornerstone of successful surgery is accurate localization of the brain region of seizure onset. Traditional techniques of seizure onset localization, e.g. surface electroencephalography (EEG) recording and magnetic resonance imaging (MRI), allow accurate localization in a significant number of patients. When the focus of seizure onset is not apparent from these non-invasive techniques, other methods of localization, e.g. intracranial EEG recording, may be needed before resection of the focus. Single-photon emission computed tomography (SPECT) is a nuclear medicine blood-flow technique that has been used to identify a region of epileptogenic brain associated with low blood flow in the resting state (interictal SPECT) or increased blood flow at the time of seizure activity (ictal SPECT). This report describes the validation and utility of a computer-assisted method of subtracting the interictal from the ictal SPECT scans and co-registering the difference image on the MRI. This method, called subtraction ictal SPECT co-registered on MRI (SISCOM), is used in guiding the location and the extent of intracranial electrode implantation, or in obviating the need for the implantation in some cases.     

The human epidermis models EpiSkin, SkinEthic and EpiDerm: an evaluation of morphology and their suitability for testing phototoxicity, irritancy, corrosivity, and substance transport.

The commercially available reconstructed human epidermis models EpiSkin, SkinEthic and EpiDerm demonstrate reasonable similarities to the native human tissue in terms of morphology, lipid composition and biochemical markers. These models have been identified as useful tools for the testing of phototoxicity, corrosivity and irritancy, and test protocols have been developed for such applications. For acceptance of these tests by the authorities, prevalidation or validation studies are currently in progress. Furthermore, first results also indicate their suitability for transport experiments of drugs and other xenobiotics across skin. Still, however, the barrier function of these reconstructed human epidermis models appears to be much less developed compared to native skin. Further adaptation of the models to the human epidermis, especially concerning the barrier function, therefore remains an important challenge in this area of research.     

The role of bone scintigraphy in patients with Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a rare disorder that has been reported fewer than 60 times in the literature. Although clinical findings seem to be specific at first sight, histologic classification remains unclear. It has not been decided whether ECD is part of the spectrum of histiocytoses or whether it may be a lipid storage disorder or even a primary macrophage cell disorder, although it does show a distinct histologic pattern. However, the clinical appearance alone shows several typical features, rendering the diagnosis very probable if present. This article illustrates the importance of bone scanning in ECD, because the scintigraphic pattern of involved skeletal sites may in themselves lead to the diagnosis. Several differential diagnoses are considered. The importance of bone scintigraphy as an imaging method in patients with an unclear diagnosis is discussed, as exemplary in ECD, as is its role for the detection of sites of skeletal involvement in other diseases.     

易感小鼠花生过敏诱导的中毒反应

花生过敏是造成人ＩｇＥ诱导中毒反应的主要原因之一,本试验组制作Ｃ３Ｈ小鼠动物模型,并给其口服花生蛋白（ＰＮ）及霍乱毒素（ＣＴｘ）,然后在腹腔内注射ＰＮ（溶于明矾中的ＰＮ）,使这种鼠即刻发生高度敏感症状（包括致死性的中毒反应）及花生特异性ＩｇＥ水平增高,血浆息斯地明水平、脱颗粒肥大细胞及血管渗漏水平也大幅度升高。对照组小鼠未给药或仅仅接受了ＣＴｘ,则未显示出花生特异性ＩｇＥ水平升高及中毒症状。本文又分析了几种与中毒反应有关的参数。结果证明,小鼠花生过敏中毒反应与人花生过敏类似,同时小鼠花生过敏中毒反应模型,为研究中毒性免疫病理发生机制及研究更有效的治疗方案提供了一个有用的工具。     

Modulation of biliverdin dynamics and spectral properties by Sandercyanin

Biliverdin IX-alpha (BV), a tetrapyrrole, is found ubiquitously in most living organisms. It functions as a metabolite, pigment, and signaling compound. While BV is known to bind to diverse protein families such as heme-metabolizing enzymes and phytochromes, not many BV-bound lipocalins (ubiquitous, small lipid-binding proteins) have been studied. The molecular basis of binding and conformational selectivity of BV in lipocalins remains unexplained. Sandercyanin (SFP)–BV complex is a blue lipocalin protein present in the mucus of the Canadian walleye (Stizostedion vitreum). In this study, we present the structures and binding modes of BV to SFP. Using a combination of designed site-directed mutations, X-ray crystallography, UV/VIS, and resonance Raman spectroscopy, we have identified multiple conformations of BV that are stabilized in the binding pocket of SFP. In complex with the protein, these conformers generate varied spectroscopic signatures both in their absorption and fluorescence spectra. We show that despite no covalent anchor, structural heterogeneity of the chromophore is primarily driven by the D-ring pyrrole of BV. Our work shows how conformational promiscuity of BV is correlated to the rearrangement of amino acids in the protein matrix leading to modulation of spectral properties.

Biliverdin IX-alpha undergoes rotation around the D-ring pyrrole and displays a broad far-red absorbance on binding to monomeric Sandercyanin variant (orange) compared to the wild-type tetrameric protein (cyan).