It can influence both the activity and the

stability of t

It can influence both the activity and the

stability of the protein. The glycosylation pattern has been shown to depend on the cell type where the protein is expressed. We examined if differences in the glycosylation of this protein could be detected when it was expressed in the two commonly used mammalian expression systems, HEK and CHO. Differences in the glycosylation were detected. (c) 2007 Elsevier Inc. All rights reserved.”
“Most patients with acute myeloid selleck screening library leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC + ATO. Patients with AML according to WHO criteria Selleck RO4929097 or myelodysplastic syndrome with > 10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice

of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML. Leukemia (2011) 25, 1122-1127; doi:10.1038/leu.2011.59; published online 8 April 2011″
“Parkinson’s Niclosamide disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons of the substantia nigra pars compacta

with unknown aetiology. 6-Hydroxydopamine (6-OHDA) treatment of neuronal cells is an established in vivo model for mimicking the effect of oxidative stress found in PD brains. We examined the effects of 6-OHDA treatment on human neuroblastoma cells (SH-SY5Y) and primary mesencephalic cultures. Using a reverse arbitrarily primed polymerase chain reaction (RAP-PCR) approach we generated reproducible genetic fingerprints of differential expression levels in cell cultures treated with 6-OHDA. Of the resulting sequences, 23 showed considerable homology to known human coding sequences. The results of the RAP-PCR were validated by reverse transcription PCR, real-time PCR and, for selected genes, by Western blot analysis and immunofluorescence.

Results support the possibility that different levels of dopamine

Results support the possibility that different levels of dopaminergic neuromodulation can subtend hemispheric differences in semantic priming, corresponding to focused priming in the left hemisphere and to extended priming in the right hemisphere. Furthermore, results can account for priming perturbations in schizophrenia depending on the level of dopamine. (c) 2008 Elsevier Ltd. All

rights reserved.”
“Errors in the production of verb inflections, especially tense inflections, are pervasive in agrammatic Broca’s aphasia (*The boy eat). The neurolinguistic underpinnings of these errors are debated. One group of theories attributes verb inflection errors to disruptions in encoding the verb’s morphophonological form, resulting from either a general phonological deficit or a morphological affixation impairment. A second check details group of theories attribute verb inflection errors to disruptions that arise during sentence formulation, either for syntactic reasons or due to impairments in making fine semantic distinctions between inflectional variants of a verb (+PAST -> ate, hugged; +FUTURE -> will eat, will hug). These morphophonological and morphosemantic accounts were evaluated by comparing the efficacy of two treatment protocols that exclusively targeted either morphophonological operations or morphosemantic

distinctions. Using a single participant design, it was found that aphasic individuals who received morphosemantic treatment showed significant improvement in accurate production of trained and untrained verb inflections in sentence

contexts. In contrast, individuals who received morphophonological treatment failed to show improvements in accuracy of sentence production, although the number and diversity of inflected verbs increased. The differential outcomes suggest that morphosemantic impairments contribute to verb inflection deficits in agrammatic aphasia to a greater extent than morphophonological impairments, at least in this group of participants. (c) 2008 Elsevier Ltd. All rights reserved.”
“After hemispherectomy (removal or disconnection of an entire cerebral hemisphere) in childhood for treatment of intractable epilepsy, gross speech and language functions are often rescued. Whether more complex functions, such as syntactic processing, are BCKDHA selectively impaired, remains controversial. Here we present a cross-sectional study of expressive and receptive language functions in 30 patients who have undergone hemispherectomy (17 left, 13 right). The patients had developed epilepsy-induced pathology either during the pre/perinatal period (19 cases), or after a period of normal development (11 cases; onset range=20 months to 10 years). The patients were assessed at least 1 year post surgery on tests of receptive vocabulary, expressive and receptive grammar, instruction comprehension, and semantic association.

We propose that interactions among the granular prefrontal areas

We propose that interactions among the granular prefrontal areas create the kind of cross-domain, analogical and self-referential knowledge that underlies advanced cognition in modern humans. When these products of frontal-lobe CA-4948 chemical structure function interact with the hippocampus, and its ancestral function in navigation, what

emerges is the human ability to embed ourselves in scenarios real and imagined, self-generated and received thereby creating a coherent, conscious life experience. Published by Elsevier Ltd.”
“Stiff polymers, such as single-stranded DNA, unstructured RNA and cellulose, are all basically extremely long rods with relatively short repeating monomers. The simplest model for describing such stiff polymers is called the freely jointed chain

model, which treats a molecule as a chain of perfectly rigid subunits of orientationally independent statistical segments, joined together by perfectly flexible hinges. A more realistic model that incorporates the entropic elasticity of a molecule, called the wormlike chain model, has been proposed by assuming that each monomer resists the bending force. Some force-extension formulae for the worm-like chain model have been previously found in terms of interpolation and numerical solutions resulting from statistical mechanics. In this paper, however, we adopt a variational principle to seek AZD1390 clinical trial the minimum energy configuration of a stretched molecule by incorporating all the possible orientations of each monomer under thermal equilibrium, i.e., constant temperature. We determine a force-extension formula for the worm-like chain model analytically. We find that our formula suggests new terms such as the free energy and the cut-off force of a molecule, which define a clear transition from the entropic regime to the enthalpic regime and the fracture of the molecule, respectively. In addition, we predict two possible

phase Protein kinase N1 changes for a stretched molecule, i.e., from a super-helix to a soliton and then from a soliton to a vertical twisted line. We show theoretically that a molecule must undergo at least one phase change before it is fully stretched into its total contour length. This new formula is used to fit recent experimental data and shows a good agreement with some current literature that uses a statistical approach. Finally, an instability analysis is adopted to investigate the sensitivity of the new formula subject to small changes in temperature. (C) 2009 Elsevier Ltd. All rights reserved.”
“Unilateral spatial neglect (USN) is a highly prevalent and disabling consequence of stroke that often responds poorly to existing interventions. Its underlying neural mechanisms are still unclear.

9%] of 1119; p=0 44) Radiotherapy toxicity (Radiation Therapy On

9%] of 1119; p=0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p=0.002).

Interpretation For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered

as an alternative to external beam radiotherapy delivered over several weeks.”
“Background The evolving epidemic of type 2 diabetes has challenged health-care providers to assess the safety and efficacy of various diabetes prevention strategies. The CANOE (CAnadian Normoglycemia Outcomes Evaluation) Berzosertib supplier trial investigated whether low-dose combination therapy would affect development of type 2 diabetes.

Methods In this double-blind, randomised controlled trial undertaken in clinics in Canadian centres, 207 patients with impaired glucose tolerance were randomly assigned to receive combination rosiglitazone (2 mg) and metformin (500 mg) twice daily or matching placebo for a median of 3.9 years (IQR 3.0-4.6). Randomisation was computer-generated in blocks of four, with both participants and investigators masked

to treatment allocation. The primary outcome was time to development of diabetes, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7.0 mmol/L or greater. Analysis was by intention GS-4997 supplier to treat. This study is registered with, number NCT00116932.

Findings 103 participants were assigned to rosiglitazone and metformin, and 104 to placebo; all

were analysed. Vital status was obtained in 198 (96%) participants, and medication compliance (taking at least 80% of assigned medication) was 78% (n=77) in the metformin and rosiglitazone group and 81% (n=80) in the placebo group. Incident diabetes occurred in significantly fewer individuals in the active treatment group (n=14 [14%]) than in the placebo group (n=41 [39%]; p<0.0001). Flavopiridol (Alvocidib) The relative risk reduction was 66% (95% CI 41-80) and the absolute risk reduction was 26% (14-37), yielding a number needed to treat of 4 (2.70-7.14). 70 (80%) patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group (p=0.0002). Insulin sensitivity decreased by study end in the placebo group (median -1.24, IQR -2.38 to -0.08) and remained unchanged with rosiglitazone and metformin treatment (-0.39, -1.30 to 0.84; p=0.0006 between groups). The change in beta-cell function, as measured by the insulin secretion-sensitivity index-2, did not differ between groups (placebo -252.3, -382.2 to -58.0 vs rosiglitazone and metformin -221.8, -330.4 to -87.8; p=0.28). We recorded an increase in diarrhoea in participants in the active treatment group compared with the placebo group (16 [16%] vs 6 [6%]; p=0.0253).

Methods: Patients with lower extremity ischemic tissue loss (Ruth

Methods: Patients with lower extremity ischemic tissue loss (Rutherford 5 and 6) received three sets of eight intramuscular injections every 2 weeks of HGF plasmid under duplex ultrasound guidance. Injection locations were individualized for each patient based on arteriographically defined vascular anatomy. Primary safety end point was incidence of adverse events (AE) or serious adverse events (SAE). Clinical

end points included change from baseline in toe brachial index (TBI), rest pain assessment by a 10 cm visual analogue scale (VAS) as well as wound healing, amputation, and survival at 3 and 6 months.

Results: Randomization ratio was 3:1 HGF (n = 21) vs placebo (n = 6). Mean age was 76 +/- 2 years, with 56% male and 59% diabetic. There was no difference in demographics between groups. There was no difference in AEs or SAEs, which consisted mostly of transient HKI-272 supplier injection site discomfort, worsening of CLI, and intercurrent illnesses. Change in TBI significantly improved from baseline at 6 months in the HGF-treated group compared with placebo (0.05 +/- 0.05 vs -0.17 +/- 0.04; P = .047). Change in VAS from baseline

at 6 months was also significantly improved in the HGF-treated group compared with placebo (-1.9 +/- 1.3 vs +0.06 +/- 0.2; P = .04). Complete ulcer healing at 12 months occurred in 31% of the HGF group and 0% of the placebo (P = .28) There was no difference in major amputation of the treated limb (HGF 29% vs placebo 33%) or mortality at 12 months (HGF 19% vs placebo 17%) between groups.

Conclusion: HGF gene therapy using a patient vascular anatomy Carteolol HCl specific delivery technique appears safe, Selleckchem CB-839 maintained limb perfusion, and decreased rest pain in patients with CLI compared with placebo. A larger study to assess

the efficacy of this therapy on more clinically relevant end points is warranted. (J Vase Surg 2010;52:1525-30.)”
“Volatile organic solvents such as toluene are voluntarily inhaled for their intoxicating effects. Solvent use is especially prevalent among adolescents, and is associated with deficits in a wide range of cognitive tasks including attention, behavioral control, and risk assessment. Despite these findings, little is known about the effects of toluene on brain areas mediating these behaviors. In this study, whole-cell patch-clamp recordings were used to determine the effect toluene on neurons within the medial PFC, a region critically involved in cognitive function. Toluene had no effect on measures of intrinsic excitability, but enhanced stimulus-evoked g-amino butyric acid A-mediated inhibitory postsynaptic currents (IPSCs). In the presence of tetrodotoxin (TTX) to block action potentials, toluene increased the frequency and amplitude of miniature IPSCs. In contrast, toluene induced a delayed but persistent decrease in evoked or spontaneous AMPA-mediated excitatory postsynaptic currents (EPSCs).


Vaginal distention results in up-regulation


Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1 alpha and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia.”
“Human embryonic stem cells (hESCs) are of immense interest for regenerative medicine as a source of tissue replacement. Expansion A-1331852 molecular weight of hESCs as a pluripotent population requires a balance between survival, proliferation and self-renewal signals. One of the key growth factors that maintains this balance is fibroblast growth factor-2 (FGF-2). However, the underlying molecular mechanisms are poorly understood. We recently profiled specifically tyrosine phosphorylation events that occur during FGF-2 Lorlatinib stimulation of hESCs (Ding et al., J. Cell. Physiol. 2010, 225, 417-428). Here, we complement this phosphoproteome profiling by analyzing temporal dynamics of mostly serine and threonine protein phosphorylation events. Our multi-dimensional strategy combines strong cation exchange chromatography to reduce the sample complexity followed by titanium dioxide off-line for the enrichment of phosphopeptides and dimethylation-based stable isotope labeling for quantification.

This approach allowed us to identify and quantify 3261 unique proteins from which 1064 proteins were found to be phosphorylated in one or more residues (representing 1653 unique phosphopeptides). Approximately 40% of the proteins (553 unique phosphopeptides) showed differential phosphorylation upon FGF-2 treatment. Among those are several members of the canonical pathways involved in

pluripotency and self-renewal (e.g. Wnt and PI3K/AKT), hESC-associated proteins such as SOX2, RIF1, SALL4, DPPA4, DNMT3B and 53 proteins that are target genes of the pluripotency transcription factors SOX2, OCT4 and NANOG. These findings complement existing pluripotency analyses and provide new insights into how FGF-2 assists in maintaining the undifferentiated state of hESCs.”
“During recent years, increased efforts have focused on elucidating the pluripotency and self-renewal of stem cells. ifoxetine Differentiation towards the different lineages has attracted significant attention given the potential use of stem cells in regenerative medicine. Embryonic stem cell differentiation is a complex process coordinated by strictly regulated extracellular signals that act in an autocrine and/or paracrine manner. Through secreted molecules, stem cells affect local niche biology and influence the cross-talking with the surrounding tissues. Emerging evidence supports the hypothesis that fundamental cell functions, including proliferation and differentiation, are strictly regulated by the complex set of molecules secreted from cells.

(C) 2011 Elsevier Ltd All rights reserved “
“Although prote

(C) 2011 Elsevier Ltd. All rights reserved.”
“Although protein Z ( PZ) has a domain arrangement similar to the essential coagulation proteins FVII, FIX, FX, and protein C, its serine

protease ( SP)- like domain is incomplete and does not exhibit proteolytic activity. We have generated a trial sequence of putative activated protein Z ( PZa) by identifying amino acid mutations in the SP- like domain that might reasonably resurrect the serine protease catalytic activity of PZ. The structure of the activated form was then modeled based on the proposed sequence using homology modeling and solvent- equilibrated molecular dynamics simulations. In silico docking of inhibitors of FVIIa and FXa to the putative active site of equilibrated PZa, along with structural comparison with its homologous proteins, PLX3397 molecular weight suggest that the designed PZa can possibly act as a serine protease.”
“The left-handed beta-helix (L beta H) has received interest recently

as it folds as a possible solution for the structure of misfolded proteins associated with prion and Huntington’s diseases. Through a combination of sequence and structure analysis, we uncover a novel feature that is common to this unique fold: a two-fold symmetry in both sequence and structure, and this feature always coupled with extended loops in the middle of the helix. Since the results reveal a two-fold symmetric pattern both in the sequence and structure, it may indicate that the symmetry in tertiary structure is coded by the symmetry in primary sequence, which agrees with Anfisen’s proposal that a protein’s amino-acid sequence specify its three-dimensional structure. It 4��8C may also indicate that L beta H adopts

a two-fold repeat pattern during the evolution process and symmetry helps maintaining the stability of the helix structure. The two-fold symmetric pattern and extended loops might be important in maintaining stability of helix proteins. This discovery can be useful in understanding the folding mechanisms of this protein fold and provide insights in the relation between sequences and structures. (C) 2011 Elsevier Ltd. All rights reserved.”
“Dioxygenases catalyze dioxygen incorporation into various organic compounds and play a key role in the complex degradation pathway of mono- and polycyclic aromatic and hetero- aromatic compounds. Here we report the crystal structure of gentisate 1,2- dioxygenase from Silicibacter pomeroyi ( GDOsp) at a 2.8 A resolution. The enzyme possessed a conserved three- dimensional structure of the bicupin family, forming a homotetramerization. However, each subunit of GDOsp unusually contained two ferrous centers that were located in its two homologous cupin domains, respectively. Further mutagenic analysis indicated that the enzyme activity of GDOsp depends on the microenvironment in both metal- binding sites.

5 (95% confidence interval 1 4-1 5)] as the most important socio-

5 (95% confidence interval 1.4-1.5)] as the most important socio-economic risk factor for the non-adopted.


The main familial effects of parental suicide and psychiatric morbidity on offspring suicide are not mediated by the post-natal environment or imitation, in contrast to effects of parental alcohol abuse that are primarily mediated by the post-natal environment. Social drift over generations because of psychiatric disorders does not seem likely to explain the association of socio-economic living conditions in childhood to suicide.”
“Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced AZD1390 reinstatement of cocaine-seeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically LXH254 price regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaine-seeking behavior. To test this hypothesis, rats were trained to lever press

for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 mu g/0.5 mu l/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 mu l/hemisphere), Ro25-6981 (NR2B subunit-containing NMDAR antagonist; 0.2 or 2 mu g/0.5 mu l/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently

impaired drug next context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments. Cocaine-seeking behavior during the first 20 min of the test session in the cocaine-paired context was associated with an increase in NR2B subunit activation, and intra-DH PP2 pretreatment disrupted this relationship. Together, these findings suggest that Src-family kinase activation, NMDAR stimulation, and likely Src-family kinase-mediated NR2B subunit-containing NMDAR activation in the DH are necessary for incentive motivational and/or memory processes that promote contextual cocaine-seeking behavior.”
“Objective: Asymmetric septal hypertrophy frequently coexists with severe aortic stenosis and can be unmasked after successful aortic valve replacement (AVR), jeopardizing the clinical and echocardiographic results. The aim of our study was to investigate, at 5 years postoperatively, the effectiveness of myectomy associated with AVR on left ventricular (LV) mass regression and LV diastolic function.

Additionally, the calibrated parameter values indicate that the a

Additionally, the calibrated parameter values indicate that the accessibilities of intentions decay at the same rate as retrospective memories. However, the accessibilities may stay high

due to a reminder, the effectiveness of which depends on a person’s commitment to performing the behavior. Furthermore, the effect of the reminder decays over time. This decay is much slower than the development of habits, which, after about a month, were nearly fully developed if the person had executed the behavior sufficiently often. Finally, over time, habits were shown to Bortezomib nmr replace the reminding effect of the external memoryf aid. This article points to a new understanding of the role of habits in supporting the performance of repeated behaviors through remembering.”
“This study reports temperature effects on paralarvae from a benthic octopus species, Octopus huttoni, found throughout New Zealand and temperate Australia. We quantified the thermal tolerance, thermal preference and temperature-dependent respiration rates in 1-5 days old paralarvae. Thermal stress (1 degrees C increase h(-1)) and thermal selection (similar to 10-24 degrees C vertical gradient) experiments were conducted with paralarvae reared for 4 days at 16 degrees C. In addition, measurement CA-4948 research buy of oxygen consumption at 10, 15, 20 and 25 degrees C was made for paralarvae aged 1,4 and 5 days using microrespirometry. Onset of spasms,

rigour (CTmax) and mortality

(upper lethal limit) occurred for 50% of experimental animals at, respectively, 26.0 +/- 0.2 degrees C, 27.8 +/- 0.2 degrees C and 31.4 +/- 0.1 degrees C. The upper, 23.1 +/- 0.2 degrees C, and lower, 15.0 +/- 1.7 C, temperatures actively avoided by paralarvae correspond with the temperature range over which normal behaviours were observed in the thermal stress Carnitine palmitoyltransferase II experiments. Over the temperature range of 10 degrees C-25 degrees C, respiration rates, standardized for an individual larva, increased with age, from 54.0 to 165.2 nmol larvae(-1) h(-1) in one-day old larvae to 40.1-99.4 nmol h(-1) at five days. Older larvae showed a lesser response to increased temperature: the effect of increasing temperature from 20 to 25 degrees C (Q(10)) on 5 days old larvae (Q(10)=1.35) was lower when compared with the 1 day old larvae (Q(10)=1.68). The lower Q(10) in older larvae may reflect age-related changes in metabolic processes or a greater scope of older larvae to respond to thermal stress such as by reducing activity. Collectively, our data indicate that temperatures > 25 degrees C may be a critical temperature. Further studies on the population-level variation in thermal tolerance in this species are warranted to predict how continued increases in ocean temperature will limit O. huttoni at early larval stages across the range of this species. (C) 2011 Elsevier Ltd. All rights reserved.

As an example, we discuss the theoretical characterization of the

As an example, we discuss the theoretical characterization of the two human choline kinase species, alpha-1 and alpha-2, sharing the same catalytic activity but generated by alternative splicing on CHKA gene.”
“The presence of viral respiratory infections is associated closely with exacerbations in patients with cystic

fibrosis. Viral and bacterial multiplex PCRs were developed and applied to nasal swab samples from children with cystic fibrosis. This showed a large number of individuals with cystic fibrosis were infected with rhinoviruses, Silmitasertib chemical structure and more were infected with viral than bacterial pathogens. All individuals with parainfluenza 3 virus had clinical exacerbations of their cystic fibrosis, and although 3/4 of these children were co-infected with HRV. The findings do not suggest a significant association for any other virus or bacteria with exacerbation. There is clear evidence some viral infections are associated with cystic fibrosis that dual infection

is more likely to produce symptoms, and mechanisms of viral-induced exacerbation should be elucidated. Crown Copyright (C) 2012 Published by Elsevier B.V. All rights reserved.”
“The simultaneous analysis of a wide array of proteins may provide valuable information on the activation and suppression of cellular systems at different stages of the exposure-disease continuum. In this review, results oxyclozanide of proteomic studies in the field of toxicology are covered, focusing on the effects of chemical carcinogens. So far, alterations of highly abundant proteins have Bromosporine order been identified which, irrespective of the wide differences in study design and technologies used, can be grossly assigned to three functional classes:

proteins related to cellular stress response, inflammation, and stimulation of the immune system. It is obvious that the observed protein alterations are not causal factors in the development of chemically induced cancer but rather reflect common reactions to cellular perturbations. In order to gain deeper insights into the process of chemical carcinogenesis, the previously applied “”shotgun”" analyses have to be abandoned in favour of targeted proteomic approaches focusing on the accurate identification and quantification of selected proteins. Advanced analytical techniques such as selective reaction monitoring (SRM) and multiple reaction monitoring (MRM) offer this opportunity. If toxicoproteomic research moves into that direction and takes advantage of such techniques it will have the potential to contribute to the elucidation of chemical carcinogenesis.”
“The main objective of the study is to optimize a subtype specific polymerase chain reaction (PCR) for identification of hepatitis C virus (HCV) subtypes in patients with renal disease.