bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emergence of Developmental Delay in Infants and Toddlers With an FMR1 Mutation
Authors: Wheeler Anne C. , Gwaltney Angela , Raspa Melissa , Okoniewski Katherine C. , Berry-Kravis Elizabeth , Botteron Kelly N. , Budimirovic Dejan , Hazlett Heather Cody , Hessl David , Losh Molly , Martin Gary E. , Rivera Susan M. , Roberts Jane E. , Bailey Donald B. 
Published: April 2021

BACKGROUND:
Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options.

METHODS:
Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of &gt;500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children &lt;5 years of age.

RESULTS:
Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected.

CONCLUSIONS:
Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness.
Ochratoxin A Secretion in Primary Cultures of Rabbit Renal Proximal Tubule Cells
Authors: GROVES CARLOTTA E. , NOWAK GRAZYNA , MORALES MARK 
Published: April 2021

Abstract.
Primary cultures of rabbit renal proximal tubule cells grown under improved culture conditions were used to study the transepithelial transport of the nephrotoxic mycotoxin ochratoxin A. The basal-to-apical transepithelial flux, i.e., secretion, of this fluorescence organic acid was measured in primary cultures of rabbit renal proximal tubule cells. The basal-to-apical flux of ochratoxin A increased with time and reached a steady state after 12 h. On the other hand, the apical-to-basal flux, i.e., reabsorption, of ochratoxin A was minimal over time. The secretory flux of ochratoxin A was as much as eightfold greater than the reabsorptive flux, indicating that net secretion is the primary mechanism for ochratoxin A clearance by the proximal tubule. The kinetic analysis of ochratoxin A flux revealed secretion to be a saturable and very high-affinity process with an apparent K50 of 0.33 ± 0.21 mM. A saturating concentration of the prototypical organic anion substrate para-aminohippurate (PAH) reduced ochratoxin A secretion by approximately 75%. The kinetic analysis of PAH inhibition of ochratoxin A secretion revealed an IC50 of 195 mM, which is similar to the IC50 for PAH inhibition of peritubular ochratoxin A uptake in tubule suspensions and the K
m values for peritubular PAH uptake. The organic anions probenecid, octanoate, and α-ketoglutarate reduced ochratoxin A excretion to the same degree as PAH, whereas the amino acid phenylalanine had a minimal effect on ochratoxin A secretion. Thus, collectively, these observations indicate that the secretion of ochratoxin A in primary cultures of rabbit renal proximal tubules is limited to the organic anion secretory pathway. The high affinity measured for the basal-to-apical flux of ochratoxin A suggests that at concentrations typical of naturally occurring exposures, transepithelial secretion by the organic anion transport pathway represents a significant avenue for excretion of this mycotoxin by the renal proximal tubule.
Serum Cystatin C as a Determinant of Fasting Total Homocysteine Levels in Renal Transplant Recipients with a Normal Serum Creatinine
Authors: BOSTOM ANDREW G. , GOHH REGINALD Y. , BAUSSERMAN LINDA , HAKAS DAVID , JACQUES PAUL F. , SELHUB JACOB , DWORKIN LANCE , ROSENBERG IRWIN H. 
Published: April 2021

Abstract.
Serum creatinine, a surrogate for both renal function and homocysteine generation, is an important determinant of fasting plasma total homocysteine levels in stable renal transplant recipients. In this study, it is hypothesized that among stable renal transplant recipients with normal creatinine levels (i.e., ≤ 1.5 mg/dl), serum cystatin C, a more sensitive indicator of GFR, would better predict fasting total homocysteine levels compared with serum creatinine. Fasting plasma total homocysteine, folate, vitamin B12, and pyridoxal 5′-phosphate levels, along with serum cystatin C, creatinine, and albumin levels, were determined in 28 consecutive renal transplant recipients (mean age 47 ± 14 yr; 60.7% men) with stable allograft function, whose serum creatinine was ≤1.5 mg/dl. General linear modeling with analysis of covariance revealed that serum cystatin C was independently predictive (partial R = 0.494; P = 0.023) of fasting total homocysteine levels after adjustment for age, gender, vitamin status, albumin, and creatinine levels. In contrast, creatinine levels were not predictive of fasting total homocysteine levels in this model (P = 0.110) or an identical model that excluded cystatin C (P = 0.131). Serum cystatin C levels may reflect subtle decreases in renal function that independently predict fasting total homocysteine levels among stable renal transplant recipients with a normal serum creatinine.
Neutrophil Apoptosis and Dysfunction in Uremia
Authors: CENDOROGLO MIGUEL , JABER BERTRAND L. , BALAKRISHNAN V. S. , PERIANAYAGAM MARY , KING ANDREW J. , PEREIRA BRIAN J. G. 
Published: April 2021

Abstract.
The high prevalence of bacterial infections among patients with end-stage renal disease suggests that “professional” phagocytes such as neutrophils are functionally impaired. This dysfunction has been ascribed to uremic toxins, malnutrition, and dialysis. The aim of this study was to investigate the contribution of apoptosis to neutrophil dysfunction in uremia. Neutrophils harvested from uremic patients (n = 6) and age-/gender-matched healthy control subjects (n = 6) were incubated with either 50% autologous plasma or 10% fetal calf serum. After 24-h incubation, apoptosis was quantified by flow cytometry by using propidium iodide nuclear staining. Neutrophils from healthy volunteers were also incubated with either 50% heterologous normal or uremic plasma. After 24-h incubation, apoptosis was quantified by flow cytometry and transmission electron microscopy. In addition, superoxide production was determined by measuring the capacity to reduce ferri- to ferro-cytochrome C by using 4-β-phorbol 12-β-myristate 13-α-acetate or N-formyl methionyl-leucyl-phenylalanine (fMLP) for stimulus. Phagocytosis was determined by the uptake of 14C-labeled heat-killed Staphylococcus aureus. Compared with normal neutrophils, uremic neutrophils demonstrated greater apoptosis in the presence of autologous plasma (9 ± 4 versus 19 ± 6%, P = 0.01) as well as 10% fetal calf serum (19 ± 7 versus 31 ± 6%, P = 0.03). Furthermore, compared with normal neutrophils exposed to heterologous normal plasma, those exposed to heterologous uremic plasma exhibited higher apoptosis rates (19 ± 3 versus 40 ± 5%, P = 0.002), lower fMLP-stimulated superoxide production (22.6 ± 2.5 versus 15.5 ± 1.1 nmol O2
[UNK] /3.12 × 105 cells/30 min, P = 0.01), and a lower phagocytosis index (38 ± 3% versus 27 ± 5%, P = 0.04). Apoptosis correlated inversely with fMLP-stimulated superoxide production (r = -0.60, P = 0.04) and phagocytosis (r = -0.57, P = 0.05). These results suggest that uremic neutrophils undergo accelerated in vitro apoptosis. Furthermore, uremic plasma accelerates apoptosis of normal neutrophils, resulting in a dysfunctional pattern that is similar to that observed in uremia.
P2 Purinoceptor Saturation by Adenosine Triphosphate Impairs Renal Autoregulation in Dogs
Authors: MAJID DEWAN S. A. , INSCHO EDWARD W. , NAVAR L. GABRIEL 
Published: April 2021

Abstract.
Recent studies have suggested a role for P2 purinoceptors on vascular smooth muscle cells in the mechanism of renal autoregulation. Experiments were performed in anesthetized dogs (n = 9) to examine renal blood flow (RBF) auto-regulatory efficiency before and after saturation of P2 purinoceptors with acute intra-arterial administration of ATP (1 mg/kg per min). Dogs were pretreated with the nitric oxide synthase inhibitor nitro-L-arginine (NLA) (50 μg/kg per min), to avoid endothelial P2 receptor-mediated effects on nitric oxide release caused by the intra-arterial ATP infusions. NLA treatment decreased RBF (5.3 ± 0.3 to 3.6 ± 0.2 ml/min per g) and sodium excretion (3.6 ± 0.4 to 0.9 ± 0.2 ml/min per g) without producing significant changes in GFR (0.92 ± 0.04 to 0.90 ± 0.06 ml/min per g) or RBF autoregulatory efficiency. ATP administration to NLA-treated dogs resulted in further decreases in RBF (2.8 ± 0.2 ml/min per g), GFR (0.58 ± 0.05 ml/min per g), and sodium excretion (0.6 ± 0.2 μmol/min per g). In addition, there was marked impairment of RBF autoregulatory efficiency during ATP infusion. The slopes of the arterial pressure-blood flow relationships at renal arterial pressures of >75 mmHg were significantly altered, from 0.003 ± 0.001 to 0.2 ± 0.002 ml/min per g per mmHg. Discontinuation of ATP infusion restored RBF autoregulatory efficiency. Norepinephrine (5 μg/kg per min) administration in these NLA-treated dogs decreased RBF (2.5 ± 0.3 ml/min per g; n = 4) to a similar extent, compared with ATP, but did not impair RBF autoregulation. These results support the hypothesis that P2 purinoceptors may be involved in mediating autoregulatory adjustments in renal vascular resistance.
Th1 and Th2 Cytokine mRNA Profiles in Childhood Nephrotic Syndrome
Authors: YAP HUI-KIM , CHEUNG WAI , MURUGASU BELINDA , SIM SZE-KEEN , SEAH CHING-CHING , JORDAN STANLEY C. 
Published: April 2021

Abstract.
Idiopathic nephrotic syndrome of childhood is thought to be associated with T lymphocyte dysfunction often triggered by viral infections, with the production of circulating factor(s) resulting in proteinuria. In view of the conflicting evidence of T cell activation and Th1 or Th2 pattern of cytokine synthesis in this disease, this study examined the mRNA expression of interleukin-2 (IL-2), interferon-γ, IL-4, and IL-13 from CD4+ and CD8+ T cells in steroid-responsive nephrotic patients in relapse and remission. Fifty-five children with steroid-responsive nephrotic syndrome were included in this study, together with 34 normal controls and 24 patient controls with viral infections. RNA was isolated from purified CD4+ or CD8+ cells from peripheral blood and subjected to reverse transcription-PCR. Cytokine mRNA expression was measured semiquantitatively, and a cytokine index was derived from densitometric readings, with cyclophilin as the housekeeping gene. Both cross-sectional and paired data showed an increased CD4+ and CD8+ IL-13 mRNA expression in patients with nephrotic relapse as compared to remission, normal, and patient controls (P <0.008). This was also associated with increased cytoplasmic IL-13 expression in phorbol myristate acetate/ionomycin-activated CD3+ cells (6.66 ± 3.39%) from patients with nephrotic relapse compared to remission (2.59 ± 1.35%) (P < 0.0001). However, there was no significant difference in CD4+ or CD8+ IL-2, interferon-γ and IL-4 mRNA expression. IL-13 is an important T cell cytokine with anti-inflammatory and immunomodulatory functions on B cells and monocytes. It is conceivable that IL-13 may act on monocytes to produce vascular permeability factor(s) involved in the pathogenesis of proteinuria in patients with relapse nephrotic syndrome.
Regulation of Renal Urea Transportersa
Authors: SANDS JEFF M. 
Published: April 2021

Abstract.
Urea is important for the conservation of body water due to its role in the production of concentrated urine in the renal inner medulla. Physiologic data demonstrate that urea is transported by facilitated and by active urea transporter proteins. The facilitated urea transporter (UT-A) in the terminal inner medullary collecting duct (IMCD) permits very high rates of transepithelial urea transport and results in the delivery of large amounts of urea into the deepest portions of the inner medulla where it is needed to maintain a high interstitial osmolality for concentrating the urine maximally. Four isoforms of the UT-A urea transporter family have been cloned to date. The facilitated urea transporter (UT-B) in erythrocytes permits these cells to lose urea rapidly as they traverse the ascending vasa recta, thereby preventing loss of urea from the medulla and decreasing urine-concentrating ability by decreasing the efficiency of countercurrent exchange, as occurs in Jk null individuals (who lack Kidd antigen). In addition to these facilitated urea transporters, three sodium-dependent, secondary active urea transport mechanisms have been characterized functionally in IMCD subsegments: (1) active urea reabsorption in the apical membrane of initial IMCD from low-protein fed or hypercalcemic rats; (2) active urea reabsorption in the basolateral membrane of initial IMCD from furosemide-treated rats; and (3) active urea secretion in the apical membrane of terminal IMCD from untreated rats. This review focuses on the physiologic, biophysical, and molecular evidence for facilitated and active urea transporters, and integrative studies of their acute and long-term regulation in rats with reduced urine-concentrating ability.
Inducible Nitric Oxide Synthase Can Be Induced in the Absence of Active Nuclear Factor-κB in Rat Mesangial Cells
Authors: NAKASHIMA OSAMU , TERADA YOSHIO , INOSHITA SEIJI , KUWAHARA MICHIO , SASAKI SEI , MARUMO FUMIAKI 
Published: April 2021

Abstract.
The contribution of nuclear factor-κB (NF-κB) and interferon-γ (IFN-γ) signaling to nitric oxide generation is not completely understood. The effect of NF-κB release and its inhibition on nitrite production and the involvement of Janus kinase 2 (JAK2) in inducible nitric oxide synthase (iNOS) induction were investigated. The following assays were performed. (1) Nitrite produced by rat mesangial cells in primary culture was measured in incubations with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), with or without IFN-γ. Cells were stimulated with TNF-α or LPS plus IFN-γ in the presence of NF-κB inhibitors, herbimycin A (HerA), or the more specific JAK2 inhibitor AG490. (2) Immunoblotting was performed against the p65 and p50 subunits of NF-κB and iNOS. (3) Electrophoretic mobility shift assays were performed against NF-κB in the presence of NF-κB inhibitors or AG490. (4) iNOS promoter activity was measured in the presence of AG490 or JAK2 antisense oligonucleotides. TNF-α or LPS alone did not induce nitrite production, but with IFN-γ these compounds did induce nitrite production. Pyrrolidine dithiocarbamate (PDTC), N-acetyl-L-cysteine, dexamethasone (Dex), HerA, and AG490 partially inhibited LPS/IFN-γ- or TNF-α/IFN-γ-induced nitrite production. p65 was inhibited by the three NF-κB inhibitors described above, whereas p50 was not. PDTC and Dex completely inhibited the p65/p50 heterodimer, but HerA and AG490 had little effect on p65/p50. AG490 and JAK2 antisense oligonucleotides suppressed iNOS promoter activity. It can be concluded that (1) iNOS can be induced without active NF-κB; (2) Dex, acetylsalicylic acid, and PDTC inhibit only p65; and (3) JAK2 is involved in iNOS induction, and the contribution of JAK2 to nitrite production is greater than that of NF-κB.
Serum Levels and Metabolic Clearance of the Isoflavones Genistein and Daidzein in Hemodialysis Patients
Authors: FANTI PAOLO , SAWAYA B. PETER , CUSTER LAURIE J. , FRANKE ADRIAN A. 
Published: April 2021

Abstract.
Genistein and daidzein are biologically active isoflavones that are especially abundant in soybeans. After intestinal absorption, circulating genistein and daidzein are eliminated primarily by the kidneys. This study was undertaken to assess the metabolism of genistein and daidzein in patients with end-stage renal disease (ESRD) on hemodialysis therapy, and to test whether this treatment modality can replace the lack of kidney function, with respect to the elimination of the isoflavones. Twenty-three hemodialysis patients and 10 healthy subjects were studied. While consuming a self-selected low isoflavone diet, baseline blood levels were undetectable in eight of 10 healthy subjects and in 14 of 23 dialysis patients. The remaining participants had detectable levels, with the nine dialysis patients displaying much higher blood concentrations than the two healthy control subjects. After the evening intake of one dose of an isoflavone-rich soy protein isolate drink, the early morning blood levels of genistein and daidzein were higher in seven dialysis patients than in eight healthy subjects (genistein 1271 ± 321 versus 425 ± 104, P < 0.05; daidzein 1304 ± 352 versus 292 ± 78, P < 0.05). The blood clearance of the isoflavones was studied in two healthy subjects and in three dialysis patients. Genistein and daidzein were eliminated within 2 d in the healthy subjects, but had not returned to baseline in two of three ESRD patients, 7 d after intake. The half-life of both compounds was estimated to be 10-fold longer in the ESRD patients than in the healthy subjects. Finally, genistein and daidzein levels were measured before and after dialysis in five patients, both while on their regular diet and after one dose of a soy protein isolate drink. In both instances, the dialysis treatment did not affect the blood isoflavone levels. In conclusion, approximately one-third of hemodialysis patients eating the standard American renal diet experience high blood levels of the isoflavones genistein and daidzein, while the remaining two-thirds have undetectable levels. After ingestion of isoflavone-rich food such as soy products, all patients have detectable levels that remain very high for several days due to lack of renal excretion.
TT Virus
Authors: BONIS PETER A. L. 
Published: April 2021

Abstract.
TT virus (TTV) is a newly described DNA virus that was first detected in the blood of three patients with elevated serum aminotransferases following transfusion who tested negatively for all known hepatitis viruses. The virus has been found worldwide with a high prevalence in the general population. However, accumulating evidence suggests that the virus is not a significant cause of acute or chronic liver disease. No other disease associations with infection have been described.
Stimulation of NADPH Oxidase by Oxidized Low-Density Lipoprotein Induces Proliferation of Human Vascular Endothelial Cells
Authors: HEINLOTH ALEXANDRA , HEERMEIER KATHRIN , RAFF ULRIKE , WANNER CHRISTOPH , GALLE JAN 
Published: April 2021

Abstract.
Oxidized low-density lipoprotein (OxLDL) exerts proliferation and apoptosis in vascular cells, depending on its concentration and the duration of exposure. Recent studies indicate that O2
- is involved in cell cycle regulation and that OxLDL stimulates endothelial cells to produce O2
-. This study examined the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a potential source for O2
- in the proliferation-inducing activity of OxLDL in cultured human umbilical vein endothelial cells (HUVEC). Human LDL was oxidized by Cu++, and proliferation of HUVEC was detected by 3H-thymidine incorporation. OxLDL (5 μg/ml) caused an increase in proliferation of HUVEC of 250 to 300%. OxLDL-induced proliferation was blocked by addition of the antioxidants superoxide dismutase and catalase, suggesting that enhanced O2
- formation was involved. Diphenylene iodonium (DPI, 1 μM), an inhibitor of NADPH oxidase, also prevented OxLDL-induced proliferation of HUVEC, indicating that NADPH oxidase was the source for enhanced O2
- formation. The OxLDL effect was mimicked by lysophosphatidylcholine (LPC, 10 μM), a compound formed during oxidation of LDL. LPC-induced proliferation was also prevented by coincubation with DPI. Treatment of HUVEC with O2
- generated by the xanthine/xanthine oxidase reaction resulted in proliferation as did treatment with OxLDL. As expected, this stimulation could not be blocked by DPI. With the use of the cytochrome c-assay, it was demonstrated that OxLDL and LPC enhanced O2
- formation in HUVEC (by factor 3.2 and by factor 3.5, respectively). Supporting the assumption that NADPH oxidase was the enzyme responsible for O2
- formation, cells transfected with antisense oligonucleotides for NADPH oxidase showed a significantly reduced O2
- formation after stimulation with OxLDL and LPC. OxLDL and its compound LPC induce proliferation of HUVEC through activation of NADPH oxidase. The active NADPH oxidase generates O2
-, which mediates the proliferative effects.
1,25-Dihydroxy-19-nor-vitamin D2, a Vitamin D Analog with Reduced Bone Resorbing Activity In Vitro
Authors: HOLLIDAY L. SHANNON , GLUCK STEPHEN L. , SLATOPOLSKY EDUARDO , BROWN ALEX J. 
Published: April 2021

Abstract.
1,25-Dihydroxy-19-nor-vitamin D2 (19-norD2), a new analog of 1,25(OH)2D3, suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)2D3. Although 19-norD2 has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)2D3, it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD2 on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD2 and 1,25(OH)2D3 (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD2, as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)2D3-stimulated osteoclasts (P < 0.05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD2 in cultures was approximately 20% greater than 1,25(OH)2D3, not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD2 and 1,25(OH)2D3. In summary, 19-norD2 is less effective than 1,25(OH)2D3 in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD2 compared with 1,25(OH)2D3.