bluuebunny/crossref_metadata_2025 huggingface dataset:
Sub-Nanosecond Greater-Than-10-V Compact Tunable Pulse Generator for Low-Duty-Cycle High-Peak-Power Ultra-Wideband Applications
Authors: Jin Renfeng , Halder Subrata , Curtice Walter R. , Hwang James C. M. , Law Choi L.
Published: August 2011

An ultra-wideband pulse generator was designed and fabricated in GaAs HBT IC technology. The generator includes delay and differential circuits to convert a TTL input into a Gaussian pulse signal as well as a Class-C amplifier to boost the pulse amplitude while compressing the pulse width. By adjusting the collector bias of the Class-C amplifier, the pulse amplitude can be varied linearly between 3.5 V and 11.5 V while maintaining the pulse width at 0.3 ± 0.1 nanosecond. Alternatively, by adjusting the base bias of the Class-C amplifier, the pulse width can be varied linearly between 0.25 ns and 0.65 ns while maintaining the pulse amplitude at 10 ± 1 V. Finally, the amplified Gaussian signal can be shaped into a monocycle signal by anL-Cderivative circuit. The present pulse generator compares favorably with pulse generators fabricated in CMOS ICs, step-recovery diodes, or other discrete devices.
Stepwise Increases in Left Ventricular Mass Index and Decreases in Left Ventricular Ejection Fraction Correspond with the Stages of Chronic Kidney Disease in Diabetes Patients
Authors: Chen Szu-Chia , Chang Jer-Ming , Liu Wan-Chun , Tsai Yi-Chun , Tsai Jer-Chia , Su Ho-Ming , Hwang Shang-Jyh , Chen Hung-Chun
Published: August 2011

Aims. Patients with diabetic nephropathy are reported to have a high prevalence of left ventricular structural and functional abnormalities. This study was designed to assess the determinants of left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF) in diabetic patients at various stages of chronic kidney disease (CKD).Methods. This cross-sectional study enrolled 285 diabetic patients with CKD stages 3 to 5 from our outpatient department of internal medicine. Clinical and echocardiographic parameters were compared and analyzed.Results. We found a significant stepwise increase in LVMI (P<0.001), LVH (P<0.001), and LVEF<55%(P=0.013) and a stepwise decrease in LVEF (P=0.038) corresponding to advance in CKD stages.Conclusions. Our findings suggest that increases in LVMI and decreases in LVEF coincide with advances in CKD stages in patients with diabetes.
The Applications and Obstacles of Metabonomics in Traditional Chinese Medicine
Authors: Liu Ping , Liu Songlin , Tian Daizhi , Wang Ping
Published: August 2011

In the recent years, a wide range of metabonomic technologies are widely used in the modern research of traditional chinese medicine (TCM). At present, the most prevailing methods for TCM research are mainly nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). With these techniques, metabonomics will help to understand syndromes, efficacy and toxicity of TCM. However, every analytical technique has its advantages and drawbacks, and there exist some obstacles of its applications on TCM. So, we discuss metabonomics in TCM and analyze some problems of its applications to study TCM in recent years. We believe that with the further development of metabonomic analytical technology, especially multianalysed techniques, metabonomics will greatly promote TCM research and be beneficial to the modernization of TCM.
Salvianolic Acid B Inhibits ERK and p38 MAPK Signaling in TGF-β1-Stimulated Human Hepatic Stellate Cell Line (LX-2) via Distinct Pathways
Authors: Lv Zhigang , Xu Lieming
Published: August 2011

Salvianolic acid B (SA-B) is water-soluble component ofRadix Salvia miltiorrhiza. The previous work indicated that SA-B can inhibit MAPK and Smad signaling in activated hepatic stellate cells (HSCs) to perform anti-fibrotic activity Lv et al. 2010. However, some studies have shown that there is cross-talk between MAPK and Smad in certain cell types. Thus, the anti-fibrotic action of SA-B may be through the cross-talk. In order to clarify the mechanism of SA-B further, we knocked down Smad in LX-2 cells (SRV4) via RNAi, and then added TGF-β1, and PD98059 or SB203580 and SA-B. The levels of p-MEK and p-p38 were inhibited by SA-B in SRV4 independent of TGF-β1. The expression of Col I andα-SMA in SRV4 could be reduced by SA-B independent TGF-β1. SB203580 had not significant effect on p-MEK in SRV4 stimulated by TGF-β1. The levels of p-MEK in SRV4 were not increased significantly after TGF-β1 stimulation. PD98059 had no effect on the levels of p-p38 in SRV4 irrespective of TGF-β1. In conclusion, SA-B inhibits the synthesis of Col I in LX-2 cells independent of TGF-β1 stimulation, and the anti-fibrotic effect of SA-B is due to direct inhibition of p38 signaling and inhibition the cross-talk of Smad to ERK signaling.
A Phase 1 Dose Escalation, Pharmacokinetic, and Pharmacodynamic Evaluation of eIF-4E Antisense Oligonucleotide LY2275796 in Patients with Advanced Cancer
Authors: Hong David S. , Kurzrock Razelle , Oh Yun , Wheler Jennifer , Naing Aung , Brail Les , Callies Sophie , André Valérie , Kadam Sunil K. , Nasir Aejaz , Holzer Timothy R. , Meric-Bernstam Funda , Fishman Mayer , Simon George
Published: August 2011

Purpose: The antisense oligonucleotide LY2275796 blocks expression of cap-binding protein eukaryotic initiation factor 4E (eIF-4E), an mRNA translation regulator upregulated in tumors. This phase I study sought an appropriate LY2275796 dose in patients with advanced tumors.

Experimental Design: A 3-day loading dose, then weekly maintenance doses, were given to 1 to 3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations and tumor biopsies to quantify eIF-4E mRNA/protein.

Results: Thirty patients with stage 4 disease received 1 or more LY2275796 dose. A dose-limiting toxicity was observed at 1,200 mg, with 1,000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1 to 2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and postdose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and 7 patients achieved stable disease (minimum of 6 weeks) as best response, with 2 patients on therapy for more than 3 months (one with melanoma, one with cystadenocarcinoma of the head/neck).

Conclusions: LY2275796 was well tolerated up to 1,000 mg. Because tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities. Clin Cancer Res; 17(20); 6582–91. ©2011 AACR.
Phase I Dose-Finding Study of Pazopanib in Hepatocellular Carcinoma: Evaluation of Early Efficacy, Pharmacokinetics, and Pharmacodynamics
Authors: Yau Thomas , Chen Pei-Jer , Chan Pierre , Curtis C. Martin , Murphy Philip S. , Suttle A. Benjamin , Gauvin Jennifer , Hodge Jeffrey P. , Dar Mohammed M. , Poon Ronnie T.
Published: August 2011

Background: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC).

Experimental Design: Asian patients (N = 28) were dose escalated on pazopanib (200–800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE—MRI).

Results: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child–Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean Cmax and area under the concentration-time curve (AUC0–6) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and Ktrans were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C24 and Cmax values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease.

Conclusion: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. Clin Cancer Res; 17(21); 6914–23. ©2011 AACR.
CBP501-Calmodulin Binding Contributes to Sensitizing Tumor Cells to Cisplatin and Bleomycin
Authors: Mine Naoki , Yamamoto Sayaka , Saito Naoya , Yamazaki Satoshi , Suda Chikako , Ishigaki Machiyo , Kufe Donald W. , Von Hoff Daniel D. , Kawabe Takumi
Published: August 2011

CBP501 is an anticancer drug currently in randomized phase II clinical trials for patients with non–small cell lung cancer and malignant pleural mesothelioma. CBP501 was originally described as a unique G2 checkpoint-directed agent that binds to 14-3-3, inhibiting the actions of Chk1, Chk2, mitogen-activated protein kinase-activated protein kinase 2, and C-Tak1. However, unlike a G2 checkpoint inhibitor, CBP501 clearly enhances the accumulation of tumor cells at G2–M phase that is induced by cisplatin or bleomycin at low doses and short exposure. By contrast, CBP501 does not similarly affect the accumulation of tumor cells at G2–M that is induced by radiation, doxorubicin, or 5-fluorouracil treatment. Our recent findings point to an additional mechanism of action for CBP501. The enhanced accumulation of tumor cells at G2–M upon combined treatment with cisplatin and CBP501 results from an increase in intracellular platinum concentrations, which leads to increased binding of platinum to DNA. The observed CBP501-enhanced platinum accumulation is negated in the presence of excess Ca2+. Some calmodulin inhibitors behave similarly to, although less potently than, CBP501. Furthermore, analysis by surface plasmon resonance reveals a direct, high-affinity molecular interaction between CBP501 and CaM (Kd = 4.62 × 10−8 mol/L) that is reversed by Ca2+, whereas the Kd for the complex between CBP501 and 14-3-3 is approximately 10-fold weaker and is Ca2+ independent. We conclude that CaM inhibition contributes to CBP501′s activity in sensitizing cancer cells to cisplatin or bleomycin. This article presents an additional mechanism of action which might explain the clinical activity of the CBP501–cisplatin combination. Mol Cancer Ther; 10(10); 1929–38. ©2011 AACR.
BRCA Mutation Status and Determinant of Outcome in Women with Recurrent Epithelial Ovarian Cancer Treated with Pegylated Liposomal Doxorubicin
Authors: Safra Tamar , Borgato Lucia , Nicoletto Maria Ornella , Rolnitzky Linda , Pelles-Avraham Sharon , Geva Ravit , Donach Martin Edward , Curtin John , Novetsky Akiva , Grenader Tal , Lai Wei-Chu V. , Gabizon Alberto , Boyd Leslie , Muggia Franco
Published: August 2011

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31–83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4–21.6] versus 8.1 months (95% CI: 6.1–10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI: 32.5–indeterminate) versus 22.6 months (95% CI: 17.0–34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08–2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18–3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93–2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance. Mol Cancer Ther; 10(10); 2000–7. ©2011 AACR.
Dietary Folate Deficiency Blocks Prostate Cancer Progression in the TRAMP Model
Authors: Bistulfi Gaia , Foster Barbara A. , Karasik Ellen , Gillard Bryan , Miecznikowski Jeff , Dhiman Vineet K. , Smiraglia Dominic J.
Published: August 2011

Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies have found that dietary folate interventions can affect colon cancer biology in rodent models, its impact on prostate is unknown. The purpose of this study was to determine whether dietary folate manipulation, possibly being of primary importance for prostate epithelial cell metabolism, could significantly affect prostate cancer progression. Strikingly, mild dietary folate depletion arrested prostate cancer progression in 25 of 26 transgenic adenoma of the mouse prostate (TRAMP) mice, in which tumorigenesis is prostate-specific and characteristically aggressive. The significant effect on prostate cancer growth was characterized by size, grade, proliferation, and apoptosis analyses. Folate supplementation had a mild, nonsignificant, beneficial effect on grade. In addition, characterization of folate pools (correlated with serum), metabolite pools (polyamines and nucleotides), genetic and epigenetic damage, and expression of key biosynthetic enzymes in prostate tissue revealed interesting correlations with tumor progression. These findings indicate that prostate cancer is highly sensitive to folate manipulation and suggest that antifolates, paired with current therapeutic strategies, might significantly improve treatment of prostate cancer, the most commonly diagnosed cancer in American men. Cancer Prev Res; 4(11); 1825–34. ©2011 AACR.
Staphylococcal α-Toxin Induces a Higher T Cell Proliferation and Interleukin-31 in Atopic Dermatitis
Authors: Niebuhr Margarete , Mamerow Diana , Heratizadeh Annice , Satzger Imke , Werfel Thomas
Published: August 2011

Background: Patients with atopic dermatitis (AD) are frequently colonized with α-toxin-producing Staphylococcus aureus which is in turn positively correlated with the severity of eczema. Methods: In this study we addressed T cell proliferation and T cell as well as monocyte cytokine secretion upon α-toxin stimulation in peripheral blood mononuclear cells (PBMCs) from AD patients compared to healthy controls. Results: We found that α-toxin stimulation of PBMCs markedly enhanced T cell proliferation both in patients with AD and healthy controls and was significantly increased in AD patients compared to healthy controls. PBMCs of AD patients secreted significantly more IL-31 compared to those of healthy controls upon α-toxin and SEB stimulation. Moreover, α-toxin stimulation yielded an increase in T cell (IL-2, IL-9, IL-10 and IFN-γ) as well as monocyte (IL-1β and TNF-α) cytokine secretion. Conclusion: Our results could partly explain how skin colonization and infection with S. aureus can contribute to chronic skin inflammation and pruritus in AD.
The Turkish Hereditary Angioedema Pilot Study (TURHAPS): The First Turkish Series of Hereditary Angioedema
Authors: Kesim Belgin , Uyguner Zehra Oya , Gelincik Aslı , Mete Gökmen Nihal , Sin Aytül Z. , Karakaya Gül , Erdenen Füsun , Ardeniz Ömür , Özşeker Ferhan , Gülbahar Okan , Çolakoğlu Bahattin , Dal Murat , Büyüköztürk Suna
Published: August 2011

Background: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients. Methods: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE. Results: The majority of patients were female (60%), the mean age was 37.7 ± 14.1 years. The mean age at the time of first angioedema symptom was 12.5 ± 9.2 years. Mean time lag between first symptom and diagnosis was 26 ± 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described. Conclusion: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease.
Anatomic Predictors of Retropalatal Mechanical Loads in Patients with Obstructive Sleep Apnea
Authors: Li Yanru , Ye Jingying , Li Tianzuo , Lin Na , Wang Zhenchang , Liang Chenyang , Sperry Al , Han Demin
Published: August 2011

Background: The retropalatal airway is one of the most collapsible sites during sleep in patients with obstructive sleep apnea (OSA). The primary anatomical contributors to increased collapsibility in the retropalatal segment remain unclear. Objectives: This study seeks to investigate how the balance between pharyngeal soft tissues and the bony enclosure influences retropalatal mechanical loads in patients with OSA. Methods: The segmental mechanical load of the retropalatal pharynx was determined by the region’s critical closing pressure in 30 anesthetized, paralyzed and intubated subjects with OSA. The volumetric anatomical parameters of the retropalatal airway were evaluated using magnetic resonance imaging, and their associations with retropalatal closing pressures were analyzed. Results: Increased retropalatal closing pressure was associated with the increased proportion of volumetric pharyngeal soft tissues to the surrounding cervicomandibular bony frame (r = 0.791, p < 0.001), enlarged soft tissues of the lateral wall (r = 0.752, p < 0.001) and soft palate (r = 0.726, p < 0.001). The decreased volume of the nasopharynx (r = –0.650, p < 0.001) and pharyngeal cavity (r = –0.653, p < 0.001) indicated a relatively higher retropalatal closing pressure. The multivariate linear regression model demonstrated that the proportion of retropalatal soft tissues to the bony frame and volume of the soft palate predicted 69.4% of the variability in closing pressure (F = 30.674, p < 0.001). Conclusions: The increased volumetric proportion of pharyngeal soft tissue to the bone enclosure may be an important contributor to increased retropalatal mechanical loads.
Is Doubling of Serum Creatinine a Valid Clinical ‘Hard’ Endpoint in Clinical Nephrology Trials?
Authors: Lambers Heerspink H.J. , Perkovic V. , de Zeeuw D.
Published: August 2011

The composite of end stage renal disease (ESRD), doubling of serum creatinine and (renal) death, is a frequently used endpoint in randomized clinical trials in nephrology. Doubling of serum creatinine is a well-accepted part of this endpoint because a doubling of serum creatinine reflects a large sustained change in glomerular filtration rate (GFR) and predicts the development of ESRD. Although doubling of serum creatinine is frequently used, the validity of using this outcome as part of a composite endpoint is hampered by various factors. Firstly, serum creatinine may reflect changes in muscle mass unrelated to true GFR changes. Secondly, changes in serum creatinine may reflect hemodynamic changes in renal perfusion and not a structural effect on renal function. Finally, doubling of serum creatinine is an arbitrary choice and different proportional changes may represent a better indicator for ESRD. In this minireview, each of these factors will be discussed and recommendations are made for interpretation of clinical trials using doubling of serum creatinine as a composite endpoint in nephrology trials.
Mechanisms of TGF-β-Induced Differentiation in Human Vascular Smooth Muscle Cells
Authors: Tang Yuefeng , Yang Xuehui , Friesel Robert E. , Vary Calvin P.H. , Liaw Lucy
Published: August 2011

Background: Transforming growth factor-β (TGF-β) plays an important role in vascular homeostasis through effects on vascular smooth muscle cells (SMC). Fine-tuning of TGF-β signaling occurs at the level of ALK receptors or Smads, and is regulated with cell type specificity. Methods: Our goal was to understand TGF-β signaling in regulating SMC differentiation marker expression in human SMC. Activation of Smads was characterized, and loss- and gain-of-function reagents used to define ALK pathways. In addition, Smad-independent mechanisms were determined. Results: TGF-β type I receptors, ALK1 and ALK5, are expressed in human SMC, and TGF-β1 phosphorylates Smad1/5/8 and Smad2/3 in a time- and dosage-dependent pattern. ALK5 activity, not bone morphogenetic protein type I receptors, is required for Smad phosphorylation. Endoglin, a TGF-β type III receptor, is a TGF-β1 target in SMC, yet endoglin does not modify TGF-β1 responsiveness. ALK5, not ALK1, is required for TGF-β1-induction of SMC differentiation markers, and ALK5 signals through an ALK5/Smad3- and MAP kinase-dependent pathway. Conclusion: The definition of the specific signaling downstream of TGF-β regulating SMC differentiation markers will contribute to a better understanding of vascular disorders involving changes in SMC phenotype.
Aging and Physiological Changes of the Kidneys Including Changes in Glomerular Filtration Rate
Authors: Musso Carlos G. , Oreopoulos Dimitrios G.
Published: August 2011

In addition to the structural changes in the kidney associated with aging, physiological changes in renal function are also found in older adults, such as decreased glomerular filtration rate, vascular dysautonomia, altered tubular handling of creatinine, reduction in sodium reabsorption and potassium secretion, and diminished renal reserve. These alterations make aged individuals susceptible to the development of clinical conditions in response to usual stimuli that would otherwise be compensated for in younger individuals, including acute kidney injury, volume depletion and overload, disorders of serum sodium and potassium concentration, and toxic reactions to water-soluble drugs excreted by the kidneys. Additionally, the preservation with aging of a normal urinalysis, normal serum urea and creatinine values, erythropoietin synthesis, and normal phosphorus, calcium and magnesium tubular handling distinguishes decreased GFR due to normal aging from that due to chronic kidney disease.
Senile Nephrosclerosis – Does It Explain the Decline in Glomerular Filtration Rate with Aging
Authors: Rule Andrew D. , Cornell Lynn D. , Poggio Emilio D.
Published: August 2011

Nephrosclerosis can be defined by the presence of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis on renal biopsy. Chronic kidney disease is identified clinically by a reduction in glomerular filtration rate (GFR) and has been characterized histologically by nephrosclerosis. Many relatively healthy older adults have been diagnosed with chronic kidney disease because of a decline in GFR with normal aging. Recent data show that in healthy adults (living kidney donors), nephrosclerosis on renal biopsy does not associate with GFR independent of age. This may be explained by the decline in GFR and nephrosclerosis being universal with aging (i.e. senescence), by structural changes in the kidney other than nephrosclerosis impacting GFR, or by extrarenal factors affecting GFR decline with age. However, the argument that the age-related decline in GFR can be fully explained by the development of nephrosclerosis in a subset of older adults is not supported by existing data.
Dialysis Options for End-Stage Renal Disease in Older People
Authors: Brown Edwina A. , Johansson Lina
Published: August 2011

The numbers of older patients requiring dialysis therapy is rising, reflecting the ageing of the general population. Older dialysis patients have a tendency to present later for dialysis, have a higher number of comorbid conditions, are at higher risk of cognitive dysfunction and have increased levels of frailty. These are all barriers to home dialysis therapy so hospital haemodialysis (HD) is the predominant dialysis modality for older patients. Evidence suggests, however, that home treatment with peritoneal dialysis (PD) intrudes less into the life of older patients than hospital HD. Assisted PD is available in some countries and this enables more older patients to be treated in their own homes. Adjustments to patient education also need to be made to accommodate the barriers to learning and decision-making that often exist in older people.
Cautious Renal Transplantation for the Elderly Is Realistic
Authors: Friedman Amy L.
Published: August 2011

Excellent results of transplantation in elderly recipients, together with regulatory requirements encourage continued consideration of this modality. The organ shortage compels the use of deceased-donor kidneys and may be a suboptimal therapy. However, the elderly patient may not tolerate the prolonged wait for an optimal organ. While individual comorbidities can be evaluated, patient selection requires the transplantation team to render a judgment based on the candidate’s overall condition, which is best correlated with the ability to accomplish activities of daily living and to perform moderate exercise. Psychosocial considerations are complex in the elderly patient because of frequent dementia, absence of a sufficient support mechanism and the need for more resources than those required by younger patients. After transplantation, appropriate management of immunosuppression typically entails lower doses in elderly patients, a logical consequence of immunosenescence. Transplantation should not be considered an acceptable exercise in futility when the ability to offer this life-saving therapy to other patients will be adversely affected by doing so.
Acute Kidney Injury in the Elderly: Predisposition to Chronic Kidney Disease and Vice Versa
Authors: Coca Steven G. , Cho Kerry C. , Hsu Chi-yuan
Published: August 2011

There have been considerable advances in the past few years in our understanding of how chronic kidney disease (CKD) predisposes to acute kidney injury (AKI) and vice versa. This review shows, however, that few studies have focused on the elderly or conducted stratified analysis by age. It does appear that elderly patients with estimated glomerular filtration rate (eGFR) 45–59 ml/min/1.73 m2 are at higher risk for AKI compared with their counterparts with eGFR >60 ml/min/1.73 m2. This is a similar relationship to that seen in younger patients, although effect size appears smaller. As the incidence of AKI has been increasing over the past several years, the proportion of elderly patients surviving after AKI has also been increasing. Since AKI heightens the risk for the development and acceleration of CKD, this implies significant public health concerns with regard to the absolute number of elderly persons developing incident CKD.
Trimethoprim, Creatinine and Creatinine-Based Equations
Authors: Delanaye Pierre , Mariat Christophe , Cavalier Etienne , Maillard Nicolas , Krzesinski Jean-Marie , White Christine A.
Published: August 2011

Co-trimoxazole is a frequently prescribed antibiotic worldwide. It is composed of both trimethoprim and sulfamethoxazol (Sfx) and is used in the treatment and prophylaxis of urinary tract and Pneumocystis jirovecii infections. The Sfx component appears to be nephrotoxic at high doses or doses inappropriately adjusted for glomerular filtration rate (GFR). The trimethoprim component, even at recommended doses, inhibits tubular creatinine secretion, leading to a rapid but ultimately reversible increase in serum creatinine independent of any changes in GFR. This translates into a falsely low estimated GFR when creatinine-based equations are used. This review focuses on evidence of the differential effects of trimethoprim and Sfx on serum creatinine concentrations and GFR and their relevance to clinical practice, with particular attention to kidney transplantation.
The Kidney, a Victim and Culprit of Autoimmune and Alloimmune Responses
Authors: Ponticelli Claudio , Salvadori Maurizio , Coppo Rosanna
Published: August 2011

The Working Group of the European Renal Association-European Nephrology and Dialysis Association (ERA-EDTA) dedicated to immune system involvement in renal disease (Immunonephrology Working Group) was established in 2009 to facilitate exchanges of ideas on basic science research and new treatment protocols among European nephrologists. A section of the ERA-EDTA website describes activities and is open for new applications and proposals. In 2010, the first meeting of this Working Group focused on aspects of immune-mediated renal damage shared by kidney during glomerulonephritides or after kidney transplantation. From the large series of data reported, a previously disregarded presence of pathogenetic and therapeutic aspects common to glomerular diseases and transplanted kidneys was highlighted. Although the antigens involved in transplant rejection and in glomerulonephritis are different, a number of factors involved in the effector response are similar, mainly those based on the interaction between innate and adaptive immune mechanisms and on the strict cooperation between T and B cells. Moreover, the common target for the allo- and autoimmune attacks is represented by the endothelial cells, of which the kidney is particularly rich. These similarities may explain why immunomodulating treatments used in alloimmunity may also be useful in autoimmune diseases and vice versa. Considering renal damage from a holistic point of view may favour exchange of news for two formerly considered non-communicant areas, i.e. glomerular disease and renal transplantation nephrology sections.
Potential Role of Serine Proteases in Modulating Renal Sodium Transport in vivo
Authors: Jacquillet G. , Rubera I. , Unwin R.J.
Published: August 2011

The maintenance of sodium (Na+) homeostasis is an essential function of the kidney. It is achieved by a variety of transport processes localized all along the highly specialised segments of the nephron. Impairment of these transport mechanisms, and thereby Na+ handling, is associated with disturbed Na+ and water balance, leading to hypertension and oedema. This review focuses on the novel regulation of sodium reabsorption by serine proteases acting along the entire nephron.
Vitamin D Deficiency, Mortality, and Hospitalization in Hemodialysis Patients with or without Protein-Energy Wasting
Authors: Fiedler Roman , Dorligjav Otgontogoo , Seibert Eric , Ulrich Christof , Markau Silke , Girndt Matthias
Published: August 2011

Background:Vitamin D deficiency and protein-energy wasting (PEW) are highly prevalent in hemodialysis (HD) patients. The goal of our study was to investigate if a lack of vitamin D influences mortality and hospitalization of HD patients with or without PEW. Methods: In 81 chronic HD patients with different nutritional status assessed by the Malnutrition Inflammation Score (MIS), vitamin D deficiency (25-OH-vitamin D3 levels ≤30 nmol/l or ≤12 ng/ml) was prospectively investigated for its prognostic impact on mortality and hospitalization. Over a 3-year follow-up, all-cause mortality and hospitalization were determined. The predictive value of low vitamin D levels and PEW as well as their combined effect were evaluated using a multivariate Cox regression model. Results: Vitamin D deficiency was frequent in HD patients with and without PEW. It significantly increased mortality rate in HD patients (HR 2.76 (1.33–5.73), p < 0.01), which was aggravated by concomitant PEW (HR 5.88 (2.29–15.09), p < 0.001). The hospitalization rate, however, was not influenced independently by nutritional status. Conclusions: Low 25-OH-vitamin D3 concentration is an independent predictor for survival, but not for hospitalization of HD patients. It is not merely a malnutrition-associated finding, although a MIS ≧8 further impaired survival prognosis.
Cocaine- and Amphetamine-Regulated Transcript in Neuroendocrine Tumors
Authors: Landerholm Kalle , Falkmer Sture E. , Järhult Johannes , Sundler Frank , Wierup Nils
Published: August 2011

Background/Aims: Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic regulatory peptide highly expressed in the brain’s appetite control centers, but also in peripheral neurons and in endocrine cells in the adrenal medulla, thyroid, pancreatic islets, and in the gastrointestinal tract. Plasma levels of CART were recently shown to be elevated in patients with neuroendocrine tumors (NETs), but the cellular sources of CART in NETs have remained unknown. The aim of the study was to establish whether CART is expressed in various types of NETs and, if so, to examine the frequency, distribution and phenotype of CART-expressing cells. Methods: Tumor specimens from 133 NETs originating in the stomach, ileum, rectum, pancreas and thyroid were examined with immunohistochemistry and in situ hybridization. The expression of CART was quantified and the CART-expressing cells were phenotyped by double staining for established markers and hormones. Results: CART-expressing tumor cells were found in the majority of the examined NETs. The expression pattern of CART was highly heterogeneous not only between tumors, but also within individual tumors. In 14% of the NETs, CART was found in a major population of the tumor cells. Conclusion: CART is produced in the majority of NETs, regardless of tumor origin. This likely explains the elevated levels of circulating CART in certain NETs patients, as recently described. CART could therefore prove to be a useful tool in the diagnostics of NETs not only in blood samples, but also in histopathological specimens.
Choosing Not to Take Phosphate Binders: The Role of Dialysis Patients’ Medication Beliefs
Authors: Wileman Vari , Chilcot Joseph , Norton Sam , Hughes Lyndsay , Wellsted David , Farrington Ken
Published: August 2011

Objective: Patients with end-stage renal disease (ESRD) receiving haemodialysis are at risk of cardiovascular disease and bone disorders related to high levels of serum phosphate (PO4). Phosphate binders are an important treatment; however, non-adherence remains a significant issue. This study investigates whether patients’ beliefs about medicines predict intentional non-adherence to phosphate binders. Method: This was a cross-sectional study of ESRD patients (n = 76). Non-adherence was measured in two ways: (1) the self-report Medication Adherence Questionnaire (MAQ) and (2) 3-month average level of serum phosphate. The Beliefs about Medicines questionnaire was used to assess general and specific beliefs towards phosphate medicines. Results: Eleven (14.5% of 76) patients reported being intentionally non-adherent to phosphate binders. Patients’ beliefs that phosphate binders were less necessary were significantly associated with intentional self-reported non- adherence. Furthermore, patients with greater concerns about phosphate binders had higher serum phosphate levels. Conclusion: Assessing patient beliefs about medicines is a reliable indicator of intentional non-adherence to treatment with phosphate binders. These findings may help in identifying ways in which adherence rates to phosphate binders can be improved.
Spirometric Maneuvers and Inhaled Salbutamol Do Not Affect Exhaled Nitric Oxide Measurements among Patients with Allergic Asthma
Authors: Garriga Teresa , Labrador-Horrillo Moisés , Guillén Mercè , Luengo Olga , Eseverri Jose Luis , Guilarte Mar , Marin Ana María , Cardona Victòria
Published: August 2011

Background: Exhaled nitric oxide (ENO) is used as a marker of airway inflammation. Factors such as spirometric maneuvers (SPM), β2-agonists, or tobacco smoking have been postulated to affect ENO measurements. Guidelines on measurement techniques have been published based on expert opinions. Nevertheless, there is no strong clinical evidence of many aspects because they have not been supported by research data. Objectives: The aim of this study was to evaluate the influence of performing a spirometry or receiving inhaled salbutamol on ENO readings. Methods: One hundred forty-five adults and 62 children with allergic asthma were included with a mean age of 36 ± 13 years for adults and 13 ± 2 years for children. A control group comprised 30 healthy adults and 30 children with a mean age of 37 ± 14 years and 13 ± 2 years, respectively. ENO measurements were performed with a NIOX-MINO® electrochemical device. In 179 patients ENO was measured before and after performing SPM and in 88 patients before and 15 min after SPM plus 2 puffs of salbutamol (100 µg/puff). Results: There were no significant differences in mean ENO levels before and after SPM or before and after SPM plus 2 puffs of inhaled salbutamol in adults or children (asthmatic or healthy). Conclusions: Levels of ENO are not significantly affected by SPM or salbutamol inhalation.
Association of Th1/Th2-Related Chemokine Receptors in Peripheral T Cells with Disease Activity in Patients with Multiple Sclerosis and Neuromyelitis Optica
Authors: Shimizu Yuko , Ota Kohei , Kubo Sachiko , Kabasawa Chiaki , Kobayashi Masaki , Ohashi Takashi , Uchiyama Shinichiro
Published: August 2011

We evaluated 30 patients with clinically definite multiple sclerosis (MS) and 8 patients with neuromyelitis optica (NMO) to investigate correlations between Th1/Th2 balance, disease activity, effects of interferon (IFN)-β treatment, and expressions of chemokine receptors CXCR3 and CCR4 on CD4+ and CD8+ T cells in peripheral blood. MS and NMO patients in the relapsing phase showed a significantly increased CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio compared with respective patients in the remission phase. After IFN-β treatment, the CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio were significantly decreased compared with the relapsing phase and slightly lower than in the remission phase. The CD8+CXCR3+/CD8+CCR4+ ratio showed a more marked change associated with disease activity than CD4+ T cells in MS and NMO patients. Moreover, in patients in the relapsing phase of NMO, the CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio were significantly higher than in MS patients in the relapsing phase. We confirmed marked changes in the CD8+CXCR3+/CD8+CCR4+ ratio according to disease activity and treatment of MS and NMO. Furthermore, this ratio was more strongly linked to immune and inflammatory activity in NMO patients than in MS patients, and may represent an important factor in differentiating the pathogenesis of MS and NMO.
Incidence of Bactobilia Increases over Time after Endoscopic Sphincterotomy
Authors: Reinders J.S. , Kortram K. , Vlaminckx B. , van Ramshorst B. , Gouma D.J. , Boerma D.
Published: August 2011

Patients with choledochocystolithiasis are usually treated by endoscopic retrograde cholangiography with endoscopic sphincterotomy (ES) followed by laparoscopic cholecystectomy (LC). LC after ES is more difficult than in uncomplicated gallstone disease, possibly due to bacterial colonization of the common bile duct. The goal of this study was to evaluate if bactobilia influences the peri- and postoperative outcomes. Data were obtained from a randomized trial on the timing of LC after ES. Ninety-six patients were randomized after ES to LC either within 72 h (early LC [ELC]) or in 6–8 weeks (delayed LC [DLC]). In 64 of 96 patients bile samples were obtained peroperatively. The overall prevalence of bactobilia was 62.5% [40/64; 50% of ELC patients (n = 13) vs. 71.1% in the DLC group (n = 27); p = 0.088]. Age and group (i.e. ELC/DLC) were independent and significant predictors for the presence of bactobilia. The presence of bactobilia did not influence operating time and difficulty or conversion rate. Patients with bactobilia developed more biliary events in the period between ES and LC (44 vs. 28%). After ES for choledochocystolithiasis, 62.5% of patients have bactobilia at the time of surgery. The prevalence of bactobilia increases with age and time. Patients with bactobilia tend to develop more biliary-related complications awaiting surgery.
Insulin Increases Acid Production and May Directly Stimulate Na+/H+ Exchange Activity in Cultured Vascular Smooth Muscle Cells
Authors: Kahn Andrew M. , Yang Ming
Published: August 2011

Insulin was reported to decrease Na+/H+ exchange activity in murine vascular smooth muscle (VSM) tissue. In most other cells, insulin increases activity. We tested the effects of insulin on Na+/H+ exchange activity in primary cultured canine VSM cells. Intracellular pH (pHi) was measured with 2′,7′-bis(2-carboxyethyl)-5-carboxyfluorescein fluorescence and Na+ uptake by isotopic methods. Insulin alone did not significantly affect pHi (7.13 ± 0.05 vs. 7.10 ± 0.03 for control and insulin, respectively; p = not significant), and EIPA alone lowered it to 6.98 ± 0.04 (p < 0.05), upon which insulin lowered it further to 6.91 ± 0.04 (p < 0.05). In the presence of a pHi clamp, pHi/extracellular pH (pHo) 7.1/7.4, insulin increased amiloride-sensitive 22Na uptake by 98 ± 25% (p < 0.05). At pHi/pHo 6.0/7.4 or 6.7/7.4, amiloride-sensitive 22Na uptake was stimulated by 378 ± 59 and 105 ± 27%, respectively, compared to pHi/pHo 7.1/7.4 (p < 0.05 for all 3 versus each other), but was insulin insensitive. In acid-loaded cells (pHi 6.0), addition of extracellular Na+ (pHo 7.4) caused rapid intracellular alkalinization, and the initial rate was not affected by insulin. It is concluded that insulin stimulates acid accumulation in VSM cells that is normally effluxed by increased Na+/H+ exchange activity, and insulin may directly stimulate Na+/H+ exchange activity when cells are clamped at resting pHi but not at acidic pHi.
High-Resolution Computed Tomography Quantitation of Emphysema Is Correlated with Selected Lung Function Values in Stable COPD
Authors: D’Anna Silvestro Ennio , Asnaghi Roberto , Caramori Gaetano , Appendini Lorenzo , Rizzo Manfredi , Cavallaro Carmelo , Marino Giorgio , Cappello Francesco , Balbi Bruno , Di Stefano Antonino
Published: August 2011

Background: The literature shows conflicting results when high-resolution computed tomography (HRCT) scores of emphysema were correlated with different indices of airflow obstruction. Objectives: We correlated HRCT scores of emphysema with different indices of airflow obstruction. Methods: We performed HRCT of the chest in 59 patients, all smokers or ex-smokers, with stable chronic obstructive pulmonary disease of different severity [GOLD stages I–IV; mean age ± SD 67.8 ± 7.3 years; pack/years 51.0 ± 34.6; percent predicted forced expiratory volume in 1 s (FEV1% predicted) 52.3 ± 17.6; post-bronchodilator FEV1% predicted 56.5 ± 19.1; FEV1/forced vital capacity (FVC) ratio 50.8 ± 10.2; post-bronchodilator FEV1/FVC ratio 51.6 ± 11.0; percent diffusion lung capacity for carbon monoxide (DLCO%) 59.2 ± 21.1; DLCO/percent alveolar volume (VA%) 54.5 ± 18.2; percent residual volume 163.0 ± 35.6; percent total lung capacity (TLC%) 113.2 ± 15; residual volume/TLC 1.44 ± 0.2]. All patients were in stable phase. Results: The mean ± SD visual emphysema score in all patients was 25.6 ± 25.4%. There was a weak but significant correlation between the percentage of pulmonary emphysema and numbers of pack/years (R = +0.31, p = 0.024). The percentage of emphysema was inversely correlated with the FEV1/FVC ratio before and after bronchodilator use (R = –0.44, p = 0.002, and R = –0.39, p = 0.005), DLCO% (R = –0.64, p = 0.0003) and DLCO/VA% (R = –0.68, p < 0.0001). A weak positive correlation was also found with TLC% (R = +0.28, p = 0.048). When patients with documented emphysema were considered separately, the best significant correlation observed was between DLCO/VA% and HRCT scan score (p = 0.007). Conclusions: These data suggest that in patients with stable chronic obstructive pulmonary disease of varying severity, the presence of pulmonary emphysema is best represented by the impaired gas exchange capability of the respiratory system.
Low Doses of Cadmium Chloride and Methallothionein-1-Bound Cadmium Display Different Accumulation Kinetics and Induce Different Genes in Cells of the Human Nephron
Authors: Cucu Dana , D’Haese Patrick C. , De Beuf Annelies , Verhulst Anja
Published: August 2011

Background/Aims: The present study was conducted to investigate the renal tubular handling of inorganic cadmium (Cd2+) by exposing primary human tubular cell cultures to physiologically relevant doses of cadmium chloride (CdCl2). Furthermore, the cellular accumulation of Cd2+ was compared to that of metallothionein-1-bound Cd (Cd7MT-1). Finally, this study aimed to investigate the effect of the accumulation of Cd (both Cd2+ and Cd7MT-1) in renal cells on the expression of genes relevant to nephrotoxic processes. Methods: Cd concentration was measured using atomic absorption spectrometry. mRNA expression was evaluated by quantitative real-time RT-PCR. Results: Cd2+ accumulated into human tubular cells in a concentration- and time-dependent way. Furthermore, cellular accumulation of Cd2+ was different from the cellular accumulation of Cd7MT-1, indicative for different uptake routes. Finally, mRNA expression of the genes encoding the anti-oxidative proteins metallothionein-1 (MT-1) and heme-oxygenase-1 (HO-1) as well as the pro-apoptotic Bcl-2-associated X protein (Bax) were upregulated by CdCl2 and not by Cd7MT1. Conclusion: In the presence of physiologically relevant Cd concentrations, tubular accumulation of the element in its inorganic form is different from that of Cd7MT-1. Furthermore, the tubular accumulation of inorganic Cd induces mRNA expression of genes of which the protein products may play a role in Cd-associated renal toxicity.