bluuebunny/crossref_metadata_2025 huggingface dataset:
Ligustrazine Injection for Chronic Pulmonary Heart Disease: A Systematic Review and Meta-Analysis
Authors: Jian-sheng Li , Hai-feng Wang , Yun-ping Bai , Su-yun Li , Xue-qing Yu , Ya Li
Published: August 2011

Objective. This study was intended to evaluate the efficacy and safety of ligustrazine injection for chronic pulmonary heart disease (CPHD).Method. Randomized controlled trials (RCTs) of clinical therapeutic studies on CPHD when using ligustrazine injection were included. Searches were applied to the following electronic databases: the PubMed, the Cochrane Library, EMBASE, CBM, and AMED. No language restriction was used. All trials included were analyzed according to the criteria of the Cochrane Handbook. Review Manager 5.0 software was used for data analysis.Result. 34 RCTs with low methodological quality were included. Compared to conventional medicine treatment alone, ligustrazine injection plus conventional medicine treatment showed improvement in New York Heart Association classification of clinical status (Odds ratio 0.22; 95% CI 0.17 to 0.28) and depression of pulmonary artery hypertension (weighted mean difference −4.77; 95% CI −5.85 to −3.68). Three studies had reported adverse events. No serious adverse effects were reported.Conclusion. While there is some evidence that suggests potential effectiveness of ligustrazine injection for CPHD, the results were limited by the methodological flaws of the studies. High quality studies are needed to provide clear evidence for the future use of ligustrazine injection.
Synergistic Action of a RAF Inhibitor and a Dual PI3K/mTOR Inhibitor in Thyroid Cancer
Authors: Jin Ning , Jiang Tianyun , Rosen David M. , Nelkin Barry D. , Ball Douglas W.
Published: August 2011

Purpose: In thyroid cancer clinical trials, agents targeting VEGF receptors (VEGFR) and RET, among other kinases, have led to partial responses but few complete or durable responses. The RAF–MEK–ERK and PI3K–AKT–mTOR signaling pathways are frequently activated in differentiated and medullary thyroid cancer (DTC and MTC) and may provide therapeutic targets for these diseases. We tested a novel drug combination targeting RAF, phosphoinositide 3-kinase (PI3K), and mTOR, plus VEGFR2 and RET, in thyroid cancer preclinical models with defined genetic backgrounds.

Experimental Design: RAF265, an ATP-competitive pan-RAF inhibitor active against VEGFR2, and BEZ-235, a PI3K inhibitor also active against Torc1 and Torc2, were tested alone and in combination in a panel of thyroid cancer lines. We tested RAF265 and BEZ-235 for kinase inhibition, growth inhibition and cell-cycle alterations, and inhibition of signaling targets and tumor growth in xenograft models.

Results: Both drugs potently inhibited their kinase targets in the extracellular signal-regulated kinase (ERK) and PI3K pathways. In addition, RAF265 had significant RET inhibitory activity (IC50 = 25–50 nmol/L for RETC634W). The combination strongly inhibited proliferation of DTC and MTC cell lines with mutations in RAS, BRAF, PTEN, and RET. Synergy was shown for B-CPAP (BRAFV600E) and TT cells (RETC634W). The combination of both drugs significantly inhibited growth of CAL62 (KRASG12R/G12R) and TT xenografts, thoroughly inhibiting ERK and PI3K pathway signaling.

Conclusions: Combined blockade of ERK and PI3K signaling potently inhibits growth in preclinical models representing the key genotypes seen in refractory thyroid cancer. These targets and therapies are promising for further development in both differentiated and medullary thyroid cancers. Clin Cancer Res; 17(20); 6482–9. ©2011 AACR.
Maintained Sensitivity to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer Recurring after Adjuvant Erlotinib or Gefitinib
Authors: Oxnard Geoffrey R. , Janjigian Yelena Y. , Arcila Maria E. , Sima Camelia S. , Kass Samantha L. , Riely Gregory J. , Pao William , Kris Mark G. , Ladanyi Marc , Azzoli Christopher G. , Miller Vincent A.
Published: August 2011

Purpose: Given the unprecedented efficacy of EGFR tyrosine kinase inhibitors (TKI) in advanced EGFR-mutant lung cancer, adjuvant TKI therapy is an appealing strategy. However, there are conflicting findings regarding the potential benefit of adjuvant EGFR-TKI in patients with lung cancer harboring EGFR mutations. To better understand these results, we studied the natural history of lung cancers which recurred despite adjuvant TKI.

Experimental Design: Patients with recurrent EGFR-mutant lung cancer following adjuvant TKI were identified using an Institutional Review Board-approved mechanism. Recurrent cancer specimens were tested for resistance mutations. Sensitivity to retreatment with EGFR-TKI was evaluated.

Results: Twenty-two patients with cancers harboring an EGFR sensitizing mutation received adjuvant erlotinib or gefitinib for a median of 17 months (range 1–37 months). T790M was more common in cancers which recurred while receiving TKI than in those which recurred after stopping TKI (67% vs. 0%, P = 0.011). Fourteen patients who developed recurrence after stopping EGFR-TKI were retreated, with a median time to progression of 10 months and radiographic response seen in 8 of 11 patients with evaluable disease (73%).

Conclusions: Recurrence of EGFR-mutant lung cancer after stopping adjuvant TKI should not preclude a trial of TKI retreatment; a phase II trial of erlotinib in this setting is underway. Studies of adjuvant EGFR-TKI will underestimate the potential survival benefit of adjuvant TKI for patients with EGFR-mutant lung cancers if retreatment at recurrence is not given. Clin Cancer Res; 17(19); 6322–8. ©2011 AACR.
A Phase I First-in-Human Pharmacokinetic and Pharmacodynamic Study of Serdemetan in Patients with Advanced Solid Tumors
Authors: Tabernero Josep , Dirix Luc , Schöffski Patrick , Cervantes Andrés , Lopez-Martin Jose Antonio , Capdevila Jaume , van Beijsterveldt Ludy , Platero Suso , Hall Brett , Yuan Zhilong , Knoblauch Roland , Zhuang Sen Hong
Published: August 2011

Purpose: Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose.

Patients and Methods: Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction.

Results: The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (Cmax) was 2,330 ng/mL and mean area under plasma concentration curve (AUC0–24h) was 43.0 μg.h/mL, with serdemetan 300 mg/d. There was a dose- and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease.

Conclusions: Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed. Clin Cancer Res; 17(19); 6313–21. ©2011 AACR.
CYP2S1 and CYP2W1 Mediate 2-(3,4-Dimethoxyphenyl)-5-Fluorobenzothiazole (GW-610, NSC 721648) Sensitivity in Breast and Colorectal Cancer Cells
Authors: Tan Boon Shing , Tiong Kai Hung , Muruhadas Ashwin , Randhawa Nirmal , Choo Heng Lungh , Bradshaw Tracey D. , Stevens Malcolm F.G. , Leong Chee-Onn
Published: August 2011

Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203; NSC 703786) and 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610; NSC 721648) are antitumor agents with novel mechanism(s). Previous studies have indicated that cytochrome (CYP) P450 1A1 is crucial for 5F-203 activity. In the present study, we investigated the functional role of 2 newly identified CYP P450 enzymes, CYP2S1 and CYP2W1, in mediating antitumor activity of benzothiazole compounds. We generated isogenic breast cancer (MDA-MB-468, MCF-7) and colorectal cancer (CRC; KM12 and HCC2998) cell lines depleted for CYP1A1, CYP2S1, or CYP2W1. The sensitivity of these cells to 5F-203 and GW-610 was then compared with vector control cells. 5F-203 exhibited potent activity against breast cancer cells, whereas GW-610 was effective against both breast and colorectal cancer cells. CYP1A1 was induced in both breast cancer and CRC cells, while CYP2S1 and CYP2W1 were selectively induced in breast cancer cells only following treatment with 5F-203 or GW-610. Depletion of CYP1A1 abrogated the sensitivity of breast cancer and CRC cells to 5F-203 and GW-610. Although depletion of CYP2S1 sensitized both breast cancer and CRC cells toward 5F-203 and GW-610, CYP2W1 knockdown caused marked resistance to GW-610 in CRC cells. Our results indicate that CYP-P450 isoforms, with the exception of CYP1A1, play an important role in mediating benzothiazole activity. CYP2S1 appears to be involved in deactivation of benzothiazoles, whereas CYP2W1 is important for bioactivation of GW-610 in CRC cells. Because CYP2W1 is highly expressed in colorectal tumors, GW-610 represents a promising agent for CRC therapy. Mol Cancer Ther; 10(10); 1982–92. ©2011 AACR.
Analysis of Switched Memory B Cells in Patients with IgA Deficiency
Authors: Aghamohammadi Asghar , Abolhassani Hassan , Biglari Mohammad , Abolmaali Sarah , Moazzami Kasra , Tabatabaeiyan Maryam , Asgarian-Omran Hossein , Parvaneh Nima , Mirahmadian Mahroo , Rezaei Nima
Published: August 2011

Background: Selective IgA deficiency (SIGAD) is the most common primary antibody deficiency, characterized by significant decreased serum levels of IgA in the presence of normal IgG and IgM. Despite several investigations into the nature of the disease, the exact pathophysiology of SIGAD is still unknown. Methods: In this study, switched memory B cells (CD19+/CD27+/IgD– cell population) of 28 patients with SIGAD and 28 matched healthy controls were investigated using flow cytometry. Results: The percentage of switched memory B cells in all healthy controls was more than 0.4%. In SIGAD patients, who were classified as group I, the percentage of switched memory B cells was less than 0.4% (0.34 ± 0.06) in 7 patients (25%). The remaining 21 patients were designated as group II (1.74 ± 0.12%). The mean concentration of IgG in group I was significantly lower than in group II (1,014 ± 278 vs. 1,388 ± 406 mg/dl, p = 0.028). Comparison of clinical features between the 2 groups revealed that episodes of pneumonia during the course of disease were significantly higher in group I than in group II (p = 0.002). Autoimmune diseases in group I (57.1%) were also significantly higher (p = 0.01) than in group II (23.8%). The prevalence of bronchiectasis was 57% in group I, while only 1 patient (4.7%) in group II developed bronchiectasis (p = 0.006). Specific antibody deficiency in group I was documented in 5 patients and in group II in 4 patients (p = 0.01). Conclusions: The classification of SIGAD patients by assessment of switched memory B cells could help physicians with the clinical prognosis for these patients, whereas the patients with reduced switched memory B cells are prone to severe phenotypes.
Birch-Apple Syndrome Treated with Birch Pollen Immunotherapy
Authors: Mauro Marina , Russello Marina , Incorvaia Cristoforo , Gazzola Gianbattista , Frati Franco , Moingeon Philippe , Passalacqua Gianni
Published: August 2011

Background: The most common pollen-fruit cross-reaction is the birch-apple syndrome. Allergen immunotherapy (IT) is clearly effective for birch allergy, but its efficacy on apple allergy is controversial. We performed a randomized study on patients with birch-apple syndrome to evaluate the outcome of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). Methods: Forty patients underwent IT with a birch extract (Staloral; Stallergenes, Antony, France), 20 by SCIT and 20 by SLIT. After 1 year of treatment, 15 patients (8 for SCIT and 7 for SLIT) accepted to undergo an oral apple challenge. Measurements of specific IgE to Bet v 1 and Mal d 1 and related allergens Api g 1 and Dau c 1 were obtained in 10 patients, at baseline and after IT. Results: Two of 8 SCIT-treated patients (25%) and 1 of 7 SLIT-treated patients (14.2%) developed complete tolerance to apple. In the remaining patients, an increase in the provocative dose was found in 3 of the SCIT-treated (37.5%) and 2 of the SLIT-treated patients (28.6%). Changes in the levels of specific IgE to Mal d 1 were unrelated to clinical results. Conclusions: These findings suggest that different doses of birch extract may be needed in different patients to improve the associated apple allergy and that a finer diagnostic work-up in selecting patients with birch-apple syndrome who are candidates to respond to birch pollen IT also concerning apple allergy is required.
IgE-Mediated Hypersensitivity Reactions to Cannabis in Laboratory Personnel
Authors: Herzinger T. , Schöpf P. , Przybilla B. , Ruëff F.
Published: August 2011

Background: There have been sporadic reports of hypersensitivity reactions to plants of the Cannabinaceae family (hemp and hops), but it has remained unclear whether these reactions are immunologic or nonimmunologic in nature. Objective: We examined the IgE-binding and histamine-releasing properties of hashish and marijuana extracts by CAP-FEIA and a basophil histamine release test. Methods: Two workers at a forensic laboratory suffered from nasal congestion, rhinitis, sneezing and asthmatic symptoms upon occupational contact with hashish or marijuana, which they had handled frequently for 25 and 16 years, respectively. Neither patient had a history of atopic disease. Serum was analyzed for specific IgE antibodies to hashish or marijuana extract by research prototype ImmunoCAP, and histamine release from basophils upon exposure to hashish or marijuana extracts was assessed. Results were matched to those of 4 nonatopic and 10 atopic control subjects with no known history of recreational or occupational exposure to marijuana or hashish. Results: Patient 1 had specific IgE to both hashish and marijuana (CAP class 2), and patient 2 to marijuana only (CAP class 2). Controls proved negative for specific IgE except for 2 atopic individuals with CAP class 1 to marijuana and 1 other atopic individual with CAP class 1 to hashish. Stimulation of basophils with hashish or marijuana extracts elicited histamine release from basophils of both patients and 4 atopic control subjects. Conclusions: Our results suggest an IgE-related pathomechanism for hypersensitivity reactions to marijuana or hashish.
Lower Expression of Tight Junction Protein 1 Gene and Increased FOXP3 Expression in the Small Bowel Mucosa in Coeliac Disease and Associated Type 1 Diabetes Mellitus
Authors: Vorobjova Tamara , Uibo Oivi , Ojakivi Ivi , Teesalu Kaupo , Panarina Marina , Heilman Kaire , Uibo Raivo
Published: August 2011

Background: The role of regulatory T cells expressing FOXP3 in the pathogenesis of coeliac disease (CD) and type 1 diabetes (T1D) has been reported. Recent data have placed special focus on the interplay between the intestinal barrier and immunoregulatory processes. We aimed to determine whether the expression of tight junction protein 1 (TJP1), which reflects small bowel mucosa permeability, is changed in CD and T1D. Methods: Transcription levels of TJP1 and FOXP3 genes were evaluated in the small bowel biopsies of 14 children with CD, 12 with CD and coexisting T1D and 40 controls using real-time PCR. Serum IgA and IgG to deamidated gliadin, bovine β-lactoglobulin, bovine α-casein and human tissue transglutaminase (tTG) were determined by ELISA. Results: The highest expression of FOXP3 mRNA was seen in patients with CD and T1D compared to patients with CD alone and controls (p = 0.02). In contrast, the lowest level of TJP1 mRNA expression was found in patients with CD and T1D (p = 0.01). The levels of IgA to deamidated gliadin and tTG were highest in patients with CD and T1D (p = 0.0001 and 0.01, respectively). The expression of FOXP3 mRNA correlated highly with the level of anti-gliadin IgA (p = 0.02) and anti-tTG IgA antibodies (p = 0.004). Conclusion: The significant decline in TJP1 expression in CD patients, particularly in those with coexisting T1D, was accompanied by an increase in FOXP3 expression. This might reflect an attempt to maintain immune tolerance to counterbalance the loss of mucosal integrity in the small intestine in CD associated with T1D.
Risk Assessment of Immediate Systemic Reactions from Skin Tests with β-Lactam Antibiotics
Authors: Antico A. , Pagani M. , Compalati E. , Vescovi P.P. , Passalacqua G.
Published: August 2011

Background: Some clinical studies have demonstrated that skin tests for β-lactam antibiotics may cause more adverse reactions than skin tests for common allergens. Objective: To assess the risk of systemic reactions from penicillin skin testing, based on a pre-test categorization of patients, in order to establish an appropriate strategy for preempting and dealing with cases. Methods: A case series of 175 patients with a suspected allergy to penicillin was reviewed, and patients were classified as having a low or high probability of allergic sensitization to penicillin, according to their clinical history. For every group, the rate and the increase in the relative risk (RRI) of systemic reactions by skin testing were calculated. The results were compared to those reported in the available literature. Results: In our case series of 175 patients, 52 were classified as having a high probability of being allergic to penicillin, according to their clinical history. Five systemic reactions to skin testing were observed, and these were exclusively in this group (9.61%, RRI = 479). In agreement with the literature, patients with a high likelihood of penicillin allergy showed an increase of up to 10% in the occurrence of systemic reactions at skin testing; in patients who had had severe allergic reactions, this figure was up to 20%. Conclusions: The RRI of systemic reactions by skin testing is proportional to the pre-test probability of a true immediate hypersensitivity reaction to β-lactam antibiotics. In the present case series, only patients with high pre-test probability were at risk, and this group should therefore be skin tested and monitored in a hospitalization regimen, where resuscitation staff and access to an emergency room are immediately available.
Exercise-Independent Wheat-Induced Anaphylaxis Caused by ω-5 Gliadin in Mice
Authors: Tanaka Mamoru , Nagano Takao , Yano Hiromi , Haruma Ken , Kato Yasuko
Published: August 2011

Background: ω-5 Gliadin is known as a major allergen in wheat-dependent exercise-induced anaphylaxis. The characteristics that make ω-5 gliadin an allergen remain unclear. Methods: Mice were sensitized by means of intraperitoneal injection of gliadin fractions together with the adjuvant alum. Anaphylactic responses were assessed by measuring body temperature and voluntary physical activity. Specific IgE levels in mouse serum were evaluated by ELISA. After oral administration of proteins to mice, concentrations of administered proteins in their portal blood were also analyzed by competitive inhibition ELISA. Results: Oral administration of ω-5 gliadin evoked significant decreases in body temperature and physical activity of sensitized mice, whereas the gliadin fraction did not induce these effects at the same dose. These responses were exercise independent. ELISA analysis revealed that IgE antibodies from sensitized mice react to ω-5 gliadin with great efficacy. After oral administration of either the gliadin fraction or ω-5 gliadin, blood levels of ω-5 gliadin were much higher than those of the gliadin fraction. Conclusions: ω-5 Gliadin caused anaphylaxis in sensitized mice, whereas the gliadin fraction did not at the same dose. The anaphylactic response was exercise independent. It is likely that IgE of sensitized mice reacts strongly to ω-5 gliadin and that ω-5 gliadin is better absorbed from the gastrointestinal tract than other components of the gliadin fraction. These results indicated that ω-5 gliadin has prominent characteristics as an allergen and that exercise might be an indirect factor in anaphylaxis induction.
Anemia of Chronic Disease in Chronic Obstructive Pulmonary Disease: A Case-Control Study of Cardiopulmonary Exercise Responses
Authors: Boutou Afroditi K. , Stanopoulos Ioannis , Pitsiou Georgia G. , Kontakiotis Theodoros , Kyriazis George , Sichletidis Lazaros , Argyropoulou Paraskevi
Published: August 2011

Background: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity. Objectives: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET). Methods: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 µg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups. Results: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O2 uptake (VO2) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO2/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups. Conclusions: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise.
Why Do Our Kidneys Get Old
Authors: Wiggins Jocelyn
Published: August 2011

The majority of the human population shows a decline in renal clearance with age and a loss of renal physiologic reserve. Kidneys are increasingly less able to deal with stressful challenges such as a salt or acid load. It is not clear what underlies this aging-related change and whether it is inevitable or can be modified in such a way as to preserve renal function throughout the life span. This is a very brief review of aging biology and how it might impact on renal aging.
Classification of Chronic Kidney Disease in the Elderly: Pitfalls and Errors
Authors: Winearls Christopher G. , Glassock Richard J.
Published: August 2011

The average glomerular filtration rate (GFR) is lower in the elderly than in the young and is usually a consequence of biological ageing, the rate of which varies between individuals. In some subjects, the decline is aggravated by concomitant vascular disease. The prevalence of significant kidney disease in the elderly has been overestimated – largely by rendering a diagnosis of chronic kidney disease by reference to estimates of GFR which are found in the young. A stable low GFR in the elderly, provided it is physiologically sufficient to meet homeostatic demands, is not a disease per se and seldom progresses to true kidney failure. However, it can be a risk factor for acute kidney injury drug misdosing, and possibly cardiovascular disease, so it should be noted.
Microalbuminuria: Marker or Maker of Cardiovascular Disease
Authors: Abdelhafiz Ahmed H. , Ahmed Shameela , El Nahas Meguid
Published: August 2011

Advancing age is associated with albuminuria and vascular changes. This review will explore the putative links between the two. Vascular ageing involves endothelial dysfunction as well as increased arterial diameter, wall thickness and stiffness, ultimately leading to arterial sclerosis. This process is accelerated by a defective vascular repair process. Endothelial dysfunction is likely to be involved in the initiation and development of microalbuminuria. It is often followed by the development and progression of atherosclerosis. Initially, microalbuminuria is reversible but becomes fixed with the progression of vascular structural changes including glomerulosclerosis. The prevalence of microalbuminuria increases with age and has been shown to be a marker of widespread microvasculopathy at various levels including cerebral, cardiac and renal microcirculations. This has been linked to endpoint clinical events, with microalbuminuria increasing the risk of cognitive impairment and strokes, cardiovascular disease outcomes, and progression to end-stage renal failure. Evidence of microvascular damage such as microalbuminuria associated with increased cardiovascular risk may suggest that microvascular damage and dysfunction predate overt macrovascular disease. Microalbuminuria and reduced glomerular filtration rate (GFR) may be markers of different pathologic processes. It is likely that microalbuminuria and reduced GFR simply represent, respectively, the spectrum of renal vascular manifestations from systemic endothelial dysfunction (microvascular disease) to systemic atherosclerosis (macrovascular disease).
Non-Dialysis Care: An Important Component of Care for Elderly Individuals with Advanced Stages of Chronic Kidney Disease
Authors: Jassal Sarbjit V. , Kelman Elizabeth E. , Watson Diane
Published: August 2011

Non-dialysis care (NDC) is the provision of all aspects of renal care except for the dialysis process. While the nomenclature may vary, with terms such as ‘conservative care’, ‘maximal conservative management’ or ‘non-dialytic treatment’ having been associated with NDC, the clinical principle is to provide comprehensive care to patients who opt to forgo dialysis despite increasing uraemic symptoms. NDC therapies focus on pain relief, the use of erythropoietin-stimulating agents, anti-pruritics and anti-nausea therapies, with lower emphasis on strategies used to modulate the rate of renal progression. Patient selection remains the most challenging aspect of developing an NDC program, with selection often being based on physician instinct, family principles and population-based prognostic risk measures. Outcomes are fair with a significant proportion of NDC patients experiencing lower hospitalization days and higher rates of death at home (or in a preferred environment) rather than in acute-care hospitals.
Successful Salvage of Peritoneal Catheter in Unresolved Methicillin-Resistant Staphylococcus aureus Peritonitis by Combination Treatment with Daptomycin and Rifampin
Authors: Lin Shih-Yi , Ho Mao-Wang , Liu Jiung-Hsiun , Liu Yao-Long , Yeh Hung-Chieh , Hsieh Tsung-Lin , Wang I-Kuan , Lin Hsin-Hung , Huang Chiu-Ching
Published: August 2011

Peritoneal dialysis patients are at an increased risk of Gram-positive organism infections because of disrupted skin barrier function, presence of a peritoneal catheter, and a deficient immunological system. In particular, the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections is clinically challenging. Herein, we present a case of MRSA peritonitis that showed no response to a 14-day treatment with intraperitoneal vancomycin. To overcome unresponsiveness to vancomycin, we shifted the regimen to intraperitoneal daptomycin (given every 6 h through manual peritoneal dialysate exchanges) and oral rifampin (300 mg twice daily). The peritonitis resolved without sequelae or relapse. We suggest daptomycin and rifampin as an alternative combination therapy for MRSA infections that may otherwise remain unresolved.
Xanthine Oxidase Inhibition Attenuates Endothelial Dysfunction Caused by Chronic Intermittent Hypoxia in Rats
Authors: Dopp John M. , Philippi Nathan R. , Marcus Noah J. , Olson E. Burt , Bird Cynthia E. , Moran John J.M. , Mueller Scott W. , Morgan Barbara J.
Published: August 2011

Background: Xanthine oxidase is a major source of superoxide in the vascular endothelium. Previous work in humans demonstrated improved conduit artery function following xanthine oxidase inhibition in patients with obstructive sleep apnea. Objectives: To determine whether impairments in endothelium-dependent vasodilation produced by exposure to chronic intermittent hypoxia are prevented by in vivo treatment with allopurinol, a xanthine oxidase inhibitor. Methods: Sprague-Dawley rats received allopurinol (65 mg/kg/day) or vehicle via oral gavage. Half of each group was exposed to intermittent hypoxia (FIO2 = 0.10 for 1 min, 15×/h, 12 h/day) and the other half to normoxia. After 14 days, gracilis arteries were isolated, cannulated with micropipettes, and perfused and superfused with physiological salt solution. Diameters were measured before and after exposure to acetylcholine (10–6M) and nitroprusside (10–4M). Results: In vehicle-treated rats, intermittent hypoxia impaired acetylcholine-induced vasodilation compared to normoxia (+4 ± 4 vs. +21 ± 6 µm, p = 0.01). Allopurinol attenuated this impairment (+26 ± 6 vs. +34 ± 9 µm for intermittent hypoxia and normoxia groups treated with allopurinol, p = 0.55). In contrast, nitroprusside-induced vasodilation was similar in all rats (p = 0.43). Neither allopurinol nor intermittent hypoxia affected vessel morphometry or systemic markers of oxidative stress. Urinary uric acid concentrations were reduced in allopurinol- versus vehicle-treated rats (p = 0.02). Conclusions: These data confirm previous findings that exposure to intermittent hypoxia impairs endothelium-dependent vasodilation in skeletal muscle resistance arteries and extend them by demonstrating that this impairment can be prevented with allopurinol. Thus, xanthine oxidase appears to play a key role in mediating intermittent hypoxia-induced vascular dysfunction.
CTLA-4 +49A>G Polymorphism Is Associated with Advanced Non-Small Cell Lung Cancer Prognosis
Authors: Song Bao , Liu Yanbing , Liu Jie , Song Xianrang , Wang Zhehai , Wang Mingyu , Zhu Yufang , Han Jinxiang
Published: August 2011

Background: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by downregulating T cell activation. The most studied +49A>G polymorphism of the CTLA-4 gene has been associated with several autoimmune diseases. However, little is known about the association between this functional polymorphism of CTLA-4 and cancer prognosis. Objective: To investigate the association between CTLA-4 +49A>G polymorphism and prognosis of advanced non-small cell lung cancer (NSCLC) patients in a Chinese population. Methods: The CTLA-4 +49A>G polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 338 advanced NSCLC patients. Results: The frequencies of CTLA-4 +49 GG, GA and AA in advanced NSCLC patients were 44.4%, 42.0% and 13.6%, respectively. No significant association was observed between CTLA-4 +49A>G polymorphism and clinicopathologic features of advanced NSCLC including gender, histopathological type, clinical stage and tumor markers. Patients with the AA genotype had a survival time of 9.8 months, significantly shorter than those with the GG genotype (12.5 months) or the GA genotype (12.0 months) (p < 0.001; log-rank test). Multivariate Cox analysis further revealed that the CTLA-4 +49AA genotype is an independent adverse prognostic indicator for NSCLC patients. Conclusion: Our data suggest that the polymorphism of CTLA-4 +49A>G is a prognostic predictor for advanced NSCLC.
Partial Deafness Treatment with the Nucleus Straight Research Array Cochlear Implant
Authors: Skarzynski Henryk , Lorens Artur , Matusiak Monika , Porowski Marek , Skarzynski Piotr H. , James Chris J.
Published: August 2011

Introduction: The Nucleus Straight Research Array (SRA) cochlear implant has a new 25-mm electrode carrier designed to minimize insertion trauma, in particular allowing easy insertion via the round window. The aims of this study were to measure preoperative to postoperative benefit in terms of speech recognition in quiet and in noise in three groups of patients (electrical complement, EC; electrical stimulation, ES; electro-acoustic stimulation, EAS) with varying levels of low-frequency hearing, and to evaluate the preservation of residual hearing after implantation with the SRA cochlear implant. Methods: The study design was prospective with sequential enrolment and within-subject comparisons: 23 adult cochlear implant candidates were divided into three groups according to their level of preoperative residual hearing at 500 Hz (EC ≤50 dB; 50 dB < EAS < 80 dB; ES ≧80 dB). Monosyllabic word recognition using the SRA cochlear implant in combination with residual low-frequency hearing was assessed at 4 and 13 months after implantation. Hearing threshold levels were also monitored over time. Results: Subjects across all three groups had significant improvements in speech recognition scores (i.e. >20 percentage points) both for listening in quiet (71% of subjects) and in noise (100% of subjects). The average score at 4 months after operation for words presented in quiet was 61.7%, and in 10 dB SNR noise 46.5%, compared to 34.4 and 10.6% preoperatively (p < 0.001). All subjects retained measurable hearing at 500 Hz in the implanted ear at 4 months after the operation; mean increases were 19, 29 and 1 dB for the EC, EAS and ES groups (n = 21). Across frequencies of 125–1000 Hz, the median increase in thresholds was 15 dB up to 13 months postoperatively (n = 15). Conclusions: Speech recognition performance of subjects with various levels of residual low-frequency hearing was significantly improved with the SRA cochlear implant. A high level and rate of hearing preservation was achieved with the SRA implanted using a round window surgical technique. Subjects with preoperative low-frequency hearing levels between 50 and 80 dB HL (EAS group) tended to lose more hearing than those with either better or worse hearing.
Correlation between Progressive Changes in Piriform Cortex and Olfactory Performance in Early Parkinson’s Disease
Authors: Wu Xiaoli , Yu Chunshui , Fan Fengmei , Zhang Kaiyuan , Zhu Chaozhe , Wu Tao , Li Kuncheng , Chan Piu
Published: August 2011

Objectives: The mechanism underlying olfactory dysfunction in Parkinson’s disease (PD) remains unknown. The current study aims to investigate the relationship between sequential changes of volume change of cortex associated with olfactory function and degree of deficiency of olfactory performance in PD. Methods: Based on the arbitrary cut-off score of olfactory performance measured by ‘five odors olfactory detection arrays’, subjects were classified into three groups: PD patients with olfactory impairment (OPD, n = 12), PD without olfactory impairment (NPD, n = 14), and healthy controls without olfactory impairment (NC, n = 26). A morphometric analysis of magnetic resonance images (voxel-based morphometry; VBM) was used to investigate cortical volume change. Results: The scores of olfactory performance were higher in both NPD and OPD groups than in the NC group independent of age and disease duration, indicating that NPD subjects did have board line deficiency of olfaction though not meet the cut-off score for abnormal olfactory function. Both NPD and OPD had cortical atrophy in the parahippocampal gyrus (PCG), but only OPD also had change in orbitofrontal cortex (OFC). Correlation analysis revealed that decrement of volumes of PCG and right OFC was associated with decreased olfactory detection sensitivity, and the right OFC was also correlated to olfactory identification. However, no correlation was found between structural changes and the severity of the disease measured by UPDRS score. Conclusions: The results confirmed that atrophy in piriform cortex and orbitofrontal cortex is associated with olfactory dysfunction in early PD. Atrophy of the orbitofrontal cortex becomes significant as olfactory damage progresses. Volume measurement of olfaction-associated areas together with the assessment of olfactory function may be a sensitive indicator for the early diagnosis of PD.
Evaluating the Quality of Life of People with Dementia in Residential Care Facilities
Authors: Nakanishi Kosuke , Hanihara Tokiji , Mutai Hitoshi , Nakaaki Shutaro
Published: August 2011

Aims: Our purpose was to compare recipient and caregiver perception of the quality of life (QoL) of people with dementia in residential care facilities and to identify the factors associated with their perception of QoL. Methods: Residents’ QoL was evaluated by both the patient and the caregiver, using the Quality of Life in Alzheimer’s Disease and several other indices. Results: The correlation between the self-rated QoL score and the staff-rated QoL score was low. Conclusions: The staff tended to underestimate QoL. The main determinants of QoL were the functional status and depression. Improving physical function and mood may be beneficial in providing a better QoL.
Reverse Epidemiology of Lipid-Death Associations in a Cohort of End-Stage Renal Disease Patients
Authors: Bowden Rodney G. , La Bounty Paul , Shelmadine Brian , Beaujean A. Alexander , Wilson Ronald L. , Hebert Stuart
Published: August 2011

Background and Aims: Cardiovascular disease is the leading cause of death among end-stage renal disease (ESRD) patients with hypercholesterolemia as a major cause. A few studies have demonstrated counter-intuitive findings known as reverse epidemiology where normal levels of cholesterol are associated with higher levels of mortality. The purpose of this study was to determine if there are reverse epidemiological associations between lipid risk factors and mortality in ESRD patients. Methods: ESRD (n = 438) patients were recruited from 4 outpatient dialysis units. Patients were tracked for 36 months until study completion or death with mortality status as the outcome measure. Results: Analysis of covariance revealed significant differences at posttest and reverse epidemiological effects for total cholesterol (p = 0.0001), low-density lipoprotein cholesterol (LDL) (p = 0.023), LDL particle number (p = 0.0001), LDL size (p = 0.009), triglycerides (p = 0.0001), and very low-density lipoprotein cholesterol (p = 0.036). A step-wise linear regression revealed weak, but significant predictors of mortality with total cholesterol (β = 0.263, p = 0.017) and LDL (β = –0.177, p = 0.045). A Cox death hazard ratio revealed LDL size as a significant predictor of mortality in this study. Conclusions: Our study discovered reverse epidemiology in a number of lipid variables. Additionally regression revealed that LDL and total cholesterol were predictors of mortality with lower levels being more predictive of death.
Three Cases of Focal Embouchure Dystonia: Classifications and Successful Therapy Using a Dental Splint
Authors: Satoh Masayuki , Narita Motoshi , Tomimoto Hidekazu
Published: August 2011

Background: Focal embouchure dystonia (FED) is a type of task-specific dystonia affecting wind instrument players, and it frequently ends their professional careers. The results of the treatments of FED in the reported literature are disappointing. Objective: We report 3 patients with FED who were brass instrument players. In 1 patient, we evaluated the usefulness of a dental splint. Methods and Results: Patient 1 was a 28-year-old trumpeter who was suffering from an intermittent tremor of the lower jaw. Following the usage of a dental splint, her symptoms disappeared completely. Patient 2 was a 29-year-old horn player with atonia of the lower facial muscles. In this case, medication with various drugs brought no benefit, and he ended his career. Patient 3 was a 43-year-old trombone player who suffered involuntary contractions and relaxation of the perioral muscles along with clumsiness of tongue movement. Extraction of double teeth and long-term cessation of playing for 20 years did not bring any positive effects. Conclusion: We propose that FED can be categorized into three subgroups according to masticatory, facial and lingual types, and that the dental splint might be a useful therapeutic strategy for the masticatory type of FED.
Regional Atherosclerotic Plaque Properties in ApoE–/– Mice Quantified by Atomic Force, Immunofluorescence, and Light Microscopy
Authors: Hayenga H.N. , Trache A. , Trzeciakowski J. , Humphrey J.D.
Published: August 2011

Elucidating regional material properties of arterial tissue is fundamental to predicting transmural stresses and understanding how tissue stiffness influences cellular responses and vice versa. Atomic force microscopy (AFM) was used to measure point-wise the axial compressive stiffness of healthy aortas and atherosclerotic plaques at micron level separation distances. Cross sections of plaques were obtained from a widely used animal model of atherosclerosis (ApoE–/– mice). Median point-wise values of material stiffness were 18.7 and 1.5 kPa for the unloaded healthy wall (n = 25 specimens) and plaque (n = 18), respectively. When the healthy wall was distended uniformly during AFM testing, two mechanically distinct populations emerged from comparisons of normal cumulative distributions, with median values of 9.8 and 76.7 kPa (n = 16). The higher values of stiffness may have been due to extended elastin, which was not present in the plaques. Rather, most plaques were identified via standard and immunofluorescent histology to be largely lipid laden, and they exhibited a nearly homogeneous linear elastic behavior over the small AFM indentations. Understanding the mechanics and mechanobiological factors involved in lesion development and remodeling could lead to better treatments for those lesions that are vulnerable to rupture.
Atherosclerosis and PTPN22: A Study in Coronary Artery Disease
Authors: Saccucci P. , Banci M. , Cozzoli E. , Neri A. , Magrini A. , Bottini E. , Gloria-Bottini F.
Published: August 2011

Objectives: Recently, it has been shown that PTPN22 genetic polymorphism is associated with phenotypes related to the risk of atherosclerosis. In the present note, we have searched for a possible association of PTPN22 polymorphism with coronary artery disease (CAD). Methods: One hundred and thirty-four non-diabetic subjects admitted to hospital for CAD and 174 healthy subjects (blood donors) were studied. PTPN22 genotypes were determined by DNA analysis. Statistical analyses were performed by SPSS programs. Results: In CAD patients, the proportion of carriers of the *T allele of PTPN22 is significantly higher compared to healthy controls (OR 2.66; 95% CI 1.07–6.72). Conclusions: The present observation confirms the association of PTPN22 phenotype with atherosclerosis and suggests a role of immune mechanism in the pathogenesis of CAD.
Bone-Conducted Hearing Assessment with 80-Hz Multiple Auditory Steady-State Responses to Brief Tones in Adults with Normal Hearing
Authors: Mo Lingyan , Zhang Fan , Han Demin , Zhang Luo
Published: August 2011

Objective: To investigate interactions (if any) in the bone-conduction auditory steady-state response (BC ASSR) between multiple brief tones presented simultaneously. Methods: 500-, 1,000-, 2,000-, and 4,000-Hz brief tones, repeated at a rate of 77–101 Hz, were presented using a B-71 vibrator. BC ASSR thresholds and amplitudes at 50 dB nHL were measured in two conditions where the stimulus was either presented alone or together with other stimuli. Results: Significantly larger amplitudes in the single-stimulus condition were found at 50 dB nHL. However, there was no significant threshold difference between single- and multiple-stimulus conditions. The BC ASSR thresholds (means ± SD) at 500, 1,000, 2,000, and 4,000 Hz were 96.7 ± 9.7, 75.3 ± 11.5, 65.6 ± 7.4, and 57.8 ± 7.2 dB re 1 µN ppe, respectively. Conclusion: Interactions occurred in the multiple-stimulus condition at high presentation levels, but not at threshold levels. The results of the present study imply that BC ASSR thresholds to multiple brief-tone stimuli can be assessed at the same time, at least in normal-hearing adults.
Roles of Different Sources of Social Support on Caries Experience and Caries Increment in Adolescents of East London
Authors: Bernabé E. , Stansfeld S.A. , Marcenes W.
Published: August 2011

Evidence on the contribution of social support to oral health is scarce. We first explored the association of social support with caries experience and the relative roles of support from family, friends and a special person on caries experience in 15–16-year-old adolescents. We then explored whether social support at 11–12 years of age predicts caries increment in second permanent molars over 4 years and the relative roles of different sources of support on 4-year caries increment. Data from phases 1 and 3 of the Research with East London Adolescents Community Health Survey (RELACHS), a school-based prospective study of a representative sample of adolescents in East London, were used for cross-sectional (phase 3) and longitudinal analyses (phases 1 and 3). Data were collected by questionnaires including the same questions on demographic characteristics, socioeconomic measures and the Multidimensional Scale of Perceived Social Support at phases 1 and 3. A questionnaire section on dental behaviours and an oral clinical examination were also included in phase 3. Social support was negatively related to both caries experience and increment independently of demographic characteristics, socioeconomic measures and dental behaviours. Furthermore, only support from a special person was significantly related to caries experience and increment in unadjusted and adjusted regression models. In conclusion, adolescents who perceived higher levels of social support had lower caries experience and increment. However, support from a special person was more relevant for these adolescents than support from family and peers.
Thirteen-Month-Old Boy with Malignant Lymphoma Having Symptoms Mimicking Acute Otitis Media and Mastoiditis with Facial Palsy
Authors: Kanzaki Sho , Saito Hideyuki , Mori Tetsuya , Shimasaki Noriko , Mukai Makio , Ogawa Kaoru
Published: August 2011

Non-Hodgkin diffuse large B-cell lymphomas of the mastoid that extend from the nasopharynx are extremely rare in children. Moreover, in lymphoproliferative diseases, the presence of otoneurological signs prior to systemic disease involvement is rare. Here, we present a rare case of non-Hodgkin B-cell lymphoma invading the middle ear and mastoid in a 1-year-old boy that mimicked acute mastoiditis with complete facial nerve palsy. As this case illustrates, physicians should consider a diagnosis of malignant lymphoma if a patient presents with otitis media and mastoiditis accompanied by facial palsy.
Validity of the Current NCAA Minimum Weight Protocol: A Brief Review
Authors: Loenneke Jeremy P. , Wilson Jacob M. , Barnes Jeremy T. , Pujol Thomas J.
Published: August 2011

Historically, collegiate wrestlers have been associated with utilizing rapid weight loss methods to reach a desired weight class. Following three deaths in 1997, the National Collegiate Athletic Association (NCAA) implemented a program which prevents wrestlers from wrestling below a minimum weight (MW) of 5% body fat. Although numerous studies have investigated adolescent wrestlers, few have investigated collegiate wrestlers using the methods outlined by the NCAA. The purpose of this review paper is to outline potential problems with the current NCAA protocol as well as critique studies investigating the validity of methods to assess MW.